Melt-processed polymeric cellular dosage forms for immediate drug release.

PubMed

Blaesi, Aron H; Saka, Nannaji

2015-12-28

The present immediate-release solid dosage forms, such as the oral tablets and capsules, comprise granular matrices. While effective in releasing the drug rapidly, they are fraught with difficulties inherent in processing particulate matter. By contrast, liquid-based processes would be far more predictable; but the standard cast microstructures are unsuited for immediate-release because they resist fluid percolation and penetration. In this article, we introduce cellular dosage forms that can be readily prepared from polymeric melts by incorporating the nucleation, growth, and coalescence of microscopic gas bubbles in a molding process. We show that the cell topology and formulation of such cellular structures can be engineered to reduce the length-scale of the mass-transfer step, which determines the time of drug release, from as large as the dosage form itself to as small as the thickness of the cell wall. This allows the cellular dosage forms to achieve drug release rates over an order of magnitude faster compared with those of cast matrices, spanning the entire spectrum of immediate-release and beyond. The melt-processed polymeric cellular dosage forms enable predictive design of immediate-release solid dosage forms by tailoring microstructures, and could be manufactured efficiently in a single step.

Model‐Informed Development and Registration of a Once‐Daily Regimen of Extended‐Release Tofacitinib

PubMed Central

Lamba, M; Hutmacher, MM; Furst, DE; Dikranian, A; Dowty, ME; Conrado, D; Stock, T; Nduaka, C; Cook, J

2017-01-01

Extended‐release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model‐informed, exposure–response (E‐R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E‐R analyses were conducted using validated clinical endpoints from phase II dose–response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration. PMID:27859030

Comparative steady-state pharmacokinetic study of an extended-release formulation of itopride and its immediate-release reference formulation in healthy volunteers.

PubMed

Yoon, Seonghae; Lee, Howard; Kim, Tae-Eun; Lee, SeungHwan; Chee, Dong-Hyun; Cho, Joo-Youn; Yu, Kyung-Sang; Jang, In-Jin

2014-01-01

This study was conducted to compare the oral bioavailability of an itopride extended-release (ER) formulation with that of the reference immediate-release (IR) formulation in the fasting state. The effect of food on the bioavailability of itopride ER was also assessed. A single-center, open-label, randomized, multiple-dose, three-treatment, three-sequence, crossover study was performed in 24 healthy male subjects, aged 22-48 years, who randomly received one of the following treatments for 4 days in each period: itopride 150 mg ER once daily under fasting or fed conditions, or itopride 50 mg IR three times daily in the fasting state. Steady-state pharmacokinetic parameters of itopride, including peak plasma concentration (Cmax) and area under the plasma concentration versus time curve over 24 hours after dosing (AUC(0-24h)), were determined by noncompartmental analysis. The geometric mean ratio of the pharmacokinetic parameters was derived using an analysis of variance model. A total of 24 healthy Korean subjects participated, 23 of whom completed the study. The geometric mean ratio and its 90% confidence interval of once-daily ER itopride versus IR itopride three times a day for AUC(0-24h) were contained within the conventional bioequivalence range of 0.80-1.25 (0.94 [0.88-1.01]), although Cmax was reached more slowly and was lower for itopride ER than for the IR formulation. Food delayed the time taken to reach Cmax for itopride ER, but AUC(0-24h) was not affected. There were no serious adverse events and both formulations were generally well tolerated. At steady state, once-daily itopride ER at 150 mg has a bioavailability comparable with that of itopride IR at 50 mg given three times a day under fasting conditions. Food delayed the absorption of itopride ER, with no marked change in its oral bioavailability.

Comparative steady-state pharmacokinetic study of an extended-release formulation of itopride and its immediate-release reference formulation in healthy volunteers

PubMed Central

Yoon, Seonghae; Lee, Howard; Kim, Tae-Eun; Lee, SeungHwan; Chee, Dong-Hyun; Cho, Joo-Youn; Yu, Kyung-Sang; Jang, In-Jin

2014-01-01

Background This study was conducted to compare the oral bioavailability of an itopride extended-release (ER) formulation with that of the reference immediate-release (IR) formulation in the fasting state. The effect of food on the bioavailability of itopride ER was also assessed. Methods A single-center, open-label, randomized, multiple-dose, three-treatment, three-sequence, crossover study was performed in 24 healthy male subjects, aged 22–48 years, who randomly received one of the following treatments for 4 days in each period: itopride 150 mg ER once daily under fasting or fed conditions, or itopride 50 mg IR three times daily in the fasting state. Steady-state pharmacokinetic parameters of itopride, including peak plasma concentration (Cmax) and area under the plasma concentration versus time curve over 24 hours after dosing (AUC0–24h), were determined by noncompartmental analysis. The geometric mean ratio of the pharmacokinetic parameters was derived using an analysis of variance model. Results A total of 24 healthy Korean subjects participated, 23 of whom completed the study. The geometric mean ratio and its 90% confidence interval of once-daily ER itopride versus IR itopride three times a day for AUC0–24h were contained within the conventional bioequivalence range of 0.80–1.25 (0.94 [0.88–1.01]), although Cmax was reached more slowly and was lower for itopride ER than for the IR formulation. Food delayed the time taken to reach Cmax for itopride ER, but AUC0–24h was not affected. There were no serious adverse events and both formulations were generally well tolerated. Conclusion At steady state, once-daily itopride ER at 150 mg has a bioavailability comparable with that of itopride IR at 50 mg given three times a day under fasting conditions. Food delayed the absorption of itopride ER, with no marked change in its oral bioavailability. PMID:24470753

Prospective, open-label trial measuring satisfaction and convenience of two formulations of lamotrigine in subjects with mood disorders.

PubMed

Sajatovic, Martha; Thompson, Thomas R; Nanry, Kevin; Edwards, Suzanne; Manjunath, Ranjani

2013-01-01

Lamotrigine is an anticonvulsant drug indicated for the maintenance treatment of bipolar I disorder and for various types of epilepsy. An orally disintegrating tablet (ODT) of lamotrigine was developed to provide a formulation option that might increase patient convenience and satisfaction. Subjects with mood disorders who reported difficulty swallowing currently prescribed lamotrigine immediate-release medication (baseline) were enrolled and treated with lamotrigine ODT for three weeks (end of treatment). Subject satisfaction and convenience were measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). Also measured were global psychopathology using the Clinical Global Impression severity index (CGI-S) and depressive symptoms using the Beck Depression Inventory (BDI-II). Lamotrigine ODT was found to be significantly more convenient to use than lamotrigine immediate-release (change in baseline TSQM convenience score: 23.3, n = 97, P < 0.001). The mean TSQM global satisfaction score was similar at baseline (76.3) and after treatment with lamotrigine ODT (76.0). There were no significant changes on CGI-S and BDI-II. Subjects reported that lamotrigine ODT was significantly more convenient than lamotrigine immediate-release, while both formulations were associated with good satisfaction. Lamotrigine ODT may be a treatment option for patients who have difficulty swallowing medication.

Application of hot-melt extrusion technology in immediate-release abuse-deterrent formulations.

PubMed

Wening, Klaus; Schwier, Sebastian; Stahlberg, Hans-J; Galia, Eric

Hot-melt extrusion (HME) technology has been used for manufacturing extended-release abuse-deterrent formulations (ADFs) of opioid-type analgesics with improved tamper-resistant properties. Our objective was to describe application of this technology to immediate-release (IR) ADFs. For development of a sample IR ADF (hydrocodone 10 mg/acetaminophen 325 mg) based on HME, feasibility studies were performed using different excipients. The formulation selected for further development was evaluated via in vitro test battery. Moreover, in vivo performance of IR ADF technologies was investigated in an open-label, randomized, cross-over, phase 1, relative oral bioavailability study with another opioid (model compound). Single-center bioavailability trial. Twenty-four healthy white male subjects. ADF IR formulation of an opioid and marketed IR formulation. For feasibility and in vitro studies, dissolution profiles, syringeability, particle size distribution after physical manipulation, and extractability were evaluated. For the phase 1 study, pharmacokinetic parameters were evaluated and compared for ADF IR and a marketed IR formulation. After manipulation, the majority of particles from the ADF IR formulation were >500µm and, thus, not considered suitable for intranasal abuse, while the majority of particles for the reference marketed IR formulation were <500µm. The ADF IR formulation was resistant to syringing and preparation for potential intravenous injection. In healthy subjects, pharmacokinetics of an ADF and marketed IR formulation of an opioid were nearly identical. Application of HME to IR formulations led to development of products with improved mechanical resistance to manipulation for intranasal or intravenous preparation, but similar bioavailability.

Tapioca starch blended alginate mucoadhesive-floating beads for intragastric delivery of Metoprolol Tartrate.

PubMed

Biswas, Nikhil; Sahoo, Ranjan Kumar

2016-02-01

The objective of the study was to develop tapioca starch blended alginate mucoadhesive-floating beads for the intragastric delivery of Metoprolol Tartrate (MT). The beads were prepared by ionotropic gelation method using calcium chloride as crosslinker and gas forming calcium carbonate (CaCO3) as floating inducer. The alginate gel beads having 51-58% entrapped MT showed 90% release within 45 min in gastric medium (pH 1.2). Tapioca starch blending markedly improved the entrapment efficiency (88%) and sustained the release for 3-4 h. A 12% w/w HPMC coating on these beads extended the release upto 9-11 h. In vitro wash off and buoyancy test in gastric media revealed that the beads containing CaCO3 has gastric residence of more than 12 h. In vitro optimized multi-unit formulation consisting of immediate and sustained release mucoadhesive-floating beads (40:60) showed good initial release of 42% MT within 1h followed by a sustained release of over 90% for 11 h. Pharmacokinetic study performed in rabbit model showed that the relative oral bioavailability of MT after administration of oral solution, sustain release and optimized formulation was 51%, 67% and 87%, respectively. Optimized formulation showed a higher percent inhibition of isoprenaline induced heart rate in rabbits for almost 12 h. Copyright © 2015 Elsevier B.V. All rights reserved.

Extended-Release Once-Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate-Release Tofacitinib and Impact of Food.

PubMed

Lamba, Manisha; Wang, Rong; Fletcher, Tracey; Alvey, Christine; Kushner, Joseph; Stock, Thomas C

2016-11-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended-release (XR) formulation has been designed to provide a once-daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice-daily immediate-release (IR) formulation. We conducted 2 randomized, open-label, phase 1 studies in healthy volunteers. Study A characterized single-dose and steady-state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single-dose and steady-state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high-fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half-life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) after single- and multiple-dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. C max increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. © 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Curse of the ghost pills: the role of oral controlled-release formulations in the passage of empty intact shells in faeces. Two case reports and a literature review relevant to psychiatry

PubMed Central

Talapan-Manikoth, Pravija; Jenkins, Rosemary

2013-01-01

Orally taken tablets in different formulations continue to have a central role in the treatment of various psychiatric and medical conditions. In order to improve compliance, reduce the frequency of taking medications and minimize the peaks and troughs associated with certain immediate-release formulations, pharmaceutical companies have developed a number of novel methods of delivering oral solid dosage medications in the form of controlled-release (CR) formulations. Some CR formulations have been associated with pharmacobezoars and false-positive findings on certain physical investigations. Though CR drugs are commonly used in psychiatry, clinicians appear to have a limited understanding of how they are released for absorption once ingested. Some have insoluble parts that are excreted in faeces as ‘ghost pills’. Due to lack of awareness of this phenomenon to both patients and the physicians, anxiety has ensued in some patients. Some clinicians have been puzzled or have been dismissive when faced with curious patients wanting to know more after they had observed tablet-like looking structures in faeces. We present two cases from our clinical setting and a few drawn from the World Wide Web to highlight the role of CR medications and their association with the ghost pill phenomenon. The mechanisms involved in drug release relevant to psychiatry medications are also briefly reviewed. The ghost pill phenomenon occurs with certain CR medications. This is a normal and expected outcome related to drug-release mechanisms of some of these products. It is inevitable that some patients will see what looks like tablets or capsules in faeces. Raising awareness of this phenomenon among clinicians would facilitate discussions and information sharing at the initial process of medication prescribing. Awareness among patients and carers would also help to allay anxiety. PMID:25083252

Pharmacokinetics of gabapentin in a novel gastric-retentive extended-release formulation: comparison with an immediate-release formulation and effect of dose escalation and food.

PubMed

Chen, Cuiping; Cowles, Verne E; Hou, Eddie

2011-03-01

The objectives of the 3 phase I studies described herein were (1) to compare the pharmacokinetics of gabapentin delivered from a novel gastric-retentive dosage form vs an immediate-release formulation, (2) to assess the dose proportionality of the gastric-retentive extended-release formulation, and (3) to determine the effect of food on the pharmacokinetics of gabapentin delivered from this formulation. The time to reach maximum plasma concentration (t(max)) was extended for gabapentin delivered from the gastric-retentive extended-release formulation compared with the immediate-release formulation. A dose-related increase in both the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) was observed as the gabapentin dose increased from 600 to 2400 mg. Fed status and increased fat content delayed t(max) and enhanced C(max) and AUC in proportion to the fat content. The pharmacokinetics of gabapentin delivered from this extended-release formulation allows a reduced dosing frequency while maintaining bioavailability and possibly diminishing the occurrence of adverse events attributable to a slower increase to the peak concentration compared with the immediate-release dosage form.

Memantine extended release (28 mg once daily): a review of its use in Alzheimer's disease.

PubMed

Plosker, Greg L

2015-05-01

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that is a well-established treatment option for moderate to severe dementia of the Alzheimer's type, either alone or in combination with cholinesterase inhibitors. The immediate-release (IR) formulations of memantine (tablets and oral solution) have been available in numerous countries, including the USA, for more than a decade and are administered orally twice daily at a maximum recommended total daily dosage of 20 mg/day. The memantine extended-release (ER) (Namenda XR(®)) 28 mg once-daily capsule formulation was approved in the USA in 2010 and became available more recently. The potential advantages of memantine ER over the IR formulation include a more convenient dosage regimen and lower pill burden that may improve adherence to therapy; also, memantine ER capsules may be opened and the contents sprinkled on applesauce for patients who have difficulty swallowing. Memantine ER provides a higher total daily dosage than the recommended memantine IR regimen and pharmacokinetic data indicate greater exposure with the ER formulation, but the clinical implications of this are unclear, as the two formulations have not been assessed in a comparative clinical trial. The efficacy of memantine ER 28 mg once daily was demonstrated in a large, multinational, phase III trial, which showed that the addition of memantine ER to ongoing oral cholinesterase inhibitors improved key outcomes compared with cholinesterase inhibitor monotherapy, including measures of cognition and global status, which were the co-primary endpoints of the study. The most common adverse events were headache, diarrhoea and dizziness.

IVIVC for fenofibrate immediate release tablets using solubility and permeability as in vitro predictors for pharmacokinetics.

PubMed

Buch, Philipp; Holm, Per; Thomassen, Jesper Qvist; Scherer, Dieter; Branscheid, Robert; Kolb, Ute; Langguth, Peter

2010-10-01

The goal of this study was to investigate the in vitro-in vivo correlation (IVIVC) for fenofibrate immediate release (IR) tablet formulations based on MeltDose-technique. The in vitro determined drug solubility and permeability data were related to the C(max) values observed from two in vivo human studies. Solubility and permeation studies of fenofibrate were conducted in medium simulating the fasted state conditions in the upper jejunum, containing the surfactant compositions of the six formulations at different concentrations. The behavior of all surfactant compositions was characterized by surface tension, dynamic light scattering, and cryo-TEM. The obtained solubility and permeation data were combined and compared with the C(max) values for the fenofibrate formulations, assuming a 50 mL in vivo dissolution volume. A good IVIVC was observed for five fenofibrate formulations (R(2) = 0.94). The in vitro studies revealed that the formulation compositions containing sodium lauryl sulfate (SLS) interfered with the vesicular drug solubilizing system of the biorelevant medium and antagonized its solubilization capacity. The opposing interaction of surfactants with the emulsifying physiological constituents in intestinal juice should be taken into consideration in order to prevent unsatisfactory in vivo performance of orally administered formulations with low soluble active pharmaceutical ingredients.

Development of an Extended-Release Formulation for Apremilast and a Level A in Vitro-in Vivo Correlation Study in Beagle Dogs.

PubMed

Tang, Meiqiong; Hu, Ping; Huang, Shigui; Zheng, Qiang; Yu, Hao; He, Yun

2016-11-01

The primary objective of the present study was to develop extended-release matrix formulations of apremilast for the oral delivery and to study their in vitro and in vivo correlation. Five extended-release formulations containing hydroxypropylmethylcellulose (HPMC) as the retarding excipient with different release rate of apremilast were prepared. Dissolution tests of all the formulated tablets were performed in water, pH 4.0 and 6.8 buffer solutions. The in vitro release kinetics was studied and supported by Korsmeyer-Peppas's equation as it presented highest values of correlation coefficients (r 2 up to 0.966). Among all formulated tablets, F2 (HPMC 25%) and F4 (HPMC 35%) were selected to perform an in vivo study in beagle dogs to obtain various pharmacokinetic parameters, i.e., peak plasma concentration (C max ), time to peak plasma concentration (t max ), area under the plasma-concentration vs. time curve (AUC). Higher t max and t 1/2 , lower C max and elimination coefficient (K e ) were observed for both extended formulations compared to marketed immediate-release products (Otezla ® ). Level A in vitro-in vivo correlations were created with the help of Wagner-Nelson and numeric deconvolution methods. Both formulations showed good in vitro-in vivo correlations whose accuracies were further verified by an internal validation.

Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract☆

PubMed Central

Glube, Natalie; Moos, Lea von; Duchateau, Guus

2013-01-01

Purpose In vitro disintegration and dissolution are routine methods used to assess the performance and quality of oral dosage forms. The purpose of the current work was to determine the potential for interaction between capsule shell material and a green tea extract and the impact it can have on the release. Methods A green tea extract was formulated into simple powder-in-capsule formulations of which the capsule shell material was either of gelatin or HPMC origin. The disintegration times were determined together with the dissolution profiles in compendial and biorelevant media. Results All formulations disintegrated within 30 min, meeting the USP criteria for botanical formulations. An immediate release dissolution profile was achieved for gelatin capsules in all media but not for the specified HPMC formulations. Dissolution release was especially impaired for HPMCgell at pH 1.2 and for both HPMC formulations in FeSSIF media suggesting the potential for food interactions. Conclusions The delayed release from studied HPMC capsule materials is likely attributed to an interaction between the catechins, the major constituents of the green tea extract, and the capsule shell material. An assessment of in vitro dissolution is recommended prior to the release of a dietary supplement or clinical trial investigational product to ensure efficacy. PMID:25755998

Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract.

PubMed

Glube, Natalie; Moos, Lea von; Duchateau, Guus

2013-01-01

In vitro disintegration and dissolution are routine methods used to assess the performance and quality of oral dosage forms. The purpose of the current work was to determine the potential for interaction between capsule shell material and a green tea extract and the impact it can have on the release. A green tea extract was formulated into simple powder-in-capsule formulations of which the capsule shell material was either of gelatin or HPMC origin. The disintegration times were determined together with the dissolution profiles in compendial and biorelevant media. All formulations disintegrated within 30 min, meeting the USP criteria for botanical formulations. An immediate release dissolution profile was achieved for gelatin capsules in all media but not for the specified HPMC formulations. Dissolution release was especially impaired for HPMCgell at pH 1.2 and for both HPMC formulations in FeSSIF media suggesting the potential for food interactions. The delayed release from studied HPMC capsule materials is likely attributed to an interaction between the catechins, the major constituents of the green tea extract, and the capsule shell material. An assessment of in vitro dissolution is recommended prior to the release of a dietary supplement or clinical trial investigational product to ensure efficacy.

Single-dose evaluation of safety, tolerability and pharmacokinetics of newly formulated hydromorphone immediate-release and hydrophilic matrix extended-release tablets in healthy Japanese subjects without co-administration of an opioid antagonist.

PubMed

Toyama, Kaoru; Uchida, Naoki; Ishizuka, Hitoshi; Sambe, Takehiko; Kobayashi, Shinichi

2015-09-01

This single dose, open-label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate-release (IR) and hydrophilic matrix extended-release (ER) hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquid-chromatography tandem mass-spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0-inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0-inf and Cmax increased with food for both IR and ER tablets. The AUC0-inf of hydromorphone-3-glucoside was one-tenth of that of hydromorphone-3-glucuronide. A single oral administration of the hydromorphone tablets would be well-tolerated in healthy Japanese subjects despite a lack of co-administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once-daily dosing. © 2015, The American College of Clinical Pharmacology.

Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers▿

PubMed Central

Di Stefano, A. F. D.; Rusca, A.; Loprete, L.; Dröge, M. J.; Moro, L.; Assandri, A.

2011-01-01

The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single- and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single- and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (ΣXu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410 ± 0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed. PMID:21402860

In vitro-in vivo correlation strategy applied to an immediate-release solid oral dosage form with a biopharmaceutical classification system IV compound case study.

PubMed

Bredael, Gerard M; Bowers, Niya; Boulineau, Fabien; Hahn, David

2014-07-01

The ability to predict in vivo response of an oral dosage form based on an in vitro technique has been a sought after goal of the pharmaceutical scientist. Dissolution testing that demonstrates discrimination to various critical formulations or process attributes provides a sensitive quality check that may be representative or may be overpredictive of potential in vivo changes. Dissolution methodology with an established in vitro-in vivo relationship or correlation may provide the desired in vivo predictability. To establish this in vitro-in vivo link, a clinical study must be performed. In this article, recommendations are given in the selection of batches for the clinical study followed by potential outcome scenarios. The investigation of a Level C in vitro-in vivo correlation (IVIVC), which is the most common correlation for immediate-release oral dosage forms, is presented. Lastly, an IVIVC case study involving a biopharmaceutical classification system class IV compound is presented encompassing this strategy and techniques. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin.

PubMed

Olivares-Morales, Andrés; Ghosh, Avijit; Aarons, Leon; Rostami-Hodjegan, Amin

2016-11-01

A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

Terbinafine: novel formulations that potentiate antifungal activities.

PubMed

Ma, Y; Chen, X; Guan, S

2015-03-01

Terbinafine, an orally and topically active antifungal agent, has been available for the treatment of dermatophytic infections and onychomycosis for more than a decade. In addition, oral administration has been shown to be associated with drug-drug interactions, hepatotoxicity, low concentration at the infected sites, gastrointestinal and systemic side effects and other adverse effects. Since topical drug delivery can provide higher patient compliance, allow immediate access to the infected site and reduce unwanted systemic drug exposure, an improved topical drug delivery approach with high permeability, sustained release and prolonged retainment could overcome the limitations and side effects caused by oral administration. Conventional topical formulations cannot keep the drug in the targeted sites for a long duration of time and hence a novel drug delivery that can avoid the side effects while still providing sustained efficacy in treatment should be developed. This brief review of novel formulations based on polymers and nanostructure carriers provides insight into the efficacy and topical delivery of terbinafine. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect.

PubMed

Sonvico, Fabio; Conti, Chiara; Colombo, Gaia; Buttini, Francesca; Colombo, Paolo; Bettini, Ruggero; Barchielli, Marco; Leoni, Barbara; Loprete, Luca; Rossi, Alessandra

2017-09-28

In this work, a fixed-dose combination of gabapentin and flurbiprofen formulated as multilayer tablets has been designed, developed and studied in vitro and in vivo. The aim was to construct a single dosage form of the two drugs, able to perform a therapeutic program involving three release kinetics and two delivery sites, i.e., immediate release of gabapentin, intra-gastric prolonged release of gabapentin and intestinal (delayed) release of flurbiprofen. An oblong three-layer tablet was manufactured having as top layer a floating hydrophilic polymeric matrix for gastric release of gabapentin, as middle layer a disintegrating formulation for immediate release of a gabapentin loading dose and as bottom layer, an uncoated hydrophilic polymeric matrix, swellable but insoluble in gastric fluids, for delayed and prolonged release of flurbiprofen in intestinal environment. The formulations were studied in vitro and in vivo in healthy volunteers. The in vitro release rate assessment confirmed the programmed delivery design. A significant higher bioavailability of gabapentin administered 30min after meal, compared to fasting conditions or to dose administration 10min before meal, argued in favor of the gastro-retention of gabapentin prolonged release layer. The two drugs were delivered at different anatomical sites, since the food presence prolonged the gastric absorption of gabapentin from the floating layer and delayed the flurbiprofen absorption. The attainment of a successful delayed release of flurbiprofen was realized by a matrix based on a polymers' combination. The combined use of three hydrophilic polymers with different pH sensitivity provided the dosage form layer containing flurbiprofen with gastro-resistant characteristics without the use of film coating. Copyright © 2017 Elsevier B.V. All rights reserved.

Donepezil dosing strategies: pharmacokinetic considerations.

PubMed

Gomolin, Irving H; Smith, Candace; Jeitner, Thomas M

2011-10-01

Donepezil (Aricept) is a cholinesterase inhibitor approved for the treatment of Alzheimer's disease. Immediate release formulations of 5- and 10-mg tablets were approved by the Food and Drug Administration in the United States in 1996. In July 2010, the Food and Drug Administration approved a 23-mg sustained release (SR) formulation. The SR formulation may provide additional benefit to patients receiving 10 mg daily but the incidence of adverse reactions is increased. We derived plasma concentration profiles for higher dose immediate-release formulations (15 mg once daily, 10 mg twice daily, and 20 mg once daily) and for the profile anticipated to result from the 23-mg SR formulation. Our model predicts similar steady-state concentration profiles for 10 mg twice daily, 20 mg once daily, and 23 mg SR once daily. This provides the theoretical basis for incremental immediate release dose escalation to minimize the emergence of adverse reactions and the potential to offer a cost-effective alternative to the SR formulation with currently approved generic immediate release formulations. Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.

Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users.

PubMed

Bjarnadottir, G D; Johannsson, M; Magnusson, A; Rafnar, B O; Sigurdsson, E; Steingrimsson, S; Asgrimsson, V; Snorradottir, I; Bragadottir, H; Haraldsson, H M

2017-09-01

Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (p<0.0001). The viscosity of the disintegrated MPH was significantly higher for MPH OROS and MPH OCR and the preparation was significantly more time-consuming than for the other MPH samples. No differences were observed between users and non-users. To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug delivery systems with modified release for systemic and biophase bioavailability.

PubMed

Leucuta, Sorin E

2012-11-01

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

Recent advances in oral pulsatile drug delivery.

PubMed

Kalantzi, Lida E; Karavas, Evangelos; Koutris, Efthimios X; Bikiaris, Dimitrios N

2009-01-01

Pulsatile drug delivery aims to release drugs on a programmed pattern i.e.: at appropriate time and/or at appropriate site of action. Currently, it is gaining increasing attention as it offers a more sophisticated approach to the traditional sustained drug delivery i.e: a constant amount of drug released per unit time or constant blood levels. Technically, pulsatile drug delivery systems administered via the oral route could be divided into two distinct types, the time controlled delivery systems and the site-specific delivery systems. The simplest pulsatile formulation is a two layer press coated tablet consisted of polymers with different dissolution rates. Homogenicity of the coated barrier is mandatory in order to assure the predictability of the lag time. The disadvantage of such formulation is that the rupture time cannot be always adequately manipulated as it is strongly correlated with the physicochemical properties of the polymer. Gastric retentive systems, systems where the drug is released following a programmed lag phase, chronopharmaceutical drug delivery systems matching human circadian rhythms, multiunit or multilayer systems with various combinations of immediate and sustained-release preparation, are all classified under pulsatile drug delivery systems. On the other hand, site-controlled release is usually controlled by factors such as the pH of the target site, the enzymes present in the intestinal tract and the transit time/pressure of various parts of the intestine. In this review, recent patents on pulsatile drug delivery of oral dosage forms are summarized and discussed.

Miconazole Nitrate-loaded Microparticles For Buccal Use: Immediate Drug Release and Antifungal Effect.

PubMed

Cartagena, Andres Felipe; Lyra, Amanda Martinez; Kapuchczinski, Aline Cristina; Urban, Amanda Migliorini; Esmerino, Luis Antonio; Klein, Traudi; Nadal, Jessica Mendes; Farago, Paulo Vitor; Campanha, Nara Hellen

2017-01-01

Miconazole nitrate has been widely employed in treatment of oral mycoses, however your immediate bio-availability and location in the affected area is critical. The aim of this study was to prepare and evaluate Eudragit® L100 and Gantrez MS-955 microparticles containing miconazole nitrate for oral delivery. Microparticles were prepared by spray-drying method to achieve high encapsulation efficiency and increase the drug solubility. The microparticles were formed containing 10% and 20% of drug on polymer Eudragit® L100 (E10 and E20), Gantrez MS-955 (G10 and G20) or their combination (EG10 and EG20). The influence of formulation factors (polymer:drug ratio, type of polymer) on yield percent, encapsulation efficiency, particle size, Fourier-transformed infrared spectroscopy (FTIR), X-ray diffraction, differential scanning calorimetry, in vitro drug release and antifungal activity were investigated. Acceptable yield, micrometer-sized and drug-loading efficiencies higher than 89% were obtained. No change in FTIR assignments was recorded after the microencapsulation procedure. X-ray and differential scanning calorimetry studies revealed amorphous/non-crystalline formulations. Miconazole nitrate-microparticles provided a remarkable increase of dissolution rate of the drug. Miconazole nitrate and G10, G20 and EG20 microparticles fitted to biexponential kinetic model, and E10, E20 and EG10 microparticles, monoexponential kinetic model. The antifungal activity test demonstrated that miconazole nitrate-microparticles possessed the same anti-Candida albicans activity as the pure drug. These results indicate that miconazole nitrate-microparticles are feasible carriers for increased release of miconazole at oral environment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients.

PubMed

Tanzi, Maria G; Undre, Nasrullah; Keirns, James; Fitzsimmons, William E; Brown, Malcolm; First, M Roy

2016-08-01

Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

3D extrusion printing of high drug loading immediate release paracetamol tablets.

PubMed

Khaled, Shaban A; Alexander, Morgan R; Wildman, Ricky D; Wallace, Martin J; Sharpe, Sonja; Yoo, Jae; Roberts, Clive J

2018-03-01

The manufacture of immediate release high drug loading paracetamol oral tablets was achieved using an extrusion based 3D printer from a premixed water based paste formulation. The 3D printed tablets demonstrate that a very high drug (paracetamol) loading formulation (80% w/w) can be printed as an acceptable tablet using a method suitable for personalisation and distributed manufacture. Paracetamol is an example of a drug whose physical form can present challenges to traditional powder compression tableting. Printing avoids these issues and facilitates the relatively high drug loading. The 3D printed tablets were evaluated for physical and mechanical properties including weight variation, friability, breaking force, disintegration time, and dimensions and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). X-ray Powder Diffraction (XRPD) was used to identify the physical form of the active. Additionally, XRPD, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to assess possible drug-excipient interactions. The 3D printed tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed a profile characteristic of the immediate release profile as intended based upon the active/excipient ratio used with disintegration in less than 60 s and release of most of the drug within 5 min. The results demonstrate the capability of 3D extrusion based printing to produce acceptable high-drug loading tablets from approved materials that comply with current USP standards. Copyright © 2018 Elsevier B.V. All rights reserved.

Oral heroin in opioid-dependent patients: pharmacokinetic comparison of immediate and extended release tablets

PubMed Central

Perger, Ludwig; Rentsch, Katharina M.; Kullak-Ublick, Gerd A.; Verotta, Davide; Fattinger, Karin

2009-01-01

In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (±SD) immediate and extended release doses were 719 ± 297 mg and 956 ± 404 mg, with high absolute morphine bioavailabilities of 56% to 61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10 to 15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only ~30% of maximal immediate release absorption being reached after 10 min and maintained for 3 to 4 h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially. PMID:19084595

Effect of decrease in both postprandial blood glucose (PBG) and fasting blood glucose (FBG) levels in normal beagle dogs with nateglinide enteric coated granules and immediate release tablets.

PubMed

Makino, Chisato; Ninomiya, Nobutaka; Sakai, Hidetoshi; Orita, Haruo; Okano, Akira; Yabuki, Akira

2006-04-01

Nateglinide is a new quick action/short duration (QRSD) type of oral blood glucose regulator, and nateglinide immediate release tablets are used for patients with mild diabetes under the trade name of Fastic((R)) tablets. In this study, we attempted to determine if it was possible to control both post-prandial blood glucose level (PBG) and fasting blood glucose level (FBG) for moderate or severe diabetes through controlled release of nateglinide. Enteric coated granules were selected for the administration form for controlled release of nateglinide, and three types of enteric coated granules were prepared having dissolution pH values of 5.5, 6.5 and 7.2. The three types of enteric coated granules were each administered separately or the enteric coated granules having an dissolution pH of 6.5 were administered simultaneous to administration of nateglinide immediate release tablets to normal beagle dogs just before feeding followed by measurement of plasma nateglinide concentration, plasma insulin concentration and blood glucose level. In the case of administering enteric coated granules alone (nateglinide: 9 mg/kg), the absorption of nateglinide was confirmed to tend to be delayed as the dissolution pH increased. In the case of an dissolution pH of 5.5, decreases in both PBG and FBG were observed. In the case of dissolution pH values of 6.5 and 7.2, only decrease in FBG was observed. In case of nateglinide immediate release tablets (nateglinide: 9 mg/kg), only decrease in PBG was observed. Decreases in both PBG and FBG were observed in the case of simultaneous administration of dissolution pH 6.5 enteric coated granules and nateglinide immediate release tablets just before feeding (nateglinide: 90 mg/head+60 mg/head). A correlation was observed between plasma nateglinide concentrations and blood glucose levels. On the other hand, there were no correlations observed between changes in plasma insulin concentrations and blood glucose levels. In case of nateglinide immediate release tablets (nateglinide: 150 mg/head), Decreases in both PBG and FBG were observed. However, the nateglinide controlled release formulation is more useful than the nateglinide immediate release tablets from the view point of avoidance of side effect, or of easy control of both PBG and FBG. On the basis of these results, the design of a controlled release formulation that contains nateglinide was suggested to enable control of both PBG and FBG for moderate and severe diabetes patients.

Development of modified in situ gelling oral liquid sustained release formulation of dextromethorphan.

PubMed

El Maghraby, Gamal M; Elzayat, Ehab M; Alanazi, Fars K

2012-08-01

Alternative strategies are being employed to develop liquid oral sustained release formulation. These included ion exchange resin, sustained release suspensions and in situ gelling systems. The later mainly utilizes alginate solutions that form gels upon contact with calcium which may be administered separately or included in the alginate solution as citrate complex. This complex liberates calcium in the stomach with subsequent gellation. The formed gel can break after gastric emptying leading to dose dumping. Development of modified in situ gelling system which sustain dextromethorphan release in the stomach and intestine. Solutions containing alginate with calcium chloride and sodium citrate were initially prepared to select the formulation sustaining the release in the stomach. The best formulation was combined with chitosan. All formulations were characterized with respect to flow, gelling capacity, gelling strength and drug release. Increasing the concentration of alginate increased the gelling capacity and strength and reduced the rate of drug release in gastric conditions with 2% w/v alginate being the best formulation. However, these formulations failed to sustain the release in the intestinal conditions. Incorporation of chitosan with alginate increased the gelling capacity and strength and reduced the rate of drug release compared to alginate only system. The effect was optimum in formulation containing 1.5% w/v chitosan. The sustained release pattern was maintained both in the gastric and intestinal conditions and was comparable to that obtained from the marketed product. Alginate-chitosan based in situ gelling system is promising for developing liquid oral sustained release.

Preparation and in-vivo pharmacokinetic study of a novel extended release compression coated tablets of fenoterol hydrobromide.

PubMed

Elshafeey, Ahmed H; Sami, Elshaimaa I

2008-01-01

The aim of this study was to formulate extended release compression coated core tablets of fenoterol hydrobromide, a selective beta(2) adrenergic receptor agonist, in an attempt to prevent nocturnal asthma. Two hydrophilic polymers viz Kollidon SR, Polyox WSR 303 and a hydrophobic one (Precirol ATO5) were employed. Compression coated tablets were formulated by preparing a core tablet containing 7.5 mg drug and various amounts of polymer and Emcompress then compressed coated with the same polymeric materials. For comparison purpose different matrix tablets were also prepared employing the same polymers. In-vitro release studies were carried out at different pH (1.2 and 6.8). Pharmacokinetics of extended release tablets as well as commercially available immediate release tablets (Berotec) were studied after oral administration to beagle dogs using a new developed LC-MS/MS method with a lower limit of quantification of 1 ng/ml. Fenoterol release from compression coated tablets was significantly lower than matrix tablets. The mechanism of release was changed with the nature and content of polymer. The release pattern of drug from F16 containing 40 mg Kollidon SR divided in the core tablet (15 mg) and the rest in the compressed coat (25 mg) showed a typical zero order release kinetic that could extend drug release >10 h and reasonable time for 75% to be released (t(75)) (8.92 h). When compared to immediate release Berotec tablet the MRT was significantly extended from 7.03 +/- 0.76 to 10.93 +/- 1.25 h (P < 0.001) and HVD(t 50%Cmax) was also significantly extended from 2.71 +/- 0.68 to 6.81 +/- 0.67 h with expected prevention of nocturnal asthma.

Impact of vibration and agitation speed on dissolution of USP prednisone tablets RS and various IR tablet formulations.

PubMed

Seeger, Nicole; Lange, Sigrid; Klein, Sandra

2015-08-01

Dissolution testing is an in vitro procedure which is widely used in quality control (QC) of solid oral dosage forms and, given that real biorelevant test conditions are applied, can also be used as a predictive tool for the in vivo performance of such formulations. However, if a dissolution method is intended to be used for such purposes, it has to deliver results that are only determined by the quality of the test product, but not by other variables. In the recent past, more and more questions were arising on how to address the effects of vibration on dissolution test results. The present study was performed to screen for the correlation of prednisone dissolution of USP Prednisone Tablets RS with vibration caused by a commercially available vibration source as well as to investigate how drug release from a range of immediate release formulations containing class 1-4 drugs of the biopharmaceutical classification scheme is affected by vibration when performing dissolution experiments at different agitation rates. Results of the present study show that the dissolution process of oral drug formulations can be affected by vibration. However, it also becomes clear that the degree of which a certain level of vibration impacts dissolution is strongly dependent on several factors such as drug properties, formulation parameters, and the design of the dissolution method. To ensure the establishment of robust and predictive dissolution test methods, the impact of variation should thus be considered in method design and validation.

Evaluating bioequivalence of meloxicam tablets: is in-vitro dissolution test overdiscriminating?

PubMed

Jin, Chan; Zhao, Chenyao; Shen, Dachao; Dong, Wenxiang; Liu, Hongzhuo; He, Zhonggui

2018-02-01

The aim of the study was to assess the impact of the differences in dissolution profiles of meloxicam tablets on the in-vivo bioavailability parameters after oral administration. Compare in-vitro dissolution testing in the recommended media to evaluate in-vivo bioequivalence outcomes for the Biopharmaceutics Classification System Class II weak acidic drugs. Nine Beagle dogs received a single oral administration of each formulation (7.5 mg) in a three-way crossover design. The dissolution of meloxicam from both test products showed marked differences with that from the reference tablet in pH 1.0, 4.5 and 6.8 media at 50 or 75 rpm. Both formulations exhibiting slow or fast dissolution were then compared with the reference product for in-vivo bioequivalence study. Both products were bioequivalent with the reference tablet in either extent or rate of oral absorption. It indicated that the dissolution profiles which discriminated between the formulations in vitro did not accurately predict the in-vivo bioequivalence outcomes. Comparative dissolution profiles using similarity factor (f 2 ) in the recommended media should be relaxed to fulfil the requirements for the development, scale-up and postapproval changes to immediate release oral solid dosage forms of meloxicam. © 2017 Royal Pharmaceutical Society.

Formulation and Evaluation of Solid Lipid Nanoparticles of Ramipril

PubMed Central

Ekambaram, P; Abdul, Hasan Sathali A

2011-01-01

Solid lipid nanoparticles are typically spherical with an average diameter between 1 and 1000 nm. It is an alternative carrier system to tradition colloidal carriers, such as, emulsions, liposomes, and polymeric micro and nanoparticles. Ramipril is an antihypertensive agent used in the treatment of hypertension. Its oral bioavailability is 28% and it is rapidly excreted through the renal route. This drug has many side effects such as, postural hypotension, hyperkalemia, and angioedema, when given as an immediate dosage form. To overcome the side effects and to increase the bioavailability of ramipril, solid lipid nanoparticles of ramipril are prepared by using lipids (glyceryl monostearate and glyceryl monooleate) with stabilizers (tween 80, poloxamer 188, and span 20). The prepared formulations have been evaluated for entrapment efficiency, drug content, in-vitro drug release, particle size analysis, scanning electron spectroscopy, Fourier transform-infrared studies, and stability. A formulation containing glyceryl monooleate, stabilized with span 20 as surfactant showed prolonged drug release, smaller particle size, and narrow particle size distribution, as compared to other formulations with different surfactants and lipids. PMID:21897661

Differential pharmacokinetics of diclofenac potassium for oral solution vs immediate-release tablets from a randomized trial: effect of fed and fasting conditions.

PubMed

Chen, Cuiping; Bujanover, Shay; Kareht, Stephanie; Rapoport, Alan M

2015-02-01

To compare the pharmacokinetics of, and food effect on, diclofenac potassium delivered as an oral solution vs an immediate-release tablet. Diclofenac potassium for oral solution is the only nonsteroidal anti-inflammatory drug approved as monotherapy for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older. It is formulated with potassium bicarbonate as a buffering agent to raise the pH and consequently increase the aqueous solubility of diclofenac in the acidic environment of the stomach following oral administration. The dosage is 50 mg of powdered diclofenac potassium dissolved in 1 to 2 ounces (30 to 60 mL) of water prior to administration, with dosing time in relation to food intake not specified - this was the case for the pivotal efficacy and safety trials in subjects with acute migraine attacks in which the primary endpoints were achieved. For acute treatment of migraine attacks, rapid onset of pain relief is desirable and is likely related to a rapid appearance of an effective concentration of the drug in the systemic circulation. The rate at which an orally administered drug reaches the blood is affected by both its formulation and the presence of food in the stomach. The present study was designed to investigate the pharmacokinetics of 2 formulations of diclofenac potassium, an immediate-release tablet and an oral solution, and to ascertain the effect of food. This was an open-label, randomized, single-center, crossover trial in healthy volunteers. Subjects were randomized using computer-generated list to 1:1:1:1 ratio. They received a single 50-mg dose of diclofenac potassium in 4 sequences (ABCD, BADC, CDBA, and DCAB) during each of the 4 treatment periods. The 4 treatments were: A, oral solution fasting; B, tablet fasting; C, oral solution fed; and D, tablet fed. There was a ≥7-day washout period between dosing. Blood samples for pharmacokinetic analysis were taken for up to 12 hours post-dose and analyzed for diclofenac concentrations. Pharmacokinetic parameters, including peak concentration (Cmax ), time to Cmax (tmax ), area under the concentration-time curve (AUC) from time 0 to last measurable concentration (AUCt ), and extrapolation to infinity (AUC∞ ) were obtained using non-compartmental analysis. Comparative assessments for Cmax and AUC were performed between the solution and tablet under fed and fasting conditions and between fed and fasting states for both formulations. Bioequivalent exposure was defined as the geometric mean ratio and its 90% confidence interval falling within 80.0-125.0% for Cmax and AUC. Adverse events (AEs) were monitored throughout the trial. Sixty-one percent of the 36 randomized subjects were male, 91.7% were Caucasian, and the mean (standard deviation [SD]) age was 31.9 (7.6) years. Thirty-three (91.7%) subjects completed all 4 treatments. When taken under fed conditions, the oral solution resulted in an approximately 80% faster median tmax (0.17 vs 1.25 hours, P = .00015) and a 21% lower Cmax (mean ± SD, ng/mL: 506 ± 305 vs 835 ± 449, P = .00061) compared with the tablet. AUC values were similar between the 2 formulations. When taken under fasting conditions, the oral solution exhibited a 50% faster median tmax (0.25 vs 0.50 hours, P = .00035) to achieve a 77% higher Cmax (mean ± SD, ng/mL: 1620 ± 538 vs 1160 ± 452, P = .00032) compared with the tablet. AUCt and AUC∞ were similar between the 2 formulations. When taken under fed conditions, the oral solution resulted in a similar median tmax (0.17 vs 0.25 hours, P = .185) and 64% lower Cmax (mean ± SD, ng/mL: 506 ± 305 vs 1620 ± 538, P < .00001) compared with fasting conditions. In comparison, the tablets under fed conditions resulted in a statistically significantly delayed median tmax (1.25 vs 0.50, P = .00143) and ∼30% lower Cmax (mean ± SD, ng/mL: 835 ± 449 vs 1160 ± 452, P = .00377). AUC values were similar between fed and fasting conditions for both formulations. Twelve subjects (33%) experienced ≥1 treatment-emergent AE during the study. All AEs were mild and resolved without treatment; none resulted in study discontinuation. More treatment-emergent AEs were reported in subjects receiving the tablet compared with the solution formulation (20.0% vs 11.8 % in fasting and 17.1% vs 8.6% in fed conditions). Diclofenac potassium oral solution and tablet formulations produced statistically significantly different Cmax and tmax but similar AUC under fed and fasting conditions. Fed conditions produced significantly lower Cmax for both formulations and profoundly delayed tmax for the tablet, but had no effect on tmax for the solution formulation. These data provide insights into the importance of an earlier and greater exposure to diclofenac arising from the solution formulation than the tablet, which may account for the superiority in the onset and sustained pain reduction for the solution than the tablet formulation observed in the double-blind, efficacy/safety study in migraine patients conducted in Europe. © 2014 American Headache Society.

77 FR 41415 - Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-13

... INFORMATION CONTACT: Astrid Lopez-Goldberg, Center for Drug Evaluation and Research, Food and Drug... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0563] Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration and...

Absence of food effect on the extent of alprazolam absorption from an orally disintegrating tablet.

PubMed

Erdman, Keith; Stypinski, Daria; Combs, Michelle; Witt, Patricia; Stiles, Mark; Pollock, Steve

2007-08-01

To evaluate the effect of a standardized meal on the bioavailability of alprazolam formulated as an immediate-release orally disintegrating tablet (ODT) in healthy volunteers. Single-dose, randomized, open-label, two-period crossover study. Contract research organization clinic. Sixteen healthy volunteers (seven men, nine women), aged 20-50 years. Intervention. Subjects were administered a single dose of alprazolam ODT 1.0 mg during two treatment periods-under fasting conditions and after a standard high-fat breakfast-separated by a 7-day washout period, Blood samples for determination of alprazolam pharmacokinetics were collected by venipuncture up to 72 hours after dosing. A validated liquid chromatography with tandem mass spectrometry detection method was used to quantify the alprazolam plasma concentration. The overall extent of alprazolam absorption from the ODT formulation, as measured by area under the concentration-time curve, was unaffected during fed conditions. However, the rate of alprazolam absorption was slower after administration during fed relative to fasted conditions. The mean maximum observed plasma concentration (Cmax) decreased approximately 25%, and time to Cmax (Tmax) was delayed approximately 1.5 hours when food was administered before dosing. Coadministration of food was shown to have no effect on extent of absorption of immediate-release alprazolam ODT 1.0 mg when compared with drug administration in the fasted condition; however, the rate of drug absorption was decreased. The clinical significance of the difference in rate of alprazolam absorption is unknown but thought to be minimal.

Formulation and Evaluation of New Glimepiride Sublingual Tablets.

PubMed

Al-Madhagi, Wafa; Abdulbari Albarakani, Ahmed; Khaled Alhag, Abobakr; Ahmed Saeed, Zakaria; Mansour Noman, Nahlah; Mohamed, Khaldon

2017-01-01

Oral mucosal delivery of drugs promotes rapid absorption and high bioavailability, with a subsequent immediate onset of pharmacological effect. However, many oral mucosal deliveries are compromised by the possibility of the patient swallowing the active substance before it has been released and absorbed locally into the systemic circulation. The aim of this research was to introduce a new glimepiride formula for sublingual administration and rapid drug absorption that can be used in an emergency. The new sublingual formulation was prepared after five trials to prepare the suitable formulation. Two accepted formulations of the new sublingual product were prepared, but one of them with disintegration time of 1.45 min and searching for preferred formulation, the binder, is changed with Flulac and starch slurry to prepare formula with disintegration time of 21 seconds that supports the aim of research to be used in an emergency. The five formulations were done, after adjusting to the binder as Flulac and aerosil with disintegration time of 21 seconds and accepted hardness as well as the weight variation. The assay of a new product (subglimepiride) is 103% which is a promising result, confirming that the formula succeeded. The new product (subglimepiride) is accepted in most quality control tests and it is ready for marketing.

Floating tablets for controlled release of ofloxacin via compression coating of hydroxypropyl cellulose combined with effervescent agent.

PubMed

Qi, Xiaole; Chen, Haiyan; Rui, Yao; Yang, Fengjiao; Ma, Ning; Wu, Zhenghong

2015-07-15

To prolong the residence time of dosage forms within gastrointestinal trace until all drug released at desired rate was one of the real challenges for oral controlled-release drug delivery system. Herein, we developed a fine floating tablet via compression coating of hydrophilic polymer (hydroxypropyl cellulose) combined with effervescent agent (sodium bicarbonate) to achieve simultaneous control of release rate and location of ofloxacin. Sodium alginate was also added in the coating layer to regulate the drug release rate. The effects of the weight ratio of drug and the viscosity of HPC on the release profile were investigated. The optimized formulations were found to immediately float within 30s and remain lastingly buoyant over a period of 12 h in simulated gastric fluid (SGF, pH 1.2) without pepsin, indicating a satisfactory floating and zero-order drug release profile. In addition, the oral bioavailability experiment in New Zealand rabbits showed that, the relative bioavailability of the ofloxacin after administrated of floating tablets was 172.19%, compared to marketed common release tablets TaiLiBiTuo(®). These results demonstrated that those controlled-released floating tables would be a promising gastro-retentive delivery system for drugs acting in stomach. Copyright © 2015 Elsevier B.V. All rights reserved.

Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications.

PubMed

Suarez-Sharp, Sandra; Delvadia, Poonam R; Dorantes, Angelica; Duan, John; Externbrink, Anna; Gao, Zongming; Ghosh, Tapash; Miksinski, Sarah Pope; Seo, Paul

2016-05-01

Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles. The paths highlighted in the article include (1) approaches to address biowaiver requests, such as the use of multi-unit dissolution testing to account for sink condition differences between the higher and lower strengths; (2) the use of a single- vs. strength-dependent dissolution method; and (3) the use of single- vs. strength-dependent dissolution acceptance criteria. These approaches are cost- and time-effective and can avoid unnecessary bioequivalence studies.

Stability of dry coated solid dosage forms.

PubMed

Kablitz, Caroline Désirée; Urbanetz, Nora Anne

2009-01-01

The dry coating process was evaluated in terms of storage stability investigating drug release and agglomeration tendency of the different coated oral dosage forms; hydroxypropyl methylcellulose acetate succinate (HPMCAS) was used with triethylcitrate (TEC) as plasticizer and acetylated monoglyceride (Myvacet) as wetting agent. Talc or colloidal silicon dioxide (Aerosil) was used as anti-tacking agents. In contrast to coating formulations consisting of HPMCAS and Myvacet all formulations containing TEC showed enteric resistance and no agglomeration tendency after preparation. After storage at 10% RH +/- 5% enteric resistance is increased slightly. This increase is more pronounced at 60% RH +/- 5%. The formulations without anti-tacking agents showed higher drug releases after 12 and 24 months due to the damage of the film's integrity during sample preparation caused by the high tackiness of the film. Tackiness is not affected by storing if samples are stored at low relative humidity. At high relative humidity tackiness increases upon storage especially for formulations without anti-tacking agents. The sieving results of the agglomeration measurements after storage can be confirmed by ring shear measurements performed immediately after preparation and approved to be a tool, which is able to predict the agglomeration during storage.

Release of 5-Aminosalicylic Acid (5-ASA) from Mesalamine Formulations at Various pH Levels.

PubMed

Abinusawa, Adeyinka; Tenjarla, Srini

2015-05-01

Oral formulations of 5-aminosalicylic acid (5-ASA) for treatment of ulcerative colitis have been developed to minimize absorption prior to the drug reaching the colon. In this study, we investigate the release of 5-ASA from available oral mesalamine formulations in physiologically relevant pH conditions. Release of 5-ASA from 6 mesalamine formulations (APRISO®, Salix Pharmaceuticals, Inc., USA; ASACOL® MR, Procter & Gamble Pharmaceuticals UK Ltd.; ASACOL® HD, Procter & Gamble Pharmaceuticals, USA; MEZAVANT XL®, Shire US Inc.; PENTASA®, Ferring Pharmaceuticals, Ltd., UK; SALOFALK®, Dr. Falk Pharma UK Ltd.) was evaluated using United States Pharmacopeia apparatus I and II at pH values of 1.0 (2 h), 6.0 (1 h), and 6.8 (8 h). Dissolution profiles were determined for each formulation, respectively. Of the tested formulations, only the PENTASA formulation demonstrated release of 5-ASA at pH 1.0 (48%), with 56% cumulative release after exposure to pH 6.0 and 92% 5-ASA release after 6-8 h at pH 6.8. No other mesalamine formulation showed >1% drug release at pH 1.0. The APRISO formulation revealed 36% 5-ASA release at pH 6.0, with 100% release after 3 h at pH 6.8. The SALOFALK formulation revealed 11% 5-ASA release at pH 6.0, with 100% release after 1 h at pH 6.8. No 5-ASA was released by the ASACOL MR, ASACOL HD, and MEZAVANT XL formulations at pH 6.0. At pH 6.8, the ASACOL MR and ASACOL HD formulations exhibited complete release of 5-ASA after 4 and 2 h, respectively, and the MEZAVANT XL formulation demonstrated complete 5-ASA release over 6-7 h. 5-Aminosalicylic acid release profiles were variable among various commercially available formulations. Shire Development LLC.

Biowaiver monograph for immediate-release solid oral dosage forms: fluconazole.

PubMed

Charoo, Naseem; Cristofoletti, Rodrigo; Graham, Alexandra; Lartey, Paul; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

2014-12-01

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration.

PubMed Central

Van Os, E C; Zins, B J; Sandborn, W J; Mays, D C; Tremaine, W J; Mahoney, D W; Zinsmeister, A R; Lipsky, J J

1996-01-01

BACKGROUND: 6-Mercaptopurine and its prodrug azathioprine are effective medications for refractory inflammatory bowel disease. However, use of these drugs has been limited by concerns about their toxicity. Colonic delivery of azathioprine may reduce its systemic bioavailability and limit toxicity. AIM: To determine the bioavailability of 6-mercaptopurine after administration of azathioprine via three colonic delivery formulations. METHODS: Twenty four healthy human subjects each received 50 mg of azathioprine by one of four delivery formulations (each n = 6): oral; delayed release oral; hydrophobic rectal foam; and hydrophilic rectal foam. All subjects also received a 50 mg dose of intravenous azathioprine during a separate study period. Plasma concentrations of 6-mercaptopurine were determined by high pressure liquid chromatography. RESULTS: The bioavailabilities of 6-mercaptopurine after colonic azathioprine administration via delayed release oral, hydrophobic rectal foam, and hydrophilic rectal foam (7%, 5%, 1%; respectively) were significantly lower than the bioavailability of 6-mercaptopurine after oral azathioprine administration (47%) by Wilcoxon rank sum pairwise comparison. CONCLUSIONS: Azathioprine delivered to the colon by delayed release oral and rectal foam formulations considerably reduced systemic 6-mercaptopurine bioavailability. The therapeutic potential of these colonic delivery methods, which can potentially limit toxicity by local delivery of high doses of azathioprine, should be investigated in patients with inflammatory bowel disease. PMID:8881811

Heterogeneity in the pharmacodynamics of two long-acting methylphenidate formulations for children with attention deficit/hyperactivity disorder. A growth mixture modelling analysis.

PubMed

Sonuga-Barke, Edmund J S; Van Lier, Pol; Swanson, James M; Coghill, David; Wigal, Sharon; Vandenberghe, Mieke; Hatch, Simon

2008-06-01

To use growth mixture modelling (GMM) to identify subgroups of children with attention deficit hyperactive disorder (ADHD) who have different pharmacodynamic profiles in response to extended release methylphenidate as assessed in a laboratory classroom setting. GMM analysis was performed on data from the COMACS study (Comparison of Methylphenidates in the Analog Classroom Setting): a large (n = 184) placebo-controlled cross-over study comparing three treatment conditions in the Laboratory School Protocol (with a 1.5-h cycle of attention and deportment assessments). Two orally administered, once-daily methylphenidate (MPH) bioequivalent formulations [Metadate CD/Equasym XL (MCD-EQXL) and Concerta XL (CON)] were compared with placebo (PLA). Three classes of children with distinct severity profiles in the PLA condition were identified. For both MCD-EQXL and CON, the more severe their PLA symptoms the better, the children's response. However, the formulations produced different growth curves by class, with CON having essentially a flat profile for all three classes (i.e. no effect of PLA severity) and MCD-EQXL showing a marked decline in symptoms immediately post-dosing in the two most severe classes compared with the least severe. Comparison of daily doses matched for immediate-release (IR) components accounted for this difference. The results suggest considerable heterogeneity in the pharmacodynamics of MPH response by children with ADHD. When treatment response for near-equal, bioequivalent daily doses the two formulations was compared, marked differences were seen for children in the most severe classes with a strong curvilinear trajectory for MCD-EQXL related to the greater IR component.

Formulation and Evaluation of Multilayered Tablets of Pioglitazone Hydrochloride and Metformin Hydrochloride

PubMed Central

Chowdary, Y. Ankamma; Raparla, Ramakrishna; Madhuri, Muramshetty

2014-01-01

In the treatment of type 2 diabetes mellitus a continuous therapy is required which is a more complex one. As in these patients there may be a defect in both insulin secretion and insulin action exists. Hence, the treatment depends on the pathophysiology and the disease state. In the present study, multilayered tablets of pioglitazone hydrochloride 15 mg and metformin hydrochloride 500 mg were prepared in an attempt for combination therapy for the treatment of type 2 diabetes mellitus. Pioglitazone HCl was formulated as immediate release layer to show immediate action by direct compression method using combination of superdisintegrants, namely, crospovidone and avicel PH 102. Crospovidone at 20% concentration showed good drug release profile at 2 hrs. Metformin HCl was formulated as controlled release layer to prolong the drug action by incorporating hydrophilic polymers such as HPMC K4M by direct compression method and guar gum by wet granulation method in order to sustain the drug release from the tablets and maintain its integrity so as to provide a suitable formulation. The multilayered tablets were prepared after carrying out the optimization of immediate release layer and were evaluated for various precompression and postcompression parameters. Formulation F13 showed 99.97% of pioglitazone release at 2 hrs in 0.1 N HCl and metformin showed 98.81% drug release at 10 hrs of dissolution in 6.8 pH phosphate buffer. The developed formulation is equivalent to innovator product in view of in vitro drug release profile. The results of all these evaluation tests are within the standards. The procedure followed for the formulation of these tablets was found to be reproducible and all the formulations were stable after accelerated stability studies. Hence, multilayered tablets of pioglitazone HCl and metformin HCl can be a better alternative way to conventional dosage forms. PMID:26556204

An investigation into the influence of experimental conditions on in vitro drug release from immediate-release tablets of levothyroxine sodium and its relation to oral bioavailability.

PubMed

Kocic, Ivana; Homsek, Irena; Dacevic, Mirjana; Parojcic, Jelena; Miljkovic, Branislava

2011-09-01

The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min), are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation. The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine sodium products.

Pharmacokinetics of hydrocodone extended-release tablets formulated with different levels of coating to achieve abuse deterrence compared with a hydrocodone immediate-release/acetaminophen tablet in healthy subjects.

PubMed

Darwish, Mona; Bond, Mary; Tracewell, William; Robertson, Philmore; Yang, Ronghua

2015-01-01

A hydrocodone extended-release (ER) formulation employing the CIMA(®) Abuse-Deterrence Technology platform was developed to provide resistance against rapid release of hydrocodone when tablets are comminuted or taken with alcohol. This study evaluated the pharmacokinetics of three hydrocodone ER tablet prototypes with varying levels of polymer coating to identify the prototype expected to have the greatest abuse deterrence potential based on pharmacokinetic characteristics that maintain systemic exposure to hydrocodone comparable to that of a commercially available hydrocodone immediate-release (IR) product. In this four-period crossover study, healthy subjects aged 18-45 years were randomized to receive a single intact, oral 45-mg tablet of one of three hydrocodone ER prototypes (low-, intermediate-, or high-level coating) or an intact, oral tablet of hydrocodone IR/acetaminophen (APAP) 10/325 mg every 6 h until four tablets were administered, with each of the four treatments administered once over the four study periods. Dosing periods were separated by a minimum 5-day washout. Naltrexone 50 mg was administered to block opioid receptors. Blood samples for pharmacokinetic assessments were collected predose and through 72 h postdose. Parameters assessed included maximum observed plasma hydrocodone concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve from time 0 to infinity (AUC(0-∞)). Mean C(max) values were 49.2, 32.6, and 28.4 ng/mL for the low-, intermediate-, and high-level coating hydrocodone ER tablet prototypes, respectively, and 37.3 ng/mL for the hydrocodone IR/APAP tablet; respective median t(max) values were 5.9, 8.0, 8.0, and 1.0 h. Total systemic exposure to hydrocodone (AUC(0-∞)) was comparable between hydrocodone ER tablet prototypes (640, 600, and 578 ng·h/mL, respectively) and hydrocodone IR/APAP (581 ng·h/mL). No serious adverse events or deaths were reported. The most common adverse events included headache (26%) and nausea (18%). All three hydrocodone ER tablet prototypes (low-, intermediate-, and high-level polymer coating) demonstrated ER pharmacokinetic characteristics. The hydrocodone ER tablet prototype with the high-level coating was selected for development because of its comparable exposure to the hydrocodone IR/APAP formulation and potentially increased ability to resist rapid drug release upon product tampering because of a higher polymer coating level. All study medications were well tolerated in healthy naltrexone-blocked volunteers.

Development, characterization, and in vivo assessment of mucoadhesive nanoparticles containing fluconazole for the local treatment of oral candidiasis.

PubMed

Rençber, Seda; Karavana, Sinem Yaprak; Yılmaz, Fethiye Ferda; Eraç, Bayri; Nenni, Merve; Özbal, Seda; Pekçetin, Çetin; Gurer-Orhan, Hande; Hoşgör-Limoncu, Mine; Güneri, Pelin; Ertan, Gökhan

2016-01-01

This study aimed to develop a suitable buccal mucoadhesive nanoparticle (NP) formulation containing fluconazole for the local treatment of oral candidiasis. The suitability of the prepared formulations was assessed by means of particle size (PS), polydispersity index, and zeta potential measurements, morphology analysis, mucoadhesion studies, drug entrapment efficiency (EE), in vitro drug release, and stability studies. Based on the optimum NP formulation, ex vivo drug diffusion and in vitro cytotoxicity studies were performed. Besides, evaluation of the antifungal effect of the optimum formulation was evaluated using agar diffusion method, fungicidal activity-related in vitro release study, and time-dependent fungicidal activity. The effect of the optimum NP formulation on the healing of oral candidiasis was investigated in an animal model, which was employed for the first time in this study. The zeta potential, mucoadhesion, and in vitro drug release studies of various NP formulations revealed that chitosan-coated NP formulation containing EUDRAGIT(®) RS 2.5% had superior properties than other formulations. Concerning the stability study of the selected formulation, the formulation was found to be stable for 6 months. During the ex vivo drug diffusion study, no drug was found in receptor phase, and this is an indication of local effect. The in vitro antifungal activity studies showed the in vitro efficacy of the NP against Candida albicans for an extended period. Also, the formulation had no cytotoxic effect at the tested concentration. For the in vivo experiments, infected rabbits were successfully treated with local administration of the optimum NP formulation once a day. This study has shown that the mucoadhesive NP formulation containing fluconazole is a promising candidate with once-a-day application for the local treatment of oral candidiasis.

pH-independent immediate release polymethacrylate formulations--an observational study.

PubMed

Claeys, Bart; Vandeputte, Reinout; De Geest, Bruno G; Remon, Jean Paul; Vervaet, Chris

2016-01-01

Using Eudragit® E PO (EudrE) as a polymethacrylate carrier, the aim of the study was to develop a pH-independent dosage form containing ibuprofen (IBP) as an active compound via chemical modification of the polymer (i.e. quaternization of amine function) or via the addition of dicarboxylic acids (succinic, glutaric and adipic acid) to create a pH micro-environment during dissolution. Biconvex tablets (diameter: 10 mm; height: 5 mm) were produced via hot melt extrusion and injection molding. In vitro dissolution experiments revealed that a minimum of 25% of quaternization was sufficient to partially (up to pH 5) eliminate the pH-dependent effect of the EudrE/IBP formulation. The addition of dicarboxylic acids did not alter IBP release in a pH 1 and 3 medium as the dimethyl amino groups of EudrE are already fully protonated, while in a pH 5 solvent IBP release was significantly improved (cf. from 0% to 92% release after 1 h dissolution experiments upon the addition of 20 wt.% succinic acid). Hence, both approaches resulted in a pH-independent (up to pH 5) immediate release formulation. However, the presence of a positively charged polymer induced stability issues (recrystallization of API) and the formulations containing dicarboxylic acids were classified as mechanically unstable. Hence, further research is needed to obtain a pH-independent immediate release formulation while using EudrE as a polmethacrylate carrier.

Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

PubMed

Muenster, Uwe; Mueck, Wolfgang; van der Mey, Dorina; Schlemmer, Karl-Heinz; Greschat-Schade, Susanne; Haerter, Michael; Pelzetter, Christian; Pruemper, Christian; Verlage, Joerg; Göller, Andreas H; Ohm, Andreas

2016-05-01

The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

Controlling Release of Integral Lipid Nanoparticles Based on Osmotic Pump Technology.

PubMed

Tian, Zhiqiang; Yu, Qin; Xie, Yunchang; Li, Fengqian; Lu, Yi; Dong, Xiaochun; Zhao, Weili; Qi, Jianping; Wu, Wei

2016-08-01

To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles. NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references. NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation. Controlled release of integral NLCs is achieved by the osmotic pump strategy.

Cancer inpatients morphine usage: a new England area survey.

PubMed

Trollor, John

2003-08-01

This is a one year study of the use of morphine in cancer patients in 10 inpatient facilities in the New England Area Health Service in the north-west of New South Wales. The study explored 170 admissions relating to 122 patients, most of whom were cared for by their general practitioners. The use of morphine in these cancer patients was compared with the recommendations made by the expert working group of the European Association of Palliative Care.1 Those items which matched the recommendations included the initial doses for new users of morphine and the subcutaneous route being the preferred parenteral route. The data in this study differed from the recommendations in that only half of the patients received the immediate release morphine when first given oral morphine, only 43% had orders for immediate release oral morphine for breakthrough pain (with a variable frequency) and a significant number of orders for parenteral and immediate release oral morphine for breakthrough pain were outside the recommended doses (100% and 86.2%, respectively). Written orders for immediate release oral and parenteral morphine involved a dose range in significant numbers while only 30% of patients had orders for parenteral morphine for breakthrough pain. There was a low use of fixed interval variable dose (FIVD) morphine charts despite these being available in most facilities.

The Clinical Pharmacokinetics of Amphetamines Utilized in the Treatment of Attention-Deficit/Hyperactivity Disorder.

PubMed

Markowitz, John S; Patrick, Kennerly S

2017-10-01

Amphetamine (AMP), an indirectly acting psychostimulant approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults, is among the most long-standing therapeutic agents in all of clinical psychopharmacology. This review focuses on AMP absorption, metabolism, and elimination brought to bear on comparative pharmacokinetics in its various formulations. A comprehensive search of the published literature was conducted using MEDLINE (PubMed) and Google Scholar databases through April 2017 to retrieve all pertinent in vitro and human studies for review and synthesis. Additionally, Food and Drug Administration (FDA) databases were accessed for otherwise unavailable data when possible. Initially available as racemic (dl)-AMP, this drug was later supplanted by enantiopure (d)-AMPH or enantioenriched (75:25 dl)-AMP formulations; although racemic AMP returned as an approved drug to treat ADHD in 2014. Presently, there are several immediate-release (IR) formulations available, including d-AMP, dl-AMP, and mixed amphetamine salts, which are neither racemic nor the pure d-enantiomer (i.e., a 3:1 mixture of d-AMP and l-AMP). Furthermore, new modified-release AMP formulations, including an oral suspension and an orally disintegrating tablet, are now available. A lysine-bonded prodrug form of d-AMP also serves as a treatment option. Oral AMP is rapidly absorbed, with high absolute bioavailability, followed by extensive metabolism involving multiple enzymes. Some metabolic pathways exhibit stereoselective biotransformations favoring the l-isomer substrate. Drug exposure exhibits dose-proportional pharmacokinetics. Body weight is a fundamental determinant of differences in observed AMP plasma concentrations. IR formulations typically provide a T max from 2 to 3 hours. In replicated studies, children exhibit a shorter plasma T 1/2 (∼7 hours) relative to adults (∼10 to 12 hours). There are few documented pharmacokinetic drug interactions of clinical significance beyond influences of drug-induced alteration of urinary pH. The array of AMP formulations addressed in this review offer flexibility in dosing, drug onset, and offset to assist in individualized pharmacotherapy of ADHD.

Food effect: The combined effect of media pH and viscosity on the gastrointestinal absorption of ciprofloxacin tablet.

PubMed

Radwan, Asma; Zaid, Abdel Naser; Jaradat, Nidal; Odeh, Yousef

2017-04-01

The clinical implications of food-drug interactions may have to be taken seriously into account with oral drugs administration in order to minimize variations in drug bioavailability. Food intake may alter physiological changes in the pH and viscosity of the gastrointestinal lumen, which could affect the oral absorption of drugs. The aim of the present study was to have an insight on the effect of media parameters: viscosity and pHon the oral absorption of ciprofloxacin HCl from solid formulations using a model food: Corchorus olitorius (Jute) Soup. In vitro disintegration and dissolution rates of ciprofloxacin tablet were evaluated using compendia buffer media in the presence/absence of C. olitorius leaves. These in vitro data were then input to GastroPlus™ to predict ciprofloxacin absorption profiles under fasted and fed states. The present study demonstrated the significance of luminal pH and viscosity on the dissolution and disintegration of solid formulations following postprandial ingestion of the viscous soup. The tablets showed prolonged disintegration times and reduced dissolution rates in this soup, which could be attributed to the postprandial elevation in media viscosity and reduced solubility at elevated gastricpH. The predicted model under fed state showed no impact on AUC but prolonged T max and a decrease in C max . Concomitant intake of C. olitorius soup with ciprofloxacin might have negative effect on the rate of drug release from conventional immediate release tablets. Copyright © 2017 Elsevier B.V. All rights reserved.

Microstructural investigation using synchrotron radiation X-ray microtomography reveals taste-masking mechanism of acetaminophen microspheres.

PubMed

Guo, Zhen; Yin, Xianzhen; Liu, Congbiao; Wu, Li; Zhu, Weifeng; Shao, Qun; York, Peter; Patterson, Laurence; Zhang, Jiwen

2016-02-29

The structure of solid drug delivery systems has considerable influence on drug release behaviors from particles and granules and also impacts other properties relevant to release characteristics such as taste. In this study, lipid-based microspheres of acetaminophen were prepared to mask the undesirable taste of drug and therefore to identify the optimal formulation for drug release. Synchrotron radiation X-ray computed microtomography (SR-μCT) was used to investigate the fine structural architectures of microspheres non-destructively at different sampling times during drug release test, which were simultaneously determined to quantitatively correlate the structural data with drug release behaviors. The results demonstrated that the polymeric formulation component, namely, cationic polymethacrylate (Eudragit E100), was the key factor to mask the bitter taste of acetaminophen by inhibiting immediate drug release thereby reducing the interaction intensity of the bitter material with the oral cavity taste buds. The structure and morphology of the microspheres were found to be influenced by the shape and particle size of the drug, which was also an important factor for taste-masking performance. The quantitative analysis generated detailed structural information which was correlated well with drug release behaviors. Thus, SR-μCT has been proved as a powerful tool to investigate the fine microstructure of particles and provides a new approach in the design of particles for taste masking. Copyright © 2015 Elsevier B.V. All rights reserved.

An extended-release formulation of oxybutynin chloride for the treatment of overactive urinary bladder.

PubMed

Goldenberg, M M

1999-04-01

Detrusor instability, or urinary incontinence, is common in elderly patients, particularly elderly women. The clinical symptoms of overactive, or unstable, urinary bladder include urge urinary incontinence, urgency, and frequency. Mixed urinary incontinence, which comprises urge urinary incontinence and stress incontinence, is manifested by increased intraabdominal pressure on coughing or sneezing. The detrusor muscle of the bladder is under the control of the parasympathetic, or muscarinic, nervous system. The drug of choice in this condition is oxybutynin chloride, which has the ability to block acetylcholine released from parasympathetic nerves in the urinary bladder, preventing contractions of the muscle and exerting a direct spasmolytic effect on the bladder. A new extended-release oral tablet formulation, OROS oxybutynin, uses osmotic pressure to deliver the drug at a controlled rate over approximately 24 hours. It resembles a conventional tablet but has a two-part core consisting of a drug layer and below it, a "push" layer containing osmotically active components, the whole surrounded by a semipermeable membrane with a laser-drilled opening in the drug side. Water in the gastrointestinal tract enters the tablet and mixes with the drug to form a suspension. The "push" layer expands and pushes the suspended drug out of the orifice and into the gastrointestinal tract for eventual absorption. Pharmacokinetic studies have indicated a slow rise in mean plasma concentration of the isomer R-oxybutynin for 4 to 6 hours after a single dose of OROS oxybutynin, followed by maintenance of steady concentrations for up to 24 hours, minimizing the fluctuations between peak and trough associated with TID dosing of 5-mg immediate-release oxybutynin tablets. Efficacy and safety studies comparing the extended-release with the immediate-release formulation of oxybutynin demonstrated equivalent efficacy in patients with overactive urinary bladder. The adverse-event profile of oxybutynin is similar to that of a typical anticholinergic agent such as atropine--dry mouth, constipation, somnolence, blurred vision, headache, and gastrointestinal pain--although in 2 clinical studies, the incidence of dry mouth was less with the extended-release formulation. Once-daily dosing with OROS oxybutynin appears to be well tolerated and effective, as well as convenient, for the treatment of overactive bladder, particularly for elderly patients using multiple medications.

A review of OROS methylphenidate (Concerta(®)) in the treatment of attention-deficit/hyperactivity disorder.

PubMed

Katzman, Martin A; Sternat, Tia

2014-11-01

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioural disorder with onset during childhood. It affects a child's development, both at home and at school, and impacts on social, emotional and cognitive functioning, in both the home and the school environment. Untreated ADHD is very often associated with poor academic achievement, low occupational status, increased risk of substance abuse and delinquency. Current practice guidelines recommend a multimodal approach in the treatment of ADHD, which includes educational, behavioural and mental health interventions, and pharmacological management. Stimulant medications, including methylphenidate (MPH) and amphetamine products, are recommended as first-line pharmacotherapy in the treatment of ADHD. The choice of stimulant is influenced by several factors; the most influential factor is the duration of action. Long-acting medication provides benefits long after school and work. It also increases the likelihood of once-daily dosing, thereby eliminating the need for mid-day dosing, making the treatment more private, avoiding stigma and improving adherence to medication. MPH is the most widely used psychotropic medication in child psychiatry. It was first developed for use in children as an oral, immediate-release formulation and more recently as various extended-release formulations. These latter formulations include the 12 h preparation Concerta(®) (osmotic-release oral system [OROS] MPH), which utilizes an osmotic pump system, designed to overcome the difficulties of multiple daily dosing. Since it received approval from the US Food and Drug Administration in August 2000, OROS MPH has been quickly and widely accepted as one of the preferred treatments for ADHD because of its once-daily dosing. This paper reviews the data in support of long-acting OROS MPH in children, adolescents and adults, both in ADHD and in association with its comorbidities.

Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose.

PubMed

Yi, Tao; Wan, Jiangling; Xu, Huibi; Yang, Xiangliang

2008-08-07

The objective of this work was the development of a controlled release system based on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drugs. HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system (SMES) consisting of ethyl oleate, Cremophor RH 40 and Labrasol. Based on investigation by transmission electron microscopy (TEM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction, differences were found in the particle structure between both types of formulations. In vitro release was performed and characterized by the power law. Nimodipine release from both types of formulations showed a controlled release profile and the two power law parameters, n and K, correlated to the viscosity of HPMC. The parameters were also influenced by the presence of SMES. For the controlled release solid SMES, oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. Thus, it is possible to control the in vitro release of poorly soluble drugs from solid oral dosage forms containing SMES.

Hypnotics in insomnia: the experience of zolpidem.

PubMed

MacFarlane, James; Morin, Charles M; Montplaisir, Jacques

2014-11-01

One of the most commonly prescribed medications to treat insomnia is zolpidem, a nonbenzodiazepine compound that is available as an immediate-release oral tablet formulation, an extended-release oral formulation, an oral spray formulation, and as sublingual formulations. The purpose of this review was to summarize the data currently available on the efficacy and safety of zolpidem in the treatment of insomnia among adults. Published studies on the use of zolpidem in the treatment of insomnia were identified by using combinations of relevant search terms in PubMed and Google Scholar. Studies were included if they were placebo- or active comparator-controlled studies, with the exception of trials on the long-term use of zolpidem. Studies were limited to those conducted in adults. Studies were not included if the patient population was small, if the study was not designed or powered to assess the efficacy or safety of zolpidem, if insomniac patients had a medical condition in addition to insomnia (with the exception of comorbid depression or anxiety for studies on comorbid insomnia), or if zolpidem was given concomitantly with any other therapy (with the exception of selective serotonin reuptake inhibitors for studies on comorbid insomnia). Twenty-five studies designed to evaluate the efficacy of zolpidem in insomnia and 51 studies reporting the safety of zolpidem in insomnia were included in this review. The studies discussed in this review report the efficacy and safety of zolpidem in both young adults and the elderly. It can be used for either bedtime or middle-of-the-night administration, over the short or long term, with minimal risk of withdrawal or abuse. The use of zolpidem is associated with rebound insomnia, complex sleep-related behaviors, and next-day residual effects (after middle-of-the-night dosing) on driving ability, memory, and psychomotor performance. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding.

PubMed

Claeys, Bart; Vervaeck, Anouk; Hillewaere, Xander K D; Possemiers, Sam; Hansen, Laurent; De Beer, Thomas; Remon, Jean Paul; Vervaet, Chris

2015-02-01

This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions - crystalline API in a crystalline carrier - at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24h, whereas a complete release of diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65 wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM. Copyright © 2014 Elsevier B.V. All rights reserved.

Pharmaceutical suspension containing both immediate/sustained-release amoxicillin-loaded gelatin nanoparticles: preparation and in vitro characterization.

PubMed

Harsha, Sree

2013-01-01

Pharmaceutical suspension containing oral dosage forms delivering both immediate-release and sustained-release amoxicillin was developed as a new dosage form to eradicate Helicobacter pylori. Amoxicillin-loaded gelatin nanoparticles are able to bind with the mucosal membrane after delivery to the stomach and could escalate the effectiveness of a drug, providing dual release. The objective of this study was to develop amoxicillin nanoparticles using innovative new technology--the Büchi Nano Spray Dryer B-90 - and investigate such features as drug content, particle morphology, yield, in vitro release, flow properties, and stability. The nanoparticles had an average particle size of 571 nm. The drug content and percentage yield was 89.2% ± 0.5% and 93.3% ± 0.6%, respectively. Angle of repose of nanoparticle suspension was 26.3° and bulk density was 0.59 g/cm(3). In vitro drug release of formulations was best fitted by first-order and Peppas models with R (2) of 0.9841 and 0.9837 respectively; release profile was 15.9%, while; for the original drug, amoxicillin, under the same conditions, 90% was released in the first 30 minutes. The nanoparticles used in this study enabled sustained release of amoxicillin over an extended period of time, up to 12 hours, and were stable for 12 months under accelerated storage conditions of 25 °C ± 2 °C and 60% ± 5% relative humidity.

Preparation and evaluation of a controlled drug release of repaglinide through matrix pellets: in vitro and in vivo studies.

PubMed

Tavakoli, Naser; Minaiyan, Mohsen; Tabbakhian, Majid; Pendar, Yaqub

2014-01-01

Repaglinide, an oral antidiabetic agent, has a rapid onset of action and short half-life of approximately 1 h. Designing a controlled release dosage form of the drug is required to maintain its therapeutic blood level and to eliminate its adverse effects, particularly the hypoglycaemia. Repaglinide sustained release matrix pellets consisting of Avicel, lactose and different polymers were prepared using extrusion-spheronisation method. The effect of different formulation components on in vitro drug release were evaluated using USP apparatus (paddle) for 12 h in phosphate buffer. The optimised formulation was orally administrated to normal and STZ induced diabetic rats. Most pellet formulations had acceptable physical properties with regard to size distribution, flowability and friability. Repaglinide pellets comprising Avicel 50%, lactose 47% and SLS 1% were released 94% of its drug content after 12 h. The optimised formulation was able to decrease blood glucose level in normal rats and those with diabetes throughout 8-12 h.

Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology.

PubMed

Mohammed, Noorullah Naqvi; Majumdar, Soumyajit; Singh, Abhilasha; Deng, Weibin; Murthy, Narasimha S; Pinto, Elanor; Tewari, Divya; Durig, Thomas; Repka, Michael A

2012-12-01

The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing conditions for hot-melt extrusion. Extrudates pelletized and filled into capsules exhibited a carrier-dependent release with ELF polymer exhibiting a faster release. Tablets compressed from milled extrudates exhibited rapid release owing to the increased surface area of the milled extrudate. Addition of mannitol (MNT) further enhanced the release by forming micro-pores and increasing the porosity of the extrudates. An optimized tablet formulation constituting KPR, MNT, and ELF in a 1:1:1 ratio exhibited 90% release in 15 min similar to a commercial capsule formulation. HPC polymers are non-ionic hydrophilic polymers that undergo polymer-chain-length-dependent solubilization and can be used to enhance solubility or dissolution rate of poorly soluble drugs. Dissolution/release rate could be tailored for rapid-release applications by selecting a suitable HPC polymer and altering the final dosage form. The release obtained from pellets was carrier-dependent and not drug-dependent, and hence, such a system can be effectively utilized to address solubility or precipitation issues with poorly soluble drugs in the gastrointestinal environment.

PD-PK evaluation of freeze-dried atorvastatin calcium-loaded poly-ε-caprolactone nanoparticles.

PubMed

Ahmed, Iman S; El-Hosary, Rania; Shalaby, Samia; Abd-Rabo, Marwa M; Elkhateeb, Dalia G; Nour, Samia

2016-05-17

In this work lyophilized poly-ε-caprolactone nanoparticles (NPs) loaded with atorvastatin calcium (AC) were developed in an attempt to improve the in-vivo performance of AC following oral administration. The individual and combined effects of several formulation variables were previously investigated using step-wise full factorial designs in order to produce optimized AC-NPs with predetermined characteristics including particle size, drug loading capacity, drug release profile and physical stability. Four optimized formulations were further subjected in this work to lyophilization to promote their long-term physical stability and were fully characterized. The pharmacodynamics (PD)/pharmacokinetics (PK) properties of two optimized freeze-dried AC-NPs formulations showing acceptable long-term stability were determined and compared to a marketed AC immediate release tablet (Lipitor(®)) in albino rats. PD results revealed that the two tested formulations were equally effective in reducing low density lipoproteins (LDL) and triglycerides (TG) levels when given in reduced doses compared to Lipitor(®) and showed no adverse effects. PK results, on the other hand, revealed that the two freeze-dried AC-NPs formulations were of significantly lower bioavailability compared to Lipitor(®). Taken together the PD and PK results demonstrate that the improved efficacy obtained at reduced doses from the freeze-dried AC-NPs could be due to increased concentration of AC in the liver rather than in the plasma. Copyright © 2016 Elsevier B.V. All rights reserved.

Changes in drug use patterns reported on the web after the introduction of ADF OxyContin: findings from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Web Monitoring Program.

PubMed

Vosburg, Suzanne K; Haynes, Colleen; Besharat, Andrea; Green, Jody L

2017-09-01

This qualitative study summarizes information that individuals shared online about use of OxyContin following the August 2010 introduction of the abuse deterrent formulation (ADF). The primary objective was to study online posts that endorsed continued use of OxyContin or a switch from OxyContin to another formulation of oxycodone or another substance altogether following the introduction of the ADF. A secondary objective was to determine whether posts revealed that the ADF led to cessation of OxyContin use. Data were collected with the Researched Abuse, Diversion, and Addiction-Related Surveillance System Web Monitoring Program, an online surveillance system that collects and organizes posts about prescription drugs from social media websites, blogs, and forums from 3Q2009 to 4Q2014 using a commercially available web platform. Posts were categorized by whether they conveyed a switch to drugs other than reformulated OxyContin or a continuation of reformulated OxyContin abuse. "Switch posts" primarily discussed switching to immediate-release opioids. "Continue abusing" posts identified tampering strategies for alternate routes of administration, oral use, and continued use although post authors were generally unhappy with the experience. No reference to OxyContin cessation as a function of the introduction of the ADF was found; however, discontinued use was discussed. Web Monitoring data are useful for capturing cross sections of Internet conversation reflecting reactions to new drug formulations. These data support the notion that users will gravitate to non-ADFs generally, and to immediate-release non-ADF opioid formulations, specifically, as long as these options remain on the market. Copyright © 2017 John Wiley & Sons, Ltd.

A Randomized, Single-Blind, Substitution Study of OROS Methylphenidate (Concerta) in ADHD Adults Receiving Immediate Release Methylphenidate

ERIC Educational Resources Information Center

Spencer, Thomas J.; Mick, Eric; Surman, Craig B. H.; Hammerness, Paul; Doyle, Robert; Aleardi, Megan; Kotarski, Meghan; Williams, Courtney G.; Biederman, Joseph

2011-01-01

Objective: The main aim of this study was to examine the efficacy, tolerability, and compliance of an extended-release formulation of methylphenidate (OROS-MPH) in adults with ADHD receiving immediate-release methylphenidate (IR-MPH). Method: Participants were outpatient adults with ADHD who were stable on IR-MPH-administered TID. Participants…

A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling.

PubMed

Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

2016-01-01

Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of amoxicillin. In vitro release study firstly indicated a three-pulse release profile of the tablet. Later the pulse tablet was found to generate the sustained release of amoxicillin in beagle dogs. Furthermore, the Simcyp® software was used to simulate the in vivo concentration time curve model of the three-pulse release tablet for amoxicillin in both human and beagle dog. The prediction by PBPK model nicely fitted the observation in human and beagle dog. This study has demonstrated the interrelation of factors affecting the pulsatile formulation of amoxicillin using a Box-Behnken design. The three-pulse release tablets of amoxicillin were proven to generate pulsatile release in vitro and sustained release in vivo. This formulation was also found to extend the effective plasma concentration in human compared to the tablet of immediate release based on the simulation data by PBPK modeling. This study provides an example of using PBPK to guide the development of pulsatile dosage forms.

The effects of a new therapeutic triclosan/copolymer/sodium-fluoride dentifrice on oral bacteria, including odorigenic species.

PubMed

Furgang, David; Sreenivasan, Prem K; Zhang, Yun Po; Fine, Daniel H; Cummins, Diane

2003-09-01

This investigation examined the in vitro and ex vivo antimicrobial effects of a new dentifrice, Colgate Total Advanced Fresh, formulated with triclosan/copolymer/sodium fluoride, on oral bacteria, including those odorigenic bacteria implicated in bad breath. The effects of Colgate Total Advanced Fresh were compared to commercially available fluoride dentifrices that served as controls. Three experimental approaches were undertaken for these studies. In the first approach, the dentifrice formulations were tested in vitro against 13 species of oral bacteria implicated in bad breath. The second approach examined the antimicrobial activity derived from dentifrice that was adsorbed to and released from hydroxyapatite disks. In this approach, dentifrice-treated hydroxyapatite disks were immersed in a suspension of bacteria, and reduction in bacterial viability from the release of bioactive agents from hydroxyapatite was determined. The third approach examined the effect of treating bacteria immediately after their removal from the oral cavity of 11 adult human volunteers. This ex vivo study examined the viability of cultivable oral bacteria after dentifrice treatment for 2 minutes. Antimicrobial effects were determined by plating Colgate Total Advanced Fresh and control-dentifrice-treated samples on enriched media (for all cultivable oral bacteria) and indicator media (for hydrogen-sulfide-producing organisms), respectively. Results indicated that the antimicrobial effects of Colgate Total Advanced Fresh were significantly greater than either of the other dentifrices for all 13 oral odorigenic bacterial strains tested in vitro (P < or = 0.05). In the second approach, Colgate Total Advanced Fresh-treated hydroxyapatite disks were significantly more active in reducing bacterial growth than the other dentifrices tested (P < or = 0.05). Finally, ex vivo treatment of oral bacteria with Colgate Total Advanced Fresh demonstrated a 90.9% reduction of all oral cultivable bacteria and a 91.5% reduction of oral bacteria producing hydrogen sulfide compared with the control dentifrice. In conclusion, these results, taken together with the significant reductions in clinical malodor scores by Colgate Total Advanced Fresh demonstrated in organoleptic studies, strongly suggest that this dentifrice kills the bacteria that are implicated in the cause of bad breath.

Investigation of an artificial intelligence technology--Model trees. Novel applications for an immediate release tablet formulation database.

PubMed

Shao, Q; Rowe, R C; York, P

2007-06-01

This study has investigated an artificial intelligence technology - model trees - as a modelling tool applied to an immediate release tablet formulation database. The modelling performance was compared with artificial neural networks that have been well established and widely applied in the pharmaceutical product formulation fields. The predictability of generated models was validated on unseen data and judged by correlation coefficient R(2). Output from the model tree analyses produced multivariate linear equations which predicted tablet tensile strength, disintegration time, and drug dissolution profiles of similar quality to neural network models. However, additional and valuable knowledge hidden in the formulation database was extracted from these equations. It is concluded that, as a transparent technology, model trees are useful tools to formulators.

Methotrexate-loaded porous polymeric adsorbents as oral sustained release formulations.

PubMed

Wang, Xiuyan; Yan, Husheng

2017-09-01

Methotrexate as a model drug with poor aqueous solubility was adsorbed into porous polymeric adsorbents, which was used as oral sustained release formulations. In vitro release assay in simulated gastrointestinal fluids showed that the methotrexate-loaded adsorbents showed distinct sustained release performance. The release rate increased with increase in pore size of the adsorbents. In vivo pharmacokinetic study showed that the maximal plasma methotrexate concentrations after oral administration of free methotrexate and methotrexate-loaded DA201-H (a commercial porous polymeric adsorbent) to rats occurred at 40min and 5h post-dose, respectively; and the plasma concentrations decreased to 22% after 5h for free methotrexate and 44% after 24h for methotrexate-loaded DA201-H, respectively. The load of methotrexate into the porous polymeric adsorbents not only resulted in obvious sustained release, but also enhanced the oral bioavailability of methotrexate. The areas under the curve, AUC 0-24 and AUC 0-inf , for methotrexate-loaded DA201-H increased 3.3 and 7.7 times, respectively, compared to those for free methotrexate. Copyright © 2017 Elsevier B.V. All rights reserved.

Interchangeability, Safety and Efficacy of Modified-Release Drug Formulations in the USA: The Case of Opioid and Other Nervous System Drugs.

PubMed

Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Hansen, Richard

2016-04-01

Modified-release drugs may provide clinical advantages compared to immediate-release forms and improve convenience to the patient and health outcomes. Concerns have been raised regarding interchangeability, efficacy, and safety of modified-release formulations. This study analyses all US Food and Drug Administration (FDA)-approved modified-release formulations and market trends, and illustrates how bioequivalence and safety of generic modified-release products compare to their respective brand name drugs and other generic drugs with different formulation design characteristics. This study also examines major concerns related to modified-release formulations: safety of opioids and bioequivalence of generic bupropion and methylphenidate. Study data were derived from the FDA electronic versions of the FDA's Orange Book (OB) and the FDA safety communications web page. Medicare Part D utilization and expenditures data were extracted from the Centers for Medicare and Medicaid. In May 2015, 276 (11.9 %) of the 2325 active ingredients and fixed-dose combinations listed in the FDA's Orange Book had at least one modified-release form approved by the FDA. The number of approvals increased over time; 52.5 % of modified releases were approved in the period 2000-May 2015. The FDA required a risk evaluation and mitigation strategy (REMS) to ensure that the benefits of extended-release opioids outweighed its risks of overdose and abuse. The REMS involved 16 new drug applications and 25 abbreviated new drug applications. The FDA addressed interchangeability problems with generic modified-release alternatives of bupropion and methylphenidate including lack of bioequivalence, reduced efficacy, and increased incidence of adverse events. Systematic post-marketing surveillance studies are needed to assess differences in safety, interchangeability, and efficacy of drugs with modified- and immediate-release formulations.

Effect of crospovidone and hydroxypropyl cellulose on carbamazepine in high-dose tablet formulation.

PubMed

Flicker, Felicia; Betz, Gabriele

2012-06-01

The aim of this study was to develop a high-dose tablet formulation of the poorly soluble carbamazepine (CBZ) with sufficient tablet hardness and immediate drug release. A further aim was to investigate the influence of various commercial CBZ raw materials on the optimized tablet formulation. Hydroxypropyl cellulose (HPC-SL) was selected as a dry binder and crospovidone (CrosPVP) as a superdisintegrant. A direct compacted tablet formulation of 70% CBZ was optimized by a 3² full factorial design with two input variables, HPC (0--10%) and CrosPVP (0--5%). Response variables included disintegration time, amount of drug released at 15 and 60 min, and tablet hardness, all analyzed according to USP 31. Increasing HPC-SL together with CrosPVP not only increased tablet hardness but also reduced disintegration time. Optimal condition was achieved in the range of 5--9% HPC and 3--5% CrosPVP, where tablet properties were at least 70 N tablet hardness, less than 1 min disintegration, and within the USP requirements for drug release. Testing the optimized formulation with four different commercial CBZ samples, their variability was still observed. Nonetheless, all formulations conformed to the USP specifications. With the excipients CrosPVP and HPC-SL an immediate release tablet formulation was successfully formulated for high-dose CBZ of various commercial sources.

A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling

PubMed Central

Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

2016-01-01

Background Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients’ compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. Methods The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box–Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Results and Discussion Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box–Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of amoxicillin. In vitro release study firstly indicated a three-pulse release profile of the tablet. Later the pulse tablet was found to generate the sustained release of amoxicillin in beagle dogs. Furthermore, the Simcyp® software was used to simulate the in vivo concentration time curve model of the three-pulse release tablet for amoxicillin in both human and beagle dog. The prediction by PBPK model nicely fitted the observation in human and beagle dog. Conclusions This study has demonstrated the interrelation of factors affecting the pulsatile formulation of amoxicillin using a Box–Behnken design. The three-pulse release tablets of amoxicillin were proven to generate pulsatile release in vitro and sustained release in vivo. This formulation was also found to extend the effective plasma concentration in human compared to the tablet of immediate release based on the simulation data by PBPK modeling. This study provides an example of using PBPK to guide the development of pulsatile dosage forms. PMID:27479702

Hydrophobin-nanofibrillated cellulose stabilized emulsions for encapsulation and release of BCS class II drugs.

PubMed

Paukkonen, Heli; Ukkonen, Anni; Szilvay, Geza; Yliperttula, Marjo; Laaksonen, Timo

2017-03-30

The purpose of this study was to construct biopolymer-based oil-in-water emulsion formulations for encapsulation and release of poorly water soluble model compounds naproxen and ibuprofen. Class II hydrophobin protein HFBII from Trichoderma reesei was used as a surfactant to stabilize the oil/water interfaces of the emulsion droplets in the continuous aqueous phase. Nanofibrillated cellulose (NFC) was used as a viscosity modifier to further stabilize the emulsions and encapsulate protein coated oil droplets in NFC fiber network. The potential of both native and oxidized NFC were studied for this purpose. Various emulsion formulations were prepared and the abilities of different formulations to control the drug release rate of naproxen and ibuprofen, used as model compounds, were evaluated. The optimal formulation for sustained drug release consisted of 0.01% of drug, 0.1% HFBII, 0.15% oxidized NFC, 10% soybean oil and 90% water phase. By comparison, the use of native NFC in combination with HFBII resulted in an immediate drug release for both of the compounds. The results indicate that these NFC originated biopolymers are suitable for pharmaceutical emulsion formulations. The native and oxidized NFC grades can be used as emulsion stabilizers in sustained and immediate drug release applications. Furthermore, stabilization of the emulsions was achieved with low concentrations of both HFBII and NFC, which may be an advantage when compared to surfactant concentrations of conventional excipients traditionally used in pharmaceutical emulsion formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of neurofuzzy logic and decision trees in discovering knowledge from experimental data of an immediate release tablet formulation.

PubMed

Shao, Q; Rowe, R C; York, P

2007-06-01

Understanding of the cause-effect relationships between formulation ingredients, process conditions and product properties is essential for developing a quality product. However, the formulation knowledge is often hidden in experimental data and not easily interpretable. This study compares neurofuzzy logic and decision tree approaches in discovering hidden knowledge from an immediate release tablet formulation database relating formulation ingredients (silica aerogel, magnesium stearate, microcrystalline cellulose and sodium carboxymethylcellulose) and process variables (dwell time and compression force) to tablet properties (tensile strength, disintegration time, friability, capping and drug dissolution at various time intervals). Both approaches successfully generated useful knowledge in the form of either "if then" rules or decision trees. Although different strategies are employed by the two approaches in generating rules/trees, similar knowledge was discovered in most cases. However, as decision trees are not able to deal with continuous dependent variables, data discretisation procedures are generally required.

Improved oral bioavailability of valsartan using proliposomes: design, characterization and in vivo pharmacokinetics.

PubMed

Nekkanti, Vijaykumar; Venkatesan, Natarajan; Wang, Zhijun; Betageri, Guru V

2015-01-01

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6 ± 2.9% with a vesicle size of 364.1 ± 14.9 nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12 h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.

Assessing the influence of media composition and ionic strength on drug release from commercial immediate-release and enteric-coated aspirin tablets.

PubMed

Karkossa, Frank; Klein, Sandra

2017-10-01

The objective of this test series was to elucidate the importance of selecting the right media composition for a biopredictive in-vitro dissolution screening of enteric-coated dosage forms. Drug release from immediate-release (IR) and enteric-coated (EC) aspirin formulations was assessed in phosphate-based and bicarbonate-based media with different pH, electrolyte composition and ionic strength. Drug release from aspirin IR tablets was unaffected by media composition. In contrast, drug release from EC aspirin formulations was affected by buffer species and ionic strength. In all media, drug release increased with increasing ionic strength, but in bicarbonate-based buffers was delayed when compared with that in phosphate-based buffers. Interestingly, the cation species in the dissolution medium had also a clear impact on drug release. Drug release profiles obtained in Blank CarbSIF, a new medium simulating pH and average ionic composition of small intestinal fluid, were different from those obtained in all other buffer compositions studied. Results from this study in which the impact of various media parameters on drug release of EC aspirin formulations was systematically screened clearly show that when developing predictive dissolution tests, it is important to simulate the ionic composition of intraluminal fluids as closely as possible. © 2017 Royal Pharmaceutical Society.

Improved Bioavailability of Levodopa Using Floatable Spray-Coated Microcapsules for the Management of Parkinson's Disease.

PubMed

Baek, Jong-Suep; Tee, Jie Kai; Pang, Yi Yun; Tan, Ern Yu; Lim, Kah Leong; Ho, Han Kiat; Loo, Say Chye Joachim

2018-06-01

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.

Comparison of the pharmacokinetics of a new 30 mg modified-release tablet formulation of metoclopramide for once-a-day administration versus 10 mg immediate-release tablets: a single and multiple-dose, randomized, open-label, parallel study in healthy male subjects.

PubMed

Bernardo-Escudero, Roberto; Alonso-Campero, Rosalba; Francisco-Doce, María Teresa de Jesús; Cortés-Fuentes, Myriam; Villa-Vargas, Miriam; Angeles-Uribe, Juan

2012-12-01

The study aimed to assess the pharmacokinetics of a new, modified-release metoclopramide tablet, and compare it to an immediate-release tablet. A single and multiple-dose, randomized, open-label, parallel, pharmacokinetic study was conducted. Investigational products were administered to 26 healthy Hispanic Mexican male volunteers for two consecutive days: either one 30 mg modified-release tablet every 24 h, or one 10 mg immediate-release tablet every 8 h. Blood samples were collected after the first and last doses of metoclopramide. Plasma metoclopramide concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed through vital signs measurements, clinical evaluations, and spontaneous reports from study subjects. All 26 subjects were included in the analyses [mean (SD) age: 27 (8) years, range 18-50; BMI: 23.65 (2.22) kg/m², range 18.01-27.47)]. Peak plasmatic concentrations were not statistically different with both formulations, but occurred significantly later (p < 0.05) with the modified-release form [tmax: 3.15 (1.28) vs. 0.85 (0.32) h and tmax-ss: 2.92 (1.19) vs. 1.04 (0.43) h]. There was no difference noted in the average plasma concentrations [Cavgτ: 23.90 (7.90) vs. 20.64 (7.43) ng/mL after the first dose; and Cavg-ss: 31.14 (9.64) vs. 35.59 (12.29) ng/mL after the last dose, (p > 0.05)]. One adverse event was reported in the test group (diarrhea), and one in the reference group (headache). This study suggests that the 30 mg modified-release metoclopramide tablets show features compatible with slow-release formulations when compared to immediate-release tablets, and is suitable for once-a-day administration.

Quality improvement of melt extruded laminar systems using mixture design.

PubMed

Hasa, D; Perissutti, B; Campisi, B; Grassi, M; Grabnar, I; Golob, S; Mian, M; Voinovich, D

2015-07-30

This study investigates the application of melt extrusion for the development of an oral retard formulation with a precise drug release over time. Since adjusting the formulation appears to be of the utmost importance in achieving the desired drug release patterns, different formulations of laminar extrudates were prepared according to the principles of Experimental Design, using a design for mixtures to assess the influence of formulation composition on the in vitro drug release from the extrudates after 1h and after 8h. The effect of each component on the two response variables was also studied. Ternary mixtures of theophylline (model drug), monohydrate lactose and microcrystalline wax (as thermoplastic binder) were extruded in a lab scale vertical ram extruder in absence of solvents at a temperature below the melting point of the binder (so that the crystalline state of the drug could be maintained), through a rectangular die to obtain suitable laminar systems. Thanks to the desirability approach and a reliability study for ensuring the quality of the formulation, a very restricted optimal zone was defined within the experimental domain. Among the mixture components, the variation of microcrystalline wax content played the most significant role in overall influence on the in vitro drug release. The formulation theophylline:lactose:wax, 57:14:29 (by weight), selected based on the desirability zone, was subsequently used for in vivo studies. The plasma profile, obtained after oral administration of the laminar extruded system in hard gelatine capsules, revealed the typical trend of an oral retard formulation. The application of the mixture experimental design associated to a desirability function permitted to optimize the extruded system and to determine the composition space that ensures final product quality. Copyright © 2015 Elsevier B.V. All rights reserved.

A review on oral liquid as an emerging technology in controlled drug delivery system.

PubMed

Torne, Sangmesh Raosaheb; Sheela, Angappan; Sarada, N C

2017-12-03

The oral liquid drug delivery system (OLDDS) remains as the primary choice of dosage form, though challenging, for the pharmaceutical scientists. In the last two decades, Oral Liquid Controlled Release (OLCR) formulation has gained a lot of attention because of its advantages over the conventional dosage forms. The world of nanotechnology has paved multiple ways to administer the drug through oral cavity in liquid dosage form with an additional advantage of control over the release. In the current study, the various approaches towards the same have been discussed comprehensively to understand the different mechanisms of OLCR. This review also emphasizes on the existing techniques and the developments that have been made to improve on its efficacy including various formulation related factors. It also provides valuable insights into the role of polymers in the development of OLCR formulation that can be used in the management of Gastroesophageal reflux disease (GERD). Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacokinetic analysis of modified-release metoprolol formulations: An interspecies comparison.

PubMed

De Thaye, Elien; Vervaeck, Anouk; Marostica, Eleonora; Remon, Jean Paul; Van Bocxlaer, Jan; Vervaet, Chris; Vermeulen, An

2017-01-15

In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID ® (reservoir) and Slow-Lopresor ® (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach. The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic β 1 -receptor antagonist, in dogs and rabbits and to contrast the observed differences. To that end, metoprolol (50 to 200mg) was administered to 6 Beagle dogs and 6 New Zealand White rabbits as a single intravenous (IV) bolus injection and to 8 dogs and 6 rabbits as an oral modified release formulation. To derive pharmacokinetic parameters from the data, a non-linear mixed-effects model was developed using NONMEM ® where the contribution of observations below the limit of detection (BDL, below detection limit) to the parameter estimates was taken into account in the parameter estimation procedure. In both species and for the three modified release formulations, different absorption models were tested to describe the PK of metoprolol following oral dosing. In Beagle dogs, plasma concentration-time profiles were best described using a sequential zero- and first-order absorption model. In rabbits though, the absorption phase was best described using a first-order process only. In both species, the reservoir formulation ZOK-ZID ® was behaving quite similarly. In contrast, the absorption properties of both matrix formulations were rather different between species. This study indicates that the PK of the reservoir formulation is similar in both species, even after accounting for the almost completely missed absorption phase in rabbits. The insights gained further illustrate that rabbits are not very well suited to study the PK of the current matrix formulations in view of their less optimal prolonged release characteristics and the resulting fast decline in metoprolol plasma levels. Copyright © 2016 Elsevier B.V. All rights reserved.

A comparative study between melt granulation/compression and hot melt extrusion/injection molding for the manufacturing of oral sustained release thermoplastic polyurethane matrices.

PubMed

Verstraete, G; Mertens, P; Grymonpré, W; Van Bockstal, P J; De Beer, T; Boone, M N; Van Hoorebeke, L; Remon, J P; Vervaet, C

2016-11-20

During this project 3 techniques (twin screw melt granulation/compression (TSMG), hot melt extrusion (HME) and injection molding (IM)) were evaluated for the manufacturing of thermoplastic polyurethane (TPU)-based oral sustained release matrices, containing a high dose of the highly soluble metformin hydrochloride. Whereas formulations with a drug load between 0 and 70% (w/w) could be processed via HME/(IM), the drug content of granules prepared via melt granulation could only be varied between 85 and 90% (w/w) as these formulations contained the proper concentration of binder (i.e. TPU) to obtain a good size distribution of the granules. While release from HME matrices and IM tablets could be sustained over 24h, release from the TPU-based TSMG tablets was too fast (complete release within about 6h) linked to their higher drug load and porosity. By mixing hydrophilic and hydrophobic TPUs the in vitro release kinetics of both formulations could be adjusted: a higher content of hydrophobic TPU was correlated with a slower release rate. Although mini-matrices showed faster release kinetics than IM tablets, this observation was successfully countered by changing the hydrophobic/hydrophilic TPU ratio. In vivo experiments via oral administration to dogs confirmed the versatile potential of the TPU platform as intermediate-strong and low-intermediate sustained characteristics were obtained for the IM tablets and HME mini-matrices, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

Soluplus®/TPGS-based solid dispersions prepared by hot-melt extrusion equipped with twin-screw systems for enhancing oral bioavailability of valsartan.

PubMed

Lee, Jae-Young; Kang, Wie-Soo; Piao, Jingpei; Yoon, In-Soo; Kim, Dae-Duk; Cho, Hyun-Jong

2015-01-01

Soluplus(®) (SP) and D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS)-based solid dispersion (SD) formulations were developed by hot-melt extrusion (HME) to improve oral bioavailability of valsartan (VST). HME process with twin-screw configuration for generating a high shear stress was used to prepare VST SD formulations. The thermodynamic state of the drug and its dispersion in the polymers were evaluated by solid-state studies, including Fourier-transform infrared, X-ray diffraction, and differential scanning calorimetry. Drug release from the SD formulations was assessed at pH values of 1.2, 4.0, and 6.8. Pharmacokinetic study was performed in rats to estimate the oral absorption of VST. HME with a high shear rate produced by the twin-screw system was successfully applied to prepare VST-loaded SD formulations. Drug amorphization and its molecular dispersion in the polymer matrix were verified by several solid-state studies. Drug release from SD formulations was improved, compared to the pure drug, particularly at pH 6.8. Oral absorption of drug in rats was also enhanced in SP and TPGS-based SD groups compared to that in the pure drug group. SP and TPGS-based SDs, prepared by the HME process, could be used to improve aqueous solubility, dissolution, and oral absorption of poorly water-soluble drugs.

Dual delivery of hydrophilic and hydrophobic drugs from chitosan/diatomaceous earth composite membranes.

PubMed

López-Cebral, Rita; Peng, Guangjia; Reys, Lara L; Silva, Simone S; Oliveira, Joaquim M; Chen, Jie; Silva, Tiago H; Reis, Rui L

2018-02-02

Oral administration of drugs presents important limitations, which are frequently not granted the importance that they really have. For instance, hepatic metabolism means an important drug loss, while some patients have their ability to swell highly compromised (i.e. unconsciousness, cancer…). Sublingual placement of an accurate Pharmaceutical Dosage Form is an attractive alternative. This work explores the use of the β-chitosan membranes, from marine industry residues, composed with marine sediments for dual sublingual drug delivery. As proof of concept, the membranes were loaded with a hydrophilic (gentamicin) and a hydrophobic (dexamethasone) drug. The physico-chemical and morphological characterization indicated the successful incorporated of diatomaceous earth within the chitosan membranes. Drug delivery studies showed the potential of all formulations for the immediate release of hydrophilic drugs, while diatomaceous earth improved the loading and release of the hydrophobic drug. These results highlight the interest of the herein developed membranes for dual drug delivery.

Development and characterization of enteric-coated immediate-release pellets of aceclofenac by extrusion/spheronization technique using kappa-carrageenan as a pelletizing agent.

PubMed

Kilor, Vaishali A; Sapkal, Nidhi P; Awari, Jasmine G; Shewale, Bharti D

2010-03-01

In the present study, an attempt was made to prepare immediate-release enteric-coated pellets of aceclofenac, a poorly soluble nonsteroidal anti-inflammatory drug that has a gastrointestinal intolerance as its serious side effect. Formulation of enteric-coated pellets with improved solubility of aceclofenac could address both of these problems. To achieve these goals, pellets were prepared by extrusion-spheronization method using pelletizing agents that can contribute to the faster disintegration and thereby improve the solubility of the drug. Different disintegrants like beta-cyclodextrin, kollidon CL, Ac-Di-Sol, and sodium starch glycolate were tried in order to further improve disintegration time. The pellets were characterized for drug content, particle size distribution, flow properties, infrared spectroscopy, surface morphology, disintegration rate, and dissolution profile. The formulations, which showed best disintegration and dissolution profiles, were coated with Eudragit L100-55, an enteric-coated polymer which does not dissolve at gastric pH but dissolves at intestinal pH, releasing the drug immediately in the dissolution medium. The optimized enteric-coated formulation containing 20% kappa-carrageenan, lactose, and sodium starch glycolate as a disintegrant did inhibit the release of the drug for 2 h in 0.1 N HCl, whereas 87% of the drug was released within 45 min. The improvement was substantial when it was compared with solubility of pure drug under the same conditions. Thus, dissolution profiles suggested that combination of kappa-carrageenan and sodium starch glycolate resulted into fast-disintegrating, immediate-release pellets, overcoming the bioavailability problem of the poorly soluble drug, aceclofenac, and enteric coating of these pellets avoids the exposure of aceclofenac to ulcer-prone areas of the gastrointestinal tract.

Baclofen novel gastroretentive extended release gellan gum superporous hydrogel hybrid system: in vitro and in vivo evaluation.

PubMed

El-Said, Ibrahim A; Aboelwafa, Ahmed A; Khalil, Rawia M; ElGazayerly, Omaima N

2016-01-01

Baclofen is a centrally acting skeletal muscle relaxant with a short elimination half-life, which results in frequent daily dosing and subsequent poor patient compliance. The narrow absorption window of baclofen in the upper gastrointestinal tract limits its formulation as extended release dosage forms. In this study, baclofen extended release superporous hydrogel (SPH) systems, including conventional SPH, SPH composite and SPH hybrid (SPHH), were prepared aiming to increase the residence of baclofen at its absorption window. The applicability of different polymers, namely, gellan gum, guar gum, polyvinyl alcohol and gelatin, was investigated in preparation of SPHH systems. The prepared SPH systems were evaluated regarding weight and volume swelling ratio, porosity, mechanical properties, incorporation efficiency, degree of erosion and drug release. In vivo assessment was performed in dogs to evaluate gastric residence time by X-ray studies. In addition, the oral bioavailability of baclofen relative to commercially available Lioresal® immediate release tablets was also investigated. The novel baclofen gellan SPHH cross linked with calcium chloride was characterized by optimum mechanical properties, acceptable swelling properties as well as extended drug release. It also exhibited a prolonged plasma profile when compared to twice daily administered Lioresal®.

Undigested Pills in Stool Mimicking Parasitic Infection.

PubMed

Mir, Fazia; Achakzai, Ilyas; Ibdah, Jamal A; Tahan, Veysel

2017-01-01

Background . Orally ingested medications now come in both immediate release and controlled release preparations. Controlled release preparations were developed by pharmaceutical companies to improve compliance and decrease frequency of pill ingestion. Case Report . A 67-year-old obese male patient presented to our clinic with focal abdominal pain that had been present 3 inches below umbilicus for the last three years. This pain was not associated with any trauma or recent heavy lifting. Upon presentation, the patient reported that for the last two months he started to notice pearly oval structures in his stool accompanying his chronic abdominal pain. This had coincided with initiation of his nifedipine pills for his hypertension. He reported seeing these undigested pills daily in his stool. Conclusion . The undigested pills may pose a cause of concern for both patients and physicians alike, as demonstrated in this case report, because they can mimic a parasitic infection. This can result in unnecessary extensive work-up. It is important to review the medication list for extended release formulations and note that the outer shell can be excreted whole in the stool.

Microenvironmental pH-modification to improve dissolution behavior and oral absorption for drugs with pH-dependent solubility.

PubMed

Taniguchi, Chika; Kawabata, Yohei; Wada, Koichi; Yamada, Shizuo; Onoue, Satomi

2014-04-01

Drug release and oral absorption of drugs with pH-dependent solubility are influenced by the conditions in the gastrointestinal tract. In some cases, poor oral absorption has been observed for these drugs, causing insufficient drug efficacy. The pH-modification of a formulation could be a promising approach to overcome the poor oral absorption of drugs with pH-dependent solubility. The present review aims to summarize the pH-modifier approach and strategic analyses of microenvironmental pH for formulation design and development. We also provide literature- and patent-based examples of the application of pH-modification technology to solid dosage forms. For the pH-modification approach, the microenvironmental pH at the diffusion area can be altered by dissolving pH-modifying excipients in the formulation. The modulation of the microenvironmental pH could improve dissolution behavior of drugs with pH-dependent solubility, possibly leading to better oral absorption. According to this concept, the modulated level of microenvironmental pH and its duration can be key factors for improvement in drug dissolution. The measurement of microenvironmental pH and release of pH-modifier would provide theoretical insight for the selection of an appropriate pH-modifier and optimization of the formulation.

Ketoprofen-loaded Eudragit electrospun nanofibers for the treatment of oral mucositis

PubMed Central

Reda, Rana Ihab; Wen, Ming Ming; El-Kamel, Amal Hassan

2017-01-01

Purpose The purpose of this study was to formulate ketoprofen (KET)-loaded Eudragit L and Eudragit S nanofibers (NFs) by the electrospinning technique for buccal administration to treat oral mucositis as a safe alternative to orally administered KET, which causes gastrointestinal tract (GIT) side effects. Materials and methods NFs were prepared by electrospinning using Eudragit L and Eudragit S. Several variables were evaluated to optimize NF formulation, such as polymer types and concentrations, applied voltage, flow rate and drug concentrations. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) and analyses of drug contents, hydration capacity, surface pH, drug release and ex vivo permeation were performed to evaluate the NFs. The selected formulation (F1) was evaluated in vivo on induced oral mucositis in rabbits. Results SEM revealed that 20% polymer formed smooth and bead-free NFs. DSC results confirmed the amorphous nature of KET in the NFs. FTIR confirmed hydrogen bond formation between the drug and polymer, which stabilized the NFs. Both formulations (F1 and F2) had an acceptable surface pH. The drug loading was >90%. The amount of KET released from NF formulations was statistically significantly higher (P≤0.001) than that released from the corresponding solvent-casted films. The complete release of KET from F1 occurred within 2 hours. Ex vivo permeation study revealed that only a small fraction of drug permeated from F1, which was a better candidate than F2 for local buccal delivery. In vivo evaluation of F1 on oral mucositis induced in rabbits demonstrated that F1 reduced the clinical severity of mucositis in rabbits under the current experimental conditions. The attenuated clinical severity was accompanied by a marked reduction in inflammatory infiltrate and re-epithelization of the epithelial layer. Conclusion Eudragit L100 nanofibers (EL-NF) loaded with KET (F1) suppressed the inflammatory response associated with mucositis, which confirmed the efficacy of local buccal delivery of KET-loaded EL-NF in treating oral mucositis. PMID:28392691

Intranasal abuse potential of an abuse-deterrent oxycodone formulation compared to oxycodone immediate release and placebo in nondependent, recreational opioid users.

PubMed

Setnik, Beatrice; Schoedel, Kerri; Bartlett, Cindy; Dick, Chris; Hakim, Nasrat; Geoffroy, Pierre

To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone. Randomized, double-blind, double-dummy, active and placebo-controlled, five-way crossover study. Pharmacodynamics, safety, and pharmacokinetics (PKs) were evaluated for up to 36 hours postdose. Single site in Canada (INC Research Toronto). Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test. Single IN dose of ground ELI-200 (30-mg oxycodone hydrochloride [HCl]/3-mg naltrexone HCl), crushed 30-mg oxycodone HCl IR (Roxicodone®), placebo, fixed placebo, and single oral dose of intact ELI-200 (30mg/3mg). Peak effect (E max ) for bipolar Drug Liking (0-100 point visual analog scale). Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p<0.001) median Drug Liking E max relative to placebo. Significant reductions (p<0.001) in median Drug Liking [E max ] were observed for IN ELI-200 [56.0] compared to IN oxycodone IR [100.0]. Secondary positive or objective measures (High, Good Drug Effects, Overall Drug Liking, Take Drug Again, and maximum pupil constriction) showed significantly lower E max for IN ELI-200 (p<0.001) compared to IN oxycodone IR. IN administration of ELI-200 demonstrated significantly decreased effects on subjective and physiologic measures, and greater nasal irritation, compared to IN oxycodone IR. These findings, along with the PK profile of naltrexone, demonstrated that when ELI-200 capsules were ground and administered intranasally, the naltrexone component was rapidly released and conferred meaningful abuse-deterrent properties.

Melts of Octaacetyl Sucrose as Oral-Modified Release Dosage Forms for Delivery of Poorly Soluble Compound in Stable Amorphous Form.

PubMed

Haznar-Garbacz, Dorota; Kaminska, Ewa; Zakowiecki, Daniel; Lachmann, Marek; Kaminski, Kamil; Garbacz, Grzegorz; Dorożyński, Przemysław; Kulinowski, Piotr

2018-02-01

The presented work describes the formulation and characterization of modified release glassy solid dosage forms (GSDFs) containing an amorphous nifedipine, as a model BCS (Biopharmaceutical Classification System) class II drug. The GSDFs were prepared by melting nifedipine together with octaacetyl sucrose. Dissolution profiles, measured under standard and biorelevant conditions, were compared to those obtained from commercially available formulations containing nifedipine such as modified release (MR) tablets and osmotic release oral system (OROS). The results indicate that the dissolution profiles of the GSDFs with nifedipine are neither affected by the pH of the dissolution media, type and concentration of surfactants, nor by simulated mechanical stress of biorelevant intensity. Furthermore, it was found that the dissolution profiles of the novel dosage forms were similar to the profiles obtained from the nifedipine OROS. The formulation of GSDFs is relatively simple, and the dosage forms were found to have favorable dissolution characteristics.

PREPARATION, IN VITRO AND IN VIVO CHARACTERIZATION OF HYDROPHOBIC PATCHES OF A HIGHLY WATER SOLUBLE DRUG FOR PROLONGED PLASMA HALF LIFE: EFFECT OF PERMEATION ENHANCERS.

PubMed

Yaqoob, Ayesha; Ahmad, Mahmood; Mahmood, Asif; Sarfraz, Rai Muhammad

2016-11-01

Aim of present study was to develop metoprolol matrix patches using different enhancers. Combination of two hydrophobic polymers, ethyl cellulose and eudragit RL 100 (8 : 2) were used for preparation of unilaminated matrix patch. 10% w/w of isopropyl myristate (IPM), dimethyl sulfoxide (DMSO), span (20 (S20), Tween 20 (T20) and eucalyptus oil as enhancers and 40% of dibutyl phthalate as plasticizer were used. Prepared patches were evaluated for physical appearance, weight uniformity and thickness. FTIR studies were performed to assess compatibility among ingredients and developed formulation. Dissolution and permeation studies were performed to compare effects of enhancers. Surface morphology after release was examined by scanning electron microscopy. Selected formulation was subjected to in vivo studies by randomized crossover design in rabbits (n = 6) for pharmacokinetic comparison with oral solution administration. Physical evaluation revealed that translucent, flexible, non brittle patches of uniform weight and thickness were prepared. Release from patches followed Higuchi model. Mechanism of release was Fickian. Formulation containing IPM showed that release was by anomalous transport. Highest permeation flux was observed for formulation containing IPM with 2-fold enhancement in permeation. Permeation flux for patches was in order of formulation with no enhancer > IPM > T20 > S20 > DMSO = eucalyptus oil. Plasma concentration from in vivo studies exhibited sustained plasma levels of metoprolol after transdermal patch application in comparison to oral solution administration. Pharmacokinetic analysis of in vivo data elucidated that half life was increased 8 times when compared to oral administration, due to controlled release of drug for longer period of time. These findings suggested that hydrophobic transdermal patches of highly water soluble drug metoprolol were successfully prepared with 10% of IPM for sustained systemic delivery for prolonged half life.

Metronidazole immediate release formulations: a fasting randomized open-label crossover bioequivalence study in healthy volunteers.

PubMed

de Freitas Silva, M; Schramm, S G; Kano, E K; Koono, E E M; Manfio, J L; Porta, V; dos Reis Serra, C H

2012-10-01

Metronidazole is a BCS (Biopharmaceutics Classification System) class 1 drug, traditionally considered the choice drug in the infections treatment caused by protozoa and anaerobic microorganisms. This study aimed to evaluate bioequivalence between 2 different marketed 250 mg metronidazole immediate release tablets. A randomized, open-label, 2×2 crossover study was performed in healthy Brazilian volunteers under fasting conditions with a 7-day washout period. The formulations were administered as single oral dose and blood was sampled over 48 h. Metronidazole plasma concentrations were determined by a liquid chromatography mass spectrometry (LC-MS/MS) method. The plasma concentration vs. time profile was generated for each volunteer and the pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC0-∞, ke, and t1/2 were calculated using a noncompartmental model. Bioequivalence between pharmaceutical formulations was determined by calculating 90% CIs (Confidence Intervall) for the ratios of Cmax, AUC0-t, and AUC0-∞ values for test and reference using log-transformed data. 22 healthy volunteers (11 men, 11 women; mean (SD) age, 28 (6.5) years [range, 21-45 years]; mean (SD) weight, 66 (9.3) kg [range, 51-81 kg]; mean (SD) height, 169 (6.5) cm [range, 156-186 cm]) were enrolled in and completed the study. The 90% CIs for Cmax (0.92-1.06), AUC0-t (0.97-1.02), and AUC0-∞ (0.97-1.03) values for the test and reference products fitted in the interval of 0.80-1.25 proposed by most regulatory agencies, including the Brazilian agency ANVISA. No clinically significant adverse effects were reported. After pharmacokinetics analysis, it concluded that test 250 mg metronidazole formulation is bioequivalent to the reference product according to the Brazilian agency requirements. © Georg Thieme Verlag KG Stuttgart · New York.

Oral, Slow-Release Ivermectin: Biting Back at Malaria Vectors.

PubMed

Chaccour, Carlos J; Rabinovich, N Regina

2017-03-01

Bellinger and colleagues offer an elegant twist for a promising new tool against malaria. This formulation is designed to release ivermectin, a mosquito-killing drug for 10 days after a single oral dose. This could reduce the vector population and serve as a complementary tool for malaria elimination. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development and experimental design of a novel controlled-release matrix tablet formulation for indapamide hemihydrate.

PubMed

Antovska, Packa; Ugarkovic, Sonja; Petruševski, Gjorgji; Stefanova, Bosilka; Manchevska, Blagica; Petkovska, Rumenka; Makreski, Petre

2017-11-01

Development, experimental design and in vitro in vivo correlation (IVIVC) of controlled-release matrix formulation. Development of novel oral controlled delivery system for indapamide hemihydrate, optimization of the formulation by experimental design and evaluation regarding IVIVC on a pilot scale batch as a confirmation of a well-established formulation. In vitro dissolution profiles of controlled-release tablets of indapamide hemihydrate from four different matrices had been evaluated in comparison to the originator's product Natrilix (Servier) as a direction for further development and optimization of a hydroxyethylcellulose-based matrix controlled-release formulation. A central composite factorial design had been applied for the optimization of a chosen controlled-release tablet formulation. The controlled-release tablets with appropriate physical and technological properties had been obtained with a matrix: binder concentration variations in the range: 20-40w/w% for the matrix and 1-3w/w% for the binder. The experimental design had defined the design space for the formulation and was prerequisite for extraction of a particular formulation that would be a subject for transfer on pilot scale and IVIV correlation. The release model of the optimized formulation has shown best fit to the zero order kinetics depicted with the Hixson-Crowell erosion-dependent mechanism of release. Level A correlation was obtained.

Biowaiver monographs for immediate release solid oral dosage forms: piroxicam.

PubMed

Shohin, Igor E; Kulinich, Julia I; Ramenskaya, Galina V; Abrahamsson, Bertil; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Groot, D W; Barends, Dirk M; Dressman, Jennifer B

2014-02-01

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bioinequivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of Cmax ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of Cmax for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Evaluation of synthetic zeolites as oral delivery vehicle for anti-inflammatory drugs

PubMed Central

Khodaverdi, Elham; Honarmandi, Reza; Alibolandi, Mona; Baygi, Roxana Rafatpanah; Hadizadeh, Farzin; Zohuri, Gholamhossein

2014-01-01

Objective(s): In this research, zeolite X and zeolite Y were used as vehicle to prepare intestine targeted oral delivery systems of indomethacin and ibuprofen. Materials and Methods: A soaking procedure was implemented to encapsulate indomethacin or ibuprofen within synthetic zeolites. Gravimetric methods and IR spectra of prepared formulations were used to assess drug loading efficiencies into zeolite structures. Scanning Electron Microscopy (SEM) was also utilized to determine morphologies changes in synthetic zeolites after drug loading. At the next stage, dissolution studies were used to predict the in vivo performance of prepared formulations at HCl 0.1 N and PBS pH 6.5 as simulated gastric fluid (SGF) and simulated intestine fluid (SIF), respectively. Results: Drug loadings of prepared formulations was determined between 24-26 % w/w. Dissolution tests at SGF were shown that zeolites could retain acidic model drugs in their porous structures and can be able to limit their release into the stomach. On the other hand, all prepared formulations completely released model drugs during 3 hr in simulated intestine fluid. Conclusion: Obtained results indicated zeolites could potentially be able to release indomethacin and ibuprofen in a sustained and controlled manner and reduced adverse effects commonly accompanying oral administrations of NSAIDs. PMID:24967062

Silymarin liposomes improves oral bioavailability of silybin besides targeting hepatocytes, and immune cells.

PubMed

Kumar, Nitesh; Rai, Amita; Reddy, Neetinkumar D; Raj, P Vasanth; Jain, Prateek; Deshpande, Praful; Mathew, Geetha; Kutty, N Gopalan; Udupa, Nayanabhirama; Rao, C Mallikarjuna

2014-10-01

Silymarin, a hepatoprotective agent, has poor oral bioavailability. However, the current dosage form of the drug does not target the liver and inflammatory cells selectively. The aim of the present study was to develop lecithin-based carrier system of silymarin by incorporating phytosomal-liposomal approach to increase its oral bioavailability and to make it target-specific to the liver for enhanced hepatoprotection. The formulation was prepared by film hydration method. Release of drug was assessed at pH 1.2 and 7.4. Formulation was assessed for in vitro hepatoprotection on Chang liver cells, lipopolysaccharide-induced reactive oxygen species (ROS) production by RAW 267.4 (murine macrophages), in vivo efficacy against paracetamol-induced hepatotoxicity and pharmacokinetic study by oral route in Wistar rat. The formulation showed maximum entrapment (55%) for a lecithin-cholesterol ratio of 6:1. Comparative release profile of formulation was better than silymarin at pH 1.2 and pH 7.4. In vitro studies showed a better hepatoprotection efficacy for formulation (one and half times) and better prevention of ROS production (ten times) compared to silymarin. In in vivo model, paracetamol showed significant hepatotoxicity in Wistar rats assessed through LFT, antioxidant markers and inflammatory markers. The formulation was found more efficacious than silymarin suspension in protecting the liver against paracetamol toxicity and the associated inflammatory conditions. The liposomal formulation yielded a three and half fold higher bioavailability of silymarin as compared with silymarin suspension. Incorporating the phytosomal form of silymarin in liposomal carrier system increased the oral bioavailability and showed better hepatoprotection and better anti-inflammatory effects compared with silymarin suspension. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Are there any differences in the efficacy and safety of different formulations of Oral 5-ASA used for induction and maintenance of remission in ulcerative colitis? evidence from cochrane reviews.

PubMed

Feagan, Brian G; Chande, Nilesh; MacDonald, John K

2013-08-01

We systematically reviewed and compared the efficacy and safety of oral mesalamine formulations (sustained release, delayed release, and prodrugs) used for induction and maintenance of remission in ulcerative colitis. The main objective of this review was to determine if there are any differences in efficacy or safety among the oral 5-ASA drugs. A literature search in February 2013 identified all applicable randomized trials. Study quality was evaluated using the Cochrane risk of bias tool. The Grading of Recommendations Assessment, Development and Evaluation criteria were used to assess the overall quality of the evidence. Studies were subgrouped by common mesalamine comparators for meta-analysis. Studies were pooled for analysis if they compared equimolar doses of oral 5-ASA. Seventeen studies that evaluated 2925 patients were identified. The risk of bias was low for most factors, although 1 study was single blind and 3 were open label. No difference was observed between oral 5-ASA and comparator 5-ASA formulations in the proportion of patients with clinical remission (relative risk, 0.94; 95% confidence interval, 0.86-1.02), clinical improvement (relative risk, 0.89; 95% confidence interval, 0.77-1.01), or relapse at 12 months (relative risk, 1.01; 95% confidence interval, 0.80-1.28). Subgroup analyses showed no important differences in efficacy. No significant difference was demonstrated in rates of adverse events or withdrawal due to adverse events. There does not seem to be any difference in efficacy or safety among the various formulations of oral 5-ASA. Oral mesalamine is an effective and safe treatment of mild-to-moderate or quiescent ulcerative colitis regardless of the chosen formulation.

Dissolution rate enhancement of the poorly water-soluble drug Tibolone using PVP, SiO2, and their nanocomposites as appropriate drug carriers.

PubMed

Papadimitriou, Sofia; Bikiaris, Dimitrios

2009-09-01

Creation of immediate release formulations for the poorly water-soluble drug Tibolone through the use of solid dispersions (SDs). SD systems of Tibolone (Tibo) with poly(vinylpyrrolidone) (PVP), fumed SiO(2) nanoparticles, and their corresponding ternary systems (PVP/SiO(2)/Tibo) were prepared and studied in order to produce formulations with enhanced drug dissolution rates. The prepared SDs were characterized by the use of differential scanning calorimetry and wide-angle X-ray diffractometry techniques. Also dissolution experiments were performed. From the results it was concluded that PVP as well as SiO(2) can be used as appropriate carriers for the amorphization of Tibo, even when the drug is used at high concentrations (20-30%, w/w). This is due to the evolved interactions taking place between the drug and the used carriers, as was verified by Fourier transform infrared spectroscopy. At higher concentrations the drug was recrystallized. Similar are the observations on the ternary PVP/SiO(2)/Tibo SDs. The dissolution profiles of the drug in PVP/Tibo and SiO(2)/Tibo SDs are directly dependent on the physical state of the drug. Immediately release rates are observed in SD with low drug concentrations, in which Tibo was in amorphous state. However, these release profiles are drastically changed in the ternary PVP/SiO(2)/Tibo SDs. An immediate release profile is observed for low drug concentrations and an almost sustained release as the concentration of Tibo increases. This is due to the weak interactions that take place between PVP and SiO(2), which result in alterations of the characteristics of the carrier (PVP/SiO(2) nanocomposites). Immediate release formulation was created for Tibolone as well as new nanocomposite matrices of PVP/SiO((2)), which drastically change the release profile of the drug to a sustained delivery.

Fabricating 3D printed orally disintegrating printlets using selective laser sintering.

PubMed

Fina, Fabrizio; Madla, Christine M; Goyanes, Alvaro; Zhang, Jiaxin; Gaisford, Simon; Basit, Abdul W

2018-04-25

Selective laser sintering (SLS) is a three-dimensional printing (3DP) technology employed to manufacture plastic, metallic or ceramic objects. The aim of this study was to demonstrate the feasibility of using SLS to fabricate novel solid dosage forms with accelerated drug release properties, and with a view to create orally disintegrating formulations. Two polymers (hydroxypropyl methylcellulose (HPMC E5) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon ® VA 64)) were separately mixed with 5% paracetamol (used as a model drug) and 3% Candurin ® Gold Sheen colorant; the powder mixes were subjected to SLS printing, resulting in the manufacture of printlets (3DP tablets). Modulating the SLS printing parameters altered the release characteristics of the printlets, with faster laser scanning speeds accelerating drug release from the HPMC formulations. The same trend was observed for the Kollidon ® based printlets. At a laser scanning speed of 300 mm/s, the Kollidon ® printlets exhibited orally disintegrating characteristics by completely dispersing in <4 s in a small volume of water. X-ray micro-CT analysis of these printlets indicated a reduction in their density and an increase in open porosity, therefore, confirming the unique disintegration behaviour of these formulations. The work reported here is the first to demonstrate the feasibility of SLS 3DP to fabricate printlets with accelerated drug release and orally disintegrating properties. This investigation has confirmed that SLS is amenable to the pharmaceutical research of modern medicine manufacture. Copyright © 2018 Elsevier B.V. All rights reserved.

A novel pH-sensitive interferon-β (INF-β) oral delivery system for application in multiple sclerosis.

PubMed

Kondiah, Pierre P D; Tomar, Lomas K; Tyagi, Charu; Choonara, Yahya E; Modi, Girish; du Toit, Lisa C; Kumar, Pradeep; Pillay, Viness

2013-11-18

pH-sensitive microparticles were prepared using trimethyl-chitosan (TMC), poly(ethylene glycol)dimethacrylate (PEGDMA) and methacrylic acid (MAA) by free radical suspension polymerization, for the oral delivery of interferon-β (INF-β). The microparticles were subsequently compressed into a suitable oral tablet formulation. A Box-Behnken experimental design was employed for generating a series of formulations with varying concentrations of TMC (0.05-0.5 g/100 mL) and percentage crosslinker (polyethylene glycol diacrylate) (3-8%, w/w of monomers), for establishment of an optimized TMC-PEGDMA-MAA copolymeric microparticles. For pragmatism, insulin was initially employed as the model peptide for undertaking the preliminary experimentation and the optimized formulation was subsequently evaluated using INF-β. The prepared copolymeric microparticulate system was characterized for its morphological, porositometric and mucoadhesive properties. The optimized microparticles with 0.5 g/100 mL TMC and 3% crosslinker had an INF-β loading efficiency of 53.25%. The in vitro release of INF-β was recorded at 74% and 3% in intestinal (pH 6.8) and gastric (pH 1.2) pH from the oral tablet formulation, respectively. The tablet was further evaluated for plasma concentration of INF-β in the New Zealand White rabbit, and compared to a known subcutaneous formulation. The system showed an astounding effective release profile over 24h with higher INF-β plasma concentrations compared with the subcutaneous injection formulation. Copyright © 2013 Elsevier B.V. All rights reserved.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Folic Acid.

PubMed

Hofsäss, Martin A; Souza, Jacqueline de; Silva-Barcellos, Neila M; Bellavinha, Karime R; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Parr, Alan; Langguth, Peter; Polli, James E; Shah, Vinod P; Tajiri, Tomokazu; Mehta, Mehul U; Dressman, Jennifer B

2017-12-01

This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 μg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid. Copyright © 2017 American Pharmacists Association®. All rights reserved.

Chlorogenic acid stabilized nanostructured lipid carriers (NLC) of atorvastatin: formulation, design and in vivo evaluation.

PubMed

Khan, Saba; Baboota, Sanjula; Ali, Javed; Narang, R S; Narang, Jasjeet K

2016-01-01

The present work was aimed at developing an optimized oral nanostructured lipid carrier (NLC) formulation of poorly soluble atorvastatin Ca (AT Ca) and assessing its in vitro release, oral bioavailability and pharmacodynamic activity. In this study, chlorogenic acid, a novel excipient having synergistic cholesterol lowering activity was utilized and explored in NLC formulation development. The drug-loaded NLC formulations were prepared using a high pressure homogenization technique and optimized by the Box-Behnken statistical design using the Design-Expert software. The optimized NLC formulation was composed of oleic acid and stearic acid as lipid phase (0.9% w/v), poloxamer 188 as surfactant (1% w/v) and chlorogenic acid (0.05% w/v). The mean particle size, polydispersity index (PDI) and % drug entrapment efficiency of optimized NLC were 203.56 ± 8.57 nm, 0.27 ± 0.028 and 83.66 ± 5.69, respectively. In vitro release studies showed that the release of drug from optimized NLC formulations were markedly enhanced as compared to solid lipid nanoparticles (SLN) and drug suspension. The plasma concentration time profile of AT Ca in rats showed 3.08- and 4.89-fold increase in relative bioavailability of developed NLC with respect to marketed preparation (ATORVA® tablet) and drug suspension, respectively. Pharmacodynamic study suggested highly significant (**p < 0.01) reduction in the cholesterol and triglyceride values by NLC in comparison with ATORVA® tablet. Therefore, the results of in vivo studies demonstrated promising prospects for successful oral delivery of AT Ca by means of its chlorogenic acid integrated NLC.

Combining strategies to optimize a gel formulation containing miconazole: the influence of modified cyclodextrin on textural properties and drug release.

PubMed

Ribeiro, Andreza Maria; Figueiras, Ana; Freire, Cristina; Santos, Delfim; Veiga, Francisco

2010-06-01

Miconazol, an antimycotic drug, is commonly formulated into semisolid formulations designed to be applied in the oral cavity to treat oral candidiasis. However, given its limited aqueous solubility, permeation through the biological membranes is low and therefore its activity is also limited. Cyclodextrins (CDs) have been widely used to increase the solubility and stability of poorly water-soluble drugs. The aim of this study is to formulate a gel containing an inclusion complex between a modified CD, methyl-beta-cyclodextrin (MbetaCD), and miconazole (MCZ). The influence of the CD on the textural properties of the prepared gel and the drug release from formulation were evaluated. The gels were prepared using two polymers, Carbopol 71G and Pluronic F127, which were selected taking into account their bioadhesiveness and thermal-sensitive gelling properties, respectively. Texture profile analyses were performed at two different temperatures to ascertain the influence of the temperature on the gel texture properties. The in vitro MCZ release profiles from the prepared gel and the commercial gel formulations were evaluated and compared using modified Franz diffusion cells. The addition of MbetaCD to the gel resulted in a decrease of the gel adhesiveness and firmness, and the MCZ release profile through f1 and f2 proved to be similar to the commercial product. A gel comprising miconazol in the form of an inclusion complex with MbetaCD showed suitable textural properties to be applied to the buccal mucosa. The MbetaCD enhanced the solubility of the MCZ in the gel formulation resulting in adequate in vitro drug release profiles.

Evolution of the treatment of attention-deficit/hyperactivity disorder in children: a review.

PubMed

Findling, Robert L

2008-05-01

Efficacious and well-tolerated medications are available for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants such as methylphenidate (MPH) and amphetamines are the most widely used medications approved by the US Food and Drug Administration for the treatment of ADHDin children. This article reviews the literature on the development and use of medications for the treatment of ADHD in children. A search of MEDLINE was conducted toidentify relevant studies and critical reviews on the treatment of ADHD in children. The main criteria for inclusion of a study were that it have a controlled design, enroll >100 subjects if a clinical trial and >20 subjects if a classroom study, assess symptoms with the most widely used scales and tests,and be published from 2000 to 2008.A few older pivotal studies were also included. Many studies have reported the long-term efficacy and tolerability of immediate-release formulations of MPH. The disadvantages of such formulations include the need for multiple daily dosing and a potential for abuse. Various extended-release formulations of MPH have been found effective in controlled studies enrolling large numbers of children with ADHD. The efficacy and tolerability of dexmethylphenidate, the active D-isomer of MPH, in an extended-release formulation have also been reported. An extended-release formulation of mixed amphetamine salts (MMAS-XR) that is dosed once daily has been found to be efficacious and well tolerated. The non-stimulant atomoxetine has been reported to be well tolerated and efficacious, although it may not be as effective as stimulants; this formulation is, however, less likely than stimulants to be associated with abuse and diversion. A recently approved prodrug stimulant, lisdexamfetamine dimesylate (LDX), was developed to provide a long duration of effect that is consistent throughout the day, with a reduced potential for abuse. In a placebo-controlled study in children with ADHD, less intersubject variability in T(max), C(max), and AUC from time zero to the last quantifiable concentration was seen in the 8 subjects who received LDX (percent coefficient of variation, 15.3, 20.3, and 21.6, respectively) compared with the 9 subjects who received MAS-XR (52.8, 44.0, and 42.8).In 2 clinical trials, significantly greater improvements in teacher and parent ratings of ADHD symptoms were seen with LDX compared with placebo (P<0.001).A study of the abuse potential of LDX evaluated subjective responses to the effects of oral LDX and immediate-release d-amphetamine in adults with a history of stimulant abuse. LDX was associated with a significantly lower abuse-related liking effect than d-aamphetamine (P = 0.039). Currently available treatments for ADHD in children are efficacious and well tolerated, but many of them are limited by the requirement for multiple daily dosing and abuse potential. LDX, a long-acting prodrug of d-amphetamine, has been reported to be effective and appears to overcome some of these limitations.

Pharmacokinetic comparison of sustained- and immediate-release oral formulations of cilostazol in healthy Korean subjects: a randomized, open-label, 3-part, sequential, 2-period, crossover, single-dose, food-effect, and multiple-dose study.

PubMed

Lee, Donghwan; Lim, Lay Ahyoung; Jang, Seong Bok; Lee, Yoon Jung; Chung, Jae Yong; Choi, Jong Rak; Kim, Kiyoon; Park, Jin Woo; Yoon, Hosang; Lee, Jaeyong; Park, Min Soo; Park, Kyungsoo

2011-12-01

A sustained-release (SR) formulation of cilostazol was recently developed in Korea and was expected to yield a lower C(max) and a similar AUC to the immediate-release (IR) formulation. The goal of the present study was to compare the pharmacokinetic profiles of a newly developed SR formulation and an IR formulation of cilostazol after single- and multiple-dose administration and to evaluate the influence of food in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. This was a randomized, 3-part, sequential, open-label, 2-period crossover study. Each part consisted of different subjects between the ages of 19 and 55 years. In part 1, each subject received a single dose of SR (200 mg × 1 tablet, once daily) and IR (100 mg × 2 tablets, BID) formulations of cilostazol orally 7 days apart in a fasted state. In part 2, each subject received a single dose of the SR (200 mg × 1 tablet, once daily) formulation of cilostazol 7 days apart in a fasted and a fed state. In part 3, each subject received multiple doses of the 2 formulations for 8 consecutive days 21 days apart. Blood samples were taken for 72 hours after the dose. Cilostazol pharmacokinetics were determined for both the parent drug and its metabolites (OPC-13015 and OPC-13213). Adverse events were evaluated through interviews and physical examinations. Among the 92 enrolled subjects (66 men, 26 women; part 1, n = 26; part 2, n = 26; part 3, n = 40), 87 completed the study. In part 1, all the primary pharmacokinetic parameters satisfied the criterion for assumed bioequivalence both in cilostazol and its metabolites, yielding 90% CI ratios of 0.9624 to 1.2323, 0.8873 to 1.1208, and 0.8919 to 1.1283 for C(max) and 0.8370 to 1.0134, 0.8204 to 0.9807, and 0.8134 to 0.9699 for AUC(0-last) of cilostazol, OPC-13015, and OPC-13213, respectively. In part 2, food intake increased C(max) and AUC significantly (P < 0.0001), yielding geometric mean ratios of 3.2879, 2.9894, and 3.0592 for C(max) and 1.7001, 1.7689, and 1.6976 for AUC(0-last) of cilostazol, OPC-13015, and OPC-13213. In part 3, only the C(ssmax) of clilostazol in the reference formulation did not satisfy the criterion for assumed bioequivalence, yielding 90% CI ratios of 1.2693 to 1.4238 and 1.2038 to 1.3441, respectively. When each dose was normalized, the C(max) for the SR formulation was significantly lower (P < 0.005 for cilostazol). Headache was the most frequently noted adverse effect (part 1, a total of 14 subjects with the IR formulation and 14 with the SR formulation; part 2, a total of 10 without food and 23 with a high-fat meal; part 3, a total of 10 with the IR formulation and 24 with the SR formulation), followed by nausea (part 1, none; part 2, only 1 without food and 3 with a high-fat meal; part 3, a total of 3 with the IR formulation and 3 with the SR formulation), and then dizziness (parts 1 and 2, none; part 3, a total of 4 with the IR formulation and 5 with the SR formulation). All other AEs, including fever, cough, vomiting, palpitation, diarrhea, and epigastric pain, occurred in <3 subjects. These findings suggest that in this select group of healthy Korean volunteers, the SR formulation of cilostazol was not significantly different in AUC compared with that of the IR formulation, although it did display a significantly lower C(max) per dose in both the single- and multiple-dose groups. Food significantly increased the bioavailability of the SR formulation. The cilostazol SR and IR formulations were well tolerated in all parts of the study, with no serious adverse events reported. ClinicalTrials.gov identifier: NCT01455558. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: design and in vitro evaluations.

PubMed

Hiremath, Praveen S; Saha, Ranendra N

2008-10-01

The aim of the present investigation was to develop controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24h for both the drugs despite of the wide variations in their physicochemical properties.

Leflunomide biodegradable microspheres intended for intra-articular administration: Development, anti-inflammatory activity and histopathological studies.

PubMed

El-Setouhy, Doaa Ahmed; Abdelmalak, Nevine Shawky; Anis, Shady E; Louis, Dina

2015-11-30

Leflunomide, the disease-modifying anti-rheumatic drug was formulated as microspheres for prolonged drug release in the form of intraarticular injection. Eight formulations were developed using three biodegradable PDLG polymers (lactide/glycolide copolymer) and polycaprolactone (PLC) at two drug:polymer ratios (1:2 and 1:4). Solvent evaporation method was employed using polyvinyl alcohol or hydropxypropyl methylcellulose as stabilizers. Formulations were assessed for encapsulation efficiency, yield, particle size, release pattern and SEM. F6 (PDLG 5010), with appropriate particle size and prolonged drug release, was chosen for in-vivo studies using arthritis induced rats, which were intrarticularly injected with F6 or took oral Avara(®). Nuclear factor-kappa B measurements and histopathologic studies were conducted. There was significant reduction of inflammation caused by both F6 and oral Avara(®). Histopathologic studies showed minimal infiltration by chronic inflammatory cells and no angiogenesis in F6 compared to Avara(®). Results also revealed biocompatibility of the polymer used. Copyright © 2015 Elsevier B.V. All rights reserved.

Propolis--based chitosan varnish: drug delivery, controlled release and antimicrobial activity against oral pathogen bacteria.

PubMed

Franca, Juçara R; De Luca, Mariana P; Ribeiro, Tatiana G; Castilho, Rachel O; Moreira, Allyson N; Santos, Vagner R; Faraco, André A G

2014-12-12

Dental caries is the most prevalent oral disease in several Asian and Latin American countries. It is an infectious disease and different types of bacteria are involved in the process. Synthetic antimicrobials are used against this disease; however, many of these substances cause unwarranted undesirable effects like vomiting, diarrhea and tooth staining. Propolis, a resinous substance collected by honeybees, has been used to control the oral microbiota. So, the objective of this study was to develop and characterize sustained-release propolis-based chitosan varnish useful on dental cariogenic biofilm prevention, besides the in vitro antimicrobial activity. Three formulations of propolis - based chitosan varnish (PCV) containing different concentrations (5%, 10% and 15%) were produced by dissolution of propolis with chitosan on hydro-alcoholic vehicle. Bovine teeth were used for testing adhesion of coatings and to observe the controlled release of propolis associated with varnish. It was characterized by infrared spectroscopy, scanning electron microscopy, casting time, diffusion test in vitro antimicrobial activity and controlled release. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were tested for the main microorganisms involved in the cariogenic biofilm through the microdilution test in 96-well plates. The formulations presented a tooth surface adherence and were able to form films very fast on bovine tooth surface. Also, propolis-based chitosan varnishes have shown antimicrobial activity similar to or better than chlorhexidine varnish against all oral pathogen bacteria. All microorganisms were sensitive to propolis varnish and chitosan. MIC and MBC for microorganisms of cariogenic biofilme showed better results than chlorhexidine. Propolis active components were released for more than one week. All developed formulations turn them, 5%, 10% and 15% propolis content varnish, into products suitable for clinical application on dental caries prevention field, deserving clinical studies to confirm its in vivo activity.

An abuse-deterrent, microsphere-in-capsule formulation of extended-release oxycodone: alternative modes of administration to facilitate pain management in patients with dysphagia.

PubMed

McCarberg, Bill H; Kopecky, Ernest A; O'Connor, Melinda; Marseilles, Ann; Varanasi, Ravi K; Thompson, Christy; Fleming, Alison B

2016-12-01

Patients with chronic pain may experience difficulty swallowing, in part due to worsening disease, comorbid conditions, iatrogenic etiology, or age. Patients or caregivers may manipulate extended-release (ER) opioid formulations to facilitate oral dosing due to a lack of therapeutic options that allow for sprinkle or enteral feeding tube administration. If crushed or broken, current oral ER opioids can be associated with adverse sequelae, including risk of potentially fatal overdose. To review the safety, in vitro dissolution data, and in vivo pharmacokinetic data that support alternative modes of administration of oxycodone DETERx (Xtampza ER) via sprinkling onto soft foods for oral ingestion or via enteral feeding tubes. A review of oxycodone DETERx data from in vitro and in vivo studies was conducted to demonstrate support for alternative routes and modes of administration. There was no difference in the dissolution profile when administered with various soft foods or when mixed with various liquid vehicles and administered via nasogastric (NG) or gastrostomy (G) tubes, based on in vitro studies. When sprinkled onto applesauce and administered orally, the microspheres were bioequivalent to the intact oxycodone capsules. When crushed or chewed, the formulation maintained its pharmacokinetic profile; no bolus dose of opioid was released. The sprinkle-dose study was limited by the single-dose study design, as well as the small sample size. Oxycodone DETERx is the first ER oxycodone formulation that can be administered either intact, sprinkled onto soft foods, or via NG/G tubes, thereby providing options for treating pain in patients who have difficulty swallowing.

In Vitro Dissolution as a Tool for Formulation Selection: Telmisartan Two-Step IVIVC.

PubMed

Ruiz Picazo, Alejandro; Martinez-Martinez, Ma Teresa; Colón-Useche, Sarin; Iriarte, Ramon; Sánchez-Dengra, Bárbara; González-Álvarez, Marta; García-Arieta, Alfredo; González-Álvarez, Isabel; Bermejo, Marival

2018-05-17

The purpose of this investigation was to develop an exploratory two-step level A IVIVC for three telmisartan oral immediate release formulations, the reference product Micardis, and two generic formulations (X1 and X2). Correlation was validated with a third test formulation, Y1. Experimental solubility and permeability data were obtained to confirm that telmisartan is a class II compound under the Biopharmaceutic Classification System. Bioequivalence (BE) studies plasma profiles were combined using a previously published reference scaling procedure. X2 demonstrated in vivo BE, while X1 and Y1 failed to show BE due to the lower boundary of the 90% confidence interval for C max being outside the acceptance limits. Average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed ( f a ). Fractions dissolved ( f diss ) were obtained in several conditions in USP II and USP IV apparatus, and later, the results were compared in order to find the most biopredictive model, calculating the f 2 similarity factor. The apparatus and conditions showing the same rank order than in vivo data were selected for further refinement of conditions. A Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivo behavior of the different formulations of telmisartan employed the USP IV dissolution apparatus and a dissolution environment with a flow rate of 8 mL/min and a three-step pH change, from 1.2 to 4.5 and 6.8, with a 0.05% of Tween 80. Thus, these conditions gave rise to a biopredictive dissolution test. This new model is able to predict the formulation differences in dissolution that were previously observed in vivo, which could be used as a risk-analysis tool for formulation selection in future bioequivalence trials.

Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles.

PubMed

Ledet, Grace A; Graves, Richard A; Glotser, Elena Y; Mandal, Tarun K; Bostanian, Levon A

2015-02-20

Fenretinide is an effective anti-cancer drug with high in vitro cytotoxicity and low in vivo systemic toxicity. In clinical trials, fenretinide has shown poor therapeutic efficacy following oral administration - attributed to its low bioavailability and solubility. The long term goal of this project is to develop a formulation for the oral delivery of fenretinide. The purpose of this part of the study was to prepare and characterize hydrophilic nanoparticle formulations of fenretinide. Three different ratios of polyvinyl pyrrolidone (PVP) to fenretinide were used, namely, 3:1, 4:1, and 5:1. Both drug and polymer were dissolved in a mixture of methanol and dichloromethane (2:23 v/v). Rotary evaporation was used to remove the solvents, and, following reconstitution with water, a high pressure homogenizer was used to form nanoparticles. The particle size and polydispersity index were measured before and after lyophilization. The formulations were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The effectiveness of the formulations was assessed by release studies and Caco-2 cell permeability assays. As the PVP content increased, the recovered particle size following lyophilization became more consistent with the pre-lyophilization particle size, especially for those formulations with less lactose. The DSC scans of the formulations did not show any fenretinide melting endotherms, indicating that the drug was either present in an amorphous form in the formulation or that a solid solution of the drug in PVP had formed. For the release studies, the highest drug release among the formulations was 249.2±35.5ng/mL for the formulation with 4:1 polymer-to-drug. When the permeability of the formulations was evaluated in a Caco-2 cell model, the mean normalized flux for each treatment group was significantly higher (p<0.05) from the fenretinide control. The formulation containing 4:1 polymer-to-drug ratio and 6:5 lactose-to-formulation ratio emerged as the optimal choice for further evaluation as a potential oral delivery formulation for fenretinide. Copyright © 2014 Elsevier B.V. All rights reserved.

Optimizing Prednisolone Loading into Distiller's Dried Grain Kafirin Microparticles, and In vitro Release for Oral Delivery.

PubMed

Lau, Esther T L; Johnson, Stuart K; Williams, Barbara A; Mikkelsen, Deirdre; McCourt, Elizabeth; Stanley, Roger A; Mereddy, Ram; Halley, Peter J; Steadman, Kathryn J

2017-05-19

Kafirin microparticles have potential as colon-targeted delivery systems because of their ability to protect encapsulated material from digestive processes of the upper gastrointestinal tract (GIT). The aim was to optimize prednisolone loading into kafirin microparticles, and investigate their potential as an oral delivery system. Response surface methodology (RSM) was used to predict the optimal formulation of prednisolone loaded microparticles. Prednisolone release from the microparticles was measured in simulated conditions of the GIT. The RSM models were inadequate for predicting the relationship between starting quantities of kafirin and prednisolone, and prednisolone loading into microparticles. Compared to prednisolone released in the simulated gastric and small intestinal conditions, no additional drug release was observed in simulated colonic conditions. Hence, more insight into factors affecting drug loading into kafirin microparticles is required to improve the robustness of the RSM model. This present method of formulating prednisolone-loaded kafirin microparticles is unlikely to offer clinical benefits over commercially available dosage forms. Nevertheless, the overall amount of prednisolone released from the kafirin microparticles in conditions simulating the human GIT demonstrates their ability to prevent the release of entrapped core material. Further work developing the formulation methods may result in a delivery system that targets the lower GIT.

Evaluation of the resistance of a geopolymer-based drug delivery system to tampering.

PubMed

Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne

2014-04-25

Tamper-resistance is an important property of controlled-release formulations of opioid drugs. Tamper-resistant formulations aim to increase the degree of effort required to override the controlled release of the drug molecules from extended-release formulations for the purpose of non-medical use. In this study, the resistance of a geopolymer-based formulation to tampering was evaluated by comparing it with a commercial controlled-release tablet using several methods commonly used by drug abusers. Because of its high compressive strength and resistance to heat, much more effort and time was required to extract the drug from the geopolymer-based formulation. Moreover, in the drug-release test, the geopolymer-based formulation maintained its controlled-release characteristics after milling, while the drug was released immediately from the milled commercial tablets, potentially resulting in dose dumping. Although the tampering methods used in this study does not cover all methods that abuser could access, the results obtained by the described methods showed that the geopolymer matrix increased the degree of effort required to override the controlled release of the drug, suggesting that the formulation has improved resistance to some common drug-abuse tampering methods. The geopolymer matrix has the potential to make the opioid product less accessible and attractive to non-medical users. Copyright © 2014 Elsevier B.V. All rights reserved.

Formulation and Optimization of Candesartan Cilexetil Nano Lipid Carrier: In Vitro and In Vivo Evaluation.

PubMed

Paudel, Anjan; Ameeduzzafar; Imam, Syed Sarim; Fazil, Mohd; Khan, Shahroz; Hafeez, Abdul; Ahmad, Farhan Jalees; Ali, Asgar

2017-01-01

The objective of this study was to formulate and optimize Candesartan Cilexetil (CC) loaded nanostructured lipid carriers (NLCs) for enhanced oral bioavailability. Glycerol monostearate (GMS), Oleic acid, Tween 80 and Span 40 were selected as a solid lipid, liquid lipid, surfactant and co- surfactant, respectively. The CC-NLCs were prepared by hot emulsion probe sonication technique and optimized using experimental design approach. The formulated CC-NLCs were evaluated for various physicochemical parameters and further optimized formulation (CC-NLC-Opt) was assessed for in vivo pharmacokinetic and pharmacodynamic activity. The optimized formulation (CC-NLC-Opt) showed particle size (183.5±5.89nm), PDI (0.228±0.13), zeta potential (-28.2±0.99mV), and entrapment efficiency (88.9±3.69%). The comparative in vitro release study revealed that CC-NLC-Opt showed significantly better (p<0.05) release and enhanced permeation as compared to CC-suspension. The in vivo pharmacokinetic study gave many folds increase in oral bioavailability than CC suspension, which was further confirmed by antihypertensive activity in a murine model. Thus, the results of ex vivo permeation, pharmacokinetic study and pharmacodynamics study suggest the potential of CC-NLCs for improved oral delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Palatability of a Novel Oral Formulation of Prednisone in Healthy Young Adults

PubMed Central

Bai, Shasha; Dormer, Nathan; Shoults, Catherine; Meyer, Amanda; Pierce, Carol D'Ann; Neville, Kathleen A.; Kearns, Gregory L.

2017-01-01

Objectives Prednisone is a widely used anti-inflammatory for a variety of conditions. While oral liquid formulations of prednisone enable weight-based dosing, children frequently find them to be objectionable due to bitter taste. This limitation of prednisone can adversely impact patient acceptance and may result in non-compliance. Efforts to mask flavors often result in poorly controlled, heterogeneous particle distributions and can provide ineffective taste masking. The present work utilized a novel drug delivery technology developed by Orbis Biosciences, Inc., to create an oral taste-masked formulation of prednisone. Methods The study examined the palatability of Orbis’ microsphere prednisone formulation in healthy young adults (n=24). Four test articles were used in the study including a reference formulation (Roxane Laboratories), a control, and the test formulation (Orbis) prepared in two different ways. Study participants were randomized in a crossover design. Key Findings Results indicated that the test prednisone formulation was indistinguishable from the control, and both were preferable to the reference formulation in every category of palatability assessed using a validated 9-point Hedonic Scale. The data also suggested that preparing the microsphere suspension immediately prior to administration results in the most ideal palatability properties. Conclusions In conclusion, the novel microsphere formulation technology was effective in taste-masking prednisone. PMID:28271493

A review of ropinirole prolonged release in Parkinson’s disease

PubMed Central

Nashatizadeh, Muhammad M; Lyons, Kelly E; Pahwa, Rajesh

2009-01-01

Ropinirole prolonged release is a once-daily, 24-hour formulation of ropinirole, a non-ergot dopamine agonist. It is approved as monotherapy and as an adjunct to levodopa in the treatment of Parkinson’s disease (PD). Several potential advantages of ropinirole prolonged release compared to the immediate release formulation include maintaining more consistent dopaminergic activity with steadier plasma levels, increased tolerability, greater compliance from a simpler once-daily dosing regimen and ease in dose titration. In a randomized, double-blind, non-inferiority, crossover study, ropinirole prolonged release was shown to have comparable efficacy and tolerability to immediate release ropinirole in early PD patients, with significantly greater compliance. Subjects were converted overnight between ropinirole formulations without loss of efficacy and with good tolerability. In a randomized, double-blind, placebo-controlled study in advanced PD, daily “off” time was reduced by an average of 2.1 hours with ropinirole prolonged release compared to 0.4 hours with placebo. Patients on ropinirole prolonged release were also more likely to require less daily levodopa. Ropinirole prolonged release is well tolerated with a similar adverse effect profile to other non-ergot dopamine agonists. The most common adverse effects include dyskinesia, nausea, dizziness, hallucinations, somnolence, abdominal pain or discomfort and orthostatic hypotension. Ropinirole prolonged release is a safe and effective treatment option for both early and advanced PD. This manuscript briefly reviews the current pharmacological treatment options for PD and provides a more detailed review of the currently available data regarding ropinirole prolonged release as a treatment option for PD. PMID:19503779

IRIS Assessment Plan for Uranium (Scoping and Problem Formulation Materials)

EPA Science Inventory

In January 2018, EPA released the IRIS Assessment Plan for Uranium (Oral Reference Dose) (Scoping and Problem Formulation Materials). An IRIS Assessment Plan (IAP) communicates to the public the plan for assessing each individual chemical and includes summary informatio...

Controlled release hydrophilic matrix tablet formulations of isoniazid: design and in vitro studies.

PubMed

Hiremath, Praveen S; Saha, Ranendra N

2008-01-01

The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer-Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f (2) metric values. The release profiles found to follow Higuchi's square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.

Preparation and evaluation of Vinpocetine self-emulsifying pH gradient release pellets.

PubMed

Liu, Mengqi; Zhang, Shiming; Cui, Shuxia; Chen, Fen; Jia, Lianqun; Wang, Shu; Gai, Xiumei; Li, Pingfei; Yang, Feifei; Pan, Weisan; Yang, Xinggang

2017-11-01

The main objective of this study was to develop a pH gradient release pellet with self-emulsifying drug delivery system (SEDDS), which could not only improve the oral bioavailability of Vinpocetine (VIN), a poor soluble drug, but reduce the fluctuation of plasma concentration. First, the liquid VIN SEDDS formulation was prepared. Then the self-emulsifying pH gradient release pellets were prepared by extrusion spheronization technique, and formulation consisted by the liquid SEDDS, absorbent (colloidal silicon dioxide), penetration enhancer (sodium chloride), microcrystalline cellulose, ethyl alcohol, and three coating materials (HPMC, Eudragit L30D55, Eudragit FS30D) were eventually selected. Three kinds of coated pellets were mixed in capsules with the mass ratio of 1:1:1. The release curves of capsules were investigated in vitro under the simulated gastrointestinal conditions. In addition, the oral bioavailability and pharmacokinetics of VIN self-emulsifying pH gradient release pellets, commercial tablets and liquid VIN SEDDS were evaluated in Beagle dogs. The oral bioavailability of self-emulsifying pH gradient release pellets was about 149.8% of commercial VIN tablets, and it was about 86% of liquid VIN SEDDS, but there were no significant difference between liquid SEDDS and self-emulsifying pH gradient release pellets. In conclusion, the self-emulsifying pH gradient release pellets could significantly enhance the absorption of VIN and effectively achieve a pH gradient release. And the self-emulsifying pH gradient release pellet was a promising method to improve bioavailability of insoluble drugs.

An oral multi-particulate, modified release, hydrocortisone replacement therapy that provides physiological cortisol exposure

PubMed Central

Huatan, Hiep; Merke, Deborah; Arlt, Wiebke; Ross, Richard J.

2013-01-01

Objective It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multi-particulate technology. Design and Measurements Screening by in-vitro dissolution profiles, pharmacokinetic testing in dexamethasone suppressed dogs and humans, and comparison to a reference population. Setting Field laboratories and clinical research facility. Results Formulations were generated using an enteric (delayed-release) design configuration with an extended (sustained-release) dissolution profile. In-vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained release functionality. Pharmacokinetic characterisation of DIURF-006 showed that, despite absence of a sustained release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n=16) receiving a twice daily ‘toothbrush’ regimen (20mg at 23:00h and 10mg at 07:00h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 hr*nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8.5h vs clock time 08:12 hours for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89% and cortisol levels increased linearly with doses between 5 and 30mg. Conclusion A multi-particulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a ‘toothbrush’ regimen provides physiological cortisol exposure. PMID:23980724

An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure.

PubMed

Whitaker, Martin; Debono, Miguel; Huatan, Hiep; Merke, Deborah; Arlt, Wiebke; Ross, Richard J

2014-04-01

It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. Field laboratories and clinical research facility. Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily 'toothbrush' regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a 'toothbrush' regimen provides physiological cortisol exposure. © 2013 John Wiley & Sons Ltd.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride.

PubMed

Plöger, Gerlinde F; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, Dirk W; Langguth, Peter; Mehta, Mehul U; Parr, Alan; Polli, James E; Shah, Vinod P; Tajiri, Tomokazu; Dressman, Jennifer B

2018-07-01

Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To elucidate the Biopharmaceutics Classification System (BCS) classification, experimental solubility and dissolution studies were also carried out. The antimalarial proguanil hydrochloride, effective via the parent compound proguanil and the metabolite cycloguanil, is not considered to be a narrow therapeutic index drug. Proguanil hydrochloride salt was shown to be highly soluble according to the U.S. Food and Drug Administration, World Health Organization, and European Medicines Agency guidelines, but data for permeability are inconclusive. Therefore, proguanil hydrochloride is conservatively classified as a BCS class 3 substance. In view of this information and the assessment of risks associated with a false positive decision, a BCS-based biowaiver approval procedure can be recommended for orally administered solid immediate release products containing proguanil hydrochloride, provided well-known excipients are used in usual amounts and provided the in vitro dissolution of the test and reference products is very rapid (85% or more are dissolved in 15 min at pH 1.2, 4.5, and 6.8) and is performed according to the current requirements for BCS-based biowaivers. Copyright © 2018 American Pharmacists Association®. All rights reserved.

Ramizol® encapsulation into extended release PLGA micro- and nanoparticle systems for subcutaneous and intramuscular administration: in vitro and in vivo evaluation.

PubMed

Wright, Leah; Rao, Shasha; Thomas, Nicky; Boulos, Ramiz A; Prestidge, Clive A

2018-04-11

Novel antibiotic Ramizol ® is advancing to clinical trials for the treatment of gastrointestinal Clostridium difficile associated disease. Despite this, previous studies have shown a rapid plasma clearance upon intravenous administration and low oral bioavailability indicating pure drug is unsuitable for systemic infection treatment following oral dosing. The current study aims to investigate the development of poly-lactic-(co-glycolic) acid (PLGA) particles to overcome this limitation and increase the systemic half-life following subcutaneous and intramuscular dosing. The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance. Ramizol ® was encapsulated into PLGA nano and microparticles using nanoprecipitation and emulsification solvent evaporation techniques. Formulations were analyzed for particle size, loading level and encapsulation efficiency as well as in vitro drug release profiles. Final formulation was advanced to in vivo pharmacokinetic studies in Sprague-Dawley rats. Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague-Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in T max and T 1/2 when compared to the oral and IV routes. Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol ® . This formulation will allow further development of Ramizol ® for systemic infection eradication.

Formulation and evaluation of novel coated floating tablets of bergenin and cetirizine dihydrochloride for gastric delivery.

PubMed

He, Shuang; Li, Feng; Zhou, Dan; Du, Junrong; Huang, Yuan

2012-10-01

A novel coated gastric floating drug-delivery system (GFDDS) of bergenin (BN) and cetirizine dihydrochloride (CET) was developed. First, the pharmacodynamic studies were performed and the results revealed that the new compounds of bergenin/cetirizine dihydrochloride had comparative efficacy as commercial products (bergenin/chlorphenamine maleate) but with fewer side effects on central nervous system (CNS). Subsequently, bergenin was formulated as an extended-release core tablet while cetirizine dihydrochloride was incorporated into the gastric coating film for immediate release. The formulation of GFDDS was optimized by CET content uniformity test, in vitro buoyancy and drug release. Herein, the effects of sodium bicarbonate (effervescent), hydroxypropyl methylcellulose (HPMC, matrix polymer) and coating weight gain were investigated respectively. The optimized GFDDS exhibited good floating properties (buoyancy lag time < 2 min; floating duration > 10 h) and satisfactory drug-release profiles (immediate release of CET in 10 min and sustained release of BN for 12 h). In vivo gamma scintigraphy proved that the optimized GFDDS could retain in the stomach with a prolonged gastric retention time (GRT) of 5 h, and the coating layer showed no side effect for gastric retention. The novel coated gastric floating drug-delivery system offers a new approach to enhance BN's absorption at its absorption site and the efficacy of both CET and BN.

Formulation and in-vitro evaluation of floating bilayer tablet of lisinopril maleate and metoprolol tartrate.

PubMed

Ijaz, Hira; Qureshi, Junaid; Danish, Zeeshan; Zaman, Muhammad; Abdel-Daim, Mohamed; Hanif, Muhammad; Waheed, Imran; Mohammad, Imran Shair

2015-11-01

The purpose of this study was to introduce the technology for the development of rate-controlled oral drug delivery system to overcome various physiological problems. Several approaches are being used for the purpose of increasing the gastric retentive time, including floating drug delivery system. Gastric floating lisinopril maleate and metoprolol tartrate bilayer tablets were formulated by direct compression method using the sodium starch glycolate, crosscarmellose sodium for IR layer. Eudragit L100, pectin, acacia as sustained release polymers in different ratios for SR metoprolol tartrate layer and sodium bicarbonate, citric acid as gas generating agents for the floating extended release layer. The floating bilayer tablets of lisinopril maleate and metoprolol tartrate were designed to overcome the various problems associated with conventional oral dosage form. Floating tablets were evaluated for floating lag time, drug contents and in-vitro dissolution profile and different kinetic release models were applied. It was clear that the different ratios of polymers affected the drug release and floating time. L2 and M4 showed good drug release profile and floating behavior. The linear regression and model fitting showed that all formulation followed Higuchi model of drug release model except M4 that followed zero order kinetic. From the study it is evident that a promising controlled release by floating bilyer tablets of lisinopril maleate and metoprolol tartrate can be developed successfully.

Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption.

PubMed

Shi, Yi; Gao, Ping; Gong, Yuchuan; Ping, Haili

2010-10-04

A biphasic in vitro test method was used to examine release profiles of a poorly soluble model drug, celecoxib (CEB), from its immediate release formulations. Three formulations of CEB were investigated in this study, including a commercial Celebrex capsule, a solution formulation (containing cosolvent and surfactant) and a supersaturatable self-emulsifying drug delivery system (S-SEDDS). The biphasic test system consisted of an aqueous buffer and a water-immiscible organic solvent (e.g., octanol) with the use of both USP II and IV apparatuses. The aqueous phase provided a nonsink dissolution medium for CEB, while the octanol phase acted as a sink for CEB partitioning. For comparison, CEB concentration-time profiles of these formulations in the aqueous medium under either a sink condition or a nonsink condition were also explored. CEB release profiles of these formulations observed in the aqueous medium from either the sink condition test, the nonsink condition test, or the biphasic test have little relevance to the pharmacokinetic observations (e.g., AUC, C(max)) in human subjects. In contrast, a rank order correlation among the three CEB formulations is obtained between the in vitro AUC values of CEB from the octanol phase up to t = 2 h and the in vivo mean AUC (or C(max)) values. As the biphasic test permits a rapid removal of drug from the aqueous phase by partitioning into the organic phase, the amount of drug in the organic phase represents the amount of drug accumulated in systemic circulation in vivo. This hypothesis provides the scientific rationale for the rank order relationship among these CEB formulations between their CEB concentrations in the organic phase and the relative AUC or C(max). In addition, the biphasic test method permits differentiation and discrimination of key attributes among the three different CEB formulations. This work demonstrates that the biphasic in vitro test method appears to be useful as a tool in evaluating performance of formulations of poorly water-soluble drugs and to provide potential for establishing an in vitro-in vivo relationship.

Bioavailability of ambroxol sustained release preparations. Part II: Single and multiple oral dose studies in man.

PubMed

Janssen, T J; Guelen, P J; Vree, T B; Botterblom, M H; Valducci, R

1988-01-01

The bioavailability of a new ambroxol sustained release preparation (75 mg) based on a dialyzing membrane for controlled release was studied in healthy volunteers after single and multiple oral dose in comparison with a standard sustained release formulation in a cross-over study under carefully controlled conditions. Plasma concentrations of ambroxol were measured by means of a HPLC method. Based on AUC data both preparations are found to be bioequivalent, but show different plasma concentration profiles. The test preparation showed a more pronounced sustained release profile than the reference preparation (single dose) resulting in significantly higher steady state plasma levels.

Colon Targeted Guar Gum Compression Coated Tablets of Flurbiprofen: Formulation, Development, and Pharmacokinetics

PubMed Central

Bontha, Vijaya Kumar

2013-01-01

The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4) showed almost complete drug release in the colon (99.86%) within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period). The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The C max of colon targeted tablets was 11956.15 ng/mL at T max of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen. PMID:24260738

Colon targeted guar gum compression coated tablets of flurbiprofen: formulation, development, and pharmacokinetics.

PubMed

Vemula, Sateesh Kumar; Bontha, Vijaya Kumar

2013-01-01

The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4) showed almost complete drug release in the colon (99.86%) within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period). The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The C(max) of colon targeted tablets was 11956.15 ng/mL at T max of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen.

Design and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced dissolution of gemfibrozil.

PubMed

Villar, Ana Maria Sierra; Naveros, Beatriz Clares; Campmany, Ana Cristina Calpena; Trenchs, Monserrat Aróztegui; Rocabert, Coloma Barbé; Bellowa, Lyda Halbaut

2012-07-15

Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. Box-Behnken experimental design was employed as statistical tool to optimize the formulation variables, X(1) (Cremophor(®) EL), X(2) (Capmul(®) MCM-C8), and X(3) (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X(1), X(2), and X(3)) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in t(d) parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

Pharmacokinetics of an oral extended-release formulation of doxycycline hyclate containing acrylic acid and polymethacrylate in dogs.

PubMed

Ruiz, Sara Melisa Arciniegas; Olvera, Lilia Gutiérrez; Chacón, Sara del Carmen Caballero; Estrada, Dinorah Vargas

2015-04-01

To determine the pharmacokinetics of doxycycline hyclate administered orally in the form of experimental formulations with different proportions of acrylic acid-polymethacrylate-based matrices. 30 healthy adult dogs. In a crossover study, dogs were randomly assigned (in groups of 10) to receive a single oral dose (20 mg/kg) of doxycycline hyclate without excipients (control) or extended-release formulations (ERFs) containing doxycycline, acrylic acid polymer, and polymethacrylate in the following proportions: 1:0.5:0.0075 (ERF1) or 1:1:0.015 (ERF2). Serum concentrations of doxycycline were determined for pharmacokinetic analysis before and at several intervals after each treatment. Following oral administration to the study dogs, each ERF resulted in therapeutic serum doxycycline concentrations for 48 hours, whereas the control treatment resulted in therapeutic serum doxycycline concentrations for only 24 hours. All pharmacokinetic parameters for ERF1 and ERF2 were significantly different; however, findings for ERF1 did not differ significantly from those for the control treatment. Results indicated that both ERFs containing doxycycline, acrylic acid polymer, and polymethacrylate had an adequate pharmacokinetic-pharmacodynamic relationship for a time-dependent drug and a longer release time than doxycycline alone following oral administration in dogs. Given the minimum effective serum doxycycline concentration of 0.26 μg/mL, a dose interval of 48 hours can be achieved for each tested ERF. This minimum inhibitory concentration has the potential to be effective against several susceptible bacteria involved in important infections in dogs. Treatment of dogs with either ERF may have several benefits over treatment with doxycycline alone.

IRIS Assessment Plan for Uranium (Scoping and Problem Formulation Materials)

EPA Science Inventory

In January 2018, EPA released the IRIS Assessment Plan for Uranium (Oral Reference Dose) (Scoping and Problem Formulation Materials). An IRIS Assessment Plan , or IAP communicates to the public the plan for assessing each individual chemical and includes summary informat...

Hydrophilic thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding.

PubMed

Verstraete, G; Van Renterghem, J; Van Bockstal, P J; Kasmi, S; De Geest, B G; De Beer, T; Remon, J P; Vervaet, C

2016-06-15

Hydrophilic aliphatic thermoplastic polyurethane (Tecophilic™ grades) matrices for high drug loaded oral sustained release dosage forms were formulated via hot melt extrusion/injection molding (HME/IM). Drugs with different aqueous solubility (diprophylline, theophylline and acetaminophen) were processed and their influence on the release kinetics was investigated. Moreover, the effect of Tecophilic™ grade, HME/IM process temperature, extrusion speed, drug load, injection pressure and post-injection pressure on in vitro release kinetics was evaluated for all model drugs. (1)H NMR spectroscopy indicated that all grades have different soft segment/hard segment ratios, allowing different water uptake capacities and thus different release kinetics. Processing temperature of the different Tecophilic™ grades was successfully predicted by using SEC and rheology. Tecophilic™ grades SP60D60, SP93A100 and TG2000 had a lower processing temperature than other grades and were further evaluated for the production of IM tablets. During HME/IM drug loads up to 70% (w/w) were achieved. In addition, Raman mapping and (M)DSC results confirmed the homogenous distribution of mainly crystalline API in all polymer matrices. Besides, hydrophilic TPU based formulations allowed complete and sustained release kinetics without using release modifiers. As release kinetics were mainly affected by drug load and the length of the PEO soft segment, this polymer platform offers a versatile formulation strategy to adjust the release rate of drugs with different aqueous solubility. Copyright © 2016 Elsevier B.V. All rights reserved.

Therapeutic effect of orally administered microencapsulated oxaliplatin for colorectal cancer

PubMed Central

Urbanska, Aleksandra M.; Karagiannis, Emmanouil D.; Guajardo, Gonzalo; Langer, Robert S.; Anderson, Daniel G.

2013-01-01

Colorectal cancer is a significant source of morbidity and mortality in the United States and other Western countries. Oral delivery of therapeutics remains the most patient accepted form of medication. The development of an oral delivery formulation for local delivery of chemotherapeutics in the gastrointestinal tract can potentially alleviate the adverse side effects including systemic cytotoxicity, as well as focus therapy to the lesions. Here we develop an oral formulation of the chemotherapeutic drug oxaliplatin for the treatment of colorectal cancer. Oxaliplatin was encapsulated in pH sensitive, mucoadhesive chitosan-coated alginate microspheres. The microparticles were formulated to release the chemotherapeutics after passing through the acidic gastric environment thus targeting the intestinal tract. In vivo, these particles substantially reduced the tumor burden in an orthotopic mouse model of colorectal cancer, and reduced mortality. PMID:22472433

Preparation, characterization and in vivo evaluation of curcumin self-nano phospholipid dispersion as an approach to enhance oral bioavailability.

PubMed

Allam, Ahmed N; Komeil, Ibrahim A; Fouda, Mohamed A; Abdallah, Ossama Y

2015-07-15

The aim of this study was to examine the efficacy of self-nano phospholipid dispersions (SNPDs) based on Phosal(®) to improve the oral bioavailability of curcumin (CUR). SNPDs were prepared with Phosal(®) 53 and Miglyol 812 at different surfactant ratio. Formulations were evaluated for particle size, polydispersity index, zeta potential, and robustness toward dilution, TEM as well as in vitro drug release. The in vivo oral absorption of selected formulations in comparison to drug suspension was evaluated in rats. Moreover, formulations were assessed for in vitro characteristic changes before and after storage. The SNPDs were miscible with water in any ratio and did not show any phase separation or drug precipitation. All the formulas were monodisperse with nano range size from 158±2.6 nm to 610±6.24 nm. They passed the pharmacopeial tolerance for CUR dissolution. No change in dissolution profile and physicochemical characteristics was detected after storage. CUR-SNPDs are found to be more bioavailable compared with suspension during an in vivo study in rats and in vitro release studies failed to imitate the in vivo conditions. These formulations might be new alternative carriers that enhance the oral bioavailability of poorly water-soluble molecules, such as CUR. Copyright © 2015 Elsevier B.V. All rights reserved.

Thermally reversible in situ gelling carbamazepine liquid suppository.

PubMed

El-Kamel, Amal; El-Khatib, Mona

2006-01-01

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC(0 - infinity), 17.9 and 18.8 micro g x h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.

Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform.

PubMed

Choudhury, Hira; Gorain, Bapi; Karmakar, Sanmoy; Biswas, Easha; Dey, Goutam; Barik, Rajib; Mandal, Mahitosh; Pal, Tapan Kumar

2014-01-02

Paclitaxel, a potential anticancer agent against solid tumors has been restricted from its oral use due to poor water solubility as well as Pgp efflux property. The present study was aimed to improve the oral bioavailability of paclitaxel through development of (o/w) nanoemulsion consisting of Capryol 90 as internal phase with Tween 20 as emulsifier with water as an external phase. Formulations were selected from the nanoemulsion region of pseudo-ternary phase diagrams, formulated by aqueous titration method. The developed nanoemulsion has been characterized by its thermodynamic stability, morphology, droplet size, zeta potential, viscosity where in vitro release was evaluated through dialysis. Paclitaxel nanoemulsion exhibited thermodynamical stability with low viscosity, nano-sized oil droplets in water with low poly-dispersity index. The shelf life of the paclitaxel nanoemulsion was found to be approximately 2.38 years. Increased permeability through the Caco-2 cell monolayer and decreased efflux is great advantageous for nanoemulsion formulation. The effects of paclitaxel nanoemulsion on breast cancer cell proliferation, morphology and DNA fragmentation were analyzed in vitro which showed significant anti-proliferation and decreased IC50 values in nanoemulsion group which may be due to enhanced uptake of paclitaxel through the oil core. Moreover, the absolute oral bioavailability and sustained release profile of the paclitaxel nanoemulsion evaluated in mouse model was found to improve up to 55.9%. The concentration of paclitaxel in mice plasma was determined by our validated LC-MS/MS method. By reviewing the significant outcome of the present investigation based on stability study, Caco-2 permeability, cell proliferative assay and pharmacokinetic profile it may be concluded that the oral nanoemulsion has got encouraging advantages over the presently available formulations of this injectable chemotherapeutic drug. Copyright © 2013 Elsevier B.V. All rights reserved.

Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study.

PubMed

Shah, Nirmal V; Seth, Avinash K; Balaraman, R; Aundhia, Chintan J; Maheshwari, Rajesh A; Parmar, Ghanshyam R

2016-05-01

The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 3(2) factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 ± 5.12 nm average particle size and -12.8 ± 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX.

Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study

PubMed Central

Shah, Nirmal V.; Seth, Avinash K.; Balaraman, R.; Aundhia, Chintan J.; Maheshwari, Rajesh A.; Parmar, Ghanshyam R.

2016-01-01

The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 32 factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 ± 5.12 nm average particle size and −12.8 ± 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX. PMID:27222747

Correlation of dissolution and disintegration results for an immediate-release tablet.

PubMed

Nickerson, Beverly; Kong, Angela; Gerst, Paul; Kao, Shangming

2018-02-20

The drug release rate of a rapidly dissolving immediate-release tablet formulation with a highly soluble drug is proposed to be controlled by the disintegration rate of the tablet. Disintegration and dissolution test methods used to evaluate the tablets were shown to discriminate manufacturing process differences and compositionally variant tablets. In addition, a correlation was established between disintegration and dissolution. In accordance with ICH Q6A, this work demonstrates that disintegration in lieu of dissolution is suitable as the drug product quality control method for evaluating this drug product. Copyright © 2017 Elsevier B.V. All rights reserved.

Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin.

PubMed

Morçöl, T; Nagappan, P; Nerenbaum, L; Mitchell, A; Bell, S J D

2004-06-11

An oral delivery system for insulin was developed and functional activity was tested in a non-obese diabetic (NOD) mice model. Calcium phosphate particles containing insulin was synthesized in the presence of PEG-3350 and modified by aggregating the particles with caseins to obtain the calcium phosphate-PEG-insulin-casein (CAPIC) oral insulin delivery system. Single doses of CAPIC formulation were tested in NOD mice under fasting or fed conditions to evaluate the glycemic activity. The blood glucose levels were monitored every 1-2h for 12h following the treatments using an ACCU CHECK blood glucose monitoring system. Orally administered and subcutaneously injected free insulin solution served as controls in the study. Based on the results obtained we propose that: (1). the biological activity of insulin is preserved in CAPIC formulation; (2). insulin in CAPIC formulations, but not the free insulin, displays a prolonged hypoglycemic effect after oral administration to diabetic mice; (3). CAPIC formulation protects insulin from degradation while passing through the acidic environment of the GI track until it is released in the less acidic environment of the intestines where it can be absorbed in its biologically active form; (4). CAPIC formulation represents a new and unique oral delivery system for insulin and other macromolecules.

Tramadol extended-release in the management of chronic pain

PubMed Central

McCarberg, Bill

2007-01-01

Chronic, noncancer pain such as that associated with osteoarthritis of the hip and knee is typically managed according to American College of Rheumatology guidelines. Patients unresponsive to first-line treatment with acetaminophen receive nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors. However, many patients may have chronic pain that is refractory to these agents, or they may be at risk for the gastrointestinal, renal, and cardiovascular complications associated with their use. Tramadol, a mild opioid agonist and norepinephrine and serotonin reuptake inhibitor, is recommended by current guidelines for the treatment of moderate to moderately severe pain in patients who have not responded to previous oral therapy, or in patients who have contraindications to COX-2 inhibitors and nonselective NSAIDs. An extended-release (ER) formulation of tramadol was approved by the US Food and Drug Administration in September 2005. In contrast with immediate-release (IR) tramadol, this ER formulation allows once-daily dosing, providing around-the-clock analgesia. In clinical studies, tramadol ER has demonstrated a lower incidence of adverse events than that reported for IR tramadol. Unlike nonselective NSAIDs and COX-2 inhibitors, tramadol ER is not associated with gastrointestinal, renal, or cardiovascular complications. Although tramadol is an opioid agonist, significant abuse has not been demonstrated after long-term therapy. It is concluded that tramadol ER has an efficacy and safety profile that warrants its early use for the management of chronic pain, either alone or in conjunction with nonselective NSAIDs and COX-2 inhibitors. PMID:18488071

Intestine-Specific, Oral Delivery of Captopril/Montmorillonite: Formulation and Release Kinetics

PubMed Central

2011-01-01

The intercalation of captopril (CP) into the interlayers of montmorillonite (MMT) affords an intestine-selective drug delivery system that has a captopril-loading capacity of up to ca. 14 %w/w and which exhibits near-zero-order release kinetics. PMID:27502639

Preparation and pharmaceutical evaluation of glibenclamide slow release mucoadhesive buccal film

PubMed Central

Bahri-Najafi, R.; Tavakoli, N.; Senemar, M.; Peikanpour, M.

2014-01-01

Buccal mucoadhesive systems among novel drug delivery systems have attracted great attention in recent years due to their ability to adhere and remain on the oral mucosa and to release their drug content gradually. Buccal mucoadhesive films can improve the drug therapeutic effect by enhancement of drug absorption through oral mucosa increasing the drug bioavailability via reducing the hepatic first pass effect. The aim of the current study was to formulate the drug as buccal bioadhesive film, which releases the drug at sufficient concentration with a sustain manner reducing the frequency of the dosage form administration. One of the advantagees of this formulation is better patient compliances due to the ease of administration with no water to swallow the product. The mucoadhesive films of glibenclamide were prepared using hydroxypropyl methylcellulose (HPMC) K4M, K15M and Eudragit RL100 polymers and propylene glycol as plasticizer and co-solvent. Films were prepared using solvent casting method, and were evaluated with regard to drug content, thickness, weight variations, swelling index, tensile strength, ex vivo adhesion force and percentage of in vitro drug release. Films with high concentrations of HPMC K4M and K15M did not have favorable appearance and uniformity. The formulations prepared from Eudragit were transparent, uniform, flexible, and without bubble. The highest and the lowest percentages of swelling were observed for the films containing HPMC K15M and Eudragit RL100, respectively. Films made of HPMC K15M had adhesion force higher than those containing Eudragit RL100. Formulations with Eudragit RL100 showed the highest mean dissolution time (MDT). Drug release kinetics of all formulations followed Higuchi's model and the mechanism of diffusion was considered non-Fickian type. It was concluded that formulations containing Eudragit RL100 were more favorable than others with regard to uniformity, flexibility, rate and percentage of drug release. PMID:25657792

Dry elixir formulations of dexibuprofen for controlled release and enhanced oral bioavailability.

PubMed

Kim, Seo-Ryung; Kim, Jin-Ki; Park, Jeong-Sook; Kim, Chong-Kook

2011-02-14

The objective of this study was to achieve an optimal formulation of dexibuprofen dry elixir (DDE) for the improvement of dissolution rate and bioavailability. To control the release rate of dexibuprofen, Eudragit(®) RS was employed on the surface of DDE resulting in coated dexibuprofen dry elixir (CDDE). Physicochemical properties of DDE and CDDE such as particle size, SEM, DSC, and contents of dexibuprofen and ethanol were characterized. Pharmacokinetic parameters of dexibuprofen were evaluated in the rats after oral administration. The DDE and CDDE were spherical particles of 12 and 19 μm, respectively. The dexibuprofen and ethanol contents in the DDE were dependent on the amount of dextrin and maintained for 90 days. The dissolution rate and bioavailability of dexibuprofen loaded in dry elixir were increased compared with those of dexibuprofen powder. Moreover, coating DDE with Eudragit(®) RS retarded the dissolution rate of dexibuprofen from DDE without reducing the bioavailability. Our results suggest that CDDE may be potential oral dosage forms to control the release and to improve the bioavailability of poorly water-soluble dexibuprofen. Copyright © 2010 Elsevier B.V. All rights reserved.

Combining two technologies: multifunctional polymers and self-nanoemulsifying drug delivery system (SNEDDS) for oral insulin administration.

PubMed

Sakloetsakun, Duangkamon; Dünnhaupt, Sarah; Barthelmes, Jan; Perera, Glen; Bernkop-Schnürch, Andreas

2013-10-01

The aim of the study is to develop a self-nanoemulsifying drug delivery system (SNEDDS) based on thiolated chitosan for oral insulin administration. The preparations were characterized by particle size, entrapment efficiency, stability and drug release. Serum insulin concentrations were determined after oral administration of all formulations. Insulin SNEDDS formulation was served as control. The optimized SNEDDS consists of 65% (w/w) miglyol 840, 25% (w/w) cremophor EL, 10% (w/w) co-solvents (a mixture of DMSO and glycerol). The formulations in the presence or absence of insulin (5mg/mL) were spherical with the size range between 80 and 160 nm. Entrapment efficiency of insulin increased significantly when the thiolated chitosan was employed (95.14±2.96%), in comparison to the insulin SNEDDS (80.38±1.22%). After 30 min, the in vitro release profile of insulin from the nanoemulsions was markedly increased compared to the control. In vivo results showed that insulin/thiolated chitosan SNEDDS displayed a significant increase in serum insulin (p-value=0.02) compared to oral insulin solution. A new strategy to combine SNEDDS and thiolated chitosan described in the study would therefore be a promising and innovative approach to improve oral bioavailability of insulin. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Pharmacokinetic Profile and Palatability of Atomoxetine Oral Solution in Healthy Japanese Male Adults.

PubMed

Nakano, Masako; Witcher, Jennifer; Satoi, Yoichi; Goto, Taro

2016-11-01

There is a clinical need for a liquid formulation of atomoxetine. We assessed the safety and bioequivalence of an atomoxetine oral solution. This was an open-label, randomized, crossover study. Healthy adult male Japanese subjects (n = 42) with a cytochrome P450 2D6 extensive (including intermediate and ultrarapid) metabolizer genotype were administered atomoxetine 50 mg as oral solution and capsules once each, with a washout period >5 days between doses. Blood samples were used to analyze pharmacokinetic parameters, particularly maximum observed drug concentration (C max ) and area under the concentration vs. time curve from time zero to the last time point with a measurable concentration (AUC 0-last ). Bioequivalence was concluded if the 90 % confidence interval of the ratio of geometric means between formulations for both C max and AUC 0-last were within the interval of 0.8-1.25. Safety assessments included determination of adverse events. Taste was evaluated via a five-item questionnaire immediately and 10 min after taking atomoxetine oral solution. Forty subjects completed the study. Plasma concentration-time profiles of atomoxetine oral solution and capsules were similar, and the statistical analysis of systemic exposure showed that the two formulations were bioequivalent. Adverse events were mild and similar in type and frequency between the formulations. For taste acceptability, only 7.1 % of subjects responded that the oral solution would be difficult to take every day. Atomoxetine oral solution is bioequivalent to atomoxetine capsules and potentially fulfills the need for an oral solution atomoxetine formulation that will facilitate treatment of children with attention-deficit hyperactivity disorder.

Development of In Vitro-In Vivo Correlation/Relationship Modeling Approaches for Immediate Release Formulations Using Compartmental Dynamic Dissolution Data from “Golem”: A Novel Apparatus

PubMed Central

Tuszyński, Paweł K.; Polak, Sebastian; Jachowicz, Renata; Mendyk, Aleksander; Dohnal, Jiří

2015-01-01

Different batches of atorvastatin, represented by two immediate release formulation designs, were studied using a novel dynamic dissolution apparatus, simulating stomach and small intestine. A universal dissolution method was employed which simulated the physiology of human gastrointestinal tract, including the precise chyme transit behavior and biorelevant conditions. The multicompartmental dissolution data allowed direct observation and qualitative discrimination of the differences resulting from highly pH dependent dissolution behavior of the tested batches. Further evaluation of results was performed using IVIVC/IVIVR development. While satisfactory correlation could not be achieved using a conventional deconvolution based-model, promising results were obtained through the use of a nonconventional approach exploiting the complex compartmental dissolution data. PMID:26120580

Applications of Natural Polymeric Materials in Solid Oral Modified-Release Dosage Forms.

PubMed

Li, Liang; Zhang, Xin; Gu, Xiangqin; Mao, Shirui

2015-01-01

Solid oral modified-release dosage forms provide numerous advantages for drug delivery compared to dosage forms where the drugs are released and absorbed rapidly following ingestion. Natural polymers are of particular interest as drug carriers due to their good safety profile, biocompatibility, biodegradability, and rich sources. This review described the current applications of important natural polymers, such as chitosan, alginate, pectin, guar gum, and xanthan gum, in solid oral modified-release dosage forms. It was shown that natural polymers have been widely used to fabricate solid oral modified-release dosage forms such as matrix tablets, pellets and beads, and especially oral drug delivery systems such as gastroretentive and colon drug delivery systems. Moreover, chemical modifications could overcome the shortcomings associated with the use of natural polymers, and the combination of two or more polymers presented further advantages compared with that of single polymer. In conclusion, natural polymers and modified natural polymers have promising applications in solid oral modified-release dosage forms. However, commercial products based on them are still limited. To accelerate the application of natural polymers in commercial products, in vivo behavior of natural polymers-based solid oral modified-release dosage forms should be deeply investigated, and meanwhile quality of the natural polymers should be controlled strictly, and the influence of formulation and process parameters need to be understood intensively.

Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system.

PubMed

Mahapatra, Anjan Kumar; Sameeraja, N H; Murthy, P N

2015-06-01

Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium starch glycolate acts as a superdisintegrant in immediate-release part and hydroxypropyl methyl cellulose as a release retarding agent in extended-release core. Tablets were prepared by direct compression. Both the core and the coat contained the drug. The pre-compression blends were evaluated for angle of repose, bulk density, and compressibility index. The tablets were evaluated for thickness, hardness, weight variation test, friability, and in vitro release studies. No interaction was observed between zolpidem tartrate and excipients from the Fourier transform infrared spectroscopy and differential scanning calorimetry analysis. The results of all the formulations prepared were compared with reference product Stilnoct®. Optimized formulations showed release patterns that match the United States Pharmacopeia (USP) guidelines for zolpidem tartrate extended-release tablets. The mechanism of drug release was studied using different mathematical models, and the optimized formulation has shown Fickian diffusion. Accelerated stability studies were performed on the optimized formulation.

Single- and Multiple-dose Pharmacokinetics of a Lorcaserin Extended-release Tablet.

PubMed

Christopher, Ronald; Morgan, Mike; Ferry, Jim; Rege, Bhaskar; Tang, Yong; Kristensen, Allan; Shanahan, William

2016-10-01

Lorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration-approved, extended-release, 20-mg once-daily formulation. We performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions. Compared with lorcaserin IR, the T max after a single dose of lorcaserin extended-release was greater (median, 12 vs 3 hours), and the C max was 26% lower (38.8 vs 52.3 ng/mL). AUC data were bioequivalent for the 2 formulations in both single- and multiple-dose regimens, confirming no formulation effect on lorcaserin bioavailability. In fasted and fed conditions, T max after a single dose was identical (median, 12 hours), but C max was approximately 45% higher in the fed state (mean, 38.5 ng/mL fasted vs 56.1 ng/mL fed). However, at steady state, C max and AUC were determined to be bioequivalent between the fasted and fed states, indicating no clinically relevant food effect on the pharmacokinetic properties of lorcaserin extended-release. The safety profile was consistent between the 2 formulations. Overall, the results indicate that lorcaserin extended-release is a suitable once-daily alternative to the approved IR BID formulation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating tablets.

PubMed

Khan, Shagufta; Kataria, Prashant; Nakhat, Premchand; Yeole, Pramod

2007-06-22

The purpose of this research was to mask the intensely bitter taste of ondansetron HCl and to formulate a rapid-disintegrating tablet (RDT) of the taste-masked drug. Taste masking was done by complexing ondansetron HCl with aminoalkyl methacrylate copolymer (Eudragit EPO) in different ratios by the precipitation method. Drug-polymer complexes (DPCs) were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.2, and molecular property. Complex that did not release drug in SSF was considered taste-masked and selected for formulation RDTs. The complex with drug-polymer ratio of 8:2 did not show drug release in SSF; therefore, it was selected. The properties of tablets such as tensile strength, wetting time, water absorption ratio, in vitro disintegration time, and disintegration in the oral cavity were investigated to elucidate the wetting and disintegration characteristics of tablets. Polyplasdone XL-10 7% wt/wt gave the minimum disintegration time. Tablets of batch F4 containing spray-dried mannitol and microcrystalline cellulose in the ratio 1:1 and 7% wt/wt Polyplasdone XL-10 showed faster disintegration, within 12.5 seconds, than the marketed tablet (112 seconds). Good correlation between in vitro disintegration behavior and in the oral cavity was recognized. Taste evaluation of RDT in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value (0.5) ultimately reaching to 0 within 15 minutes, whereas ondansetron HCl was rated intensely bitter with a score of 3 for 10 minutes. Tablets of batch F4 also revealed rapid drug release (t(90), 60 seconds) in SGF compared with marketed formulation (t(90), 240 seconds; P < .01). Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity.

Varying efficacy of superdisintegrants in orally disintegrating tablets among different manufacturers.

PubMed

Mittapalli, R K; Qhattal, H S Sha; Lockman, P R; Yamsani, M R

2010-11-01

The main objective of the present study was to develop an orally disintegrating tablet formulation of domperidone and to study the functionality differences of superdisintegrants each obtained from two different sources on the tablet properties. Domperidone tablets were formulated with different superdisintegrants by direct compression. The effect of the type of superdisintegrant, its concentration and source was studied by measuring the in-vitro disintegration time, wetting time, water absorption ratios, drug release by dissolution and in-vivo oral disintegration time. Tablets prepared with crospovidone had lower disintegration times than tablets prepared from sodium starchglycolate and croscarmellose sodium. Formulations prepared with Polyplasdone XL, Ac-Di-Sol, and Explotab (D series) were better than formulations prepared with superdisintegrants obtained from other sources (DL series) which had longer disintegration times and lower water uptake ratios. The in-vivo disintegration time of formulation D-106 containing polyplasdone XL was significantly lower than that of the marketed formulation Domel-MT. The results from this study suggest that disintegration of orally disintegrating tablets is dependent on the nature of superdisintegrant, concentration in the formulation and its source. Even though a superdisintegrant meets USP standards there can be a variance among manufacturers in terms of performance. This is not only limited to in-vitro studies but carries over to disintegration times in the human population.

Development and evaluation of accelerated drug release testing methods for a matrix-type intravaginal ring.

PubMed

Externbrink, Anna; Eggenreich, Karin; Eder, Simone; Mohr, Stefan; Nickisch, Klaus; Klein, Sandra

2017-01-01

Accelerated drug release testing is a valuable quality control tool for long-acting non-oral extended release formulations. Currently, several intravaginal ring candidates designed for the long-term delivery of steroids or anti-infective drugs are being in the developing pipeline. The present article addresses the demand for accelerated drug release methods for these formulations. We describe the development and evaluation of accelerated release methods for a steroid releasing matrix-type intravaginal ring. The drug release properties of the formulation were evaluated under real-time and accelerated test conditions. Under real-time test conditions drug release from the intravaginal ring was strongly affected by the steroid solubility in the release medium. Under sufficient sink conditions that were provided in release media containing surfactants drug release was Fickian diffusion driven. Both temperature and hydro-organic dissolution media were successfully employed to accelerate drug release from the formulation. Drug release could be further increased by combining the temperature effect with the application of a hydro-organic release medium. The formulation continued to exhibit a diffusion controlled release kinetic under the investigated accelerated conditions. Moreover, the accelerated methods were able to differentiate between different prototypes of the intravaginal ring that exhibited different release profiles under real-time test conditions. Overall, the results of the present study indicate that both temperature and hydro-organic release media are valid parameters for accelerating drug release from the intravaginal ring. Variation of either a single or both parameters yielded release profiles that correlated well with real-time release. Copyright © 2016 Elsevier B.V. All rights reserved.

Mapping the pharmaceutical design space by amorphous ionic liquid strategies.

PubMed

Wiest, Johannes; Saedtler, Marco; Balk, Anja; Merget, Benjamin; Widmer, Toni; Bruhn, Heike; Raccuglia, Marc; Walid, Elbast; Picard, Franck; Stopper, Helga; Dekant, Wolfgang; Lühmann, Tessa; Sotriffer, Christoph; Galli, Bruno; Holzgrabe, Ulrike; Meinel, Lorenz

2017-12-28

Poor water solubility of drugs fuels complex formulations and jeopardizes patient access to medication. Simplifying these complexities we systematically synthesized a library of 36 sterically demanding counterions and mapped the pharmaceutical design space for amorphous ionic liquid strategies for Selurampanel, a poorly water soluble drug used against migraine. Patients would benefit from a rapid uptake after oral administration to alleviate migraine symptoms. Therefore, we probed the ionic liquids for the flux, supersaturation period and hygroscopicity leading to algorithms linking molecular counterion descriptors to predicted pharmaceutical outcome. By that, 30- or 800-fold improvements of the supersaturation period and fluxes were achieved as were immediate to sustained release profiles through structural counterions' optimization compared to the crystalline free acid of Selurampanel. Guided by ionic liquid structure, in vivo profiles ranged from rapid bioavailability and high maximal plasma concentrations to sustained patterns. In conclusion, the study outlined and predicted the accessible pharmaceutical design space of amorphous ionic liquid based and excipient-free formulations pointing to the enormous pharmaceutical potential of ionic liquid designs. Copyright © 2017 Elsevier B.V. All rights reserved.

Exploitation of novel gum Prunus cerasoides as mucoadhesive beads for a controlled-release drug delivery.

PubMed

Seelan, T Veenus; Kumari, Henry Linda Jeeva; Kishore, Narra; Selvamani, Palanisamy; Lalhlenmawia, H; Thanzami, K; Pachuau, Lalduhsanga; Ruckmani, Kandasamy

2016-04-01

The present study deals with the formulation of pH-sensitive mucoadhesive beads using natural gum isolated from Prunus cerasoides (PC) in combination with sodium alginate (SA) for the controlled release of diclofenac sodium (DS). PC and SA composite (PC-SA), DS loaded SA (DS-SA) and DS loaded PC-SA (DS-PC-SA) beads were prepared by ionotropic gelation method. The absence of interaction between DS and PC-SA was shown by FTIR, DSC and TGA analyses. The optimized DS-PC-SA formulation exhibited mucoadhesive property and the controlled release of DS was achieved 68% in 12h. The in vitro release kinetics follows zero order with anomalous diffusion mechanism. Therefore, the formulated mucoadhesive beads with the novel gum are preferable for the controlled release of DS by prolonging the residence time of the drug in the gastrointestinal tract, overcoming the problems associated with the immediate release dosage forms of DS. Copyright © 2016 Elsevier B.V. All rights reserved.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate.

PubMed

Thambavita, Dhanusha; Galappatthy, Priyadarshani; Mannapperuma, Uthpali; Jayakody, Lal; Cristofoletti, Rodrigo; Abrahamsson, Bertil; Groot, Dirk W; Langguth, Peter; Mehta, Mehul; Parr, Alan; Polli, James E; Shah, Vinod P; Dressman, Jennifer

2017-10-01

Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study. Copyright © 2017 American Pharmacists Association®. All rights reserved.

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

PubMed Central

Cho, Hyun-Jong; Park, Jin Woo; Yoon, In-Soo; Kim, Dae-Duk

2014-01-01

Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel. PMID:24531717

Formulation and Evaluation of Fixed-Dose Combination of Bilayer Gastroretentive Matrix Tablet Containing Atorvastatin as Fast-Release and Atenolol as Sustained-Release

PubMed Central

Dey, Sanjay; Chattopadhyay, Sankha; Mazumder, Bhaskar

2014-01-01

The objective of the present study was to develop bilayer tablets of atorvastatin and atenolol that are characterized by initial fast-release of atorvastatin in the stomach and comply with the release requirements of sustained-release of atenolol. An amorphous, solvent evaporation inclusion complex of atorvastatin with β-cyclodextrin, present in 1 : 3 (drug/cyclodextrin) molar ratio, was employed in the fast-release layer to enhance the dissolution of atorvastatin. Xanthan gum and guar gum were integrated in the sustained-release layer. Bilayer tablets composed of sustained-release layer (10% w/w of xanthan gum and guar gum) and fast-release layer [1 : 3 (drug/cyclodextrin)] showed the desired release profile. The atorvastatin contained in the fast-release layer showed an initial fast-release of more than 60% of its drug content within 2 h, followed by sustained release of the atenolol for a period of 12 h. The pharmacokinetic study illustrated that the fast absorption and increased oral bioavailability of atorvastatin as well as therapeutic concentration of atenolol in blood were made available through adoption of formulation strategy of bilayer tablets. It can be concluded that the bilayer tablets of atorvastatin and atenolol can be successfully employed for the treatment of hypertension and hypercholesterolemia together through oral administration of single tablet. PMID:24527446

Oleic acid derivative of polyethylenimine-functionalized proliposomes for enhancing oral bioavailability of extract of Ginkgo biloba.

PubMed

Zheng, Bin; Yang, Shuang; Fan, Chunyu; Bi, Ye; Du, Lin; Zhao, Lingzhi; Lee, Robert J; Teng, Lesheng; Teng, Lirong; Xie, Jing

2016-05-01

The present systematic study focused to investigate the oleic acid derivative of branched polyethylenimine (bPEI-OA)-functionalized proliposomes for improving the oral delivery of extract of Ginkgo biloba (GbE). The GbE proliposomes were prepared by a spray drying method at varying ratios of egg yolk phosphatidylcholine and cholesterol, and the optimized formulation was tailored with bPEI-OA to obtain bPEI-OA-functionalized proliposomes. The formulations were characterized for particle size, zeta potential, and entrapment efficiency. The release of GbE from proliposomes exhibited a sustained release. And the release rate was regulated by changing the amount of bPEI-OA on the proliposomes. The physical state characterization studies showed some interactions between GbE and other materials, such as hydrogen bonds and van der Waals forces during the process of preparation of proliposomes. The in situ single-pass perfusion and oral bioavailability studies were performed in rats. The significant increase in absorption constant (Ka) and apparent permeability coefficient (Papp) from bPEI-OA-functionalized proliposomes indicated the importance of positive charge for effective uptake across the gastrointestinal tract. The oral bioavailability of bPEI-OA-functionalized proliposomes was remarkable enhanced in comparison with control and conventional proliposomes. The bPEI-OA-functionalized proliposomes showed great potential of improving oral absorption of GbE as a suitable carrier.

Continuous twin screw granulation of controlled release formulations with various HPMC grades.

PubMed

Vanhoorne, V; Janssens, L; Vercruysse, J; De Beer, T; Remon, J P; Vervaet, C

2016-09-25

HPMC is a popular matrix former to formulate tablets with extended drug release. Tablets with HPMC are preferentially produced by direct compression. However, granulation is often required prior to tableting to overcome poor flowability of the formulation. While continuous twin screw granulation has been extensively evaluated for granulation of immediate release formulations, twin screw granulation of controlled release formulations including the dissolution behavior of the formulations received little attention. Therefore, the influence of the HPMC grade (viscosity and substitution degree) and the particle size of theophylline on critical quality attributes of granules (continuously produced via twin screw granulation) and tablets was investigated in the current study. Formulations with 20 or 40% HPMC, 20% theophylline and lactose were granulated with water at fixed process parameters via twin screw granulation. The torque was influenced by the viscosity and substitution degree of HPMC, but was not a limiting factor for the granulation process. An optimal L/S ratio was selected for each formulation based on the granule size distribution. The granule size distributions were influenced by the substitution degree and concentration of HPMC and the particle size of theophylline. Raman and UV spectroscopic analysis on 8 sieve fractions of granules indicated an inhomogeneous distribution of theophylline over the size fractions. However, this phenomenon was not correlated with the hydration rate or viscosity of HPMC. Controlled release of theophylline could be obtained over 24h with release profiles close to zero-order. The release of theophylline could be tailored via selection of the substitution degree and viscosity of HPMC. Copyright © 2016 Elsevier B.V. All rights reserved.

Three Newly Approved Analgesics: An Update

PubMed Central

Saraghi, Mana; Hersh, Elliot V.

2013-01-01

Since 2008, three new analgesic entities, tapentadol immediate release (Nucynta) diclofenac potassium soft gelatin capsules (Zipsor), and bupivacaine liposome injectable suspension (EXPAREL) were granted US Food and Drug Administration (FDA) approval to treat acute pain. Tapentadol immediate-release is a both a mu-opioid agonist and a norepinephrine reuptake inhibitor, and is indicated for the treatment of moderate to severe pain. Diclofenac potassium soft gelatin capsules are a novel formulation of diclofenac potassium, which is a nonsteroidal anti-inflammatory drug (NSAID), and its putative mechanism of action is through inhibition of cyclooxygenase enzymes. This novel formulation of diclofenac allows for improved absorption at lower doses. Liposomal bupivacaine is a new formulation of bupivacaine intended for single-dose infiltration at the surgical site for postoperative analgesia. Bupivacaine is slowly released from this liposomal vehicle and can provide prolonged analgesia at the surgical site. By utilizing NSAIDs and local anesthetics to decrease the transmission of afferent pain signals, less opioid analgesics are needed to achieve analgesia. Since drug-related adverse events are frequently dose related, lower doses from different drug classes may be employed to reduce the incidence of adverse effects, while producing synergistic analgesia as part of a multimodal analgesic approach to acute pain. PMID:24423420

Formulation and evaluation of sublingual tablets containing Sumatriptan succinate

PubMed Central

Prajapati, Shailesh T; Patel, Parth B; Patel, Chhagan N

2012-01-01

Objective: Sumatriptan succinate is a selective 5-hydroxytryptamine-1 receptor agonist effective in the acute treatment of migraine headaches, having low bioavailability of about 15% orally due to first-pass metabolism. The purpose of this research was to mask the intensely bitter taste of Sumatriptan succinate and to formulate fast-acting, taste-masked sublingual tablet formulation. Materials and Methods: Taste masking was performed by solid dispersion method with mannitol and ion exchange with Kyron T 114 because it releases the drug in salivary pH. The resultant batches were evaluated for in-vivo taste masking as well compatability study (Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC)). For a better feel in the mouth, menthol and sweetener Na saccharine were added to the tablet formulation. The tablets were prepared by direct compression and evaluated for weight variation, thickness, friability, drug content, hardness, disintegration time, wetting time, in vitro drug release, and in vitro permeation study. Results and Discussion: Optimized batches disintegrated in vitro within 28-34 s. Maximum drug release could be achieved with in 10 min for the solid dispersion batches and 14-15 min for the ion-exchange batches with Kyron T 114. The optimized tablet formulation showed better taste and the formulated sublingual tablets may act as a potential alternate for the Sumatriptan succinate oral tablet. Conclusion: Sumatriptan succinate can be successfully taste-masked by both the solid dispersion method using mannitol by the melting method and Ion exchange resin with Kyron T114. It was also concluded that prepared formulation improve bioavailability by prevention of first pass metabolism. PMID:23373008

A Phase 1 Pharmacokinetic Study of Cysteamine Bitartrate Delayed-Release Capsules Following Oral Administration with Orange Juice, Water, or Omeprazole in Cystinosis.

PubMed

Armas, Danielle; Holt, Robert J; Confer, Nils F; Checani, Gregg C; Obaidi, Mohammad; Xie, Yuli; Brannagan, Meg

2018-02-01

Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR. This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences. All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC 0-t , AUC 0-∞ , and C max were all within the 80-125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated. Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water). Horizon Pharma, Inc.

Microencapsulation Approach for Orally Extended Delivery of Glipizide: In vitro and in vivo Evaluation

PubMed Central

Abdelbary, A.; El-gendy, N. A.; Hosny, A.

2012-01-01

Glipizide is an effective antidiabetic agent, however, it suffers from relatively short biological half-life. To solve this encumbrance, it is a prospective candidate for fabricating glipizide extended release microcapsules. Microencapsulation of glipizde with a coat of alginate alone or in combination with chitosan or carbomer 934P was prepared employing ionotropic gelation process. The prepared microcapsules were evaluated in vitro by microscopical examination, determination of the particle size, yield and microencapsulation efficiency. The filled capsules were assessed for content uniformity and drug release characteristics. Stability study of the optimised formulas was carried out at three different temperatures over 12 weeks. In vivo bioavailability study and hypoglycemic activity of C9 microcapsules were done on albino rabbits. All formulas achieved high yield, microencapsulation efficiency and extended t1/2. C9 and C19 microcapsules attained the most optimised results in all tests and complied with the dissolution requirements for extended release dosage forms. These two formulas were selected for stability studies. C9 exhibited longer shelf-life and hence was chosen for in vivo studies. C9 microcapsules showed an improvement in the drug bioavailability and significant hypoglycemic activity compared to immediate release tablets (Minidiab® 5 mg). The optimised microcapsule formulation developed was found to produce extended antidiabetic activity. PMID:23626387

Can lipid nanoparticles improve intestinal absorption?

PubMed

Mendes, M; Soares, H T; Arnaut, L G; Sousa, J J; Pais, A A C C; Vitorino, C

2016-12-30

Lipid nanoparticles and their multiple designs have been considered appealing nanocarrier systems. Bringing the benefits of these nanosystems together with conventional coating technology clearly results in product differentiation. This work aimed at developing an innovative solid dosage form for oral administration based on tableting nanostructured lipid carriers (NLC), coated with conventional polymer agents. NLC dispersions co-encapsulating olanzapine and simvastatin (Combo-NLC) were produced by high pressure homogenization, and evaluated in terms of scalability, drying procedure, tableting and performance from in vitro release, cytotoxicity and intestinal permeability stand points. Factorial design indicated that the scaling-up of the NLC production is clearly feasible. Spray-drying was the method selected to obtain dry particles, not only because it consists of a single step procedure, but also because it facilitates the coating process of NLC with different polymers. Modified NLC formulations with the polymers allowed obtaining distinct release mechanisms, comprising immediate, delayed and prolonged release. Sureteric:Combo-NLC provided a low cytotoxicity profile, along with a ca. 12-fold OL/3-fold SV higher intestinal permeability, compared to those obtained with commercial tablets. Such findings can be ascribed to drug protection and control over release promoted by NLC, supporting them as a versatile platform able to be modified according to the intended needs. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparation, characterization and in vitro evaluation of microemulsion of raloxifene hydrochloride.

PubMed

Golmohammadzadeh, Shiva; Farhadian, Nafiseh; Biriaee, Amir; Dehghani, Faranak; Khameneh, Bahman

2017-10-01

Raloxifene hydrochloride (RLX) is a selective estrogen receptor modulator which is orally used for treatment of osteoporosis and prevention of breast cancer. The drug has low aqueous solubility and bioavailability. The aim of the present study is to formulate and characterize oil-in-water microemulsion systems for oral delivery of RLX. To enhance the drug aqueous solubility, microemulsion based on sesame oil was prepared. Sesame oil and Tween 80 were selected as the drug solvent oil and surfactant, respectively. In the first and second formulations, Edible glycerin and Span 80 were applied as co-surfactant, respectively. Pseudo-ternary phase diagrams showed that the best surfactant/co-surfactant ratios in the first and second formulations were 4:1 and 9:1, respectively. The particle size of all free drug-loaded and drug loaded samples were in the range of 31.25 ± 0.3 nm and 60.9 ± 0.1 nm, respectively. Electrical conductivity coefficient and refractive index of all microemulsion samples confirmed the formation of oil-in-water type of microemulsion. In vitro drug release profile showed that after 24 hours, 46% and 63% of the drug released through the first formulation in 0.1% (w/v) Tween 80 in distilled water as a release medium and phosphate buffer solution (PBS) at pH = 5.5, respectively. These values were changed to 57% and 98% for the second formulation. Results confirmed that the proposed microemulsion system containing RLX could improve and control the drug release profile in comparison to conventional dosage form.

Pharmacokinetics of a slow-release formulation of soybean isoflavones in healthy postmenopausal women.

PubMed

Setchell, Kenneth D R; Brzezinski, Amnon; Brown, Nadine M; Desai, Pankaj B; Melhem, Murad; Meredith, Trevor; Zimmer-Nechimias, Linda; Wolfe, Brian; Cohen, Yoram; Blatt, Yoav

2005-03-23

Pharmacokinetic studies of soybean isoflavones have shown that following oral ingestion, the two major isoflavones, daidzin and genistin, are hydrolyzed in the intestine, rapidly absorbed into the peripheral circulation, and eliminated from the body with a terminal half-life of 7-8 h. These characteristics make maintenance of steady-state plasma isoflavone concentrations difficult to attain unless there is repeated daily ingestion of foods or supplements containing isoflavones. In an attempt to sustain more constant plasma isoflavone concentrations, a new slow-release formulation of a soybean isoflavone extract was prepared by microencapsulation with a mixture of hydroxypropylcellulose and ethylcellulose to alter its dissolution characteristics. In vitro experiments confirmed slow aqueous dissolution of isoflavones from this formulation when compared with the conventional isoflavone extract. The pharmacokinetics of this slow-release isoflavone extract was studied in 10 healthy postmenopausal women after oral administration of a single capsule containing the equivalent of 22.3 mg of genistein and 7.47 mg of daidzein expressed as aglycons. A comparison of the key pharmacokinetic parameters obtained in this study with those established in extensive studies performed previously in this laboratory indicated that the mean residence time of genistein and daidzein increased 2-fold with microencapsulation. These findings are indicative of a decreased rate of absorption, consistent with the observed slow in vitro dissolution rate. These findings show that it is feasible to employ polymer matrices that slow the aqueous dissolution for preparing sustained-release formulations of soy isoflavones. Further studies to optimize such formulations are warranted.

A new amoxicillin/clavulanate therapeutic system: preparation, in vitro and pharmacokinetic evaluation.

PubMed

Kerc, Janez; Opara, Jerneja

2007-04-20

A new peroral amoxicillin/clavulanate therapeutic system composed of immediate release tablet and controlled release floating capsule was developed and evaluated by in vivo bioavailability study. Pharmacokinetic (PK) parameters for amoxicillin and clavulanic acid of the new therapeutic systems: AUCt, AUCi, (AUCt/AUCi), Cmax, Tmax, kel, T(1/2) and additionally for amoxicillin T(4) and T(2) were calculated from the plasma levels. The study confirmed enhanced pharmacokinetic parameters of a newly developed therapeutic system containing 1500 mg of amoxicillin and 125 mg of clavulanic acid. Prolonged time over MIC of amoxicillin in relation to a regular immediate release amoxicillin/clavulanate formulation was confirmed.

Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation, optimization and in vivo evaluation.

PubMed

Nooli, Mounika; Chella, Naveen; Kulhari, Hitesh; Shastri, Nalini R; Sistla, Ramakrishna

2017-04-01

Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery. Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro. The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration. In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.

Quality evaluation of extemporaneous delayed-release liquid formulations of lansoprazole.

PubMed

Melkoumov, Alexandre; Soukrati, Amina; Elkin, Igor; Forest, Jean-Marc; Hildgen, Patrice; Leclair, Grégoire

2011-11-01

The quality attributes of extemporaneous delayed-release liquid formulations of lansoprazole for oral administration were evaluated. A novel liquid formulation (3 mg/mL) of Prevacid FasTab in an Ora-Blend vehicle was prepared and compared with the Prevacid FasTab 30 mg and Prevacid-sodium bicarbonate 1 M formulation (3 mg/mL). The latter formulation was combined with hydrochloric acid 0.1 N, and the remaining lansoprazole content was assayed by high-performance liquid chromatography (HPLC). A batch of delayed-release liquid formulation was prepared to evaluate content uniformity. For content assay, three samples were prepared for each evaluated condition and each sample was analyzed in triplicate by HPLC. The lansoprazole in the sodium bicarbonate formulation was extensively degraded by quantities of hydrochloric acid 0.1 N in excess of 100 mL. Storage time and temperature had a significant effect on lansoprazole stability in the Ora-Blend formulation. The drug remained stable for seven days when the formulation was stored at 4.5-5.5 °C, but storage at 21-22 °C or the reduction of pH with citric acid accelerated lansoprazole degradation. The amount of lansoprazole released from the Ora-Blend formulation during the buffer stage of the dissolution test decreased with increases in formulation storage time, in formulation storage temperature, and in the amount of lansoprazole released and degraded during the acid stage of the test. An extemporaneous formulation consisting of lansoprazole microgranules in Ora-Blend maintained acceptable quality attributes when stored for three days at 4.5-5.5 °C.

Preparation and in vitro and in vivo evaluation of HupA PLGA microsphere.

PubMed

Ye, Liang; Fu, Fenghua; Liu, Wanhui; Sun, Kaoxiang; Li, Youxin; He, Jie; Yu, Xin; Yu, Pengfei; Tian, Jingwei

2013-03-01

Acetylcholinesterase inhibitors (AChEIs), including Huperzine A (HupA), have been the mainstay of treatment for Alzheimer's disease (AD). However, AChEIs can cause gastrointestinal side effects, which has been related to the high Cmax and short tmax after oral administration. Clinical trials have verified that extended-release formulation with lower Cmax and prolonged tmax, such as rivastigmine patch, could perform a similar efficacy with significantly improved tolerability compared with the oral formulations. In this study, we developed an extended-release microspheres formulation of HupA (called as HAM) with poly(lactide-co-glycolide) (PLGA) as drug carrier. HAM has showed the loading rate as 1.35% (w/w) and yielded 42% with mean particle size at 72.6 μm. In vitro and in vivo pharmacokinetics studies have showed that HAM produced a relatively smooth and continuous drug concentration in 14 days. Furthermore, in vivo pharmacokinetics data have demonstrated that the Cmax was lower and the tmax was considerably later in single intramuscular administration of HAM (1,000 μg/kg) than the counterparts in single intragastric administration of HAT (75 μg/kg/d). Meanwhile, HAM has performed a continuous inhibition to brain AChE activity in normal rats and improvement of memory deficit in Aβ1-40 i.c.v. infused AD rat model for 14 days. The results have suggested that HAM has performed good extended-release properties and good prolonged pharmacological efficacy in vivo in the 2-week period, and could exert a similar efficacy with significantly lowered gastrointestinal side effects as compared with oral formulation.

Synthesis and characterization of pH-sensitive drinkable nanoparticles for oral delivery of ibuprofen.

PubMed

Agostini, Azzurra; Capasso Palmiero, Umberto; Barbieri, Sara D A; Lupi, Monica; Moscatelli, Davide

2018-06-01

Ibuprofen (IBU) is a widespread drug used to treat both acute and chronic disorders. It is generally taken orally but the free drug can induce the irritation of the gastric mucosa due to its acid nature. In literature, different approaches have been adopted to prevent the release in the stomach, such as physical entrapment with film-coated tablets and drug-conjugates. Nevertheless, these solutions have many disadvantages, including the fast release of the drug and the difficulty to swallow the tablet, especially for children who may vomit or refuse the tablet. For this reason, in this work, novel formulations are proposed that do not require the encapsulation of the drug into a solid form and, in turn, their assumption as a pill. IBU has been linked to different types of methacrylates via ester bond in order to produce pH-responsive macromolecular monomers. The novelty is related to the use of these drug-conjugates macromonomer for the production of nanoparticles (NPs) via emulsion polymerization (EP), using water as solvent. The final emulsion is able to load up to 30 mg ml -1 of IBU, so less than 10 ml is required to be assumed to reach the minimum therapeutic dose of the drug (200 mg). Finally, the release of IBU from these novel drinkable formulations has been investigated in the gastric and intestinal simulated fluids to show the preferential release of IBU from the NPs in basic conditions. A comparison with an existing oral suspension has been performed to highlight the slower release in acid environment of these new formulations. Afterwards, the IBU loaded NPs were tested in vitro showing lower toxicity compared to the free drug.

Synthesis and characterization of pH-sensitive drinkable nanoparticles for oral delivery of ibuprofen

NASA Astrophysics Data System (ADS)

Agostini, Azzurra; Capasso Palmiero, Umberto; Barbieri, Sara D. A.; Lupi, Monica; Moscatelli, Davide

2018-06-01

Ibuprofen (IBU) is a widespread drug used to treat both acute and chronic disorders. It is generally taken orally but the free drug can induce the irritation of the gastric mucosa due to its acid nature. In literature, different approaches have been adopted to prevent the release in the stomach, such as physical entrapment with film-coated tablets and drug-conjugates. Nevertheless, these solutions have many disadvantages, including the fast release of the drug and the difficulty to swallow the tablet, especially for children who may vomit or refuse the tablet. For this reason, in this work, novel formulations are proposed that do not require the encapsulation of the drug into a solid form and, in turn, their assumption as a pill. IBU has been linked to different types of methacrylates via ester bond in order to produce pH-responsive macromolecular monomers. The novelty is related to the use of these drug-conjugates macromonomer for the production of nanoparticles (NPs) via emulsion polymerization (EP), using water as solvent. The final emulsion is able to load up to 30 mg ml‑1 of IBU, so less than 10 ml is required to be assumed to reach the minimum therapeutic dose of the drug (200 mg). Finally, the release of IBU from these novel drinkable formulations has been investigated in the gastric and intestinal simulated fluids to show the preferential release of IBU from the NPs in basic conditions. A comparison with an existing oral suspension has been performed to highlight the slower release in acid environment of these new formulations. Afterwards, the IBU loaded NPs were tested in vitro showing lower toxicity compared to the free drug.

Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy.

PubMed

Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Fadaeinasab, Mehran; Khaing, Si Lay; Chung, Lip Yong; Mohamad Haron, Didi Erwandi B; Noordin, Mohamed Ibrahim

2017-01-01

This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl), using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP):xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. 153 Sm 2 O 3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time ( T max ) at which the maximum concentration of metformin HCl in the blood ( C max ) was observed, and it was extended four times for the gastroretentive formulation in comparison with the formulation without polymers. C max and the half-life were found to be within an acceptable range. It is therefore concluded that MKP3 is the optimal formulation for sustained release of metformin HCl over a period of 12 h as a result of its floating properties in the gastric region.

Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy

PubMed Central

Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Fadaeinasab, Mehran; Khaing, Si Lay; Chung, Lip Yong; Mohamad Haron, Didi Erwandi B; Noordin, Mohamed Ibrahim

2017-01-01

This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl), using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP):xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. 153Sm2O3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time (Tmax) at which the maximum concentration of metformin HCl in the blood (Cmax) was observed, and it was extended four times for the gastroretentive formulation in comparison with the formulation without polymers. Cmax and the half-life were found to be within an acceptable range. It is therefore concluded that MKP3 is the optimal formulation for sustained release of metformin HCl over a period of 12 h as a result of its floating properties in the gastric region. PMID:28031701

IRIS Assessment Plan for Ammonia and Ammonium Salts Noncancer Oral (Scoping and Problem Formulation Materials)

EPA Science Inventory

In April 2018, EPA released the draft IRIS Assessment Plan for Ammonia and Ammonium Salts Noncancer Oral. The IAP communicates to the public the plan for assessing each individual chemical and includes summary information on the IRIS Program’s scoping and initial proble...

IRIS Assessment Plan for Ammonia and Ammonium Salts Noncancer Oral (Scoping and Problem Formulation Materials)

EPA Science Inventory

In April 2018, EPA released the draft IRIS Assessment Plan for Ammonia and Ammonium Salts Noncancer Oral. An IRIS Assessment Plan (IAP) communicates to the public the plan for assessing each individual chemical and includes summary information on the IRIS Program’s sco...

Soy Protein Microparticles for Enhanced Oral Ibuprofen Delivery: Preparation, Characterization, and In Vitro Release Evaluation.

PubMed

Anaya Castro, Maria Antonieta; Alric, Isabelle; Brouillet, Fabien; Peydecastaing, Jérôme; Fullana, Sophie Girod; Durrieu, Vanessa

2018-04-01

The objective of this work was to evaluate soy protein isolate (SPI) and acylated soy protein (SPA) as spray-drying encapsulation carriers for oral pharmaceutical applications. SPI acylation was performed by the Schotten-Baumann reaction. SPA, with an acylation rate of 41%, displayed a decrease in solubility in acidic conditions, whereas its solubility was unaffected by basic conditions. The drug encapsulation capacities of both SPI and SPA were tested with ibuprofen (IBU) as a model poorly soluble drug. IBU-SPI and IBU-SPA particles were obtained by spray-drying under eco-friendly conditions. Yields of 70 to 87% and microencapsulation efficiencies exceeding 80% were attained for an IBU content of 20 to 40% w/w, confirming the excellent microencapsulation properties of SPI and the suitability of the chemical modification. The in vitro release kinetics of IBU were studied in simulated gastrointestinal conditions (pH 1.2 and pH 6.8, 37°C). pH-sensitive release patterns were observed, with an optimized low rate of release in simulated gastric fluid for SPA formulations, and a rapid and complete release in simulated intestinal fluid for both formulations, due to the optimal pattern of pH-dependent solubility for SPA and the molecular dispersion of IBU in soy protein. These results demonstrate that SPI and SPA are relevant for the development of pH-sensitive drug delivery systems for the oral route.

Evaluation of mechanical and rheological properties of metronidazole gel as local delivery system.

PubMed

Jelvehgari, Mitra; Montazam, Hassan

2011-06-01

Rosacea is a chronic multifactorial vascular skin disorder that affects about 10 percent of the general population. Metronidazole is an effective antibiotic in the treatment of moderate-to severe rosacea. Metronidazole is a suitable drug in cases of resistance to tetracycline or erythromycin, but it has also been shown that oral metronidazole may increase the side effects (e.g., peripheral neuropathy). Oral metronidazole should not be used for more than three months, and hence topical metronidazole gel is the best therapeutic choice in rosacea (especially during pregnancy). This study examined the mechanical (adhesiveness, cohesiveness, extrudability, spreadability, homogeneity) and rheological (viscosity), skin irritant and drug release properties of different metronidazole gel formulations that contain anionic emulsifying wax, glycerin and lactic acid in different proportions. The release studies were conducted using Franz diffusion cells and Silastic membrane as a barrier. The results indicated that gel compressibility, hardness, and adhesiveness, are the factors that influence the ease of gel removal from the container, ease of gel application onto the mucosal membrane, and gel bioadhesion. The findings showed that there exists a strong negative correlation between the spreadability of a formulation and its cohesiveness, the spreadability of a formulation is inversely proportional to its cohesiveness. However, sorbitol solution (70%) concentration was not significantly correlated with drug release. In addition, drug release was significantly reduced as the concentration of anionic emulsifying wax increased and the concentration of lactic acid decreased. The maximum metronidazole release was achieved at a pH of 4-6. Data obtained from in vitro release studies were fitted to various kinetic models and high correlation was obtained in the Higuchi and first order models. The results showed that all the gel formulations showed good extrudability, viscosity, cohesiveness, homogeneity and spreadability.

Film coatings for oral pulsatile release.

PubMed

Maroni, Alessandra; Zema, Lucia; Loreti, Giulia; Palugan, Luca; Gazzaniga, Andrea

2013-12-05

Pulsatile delivery is generally intended as a release of the active ingredient that is delayed for a programmable period of time to meet particular chronotherapeutic needs and, in the case of oral administration, also target distal intestinal regions, such as the colon. Most oral pulsatile delivery platforms consist in coated formulations wherein the applied polymer serves as the release-controlling agent. When exposed to aqueous media, the coating initially performs as a protective barrier and, subsequently, undergoes a timely failure based on diverse mechanisms depending on its physico-chemical and formulation characteristics. Indeed, it may be ruptured because of the gradual expansion of the core, swell and/or erode due to the glassy-rubbery polymer transition or become permeable thus allowing the drug molecules to diffuse outwards. Otherwise, when the coating is a semipermeable membrane provided with one or more orifices, the drug is released through the latter as a result of an osmotic water influx. The vast majority of pulsatile delivery systems described so far have been prepared by spray-coating, which offers important versatility and feasibility advantages over other techniques such as press- and dip-coating. In the present article, the design, manufacturing and performance of spray-coated pulsatile delivery platforms is thus reviewed. Copyright © 2013 Elsevier B.V. All rights reserved.

Hydroxychloroquine niosomes: a new trend in topical management of oral lichen planus.

PubMed

Bendas, Ehab R; Abdullah, Hamoud; El-Komy, Mohamed H M; Kassem, Mohamed A A

2013-12-31

The work aimed at studying a novel topical niosomal gel formulation of hydroxychloroquine for the management of oral lichen planus. Niosomes have been reported as conceivable vesicles to deliver drug molecules to the desired mucous membrane or skin layers. Hydroxychloroquine niosomes were designed using different methods of preparation. Tween 20 and cholesterol in molar ratio (1:0.5) were used. The prepared systems were characterized for entrapment efficiency, particle size and in vitro drug release. Different factors affecting the encapsulation of hydroxychloroquine in niosomes were studied vs. varying the type of surfactant, the cholesterol:surfactant molar ratio and the amount of the drug. The selected noisome formulation was dispersed in different gel formulations and evaluated according to the in vitro drug release and the physical stability. The results showed that the type of surfactant, cholesterol ratio and incorporated amount of drug altered the entrapment efficiency and the in vitro release of hydroxychloroquine from niosomes. The optimum formulation was prepared by reverse phase evaporation technique using Brij 98:cholesterol molar ratio (1:1.5) and containing 20mg of hydroxychloroquine and incorporated in 20% w/v Pluronic F-127 gel. A double-blind, controlled clinical study was performed using two groups of patients. Group A (n=11) who received hydroxychloroquine niosomal gel formulation, one application-a-day over 4 months showed 64.28% reduction in the size of lesions and the average score of pain was reduced from "4" to "1". Compared to placebo group B (n=5), who showed only 3.94% reduction in the lesion size and the average score of pain was remained "3". Our results suggest that these niosomal formulations could constitute a promising approach for the topical treatment of oral lichen planus in short time with less side effects and no recurrence after stopping the treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

Application of a Compact Magnetic Resonance Imaging System with 1.5 T Permanent Magnets to Visualize Release from and the Disintegration of Capsule Formulations in Vitro and in Vivo.

PubMed

Takeshita, Keizo; Okazaki, Shoko; Shinada, Kyosuke; Shibamoto, Yuma

2017-01-01

Although magnetic resonance imaging (MRI) has potential in assessments of formulations, few studies have been conducted because of the size and expense of the instrument. In the present study, the processes of in vitro and in vivo release in a gelatin capsule formulation model were visualized using a compact MRI system with 1.5 T permanent magnets, which is more convenient than the superconducting MRI systems typically used for clinical and experimental purposes. A Gd-chelate of diethylenetriamine-N,N,N',N″,N″-pentaacetic acid, a contrast agent that markedly enhances proton signals via close contact with water, was incorporated into capsule formulations as a marker compound. In vitro experiments could clearly demonstrate the preparation-dependent differences in the release/disintegration of the formulations. In some preparations, the penetration of water into the formulation and generation of bubbles in the capsule were also observed prior to the disintegration of the formulation. When capsule formulations were orally administered to rats, the release of the marker into the stomach and its transit to the duodenum were visualized. These results strongly indicate that the compact MRI system is a powerful tool for pharmaceutical studies.

Solid lipid nanoparticles for enhancing vinpocetine's oral bioavailability.

PubMed

Luo, YiFan; Chen, DaWei; Ren, LiXiang; Zhao, XiuLi; Qin, Jing

2006-08-10

An ultrasonic-solvent emulsification technique was adopted to prepare vinpocetine loaded Glyceryl monostearate (GMS) nanodispersions with narrow size distribution. To increase the lipid load the process was conducted at 50 degrees C, and in order to prepare nanoparticle using an ultrasonic-solvent emulsification technique. The mean particle size and droplet size distribution, drug loading capacity, drug entrapment efficiency (EE%), zeta potential, and long-term physical stability of the SLNs were investigated in detail respectively. Drug release from two sorts of VIN-SLN was studied using a dialysis bag method. A pharmacokinetic study was conducted in male rats after oral administration of 10 mg kg(-1) VIN in different formulations, it was found that the relative bioavailability of VIN in SLNs was significantly increased compared with that of the VIN solution. The amount of surfactant also had a marked effect on the oral absorption of VIN with SLN formulations. The absorption mechanism of the SLN formulations was also discussed. These results indicated that VIN absorption is enhanced significantly by employing SLN formulations. SLNs offer a new approach to improve the oral bioavailability of poorly soluble drugs.

A Comparison between Use of Spray and Freeze Drying Techniques for Preparation of Solid Self-Microemulsifying Formulation of Valsartan and In Vitro and In Vivo Evaluation

PubMed Central

Singh, Sanjay Kumar; Vuddanda, Parameswara Rao; Singh, Sanjay; Srivastava, Anand Kumar

2013-01-01

The objective of the present study was to develop self micro emulsifying formulation (SMEF) of valsartan to improve its oral bioavailability. The formulations were screened on the basis of solubility, stability, emulsification efficiency, particle size and zeta potential. The optimized liquid SMEF contains valsartan (20% w/w), Capmul MCM C8 (16% w/w), Tween 80 (42.66% w/w) and PEG 400 (21.33% w/w) as drug, oil, surfactant and co-surfactant, respectively. Further, Liquid SMEF was adsorbed on Aerosol 200 by spray and freeze drying methods in the ratio of 2 : 1 and transformed into free flowing powder. Both the optimized liquid and solid SMEF had the particle size <200 nm with rapid reconstitution properties. Both drying methods are equally capable for producing stable solid SMEF and immediate release of drug in in vitro and in vivo conditions. However, the solid SMEF produced by spray drying method showed high flowability and compressibility. The solid state characterization employing the FTIR, DSC and XRD studies indicated insignificant interaction of drug with lipid and adsorbed excipient. The relative bioavailability of solid SMEF was approximately 1.5 to 3.0 folds higher than marketed formulation and pure drug. Thus, the developed solid SMEF illustrates an alternative delivery of valsartan as compared to existing formulations with improved bioavailability. PMID:23971048

Optimized zein nanospheres for improved oral bioavailability of atorvastatin

PubMed Central

Hashem, Fahima M; Al-Sawahli, Majid M; Nasr, Mohamed; Ahmed, Osama AA

2015-01-01

Background This work focuses on the development of atorvastatin utilizing zein, a natural, safe, and biocompatible polymer, as a nanosized formulation in order to overcome the poor oral bioavailability (12%) of the drug. Methods Twelve experimental runs of atorvastatin–zein nanosphere formula were formulated by a liquid–liquid phase separation method according to custom fractional factorial design to optimize the formulation variables. The factors studied were: weight % of zein to atorvastatin (X1), pH (X2), and stirring time (X3). Levels for each formulation variable were designed. The selected dependent variables were: mean particle size (Y1), zeta potential (Y2), drug loading efficiency (Y3), drug encapsulation efficiency (Y4), and yield (Y5). The optimized formulation was assayed for compatibility using an X-ray diffraction assay. In vitro diffusion of the optimized formulation was carried out. A pharmacokinetic study was also done to compare the plasma profile of the atorvastatin–zein nanosphere formulation versus atorvastatin oral suspension and the commercially available tablet. Results The optimized atorvastatin–zein formulation had a mean particle size of 183 nm, a loading efficiency of 14.86%, and an encapsulation efficiency of 29.71%. The in vitro dissolution assay displayed an initial burst effect, with a cumulative amount of atorvastatin released of 41.76% and 82.3% after 12 and 48 hours, respectively. In Wistar albino rats, the bioavailability of atorvastatin from the optimized atorvastatin–zein formulation was 3-fold greater than that from the atorvastatin suspension and the commercially available tablet. Conclusion The atorvastatin–zein nanosphere formulation improved the oral delivery and pharmacokinetic profile of atorvastatin by enhancing its oral bioavailability. PMID:26150716

Formulation, release characteristics, and bioavailability study of gastroretentive floating matrix tablet and floating raft system of Mebeverine HCl

PubMed Central

El Nabarawi, Mohamed A; Teaima, Mahmoud H; Abd El-Monem, Rehab A; El Nabarawy, Nagla A; Gaber, Dalia A

2017-01-01

To prolong the residence time of dosage forms within the gastrointestinal tract until all drug is released at the desired rate is one of the real challenges for oral controlled-release drug delivery systems. This study was designed to develop a controlled-release floating matrix tablet and floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for their floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the optimum matrix tablet, raft system formula, and marketed Duspatalin® 200 mg retard as reference were studied in beagle dogs. The optimized tablet formula (FT-10) and raft system formula (FRS-11) were found to float within 34±5 sec and 15±7 sec, respectively, and both remain buoyant over a period of 12 h in simulated gastric fluid. FT-10 (Compritol/HPMC K100M 1:1) showed the slowest drug release among all prepared tablet formulations, releasing about 80.2% of MbH over 8 h. In contrast, FRS-11 (Sodium alginate 3%/HPMC K100M 1%/Precirol 2%) had the greatest retardation, providing sustained release of 82.1% within 8 h. Compared with the marketed MbH product, the Cmax of FT-10 was almost the same, while FRS-11 maximum concentration was higher. The tmax was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10, and FRS-11, respectively. In addition, the oral bioavailability experiment showed that the relative bioavailability of the MbH was 104.76 and 116.01% after oral administration of FT-10 and FRS-11, respectively, compared to marketed product. These results demonstrated that both controlled-released floating matrix tablet and raft system would be promising gastroretentive delivery systems for prolonging drug action. PMID:28435220

Formulation, release characteristics, and bioavailability study of gastroretentive floating matrix tablet and floating raft system of Mebeverine HCl.

PubMed

El Nabarawi, Mohamed A; Teaima, Mahmoud H; Abd El-Monem, Rehab A; El Nabarawy, Nagla A; Gaber, Dalia A

2017-01-01

To prolong the residence time of dosage forms within the gastrointestinal tract until all drug is released at the desired rate is one of the real challenges for oral controlled-release drug delivery systems. This study was designed to develop a controlled-release floating matrix tablet and floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for their floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the optimum matrix tablet, raft system formula, and marketed Duspatalin ® 200 mg retard as reference were studied in beagle dogs. The optimized tablet formula (FT-10) and raft system formula (FRS-11) were found to float within 34±5 sec and 15±7 sec, respectively, and both remain buoyant over a period of 12 h in simulated gastric fluid. FT-10 (Compritol/HPMC K100M 1:1) showed the slowest drug release among all prepared tablet formulations, releasing about 80.2% of MbH over 8 h. In contrast, FRS-11 (Sodium alginate 3%/HPMC K100M 1%/Precirol 2%) had the greatest retardation, providing sustained release of 82.1% within 8 h. Compared with the marketed MbH product, the C max of FT-10 was almost the same, while FRS-11 maximum concentration was higher. The t max was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10, and FRS-11, respectively. In addition, the oral bioavailability experiment showed that the relative bioavailability of the MbH was 104.76 and 116.01% after oral administration of FT-10 and FRS-11, respectively, compared to marketed product. These results demonstrated that both controlled-released floating matrix tablet and raft system would be promising gastroretentive delivery systems for prolonging drug action.

Development of In Vitro-In Vivo Correlation for Amorphous Solid Dispersion Immediate-Release Suvorexant Tablets and Application to Clinically Relevant Dissolution Specifications and In-Process Controls.

PubMed

Kesisoglou, Filippos; Hermans, Andre; Neu, Colleen; Yee, Ka Lai; Palcza, John; Miller, Jessica

2015-09-01

Although in vitro-in vivo correlations (IVIVCs) are commonly pursued for modified-release products, there are limited reports of successful IVIVCs for immediate-release (IR) formulations. This manuscript details the development of a Multiple Level C IVIVC for the amorphous solid dispersion formulation of suvorexant, a BCS class II compound, and its application to establishing dissolution specifications and in-process controls. Four different 40 mg batches were manufactured at different tablet hardnesses to produce distinct dissolution profiles. These batches were evaluated in a relative bioavailability clinical study in healthy volunteers. Although no differences were observed for the total exposure (AUC) of the different batches, a clear relationship between dissolution and Cmax was observed. A validated Multiple Level C IVIVC against Cmax was developed for the 10, 15, 20, 30, and 45 min dissolution time points and the tablet disintegration time. The relationship established between tablet tensile strength and dissolution was subsequently used to inform suitable tablet hardness ranges within acceptable Cmax limits. This is the first published report for a validated Multiple Level C IVIVC for an IR solid dispersion formulation demonstrating how this approach can facilitate Quality by Design in formulation development and help toward clinically relevant specifications and in-process controls. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part II: extension to describe performance of solid dosage forms.

PubMed

Thelen, Kirstin; Coboeken, Katrin; Willmann, Stefan; Dressman, Jennifer B; Lippert, Jörg

2012-03-01

The physiological absorption model presented in part I of this work is now extended to account for dosage-form-dependent gastrointestinal (GI) transit as well as disintegration and dissolution processes of various immediate-release and modified-release dosage forms. Empirical functions of the Weibull type were fitted to experimental in vitro dissolution profiles of solid dosage forms for eight test compounds (aciclovir, caffeine, cimetidine, diclofenac, furosemide, paracetamol, phenobarbital, and theophylline). The Weibull functions were then implemented into the model to predict mean plasma concentration-time profiles of the various dosage forms. On the basis of these dissolution functions, pharmacokinetics (PK) of six model drugs was predicted well. In the case of diclofenac, deviations between predicted and observed plasma concentrations were attributable to the large variability in gastric emptying time of the enteric-coated tablets. Likewise, oral PK of furosemide was found to be predominantly governed by the gastric emptying patterns. It is concluded that the revised model for GI transit and absorption was successfully integrated with dissolution functions of the Weibull type, enabling prediction of in vivo PK profiles from in vitro dissolution data. It facilitates a comparative analysis of the parameters contributing to oral drug absorption and is thus a powerful tool for formulation design. Copyright © 2011 Wiley Periodicals, Inc.

Formulation and evaluation of bilayer tablets of metoclopramide hydrochloride and diclofenac sodium.

PubMed

Gattani, Surendra G; Khabiya, Sohan S; Amrutkar, Jitendra R; Kushare, Sachin S

2012-01-01

The main objective of the present research work was to develop a bilayer tablet of metoclopramide hydrochloride (MTH) and diclofenac sodium (DS) in separate layers to avoid incompatibility and thus to maximize the efficacy of both drugs in combination for the effective treatment of migraine headaches. MTH and DS were formulated as immediate and sustained release layers respectively. In vitro dissolution kinetic studies of an optimized (D10) batch of DS in both sustained release layer and bilayer tablet forms show good linearity of regression coefficient 0.9773 (first order equation). The results reveal that an optimized immediate release layer (M5) of MTH and a sustained release layer (D10) of DS might be suitable for the treatment of migraine by sequential release of the two drugs in a bilayer tablet. Migraine is a type of recurring headache of moderate to severe intensity associated with gastrointestinal, neurological, and autonomic symptoms. In migraine, a combination of pretreatment with antiemetics is required for symptomatic treatment, when nausea and vomiting are severe. In our present research, we have selected the metoclopramide hydrochloride (MTH) active ingredient for study because it has an antiemetic effect and is a prokinetic agent. MTH is more effective to counteract gastric stasis associated with migraine, and it enhances the rate of absorption of non-steroidal anti-inflammatory drugs (NSAIDs). In the present investigation we combine MTH and a second active ingredient, diclofenac sodium, as a formulated bilayer tablet to prevent degradation of MTH.

Characterization and evaluation of self-nanoemulsifying sustained-release pellet formulation of ziprasidone with enhanced bioavailability and no food effect.

PubMed

Miao, Yanfei; Chen, Guoguang; Ren, Lili; Pingkai, Ouyang

2016-09-01

The purpose of this work was to develop self-nanomulsifying drug delivery systems (SNEDDS) in sustained-release pellets of ziprasidone to enhance the oral bioavailability and overcome the food effect of ziprasidone. Preformulation studies including screening of excipients for solubility and pseudo-ternary phase diagrams suggested the suitability of Capmul MCM as oil phase, Labrasol as surfactant, and PEG 400 as co-surfactant for preparation of self-nanoemulsifying formulations. Preliminary composition of the SNEDDS formulations were selected from the pseudo-ternary phase diagrams. The prepared ziprasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis and zeta potential. The optimized ziprasidone-SNEDDS were used to prepare ziprasidone-SNEDDS sustained-release pellets via extrusion-spheronization method. The pellets were characterized for SEM, particle size, droplet size distribution and zeta potential. In vitro drug release studies indicated the ziprsidone-SNEDDS sustained-release pellets showed sustained release profiles with 90% released within 10 h. The ziprsidone-SNEDDS sustained-release pellets were administered to fasted and fed beagle dogs and their pharmacokinetics were compared to commercial formulation of Zeldox as a control. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolonged actions and enhanced bioavailability with no food effect was achieved simultaneously in ziprsidone-SNEDDS sustained-release pellets compared with Zeldox in fed state. The results indicated a sustained release with prolonged actions of schizophrenia and bipolar disorder treatment.

Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies

PubMed Central

2013-01-01

Background The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed. The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. Methods A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. Results Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. Conclusions Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response. PMID:24074240

Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies.

PubMed

Coghill, David; Banaschewski, Tobias; Zuddas, Alessandro; Pelaz, Antonio; Gagliano, Antonella; Doepfner, Manfred

2013-09-27

The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed.The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response.

Formulation, characterization and pharmacokinetics of praziquantel-loaded hydrogenated castor oil solid lipid nanoparticles.

PubMed

Xie, Shuyu; Pan, Baoliang; Wang, Ming; Zhu, Luyan; Wang, Fenghua; Dong, Zhao; Wang, Xiaofang; Zhou, WenZhong

2010-07-01

The purpose of this study was to formulate praziquantel (PZQ)-loaded hydrogenated castor oil (HCO) solid lipid nanoparticles (SLN) to enhance the bioavailability and prolong the systemic circulation of the drug. PZQ was encapsulated into HCO nanoparticles by a hot homogenization and ultrasonication method. The physicochemical characteristics of SLN were investigated by optical microscope, scanning electron microscopy and photon correlation spectroscopy. Pharmacokinetics were studied after oral, subcutaneous and intramuscular administration in mice. The diameter, polydispersivity index, zeta potential, encapsulation efficiency and loading capacity of the nanoparticles were 344.0 +/- 15.1 nm, 0.31 +/- 0.08, -16.7 +/- 0.5 mV, 62.17 +/- 6.53% and 12.43 +/- 1.31%, respectively. In vitro release of PZQ-loaded HCO-SLN exhibited an initial burst release followed by a sustained release. SLN increased the bioavailability of PZQ by 14.9-, 16.1- and 2.6-fold, and extended the mean residence time of the drug from 7.6, 6.6 and 8.2 to 95.9, 151.6 and 48.2 h after oral, subcutaneous and intramuscular administration, respectively. The PZQ-loaded HCO-SLN could be a promising formulation to enhance the pharmacological activity of PZQ.

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation.

PubMed

Shanmugam, Srinivasan; Im, Ho Taek; Sohn, Young Taek; Kim, Yong-Il; Park, Jae-Hyun; Park, Eun-Seok; Woo, Jong Soo

2015-01-01

The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20 min. Finally, the PK profile of SDG-T and a reference formulation Oraxol™ (oral solution formulation used in Phase I clinical study) at a dose of 60 mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10 mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol™ solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol™ solution was 132.25% at a dose of 60 mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10-150 ng/mL for a period of 24 h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.

Development of Maltodextrin-Based Immediate-Release Tablets Using an Integrated Twin-Screw Hot-Melt Extrusion and Injection-Molding Continuous Manufacturing Process.

PubMed

Puri, Vibha; Brancazio, Dave; Desai, Parind M; Jensen, Keith D; Chun, Jung-Hoon; Myerson, Allan S; Trout, Bernhardt L

2017-11-01

The combination of hot-melt extrusion and injection molding (HME-IM) is a promising process technology for continuous manufacturing of tablets. However, there has been limited research on its application to formulate crystalline drug-containing immediate-release tablets. Furthermore, studies that have applied the HME-IM process to molded tablets have used a noncontinuous 2-step approach. The present study develops maltodextrin (MDX)-based extrusion-molded immediate-release tablets for a crystalline drug (griseofulvin) using an integrated twin-screw HME-IM continuous process. At 10% w/w drug loading, MDX was selected as the tablet matrix former based on a preliminary screen. Furthermore, liquid and solid polyols were evaluated for melt processing of MDX and for impact on tablet performance. Smooth-surfaced tablets, comprising crystalline griseofulvin solid suspension in the amorphous MDX-xylitol matrix, were produced by a continuous process on a twin-screw extruder coupled to a horizontally opening IM machine. Real-time HME process profiles were used to develop automated HME-IM cycles. Formulation adjustments overcame process challenges and improved tablet strength. The developed MDX tablets exhibited adequate strength and a fast-dissolving matrix (85% drug release in 20 min), and maintained performance on accelerated stability conditions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Single dose sublingual testosterone and oral sildenafil vs. a dual route/dual release fixed dose combination tablet: a pharmacokinetic comparison

PubMed Central

van Rooij, Kim; de Leede, Leo; Frijlink, Henderik W.; Koppeschaar, Hans P. F.; Olivier, Berend; Tuiten, Adriaan

2016-01-01

Aim The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.5 h later. The dual route/dual release fixed dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner core of sildenafil with a polymeric time delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal non‐adherence through circumventing the relatively complex temporal dosing scheme. Methods Twelve healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N‐desmethyl‐sildenafil. Results Formulation 2 had a higher maximum concentration (C max) for testosterone, 8.06 ng ml–1 (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration–time curve (AUC), 7.69 ng ml–1 h (95% CI 6.22, 9.16) than formulation 1, 5.66 ng ml–1 (95% CI 4.63, 6.69) and 5.12 ng ml–1 h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower C max for sildenafil, 173 ng ml–1 (95% CI 126, 220) and a lower AUC, 476 ng ml–1 h (95% CI 401, 551) than formulation 1, 268 ng ml–1 (95% CI 188, 348) and 577 ng ml–1 h (95% CI 462, 692), respectively. Formulation 2 released sildenafil after 2.75 h (95% CI 2.40, 3.10). Conclusions The dual route/dual release fixed dose combination tablet fulfilled its design criteria and is considered suitable for further clinical testing. What is Already Known about this Subject Female sexual interest/arousal disorder (FSIAD) is a significant problem impacting psychological well‐being, but the pharmacotherapeutic options for this problem are lacking.The combined, on‐demand, sublingual administration of low dose sublingual testosterone and oral administration of sildenafil is a novel pharmacotherapeutic option under development for FSIAD.In proof‐of‐concept trials, these compounds were successfully administered via different dosage forms (sublingual and oral) at different time points (separated by 2.5 h) because of their markedly different pharmacokinetic–pharmacodynamic profiles. For future larger scale studies and the clinical practice, this raises obvious adherence issues. What this Study Adds A newly developed dual route/dual release fixed dose combination tablet containing testosterone and sildenafil mimics the pharmacokinetic profile of these components when they are administered as different dosage forms, 2.5 h apart.This combination tablet is a suitable final pharmaceutical drug product that will be used in future studies. PMID:26804967

Preabsorptive insulin release and hypoglycemia in rats.

PubMed

Louis-Sylvestre, J

1976-01-01

Peripheral blood glucose and immunologically reactive insulin levels were determined in freely moving normal rats which were submitted either to a free oral glucose load or to a gastric administration of the glucose load. Identical determinations were performed in ventromedial hypothalamic nucleus-(VMH) lesioned and vagotomized rats after the same oral intake. It was demonstrated that: 1) a free oral glucose intake was immediately followed by two peaks of insulun release and a resultant decrease in blood glucose; 2) a gastric glucose load resulted in a single peak of insulin release and the concomitant decline in blood glucose; 3) the recorded blood glucose level was the resultant of the insulin-induced hypoglycemia and the postabsorptive hyperglycemia; and 4) the responses were largely exaggerated in VMH-lesioned rats and abolished by vagotomy. It is concluded that the early prandial insulin release reflexly induced by food-related stimuli temporarily enhances the metabolic conditions which provoke feeding.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics.

PubMed

Ahmed, Osama A A; Hosny, Khaled M; Al-Sawahli, Majid M; Fahmy, Usama A

2015-01-01

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid-liquid phase separation method, according to the Box-Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance.

Population pharmacokinetic modelling of tramadol using inverse Gaussian function for the assessment of drug absorption from prolonged and immediate release formulations.

PubMed

Brvar, Nina; Mateović-Rojnik, Tatjana; Grabnar, Iztok

2014-10-01

This study aimed to develop a population pharmacokinetic model for tramadol that combines different input rates with disposition characteristics. Data used for the analysis were pooled from two phase I bioavailability studies with immediate (IR) and prolonged release (PR) formulations in healthy volunteers. Tramadol plasma concentration-time data were described by an inverse Gaussian function to model the complete input process linked to a two-compartment disposition model with first-order elimination. Although polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol, application of a mixture model to test the assumption of two and three subpopulations did not reveal any improvement of the model. The final model estimated parameters with reasonable precision and was able to estimate the interindividual variability of all parameters except for the relative bioavailability of PR vs. IR formulation. Validity of the model was further tested using the nonparametric bootstrap approach. Finally, the model was applied to assess absorption kinetics of tramadol and predict steady-state pharmacokinetics following administration of both types of formulations. For both formulations, the final model yielded a stable estimate of the absorption time profiles. Steady-state simulation supports switching of patients from IR to PR formulation. Copyright © 2014 Elsevier B.V. All rights reserved.

Oral delivery of insulin via polyethylene imine-based nanoparticles for colonic release allows glycemic control in diabetic rats.

PubMed

Salvioni, Lucia; Fiandra, Luisa; Del Curto, Maria Dorly; Mazzucchelli, Serena; Allevi, Raffaele; Truffi, Marta; Sorrentino, Luca; Santini, Benedetta; Cerea, Matteo; Palugan, Luca; Corsi, Fabio; Colombo, Miriam

2016-08-01

In this study, insulin-containing nanoparticles were loaded into pellet cores and orally administered to diabetic rats. Polyethylene imine-based nanoparticles, either placebo or loaded with insulin, were incorporated by extrusion and spheronization technology into cores that were subsequently coated with three overlapping layers and a gastroresistant film. The starting and coated systems were evaluated in vitro for their physico-technololgical characteristics, as well as disintegration and release performance. Nanoparticles-loaded cores showed homogeneous particle size distribution and shape. When a superdisintegrant and a soluble diluent were included in the composition enhanced disintegration and release performance were observed. The selected formulations, coated either with enteric or three-layer films, showed gastroresistant and release delayed behavior in vitro, respectively. The most promising formulations were finally tested for their hypoglycemic effect in diabetic rats. Only the nanoformulations loaded into the three-layer pellets were able to induce a significant hypoglycemic activity in diabetic rats. Our results suggest that this efficient activity could be attributed to a retarded release of insulin into the distal intestine, characterized by relatively low proteolytic activity and optimal absorption. Copyright © 2016 Elsevier Ltd. All rights reserved.

Methodology of oral formulation selection in the pharmaceutical industry.

PubMed

Kuentz, Martin; Holm, René; Elder, David P

2016-05-25

Pharmaceutical formulations have to fulfil various requirements with respect to their intended use, either in the development phase or as a commercial product. New drug candidates with their specific properties confront the formulation scientist with industrial challenges for which a strategy is needed to cope with limited resources, stretched timelines as well as regulatory requirements. This paper aims at reviewing different methodologies to select a suitable formulation approach for oral delivery. Exclusively small-molecular drugs are considered and the review is written from an industrial perspective. Specific cases are discussed starting with an emphasis on poorly soluble compounds, then the topics of chemically labile drugs, low-dose compounds, and modified release are reviewed. Due to the broad scope of this work, a primary focus is on explaining basic concepts as well as recent trends. Different strategies are discussed to approach industrial formulation selection, which includes a structured product development. Examples for such structured development aim to provide guidance to formulators and finally, the recent topic of a manufacturing classification system is presented. It can be concluded that the field of oral formulation selection is particularly complex due to both multiple challenges as well as opportunities so that industrial scientists have to employ tailored approaches to design formulations successfully. Copyright © 2015 Elsevier B.V. All rights reserved.

Development of a Sustained Antiplaque and Antimicrobial Chewing Gum of a Decapeptide.

PubMed

Al-Ghananeem, Abeer M; Leung, Kai P; Faraj, Jabar; DeLuca, Patrick P

2017-08-01

The objective of this paper was to design a chewing gum formulation delivery system in situations where typical dental hygiene practice is not practical. Thus, an analog of decapeptide KSL (KSL-W), known to possess antimicrobial and antiplaque activity, was incorporated into a chewing gum formulation containing cetylpyridinium chloride (CPC). The effect of the excipients, xylitol, and peppermint oil on active ingredients in vitro release was also assessed. Gum formulations were prepared with different excipient parameters, including heating xylitol and gum base at 65 or 85°C, using ground and unground xylitol, and the addition of 1.5, 3, and 7% peppermint oil, to determine the effect of these changes on the in vitro release of KSL-W and CPC using a chewing machine. The antimicrobial and antiplaque activities of solutions released from chewed gum formulation as well as prepared standard solutions with different concentrations were tested against placebo. The optimal temperature to avoid crystallization of xylitol during preparation was 65°C. Grinding xylitol to 104.5 μm improved release of active ingredients as compared to commercially unground xylitol. Peppermint oil had opposite effects on release of KSL-W and CPC. Peppermint oil at 1.5% was determined to be suitable (91 and 88% of KSL-W and CPC released, respectively, after 40 min). The gum formulation illustrated good sustained release of KSL-W and CPC with antibacterial and antiplaque activities after chewing. An effective antimicrobial and antiplaque chewing gum formulation was developed. This formulation has the potential to overcome oral hygiene issues in those unable to follow normal dental protocols.

The influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction with paroxetine

PubMed Central

Stout, Stephen M.; Nielsen, Jace; Welage, Lynda S.; Shea, Michael; Brook, Robert; Kerber, Kevin; Bleske, Barry E.

2010-01-01

Studies have demonstrated an influence of dosage release formulations on drug interactions and enantiomeric plasma concentrations. Metoprolol is a commonly used β-adrenergic antagonist metabolized by CYP2D6. The CYP2D6 inhibitor paroxetine has previously been shown to interact with metoprolol tartrate. This open-label, randomized, 4 phase crossover study assessed the potential differential effects of paroxetine on stereoselective pharmacokinetics of immediate release (IR) tartrate and extended release (ER) succinate metoprolol formulations. Ten healthy subjects received metoprolol IR (50 mg) and ER (100 mg) with and without paroxetine coadministration. Blood samples were collected over 24 hours for determination of metoprolol plasma enantiomer concentrations. Paroxetine coadministration significantly increased S and R metoprolol AUC0–24h by 4 and 5 fold, respectively for IR, and 3 and 4 fold, respectively for ER. S/R AUC ratios significantly decreased. These results demonstrate a pharmacokinetic interaction between paroxetine and both formulations of metoprolol. The interaction is greater with R metoprolol and stereoselective metabolism is lost. This could theoretically result in greater β-blockade and lost cardioselectivity. The magnitude of the interaction was similar between metoprolol formulations, which may be attributable to low doses / drug input rates employed. PMID:20400652

Provesicular granisetron hydrochloride buccal formulations: in vitro evaluation and preliminary investigation of in vivo performance.

PubMed

Ahmed, Sami; El-Setouhy, Doaa Ahmed; El-Latif Badawi, Alia Abd; El-Nabarawi, Mohamed Ahmed

2014-08-18

Granisetron hydrochloride (granisetron) is a potent antiemetic that has been proven to be effective in acute and delayed emesis in cancer chemotherapy. Granisetron suffers from reduced oral bioavailability (≈60%) due to hepatic metabolism. In this study the combined advantage of provesicular carriers and buccal drug delivery has been explored aiming to sustain effect and improve bioavailability of granisetron via development of granisetron provesicular buccoadhesive tablets with suitable quality characteristics (hardness, drug content, in vitro release pattern, exvivo bioadhesion and in vivo bioadhesion behavior). Composition of the reconstituted niosomes from different prepared provesicular carriers regarding type of surfactant used and cholesterol concentration significantly affected both entrapment efficiency (%EE) and vesicle size. Span 80 proniosome-derived niosomes exhibited higher encapsulation efficiency and smaller particle size than those derived from span 20. Also, the effect of %EE and bioadhesive polymer type on in vitro drug release and in vivo performance of buccoadhesive tablets was investigated. Based on achievement of required in vitro release pattern (20-30% at 2h, 40-65% at 6h and 80-95% at 12h), in vivo swelling behavior, and in vivo adhesion time (>14 h) granisetron formulation (F19, 1.4 mg) comprising HPMC:carbopol 974P (7:3) and maltodextrin coated with the vesicular precursors span 80 and cholesterol (9:1) was chosen for in vivo study. In vivo pharmacokinetic study revealed higher bioavailability of buccal formulation relative to conventional oral formulation of granisetron (AUC0-∞ is 89.97 and 38.18 ng h/ml for buccal and oral formulation, respectively). A significantly lower and delayed Cmax (12.09±4.47 ng/ml, at 8h) was observed after buccal application compared to conventional oral tablet (31.66±10.15 ng/ml, at 0.5 h). The prepared provesicular buccoadhesive tablet of granisetron (F19) might help bypass hepatic first-pass metabolism and improve bioavailability of granisetron with the possibility of reducing reported daily dose (2mg) and reducing dosing frequency. Copyright © 2014 Elsevier B.V. All rights reserved.

Formulation and development of bicontinuous nanostructured liquid crystalline particles of efavirenz.

PubMed

Avachat, Amelia M; Parpani, Shreekrishna S

2015-02-01

Efavirenz is a lipophilic non-nucleoside reverse transcriptase inhibitor used in the first-line pediatric therapeutic cocktail. Due to its high lipophilicity (logP = 5.4) and poor aqueous solubility (intrinsic water solubility = 8.3 μg/mL) efavirenz has low bioavailability. A 30 mg/mL solution in a medium-chain triglyceride vehicle is the only pediatric formulation available with an oral bioavailability 20% lower than the solid form. The current work was aimed at formulating and characterizing liquid crystal nanoparticles for oral delivery of efavirenz to improve oral bioavailability, provide sustained release, minimize side effects and drug resistance. Formulation of cubosomes was done by two methods; sonication and spray drying. Sonication gave highest entrapment efficiency and least particle size. Further, monoolein was substituted with phytantriol as monoolein gets degraded in the presence of lipase when administered orally with consequent loss of liquid crystalline structure. It was confirmed that there was no difference in particle size, entrapment efficiency and nature of product formed by using monoolein or phytantriol. The best formulation was found to be F9, having particle size 104.19 ± 0.21 nm and entrapment efficiency 91.40 ± 0.10%. In vitro release at the end of 12h was found to be 56.45% and zeta potential to be -23.14 mV which stabilized the cubic phase dispersions. It was further characterized for TEM, small angle X-ray scattering (SAXS), DSC and stability studies. SAXS revealed Pn3m space group, indicating a diamond cubic phase which was further confirmed by TEM. Pharmacokinetics of EFV was studied in male Wistar rats. EFV-loaded cubosome dispersions exhibited 1.93 and 1.62-fold increase in peak plasma concentration (Cmax) and 1.48 and 1.42-fold increase in AUC in comparison to that of a suspension prepared with the contents of EFV capsules suspended in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in medium-chain triglyceride respectively. Thus, stable cubosomes of efavirenz with increased bioavailability providing sustained release effect could be prepared successfully using phytantriol and poloxamer 407. Copyright © 2014 Elsevier B.V. All rights reserved.

Film-forming formulations containing porous silica for the sustained delivery of actives to the skin.

PubMed

Heck, Rouven; Hermann, Sabrina; Lunter, Dominique J; Daniels, Rolf

2016-11-01

The purpose of this study was to develop film-forming formulations facilitating long-term treatment of chronic pruritus with capsaicinoids. To this end, an oily solution of nonivamide was loaded into porous silica particles which were then suspended in the dispersion of a sustained release polymer. Such formulations form a film when applied to the skin and encapsulate the drug loaded silica particles in a dry polymeric matrix. Dermal delivery and permeation of the antipruritic drug nonivamide (NVA) are controlled by the matrix. The film-forming formulations were examined regarding homogeneity, storage stability, substantivity and ex vivo skin permeation. Confocal Raman spectral imaging proved the stability of silica-based film-forming formulations over a period of 6 months. Substantivity was found to be enhanced substantially compared to a conventional semisolid formulation. Permeation rates of nonivamide from film-forming formulations through the skin are much lower compared to those achieved with a conventional immediate release formulation with the same drug amount. Due to the drug reservoir in the polymer matrix, a sustained permeation is enabled. Film-forming formulations may therefore improve the treatment of chronic pruritus with capsaicinoids by enhancing patient compliance through a sustained release regime. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparation and Pharmacokinetics Evaluation of Solid Self-Microemulsifying Drug Delivery System (S-SMEDDS) of Osthole.

PubMed

Sun, Chaojie; Gui, Yun; Hu, Rongfeng; Chen, Jiayi; Wang, Bin; Guo, Yuxing; Lu, Wenjie; Nie, Xiangjiang; Shen, Qiang; Gao, Song; Fang, Wenyou

2018-05-29

The study was performed aiming to enhance the solubility and oral bioavailability of poorly water-soluble drug osthole by formulating solid self-microemulsifying drug delivery system (S-SMEDDS) via spherical crystallization technique. Firstly, the liquid self-microemulsifying drug delivery system (L-SMEDDS) of osthole was formulated with castor oil, Cremophor RH40, and 1,2-propylene glycol after screening various lipids and emulsifiers. The type and amount of polymeric materials, good solvents, bridging agents, and poor solvents in S-SMEDDS formulations were further determined by single-factor study. The optimal formulation contained 1:2 of ethyl cellulose (EC) and Eudragit S100, which served as matrix forming and enteric coating polymers respectively. Anhydrous ethanol and dichloromethane with a ratio of 5:3 are required to perform as good solvent and bridging agent, respectively, with the addition of 0.08% SDS aqueous solution as poor solvent. The optimized osthole S-SMEDDS had a high yield (83.91 ± 3.31%) and encapsulation efficiency (78.39 ± 2.25%). Secondly, osthole L-SMEDDS was solidified to osthole S-SMEDDS with no significant changes in terms of morphology, particle size, and zeta potential. In vitro release study demonstrated a sustained release of the drug from osthole S-SMEDDS. Moreover, in vivo pharmacokinetic study showed that the T max and mean residence time (MRT (0-t) ) of osthole were significantly prolonged and further confirmed that osthole S-SMEDDS exhibited sustained release effect in rabbits. Comparing with osthole aqueous suspension and L-SMEDDS, osthole S-SMEDDS increased bioavailability by 205 and 152%, respectively. The results suggested that S-SMEDDS was an effective oral solid dosage form, which can improve the solubility and oral bioavailability of poorly water-soluble drug osthole.

Custom fractional factorial designs to develop atorvastatin self-nanoemulsifying and nanosuspension delivery systems--enhancement of oral bioavailability.

PubMed

Hashem, Fahima M; Al-Sawahli, Majid M; Nasr, Mohamed; Ahmed, Osama A A

2015-01-01

Poor water solubility of a drug is a major challenge in drug delivery research and a main cause for limited bioavailability and pharmacokinetic parameters. This work aims to utilize custom fractional factorial design to assess the development of self-nanoemulsifying drug delivery systems (SNEDDS) and solid nanosuspensions (NS) in order to enhance the oral delivery of atorvastatin (ATR). According to the design, 14 experimental runs of ATR SNEDDS were formulated utilizing the highly ATR solubilizing SNEDDS components: oleic acid, Tween 80, and propylene glycol. In addition, 12 runs of NS were formulated by the antisolvent precipitation-ultrasonication method. Optimized formulations of SNEDDS and solid NS, deduced from the design, were characterized. Optimized SNEDDS formula exhibited mean globule size of 73.5 nm, zeta potential magnitude of -24.1 mV, and 13.5 μs/cm of electrical conductivity. Optimized solid NS formula exhibited mean particle size of 260.3 nm, 7.4 mV of zeta potential, and 93.2% of yield percentage. Transmission electron microscopy showed SNEDDS droplets formula as discrete spheres. The solid NS morphology showed flaky nanoparticles with irregular shapes using scanning electron microscopy. The release behavior of the optimized SNEDDS formula showed 56.78% of cumulative ATR release after 10 minutes. Solid NS formula showed lower rate of release in the first 30 minutes. Bioavailability estimation in Wistar albino rats revealed an augmentation in ATR bioavailability, relative to ATR suspension and the commercial tablets, from optimized ATR SNEDDS and NS formulations by 193.81% and 155.31%, respectively. The findings of this work showed that the optimized nanocarriers enhance the oral delivery and pharmacokinetic profile of ATR.

Oral Disintegration Tablets of Stavudine for HIV Management: A New Technological Approach

PubMed Central

Sankar, V.; Ramakrishna, B.; Devi, P. Shalini; Karthik, S.

2012-01-01

Stavudine oral disintegration tablets were formulated to minimize the bitter taste and to reduce the first-pass hepatic metabolism. The various precompression parameters like the angle of repose, bulk density, compressibility index and Hausner's ratio were determined for the powder blend. In this study, 14 formulations of stavudine oral disintegration tablet were prepared by direct compression method. The tablets were evaluated for weight variation, percentage friability, disintegration time, hardness, wetting time and water absorption ratio. The in vitro dissolution study results of the batch S1 (stavudine+crospovidone+sodium starch glycollate) are encouraging as highest dissolution rate (99.2% in 100 min) and lowest time of disintegration (56 s) was achieved. The in vivo drug release studies were carried out in rabbits and the relative bioavailability of formulation S1 was found to be 2.83 times greater than that of conventional tablets. PMID:23798782

Oral Disintegration Tablets of Stavudine for HIV Management: A New Technological Approach.

PubMed

Sankar, V; Ramakrishna, B; Devi, P Shalini; Karthik, S

2012-11-01

Stavudine oral disintegration tablets were formulated to minimize the bitter taste and to reduce the first-pass hepatic metabolism. The various precompression parameters like the angle of repose, bulk density, compressibility index and Hausner's ratio were determined for the powder blend. In this study, 14 formulations of stavudine oral disintegration tablet were prepared by direct compression method. The tablets were evaluated for weight variation, percentage friability, disintegration time, hardness, wetting time and water absorption ratio. The in vitro dissolution study results of the batch S1 (stavudine+crospovidone+sodium starch glycollate) are encouraging as highest dissolution rate (99.2% in 100 min) and lowest time of disintegration (56 s) was achieved. The in vivo drug release studies were carried out in rabbits and the relative bioavailability of formulation S1 was found to be 2.83 times greater than that of conventional tablets.

Microencapsulation techniques to develop formulations of insulin for oral delivery: a review.

PubMed

Cárdenas-Bailón, Fernando; Osorio-Revilla, Guillermo; Gallardo-Velázquez, Tzayhrí

2013-01-01

Oral insulin delivery represents one of the most challenging goals for pharmaceutical industry. In general, it is accepted that oral administration of insulin would be more accepted by patients and insulin would be delivered in a more physiological way than the parenteral route. From all strategies to deliverer insulin orally, microencapsulation or nanoencapsulation of insulin are the most promising approaches because these techniques protect insulin from enzymatic degradation in stomach, show a good release profile at intestine pH values, maintain biological activity during formulation and enhance intestinal permeation at certain extent. From different microencapsulation techniques, it seems that complex coacervation, multiple emulsion and internal gelation are the most appropriate techniques to encapsulate insulin due to their relative ease of preparation. Besides that, the use of organic solvents is not required and can be scaled up at low cost; however, relative oral bioavailability still needs to be improved.

In vitro biorelevant models for evaluating modified release mesalamine products to forecast the effect of formulation and meal intake on drug release.

PubMed

Andreas, Cord J; Chen, Ying-Chen; Markopoulos, Constantinos; Reppas, Christos; Dressman, Jennifer

2015-11-01

Postprandial administration of solid oral dosage forms greatly changes the dissolution environment compared to fasted state administration. The aims of this study were to investigate and forecast the effect of co-administration of a meal on drug release for delayed and/or extended release mesalamine formulations as well as design of in vitro tests to distinguish among formulations in a biorelevant way. Five different mesalamine formulations (Asacol® 400 mg, Mezavant® 1200 mg, Pentasa® 500 mg and Salofalk® in the 250 mg and 500 mg strengths) were investigated with biorelevant dissolution methods using the USP apparatus III and USP apparatus IV (open loop mode) under both fasted and fed state conditions, as well as with the dissolution methods described in pharmacopeia for delayed and extended release mesalamine products. Using the biorelevant experimental conditions proposed in this study, changes in release in the proximal gut due to meal intake are forecast to be minimal for Asacol®, Mezavant®, Pentasa® and Salofalk® 500 mg, while for Salofalk® 250 mg release was predicted to occur much earlier under fed state conditions. The USP apparatus III generally tended to result in faster dissolution rates and forecast more pronounced food effects for Salofalk® 250 mg than the USP apparatus IV. The biorelevant dissolution gradients were also able to reflect the in vivo behavior of the formulations. In vitro biorelevant models can be useful in the comparison of the release behavior from different delayed and extended release mesalamine formulations as well as forecasting effects of concomitant meal intake on drug release. Copyright © 2015 Elsevier B.V. All rights reserved.

In-vitro and in-vivo evaluation of taste-masked cetirizine hydrochloride formulated in oral lyophilisates.

PubMed

Preis, Maren; Grother, Leon; Axe, Philip; Breitkreutz, Jörg

2015-08-01

The use of solid oral dosage forms is typically favored with regard to stability and ease of administration. The aim of this study was to investigate whether cyclodextrins (CD) or ion exchange resins (IER) could be used to taste-mask cetirizine HCl when formulated in a freeze-dried oral formulation. The oral lyophilisates were produced using the Zydis(®) technology that offer the opportunity to produce the dosage form directly in the aluminum laminate blister packs. This study confirmed that a pre-formed resinate of cetirizine HCl and various cyclodextrins can be successfully incorporated into the Zydis(®) oral lyophilisate. A chemically stable product with acceptable release profile was obtained in the case of cyclodextrin. This study has also demonstrated that the Insent(®) taste sensing system is a useful technique for predicting the taste-masking potential of Zydis(®) formulations. The electronic taste sensing system (e-tongue) data can be used to provide guidance on the selection of taste-masked formulations. Principal component analysis (PCA) of sensor data by plotting the PCA scores revealed the effects of used taste-masking techniques on the e-tongue sensors, indicating the successful taste improvement. The PCA plot of the taste sensor data revealed larger distances between the non-taste-masked sample and the CD- and IER-loaded samples, and the shift toward the drug-free formulations and excipient signals indicates a modification of the product taste. The human taste trial confirms the acceptability of the selected promising formulations. The taste evaluation results showed that an effectively taste-masked formulation has been achieved using β-cyclodextrin and cherry/sucralose flavor system with over 80% of volunteers finding the tablet to be acceptable. Copyright © 2015 Elsevier B.V. All rights reserved.

A comparative histological study of alginate beads as a promising controlled release delivery for mefenamic acid.

PubMed

Sevgi, Ferhan; Kaynarsoy, Buket; Ozyazici, Mine; Pekcetin, Cetin; Ozyurt, Dogan

2008-01-01

The new mefenamic acid-alginate bead formulation prepared by ionotropic gelation method using 3 x 2(2) factorial design has shown adequate controlled release properties in vitro. In the present study, the irritation effects of mefenamic acid (MA), a prominent non-steroidal anti-inflammatory (NSAI) drug, were evaluated on rat gastric and duodenal mucosa when suspended in 0.5% (w/v) sodiumcarboxymethylcellulose (NaCMC) solution and loaded in alginate beads. Wistar albino rats weighing 200 +/- 50 g were used during in vivo animal studies. In this work, biodegradable controlled release MA beads and free MA were evaluated according to the degree of gastric or duodenal damage following oral administration in rats. The gastric and duodenal mucosa was examined for any haemorrhagic changes. Formulation code A10 showing both Case II transport and zero order drug release and t(50) % value of 5.22 h was chosen for in vivo animal studies. For in vivo trials, free MA (100 mgkg(-1)), blank and MA (100 mgkg(-1)) loaded alginate beads (formulation code A10) were suspended in 0.5% (w/v) NaCMC solution and each group was given to six rats orally by gavage. NaCMC solution was used as a control in experimental studies. In vivo data showed that the administration of MA in alginate beads prevented the gastric lesions.

Atorvastatin calcium encapsulated eudragit nanoparticles with enhanced oral bioavailability, safety and efficacy profile.

PubMed

Kumar, Nagendra; Chaurasia, Sundeep; Patel, Ravi R; Khan, Gayasuddin; Kumar, Vikas; Mishra, Brahmeshwar

2017-03-01

Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation. Morphological study exhibited homogenous spherical shape of formulated nanoparticles. In vitro release study in phosphate buffer (pH 7.4) demonstrated sustained release profile over 24 h. Pharmacokinetic study in Charles Foster rats showed significant enhancement in oral bioavailability as compared to pure drug suspension. Efficacy study (lipid profile and blood glucose level) significantly justified the effectiveness of formulation having 50% less dose of ATR as compared to pure drug suspension. The effectiveness of formulation was further justified with an improved plasma safety profile of treated rats. Hence, ATR encapsulated eudragit RSPO nanoparticles can serve as potential drug delivery approach to enhance drug bioavailability, efficacy and safety profiles to alter existing marketed drug products.

Nanoemulsion: for improved oral delivery of repaglinide.

PubMed

Akhtar, Juber; Siddiqui, Hefazat Hussain; Fareed, Sheeba; Badruddeen; Khalid, Mohammad; Aqil, Mohammed

2016-07-01

Repaglinide (RPG) is a fast-acting prandial glucose regulator. It acts by stimulating insulin release from pancreatic β-cells. Recurrent dosing of RPG before each meal is burdensome remedy. Hence the plan of the present study was to evaluate nanoemulsion as a hopeful carrier for RPG for persistent hypoglycemic effect. The drug was incorporated into oil phase of nanoemulsion to give improved biopharmaceutical properties as compared to the lipid-based systems. Pseudo ternary phase diagrams were prepared by aqueous titration method. Formulations were selected at a difference of 5% w/w of oil from the o/w nanoemulsion region of phase diagrams. The optimized nanoemulsion formulation constituted sefsol-218 (5% v/v) as an oil phase, 30% v/v of Tween-80 and transcutol as a surfactant and co-surfactant to restrain nanodroplet size and low viscosity and distilled water (65%). In vitro dissolution studies showed higher drug release (98.22%), finest droplet size (76.23 nm), slightest polydispersity value (0.183), least viscosity (21.45 cps) and immeasurable dilution capability from the nanoemulsion as compared with existing oral tablet formulation. The optimized RPG nanoemulsion formulation showed better hypoglycemic effect in comparison to tablet formulation in experimental diabetic rats. No significant variations were also observed in the optimized formulation when subjected to accelerated stability study at different temperature and relative humidity over a period of 3 months.

Synergistic antioxidant action of vitamin E and rutin SNEDDS in ameliorating oxidative stress in a Parkinson’s disease model

NASA Astrophysics Data System (ADS)

Sharma, Shrestha; Narang, Jasjeet K.; Ali, Javed; Baboota, Sanjula

2016-09-01

Purpose. Oxidative stress is the leading cause in the pathogenesis of Parkinson’s disease. Rutin is a naturally occurring strong antioxidant molecule with wide therapeutic applications. It suffers from the problem of low oral bioavailability which is due to its poor aqueous solubility. Methods. In order to increase the solubility self-nanoemulsifying drug delivery systems (SNEDDS) of rutin were prepared. The oil, surfactant and co-surfactant were selected based on solubility/miscibility studies. Optimization was done by a three-factor, four-level (34) Box-Behnken design. The independent factors were oil, surfactant and co-surfactant concentration and the dependent variables were globule size, self-emulsification time, % transmittance and cumulative percentage of drug release. The optimized SNEDDS formulation (RSE6) was evaluated for various release studies. Antioxidant activity was assessed by various in vitro tests such as 2,2-diphenyl-1-picrylhydrazyl and reducing power assay. Oxidative stress models which had Parkinson’s-type symptoms were used to determine the antioxidant potential of rutin SNEDDS in vivo. Permeation was assessed through confocal laser scanning microscopy. Results. An optimized SNEDDS formulation consisting of Sefsol + vitamin E-Solutol HS 15-Transcutol P at proportions of 25:35:17.5 (w/w) was prepared and characterized. The globule size and polydispersity index of the optimized formulation was found to be 16.08 ± 0.02 nm and 0.124 ± 0.01, respectively. A significant (p < 0.05) increase in the percentage of drug release was achieved in the case of the optimized formulation as compared to rutin suspension. Pharmacokinetic study showed a 2.3-fold increase in relative oral bioavailability. The optimized formulation had significant in vitro and in vivo antioxidant activity. Conclusion. Rutin SNEDDS have been successfully prepared and they can serve as an effective tool in enhancing the oral bioavailability and efficacy of rutin, thus helping in ameliorating oxidative stress in neurodegenerative disorders like Parkinson’s disease.

Enhanced oral bioavailability and anticancer activity of novel curcumin loaded mixed micelles in human lung cancer cells.

PubMed

Patil, Sharvil; Choudhary, Bhavana; Rathore, Atul; Roy, Krishtey; Mahadik, Kakasaheb

2015-11-15

Curcumin has a wide range of pharmacological activities including antioxidant, anti-inflammatory, antidiabetic, antibacterial, wound healing, antiatherosclerotic, hepatoprotective and anti-carcinogenic. However, its clinical applications are limited owing to its poor aqueous solubility, multidrug pump P-gp efflux, extensive in vivo metabolism and rapid elimination due to glucuronidation/sulfation. The objective of the current work was to prepare novel curcumin loaded mixed micelles (CUR-MM) of Pluronic F-127 (PF127) and Gelucire® 44/14 (GL44) in order to enhance its oral bioavailability and cytotoxicity in human lung cancer cell line A549. 3(2) Factorial design was used to assess the effect of formulation variables for optimization of mixed micelle batch. CUR-MM was prepared by a solvent evaporation method. The optimized CUR-MM was evaluated for size, entrapment efficiency (EE), in vitro curcumin release, cytotoxicity and oral bioavailability in rats. The average size of CUR-MM was found to be around 188 ± 3 nm with an EE of about 76.45 ± 1.18% w/w. In vitro dissolution profile of CUR-MM revealed controlled release of curcumin. Additionally, CUR-MM showed significant improvement in cytotoxic activity (3-folds) and oral bioavailability (around 55-folds) of curcumin as compared to curcumin alone. Such significant improvement in cytotoxic activity and oral bioavailability of curcumin when formulated into mixed micelles could be attributed to solubilization of hydrophobic curcumin into micelle core along with P-gp inhibition effect of both, PF127 and GL44. Thus the present work propose the formulation of mixed micelles of PF127 and GL44 which can act as promising carrier systems for hydrophobic drugs such as curcumin with significant improvement in their oral bioavailability. Copyright © 2015 Elsevier GmbH. All rights reserved.

Pharmacokinetics of Modified Slow-Release Oral Testosterone Over 9 Days in Normal Men With Experimental Hypogonadism

PubMed Central

Lee, Ada; Rubinow, Katya; Clark, Richard V.; Caricofe, Ralph B.; Bush, Mark A.; Zhi, Hui; Roth, Mara Y; Page, Stephanie T.; Bremner, William J.; Amory, John K.

2014-01-01

Oral administration of testosterone has potential use for the treatment of hypogonadism. We have recently demonstrated that a novel formulation of oral testosterone transiently normalized serum testosterone in a single-dose pharmacokinetic study. In this report, we present the steady-state pharmacokinetics of this formulation. Twelve healthy young men were rendered hypogonadal with the gonadotropin-releasing hormone antagonist acyline (300 µg/kg subcutaneously) and administered 300 mg of oral testosterone 3 times daily for 9 days. Serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone–binding globulin (SHBG) were measured before and 1, 2, 4, 5, 6, 8, 10, 11, 12, 14, 16, and 24 hours on the first and ninth day of dosing. Before testosterone administration, all men had serum testosterone under 75 ng/dL. Over day 1, the 24-hour average (geometric mean [%CV]) serum total testosterone was 378 (45) ng/dL. This decreased to 315 (41) ng/dL after 9 days of continuous treatment (P = .1 compared with day 1). The 24-hour average serum SHBG was 27 (46) nmol/L on day 1 and was significantly reduced to 19 (47) nmol/L by day 9 (P > .01). As a result, the calculated free testosterone values were similar between day 1 and day 9: 8.7 (43) and 8.3 (37) ng/dL, respectively. DHT was in the reference range and estradiol was slightly below on day 9. Oral testosterone (300 mg) dosed 3 times daily normalized serum testosterone in men with experimentally induced hypogonadism after 9 days of dosing and significantly suppressed SHBG. This formulation of oral testosterone may have efficacy for the treatment of testosterone deficiency. PMID:21868746

Preparation and evaluation of novel metronidazole sustained release and floating matrix tablets.

PubMed

Asnaashari, Solmaz; Khoei, Nazaninossadat Seyed; Zarrintan, Mohammad Hosein; Adibkia, Khosro; Javadzadeh, Yousef

2011-08-01

In the present study, metronidazole was used for preparing floating dosage forms that are designed to retain in the stomach for a long time and have developed as a drug delivery system for better eradication of Helicobacter Pylori in peptic ulcer diseases. For this means, various formulations were designed using multi-factorial design. HPMC, psyllium and carbopol in different concentrations were used as floating agents, and sodium bicarbonate was added as a gas-forming agent. Hardness, friability, drug loading, floating ability and release profiles as well as kinetics of release were assessed. Formulations containing HPMC as filler showed prolonged lag times for buoyancy. Adding psyllium to these formulations had reduced relative lag times. Overall, selected formulations were able to float immediately and showed buoyancy for at least 8?h. Meanwhile, sustained profiles of drug release were also obtained. Kinetically, among the 10 assessed models, the release pattern of metronidazole from the tablets fitted best to Power law, Weibull and Higuchi models in respect overall to mean percentage error values of 3.8, 4.73 and 5.77, respectively, for calcium carbonate-based tablets and, 2.95, 6.39 and 3.9, respectively, for calcium silicate-based tablets. In general, these systems can float in the gastric condition and control the drug release from the tablets.

Risk based In Vitro Performance Assessment of Extended Release Abuse Deterrent Formulations

PubMed Central

Xu, Xiaoming; Gupta, Abhay; Al-Ghabeish, Manar; Calderon, Silvia N.; Khan, Mansoor A.

2016-01-01

High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products. PMID:26784976

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

PubMed

Aggarwal, Geeta; Dhawan, Sanju; Hari Kumar, S L

2013-01-01

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.

Effect of food on the bioavailability of lesogaberan given as an oral solution or as modified-release capsules in healthy male volunteers.

PubMed

Fransson, Bo; Silberg, Debra G; Niazi, Mohammad; Miller, Frank; Ruth, Magnus; Holmberg, Ann Aurell

2012-04-01

The novel Type B gamma-aminobutyric acid (GABAB)-receptor agonist lesogaberan (AZD3355) has been evaluated as an add-on to proton pump inhibitor treatment for gastroesophageal reflux disease, but the effect of food on the bioavailability of this compound has not been assessed. In this openlabel crossover study, healthy males received single 100 mg doses of lesogaberan (oral solution (A) or oral modified release (MR) capsules with a dissolution rate of 50% (B) or 100% (C) over 4 h) with and without food. Blood plasma concentrations of lesogaberan were assessed over 48 h. A log-transformed geometric mean Cmax and AUC ratio within the 90% confidence interval (CI) range (0.80 - 1.25) was defined as excluding a clinically relevant food effect. Overall, 57 subjects completed the study. Only the oral lesogaberan solution had a fed/fasting Cmax ratio outside the 90% CI range (Cmax ratio: 0.76). AUC ratios were within the 90% CI limits for all three lesogaberan formulations. The only substantial change in tmax associated with food intake was observed for the oral solution (1.0 h without food, 1.8 h with food). In conclusion, a clinically relevant food effect could be excluded for the lesogaberan MR formulations, but not for the oral lesogaberan solution.

Bioequivalence of 2 Formulations of Sildenafil Oral Soluble Film 100 mg and Sildenafil Citrate (Viagra) 100 mg Oral Tablets in Healthy Male Volunteers.

PubMed

Dadey, Eric

Sildenafil citrate tablets (VIAGRA; Pfizer Inc) have been used since 1998 as an oral therapy for the treatment of erectile dysfunction. However, in some cases, patients may have difficulty in swallowing tablets, and the need to use water to aid in the oral administration of the tablets has the potential to interrupt the sexual encounter, reduce spontaneity, and therefore decrease the quality of the experience. Two oral soluble film (OSF) formulations of sildenafil were developed using MonoSol Rx's proprietary PharmFilm technology. Both films were formulated to dissolve rapidly on the tongue, thereby releasing the drug into the oral cavity, whereupon it is swallowed without the use of water. From a patient perspective, it is anticipated that the film formulations of sildenafil citrate will provide a more compliant and discreet dosage form. The purpose of this clinical study was to compare the bioequivalence of the 2 sildenafil OSF 100 mg formulations (MonoSol Rx, LLC) with the sildenafil citrate 100 mg tablets. The design was a single-dose, randomized, open-label, 3-period, 6-sequence, 3-treatment, single-center, crossover study conducted in 18 healthy, nonsmoking male volunteers under fasting conditions, with each treatment period separated by a 7-day washout period. Plasma sildenafil concentrations were measured predose and then periodically to 24 hours after dosing. The 90% confidence intervals for plasma sildenafil AUC0-t, AUC0-∞, and Cmax for both sildenafil OSF formulations as compared with sildenafil citrate tablets were all within the 80%-125% range, indicating bioequivalence of both film formulations to sildenafil citrate tablets. Overall, the demonstrated bioequivalence coupled with the performance advantages of an OSF dosage form (ie, rapid dissolution in the mouth, can be taken without water, and can be dosed discreetly) suggest that the sildenafil OSF may provide an attractive alternative to sildenafil citrate oral tablets.

Bilayer Tablet Formulation of Metformin HCl and Acarbose: A Novel Approach To Control Diabetes.

PubMed

Tiwari, Ruchi; Gupta, Ankita; Joshi, Meenakshi; Tiwari, Gaurav

2014-01-01

The present investigation studied a novel bilayer tablet having an extended release system of metformin HCl with Eudragit RS 100 and RL 100 and an immediate release system of acarbose with polyvinylpyrrolidone K30 (PVP K30) and polyethylene glycol 6000 (PEG 6000) in different ratios using solvent evaporation and cogrinding techniques. Solid dispersions (SDs) were characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder x-ray diffractometry (XRD), scanning electron microscopy (SEM), as well as by content uniformity, in vitro dissolution studies, and release kinetics. The selected SD system was subjected to bilayer tablet preparation by direct compression. Compressed tablets were evaluated for drug content, weight variation, friability, hardness, and thickness, and they underwent in vitro dissolution studies. The progressive disappearance of IR, x-ray, and thermotropic drug signals in SDs and physical mixtures were related to increasing amount of polymer. SEM studies suggested the homogenous dispersion of drug in polymers. FT-IR studies confirmed the formation of hydrogen bonding between drug and polymer. All tablet formulations showed compliance with pharmacopoeial standards. The formulations gave an initial burst effect to provide the loading dose of the drug followed by extended release for 12 h (Higuchi model via a non-Fickian diffusion controlled release mechanism). Stability studies conducted for the optimized formulation did not show any change in physical properties, drug content, or in vitro drug release. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of elevated blood glucose levels. Oral therapeutic options for the treatment of type 2 diabetes mellitus, until recently, have been severely limited. Metformin, a biguanide, targets additional mechanisms of hyperglycemia by inhibiting hepatic glucose production and enhancing peripheral glucose uptake and thereby reducing insulin resistance; acarbose reversibly bind to pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolases. These enzymes inhibit hydrolysis of complex starches to oligosaccharides in the lumen of the small intestine and hydrolysis of oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. The two agents were found to have a remarkable effect on glycemic control. In the present investigation a bilayer tablet was prepared in which one layer gives instant action against diabetes and another layer maintain concentration of drug in plasma for longer periods.

Formulation and in vitro evaluation of Hydrodynamically balanced system for theophylline delivery.

PubMed

Nayak, Amit Kumar; Malakar, Jadupati

2011-06-01

The objective of the present study was to formulate hydrodynamically balanced systems (HBSs) of theophylline as single unit capsules. They were formulated by physical blending of theophylline with hydroxypropyl methyl cellulose, polyethylene oxide, polyvinyl pyrrolidone, ethyl cellulose, liquid paraffin, and lactose in different ratios. These theophylline HBS capsules were evaluated for weight uniformity, drug content uniformity, in vitro floating behavior and drug release in simulated gastric fluids (pH 1.2). All these formulated HBS capsules containing theophylline were floated well over 6 hours with no floating lag time, and also showed sustained in vitro drug release in simulated gastric fluid over 6 hours. The theophylline release from these capsules was more sustained with the addition of release modifiers (ethyl cellulose and liquid paraffin). The drug release pattern from these capsules was correlated well with first order model (F-1 to F-5) and Korsmeyer-Peppas model (F-6 and F-7) with the non-Fickian (anomalous) diffusion mechanism. These experimental results clearly indicated that these theophylline HBS capsules were able to remain buoyant in the gastric juice for longer period, which may improve oral bioavailability of theophylline.

Application of in vitro biopharmaceutical methods in development of immediate release oral dosage forms intended for paediatric patients.

PubMed

Batchelor, Hannah K; Kendall, Richard; Desset-Brethes, Sabine; Alex, Rainer; Ernest, Terry B

2013-11-01

Biopharmaceutics is routinely used in the design and development of medicines to generate science based evidence to predict in vivo performance; the application of this knowledge specifically to paediatric medicines development is yet to be explored. The aim of this review is to present the current status of available biopharmaceutical tools and tests including solubility, permeability and dissolution that may be appropriate for use in the development of immediate release oral paediatric medicines. The existing tools used in adults are discussed together with any limitations for their use within paediatric populations. The results of this review highlight several knowledge gaps in current methodologies in paediatric biopharmaceutics. The authors provide recommendations based on existing knowledge to adapt tests to better represent paediatric patient populations and also provide suggestions for future research that may lead to better tools to evaluate paediatric medicines. Copyright © 2013 Elsevier B.V. All rights reserved.

Application of design of experiment for polyox and xanthan gum coated floating pulsatile delivery of sumatriptan succinate in migraine treatment.

PubMed

Jagdale, Swati C; Pawar, Chandrakala R

2014-01-01

Migraine follows circadian rhythm in which headache is more painful at the awakening time. This needs administration of dosage form at night time to release drug after lag period when pain gets worse. Sumatriptan succinate is a drug of choice for migraine. Sumatriptan succinate has bitter taste, low oral bioavailability, and shorter half-life. Present work deals with application of design of experiment for polyox and xanthan gum in development of press coated floating pulsatile tablet. Floating pulsatile concept was applied to increase gastric residence of the dosage form. Burst release was achieved through immediate release tablet using crospovidone as superdisintegrant (10%). Pulse lag time was achieved using swellable polymer polyox WSR 205 and xanthan gum. 3(2) experimental design was applied. Optimized formulation was evaluated for physical characteristics and in-vitro and in-vivo study. From results, it can be concluded that optimized batch F8 containing polyox WSR205 (72.72%) and xanthan gum (27.27%) of total weight of polymer has shown floating lag time of 55 ± 2 sec, drug content of 100.35 ± 0.4%, hardness of 6 ± 0.1 Kg/cm(2), and 98.69 ± 2% drug release in pulse manner with lag time of 7 ± 0.1 h. Optimized batch showed prolong gastric residence which was confirmed by in-vivo X-ray study.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics

PubMed Central

Ahmed, Osama AA; Hosny, Khaled M; Al-Sawahli, Majid M; Fahmy, Usama A

2015-01-01

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid–liquid phase separation method, according to the Box–Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance. PMID:25670883

Biowaiver monographs for immediate release solid oral dosage forms: efavirenz.

PubMed

Cristofoletti, Rodrigo; Nair, Anita; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Dressman, Jennifer B

2013-02-01

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products. Copyright © 2012 Wiley Periodicals, Inc.

Biowaiver monograph for immediate-release solid oral dosage forms: acetylsalicylic acid.

PubMed

Dressman, Jennifer B; Nair, Anita; Abrahamsson, Bertil; Barends, Dirk M; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Zimmer, Markus

2012-08-01

A biowaiver monograph for acetylsalicylic acid (ASA) is presented. Literature and experimental data indicate that ASA is a highly soluble and highly permeable drug, leading to assignment of this active pharmaceutical ingredient (API) to Class I of the Biopharmaceutics Classification System (BCS). Limited bioequivalence (BE) studies reported in the literature indicate that products that have been tested are bioequivalent. Most of the excipients used in products with a marketing authorization in Europe are not considered to have an impact on gastrointestinal motility or permeability. Furthermore, ASA has a wide therapeutic index. Thus, the risks to the patient that might occur if a nonbioequivalent product were to be incorrectly deemed bioequivalent according to the biowaiver procedure appear to be minimal. As a result, the BCS-based biowaiver procedure can be recommended for approval of new formulations of solid oral dosage forms containing ASA as the only API, including both multisource and reformulated products, under the following conditions: (1) excipients are chosen from those used in ASA products already registered in International Conference on Harmonization and associated countries and (2) the dissolution profiles of the test and the comparator products comply with the BE guidance. Copyright © 2012 Wiley Periodicals, Inc.

Disintegration of highly soluble immediate release tablets: a surrogate for dissolution.

PubMed

Gupta, Abhay; Hunt, Robert L; Shah, Rakhi B; Sayeed, Vilayat A; Khan, Mansoor A

2009-01-01

The purpose of the work was to investigate correlation between disintegration and dissolution for immediate release tablets containing a high solubility drug and to identify formulations where disintegration test, instead of the dissolution test, may be used as the acceptance criteria based on International Conference on Harmonization Q6A guidelines. A statistical design of experiments was used to study the effect of filler, binder, disintegrating agent, and tablet hardness on the disintegration and dissolution of verapamil hydrochloride tablets. All formulation variables, i.e., filler, binder, and disintegrating agent, were found to influence tablet dissolution and disintegration, with the filler and disintegrating agent exerting the most significant influence. Slower dissolution was observed with increasing disintegration time when either the filler or the disintegrating agent was kept constant. However, no direct corelationship was observed between the disintegration and dissolution across all formulations due to the interactions between different formulation components. Although all tablets containing sodium carboxymethyl cellulose as the disintegrating agent, disintegrated in less than 3 min, half of them failed to meet the US Pharmacopeia 30 dissolution criteria for the verapamil hydrochloride tablets highlighting the dependence of dissolution process on the formulation components other than the disintegrating agent. The results identified only one formulation as suitable for using the disintegration test, instead of the dissolution test, as drug product acceptance criteria and highlight the need for systematic studies before using the disintegration test, instead of the dissolution test as the drug acceptance criteria.

A novel spray-dried nanoparticles-in-microparticles system for formulating scopolamine hydrobromide into orally disintegrating tablets.

PubMed

Li, Feng-Qian; Yan, Cheng; Bi, Juan; Lv, Wei-Lin; Ji, Rui-Rui; Chen, Xu; Su, Jia-Can; Hu, Jin-Hong

2011-01-01

Scopolamine hydrobromide (SH)-loaded microparticles were prepared from a colloidal fluid containing ionotropic-gelated chitosan nanoparticles using a spray-drying method. The spray-dried microparticles were then formulated into orally disintegrating tablets (ODTs) using a wet granulation tablet formation process. A drug entrapment efficiency of about 90% (w/w) and loading capacity of 20% (w/w) were achieved for the microparticles, which ranged from 2 μm to 8 μm in diameter. Results of disintegration tests showed that the formulated ODTs could be completely dissolved within 45 seconds. Drug dissolution profiles suggested that SH is released more slowly from tablets made using the microencapsulation process compared with tablets containing SH that is free or in the form of nanoparticles. The time it took for 90% of the drug to be released increased significantly from 3 minutes for conventional ODTs to 90 minutes for ODTs with crosslinked microparticles. Compared with ODTs made with noncrosslinked microparticles, it was thus possible to achieve an even lower drug release rate using tablets with appropriate chitosan crosslinking. Results obtained indicate that the development of new ODTs designed with crosslinked microparticles might be a rational way to overcome the unwanted taste of conventional ODTs and the side effects related to SH's intrinsic characteristics.

Nanoemulsion-based gel formulation of diclofenac diethylamine: design, optimization, rheological behavior and in vitro diffusion studies.

PubMed

Hamed, Rania; Basil, Marwa; AlBaraghthi, Tamadur; Sunoqrot, Suhair; Tarawneh, Ola

2016-12-01

Chronic oral administration of the non-steroidal anti-inflammatory drug, diclofenac diethylamine (DDEA), is often associated with gastrointestinal ulcers and bleeding. As an alternative to oral administration, a nanoemulsion-based gel (NE gel) formulation of DDEA was developed for topical administration. An optimized formulation for the o/w nanoemulsion of oil, surfactant and cosurfactant was selected based on nanoemulsion mean droplet size, clarity, stability, and flowability, and incorporated into the gelling agent Carbopol® 971P. Rheological studies of the DDEA NE gel were conducted and compared to those of conventional DDEA gel and emulgel. The three gels exhibited an elastic behavior, where G' dominated G″ at all frequencies, indicating the formation of strong gels. NE gel exhibited higher G' values than conventional gel and emulgel, which indicated the formation of a stronger gel network. Strat-M® membrane, a synthetic membrane with diffusion characteristics that are well correlated to human skin, was used for the in vitro diffusion studies. The release of DDEA from conventional gel, emulgel and NE gel showed a controlled release pattern over 12 h, which was consistent with the rheological properties of the gels. DDEA release kinetics from the three gels followed super case II transport as fitted by Korsmeyer-Peppas model.

A novel spray-dried nanoparticles-in-microparticles system for formulating scopolamine hydrobromide into orally disintegrating tablets

PubMed Central

Li, Feng-Qian; Yan, Cheng; Bi, Juan; Lv, Wei-Lin; Ji, Rui-Rui; Chen, Xu; Su, Jia-Can; Hu, Jin-Hong

2011-01-01

Scopolamine hydrobromide (SH)-loaded microparticles were prepared from a colloidal fluid containing ionotropic-gelated chitosan nanoparticles using a spray-drying method. The spray-dried microparticles were then formulated into orally disintegrating tablets (ODTs) using a wet granulation tablet formation process. A drug entrapment efficiency of about 90% (w/w) and loading capacity of 20% (w/w) were achieved for the microparticles, which ranged from 2 μm to 8 μm in diameter. Results of disintegration tests showed that the formulated ODTs could be completely dissolved within 45 seconds. Drug dissolution profiles suggested that SH is released more slowly from tablets made using the microencapsulation process compared with tablets containing SH that is free or in the form of nanoparticles. The time it took for 90% of the drug to be released increased significantly from 3 minutes for conventional ODTs to 90 minutes for ODTs with crosslinked microparticles. Compared with ODTs made with noncrosslinked microparticles, it was thus possible to achieve an even lower drug release rate using tablets with appropriate chitosan crosslinking. Results obtained indicate that the development of new ODTs designed with crosslinked microparticles might be a rational way to overcome the unwanted taste of conventional ODTs and the side effects related to SH’s intrinsic characteristics. PMID:21720502

Innovation of novel 'Tab in Tab' system for release modulation of milnacipran HCl: optimization, formulation and in vitro investigations.

PubMed

Parejiya, Punit B; Barot, Bhavesh S; Patel, Hetal K; Shelat, Pragna K; Shukla, Arunkumar

2013-11-01

The study was aimed toward development of modified release oral drug delivery system for highly water soluble drug, Milnacipran HCl (MH). Novel Tablet in Tablet system (TITs) comprising immediate and extended release dose of MH in different parts was fabricated. The outer shell was composed of admixture of MH, lactose and novel herbal disintegrant obtained from seeds of Lepidium sativum. In the inner core, MH was matrixed with blend of hydrophilic (Benecel®) and hydrophobic (Compritol®) polymers. 3² full factorial design and an artificial neuron network (ANN) were employed for correlating effect of independent variables on dependent variables. The TITs were characterized for pharmacopoeial specifications, in vitro drug release, SEM, drug release kinetics and FTIR study. The release pattern of MH from batch A10 containing 25.17% w/w Benecel® and 8.21% w/w of Compritol® exhibited drug release pattern close proximal to the ideal theoretical profile (t(50%) = 5.92 h, t(75%) = 11.9 h, t(90%) = 18.11 h). The phenomenon of drug release was further explained by concept of percolation and the role of Benecel® and Compritol® in drug release retardation was studied. The normalized error obtained from ANN was less, compared with the multiple regression analysis, and exhibits the higher accuracy in prediction. The results of short-term stability study revealed stable chataracteristics of TITs. SEM study of TITs at different dissolution time points confirmed both diffusion and erosion mechanisms to be operative during drug release from the batch A10. Novel TITs can be a succesful once a day delivery system for highly water soluble drugs.

The metamorphosis of hydromorphone.

PubMed

Reisfield, Gary M; Wilson, George R

2005-01-01

Hydromorphone, one of the oldest and most potent of opioids, is an effective alternative to morphine. With a variety of routes of administration, it has an efficacy similar to that of morphine. The FDA has recently approved the first commercially available extended-release formulation, a once-daily hydromorphone for the management of moderate to severe pain in opioid tolerant individuals with an anticipated extended period of use. The formulation exhibits less peak-to-trough fluctuation in plasma concentration, while providing analgesia statistically indistinguishable from its immediate-release counterpart. The manufacturer and the FDA have articulated a plan to minimize unskillful prescribing and abuse/diversion through education, supply-chain integrity, and surveillance. It is anticipated that Palladone will be a valuable addition to the limited armamentarium of extended-release opioids.

Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release.

PubMed

Mahjub, Reza; Dorkoosh, Farid Abedin; Rafiee-Tehrani, Morteza; Bernkop Schnürch, Andreas

2015-01-01

It was the aim of this study to evaluate the impact of lipases on the release behaviour of a peptide drug from oral self-nanoemulsifying drug delivery systems. Octreotide was ion paired with the anionic surfactants deoxycholate, decanoate, oleate and dodecylsulphate. The lipophilic character of these complexes was characterised by determining the n-octanol/buffer pH 7.4 partition coefficient. In the following the most hydrophilic complex was incorporated in a likely lipase degradable self-nanoemulsifying drug delivery systems (SNEDDS) formulation containing a triglyceride (olive oil; Pharm.Eur.) and in a likely not lipase degradable SNEDDS containing lipids and surfactants without any ester bonds. After 1:100 dilutions in artificial intestinal fluid (AIF), the lipid droplets were characterised regarding size distribution. With these SNEDDS, drug release studies were performed in AIF with and without lipase. Results showed that the most hydrophobic complex can be formed with deoxycholate in an octreotide:anionic surfactant ratio of 1:5. Even 73.1 ± 8.1% of it could be quantified in the n-octanol phase. SNEDDS containing octreotide | olive oil | cremophor EL | propylene glycol (2|57|38|3) and octreotide | liquid paraffin | Brij 35 | propylene glycol | ethanol (2|66.5|25|5|1.5) showed after dilution in AIF, a mean droplet size of 232 ± 53 nm and 235 ± 50 nm, respectively. Drug release studies showed a sustained release of octreotide out of these formulations for at least 24 h, whereas > 80% of the drug was released within 2 h in the presence of lipase in the case of the triglyceride containing SNEEDS. In contrast the release profile from ester-free SNEDDS was not significantly altered (p < 0.05) due to the addition of lipase providing evidence for the stability of this formulation towards lipases. According to these results, SNEDDS could be identified as a useful tool for sustained oral peptide delivery taking an enzymatic degradation by intestinal lipases into considerations.

Thiolation of arabinoxylan and its application in the fabrication of controlled release mucoadhesive oral films.

PubMed

Hanif, Muhammad; Zaman, Muhammad

2017-03-20

Mucoadhesion is an important property that helps oral drug delivery system to remain attached with buccal mucosa and hence to improve the delivery of the drug. The current study was designed to achieve the thiol modification of Arabinoxylan (ARX) and to develop a mucoadhesive oral film for the improved delivery of tizanidine hydrochloride (TZN HCl). Synthesis of thiolated arabinoxylan (TARX) was accomplished by esterification of ARX with thioglycolic acid (TGA). TARX was further used for the development of mucoadhesive oral films which were prepared by using a solvent casting technique. Formulation of the films was designed and optimized by using central composite design (CCRD), selecting TARX (X 1 ) and glycerol (X 2 ) as variables. Prepared film formulations were evaluated for mechanical strength, ex-vivo mucoadhesion, in-vitro drug release, ex-vivo drug permeation, surface morphology and drug contents. Thiolation of ARX was confirmed by fourier transform infra-red spectroscopy (FTIR) as a peak related to thiol group appeared at 2516 cm -1 . The claim of successful thiolation of ARX was strengthened by the presence of 2809.003 ± 1.03 μmoles of thiol contents per gram of the polymer, which was determined by Ellman's reagent method. From the results, it was observed that the films were of satisfactory mechanical strength and mucoadhesiveness with folding endurance greater than 300 and mucoadhesive strength 11.53 ± 0.17 N, respectively. Reasonable drug retention was observed during in-vitro dissolution (85.03% cumulative drug release) and ex-vivo permeation (78.90% cumulative amount of permeated drug) studies conducted for 8 h. Effects of varying concentrations of both polymer and plasticizer on prepared mucoadhesive oral films were evaluated by ANOVA and it was observed that glycerol can enhanced the dissolution as well as permeation of the drug while TARX has opposite impact on these parameters. In nutshell, TARX in combination with glycerolwas found to be suitable for the development of controlled release mucoadhesive oral films of TZN HCl. Schematic diagram showing conversion of ARX to TARX, TARX to oral film and evaluation of fabricated oral film.

Formulation and evaluation of diclofenac controlled release matrix tablets made of HPMC and Poloxamer 188 polymer: An assessment on mechanism of drug release.

PubMed

Al-Hanbali, Othman A; Hamed, Rania; Arafat, Mosab; Bakkour, Youssef; Al-Matubsi, Hisham; Mansour, Randa; Al-Bataineh, Yazan; Aldhoun, Mohammad; Sarfraz, Muhammad; Dardas, Abdel Khaleq Yousef

2018-01-01

In this study, hydrophilic hydroxypropyl methylcellulose matrices with various concentrations of Poloxamer 188 were used in the development of oral controlled release tablets containing diclofenac sodium. Four formulations of hydrophilic matrix tablets containing 16.7% w/w HPMC and 0, 6.7, 16.7 and 25.0% w/w Poloxamer 188, respectively, were developed. Tablets were prepared by direct compression and characterized for diameter, hardness, thickness, weight and uniformity of content. The influence of various blends of hydroxypropyl methylcellulose and Poloxamer 188 on the in vitro dissolution profile and mechanism of drug release of was investigated. In the four formulations, the rate of drug release decreased with increasing the concentration of Poloxamer 188 at the initial dissolution stages due to the increase in the apparent viscosity of the gel diffusion layer. However, in the late dissolution stages, the rate of drug release increased with increasing Poloxamer 188 concentration due to the increase in wettability and dissolution of the matrix. The kinetic of drug release from the tablets followed non-Fickian mechanism, as predicted by Korsmeyer-Peppas model, which involves diffusion through the gel layer and erosion of the matrix system.

Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing.

PubMed

Goyanes, Alvaro; Chang, Hanah; Sedough, Daniel; Hatton, Grace B; Wang, Jie; Buanz, Asma; Gaisford, Simon; Basit, Abdul W

2015-12-30

The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D printing (3DP) technology with hot melt extrusion (HME) and fluid bed coating to fabricate modified-release budesonide dosage forms. Budesonide was sucessfully loaded into polyvinyl alcohol filaments using HME. The filaments were engineered into capsule-shaped tablets (caplets) containing 9mg budesonide using a FDM 3D printer; the caplets were then overcoated with a layer of enteric polymer. The final printed formulation was tested in a dynamic dissolution bicarbonate buffer system, and two commercial budesonide products, Cortiment® (Uceris®) and Entocort®, were also investigated for comparison. Budesonide release from the Entocort® formulation was rapid in conditions of the upper small intestine while release from the Cortiment® product was more delayed and very slow. In contrast, the new 3D printed caplet formulation started to release in the mid-small intestine but release then continued in a sustained manner throughout the distal intestine and colon. This work has demonstrated the potential of combining FDM 3DP with established pharmaceutical processes, including HME and film coating, to fabricate modified release oral dosage forms. Copyright © 2015. Published by Elsevier B.V.

Silymarin in liposomes and ethosomes: pharmacokinetics and tissue distribution in free-moving rats by high-performance liquid chromatography-tandem mass spectrometry.

PubMed

Chang, Li-Wen; Hou, Mei-Ling; Tsai, Tung-Hu

2014-12-03

The aim of this study was to prepare silymarin formulations (silymarin entrapped in liposomes and ethosomes, formulations referred to as LSM and ESM, respectively) to improve oral bioavailability of silymarin and evaluate its tissue distribution by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in free-moving rats. Silibinin is the major active constituent of silymarin, which is the main component to be analyzed. A rapid, sensitive, and repeatable LC-MS/MS method was developed and validated in terms of precision, accuracy, and extraction recovery. Furthermore, the established method was applied to study the pharmacokinetics and tissue distribution of silymarin in rats. The size, ζ potential, and drug release of the formulations were characterized. These results showed that the LSM and ESM encapsulated formulations of silymarin may provide more efficient tissue distribution and increased oral bioavailability, thus improving its therapeutic bioactive properties in the body.

A Novel Self-Microemulsifying System for the Simultaneous Delivery and Enhanced Oral Absorption of Curcumin and Resveratrol.

PubMed

Jaisamut, Patcharawalai; Wiwattanawongsa, Kamonthip; Wiwattanapatapee, Ruedeekorn

2017-03-01

The use of curcumin and resveratrol in combination has now become increasingly of interest because of their synergistic effects as therapeutic agents for various diseases, especially cancer. To overcome the poor oral bioavailability of both compounds and improve patient compliance, a novel self-microemulsifying formulation containing curcumin together with resveratrol was developed. Capryol 90, Cremophor EL, and Labrasol were selected as the oil, surfactant, and co-surfactant in the formulation, respectively, based on the solubility study of both compounds. More than 70 % and 80 % of curcumin and resveratrol, respectively, were released in 20 min. The formulation formed a fine oil in water microemulsion with droplet sizes in aqueous media of 15-20 nm. In addition, the formulation containing curcumin and resveratrol showed greater antioxidant activity than that of the formulations with individual compounds, while the cytotoxic activity against HT-29 of the co-formulation (IC 50  = 18.25 µM; curcumin and resveratrol in the ratio 1 : 1) was less than the formulation with only curcumin (IC 50  = 30.1 µM) and only resveratrol (IC 50  = 25.4 µM). After oral administration to rabbits, the self-microemulsifying formulation containing curcumin together with resveratrol increased the total plasma concentrations of curcumin and resveratrol by 10-fold and 6-fold, respectively, compared to the unformulated combination. This study clearly demonstrated the potential use of the self-microemulsifying formulation for co-delivery, and enhanced oral absorption of poorly water-soluble natural compounds. In addition, the combination was found to produce synergistic antioxidant activity and cytotoxicity against HT-29 cells. Georg Thieme Verlag KG Stuttgart · New York.

Building in efficacy: developing solutions to combat drug-resistant S. pneumoniae.

PubMed

Jacobs, M R

2004-04-01

The development of our understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine antimicrobial efficacy has advanced substantially over the last 10 years. We are now in a position to use PK/PD principles to set targets for antimicrobial design and optimisation so that we can predict eradication of specific pathogens or resistant variants when agents are used clinically. Optimisation of PK/PD parameters to enable the treatment of resistant pathogens with oral agents may not be possible with many current agents, such as some cephalosporins, macrolides and fluoroquinolones. Aminopenicillins, however, such as amoxicillin, have linear PK and have a good safety profile even at high doses. The new pharmacokinetically enhanced oral formulation of amoxicillin/clavulanate, 2000/125 mg twice daily, was designed using PK/PD principles to be able to eradicate Streptococcus pneumoniae with amoxicillin MICs of up to and including 4 mg/L, which includes most penicillin-resistant isolates. For amoxicillin and amoxicillin/clavulanate, a time above MIC (T > MIC) of 35-40% of the dosing interval (based on blood levels) is predictive of high bacteriological efficacy. This target was met by the design of a unique bilayer tablet incorporating 437.5 mg of sustained-release sodium amoxicillin in one layer plus 562.5 mg of immediate-release amoxicillin trihydrate and 62.5 mg of clavulanate potassium in the second layer, with two tablets administered for each dose. This unique design extends the bacterial killing time by increasing the T > MIC to 49% of the dosing interval against pathogens with MICs of 4 mg/L, and 60% of the dosing interval against pathogens with MICs of 2 mg/L. Based on these results, this new amoxicillin/clavulanate formulation should be highly effective in treating respiratory tract infections due to drug-resistant S. pneumoniae as well as beta-lactamase-producing pathogens, such as Haemophilus influenzae and Moraxella catarrhalis.

Development of near zero-order release dosage forms using three-dimensional printing (3-DP) technology.

PubMed

Wang, Chen-Chao; Tejwani Motwani, Monica R; Roach, Willie J; Kay, Jennifer L; Yoo, Jaedeok; Surprenant, Henry L; Monkhouse, Donald C; Pryor, Timothy J

2006-03-01

Three near zero-order controlled-release pseudoephedrine hydrochloride (PEH) formulations demonstrating proportional release rates were developed using 3-Dimensional Printing (3-DP) technology. Mixtures of Kollidon SR and hydroxypropylmethyl cellulose (HPMC) were used as drug carriers. The release rates were adjusted by varying the Kollidon SR-HPMC ratio while keeping fabrication parameters constant. The dosage forms were composed of an immediate release core and a release rate regulating shell, fabricated with an aqueous PEH and an ethanolic triethyl citrate (TEC) binder, respectively. The dosage form design called for the drug to be released via diffusional pathways formed by HPMC in the shell matrix. The release rate was shown to increase correspondingly with the fraction of HPMC contained in the polymer blend. The designed formulations resulted in dosage forms that were insensitive to changes in pH of the dissolution medium, paddle stirring rate, and the presence/absence of a sinker. The near zero-order release properties were unchanged regardless of the dissolution test being performed on either single cubes or on a group of eight cubes encased within a gelatin capsule shell. The chemical and dissolution properties of the three formulations remained unchanged following 1 month's exposure to 25 degrees C/60% RH or 40 degrees C/75% RH environment under open container condition. The in vivo performance of the three formulations was evaluated using a single-dose, randomized, open-label, four-way crossover clinical study composed of 10 fasted healthy volunteers. The pharmacokinetic parameters were analyzed using a noncompartmental model. Qualitative rank order linear correlations between in vivo absorption profiles and in vitro dissolution parameters (with slope and intercept close to unity and origin, respectively) were obtained for all three formulations, indicating good support for a Level A in vivo/in vitro correlation.

Preparation of acetaminophen capsules containing beads prepared by hot-melt direct blend coating.

PubMed

Pham, Loan; Christensen, John M

2014-02-01

Twelve hydrophobic coating agents were assessed for their effects on drug release after coating sugar cores by a flexible hot-melt coating method using direct blending. Drug-containing pellets were also produced and used as cores. The cores were coated with single or double wax layers containing acetaminophen (APAP). The harder the wax, the slower the resultant drug releases from single-coated beads. Wax coating can be deposited on cores up to 28% of the beads final weight and reaching 58% with wax and drug. Carnauba-coated beads dissolved in approximately 6 h releasing 80% of the loaded drug. Applying another wax layer extended drug release over 20 h, while still delivering 80% of the loaded drug. When drug-containing pellets (33-58% drug loading) were used as cores, double wax-coated pellets exhibited a near zero-order drug release for 16 h, releasing 80% of the loaded drug delivering 18 mg/h. The simple process of hot-melt coating by direct blending of pellet-containing drug-coated formulations provides excellent options for immediate and sustained release formulations when higher lipid coating or drug loading is warranted. Predicted plasma drug concentration time profiles using convolution and in vitro drug release properties of the beads were performed for optimal formulations.

Oxycodone: a pharmacological and clinical review.

PubMed

Ordóñez Gallego, A; González Barón, M; Espinosa Arranz, E

2007-05-01

Oxycodone is a semi-synthetic opioid with an agonist activity on mu, kappa and delta receptors. Equivalence with regard to morphine is 1:2. Its effect commences one hour after administration and lasts for 12 h in the controlled-release formulation. Plasma halflife is 3-5 h (half that of morphine) and stable plasma levels are reached within 24 h (2-7 days for morphine). Oral bioavailability ranges from 60 to 87%, and plasma protein binding is 45%. Most of the drug is metabolised in the liver, while the rest is excreted by the kidney along with its metabolites. The two main metabolites are oxymorphone--which is also a very potent analgesic--and noroxycodone, a weak analgesic. Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier. Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarisation of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. The clinical efficacy of oxycodone is similar to that of morphine, with a ratio of 1/1.5-2 for the treatment of cancer pain. Long-term administration may be associated with less toxicity in comparison with morphine. In the future, both opioids could be used simultaneously at low doses to reduce toxicity. It does not appear that there are any differences between immediate and slow-release oxycodone, except their half-life is 3-4 h, and 12 h, respectively. In Spain, controlled-release oxycodone (OxyContin) is marketed as 10-, 20-, 40- or 80-mg tablets for b.i.d. administration. Tablets must be taken whole and must not be broken, chewed or crushed. There is no food interference. The initial dose is 10 mg b.i.d. for new treatments and no dose reduction is needed in the elderly or in cases of moderate hepatic or renal failure. Immediate-release oxycodone (OxyNorm) is also available in capsules and oral solution. Side effects are those common to opioids: mainly nausea, constipation and drowsiness. Vomiting, pruritus and dizziness are less common. The intensity of these side effects tends to decrease over the course of time. Oxycodone causes somewhat less nausea, hallucinations and pruritus than morphine.

Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers.

PubMed

Kesisoglou, Filippos; Rossenu, Stefaan; Farrell, Colm; Van Den Heuvel, Michiel; Prohn, Marita; Fitzpatrick, Shaun; De Kam, Pieter-Jan; Vargo, Ryan

2014-11-01

Development of in vitro-in vivo correlations (IVIVCs) for extended-release (ER) products is commonly pursued during pharmaceutical development to increase product understanding, set release specifications, and support biowaivers. This manuscript details the development of Level C and Level A IVIVCs for ER formulations of niacin, a highly variable and extensively metabolized compound. Three ER formulations were screened in a cross-over study against immediate-release niacin. A Multiple Level C IVIVC was established for both niacin and its primary metabolite nicotinuric acid (NUA) as well as total niacin metabolites urinary excretion. For NUA, but not for niacin, Level A IVIVC models with acceptable prediction errors were achievable via a modified IVIVC rather than a traditional deconvolution/convolution approach. Hence, this is in contradiction with current regulatory guidelines that suggest that when a Multiple Level C IVIVC is established, Level A models should also be readily achievable. We demonstrate that for a highly variable, highly metabolized compound such as niacin, development of a Level A IVIVC model fully validated according to agency guidelines may be challenging. However, Multiple Level C models are achievable and could be used to guide release specifications and formulation/manufacturing changes. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Glipizide. A review of the pharmacoeconomic implications of the extended-release formulation in type 2 diabetes mellitus.

PubMed

Foster, R H; Plosker, G L

2000-09-01

Glipizide is a second generation sulphonylurea agent that is available in a Gastrointestinal Therapeutic System (GITS) extended-release formulation. Glipizide GITS provides more stable plasma drug concentrations than the immediate-release formulation and the once-daily regimen may optimise patient compliance. In patients with type 2 diabetes mellitus, glipizide GITS is at least as effective as the immediate-release formulation of glipizide in providing glycaemic control, and may have a greater effect on fasting plasma glucose levels. Any therapeutic advantage over other antidiabetic agents remains to be established, but in a preliminary report (n = 40) glipizide GITS provided better glycaemic control and produced less fasting insulinaemia than glibenclamide (glyburide). The incidence of hypoglycaemic symptoms with glipizide GITS is low (< or = 3%). Quality of life was improved compared with baseline after 12 weeks' treatment with glipizide GITS 5 to 20 mg/day plus diet in a US double-blind, placebo-controlled trial in 569 patients with type 2 diabetes mellitus. Hyperglycaemic symptom-related distress decreased with glipizide GITS treatment, while hypoglycaemic symptom-related distress was not significantly increased compared with placebo plus diet. Quality of life during glipizide GITS treatment has not been compared with that during treatment with other antidiabetic agents. Monthly productivity losses related to absenteeism were $US91 (1995 values) per patient lower in the glipizide GITS group compared with the placebo group in the latter prospective study. Productivity parameters improved slightly or did not change significantly in the glipizide GITS group, but deteriorated in the placebo group. Differences in direct healthcare costs between groups were small and not comprehensively reported. Glipizide GITS was the least costly strategy for first-line therapy in a US cost-of-treatment model of the first 3 years after diagnosis of type 2 diabetes mellitus. The total per-patient cost was $US4867 with glipizide GITS, $US5196 with metformin and $US5249 with acarbose (1996/1997 values). Monthly drug acquisition costs were lower, and glycosylated haemoglobin levels and patient compliance were improved, after formulary conversion from the immediate-release to the GITS formulation of glipizide in a US single-hospital retrospective analysis. Glipizide GITS produced better cost outcomes than metformin and acarbose in a model of 3 years' treatment of type 2 diabetes mellitus. Glipizide GITS had pharmacoeconomic and quality of life advantages over diet alone in the short term, but more clinically relevant comparisons with other antidiabetic agents are needed. There are limitations to the present data, but the available pharmacoeconomic data have been favourable for glipizide GITS.

Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability.

PubMed

Johnson, Franklin; Setnik, Beatrice

2011-01-01

Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain, contain pellets of extended-release morphine sulfate with a sequestered naltrexone core (MS-sNT). Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered with by crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessary to establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it is also necessary to demonstrate that product therapeutic integrity is maintained for patients. Data were reviewed from 3 studies to determine: 1) the quantity of naltrexone released when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar and pestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-induced subjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MS-sNT is taken as directed. The naltrexone bioavailability study compared naltrexone release from MS-sNTC with that from whole intact MS-sNT capsules (MS-sNTW) and an equal naltrexone solution (NS) dose. Equivalent bioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximum plasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated to infinity [AUC∞]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug liking and euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphine sulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safety of MS-sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safety assessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS). Naltrexone from MS-sNTC met criteria for equivalent bioavailability to NS. Although morphine relative bioavailability was similar for MS-sNTC and MSS, mean peak (Emax) visual analog scale (VAS) scores for drug liking and Cole/Addiction Research Center Inventory Stimulation-Euphoria were significantly reduced for MS-sNTC vs MSS (p < 0.001). In these 2 studies, a total of 6 participants had one measurement of plasma naltrexone after MS-sNTW that was above the lower limit of quantification. In the OL safety study, 72/93 participants (77%) had no quantifiable naltrexone concentrations. There was neither evidence of naltrexone accumulation for any participant nor any significant correlation with MS-sNT dose, age, or sex. Of 4 participants with the highest naltrexone concentrations, none had COWS scores consistent with moderate opioid withdrawal symptoms. Only 5 participants had COWS scores consistent with moderate opioid withdrawal; all 5 had not taken MS-sNT as directed. Study populations may not be fully representative of patients receiving opioid therapy for the management of chronic, moderate-to-severe pain and of opioid abusers. When MS-sNT capsules are crushed, all of the sequestered naltrexone (relative to oral NS) is released and immediately available to mitigate morphine-induced effects. When MS-sNT was crushed, the naltrexone released abated drug liking and euphoria relative to that from an equal dose of immediate-release morphine from MSS administration in a majority of participants. Naltrexone concentrations were low over a period of 12 months without evidence of accumulation, and there were no observable opioid withdrawal symptoms when MS-sNT was taken as directed.

pH-sensitive poly(lactide-co-glycolide) nanoparticle composite microcapsules for oral delivery of insulin

PubMed Central

Sun, Shaoping; Liang, Na; Yamamoto, Hiromitsu; Kawashima, Yoshiaki; Cui, Fude; Yan, Pengfei

2015-01-01

This study proposes a new concept of pH-sensitive poly(lactide-co-glycolide) (PLGA) nanoparticle composite microcapsules for oral delivery of insulin. Firstly, insulin–sodium oleate complex was prepared by the hydrophobic ion pairing method and then encapsulated into PLGA nanoparticles by the emulsion solvent diffusion method. In order to reduce the burst release of insulin from PLGA nanoparticles and deliver insulin to specific gastrointestinal regions, hence to enhance bioavailability of insulin, the PLGA nanoparticles were further encapsulated into Eudragit® FS 30D to prepare PLGA nanoparticle composite microcapsules by organic spray-drying method. The preparation was evaluated in vitro and in vivo, and the absorption mechanism was discussed. The in vitro drug release studies revealed that the drug release was pH dependent, and the in vivo results demonstrated that the formulation of PLGA nanoparticle composite microcapsules was an effective candidate for oral insulin delivery. PMID:25999713

pH-sensitive poly(lactide-co-glycolide) nanoparticle composite microcapsules for oral delivery of insulin.

PubMed

Sun, Shaoping; Liang, Na; Yamamoto, Hiromitsu; Kawashima, Yoshiaki; Cui, Fude; Yan, Pengfei

2015-01-01

This study proposes a new concept of pH-sensitive poly(lactide-co-glycolide) (PLGA) nanoparticle composite microcapsules for oral delivery of insulin. Firstly, insulin-sodium oleate complex was prepared by the hydrophobic ion pairing method and then encapsulated into PLGA nanoparticles by the emulsion solvent diffusion method. In order to reduce the burst release of insulin from PLGA nanoparticles and deliver insulin to specific gastrointestinal regions, hence to enhance bioavailability of insulin, the PLGA nanoparticles were further encapsulated into Eudragit(®) FS 30D to prepare PLGA nanoparticle composite microcapsules by organic spray-drying method. The preparation was evaluated in vitro and in vivo, and the absorption mechanism was discussed. The in vitro drug release studies revealed that the drug release was pH dependent, and the in vivo results demonstrated that the formulation of PLGA nanoparticle composite microcapsules was an effective candidate for oral insulin delivery.

Food, gastrointestinal pH, and models of oral drug absorption.

PubMed

Abuhelwa, Ahmad Y; Williams, Desmond B; Upton, Richard N; Foster, David J R

2017-03-01

This article reviews the major physiological and physicochemical principles of the effect of food and gastrointestinal (GI) pH on the absorption and bioavailability of oral drugs, and the various absorption models that are used to describe/predict oral drug absorption. The rate and extent of oral drug absorption is determined by a complex interaction between a drug's physicochemical properties, GI physiologic factors, and the nature of the formulation administered. GI pH is an important factor that can markedly affect oral drug absorption and bioavailability as it may have significant influence on drug dissolution & solubility, drug release, drug stability, and intestinal permeability. Different regions of the GI tract have different drug absorptive properties. Thus, the transit time in each GI region and its variability between subjects may contribute to the variability in the rate and/or extent of drug absorption. Food-drug interactions can result in delayed, decreased, increased, and sometimes un-altered drug absorption. Food effects on oral absorption can be achieved by direct and indirect mechanisms. Various models have been proposed to describe oral absorption ranging from empirical models to the more sophisticated "mechanism-based" models. Through understanding of the physicochemical and physiological rate-limiting factors affecting oral absorption, modellers can implement simplified population-based modelling approaches that are less complex than whole-body physiologically-based models but still capture the essential elements in a physiological way and hence will be more suited for population modelling of large clinical data sets. It will also help formulation scientists to better predict formulation performance and to develop formulations that maximize oral bioavailability. Copyright © 2016 Elsevier B.V. All rights reserved.

A novel pH-responsive interpolyelectrolyte hydrogel complex for the oral delivery of levodopa. Part II: characterization and formulation of an IPEC-based tablet matrix.

PubMed

Ngwuluka, Ndidi C; Choonara, Yahya E; Kumar, Pradeep; du Toit, Lisa C; Khan, Riaz A; Pillay, Viness

2015-03-01

This study was undertaken in order to apply a synthesized interpolyelectrolyte complex (IPEC) of polymethacrylate and carboxymethylcellulose as a controlled release oral tablet matrix for the delivery of the model neuroactive drug levodopa. The IPEC (synthesized in Part I of this work) was characterized by techniques such as Fourier Transform Infra-Red (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC), Advanced DSC (ADSC), and Scanning Electron Microscopy (SEM). The tablet matrices were formulated and characterized for their drug delivery properties and in vitro drug release. FTIR confirmed the interaction between the two polymers. The IPEC composite generated tablet matrices with a hardness ranging from 19.152-27.590 N/mm and a matrix resilience ranging between 42 and 46%. An IPEC of polymethacrylate and carboxymethylcellulose was indeed an improvement on the inherent properties of the native polymers providing a biomaterial with the ability to release poorly soluble drugs such as levodopa at a constant rate over a prolonged period of time. © 2014 Wiley Periodicals, Inc.

Influence of poloxamers on the dissolution performance and stability of controlled-release formulations containing Precirol ATO 5.

PubMed

Jannin, V; Pochard, E; Chambin, O

2006-02-17

Lipid excipients are usually used for the development of sustained-release formulations. When used in relatively high quantities, Precirol ATO 5 imparts sustained-release properties to solid oral dosage forms, by forming a lipid matrix. To control or adjust the drug release kinetics from such lipid matrix however, one must often resort to complementary ingredients or techniques. This study investigates the influence of poloxamers (Lutrol) included in lipid matrices composed of glyceryl palmitostearate (Precirol ATO 5) on their dissolution performance and their stability. The addition of these hydrophilic polymers in the lipid matrix increased the amount of theophylline released thanks to the swelling of the hydrophilic polymer and the creation of a porous network into the inert lipid matrix. The grade and the quantity of Lutrol could modulate the extent of drug release. Theophylline was released mainly by the matrix erosion but also by diffusion through the pores as suggested by the Peppas' model. Moreover, the addition of Lutrol enhanced the stability during storage. The theophylline release was quite steady after 6 months in different conditions (temperature and humidity). Thus, the mixture of glyceryl palmitostearate and poloxamers is an approach with many advantages for the development of controlled-release formulations by capsule molding.

Extended release dosage form of glipizide: development and validation of a level A in vitro-in vivo correlation.

PubMed

Ghosh, Animesh; Bhaumik, Uttam Kumar; Bose, Anirbandeep; Mandal, Uttam; Gowda, Veeran; Chatterjee, Bappaditya; Chakrabarty, Uday Sankar; Pal, Tapan Kumar

2008-10-01

Defining a quantitative and reliable relationship between in vitro drug release and in vivo absorption is highly desired for rational development, optimization, and evaluation of controlled-release dosage forms and manufacturing process. During the development of once daily extended-release (ER) tablet of glipizide, a predictive in vitro drug release method was designed and statistically evaluated using three formulations with varying release rates. In order to establish internally and externally validated level A in vitro-in vivo correlation (IVIVC), a total of three different ER formulations of glipizide were used to evaluate a linear IVIVC model based on the in vitro test method. For internal validation, a single-dose four-way cross over study (n=6) was performed using fast-, moderate-, and slow-releasing ER formulations and an immediate-release (IR) of glipizide as reference. In vitro release rate data were obtained for each formulation using the United States Pharmacopeia (USP) apparatus II, paddle stirrer at 50 and 100 rev. min(-1) in 0.1 M hydrochloric acid (HCl) and pH 6.8 phosphate buffer. The f(2) metric (similarity factor) was used to analyze the dissolution data. The formulations were compared using area under the plasma concentration-time curve, AUC(0-infinity), time to reach peak plasma concentration, T(max), and peak plasma concentration, C(max), while correlation was determined between in vitro release and in vivo absorption. A linear correlation model was developed using percent absorbed data versus percent dissolved from the three formulations. Predicted glipizide concentrations were obtained by convolution of the in vivo absorption rates. Prediction errors were estimated for C(max) and AUC(0-infinity) to determine the validity of the correlation. Apparatus II, pH 6.8 at 100 rev. min(-1) was found to be the most discriminating dissolution method. Linear regression analysis of the mean percentage of dose absorbed versus the mean percentage of in vitro release resulted in a significant correlation (r(2)>or=0.9) for the three formulations.

Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies

PubMed Central

Bhaskar, Kesavan; Anbu, Jayaraman; Ravichandiran, Velayutham; Venkateswarlu, Vobalaboina; Rao, Yamsani Madhusudan

2009-01-01

The aim of the study is to prepare aqueous dispersions of lipid nanoparticles – flurbiprofen solid lipid nanoparticles (FLUSLN) and flurbiprofen nanostructured lipid carriers (FLUNLC) by hot homogenization followed by sonication technique and then incorporated into the freshly prepared hydrogels for transdermal delivery. They are characterized for particle size, for all the formulations, more than 50% of the particles were below 300 nm after 90 days of storage at RT. DSC analyses were performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by TEM which revealed fairly spherical shape of the formulations. Further they were evaluated for in vitro drug release characteristics, rheological behaviour, pharmacokinetic and pharmacodynamic studies. The pharmacokinetics of flurbiprofen in rats following application of SLN gel (A1) and NLC gel (B1) for 24 h were evaluated. The Cmax of the B1 formulation was 38.67 ± 2.77 μg/ml, which was significantly higher than the A1 formulation (Cmax = 21.79 ± 2.96 μg/ml). The Cmax and AUC of the B1 formulation were 1.8 and 2.5 times higher than the A1 gel formulation respectively. The bioavailability of flurbiprofen with reference to oral administration was found to increase by 4.4 times when gel formulations were applied. Anti-inflammatory effect in the Carrageenan-induced paw edema in rat was significantly higher for B1 and A1 formulation than the orally administered flurbiprofen. Both the SLN and NLC dispersions and gels enriched with SLN and NLC possessed a sustained drug release over period of 24 h but the sustained effect was more pronounced with the SLN and NLC gel PMID:19243632

Design, Formulation and Evaluation of an Oral Gel from Punica Granatum Flower Extract for the Treatment of Recurrent Aphthous Stomatitis

PubMed Central

Aslani, Abolfazl; Zolfaghari, Behzad; Davoodvandi, Fatemeh

2016-01-01

Purpose: Recurrent aphthous stomatitis is a disease with unknown etiology that’s mostly treated symptomatically and has no definite cure. Pomegranate (Punica granatum) flowers have been used as medicinal herb that due to its antimicrobial, antioxidant, anti-inflammatory, analgesic and healing effects, has been useful in treatment of oral aphthous. Therefore, we decided to formulate a mucoadhesive gel with pomegranate flower extract to reduce the need for corticosteroid therapy in patients. Methods: Pomegranate flowers are extracted by percolation method. Several formulations with different amounts of carbomer 934, sodium carboxymethylcellulose (SCMC) and hydroxypropyl methylcellulose K4M were prepared and the condensed extract was dispersed in polyethyleneglycol (PEG) 400 and added to gel bases. Then the formulations underwent macroscopic and microscopic studies. The formulations that passed these tests successfully were studied through assay tests using spectrophotometry in 765 nm, drug release from mucoadhesive gel using cell diffusion method, viscosity test, mucoadhesion test and accelerated stability test. Results: The phenolic content of pomegranate flower dried extract was found to be 212.3±1.4 mg/g in dried extract. The F4–F6 formulations contains carbomer 934, SCMC, pomegranate flower extract, PEG 400, potassium sorbate and purified water passed all above tests. Conclusion: The F4 formulation had higher viscosity and mucoadhesion values due to its higher carbomer 934 and SCMC content. Since F4, F5 and F6 had no significant variation in drug release, the F4 formulation was chosen as the superior formulation because of proper appearance and uniformity, acceptable viscosity, mucoadhesion and stability in different temperatures. PMID:27766223

Niosomal carriers enhance oral bioavailability of carvedilol: effects of bile salt-enriched vesicles and carrier surface charge.

PubMed

Arzani, Gelareh; Haeri, Azadeh; Daeihamed, Marjan; Bakhtiari-Kaboutaraki, Hamid; Dadashzadeh, Simin

2015-01-01

Carvedilol (CRV) is an antihypertensive drug with both alpha and beta receptor blocking activity used to preclude angina and cardiac arrhythmias. To overcome the low, variable oral bioavailability of CRV, niosomal formulations were prepared and characterized: plain niosomes (without bile salts), bile salt-enriched niosomes (bilosomes containing various percentages of sodium cholate or sodium taurocholate), and charged niosomes (negative, containing dicetyl phosphate and positive, containing hexadecyl trimethyl ammonium bromide). All formulations were characterized in terms of encapsulation efficiency, size, zeta potential, release profile, stability, and morphology. Various formulations were administered orally to ten groups of Wistar rats (n=6 per group). The plasma levels of CRV were measured by a validated high-performance liquid chromatography (HPLC) method and pharmacokinetic properties of different formulations were characterized. Contribution of lymphatic transport to the oral bioavailability of niosomes was also investigated using a chylomicron flow-blocking approach. Of the bile salt-enriched vesicles examined, bilosomes containing 20% sodium cholate (F2) and 30% sodium taurocholate (F5) appeared to give the greatest enhancement of intestinal absorption. The relative bioavailability of F2 and F5 formulations to the suspension was estimated to be 1.84 and 1.64, respectively. With regard to charged niosomes, the peak plasma concentrations (Cmax) of CRV for positively (F7) and negatively charged formulations (F10) were approximately 2.3- and 1.7-fold higher than after a suspension. Bioavailability studies also revealed a significant increase in extent of drug absorption from charged vesicles. Tissue histology revealed no signs of inflammation or damage. The study proved that the type and concentration of bile salts as well as carrier surface charge had great influences on oral bioavailability of niosomes. Blocking the lymphatic absorption pathway significantly reduced oral bioavailability of CRV niosomes. Overall twofold enhancement in bioavailability in comparison with drug suspension confers the potential of niosomes as suitable carriers for improved oral delivery of CRV.

Development of aprepitant loaded orally disintegrating films for enhanced pharmacokinetic performance.

PubMed

Sharma, Radhika; Kamboj, Sunil; Singh, Gursharan; Rana, Vikas

2016-03-10

The present investigation was aimed to prepare orally disintegrating films (ODFs) containing aprepitant (APT), an antiemetic drug employing pullulan as film forming agent, tamarind pectin as wetting agent and liquid glucose as plasticizer and solubiliser. The ODFs were prepared using solvent casting method. The method was optimized employing 3(2) full factorial design considering proportion of pullulan: tamarind pectin and concentration of liquid glucose as independent variables and disintegration time, wetting time, folding endurance, tensile strength and extensibility as dependent variables. The optimized ODF was evaluated for various physicochemical, mechanical, drug release kinetics and bioavailability studies. The results suggested prepared film has uniform film surface, non-sticky and disintegrated within 18s. The in-vitro release kinetics revealed more than 87% aprepitant was released from optimized ODF as compared to 85%, 49%, and 12% aprepitant release from marketed formulation Aprecap, micronized aprepitant and non micronized aprepitant, respectively. The results of animal preference study indicated that developed aprepitant loaded ODFs are accepted by rabbits as food material. Animal pharmacokinetic (PK) study showed 1.80, 1.56 and 1.36 fold enhancement in relative bioavailability for aprepitant loaded ODF, Aprecap and micronized aprepitant respectively, in comparison with non-micronized aprepitant. Overall, the solubilised aprepitant when incorporated in the form of aprepitant loaded ODF showed enhanced bioavailability as compared to micronized/non-micronized aprepitant based oral formulations. These findings suggested that aprepitant loaded ODF could be effective for antiemesis during cancer chemotherapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro-in vivo evaluations

PubMed Central

Pimparade, Manjeet. B.; Morott, Joseph T.; Park, Jun-Bom; Kulkarni, Vijay I.; Majumdar, Soumyajit; Murthy, S. N.; Lian, Zhuoyang; Pinto, Elanor; Bi, Vivian; Durig, Thomas; Murthy, Reena; Shivakumar, H.N; Vanaja, K.; Kumar, C. P; Repka, Michael A.

2015-01-01

The objective of this study was to develop caffeine citrate orally disintegrating tablet (ODT) formulations utilizing hot-melt extrusion technology and evaluate the ability of the formulation composition to mask the unpleasant bitter taste of the drug using in vitro and in vivo methods. Ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to enhance drug release. A modified screw configuration was applied to improve the extrusion processability and to preserve the crystallinity of the API. The milled extrudates were subjected to dissolution testing in an artificial salivary fluid and investigations using e-tongue, to assess the extent of masking of bitter taste of the API. There was an insignificant amount of drug released from the formulation in the salivary medium while over 80% of drug released within 30 min in 0.1 N HCl. ODTs were also developed with the extrudate mixed with mannitol and crospovidone. The quality properties such as friability and disintegration time of the ODTs met the USP specifications. The lead extrudate formulations and the ODTs prepared using this formulation were subjected to human gustatory evaluation. The formulations were found to mask the unpleasant taste of caffeine citrate significantly. PMID:25888797

Chronic non-cancer pain: Focus on once-daily tramadol formulations

PubMed Central

Coluzzi, Flaminia; Mattia, Consalvo

2007-01-01

Despite progress in pain management, chronic non-cancer pain (CNCP) represents still a clinical challenge. The efficacy and safety profile of tramadol make it suitable as a long-term treatment in a variety of CNCP conditions. New once-daily (OD) formulations of tramadol have been marketed in various countries, in order to offer the advantage of a reduced dosing regimen and to improve patients’ compliance. This review focuses on the technology, pharmacology, clinical efficacy, and safety of different once-daily tramadol formulations. Hydrophilic vs hydrophobic matrix systems and newer technologies used in once-daily formulations to control drug delivery are discussed. Three randomized controlled trials (RCTs) established OD tramadol analgesic efficacy to be superior to that of placebo for pain management and functional improvement in patients with osteoarthritis. Three RCTs demonstrated similar rates of efficacy between OD tramadol and immediate-release (IR) or sustained-release (SR) formulations, with a better adverse events profile. An open trial on long term tolerability showed that OD tramadol is generally safe in rheumatological pain treatment. PMID:18473006

Extended‐Release Once‐Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate‐Release Tofacitinib and Impact of Food

PubMed Central

Wang, Rong; Fletcher, Tracey; Alvey, Christine; Kushner, Joseph; Stock, Thomas C.

2016-01-01

Abstract Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended‐release (XR) formulation has been designed to provide a once‐daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice‐daily immediate‐release (IR) formulation. We conducted 2 randomized, open‐label, phase 1 studies in healthy volunteers. Study A characterized single‐dose and steady‐state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single‐dose and steady‐state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high‐fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half‐life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration‐time curve (AUC) and maximum plasma concentration (Cmax) after single‐ and multiple‐dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. PMID:26970526

Development and characterization of controlled release polar lipid microparticles of candesartan cilexetil by solid dispersion

PubMed Central

Kamalakkannan, V; Puratchikody, A; Ramanathan, L

2013-01-01

Candesartan cilexetil (CC) is a newer class of angiotensin II receptor antagonist used for the treatment of hypertension. The solubility of the CC is very poor and its oral bioavailability is only 15%. The controlledrelease polar lipid microparticles of CC (formulations F1, F2, F3 and F4) were prepared using variable erodible lipophilic excipients like hydrogenated castor oil, stearic acid, cetostearyl alcohol and carnauba wax by fusion method. The particle sizes of polar lipid microparticles were less than 50 microns and they were irregular in shape. Drug content ranged between 98.96 ± 2.1 and 101.9 ± 1.6% were present in all the formulations. The formulation F3 showed better drug release throughout the study period in a controlled release manner. Moreover, the in vitro release showed that all the formulations were best fitted to Higuchi model. Accelerated stability studies indicated that there was no significant changes in the chemical and physical characteristics of the formulated drug product during initial and at the end of the study period. The FTIR and DSC studies showed that there was no interaction between the drug and lipophilic excipients and no polymorphic transitions in all formulations. The X-ray diffraction peak of solid dispersion indicated that the crystalline nature of CC disappeared and no new peaks could be observed, suggesting the absence of interaction between drug and excipients. PMID:24019822

Recent advances in small molecule drug delivery.

PubMed

Kidane, Argaw; Bhatt, Padmanabh P

2005-08-01

The majority of new drugs, and new drug products, being developed and marketed by the pharmaceutical industry are small molecules. Oral administration remains the most common route of delivering such drugs, typically in the form of immediate-release tablets or capsules. While the immediate-release dosage forms dominate the market today, more specialized and rationalized products incorporating the concepts of drug delivery are being developed to overcome the physicochemical, physiological and pharmacological challenges inherent with the drugs, and to improve the treatment regimens for the patients. Today, these specialized concepts are increasingly being applied to first-generation products and not just products intended for the life cycle management of the franchise.

Formation and functional attributes of electrostatic complexes involving casein and anionic polysaccharides: An approach to enhance oral absorption of lycopene in rats in vivo.

PubMed

Jain, Ashay; Thakur, Deepika; Ghoshal, Gargi; Katare, O P; Singh, Bhupinder; Shivhare, U S

2016-12-01

The current work entails a novel strategy of formulating the microparticles of lycopene solely using rational blends of biopolymers without using equipment-intensive techniques. The study is intended to enhance oral bioavailability of lycopene by controlling its release from micro-formulation and facilitating its absorption though lymphatic pathways. Considering the minimum particle size, maximum entrapment efficiency and loading capacity, the amounts of casein (i.e., protein) and gum tragacanth (i.e., polysaccharide) were selected as the critical factors for formulation of microparticles. Complex formation and electrostatic interaction was confirmed by Fourier transform infra red (FTIR) spectra. Size and surface properties of microparticles were studied using scanning electron microscopy (SEM). The optimized formulation (mean particle size: ∼130μm; % entrapment efficiency: ∼67% and loading capacity: ∼71%) designated noticeable improvement in lycopene release profile (over 80% in 24h). Increment in the values of C max (2.22-fold) and AUC (1.97-fold) further indicated noteworthy augmentation in the rate and extent of bioavailability by the microparticles formulation compared to plain lycopene. The resulting formulation was found to be quite stable all through two months of study episode. The resultant microparticles formulation was evaluated for antioxidant activity and tested for their effectiveness in self life enhancement of vegetable oil by calculating peroxide value under temperature and storage condition. Encapsulation strongly increased the stability of micronutrients. The current investigations, therefore, report the successful development of biopolymeric microparticles with improved bioavailability potential of lycopene. Copyright © 2016. Published by Elsevier B.V.

Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease.

PubMed

Hey, John A; Yu, Jeremy Y; Versavel, Mark; Abushakra, Susan; Kocis, Petr; Power, Aidan; Kaplan, Paul L; Amedio, John; Tolar, Martin

2018-03-01

ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [1] a single ascending dose (SAD) study; [2] a 14-day multiple ascending dose (MAD) study; and [3] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration (C max ) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

Controlled drug delivery systems: past forward and future back.

PubMed

Park, Kinam

2014-09-28

Controlled drug delivery technology has progressed over the last six decades. This progression began in 1952 with the introduction of the first sustained release formulation. The 1st generation of drug delivery (1950-1980) focused on developing oral and transdermal sustained release systems and establishing controlled drug release mechanisms. The 2nd generation (1980-2010) was dedicated to the development of zero-order release systems, self-regulated drug delivery systems, long-term depot formulations, and nanotechnology-based delivery systems. The latter part of the 2nd generation was largely focused on studying nanoparticle formulations. The Journal of Controlled Release (JCR) has played a pivotal role in the 2nd generation of drug delivery technologies, and it will continue playing a leading role in the next generation. The best path towards a productive 3rd generation of drug delivery technology requires an honest, open dialog without any preconceived ideas of the past. The drug delivery field needs to take a bold approach to designing future drug delivery formulations primarily based on today's necessities, to produce the necessary innovations. The JCR provides a forum for sharing the new ideas that will shape the 3rd generation of drug delivery technology. Copyright © 2014 Elsevier B.V. All rights reserved.

Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles.

PubMed

Jacobs, Michael R

2005-06-01

Acute bacterial respiratory tract infections cause a great deal of human morbidity and mortality. Treatment guidelines for these infections include macrolides, doxycycline, beta-lactams and beta-lactam/beta-lactamase inhibitor combinations such as amoxicillin/clavulanic acid to provide coverage for the common respiratory pathogens, including penicillin and macrolide nonsusceptible Streptococcus pneumoniae, as well as beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis. In response to recent guidelines recommending higher dose amoxicillin to extend coverage to a higher percentage of S. pneumoniae, a new formulation of amoxicillin/clavulanic acid was developed. This formulation includes a higher amoxicillin dose, with part of the amoxicillin dose being in an extended release formulation, without increasing the clavulanate dose, for twice-daily oral treatment of these infections. Clinical studies of community-acquired pneumonia and acute rhinosinusitis have shown that the new formulation is well tolerated and highly efficacious, with clinical outcomes equivalent to comparators.

Preparation and characterization of fast dissolving flurbiprofen and esomeprazole solid dispersion using spray drying technique.

PubMed

Pradhan, Roshan; Tran, Tuan Hiep; Kim, Sung Yub; Woo, Kyu Bong; Choi, Yong Joo; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

2016-04-11

We aimed to develop an immediate-release flurbiprofen (FLU) and esomeprazole (ESO) combination formulation with enhanced gastric aqueous solubility and dissolution rate. Aqueous solubility can be enhanced by formulating solid dispersions (SDs) with a polyvinylpyrrolidone (PVP)-K30 hydrophilic carrier, using spray-drying technique. Aqueous and gastric pH dissolution can be achieved by macro-environmental pH modulation using sodium bicarbonate (NaHCO3) and magnesium hydroxide (Mg(OH)2) as the alkaline buffer. FLU/ESO-loaded SDs (FLU/ESO-SDs) significantly improved aqueous solubility of both drugs, compared to each drug powder. Dissolution studies in gastric pH and water were compared with the microenvironmental pH modulated formulations. The optimized FLU/ESO-SD powder formulation consisted of FLU/ESO/PVP-K30/sodium carbonate (Na2CO3) in a weight ratio 1:0.22:1.5:0.3, filled in the inner capsule. The outer capsule consisted of NaHCO3 and Mg(OH)2, which created the macro-environmental pH modulation. Increased aqueous and gastric pH dissolution of FLU and ESO from the SD was attributed to the alkaline buffer effects and most importantly, to drug transformation from crystalline to amorphous SD powder, clearly revealed by scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction studies. Thus, the combined FLU and ESO SD powder can be effectively delivered as an immediate-release formulation using the macro-environmental pH modulation concept. Copyright © 2016. Published by Elsevier B.V.

Modulation of active pharmaceutical material release from a novel 'tablet in capsule system' containing an effervescent blend.

PubMed

Gohel, Mukesh C; Sumitra G, Manhapra

2002-02-19

The objective of the present study was to obtain programmed drug delivery from hard gelatin capsules containing a hydrophilic plug (HPMC or guar gum). The significance of factors such as type of plug (powder or tablet), plug thickness and the formulation of fill material on the release pattern of diltiazem HCl, a model drug, was investigated. The body portion of the hard gelatin capsules was cross-linked by the combined effect of formaldehyde and heat treatment. A linear relationship was observed between weight of HPMC K15M and log % drug released at 4 h from the capsules containing the plug in powder form. In order to accelerate the drug release after a lag time of 4 h, addition of an effervescent blend, NaHCO(3) and citric acid, in the capsules was found to be essential. The plugs of HPMC in tablet form, with or without a water soluble adjuvant (NaCl or lactose) were used for obtaining immediate drug release after the lag time. Sodium chloride did not cause significant influence on drug release whereas lactose favourably affected the drug release. The capsules containing HPMC K15M tablet plug (200 mg) and 35 mg effervescent blend in body portion of the capsule met the selection criteria of less than 10% drug release in 4 h and immediate drug release thereafter. It is further shown that the drug release was also dependant on the type of swellable hydrophilic agent (HPMC or guar gum) and molecular weight of HPMC (K15M or 20 cPs). The results reveal that programmed drug delivery can be obtained from hard gelatin capsules by systemic formulation approach.

Assessing bioequivalence of generic modified-release antiepileptic drugs

PubMed Central

Chang, Yi-Ting; Davit, Barbara; Gidal, Barry E.; Krauss, Gregory L.

2016-01-01

Objectives: The purpose of this study was to determine how closely generic modified-release antiepileptic drugs (MR-AEDs) resemble reference (brand) formulations by comparing peak concentrations (Cmax), total absorption (area under the curve [AUC]), time to Cmax (Tmax), intersubject variability, and food effects between generic and reference products. Methods: We tabulated Cmax and AUC data from the bioequivalence (BE) studies used to support the approvals of generic Food and Drug Administration–approved MR-AEDs. We compared differences in 90% confidence intervals of the generic/reference AUC and Cmax geometric mean ratios, and intersubject variability, Tmax and delivery profiles and food effects. Results: Forty-two MR-AED formulations were studied in 3,175 healthy participants without epilepsy in 97 BE studies. BE ratios for AUC and Cmax were similar between most generic and reference products: AUC ratios varied by >15% in 11.4% of BE studies; Cmax varied by >15% in 25.8% of studies. Tmax was more variable, with >30% difference in 13 studies (usually delayed in the fed compared to fasting BE studies). Generic and reference MR products had similar intersubject variability. Immediate-release AEDs showed less intersubject variability in AUC than did MR-AEDs. Conclusions: Most generic and reference MR-AEDs have similar AUC and Cmax values. Ratios for some products, however, are near acceptance limits and Tmax values may vary. Food effects are common with MR-AED products. High variability in pharmacokinetic values for once-a-day MR-AEDs suggests their major advantage compared to immediate-release AED formulations may be the convenience of less frequent dosing to improve adherence. PMID:27016518

Risk of emergent bradycardia associated with initiation of immediate- or slow-release metoprolol.

PubMed

Shin, Jaekyu; Gonzales, Marco; Pletcher, Mark J

2013-12-01

To estimate and compare the risk of emergent bradycardia associated with starting immediate-release (IR) and slow-release (SR) formulations of metoprolol. Retrospective analysis of administrative claims data. State of California Medicaid program (Medi-Cal) claims database. A total of 31,574 adults beginning metoprolol between May 1, 2004, and November 1, 2009, without a pharmacy claim for a β blocker within the previous 6 months of metoprolol initiation; patients with a primary or secondary diagnosis of symptomatic bradycardia, pacemaker, or implantable cardioverter-defibrillator placement before metoprolol initiation were excluded. The study outcome was the time to first occurrence of emergent bradycardia, measured at an emergency department visit or hospitalization due to diagnosis of symptomatic bradycardia, after metoprolol initiation. We calculated the incidence and compared the risk of emergent bradycardia by using a proportional hazards model that included the metoprolol formulation with adjustment for total daily metoprolol dose and the use of other drugs as time-varying covariates, as well as demographics and comorbidities. Among 31,574 patients starting metoprolol, 18,516 (58.6%) used the IR formulation. The incidence of emergent bradycardia was 19.1/1000 person-years overall but was nearly twice as common in patients using the IR versus the SR formulation (24.1/1000 person-yrs in the IR group versus 12.9/1000 person-yrs in the SR group, unadjusted hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.28-2.56). Adjustment for other drugs also associated with symptomatic bradycardia (cytochrome P450 2D6 inhibitors, class I or III antiarrhythmics, and atrioventricular node-blocking agents), metoprolol dose, and other participant characteristics somewhat attenuated the association (adjusted HR 1.48, 95% CI 1.03-2.13). The risk of emergent bradycardia associated with metoprolol initiation was higher with the IR formulation than the SR formulation, although the absolute risk was low. © 2013 Pharmacotherapy Publications, Inc.

Risk of Emergent Bradycardia Associated with Initiation of Immediate- or Slow-Release Metoprolol

PubMed Central

Shin, Jaekyu; Gonzales, Marco; Pletcher, Mark J

2013-01-01

Objectives To estimate and compare the risk of emergent bradycardia associated with initiation of immediate-release (IR) and slow-release (SR) formulations of metoprolol. Design Retrospective analysis of administrative claims data. Data Source State of California Medicaid program (Medi-Cal) claims database. Patients A total of 31,574 adults initiating metoprolol between May 1, 2004, and November 1, 2009, without a pharmacy claim for a beta blocker within the previous 6 months of metoprolol initiation; patients with a primary or secondary diagnosis of symptomatic bradycardia, pacemaker, or implantable cardioverter-defibrillator placement before metoprolol initiation were excluded. Measurements and Main Results The study outcome was the time to first occurrence of emergent bradycardia, measured at an emergency department visit or hospitalization due to diagnosis of symptomatic bradycardia, after metoprolol initiation. We calculated the incidence and compared the risk of emergent bradycardia by using a proportional hazards model that included the metoprolol formulation with adjustment for total daily metoprolol dose and the use of other medications as time-varying covariates, as well as demographics and comorbidities. Among 31,574 patients initiating metoprolol, 18,516 (58.6%) initiated the IR formulation. The incidence of emergent bradycardia was 19.1 per 1000 person-years overall but was nearly twice as common in patients using the IR versus the SR formulation (24.1 per 1000 person-years in the IR group vs. 12.9 per 1000 person-years in the SR group; unadjusted hazard ratio [HR] 1.81; 95% CI 1.28-2.56). Adjustment for other medications also associated with symptomatic bradycardia (cytochrome P450 2D6 inhibitors, class I or III antiarrhythmics, and atrioventricular node–blocking agents), metoprolol dose, and other participant characteristics somewhat attenuated the association (adjusted HR 1.48, 95% CI 1.03-2.13). Conclusion The risk of emergent bradycardia associated with metoprolol initiation was higher with the IR formulation than the SR formulation, although the absolute risk was low. PMID:23813768

Justification of disintegration testing beyond current FDA criteria using in vitro and in silico models.

PubMed

Uebbing, Lukas; Klumpp, Lukas; Webster, Gregory K; Löbenberg, Raimar

2017-01-01

Drug product performance testing is an important part of quality-by-design approaches, but this process often lacks the underlying mechanistic understanding of the complex interactions between the disintegration and dissolution processes involved. Whereas a recent draft guideline by the US Food and Drug Administration (FDA) has allowed the replacement of dissolution testing with disintegration testing, the mentioned criteria are not globally accepted. This study provides scientific justification for using disintegration testing rather than dissolution testing as a quality control method for certain immediate release (IR) formulations. A mechanistic approach, which is beyond the current FDA criteria, is presented. Dissolution testing via United States Pharmacopeial Convention Apparatus II at various paddle speeds was performed for immediate and extended release formulations of metronidazole. Dissolution profile fitting via DDSolver and dissolution profile predictions via DDDPlus™ were performed. The results showed that Fickian diffusion and drug particle properties (DPP) were responsible for the dissolution of the IR tablets, and that formulation factors (eg, coning) impacted dissolution only at lower rotation speeds. Dissolution was completely formulation controlled if extended release tablets were tested and DPP were not important. To demonstrate that disintegration is the most important dosage form attribute when dissolution is DPP controlled, disintegration, intrinsic dissolution and dissolution testing were performed in conventional and disintegration impacting media (DIM). Tablet disintegration was affected by DIM and model fitting to the Korsmeyer-Peppas equation showed a growing effect of the formulation in DIM. DDDPlus was able to predict tablet dissolution and the intrinsic dissolution profiles in conventional media and DIM. The study showed that disintegration has to occur before DPP-dependent dissolution can happen. The study suggests that disintegration can be used as performance test of rapidly disintegrating tablets beyond the FDA criteria. The scientific criteria and justification is that dissolution has to be DPP dependent, originated from active pharmaceutical ingredient characteristics and formulations factors have to be negligible.

Justification of disintegration testing beyond current FDA criteria using in vitro and in silico models

PubMed Central

Uebbing, Lukas; Klumpp, Lukas; Webster, Gregory K; Löbenberg, Raimar

2017-01-01

Drug product performance testing is an important part of quality-by-design approaches, but this process often lacks the underlying mechanistic understanding of the complex interactions between the disintegration and dissolution processes involved. Whereas a recent draft guideline by the US Food and Drug Administration (FDA) has allowed the replacement of dissolution testing with disintegration testing, the mentioned criteria are not globally accepted. This study provides scientific justification for using disintegration testing rather than dissolution testing as a quality control method for certain immediate release (IR) formulations. A mechanistic approach, which is beyond the current FDA criteria, is presented. Dissolution testing via United States Pharmacopeial Convention Apparatus II at various paddle speeds was performed for immediate and extended release formulations of metronidazole. Dissolution profile fitting via DDSolver and dissolution profile predictions via DDDPlus™ were performed. The results showed that Fickian diffusion and drug particle properties (DPP) were responsible for the dissolution of the IR tablets, and that formulation factors (eg, coning) impacted dissolution only at lower rotation speeds. Dissolution was completely formulation controlled if extended release tablets were tested and DPP were not important. To demonstrate that disintegration is the most important dosage form attribute when dissolution is DPP controlled, disintegration, intrinsic dissolution and dissolution testing were performed in conventional and disintegration impacting media (DIM). Tablet disintegration was affected by DIM and model fitting to the Korsmeyer–Peppas equation showed a growing effect of the formulation in DIM. DDDPlus was able to predict tablet dissolution and the intrinsic dissolution profiles in conventional media and DIM. The study showed that disintegration has to occur before DPP-dependent dissolution can happen. The study suggests that disintegration can be used as performance test of rapidly disintegrating tablets beyond the FDA criteria. The scientific criteria and justification is that dissolution has to be DPP dependent, originated from active pharmaceutical ingredient characteristics and formulations factors have to be negligible. PMID:28442890

Thermostability of the coating, antigen and immunostimulator in an adjuvanted oral capsule vaccine formulation.

PubMed

Longet, Stephanie; Aversa, Vincenzo; O'Donnell, Daire; Tobias, Joshua; Rosa, Monica; Holmgren, Jan; Coulter, Ivan S; Lavelle, Ed C

2017-12-20

Oral vaccines present an attractive alternative to injectable vaccines for enteric diseases due to ease of delivery and the induction of intestinal immunity at the site of infection. However, susceptibility to gastrointestinal proteolysis, limited transepithelial uptake and a lack of clinically acceptable adjuvants present significant challenges. A further challenge to mass vaccination in developing countries is the very expensive requirement to maintain the cold chain. We recently described the effectiveness of a Single Multiple Pill ® (SmPill ® ) adjuvanted capsule approach to enhance the effectiveness of a candidate enterotoxigenic Escherichia coli (ETEC) oral vaccine. Here it was demonstrated that this delivery system maintains the antigenicity of ETEC colonisation factor antigen I (CFA/I) and the immunostimulatory activity of the orally active α-Galactosylceramide (α-GalCer) adjuvant after storage of SmPill ® minispheres under room temperature and extreme storage conditions for several months. In addition, the internal structure of the cores of SmPill ® minispheres and antigen release features at intestinal pH were found to be preserved under all these conditions. However, changes in the surface morphology of SmPill ® minispheres leading to the antigen release at gastric pH were observed after a few weeks of storage under extreme conditions. Those modifications were prevented by the introduction of an Opadry ® White film coating layer between the core of SmPill ® minispheres and the enteric coating. Under these conditions, protection against antigen release at gastric pH was maintained even under high temperature and humidity conditions. These results support the potential of the SmPill ® minisphere approach to maintain the stability of an adjuvanted whole cell killed oral vaccine formulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Methylphenidate Efficacy: Immediate versus Extended Release at Short Term in Mexican Children with ADHD Assessed by Conners Scale and EEG

PubMed Central

Alatorre-Miguel, Efren; Zambrano-Sánchez, Elizabeth; Reyes-Legorreta, Celia

2015-01-01

Attention deficit hyperactivity disorder (ADHD) affects 5-6% of school aged children worldwide. Pharmacological therapy is considered the first-line treatment and methylphenidate (MPH) is considered the first-choice medication. There are two formulations: immediate release (IR) MPH and long-acting (or extended release) formulation (MPH-ER). In this work, we measure the efficacy of treatment for both presentations in one month with Conners' scales and electroencephalography (EEG). Results. for IR group, in parents and teachers Conners test, all items showed significant differences, towards improvement, except for teachers in perfectionism and emotional instability. For ER group in parent's Conners test, the items in which there were no significant differences are psychosomatic and emotional instability. For teachers, there were no significant differences in: hyperactivity and perfectionism. Comparing the Conners questionnaires (parents versus teachers) we find significant differences before and after treatment in hyperactivity, perfectionism, psychosomatics, DSM-IV hyperactive-impulsive, and DSM-IV total. In the EEG the Wilcoxon test showed a significant difference (P < 0.0001). As we can see, both presentations are suitable for managing the ADHD and have the same effect on the symptomatology and in the EEG. PMID:25838946

Methylphenidate Efficacy: Immediate versus Extended Release at Short Term in Mexican Children with ADHD Assessed by Conners Scale and EEG.

PubMed

Durand-Rivera, Alfredo; Alatorre-Miguel, Efren; Zambrano-Sánchez, Elizabeth; Reyes-Legorreta, Celia

2015-01-01

Attention deficit hyperactivity disorder (ADHD) affects 5-6% of school aged children worldwide. Pharmacological therapy is considered the first-line treatment and methylphenidate (MPH) is considered the first-choice medication. There are two formulations: immediate release (IR) MPH and long-acting (or extended release) formulation (MPH-ER). In this work, we measure the efficacy of treatment for both presentations in one month with Conners' scales and electroencephalography (EEG). Results. for IR group, in parents and teachers Conners test, all items showed significant differences, towards improvement, except for teachers in perfectionism and emotional instability. For ER group in parent's Conners test, the items in which there were no significant differences are psychosomatic and emotional instability. For teachers, there were no significant differences in: hyperactivity and perfectionism. Comparing the Conners questionnaires (parents versus teachers) we find significant differences before and after treatment in hyperactivity, perfectionism, psychosomatics, DSM-IV hyperactive-impulsive, and DSM-IV total. In the EEG the Wilcoxon test showed a significant difference (P < 0.0001). As we can see, both presentations are suitable for managing the ADHD and have the same effect on the symptomatology and in the EEG.

SLI381 (Adderall XR), a two-component, extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration.

PubMed

Tulloch, Simon J; Zhang, Yuxin; McLean, Angus; Wolf, Kathleen N

2002-11-01

To assess the bioavailability of three test formulations of a single dose of extended-release Adderall 20-mg capsules compared with two doses of immediate-release Adderall 10-mg tablets, and to assess the bioequivalence of a single 30-mg dose of the chosen extended-release Adderall formulation (designated as SLI381) administered in applesauce (sprinkled) and the same dose administered as an intact capsule with or without food. Randomized, open-label, crossover study. Clinical research unit. Forty-one healthy adults. Study A had four treatment sequences: three test formulations (A, B, and C) of a single dose of extended-release Adderall 20 mg, and two 10-mg doses of Adderall given 4 hours apart. Study B had three treatment sequences: a single dose of SLI381 30 mg as an intact capsule after overnight fast, an intact capsule after a high-fat breakfast, and the contents of a capsule sprinkled in 1 tablespoon of applesauce. The 20-mg test formulation A had comparable pharmacokinetic profiles and bioequivalence in rate and extent of drug absorption to Adderall 10 mg twice/day for both d- and l-amphetamine. Formulations B and C had statistically significant differences from the reference drug in some pharmacokinetic parameters. A 30-mg dose of SLI381 showed no significant differences in rate and extent of absorption of d- and l-amphetamine for fasted or sprinkled conditions compared with the high-fat meal condition. SLI381 20 mg/day is bioequivalent to Adderall 10 mg twice/day. SLI381 30 mg administered in applesauce is bioequivalent in terms of both rate and extent of absorption to the same dose administered as an intact capsule in both fasted and fed states.

High-amylose sodium carboxymethyl starch matrices for oral, sustained drug-release: formulation aspects and in vitro drug-release evaluation.

PubMed

Brouillet, F; Bataille, B; Cartilier, L

2008-05-22

High-amylose sodium carboxymethyl starch (HASCA), produced by spray-drying (SD), was previously shown to have interesting properties as a promising pharmaceutical sustained drug-release tablet excipient for direct compression, including ease of manufacture and high crushing strength. This study describes the effects of some important formulation parameters, such as compression force (CF), tablet weight (TW), drug-loading and electrolyte particle size, on acetaminophen-release performances from sustained drug-release matrix tablets based on HASCA. An interesting linear relationship between TW and release time was observed for a typical formulation of the system consisting of 40% (w/w) acetaminophen as model drug and 27.5% NaCl as model electrolyte dry-mixed with HASCA. Application of the Peppas and Sahlin model gave a better understanding of the mechanisms involved in drug-release from the HASCA matrix system, which is mainly controlled by surface gel layer formation. Indeed, augmenting TW increased the contribution of the diffusion mechanism. CFs ranging from 1 to 2.5 tonnes/cm(2) had no significant influence on the release properties of tablets weighing 400 or 600 mg. NaCl particle size did not affect the acetaminophen-release profile. Finally, these results prove that the new SD process developed for HASCA manufacture is suitable for obtaining similar-quality HASCA in terms of release and compression performances.

Development and Evaluation of Taste Masked Granular Formulation of Satranidazole by Melt Granulation Technique

PubMed Central

Pawar, Harshal Ashok; Joshi, Pooja Rasiklal

2014-01-01

Drugs from nitroimidazole category are generally bitter in taste. Oral formulation with bitter taste is not palatable. Geriatrics and pediatrics patients usually suffer from swallowing difficulties. Many other patients in some disease conditions avoid swallowing tablets. Satranidazole is a new nitro-imidazole derivative with bitter taste and is available in market as film coated tablet. The purpose of this research was to mask the bitter taste of Satranidazole by coating complexation with low melting point wax and Eudragit EPO. Different types of wax (glyceryl monostearate, stearic acid and cetyl alcohol) were tried for taste masking. The drug to stearic acid ratio 1 : 2 was found to be optimum on the basis of taste evaluation and in vitro release. The formulated granules were found to possess good flow property. FTIR studies confirmed that there was no interaction between drug and excipients. Scanning Electron Microscopy of drug and the optimized batch of granules was performed. The in vitro release of drug from granules was compared with marketed tablet formulation. The taste masked granules of optimized batch showed 87.65% release of drug in 1 hr which is comparable to that of marketed tablet formulation. PMID:26556200

A novel formulation of [6]-gingerol: Proliposomes with enhanced oral bioavailability and antitumor effect.

PubMed

Wang, Qilong; Wei, Qiuyu; Yang, Qiuxuan; Cao, Xia; Li, Qiang; Shi, Feng; Tong, Shan Shan; Feng, Chunlai; Yu, Qingtong; Yu, Jiangnan; Xu, Ximing

2018-01-15

[6]-Gingerol, one of the components of the rhizome of Ginger, has a variety of biological activities such as anticoagulant, antioxidative, antitumor, anti-inflammatory, antihypertensive, and so forth. However, as one of the homologous phenolic ketones, [6]-gingerol is insoluble in water which limits its applications. Herein, we prepared [6]-gingerol proliposomes through modified thin-film dispersion method, which was spherical or oval, and physicochemically stable with narrow size distribution. Surprisingly, in vitro release of [6]-gingerol loaded proliposome compared with the free [6]-gingerol was significantly higher and its oral bioavailability increased 5-fold in vivo. Intriguingly, its antitumor effect was enhanced in the liposome formulation. Thus, our prepared [6]-gingerol proliposome proved to be a novel formulation for [6]-gingerol, which significantly improved its antitumor effect. Copyright © 2017 Elsevier B.V. All rights reserved.

Challenges of treating patients with chronic pain with dysphagia (CPD): physician and patient perspectives.

PubMed

Pergolizzi, Joseph V; Taylor, Robert; Nalamachu, Srinivas; Raffa, Robert B; Carlson, Douglas R; Varanasi, Ravi K; Kopecky, Ernest A

2014-02-01

Dysphagia--difficulty eating and swallowing--can significantly impair a patient's ability to maintain adequate nutritional and medication intake. There are a large number of patients with chronic pain, including pediatric, geriatric, and palliative care patients, who suffer from dysphagia and, therefore, have difficulty achieving optimal pain management with solid, oral formulations. The objective of this study was to survey physicians and patients in the US to understand their knowledge, attitudes, and clinical management/analgesic usage patterns in the treatment of patients with chronic pain with dysphagia (CPD). Two separate surveys were administered to physicians and patients. The physician survey design was qualitative; physicians participated in a semi-structured phone interview. The patient survey design was quantitative; patients participated in a structured online survey. Purposive sampling was used to recruit participants into both studies. Physician participants were identified based on their specialty, prescribing practices, and geographic location. Patient participants were recruited through a consumer panel of pre-identified individuals who, for 3 months or longer, had chronic pain and were taking opioids. Thirty-four physicians and 1021 patients were surveyed. Physicians indicated that 5-20% of their patients had difficulty swallowing. Treatment for CPD consisted of the fentanyl patch, immediate-release opioids, methadone liquid, or extended-release morphine products. Physicians were not satisfied with currently available treatment options. Twenty-nine per cent of patients surveyed had trouble swallowing or disliked swallowing pills. Eighty per cent of patients were not asked about their ability to swallow solid, oral dosage forms by their physician. To circumvent swallowing difficulties, some patients (16%) cut/crush/grind their medication to facilitate swallowing. Most of these patients (65%) did not know that altering tablets could potentially change the drug release (pharmacokinetic) characteristics of the tablet and lead to serious adverse events. Qualitative survey research can be influenced by responder bias as well as selection bias. The number of survey participants for both the physician and patient surveys was small, thus responses may not reflect those in the general population. A proportion of patients with chronic pain have dysphagia and cannot swallow solid, oral dosage forms, which creates a serious treatment challenge for pain specialists and other healthcare providers. Currently available treatment options have limitations; new treatment options would be welcomed by both physicians and patients. Physician and patient education should be enhanced in order to promote awareness of the deleterious consequences associated with altering currently available analgesic formulations. Facilitating patient-physician communication on this topic may help to improve treatment outcomes.

Gamma scintigraphic study of the hydrodynamically balanced matrix tablets of Metformin HCl in rabbits

PubMed Central

Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Sarji, Sazilah Ahmad; Chung, Lip Yong; Nyamathulla, Shaik; Noordin, Mohamed Ibrahim

2015-01-01

The purpose of this study is to evaluate the in vitro and in vivo performance of gastro-retentive matrix tablets having Metformin HCl as model drug and combination of natural polymers. A total of 16 formulations were prepared by a wet granulation method using xanthan, tamarind seed powder, tamarind kernel powder and salep as the gel-forming agents and sodium bicarbonate as a gas-forming agent. All the formulations were evaluated for compendial and non-compendial tests and in vitro study was carried out on a USP-II dissolution apparatus at a paddle speed of 50 rpm. MOX2 formulation, composed of salep and xanthan in the ratio of 4:1 with 96.9% release, was considered as the optimum formulation with more than 90% release in 12 hours and short floating lag time. In vivo study was carried out using gamma scintigraphy in New Zealand White rabbits, optimized formulation was incorporated with 10 mg of 153Sm for labeling MOX2 formulation. The radioactive samarium oxide was used as the marker to trace transit of the tablets in the gastrointestinal tract. The in vivo data also supported retention of MOX2 formulation in the gastric region for 12 hours and were different from the control formulation without a gas and gel forming agent. It was concluded that the prepared floating gastro-retentive matrix tablets had a sustained-release effect in vitro and in vivo, gamma scintigraphy played an important role in locating the oral transit and the drug-release pattern. PMID:26124637

Pharmacokinetic Evaluation of Improved Oral Bioavailability of Valsartan: Proliposomes Versus Self-Nanoemulsifying Drug Delivery System.

PubMed

Nekkanti, Vijaykumar; Wang, Zhijun; Betageri, Guru V

2016-08-01

The objective of this study was to develop proliposomes and self-nanoemulsifying drug delivery system (SNEDDS) for a poorly bioavailable drug, valsartan, and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin-film hydration method using different lipids such as soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoyl phosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. SNEDDS formulations were prepared using varying concentrations of capmul MCM, labrafil M 2125, and Tween 80. Both proliposomes and SNEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water and 0.1 N HCl using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal permeation techniques. Among the formulations, the proliposomes with drug/DMPG/cholesterol in the ratio of 1:1:0.5 and SNEDDS with capmul MCM (16.0% w/w), labrafil M 2125 (64.0% w/w), and Tween 80 (18.0% w/w) showed the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SNEDDS as compared to pure valsartan. Valsartan permeability across PAMPA and everted rat intestinal permeation models was significantly higher with proliposomes and SNEDDS. Following single oral administration of proliposomes and SNEDDS, a relative bioavailability of 202.36 and 196.87%, respectively, was achieved compared to pure valsartan suspension. The study results indicated that both proliposomes and SNEDDS formulations are comparable in improving the oral bioavailability of valsartan.

pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms.

PubMed

Liu, Lin; Yao, WenDong; Rao, YueFeng; Lu, XiaoYang; Gao, JianQing

2017-11-01

Oral administration is a desirable alternative of parenteral administration due to the convenience and increased compliance to patients, especially for chronic diseases that require frequent administration. The oral drug delivery is a dynamic research field despite the numerous challenges limiting their effective delivery, such as enzyme degradation, hydrolysis and low permeability of intestinal epithelium in the gastrointestinal (GI) tract. pH-Responsive carriers offer excellent potential as oral therapeutic systems due to enhancing the stability of drug delivery in stomach and achieving controlled release in intestines. This review provides a wide perspective on current status of pH-responsive oral drug delivery systems prepared mainly with organic polymers or inorganic materials, including the strategies used to overcome GI barriers, the challenges in their development and future prospects, with focus on technology trends to improve the bioavailability of orally delivered drugs, the mechanisms of drug release from pH-responsive oral formulations, and their application for drug delivery, such as protein and peptide therapeutics, vaccination, inflammatory bowel disease (IBD) and bacterial infections.

Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen.

PubMed

Potthast, H; Dressman, J B; Junginger, H E; Midha, K K; Oeser, H; Shah, V P; Vogelpoel, H; Barends, D M

2005-10-01

Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8. Copyright (c) 2005 Wiley-Liss, Inc. and the American Pharmacists Association

Carrier Mediated Systemic Delivery of Protein and Peptide Therapeutics.

PubMed

Zaman, Rahela; Othman, Iekhan; Chowdhury, Ezharul Hoque

2016-01-01

Over the last few decades proteins and peptide therapeutics have occupied an enormous fraction of pharmaceutical industry. Despite their high potential as therapeutics, the big challenge often encountered is the effective administration and bioavailability of protein therapeutics in vivo system. Peptide molecules are well known for their in vivo short half-lives. In addition, due to high molecular weight and susceptibility to enzymatic degradation, often it is not easy to administer peptides and proteins orally or through any other noninvasive routes. Conventional drug management system often demands for frequent and regular interval intravenous/subcutaneous administration, which decreases overall patient compliance and increases chances of side-effects related to dose-fluctuation in systemic circulation. A controlled mode of delivery system could address all these short-comings at a time. Therefore, long-acting sustained release formulations for both invasive and noninvasive routes are under rigorous study currently. Long-acting formulations through invasive routes can address patient compliance and dose-fluctuation issues by less frequent administration. Also, any new route of administration other than invasive routes will address cost-effectiveness of the therapeutic by lessening the need to deal with health professional and health care facility. Although a vast number of studies are dealing with novel drug delivery systems, till now only a handful of controlled release formulations for proteins and peptides have been approved by FDA. This study therefore focuses on current and perspective controlled release formulations of existing and novel protein/peptide therapeutics via conventional invasive routes as well as potential novel non-invasive routes of administration, e.g., oral, buccal, sublingual, nasal, ocular, rectal, vaginal and pulmonary.

Spray Dried Chitosan Microparticles for Intravesical Delivery of Celecoxib: Preparation and Characterization.

PubMed

Lopedota, Angela; Cutrignelli, Annalisa; Laquintana, Valentino; Denora, Nunzio; Iacobazzi, Rosa Maria; Perrone, Mara; Fanizza, Elisabetta; Mastrodonato, Maria; Mentino, Donatella; Lopalco, Antonio; Depalo, Nicoletta; Franco, Massimo

2016-09-01

Chitosan microparticles containing celecoxib (CB), were developed as chemoprevention of bladder cancer. Furthermore two inclusion complexes of CB with methyl-β-cyclodextrin (C1 and C2) were prepared to improve the solubility of the drug. C1 and C2 were obtained by freeze-drying and characterized in the solid state and in solution. Microparticles loaded with CB or C1 or C2 were prepared by spray drying and fully characterized. The yield and encapsulation efficiencies of microparticles depended by both the viscosity and the presence of the inclusion complex in the feed medium nebulised. Generally, the microparticles exhibited a spherical shape with mean diameter of approximately 2 μm which was compatible with local intravesical administration using a catheter. The CB release studies from the microparticles allowed us to identify both immediate release systems (microparticles including the complexes) and prolonged release systems (microparticles including CB alone). The latter exhibited good adhesion to the bladder mucosa, as highlighted by a mucoadhesion study. Histological studies revealed a desquamation of the superficial cells when the bladder mucosa was treated with microparticles loaded with CB, while the morphology of the urothelium did not change when it was treated with microparticles loaded with the inclusion complex. A new CB intravesical formulation than can easily be administered with a catheter and is able to release the drug at the target site for several hours was realized. This new delivery system could be a good alternative to classic oral CB administration.

Application of Design of Experiment for Polyox and Xanthan Gum Coated Floating Pulsatile Delivery of Sumatriptan Succinate in Migraine Treatment

PubMed Central

Jagdale, Swati C.; Pawar, Chandrakala R.

2014-01-01

Migraine follows circadian rhythm in which headache is more painful at the awakening time. This needs administration of dosage form at night time to release drug after lag period when pain gets worse. Sumatriptan succinate is a drug of choice for migraine. Sumatriptan succinate has bitter taste, low oral bioavailability, and shorter half-life. Present work deals with application of design of experiment for polyox and xanthan gum in development of press coated floating pulsatile tablet. Floating pulsatile concept was applied to increase gastric residence of the dosage form. Burst release was achieved through immediate release tablet using crospovidone as superdisintegrant (10%). Pulse lag time was achieved using swellable polymer polyox WSR 205 and xanthan gum. 32 experimental design was applied. Optimized formulation was evaluated for physical characteristics and in-vitro and in-vivo study. From results, it can be concluded that optimized batch F8 containing polyox WSR205 (72.72%) and xanthan gum (27.27%) of total weight of polymer has shown floating lag time of 55 ± 2 sec, drug content of 100.35 ± 0.4%, hardness of 6 ± 0.1 Kg/cm2, and 98.69 ± 2% drug release in pulse manner with lag time of 7 ± 0.1 h. Optimized batch showed prolong gastric residence which was confirmed by in-vivo X-ray study. PMID:25530963

Implementing the Biopharmaceutics Classification System in Drug Development: Reconciling Similarities, Differences, and Shared Challenges in the EMA and US-FDA-Recommended Approaches.

PubMed

Cardot, J-M; Garcia Arieta, A; Paixao, P; Tasevska, I; Davit, B

2016-07-01

The US-FDA recently posted a draft guideline for industry recommending procedures necessary to obtain a biowaiver for immediate-release oral dosage forms based on the Biopharmaceutics Classification System (BCS). This review compares the present FDA BCS biowaiver approach, with the existing European Medicines Agency (EMA) approach, with an emphasis on similarities, difficulties, and shared challenges. Some specifics of the current EMA BCS guideline are compared with those in the recently published draft US-FDA BCS guideline. In particular, similarities and differences in the EMA versus US-FDA approaches to establishing drug solubility, permeability, dissolution, and formulation suitability for BCS biowaiver are critically reviewed. Several case studies are presented to illustrate the (i) challenges of applying for BCS biowaivers for global registration in the face of differences in the EMA and US-FDA BCS biowaiver criteria, as well as (ii) challenges inherent in applying for BCS class I or III designation and common to both jurisdictions.

Development, evaluation and pharmacokinetics of time-dependent ketorolac tromethamine tablets.

PubMed

Vemula, Sateesh Kumar; Veerareddy, Prabhakar Reddy

2013-01-01

The present study was intended to develop a time-dependent colon-targeted compression-coated tablets of ketorolac tromethamine (KTM) using hydroxypropyl methylcellulose (HPMC) that release the drug slowly but completely in the colonic region by retarding the drug releases in stomach and small intestine. KTM core tablets were prepared by direct compression method and were compression coated with HPMC. The formulation is optimized based on the in vitro drug release studies and further evaluated by X-ray imaging technique in healthy humans to ensure the colonic delivery. To prove these results, in vivo pharmacokinetic studies in human volunteers were designed to study the in vitro-in vivo correlation. From the in vitro dissolution study, optimized formulation F3 showed negligible drug release (6.75 ± 0.49%) in the initial lag period followed by slow release (97.47 ± 0.93%) for 24 h which clearly indicates that the drug is delivered to the colon. The X-ray imaging studies showed that the tablets reached the colon without disintegrating in upper gastrointestinal system. From the pharmacokinetic evaluation, the immediate-release tablets producing peak plasma concentration (C(max)) was 4482.74 ng/ml at 2 h T(max) and colon-targeted tablets showed C(max) = 3562.67 ng/ml at 10 h T(max). The area under the curve for the immediate-release and compression-coated tablets was 10595.14 and 18796.70 ng h/ml and the mean resident time was 3.82 and 10.75 h, respectively. Thus, the compression-coated tablets based on time-dependent approach were preferred for colon-targeted delivery of ketorolac.

Fluoride-containing nanoporous calcium-silicate MTA cements for endodontics and oral surgery: early fluorapatite formation in a phosphate-containing solution.

PubMed

Gandolfi, M G; Taddei, P; Siboni, F; Modena, E; Ginebra, M P; Prati, C

2011-10-01

To test the chemical-physical properties and apatite-forming ability of experimental fluoride-doped calcium silicate cements designed to create novel bioactive materials for use in endodontics and oral surgery. A thermally treated calcium silicate cement (wTC) containing CaCl(2) 5%wt was modified by adding NaF 1%wt (FTC) or 10%wt (F10TC). Cements were analysed by environmental scanning electron microscopy with energy-dispersive X-ray analysis, IR and micro-Raman spectroscopy in wet conditions immediately after preparation or after ageing in a phosphate-containing solution (Dulbecco's phosphate-buffered saline). Calcium and fluoride release and pH of the storage solution were measured. The results obtained were analysed statistically (Tukey's HSD test and two-way anova). The formation of calcium phosphate precipitates (spherulites) was observed on the surface of 24 h-aged cements and the formation of a thick bone-like B-type carbonated apatite layer (biocoating) on 28 day-aged cements. The rate of apatite formation was FTC>F10TC>wTC. Fluorapatite was detected on FTC and F10TC after 1 day of ageing, with a higher fluoride content on F10TC. All the cements released calcium ions. At 5 and 24 h, the wTC had the significantly highest calcium release (P<0.001) that decreased significantly over the storage time. At 3-28 days, FTC and F10TC had significantly higher calcium release than wTC (P<0.05). The F10TC had the significantly highest fluoride release at all times (P<0.01) that decreased significantly over storage time. No significant differences were observed between FTC and wTC. All the cements had a strong alkalinizing activity (OH(-) release) that remained after 28 days of storage. The addition of sodium fluoride accelerated apatite formation on calcium silicate cements. Fluoride-doped calcium silicate cements had higher bioactivity and earlier formation of fluorapatite. Sodium fluoride may be introduced in the formulation of mineral trioxide aggregate cements to enhance their biological behaviour. F-doped calcium silicate cements are promising bone cements for clinical endodontic use. © 2011 International Endodontic Journal.

Sustained Release of Antibacterial Lipopeptides from Biodegradable Polymers against Oral Pathogens

PubMed Central

Eckhard, Lea H.; Houri-Haddad, Yael; Sol, Asaf; Zeharia, Rotem; Shai, Yechiel; Beyth, Shaul; Domb, Abraham J.

2016-01-01

The development of antibacterial drugs to overcome various pathogenic species, which inhabit the oral cavity, faces several challenges, such as salivary flow and enzymatic activity that restrict dosage retention. Owing to their amphipathic nature, antimicrobial peptides (AMPs) serve as the first line of defense of the innate immune system. The ability to synthesize different types of AMPs enables exploitation of their advantages as alternatives to antibiotics. Sustained release of AMPs incorporated in biodegradable polymers can be advantageous in maintaining high levels of the peptides. In this study, four potent ultra-short lipopeptides, conjugated to an aliphatic acid chain (16C) were incorporated in two different biodegradable polymers: poly (lactic acid co castor oil) (PLACO) and ricinoleic acid-based poly (ester-anhydride) (P(SA-RA)) for sustained release. The lipopeptide and polymer formulations were tested for antibacterial activity during one week, by turbidometric measurements of bacterial outgrowth, anti-biofilm activity by live/dead staining, biocompatibility by hemolysis and XTT colorimetric assays, mode of action by fluorescence-activated cell sorting (FACS) and release profile by a fluorometric assay. The results show that an antibacterial and anti-biofilm effect, as well as membrane disruption, can be achieved by the use of a formulation of lipopeptide incorporated in biodegradable polymer. PMID:27606830

In vitro and in vivo evaluation of capsaicin-loaded microemulsion for enhanced oral bioavailability.

PubMed

Zhu, Yuan; Zhang, Jiajia; Zheng, Qianfeng; Wang, Miaomiao; Deng, Wenwen; Li, Qiang; Firempong, Caleb Kesse; Wang, Shengli; Tong, Shanshan; Xu, Ximing; Yu, Jiangnan

2015-10-01

Capsaicin, as a food additive, has attracted worldwide concern owing to its pungency and multiple pharmacological effects. However, poor water solubility and low bioavailability have limited its application. This study aims to develop a capsaicin-loaded microemulsion to enhance the oral bioavailability of the anti-neuropathic-pain component, capsaicin, which is poorly water soluble. In this study, the microemulsion consisting of Cremophor EL, ethanol, medium-chain triglycerides (oil phase) and water (external phase) was prepared and characterized (particle size, morphology, stability and encapsulation efficiency). The gastric mucosa irritation test of formulated capsaicin was performed in rats to evaluate its oral feasibility, followed by the pharmacokinetic study in vivo. Under these conditions, the encapsulated capsaicin revealed a faster capsaicin release in vitro coupled with a greater absorption in vivo when compared to the free capsaicin. The oral bioavailability of the formulated capsaicin-loaded microemulsions was 2.64-fold faster than that of free capsaicin. No significant irritation was observed on the mucosa from the pathological section of capsaicin-loaded microemulsion treated stomach. These results indicate that the developed microemulsion represents a safe and orally effective carrier for poorly soluble substances. The formulation could be used for clinical trials and expand the application of capsaicin. © 2014 Society of Chemical Industry.

Development of mucoadhesive patches for buccal administration of carvedilol.

PubMed

Vishnu, Y Vamshi; Chandrasekhar, K; Ramesh, G; Rao, Y Madhusudan

2007-01-01

A buccal patch for systemic administration of carvedilol in the oral cavity has been developed using two different mucoadhesive polymers. The formulations were tested for in vitro drug permeation studies, buccal absorption test, in vitro release studies, moisture absorption studies and in vitro bioadhesion studies. The physicochemical interactions between carvedilol and polymers were investigated by Fourier transform infrared (FTIR) Spectroscopy. According to FTIR the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. XRD studies reveal that the drug is in crystalline state in the polymer matrix. The results indicate that suitable bioadhesive buccal patches with desired permeability could be prepared. Bioavailability studies in healthy pigs reveal that carvedilol has got good buccal absorption. The bioavailability of carvedilol from buccal patches has increased 2.29 folds when compared to that of oral solution. The formulation AC5 (HPMC E 15) shows 84.85 + 0.089% release and 38.69 + 6.61% permeated through porcine buccal membrane in 4 hr. The basic pharmacokinetic parameters like the C(max), T(max) and AUC(total) were calculated and showed statistically significant difference (P<0.05) when given by buccal route compared to that of oral solution.

Developing dissolution testing methodologies for extended-release oral dosage forms with supersaturating properties. Case example: Solid dispersion matrix of indomethacin.

PubMed

Tajiri, Tomokazu; Morita, Shigeaki; Sakamoto, Ryosaku; Mimura, Hisahi; Ozaki, Yukihiro; Reppas, Christos; Kitamura, Satoshi

2015-07-25

The objective of this study was to develop an in vitro dissolution test method with discrimination ability for an extended-release solid dispersion matrix of a lipophilic drug using the United States Pharmacopeia (USP) Apparatus 4, flow-through cell apparatus. In the open-loop configuration, the sink condition was maintained by manipulating the flow rate of the dissolution medium. To evaluate the testing conditions, the drug release mechanism from an extended-release solid dispersion matrix containing hydrophobic and hydrophilic polymers was investigated. As the hydroxypropyl methylcellulose (HPMC) maintained concentrations of indomethacin higher than the solubility in a dissolution medium, the release of HPMC into the dissolution medium was also quantified using size-exclusion chromatography. We concluded that the USP Apparatus 4 is suitable for application to an in vitro dissolution method for orally administered extended-release solid dispersion matrix formulations containing poorly water-soluble drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Phospholipid complex enriched micelles: A novel drug delivery approach for promoting the antidiabetic effect of repaglinide.

PubMed

Kassem, Ahmed Alaa; Abd El-Alim, Sameh Hosam; Basha, Mona; Salama, Abeer

2017-03-01

To enhance the oral antidiabetic effect of repaglinide (RG), a newly emerging approach, based on the combination of phospholipid complexation and micelle techniques, was employed. Repaglinide-phospholipid complex (RG-PLC) was prepared by the solvent-evaporation method then characterized using Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and X-ray powder diffraction (XPRD). The results revealed obvious disappearance of the characteristic peaks of the prepared RG-PLCs confirming the formation of drug-phospholipid complex. RG-PLC enriched micelles (RG-PLC-Ms) were prepared by the solvent-evaporation technique employing poloxamer 188 as surfactant. The prepared RG-PLC-Ms showed high drug encapsulation efficiencies (93.81-99.38%), with nanometric particle diameters (500.61-665.32nm) of monodisperse distribution and high stability (Zeta potential < -29.8mV). The in vitro release of RG from RG-PLC-Ms was pH-dependant according to the release media. A higher release pattern was reported in pH=1.2 compared to a more retarded release in pH=6.8 owing to two different kinetics of drug release. Oral antidiabetic effect of two optimized RG-PLC-M formulations was evaluated in an alloxan-induced diabetic rat model for 7-day treatment protocol. The two investigated formulations depicted normal blood glucose, serum malondialdehyde and insulin levels as well as an improved lipid profile, at the end of daily oral treatment, in contrast to RG marketed tablets implying enhanced antidiabetic effect of the drug. Hence, phospholipid-complex enriched micelles approach holds a promising potential for promoting the antidiabetic effect of RG. Copyright © 2016 Elsevier B.V. All rights reserved.

Desktop 3D printing of controlled release pharmaceutical bilayer tablets.

PubMed

Khaled, Shaban A; Burley, Jonathan C; Alexander, Morgan R; Roberts, Clive J

2014-01-30

Three dimensional (3D) printing was used as a novel medicine formulation technique for production of viable tablets capable of satisfying regulatory tests and matching the release of standard commercial tablets. Hydroxypropyl methylcellulose (HPMC 2208) (Methocel™ K100M Premium) and poly(acrylic acid) (PAA) (Carbopol(®) 974P NF) were used as a hydrophilic matrix for a sustained release (SR) layer. Hypromellose(®) (HPMC 2910) was used as a binder while microcrystalline cellulose (MCC) (Pharmacel(®) 102) and sodium starch glycolate (SSG) (Primojel(®)) were used as disintegrants for an immediate release (IR) layer. Commercial guaifenesin bi-layer tablets (GBT) were used as a model drug (Mucinex(®)) for this study. There was a favourable comparison of release of the active guaifenesin from the printed hydrophilic matrix compared with the commercially available GBT. The printed formulations were also evaluated for physical and mechanical properties such as weight variation, friability, hardness and thickness as a comparison to the commercial tablet and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). All formulations (standard tablets and 3D printed tablets) showed Korsmeyer-Peppas n values between 0.27 and 0.44 which indicates Fickian diffusion drug release through a hydrated HPMC gel layer. Copyright © 2013 Elsevier B.V. All rights reserved.

[Modern polymers in matrix tablets technology].

PubMed

Zimmer, Łukasz; Kasperek, Regina; Poleszak, Ewa

2014-01-01

Matrix tablets are the most popular method of oral drug administration, and polymeric materials have been used broadly in matrix formulations to modify and modulate drug release rate. The main goal of the system is to extend drug release profiles to maintain a constant in vivo plasma drug concentration and a consistent pharmacological effect. Polymeric matrix tablets offer a great potential as oral controlled drug delivery systems. Cellulose derivatives, like hydroxypropyl methylcellulose (HPMC) are often used as matrix formers. However, also other types of polymers can be used for this purpose including: Kollidon SR, acrylic acid polymers such as Eudragits and Carbopols. Nevertheless, polymers of natural origin like: carragens, chitosan and alginates widely used in the food and cosmetics industry are now coming to the fore of pharmaceutical research and are used in matrix tablets technology. Modern polymers allow to obtain matrix tablets by 3D printing, which enables to develop new formulation types. In this paper, the polymers used in matrix tablets technology and examples of their applications were described.

Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.

PubMed

Wong, Anselm; Sivilotti, Marco L A; Graudins, Andis

2017-06-01

The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L × IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L × IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity. In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.

Design and In-vitro Evaluation of Sustained Release Floating Tablets of Metformin HCl Based on Effervescence and Swelling

PubMed Central

Senjoti, Faria Gias; Mahmood, Syed; Jaffri, Juliana Md; Mandal, Uttam Kumar

2016-01-01

An oral sustained-release floating tablet formulation of metformin HCl was designed and developed. Effervescence and swelling properties were attributed on the developed tablets by sodium bicarbonate and HPMC-PEO polymer combination, respectively. Tablet composition was optimized by response surface methodology (RSM). Seventeen (17) trial formulations were analyzed according to Box-Behnken design of experiment where polymer content of HPMC and PEO at 1: 4 ratio (A), amount of sodium bi-carbonate (B), and amount of SSG (C) were adopted as independent variables. Floating lag time in sec (Y1), cumulative percent drug released at 1 h (Y2) and 12 h (Y3) were chosen as response variables. Tablets from the optimized formulation were also stored at accelerated stability condition (40°C and 75% RH) for 3 months to assess their stability profile. RSM could efficiently optimize the tablet composition with excellent prediction ability. In-vitro drug release until 12 h, floating lag time, and duration of floating were dependent on the amount of three selected independent variables. Optimized tablets remained floating for more than 24 h with a floating lag time of less than 4 min. Based on best fitting method, optimized formulation was found to follow Korsmeyer-Peppas release kinetic. Accelerated stability study revealed that optimized formulation was stable for three months without any major changes in assay, dissolution profile, floating lag time and other physical properties. PMID:27610147

Bilayer mucoadhesive microparticles for the delivery of metoprolol succinate: Formulation and evaluation.

PubMed

Kumar, Krishan; Dhawan, Neha; Sharma, Harshita; Patwal, Pramod S; Vaidya, Shubha; Vaidya, Bhuvaneshwar

2015-01-01

Metoprolol succinate is a very potent drug for the treatment of hypertension but suffers from poor bioavailability due to its erratic absorption in lower GI tract. Therefore, in the present study, it was hypothesized that by formulating mucoadhesive particles, the residence time in the GIT and release of drug may be prolonged that will enhance the bioavailability of metoprolol succinate. Metoprolol succinate loaded chitosan microparticles were prepared by ionic gelation method. The optimized microparticles were coated with sodium alginate to form a layer over chitosan microparticles to increase the mucoadhesive strength and to release the drug in controlled manner. Coated and uncoated microparticles were evaluated for particle size, zeta potential, morphology, entrapment efficiency, drug loading and in vitro drug release. The coated microparticles showed comparatively less drug release in the 0.1 N HCl while sustained release in PBS (pH 6.8) as compared to uncoated microparticles. The in vivo study on albino rats demonstrated an increase in bioavailability of the coated microparticles as compared to marketed formulation. From the study it can be concluded that alginate coated chitosan microparticles could be a useful carrier for the oral delivery of metoprolol succinate.

The application of halloysite tubule nanoclay in drug delivery.

PubMed

Lvov, Yuri M; DeVilliers, Melgardt M; Fakhrullin, Rawil F

2016-07-01

Natural and biocompatible clay nanotubes are among the best inorganic materials for drug nanoformulations. These halloysite tubes with SiO2 on the outermost surface have diameter of ca. 50 nm, length around 1 micrometer and may be loaded with drugs at 10-30 wt. %. Narrow tube openings allow for controllable sustained drug release for hours, days or even weeks. Physical-chemical properties of these nanotubes are described followed by examples of drug-loading capabilities, release characteristics, and control of duration of release through the end tube capping with polymers. Development of halloysite-polymer composites such as tissue scaffolds and bone cement/dentist resin formulations with enhanced mechanical properties and extension of the drug release to 2-3 weeks are described. Examples of the compression properties of halloysite in tablets and capsules are also shown. We expect that clay nanotubes will be used primarily for non-injectable drug formulations, such as topical and oral dosage forms, cosmetics, as well as for composite materials with enhanced therapeutic effects. These include tissue scaffolds, bone cement and dentist resins with sustained release of antimicrobial and cell growth-promoting medicines (including proteins and DNA) as well as other formulations such as compounds for antiseptic treatment of hospitals.

[The use of natural and synthetic hydrophilic polymers in the formulation of metformin hydrochloride tablets with different profile release].

PubMed

Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Metformin hydrochloride after buformin and phenformin belongs to the group of biguanid derivatives used as oral anti-diabetic drugs. The object of the study is the technological analysis and the potential effect of biodegradable macromolecular polymers on the technological and therapeutic parameters of oral anti-diabetic medicinal products with metformin hydrochloride: Siofor, Formetic, Glucophage, Metformax in doses of 500mg and 1000mg and Glucophage XR in a dose of 500 mg of modified release. Market therapeutic products containing 500 and 1000 mg of metformin hydrochloride in a normal formulation and 500 mg of metformin hydrochloride in a formulation of modified release were analyzed. Following research methods were used: technological analysis of tablets, study of disintegration time of tablets, evaluation of pharmaceutical availability of metformin hydrochloride from tested therapeutic products, mathematical and kinetic analysis of release profiles of metformin hydrochloride, statistical analysis of mean differences of release coefficients. The percentage of excipients in the XR formulation is higher and constitutes 50.5% of a tablet mass. However, in standard formulations the percentage is lower, between 5.5% and 12.76%. On the basis of the results of disintegration time studies, the analysed therapeutic products can be divided into two groups, regardless the dose. The first one are preparations with faster (not fast!) disintegration: Glucophage i Metformax. The second group are preparations with slower disintegration, more balanced in the aspect of a high dose of the biologically active substance: Formetic and Siofor. Products with a lower content of excipients (Metformax, Glucophage) disintegrate in a faster way. The disintegration rate of the products with a higher content of excipients (Formetic, Siofor) is slower. The appearance of metformin hydrochloride concentration in the gastrointestinal contents, balanced in time, caused by a slower disintegration-dissolving of a tablet, is conducive to the reduction of gastrointestinal side effects and better tolerance of the therapeutic product by a patient. The study on pharmaceutical availability indicated relevant kinetic differences between tested therapeutic products. They are particularly visible between standard formulations and the one with prolonged release (Glucophage XR500). Its release profile bears features of kinetics similar to zero-order reactions. Tested therapeutic products contain a large amount of the biologically active substance in relation to the content of excipients. A higher content of excipients in a single tablet mass distinguishes Siofor in comparison with Glucophage i Metformax. The excipients used in the formulations of tested preparations are comparable. A higher percentage of binding agents (HPMC, PVP) is observed, but there is a lack of typical disintegrants which results in a longer disintegration time up to 15 minutes. Siofor disintegrates at the same time as Formetic, but longer than Glucophage i Metformax. Considering the large content of the active substance and pharmacological properties of metformin hydrochloride, such a disintegration might have beneficial consequences, because the amount of the free active substance in the gastrointestinal tract will increase over the longer time period what will reduce the level of gastrointestinal side effects. The release profiles of metformin hydrochloride from tested therapeutic products are comparable. The Glucophage XR 500 formulation with the release kinetics of metformin hydrochloride similar to the zero-order kinetics is completely different from the others. The above is confirmed by the mathematical analysis of release profiles of metformin hydrochloride from tested preparations where equations of lines describing the release profile are characterized by similar values of correlation coefficients.

Design Optimization and In Vitro-In Vivo Evaluation of Orally Dissolving Strips of Clobazam

PubMed Central

Bala, Rajni; Khanna, Sushil; Pawar, Pravin

2014-01-01

Clobazam orally dissolving strips were prepared by solvent casting method. A full 32 factorial design was applied for optimization using different concentration of film forming polymer and disintegrating agent as independent variable and disintegration time, % cumulative drug release, and tensile strength as dependent variable. In addition the prepared films were also evaluated for surface pH, folding endurance, and content uniformity. The optimized film formulation showing the maximum in vitro drug release, satisfactory in vitro disintegration time, and tensile strength was selected for bioavailability study and compared with a reference marketed product (frisium5 tablets) in rabbits. Formulation (F6) was selected by the Design-expert software which exhibited DT (24 sec), TS (2.85 N/cm2), and in vitro drug release (96.6%). Statistical evaluation revealed no significant difference between the bioavailability parameters of the test film (F6) and the reference product. The mean ratio values (test/reference) of C max (95.87%), t max (71.42%), AUC0−t (98.125%), and AUC0−∞ (99.213%) indicated that the two formulae exhibited comparable plasma level-time profiles. PMID:25328709

A novel three-dimensional large-pore mesoporous carbon matrix as a potential nanovehicle for the fast release of the poorly water-soluble drug, celecoxib.

PubMed

Zhang, Yanzhuo; Wang, Hong; Li, Chuanjun; Sun, Baoxiang; Wang, Yu; Wang, Siling; Gao, Cunqiang

2014-04-01

A novel mesocellular carbon foam (MSU-FC) with a large pore size and a three-dimensional porous structure for the oral delivery of poorly water-soluble drugs was prepared. The goal of this study was to improve in vitro dissolution and in vivo absorption of celecoxib (CEB), a model drug, by means of novel carbon-based nanoparticles prepared from the MSU-FC matrix. The MSU-FC matrix was synthesized by an inverse replica templating method using mesocellular silica template. A solvent immersion/evaporation method was used to load the drug molecules. The drug-loaded nanoparticles were characterized for morphology, surface area, particle size, mesoporous structure, crystallinity, solubility and dissolution. The effect of MSU-FC on cell viability was measured using the MTT conversion assay. Furthermore, the oral bioavailability of CEB-loaded MSU-FC in fasted rats was compared with that of the marketed product. Our results demonstrate that CEB incorporation into the prepared MSU-FC resulted in an approximately 9-fold increase in aqueous solubility in comparison with crystalline CEB. MSU-FC produced accelerated immediate release of CEB in comparison with crystalline CEB (pure CEB powder or marketed formulation) and the drug-loaded conventional mesoporous carbon particles. The relative bioavailability of CEB for CEB-loaded MSU-FC was 172%. In addition, MSU-FC nanoparticles exhibited very low toxicity. The MSU-FC nanomatrix has been shown to be a promising drug delivery vehicle for improving the dissolution and biopharmaceutical characteristics of poorly water-soluble drugs.

Two release rates from monolithic carboxymethyl starch tablets: formulation, characterization, and in vitro/in vivo evaluation.

PubMed

Le, Tien Canh; Mateescu, Mircea Alexandru

2017-08-01

Most of non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen at more than 1200 mg/day may generate gastrointestinal and cardiovascular side effects. Bilayer or multiparticulate devices have been developed for controlled release in order to prevent undesired side effects. A new "two release rate (2RR) monolithic tablets" approach is now proposed for controlled release of poorly soluble drugs, particularly NSAIDs. Ibuprofen was used as model drug. This concept is based on a calcium carboxymethyl-starch (CaCMS) complex as a novel, low-cost excipient for monolithic dosage forms easy to manufacture by direct compaction. The in vitro dissolution from CaCMS formulations (tablets containing 400 or 600 mg active principle) showed two distinct release rates: (i) an initial fast release (for 30 min in simulated gastric fluid) of about 200 mg ibuprofen, an amount similar to the dosage of conventional immediate-release form (Motrin® 200 mg), and (ii) a slow release of remaining about 200 or 400 mg for a period of 12 h. A preliminary in vivo study (beagle dogs) showed pharmacokinetic parameters of one single controlled-release dosage of ibuprofen (400 mg) formulated with CaCMS, near equivalence with multiple doses (three tablets of 200 mg ibuprofen) of conventional Motrin®. A marked reduction (with 33%) of administered dose (400 instead 600 mg) was achieved by the new formulation with equivalent therapeutic effects. This dose reduction may be beneficial and is expected to minimize side damage risks. Although the present study was limited to NSAIDs, the 2RR concept can be applied for other drugs, particularly for subjects unable to follow frequent administrations.

Incorporation of beads into oral films for buccal and oral delivery of bioactive molecules.

PubMed

Castro, Pedro M; Sousa, Flávia; Magalhães, Rui; Ruiz-Henestrosa, Victor Manuel Pizones; Pilosof, Ana M R; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, Manuela E

2018-08-15

The association of alginate beads and guar-gum films in a single delivery system was idealized to promote a more effective buccal and oral delivery of bioactive molecules. A response surface method (experimental design approach) was performed to obtain optimal formulations of alginate beads to be incorporated into guar gum oral films as combined buccal and oral delivery systems for caffeine delivery. The combined formulation was further characterized regarding physicochemical properties, drug release, cell viability and buccal permeability. Beads average size, determined by dynamic light scattering (DLS), was of 3.37 ± 6.36 μm. Film thickness was set to 62 μm. Scanning electron microscopy micrographs revealed that beads were evenly distributed onto the film matrix and beads size was in accordance to data obtained from DLS analysis. Evaluation of Fourier-transform infrared spectra did not indicate the formation of new covalent bonds between the matrix of guar-gum films, alginate beads and caffeine. In vitro release assays by dialysis membrane allowed understanding that the combination of guar-gum films and alginate beads assure a slower release of caffeine when compared with the delivery profile of free caffeine from alginate beads or guar-gum films alone. MTT assay, performed on human buccal carcinoma TR146 cell line, allowed concluding that neither guar-gum film, alginate beads nor guar-gum film incorporated into alginate beads significantly compromised cell viability after 12 h of exposure. As demonstrated by in vitro permeability assay using TR146 human buccal carcinoma cell lines, combination of guar-gum films and alginate beads also promoted a slower release and, thus, lower apparent permeability (1.15E-05 ± 3.50E-06) than for caffeine solution (2.68E-05 ± 7.30E-06), guar-gum film (3.12E-05 ± 4.70E-06) or alginate beads (2.01E-05 ± 3.90E-06). The conjugation of alginate beads within an orodispersible film matrix represents an effective oral/buccal delivery system that induces a controlled release along with an enhanced intimate contact with cell layers that may promote higher in vivo bioavailability of carried drugs. Copyright © 2018. Published by Elsevier Ltd.

Long-term safety and efficacy of budesonide in the treatment of ulcerative colitis

PubMed Central

Iborra, Marisa; Álvarez-Sotomayor, Diego; Nos, Pilar

2014-01-01

Ulcerative colitis (UC) is a chronic, relapsing, and remitting inflammatory disease involving the large intestine (colon). Treatment seeks to break recurrent inflammation episodes by inducing and maintaining remission. Historically, oral systemic corticosteroids played an important role in inducing remission of this chronic disease; however, their long-term use is limited and can lead to adverse events. Budesonide is a synthetic steroid with potent local anti-inflammatory effects and low systemic bioavailability due to high first-pass hepatic metabolism. Several studies have demonstrated oral budesonide’s usefulness in treating active mild to moderate ileocecal Crohn’s disease and microscopic colitis and in an enema formulation for left sided UC. However, there is limited information regarding oral budesonide’s efficacy in UC. A novel oral budesonide formulation using a multimatrix system (budesonide-MMX) to extend drug release throughout the colon has been developed recently and seems to be an effective treatment in active left sided UC patients. This article summarizes budesonide’s long-term safety and efficacy in treating UC. PMID:24523594

Development and evaluation of a sublingual film of the antiemetic granisetron hydrochloride.

PubMed

Kalia, Vani; Garg, Tarun; Rath, Gautam; Goyal, Amit Kumar

2016-05-01

The objective of this study was to develop an oral transmucosal formulation of an antiemetic drug that can not only serve in the active form but also provide a controlled release profile. In this study, sublingual films based on the biodegradable and water-soluble polymers, that is HPMCK-4M and PVPK-30, were developed by the solvent casting method, and were loaded with the antiemetic drug granisetron hydrochloride (granisetron HCl). The entrapment efficiency of the developed formulation was found to be 86%. The in vitro profile showed an instant release of the drug from the sublingual film, in a pattern following the first order kinetics array. The in vivo studies showed that granisetron HCl was delivered in its active state and showed effective results, as compared to its activity in the marketed formulation.

Transbuccal delivery of chlorpheniramine maleate from mucoadhesive buccal patches.

PubMed

Sekhar, K Chandra; Naidu, K V S; Vishnu, Y Vamshi; Gannu, Ramesh; Kishan, V; Rao, Y Madhusudan

2008-01-01

This article describes buccal permeation of chlorpheniramine maleate (CPM) and its transbuccal delivery using mucoadhesive buccal patches. Permeation of CPM was calculated in vitro using porcine buccal membrane and in vivo in healthy humans. Buccal formulations were developed with hydroxyethylcellulose (HEC) and evaluated for in vitro release, moisture absorption, mechanical properties, and bioadhesion, and optimized formulation was subjected for bioavailability studies in healthy human volunteers. In vitro flux of CPM was calculated to be 0.14 +/- 0.03 mg.h(-1).cm(-2) and buccal absorption also was demonstrated in vivo in human volunteers. In vitro drug release and moisture absorbed were governed by HEC content and formulations exhibited good tensile and mucoadhesive properties. Bioavailability from optimized buccal patch was 1.46 times higher than the oral dosage form and the results showed statistically significant difference.

An understanding of modified release matrix tablets behavior during drug dissolution as the key for prediction of pharmaceutical product performance - case study of multimodal characterization of quetiapine fumarate tablets.

PubMed

Kulinowski, Piotr; Woyna-Orlewicz, Krzysztof; Rappen, Gerd-Martin; Haznar-Garbacz, Dorota; Węglarz, Władysław P; Dorożyński, Przemysław P

2015-04-30

Motivation for the study was the lack of dedicated and effective research and development (R&D) in vitro methods for oral, generic, modified release formulations. The purpose of the research was to assess multimodal in vitro methodology for further bioequivalence study risk minimization. Principal results of the study are as follows: (i) Pharmaceutically equivalent quetiapine fumarate extended release dosage form of Seroquel XR was developed using a quality by design/design of experiment (QbD/DoE) paradigm. (ii) The developed formulation was then compared with originator using X-ray microtomography, magnetic resonance imaging and texture analysis. Despite similarity in terms of compendial dissolution test, developed and original dosage forms differed in micro/meso structure and consequently in mechanical properties. (iii) These differences were found to be the key factors of failure of biorelevant dissolution test using the stress dissolution apparatus. Major conclusions are as follows: (i) Imaging methods allow to assess internal features of the hydrating extended release matrix and together with the stress dissolution test allow to rationalize the design of generic formulations at the in vitro level. (ii) Technological impact on formulation properties e.g., on pore formation in hydrating matrices cannot be overlooked when designing modified release dosage forms. Copyright © 2015 Elsevier B.V. All rights reserved.

Development and In Vivo Evaluation of a Novel Histatin-5 Bioadhesive Hydrogel Formulation against Oral Candidiasis

PubMed Central

Kong, Eric F.; Tsui, Christina; Boyce, Heather; Ibrahim, Ahmed; Hoag, Stephen W.; Karlsson, Amy J.; Meiller, Timothy F.

2015-01-01

Oral candidiasis (OC), caused by the fungal pathogen Candida albicans, is the most common opportunistic infection in HIV+ individuals and other immunocompromised populations. The dramatic increase in resistance to common antifungals has emphasized the importance of identifying unconventional therapeutic options. Antimicrobial peptides have emerged as promising candidates for therapeutic intervention due to their broad antimicrobial properties and lack of toxicity. Histatin-5 (Hst-5) specifically has exhibited potent anticandidal activity indicating its potential as an antifungal agent. To that end, the goal of this study was to design a biocompatible hydrogel delivery system for Hst-5 application. The bioadhesive hydroxypropyl methylcellulose (HPMC) hydrogel formulation was developed for topical oral application against OC. The new formulation was evaluated in vitro for gel viscosity, Hst-5 release rate from the gel, and killing potency and, more importantly, was tested in vivo in our mouse model of OC. The findings demonstrated a controlled sustained release of Hst-5 from the polymer and rapid killing ability. Based on viable C. albicans counts recovered from tongues of treated and untreated mice, three daily applications of the formulation beginning 1 day postinfection with C. albicans were effective in protection against development of OC. Interestingly, in some cases, Hst-5 was able to clear existing lesions as well as associated tissue inflammation. These findings were confirmed by histopathology analysis of tongue tissue. Coupled with the lack of toxicity as well as anti-inflammatory and wound-healing properties of Hst-5, the findings from this study support the progression and commercial feasibility of using this compound as a novel therapeutic agent. PMID:26596951

Preparation of liposomes containing zedoary turmeric oil using freeze-drying of liposomes via TBA/water cosolvent systems and evaluation of the bioavailability of the oil.

PubMed

Yang, Zhiwen; Yu, Songlin; Fu, Dahua

2010-02-01

The purpose of this study was to enhance the absorption of zedoary turmeric oil (ZTO) in vivo and develop new formulations of a water-insoluble oily drug. This study described a method for preparing ZTO liposomes, which involved freeze-drying (FD) of liposomes with TBA/water cosolvent systems. The TBA/water cosolvent systems were used to investigate a feasible method of liposomes manufacture; the two factors, sugar/lipid mass ratio and TBA content (concentration), of the preparation process were evaluated in this study. The results showed that the addition of TBA content could significantly enhance the sublimation of ice resulting in short FD cycles time, and reduce the entrapment efficiency of liposomes. In addition, the residual TBA solvents levels were determined to be less than 0.37% under all optimum formulations and processing conditions. Several physical properties of liposomes were examined by H-600 transmission electron microscope (TEM) and zetamaster analyser system. The results revealed that the liposomes were smooth and spherical with an average particle size of 457 +/- 7.8 nm and the zeta potential was more than 3.65 Mv. The bioavailability of the liposomes was evaluated in rabbits, compared with the conventional self-emulsifying formulation for oral administration. Compared with the conventional self-emulsifying formulation, the plasma concentration-time profiles with improved sustained-release characteristics were achieved after oral administration of the liposomes with a bioavailability of 257.7% (a good strategy for improving the bioavailability of an oily drug). In conclusion, the present experimental findings clearly demonstrated the usefulness of ZTO liposome vesicles in improving therapeutic efficacy by enhancing oral bioavailability. Our study offered an alternative method for designing sustained-release preparations of oily drugs.

Comparative in vitro activity of a pharmacokinetically enhanced oral formulation of amoxicillin/clavulanic acid (2000/125 mg twice daily) against 9172 respiratory isolates collected worldwide in 2000.

PubMed

Koeth, Laura M; Jacobs, Michael R; Good, Caryn E; Bajaksouzian, Saralee; Windau, Anne; Jakielaszek, Charles; Saunders, Kay A

2004-11-01

A new, pharmacokinetically enhanced, oral formulation of amoxicillin/clavulanic acid has been developed to overcome resistance in the major bacterial respiratory pathogen Streptococcus pneumoniae, while maintaining excellent activity against Haemophilus influenzae and Moraxella catarrhalis, including beta-lactamase producing strains. This study was conducted to provide in vitro susceptibility data for amoxicillin/clavulanic acid and 16 comparator agents against the key respiratory tract pathogens. Susceptibility testing was performed on 9172 isolates collected from 95 centers in North America, Europe, Australia, and Hong Kong by broth microdilution MIC determination, according to NCCLS methods, using amoxicillin/clavulanic acid and 16 comparator antimicrobial agents. Results were interpreted according to NCCLS breakpoints and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints based on oral dosing regimens. Overall, 93.5% of Streptococcus pneumoniae isolates were susceptible to amoxicillin/clavulanic acid at the current susceptible breakpoint of < or =2 microg/mL and 97.3% at the PK/PD susceptible breakpoint of < or =4 microg/mL for the extended release formulation. Proportions of isolates that were penicillin intermediate and resistant were 13% and 16.5%, respectively, while 25% were macrolide resistant and 21.8% trimethoprim/sulfamethoxazole resistant. 21.9% of Haemophilus influenzae were beta-lactamase producers and 16.8% trimethoprim/sulfamethoxazole resistant, >99% of isolates were susceptible to amoxicillin/clavulanic acid, cefixime, ciprofloxacin and levofloxacin at NCCLS breakpoints. The most active agents against Moraxella catarrhalis were amoxicillin/clavulanic acid, macrolides, cefixime, fluoroquinolones, and doxycycline. Overall, 13% of Streptococcus pyogenes were resistant to macrolides. The extended release formulation of amoxicillin/clavulanic acid has potential for empiric use against many respiratory tract infections worldwide due to its activity against species resistant to many agents currently in use.

Sulindac loaded alginate beads for a mucoprotective and controlled drug release.

PubMed

Yegin, Betül Arica; Moulari, Brice; Durlu-Kandilci, N Tugba; Korkusuz, Petek; Pellequer, Yann; Lamprecht, Alf

2007-06-01

Ionotropic gelation was used to entrap sulindac into calcium alginate beads as a potential drug carrier for the oral delivery of this anti-inflammatory drug. Beads were investigated in vitro for a possible sustained drug release and their use in vivo as a gastroprotective system for sulindac. Process parameters such as the polymer concentration, polymer/drug ratio, and different needle diameter were analysed for their influences on the bead properties. Size augmented with increasing needle diameter (0.9 mm needle: 1.28 to 1.44 mm; 0.45 mm needle: 1.04 to 1.07 mm) due to changes in droplet size as well as droplet viscosity. Yields varied between 87% and 98% while sulindac encapsulation efficiencies of about 88% and 94% were slightly increasing with higher alginate concentrations. Drug release profiles exhibited a complete release for all formulations within 4 hours with a faster release for smaller beads. Sulindac loaded alginate beads led to a significant reduction of macroscopic histological damage in the stomach and duodenum in mice. Similarly, microscopic analyses of the mucosal damage demonstrated a significant mucoprotective effect of all bead formulation compared to the free drug. The present alginate formulations exhibit promising properties of a controlled release form for sulindac; meanwhile they provide a distinct tissue protection in the stomach and duodenum.

Orally disintegrating films: A modern expansion in drug delivery system.

PubMed

Irfan, Muhammad; Rabel, Sumeira; Bukhtar, Quratulain; Qadir, Muhammad Imran; Jabeen, Farhat; Khan, Ahmed

2016-09-01

Over the past few decades, tendency toward innovative drug delivery systems has majorly increased attempts to ensure efficacy, safety and patient acceptability. As discovery and development of new chemical agents is a complex, expensive and time consuming process, so recent trends are shifting toward designing and developing innovative drug delivery systems for existing drugs. Out of those, drug delivery system being very eminent among pediatrics and geriatrics is orally disintegrating films (ODFs). These fast disintegrating films have superiority over fast disintegrating tablets as the latter are associated with the risks of choking and friability. This drug delivery system has numerous advantages over conventional fast disintegrating tablets as they can be used for dysphasic and schizophrenic patients and are taken without water due to their ability to disintegrate within a few seconds releasing medication in mouth. Various approaches are employed for formulating ODFs and among which solvent casting and spraying methods are frequently used. Generally, hydrophilic polymers along with other excipients are used for preparing ODFs which allow films to disintegrate quickly releasing incorporated active pharmaceutical ingredient (API) within seconds. Orally disintegrating films have potential for business and market exploitation because of their myriad of benefits over orally disintegrating tablets. This present review attempts to focus on benefits, composition, approaches for formulation and evaluation of ODFs. Additionally, the market prospect of this innovative dosage form is also targeted.

A Novel Multilayered Multidisk Oral Tablet for Chronotherapeutic Drug Delivery

PubMed Central

Khan, Zaheeda; Choonara, Yahya E.; du Toit, Lisa C.; Ndesendo, Valence M. K.; Pillay, Viness

2013-01-01

A Multilayered Multidisk Tablet (MLMDT) comprising two drug-loaded disks enveloped by three drug-free barrier layers was developed for use in chronotherapeutic disorders, employing two model drugs, theophylline and diltiazem HCl. The MLMDT was designed to achieve two pulses of drug release separated by a lag phase. The polymer disk comprised hydroxyethylcellulose (HEC) and ethylcellulose (EC) granulated using an aqueous dispersion of EC. The polymeric barrier layers constituted a combination of pectin/Avicel (PBL) (1st barrier layer) and hydroxypropylmethylcellulose (HPMC) (HBL1 and HBL2) as the 2nd and 3rd barrier layers, respectively. Sodium bicarbonate was incorporated into the diltiazem-containing formulation for delayed drug release. Erosion and swelling studies confirmed the manner in which the drug was released with theophylline formulations exhibiting a maximum swelling of 97% and diltiazem containing formulations with a maximum swelling of 119%. FTIR spectra displayed no interactions between drugs and polymers. Molecular mechanics simulations were undertaken to predict the possible orientation of the polymer morphologies most likely affecting the MLMDT performance. The MLMDT provided two pulses of drug release, separated by a lag phase, and additionally it displayed desirable friability, hardness, and uniformity of mass indicating a stable formulation that may be a desirable candidate for chronotherapeutic drug delivery. PMID:24024200

Use of the direct compression aid Ludiflash(®) for the preparation of pellets via wet extrusion/spheronization.

PubMed

Roblegg, Eva; Schrank, Simone; Griesbacher, Martin; Radl, Stefan; Zimmer, Andreas; Khinast, Johannes

2011-10-01

Conventional solid oral dosage forms are unsuitable for children due to problems associated with swallowing and unpleasant taste. Additionally, the limit of tablets lays in the patient adapted dosing. Therefore, the suitability of Ludiflash(®), a direct compression aid for orally disintegrating tablets, was investigated for the preparation of individually dosable pellets. Micropellets consisting of Ludiflash(®) and small amounts of microcrystalline cellulose were prepared via the wet extrusion/spheronization technique. Paracetamol and ibuprofen were applied as model drugs. The obtained pellets were characterized with respect to drug release and disintegration characteristics, mechanical properties, as well as size and shape. Drug loading was possible up to 30% for ibuprofen and even up to 50% for paracetamol. Higher ibuprofen loadings resulted in considerably slowed drug release and higher paracetamol contents yielded in non-spherical pellets. In vitro release studies revealed that more than 80% of the drug was released within 30 and 60 min for paracetamol and ibuprofen, respectively. Drug release rates were highly influenced by the pellet disintegration behavior. Investigations of the release mechanism using the Korsemeyer-Peppas approach suggested Super Case II drug transport for all paracetamol formulations and anomalous drug transport for most ibuprofen formulations. All pellets exhibited a low porosity and friability, as well as a sufficiently high tensile strength, which was significantly influenced by the type of model drug. Ludiflash(®) can be applied as main excipient for the preparation of individually dosable pellets combining fast drug release and a high mechanical stability.

Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from a crude extract of Andrographis paniculata.

PubMed

Sermkaew, Namfa; Ketjinda, Wichan; Boonme, Prapaporn; Phadoongsombut, Narubodee; Wiwattanapatapee, Ruedeekorn

2013-11-20

The purpose of this study was to develop self-microemulsifying formulations of an Andrographis paniculata extract in liquid and pellet forms for an improved oral delivery of andrographolide. The optimized liquid self-microemulsifying drug delivery system (SMEDDS) was composed of A. paniculata extract (11.1%), Capryol 90 (40%), Cremophor RH 40 (40%) and Labrasol (8.9%). This liquid SMEDDS was further adsorbed onto colloidal silicon dioxide and microcrystalline cellulose, and converted to SMEDDS pellets by the extrusion/spheronization technique. The microemulsion droplet sizes of the liquid and pellet formulations after dilution with water were in the range of 23.4 and 30.3 nm. The in vitro release of andrographolide from the liquid SMEDDS and SMEDDS pellets was 97.64% (SD 1.97%) and 97.74% (SD 3.36%) within 15 min, respectively while the release from the initial extract was only 10%. The oral absorption of andrographolide was determined in rabbits. The C(max) value of andrographolide from the A. paniculata extract liquid SMEDDS and SMEDDS pellet formulations (equivalent to 17.5mg/kg of andrographolide) was 6-fold and 5-fold greater than the value from the initial extract in aqueous suspension (equivalent to 35 mg/kg of andrographolide), respectively. In addition, the AUC(0-12h) was increased 15-fold by the liquid SMEDDS and 13-fold by the SMEDDS pellets compared to the extract in aqueous suspension, respectively. The results clearly indicated that the liquid and solid SMEDDS could be effectively used to improve the dissolution and oral bioavailability that would also enable a reduction in the dose of the poorly water soluble A. paniculata extract. Copyright © 2013 Elsevier B.V. All rights reserved.

Development of a new esomeprazole delayed release gastro-resistant pellet formulation with improved storage stability.

PubMed

Barmpalexis, Panagiotis; Grypioti, Agni

2018-06-01

This study describes the development of a new esomeprazole (ESO) delayed release gastro-resistant formulation with improved storage stability. A three-step (drug-, sub(seal)- and enteric-) coating process was employed with the aid of a fluid bed coater. Several formulation factors (namely, size and quantity of starting non-pareil sugar spheres, binder quantity during drug-layering, sub(seal)-coating polymer type, and quantity and enteric coating quantity) were evaluated and the whole process was modeled with the aid of feed-forward back-propagation artificial neural networks (ANNs). Results showed that the selection of small-sized starting spheres (45/60 mesh size) leads to pellet agglomeration, while as sub(seal)-coating weight gain increases a reduction in ESO dissolution rate is observed. The enteric-coating applied (Eudragit L30D-55) showed good gastro-resistant performance in both 0.1 N HCl and pH 4.5 media, while immediate release profiles with more than 85% of ESO being released in less than 30 min were obtained. The effect of cellulose-based sub(seal)-coating polymers, (namely, hydroxypropyl cellulose and hydroxypropylmethyl cellulose) on formulation's storage stability at 40 ± 2 °C/75 ± 5%RH indicated that only hydroxypropylmethyl cellulose was able to stabilize ESO delayed-release formulations in terms of assay, dissolution, impurities, and gastro-resistance performance. Finally, scanning electron microscopy (SEM) analysis revealed smooth and homogeneous external surface/coating layers in all three levels (drug-, sub(seal)-, and enteric- coating), while x-ray diffraction showed no polymorphic transformations.

In vivo gastric residence and gastroprotective effect of floating gastroretentive tablet of DA-9601, an extract of Artemisia asiatica, in beagle dogs

PubMed Central

Kim, Jeong Soo; Cha, Kwang Ho; Kang, Seung Yeob; Won, Donghan; Jang, Sun Woo; Son, Miwon; Son, Moon Ho; Choi, Ho Jung; Lee, Young Won; Kang, Myung Joo

2016-01-01

Objective DA-9601, an extract of Artemisia asiatica containing eupatilin and jaceosidin as active compounds, has been prescribed to treat gastritis in Asia. In recent times, sustained-release, floating gastroretentive (GR) tablets of DA-9601 are available on the market. In the present study, the physical properties and in vitro drug release profile, in vivo gastric residence time, and gastroprotective effect of GR tablet were compared to those of immediate release (IR) tablets of DA-9601. Method In vitro buoyancy behavior (floating lag time and duration) and release profile of eupatilin were assessed in acidic medium. The in vivo intragastric behaviors of the barium sulfate-loaded IR and GR tablets were evaluated in beagle dogs by radiographic studies. Local gastroprotective effect was compared in an experimentally induced gastric lesion in beagle dogs after oral administration of IR (three times per day) or GR (twice daily) tablets for 15 days. Results Upon contact with gastric juice, a low-density floating tablet (apparent density of 0.93 g/cm3) was buoyant on the medium and was upheld for 14 hours, providing sustained drug release profile, whereas the IR tablet disintegrated within 10 minutes, showing complete drug release within 2 hours. In vivo radiographic studies showed that the GR tablet was retained for >4 hours in the stomach. Both DA-9601 formulations remarkably alleviated gastric mucosal injury compared to placebo group, when observed by gastric endoscopy. Conclusion Twice-daily GR tablets exhibited a prolonged gastric residence time and a remarkable mucosal restoration effect in animal models. Therefore, the GR system of DA-9601 could be a substitute dosage form for the treatment of gastritis, while reducing the dosing frequency and thus improving patient compliance. PMID:27354765

In vivo gastric residence and gastroprotective effect of floating gastroretentive tablet of DA-9601, an extract of Artemisia asiatica, in beagle dogs.

PubMed

Kim, Jeong Soo; Cha, Kwang Ho; Kang, Seung Yeob; Won, Donghan; Jang, Sun Woo; Son, Miwon; Son, Moon Ho; Choi, Ho Jung; Lee, Young Won; Kang, Myung Joo

2016-01-01

DA-9601, an extract of Artemisia asiatica containing eupatilin and jaceosidin as active compounds, has been prescribed to treat gastritis in Asia. In recent times, sustained-release, floating gastroretentive (GR) tablets of DA-9601 are available on the market. In the present study, the physical properties and in vitro drug release profile, in vivo gastric residence time, and gastroprotective effect of GR tablet were compared to those of immediate release (IR) tablets of DA-9601. In vitro buoyancy behavior (floating lag time and duration) and release profile of eupatilin were assessed in acidic medium. The in vivo intragastric behaviors of the barium sulfate-loaded IR and GR tablets were evaluated in beagle dogs by radiographic studies. Local gastroprotective effect was compared in an experimentally induced gastric lesion in beagle dogs after oral administration of IR (three times per day) or GR (twice daily) tablets for 15 days. Upon contact with gastric juice, a low-density floating tablet (apparent density of 0.93 g/cm(3)) was buoyant on the medium and was upheld for 14 hours, providing sustained drug release profile, whereas the IR tablet disintegrated within 10 minutes, showing complete drug release within 2 hours. In vivo radiographic studies showed that the GR tablet was retained for >4 hours in the stomach. Both DA-9601 formulations remarkably alleviated gastric mucosal injury compared to placebo group, when observed by gastric endoscopy. Twice-daily GR tablets exhibited a prolonged gastric residence time and a remarkable mucosal restoration effect in animal models. Therefore, the GR system of DA-9601 could be a substitute dosage form for the treatment of gastritis, while reducing the dosing frequency and thus improving patient compliance.

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential.

PubMed

Singh, Bhupinder; Khurana, Lalit; Bandyopadhyay, Shantanu; Kapil, Rishi; Katare, O O P

2011-11-01

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers.

PubMed

Stifft, Frank; Vanmolkot, Floris; Scheffers, Ingrid; van Bortel, Luc; Neef, Cees; Christiaans, Maarten

2014-11-01

The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered. © 2014 The British Pharmacological Society.

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

PubMed Central

Stifft, Frank; Vanmolkot, Floris; Scheffers, Ingrid; van Bortel, Luc; Neef, Cees; Christiaans, Maarten

2014-01-01

Aims The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Methods Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Results Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Conclusions Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered. PMID:24809233

Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder.

PubMed

Ermer, James C; Adeyi, Ben A; Pucci, Michael L

2010-12-01

Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology. Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmotic-release formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine dimesylate may contribute to its consistent pharmacokinetic profile. The reasons underlying observed differential responses to stimulants are likely to be multifactorial, including pharmacodynamic factors. While the use of stimulants with low inter- and intrapatient pharmacokinetic variability does not obviate the need to titrate stimulant doses, stimulants with low intraindividual variation in pharmacokinetic parameters may reduce the likelihood of patients falling into subtherapeutic drug concentrations or reaching drug concentrations at which the risk of adverse events increases. As such, clinicians are urged both to adjust stimulant doses based on therapeutic response and the risk for adverse events and to monitor patients for potential causes of pharmacokinetic variability.

Repaglinide-loaded solid lipid nanoparticles: effect of using different surfactants/stabilizers on physicochemical properties of nanoparticles.

PubMed

Ebrahimi, Hossein Ali; Javadzadeh, Yousef; Hamidi, Mehrdad; Jalali, Mohammad Barzegar

2015-09-21

Repaglinide is an efficient anti-diabetic drug which is prescribed widely as multi-dosage oral daily regimens. Due to the low compliance inherent to each multi-dosage regimen, development of prolonged-release formulations could enhance the overall drug efficacy in patient populations. Repaglinide-loaded solid lipid nanoparticles (SLNs) were developed and characterized in vitro. Various surfactants were used in this study during the nanocarrier preparation procedure and their corresponding effects on some physicochemical properties of SLNs such as size, zeta potential; drug loading parameters and drug release profiles was investigated. Stearic acid and glyceryl mono stearate (GMS) were used as lipid phase and phosphatidylcholin, Tween80, Pluronic F127, poly vinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) were used as surfactant/stabilizer. The results showed some variations between formulations; where the Tween80-based SLNs showed smallest size, the phosphatidylcholin-based SLNs indicated most prolonged drug release time and the highest loading capacity. SEM images of these formulations showed morphological variations and also confirmed the nanoscale size of these particles. The FTIR and DSC results demonstrated no interaction between drug and excipients. The invitro release profiles of different formulations were studied and observed slow release of drug from all formulations. However significant differences were found among them in terms of their initial burst release as well as the whole drug release profile. From fitting these data to various statistical models, the Peppas model was proposed as the best model to describe the statistical indices and, therefore, mechanism of drug release. The results of this study confirmed the effect of surfactant type on SLNs physicochemical properties such as morphological features, loading parameters, particle sizes and drug release kinetic. With respect to the outcome data, the mixture of phosphatidylcholin/Pluronic F127 was selected as the best surfactant/stabilizer to coat the lipid core comprising stearic acid and GMS.

In vitro dissolution of generic immediate-release solid oral dosage forms containing BCS class I drugs: comparative assessment of metronidazole, zidovudine, and amoxicillin versus relevant comparator pharmaceutical products in South Africa and India.

PubMed

Reddy, Nallagundla H S; Patnala, Srinivas; Löbenberg, Raimar; Kanfer, Isadore

2014-10-01

Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f 2 acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.

Inhibition of proteases activity in intestine needs a sustainable acidic environment rather than a transient.

PubMed

Xing, Chang; Xing, Jin-Feng; Ge, Zhi-Qiang

2017-10-01

α-Chymotrypsin (α-CT) and trypsin are important components of the enzymatic barrier. They could degrade the therapeutic proteins and peptides, inhibit their activity consequently, and thereby reduce their oral bioavailability. Acidic agents, as one type of indirect protease inhibitors, have shown proof of concept in clinical trials. We report here the inactivated proteases due to acid influence can be reactivated immediately by environmental pH recovery regardless of how long the inactivation last. To keep the inactivation time of proteases for 4-5 h, we designed and prepared a sustained-release tablet containing citric acid (CA) which can effectively reduce the pH below 5.0 and maintain it for 5 h in the dissolution-reaction medium. The activity of α-CT and trypsin was quantified by analyzing the residual amount of their respective substrates BTEE and TAME. More than 80% of the substrates were survived in 5.0 h of incubation, whereas the common tablet inhibited the proteases activity for only two hours in the same experimental medium. It indicates that the sustained-release tablet loaded with CA can efficiently inhibit the α-CT and trypsin activity longer than the common tablet. The results will be beneficial for designing and formulating the peroral administration of peptide and protein drugs.

Nanoemulsion improves the oral bioavailability of baicalin in rats: in vitro and in vivo evaluation

PubMed Central

Zhao, Ling; Wei, Yumeng; Huang, Yu; He, Bing; Zhou, Yang; Fu, Junjiang

2013-01-01

Baicalin is one of the main bioactive flavone glucuronides derived as a medicinal herb from the dried roots of Scutellaria baicalensis Georgi, and it is widely used for the treatment of fever, inflammation, and other conditions. Due to baicalin’s poor solubility in water, its absolute bioavailability after oral administration is only 2.2%. The objective of this study was to develop a novel baicalin-loaded nanoemulsion to improve the oral bioavailability of baicalin. Based on the result of pseudoternary phase diagram, the nanoemulsion formulation consisting of soy-lecithin, tween-80, polyethylene glycol 400, isopropyl myristate, and water (1:2:1.5:3.75:8.25, w/w) was selected for further study. Baicalin-loaded nanoemulsions (BAN-1 and BAN-2) were prepared by internal or external drug addition and in vivo and in vitro evaluations were performed. The results showed that the mean droplet size, polydispersity index, and drug content of BAN-1 and BAN-2 were 91.2 ± 2.36 nm and 89.7 ± 3.05 nm, 0.313 ± 0.002 and 0.265 ± 0.001, and 98.56% ± 0.79% and 99.40% ± 0.51%, respectively. Transmission electron microscopy revealed spherical globules and confirmed droplet size analysis. After dilution 30-fold with water, the solubilization capacity of BAN-1 and BAN-2 did not change. In vitro release results showed sustained-release characteristics. BAN-1 formulation was stable for at least 6 months and was more stable than BAN-2. In rats, the area under the plasma drug concentration-time curve value of BAN-1 was 1.8-fold and 7-fold greater than those of BAN-2 and free baicalin suspension after oral administration at a dose of 100 mg/kg. In conclusion, these results demonstrated that the baicalin-loaded nanoemulsion formulation, in particular BAN-1, was very effective for improving the oral bioavailability of baicalin and exhibited great potential for future clinical application. PMID:24124365

Development of olmesartan medoxomil optimized nanosuspension using the Box-Behnken design to improve oral bioavailability.

PubMed

Nagaraj, K; Narendar, D; Kishan, V

2017-07-01

The aim of the present investigation was to enhance the oral bioavailability of olmesartan medoxomil by improving its solubility and dissolution rate by preparing nanosuspension (OM-NS), using the Box-Behnken design. In this, four factors were evaluated at three levels. Independent variables include: concentration of drug (X 1 ), concentration of surfactant (X 2 ), concentration of polymer (X 3 ) and number of homogenization cycles (X 4 ). Based on preliminary studies, the size (Y 1 ), zeta potential (ZP) (Y 2 ) and % drug release at 5 min (Y 3 ) were chosen as dependent responses. OM-NS was prepared by high pressure homogenization method. The size, PDI, ZP, assay, in vitro release and morphology of OM-NS were characterized. Further, the pharmacokinetic (PK) behavior of OM-NS was evaluated in male wistar rats. Statistically optimized OM-NS formulation exhibited mean particle size of 492 nm, ZP of -27.9 mV and 99.29% release in 5 min. OM-NS showed more than four times increase in its solubility than pure OM. DSC and XRD analyses indicated that the drug incorporated into OM-NS was in amorphous form. The morphology of OM-NS was found to be nearly spherical with high dispersity by scanning electron microscopic studies. The PK results showed that OM lyophilized nanosuspension (NS) exhibited improved PK properties compared to coarse powder suspension and marketed tablet powder suspension (TS). Oral bioavailability of lyophilized NS was increased by 2.45 and 2.25 folds when compared to marketed TS and coarse powder suspension, respectively. Results of this study lead to conclusion that NS approach was effective in preparing OM formulations with enhanced dissolution and improved oral bioavailability.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril.

PubMed

Verbeeck, Roger K; Kanfer, Isadore; Löbenberg, Raimar; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Langguth, Peter; Polli, James E; Parr, Alan; Shah, Vinod P; Mehta, Mehul; Dressman, Jennifer B

2017-08-01

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate-labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient. Copyright © 2017 American Pharmacists Association®. All rights reserved.

Development and optimization of enteric coated mucoadhesive microspheres of duloxetine hydrochloride using 3(2) full factorial design.

PubMed

Setia, Anupama; Kansal, Sahil; Goyal, Naveen

2013-07-01

Microspheres constitute an important part of oral drug delivery system by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at the site of absorption. The objective of the present study was to formulate and systematically evaluate in vitro performance of enteric coated mucoadhesive microspheres of duloxetine hydrochloride (DLX), an acid labile drug. DLX microspheres were prepared by simple emulsification phase separation technique using chitosan as carrier and glutaraldehyde as a cross-linking agent. Microspheres prepared were coated with eudragit L-100 using an oil-in-oil solvent evaporation method. Eudragit L-100was used as enteric coating polymer with the aim to release the drug in small intestine The microspheres prepared were characterized by particle size, entrapment efficiency, swelling index (SI), mucoadhesion time, in vitro drug release and surface morphology. A 3(2) full factorial design was employed to study the effect of independent variables polymer-to-drug ratio (X1) and stirring speed (X2) on dependent variables, particle size, entrapment efficiency, SI, in vitro mucoadhesion and drug release up to 24 h (t24). Microspheres formed were discrete, spherical and free flowing. The microspheres exhibited good mucoadhesive property and also showed high percentage entrapment efficiency. The microspheres were able to sustain the drug release up to 24 h. Thus, the prepared enteric coated mucoadhesive microspheres may prove to be a potential controlled release formulation of DLX for oral administration.

Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer's disease patients.

PubMed

Liew, Kai Bin; Tan, Yvonne Tze Fung; Peh, Kok Khiang

2015-04-01

Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly. The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer's disease patient. The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac®, Flowlac® and Tablettose®. Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac® was found with shortest in vitro disintegration time (21.7 ± 1.67 s), in vivo disintegration time (24.0 ± 1.05 s) and in vitro disintegration time in artificial salvia (22.5 ± 1.67 s). Physical stability studies at 40 °C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four-period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug. The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer's disease patients.

Nanolayer encapsulation of insulin-chitosan complexes improves efficiency of oral insulin delivery

PubMed Central

Song, Lei; Zhi, Zheng-liang; Pickup, John C

2014-01-01

Current oral insulin formulations reported in the literature are often associated with an unpredictable burst release of insulin in the intestine, which may increase the risk for problematic hypoglycemia. The aim of the study was to develop a solution based on a nanolayer encapsulation of insulin-chitosan complexes to afford sustained release after oral administration. Chitosan/heparin multilayer coatings were deposited onto insulin-chitosan microparticulate cores in the presence of poly(ethylene) glycol (PEG) in the precipitating and coating solutions. The addition of PEG improved insulin loading and minimized an undesirable loss of the protein resulting from redissolution. Nanolayer encapsulation and the formation of complexes enabled a superior loading capacity of insulin (>90%), as well as enhanced stability and 74% decreased solubility at acid pH in vitro, compared with nonencapsulated insulin. The capsulated insulin administered by oral gavage lowered fasting blood glucose levels by up to 50% in a sustained and dose-dependent manner and reduced postprandial glycemia in streptozotocin-induced diabetic mice without causing hypoglycemia. Nanolayer encapsulation reduced the possibility of rapid and erratic falls of blood glucose levels in animals. This technique represents a promising strategy to promote the intestinal absorption efficiency and release behavior of the hormone, potentially enabling an efficient and safe route for oral insulin delivery of insulin in diabetes management. PMID:24833901

Evaluation of an Extended-Release, Abuse-Deterrent, Microsphere-in-Capsule Analgesic for the Management of Patients with Chronic Pain With Dysphagia (CPD).

PubMed

Fleming, Alison B; Carlson, Douglas R; Varanasi, Ravi K; Grima, Michael; Mayock, Stephen P; Saim, Said; Kopecky, Ernest A

2016-03-01

Patients who have chronic pain with dysphagia (difficulty swallowing) (CPD) often have difficulty taking oral medication and, as such, alter their medications by crushing or chewing in an attempt to make it easier to swallow. Such manipulation of currently marketed, extended-release (ER) opioid analgesics can significantly alter the pharmacokinetic (PK) properties of the formulations, resulting in poor treatment outcome or serious adverse events. There is an unmet medical need for oral ER opioid formulations suitable for patients with CPD. The primary objectives of this study were to conduct in vitro studies to evaluate alternate means of administration of a new, extended-release (ER), abuse-deterrent, microsphere-in-capsule formulation of oxycodone for patients with CPD. Specifically, these studies investigated the in vitro equivalence of drug release rates from Oxycodone DETERx® ER intact capsules (control condition) and administration via alternate modes-opening the capsule and sprinkling the microspheres onto soft foods or administration through enteral tubes. Secondary objectives were to compare alternate modes of administration of Oxycodone DETERx® to a commercially available ER-morphine product. Soft food study: Oxycodone DETERx® microspheres were sprinkled onto and mixed with several soft foods (ie, applesauce, vanilla pudding, strawberry jam, yogurt, and vanilla ice cream); the effect of drug contact time (0, 30, and 60 minutes) on drug release was studied. Enteral tube study: Oxycodone DETERx® microspheres were administered through varying sizes of nasogastric (10 and 12 Fr.) tubes and a 16 Fr. gastrostomy tube using 5 different delivery vehicles (ie, water, liquid nutritional feeds [Jevity®, Ensure®], and milk [whole milk and 2% milk]). Drug release rate was characterized using a standard in vitro dissolution methodology; dissolution of intact Oxycodone DETERx® capsules served as the control for both the soft food and enteral tube studies. Oxycodone concentration was measured using a standardized high-performance liquid chromatography (HPLC) assay. Similarity factor (f2) analysis was used to compare similarity of the dissolution profiles of test and control conditions. The mean dissolution profile of Oxycodone DETERx® microspheres sprinkled onto and mixed with each of the soft foods were similar (f2 > 50) to that of the control. Study drug-food contact time did not impact dissolution profiles. The dissolution data obtained from Oxycodone DETERx® microspheres passed through enteral feeding tubes of varying sizes were similar (f2 > 50) to that of the control. Unlike a marketed morphine sulfate ER pellet formulation, Oxycodone DETERx® did not clog any of the studied enteral tubes. A new ER, abuse-deterrent, microsphere-in-capsule formulation of oxycodone can be administered by sprinkling onto soft food without affecting the drug release profile of the formulation. The formulation can also be administered directly via enteral tubes without affecting drug release and without clogging enteral tubes. Oxycodone DETERx® may offer physicians and patients with CPD an alternate treatment option, especially in those patients who have dysphagia or an aversion to swallowing monolithic tablet/capsule formulations and for whom analgesic patches or other opioid formulations are not a viable therapeutic option. © 2015 World Institute of Pain.

A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods

PubMed Central

Chinna Reddy, P; Chaitanya, K.S.C.; Madhusudan Rao, Y.

2011-01-01

Owing to the ease of the administration, the oral cavity is an attractive site for the delivery of drugs. Through this route it is possible to realize mucosal (local effect) and transmucosal (systemic effect) drug administration. In the first case, the aim is to achieve a site-specific release of the drug on the mucosa, whereas the second case involves drug absorption through the mucosal barrier to reach the systemic circulation. The main obstacles that drugs meet when administered via the buccal route derive from the limited absorption area and the barrier properties of the mucosa. The effective physiological removal mechanisms of the oral cavity that take the formulation away from the absorption site are the other obstacles that have to be considered. The strategies studied to overcome such obstacles include the employment of new materials that, possibly, combine mucoadhesive, enzyme inhibitory and penetration enhancer properties and the design of innovative drug delivery systems which, besides improving patient compliance, favor a more intimate contact of the drug with the absorption mucosa. This presents a brief description of advantages and limitations of buccal drug delivery and the anatomical structure of oral mucosa, mechanisms of drug permeation followed by current formulation design in line with developments in buccal delivery systems and methodology in evaluating buccal formulations. PMID:23008684

The Effects of Screw Configuration and Polymeric Carriers on Hot-Melt Extruded Taste-Masked Formulations Incorporated into Orally Disintegrating Tablets

PubMed Central

Morott, Joseph T.; Pimparade, Manjeet; Park, Jun-Bom; Worley, Chelsea P.; Majumdar, Soumyajit; Lian, Zhuoyang; Pinto, Elanor; Bi, Yunxia; Durig, Thomas; Repka, Michael A.

2015-01-01

The primary aim of this research was to produce successfully taste masked formulations of Sildenafil Citrate (SC) using hot-melt extrusion (HME) technology. Multiple screw configurations and polymeric carriers were evaluated for their effects on taste masking efficiency, which was assessed by both E-tongue analysis and in vitro dissolution in simulated salivary fluid (SSF, pH 6.8 artificial saliva). The screw configurations were further assessed for their effects on the morphology of the API using PXRD, FT-IR and mid-infrared chemical imaging. It was determined that the screw configuration had a profound effect on the taste masking efficiency of the formulations as a result of altering the physical state of the API. Selected extruded formulations using ethylcellulose (EC) with a pore former were further formulated into orally disintegrating tablets (ODTs), which were optimized by varying the grade and percentage of the superdisintegrant used. An optimized disintegration time of approximately 8 seconds was achieved. The final ODT formulation exhibited excellent taste masking properties with over 85% drug release in gastric media as well as physical tablet properties. Interestingly, friability, which tends to be a common concern when formulating ODTs, was well within the acceptable limits (<1%) for common tablets. PMID:25410968

Application of freeze-drying technology in manufacturing orally disintegrating films.

PubMed

Liew, Kai Bin; Odeniyi, Michael Ayodele; Peh, Kok-Khiang

2016-01-01

Freeze drying technology has not been maximized and reported in manufacturing orally disintegrating films. The aim of this study was to explore the freeze drying technology in the formulation of sildenafil orally disintegrating films and compare the physical properties with heat-dried orally disintegrating film. Central composite design was used to investigate the effects of three factors, namely concentration of carbopol, wheat starch and polyethylene glycol 400 on the tensile strength and disintegration time of the film. Heat-dried films had higher tensile strength than films prepared using freeze-dried method. For folding endurance, freeze-dried films showed improved endurance than heat-dried films. Moreover, films prepared using freeze-dried methods were thicker and had faster disintegration time. Formulations with higher amount of carbopol and starch showed higher tensile strength and thickness whereas formulations with higher PEG 400 content showed better flexibility. Scanning electron microscopy showed that the freeze-dried films had more porous structure compared to the heat-dried film as a result of the release of water molecule from the frozen structure when it was subjected to freeze drying process. The sildenafil film was palatable. The dissolution profiles of freeze-dried and heat-dried films were similar to Viagra® with f2 of 51.04 and 65.98, respectively.

Delayed release film coating applications on oral solid dosage forms of proton pump inhibitors: case studies.

PubMed

Missaghi, Shahrzad; Young, Cara; Fegely, Kurt; Rajabi-Siahboomi, Ali R

2010-02-01

Formulation of proton pump inhibitors (PPIs) into oral solid dosage forms is challenging because the drug molecules are acid-labile. The aim of this study is to evaluate different formulation strategies (monolithic and multiparticulates) for three PPI drugs, that is, rabeprazole sodium, lansoprazole, and esomeprazole magnesium, using delayed release film coating applications. The core tablets of rabeprazole sodium were prepared using organic wet granulation method. Multiparticulates of lansoprazole and esomeprazole magnesium were prepared through drug layering of sugar spheres, using powder layering and suspension layering methods, respectively. Tablets and drug-layered multiparticulates were seal-coated, followed by delayed release film coating application, using Acryl-EZE(R), aqueous acrylic enteric system. Multiparticulates were then filled into capsules. The final dosage forms were evaluated for physical properties, as well as in vitro dissolution testing in both compendial acid phase, 0.1N HCl (pH 1.2), and intermediate pH, acetate buffer (pH 4.5), followed by phosphate buffer, pH 6.8. The stability of the delayed release dosage forms was evaluated upon storage in accelerated conditions [40 degrees C/75% relative humidity] for 3 months. All dosage forms demonstrated excellent enteric protection in the acid phase, followed by rapid release in their respective buffer media. Moreover, the delayed release dosage forms remained stable under accelerated stability conditions for 3 months. Results showed that Acryl-EZE enteric coating systems provide excellent performance in both media (0.1N HCl and acetate buffer pH 4.5) for monolithic and multiparticulate dosage forms.

77 FR 40069 - Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-06

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0563... Labeled for Human Use; Enforcement Action Dates AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing its intention to take enforcement...

Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide.

PubMed

Graves, Richard A; Ledet, Grace A; Glotser, Elena Y; Mitchner, Demaurian M; Bostanian, Levon A; Mandal, Tarun K

2015-08-30

Fenretinide is an anticancer drug with low water solubility and poor bioavailability. The goal of this study was to develop biodegradable polymeric nanoparticles of fenretinide with the intent of increasing its apparent aqueous solubility and intestinal permeability. Three biodegradable polymers were investigated for this purpose: two different poly lactide-co-glycolide (PLGA) polymers, one acid terminated and one ester terminated, and one poly lactide-co-glycolide/polyethylene glycol (PLGA/PEG) diblock copolymer. Nanoparticles were obtained by using an emulsification solvent evaporation technique. The formulations were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and particle size analysis. Dissolution studies and Caco-2 cell permeation studies were also carried out for all formulations. Ultra high performance liquid chromatography coupled with mass spectrometry (UPLC/MS) and ultraviolet detection was used for the quantitative determination of fenretinide. Drug loading and the type of polymer affected the nanoparticles' physical properties, drug release rate, and cell permeability. While the acid terminated PLGA nanoparticles performed the best in drug release, the ester terminated PLGA nanoparticles performed the best in the Caco-2 cell permeability assays. The PLGA/PEG copolymer nanoparticles performed better than the formulations with ester terminated PLGA in terms of drug release but had the poorest performance in terms of cell permeation. All three categories of formulations performed better than the drug alone in both drug release and cell permeation studies. Copyright © 2015 Elsevier B.V. All rights reserved.

Mesoporous silica formulation strategies for drug dissolution enhancement: a review.

PubMed

McCarthy, Carol A; Ahern, Robert J; Dontireddy, Rakesh; Ryan, Katie B; Crean, Abina M

2016-01-01

Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture. This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered. Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state.

PubMed

Miao, Yanfei; Sun, Jiqin; Chen, Guoguang; Lili, Ren; Ouyang, Pingkai

2016-08-01

The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs). The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control. The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5 min. Pharmacokinetic study showed that the AUC(0-∞) and Cmax for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption. It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.

Enhanced anticancer activity and oral bioavailability of ellagic acid through encapsulation in biodegradable polymeric nanoparticles.

PubMed

Mady, Fatma M; Shaker, Mohamed A

2017-01-01

Despite the fact that various studies have investigated the clinical relevance of ellagic acid (EA) as a naturally existing bioactive substance in cancer therapy, little has been reported regarding the efficient strategy for improving its oral bioavailability. In this study, we report the formulation of EA-loaded nanoparticles (EA-NPs) to find a way to enhance its bioactivity as well as bioavailability after oral administration. Poly(ε-caprolactone) (PCL) was selected as the biodegradable polymer for the formulation of EA-NPs through the emulsion-diffusion-evaporation technique. The obtained NPs have been characterized by measuring particle size, zeta potential, Fourier transform infrared, differential scanning calorimetry, and X-ray diffraction. The entrapment efficiency and the release profile of EA was also determined. In vitro cellular uptake and cytotoxicity of the obtained NPs were evaluated using Caco-2 and HCT-116 cell lines, respectively. Moreover, in vivo study has been performed to measure the oral bioavailability of EA-NPs compared to free EA, using New Zealand white rabbits. NPs with distinct shape were obtained with high entrapment and loading efficiencies. Diffusion-driven release profile of EA from the prepared NPs was determined. EA-NP-treated HCT-116 cells showed relatively lower cell viability compared to free EA-treated cells. Fluorometric imaging revealed the cellular uptake and efficient localization of EA-NPs in the nuclear region of Caco-2 cells. In vivo testing revealed that the oral administration of EA-NPs produced a 3.6 times increase in the area under the curve compared to that of EA. From these results, it can be concluded that incorporation of EA into PCL as NPs enhances its oral bioavailability and activity.

Enhanced anticancer activity and oral bioavailability of ellagic acid through encapsulation in biodegradable polymeric nanoparticles

PubMed Central

Mady, Fatma M; Shaker, Mohamed A

2017-01-01

Despite the fact that various studies have investigated the clinical relevance of ellagic acid (EA) as a naturally existing bioactive substance in cancer therapy, little has been reported regarding the efficient strategy for improving its oral bioavailability. In this study, we report the formulation of EA-loaded nanoparticles (EA-NPs) to find a way to enhance its bioactivity as well as bioavailability after oral administration. Poly(ε-caprolactone) (PCL) was selected as the biodegradable polymer for the formulation of EA-NPs through the emulsion–diffusion–evaporation technique. The obtained NPs have been characterized by measuring particle size, zeta potential, Fourier transform infrared, differential scanning calorimetry, and X-ray diffraction. The entrapment efficiency and the release profile of EA was also determined. In vitro cellular uptake and cytotoxicity of the obtained NPs were evaluated using Caco-2 and HCT-116 cell lines, respectively. Moreover, in vivo study has been performed to measure the oral bioavailability of EA-NPs compared to free EA, using New Zealand white rabbits. NPs with distinct shape were obtained with high entrapment and loading efficiencies. Diffusion-driven release profile of EA from the prepared NPs was determined. EA-NP-treated HCT-116 cells showed relatively lower cell viability compared to free EA-treated cells. Fluorometric imaging revealed the cellular uptake and efficient localization of EA-NPs in the nuclear region of Caco-2 cells. In vivo testing revealed that the oral administration of EA-NPs produced a 3.6 times increase in the area under the curve compared to that of EA. From these results, it can be concluded that incorporation of EA into PCL as NPs enhances its oral bioavailability and activity. PMID:29066891

[Overdose of modified-release paracetamol calls for changed treatment routines. New guidelines from the Swedish Poisons Information Centre].

PubMed

Höjer, Jonas; Salmonson, Helene; Sjöberg, Gunilla; Tellerup, Markus; Brogren, Jacob

2016-11-10

Overdose of modified-release paracetamol calls for changed treatment routines. New guidelines from the Swedish Poisons Information Centre  The sales of modified-release paracetamol tablets are steadily increasing in Sweden as are the number of overdose cases with this formulation. The Swedish Poisons Information Centre has noted that the standard treatment protocol with N-acetylcysteine (NAC), which is based on overdoses with immediate-release paracetamol formulations, is often inadequate in this setting. In this paper, an adult who overdosed on 66.5 grams of modified-release paracetamol tablets and developed severe liver impairment (max ALT 6,660 U/l) despite timely and rigorous NAC treatment is presented. The patient's peak S-paracetamol of 2,800 µmol/l was delayed to 19 hours post-ingestion. Moreover, a pharmacokinetic and clinical study of similar cases showed that seven (21%) of the 34 patients who received NAC treatment within 8 hours after ingestion developed liver impairment. Finally, new Swedish guidelines for management of these cases are presented. The guidelines are also available on www.giftinfo.se.

Pediatric suppositories of sulpiride solid dispersion for treatment of Tourette syndrome: in vitro and in vivo investigations.

PubMed

Zidan, Ahmed S; Emam, Sherif E; Shehata, Tamer M; Ghazy, Fakhr-eldin S

2015-06-01

Pharmaceutical development was adopted in the current study to propose a pediatric rectal formulation of sulpiride as a substitute to the available oral or parenteral formulations in the management of Tourette syndrome (TS). The goal was to formulate a product that is easy to use, stable, and highly bioavailable and to achieve a rapid clinical efficacy. Towards this aim, sulpiride solid dispersion (SD) with tartaric acid at a weight ratio of 1:0.25 was incorporated into different suppository bases, namely witepsol W25, witepsol H15, witepsol E75, suppocire NA, suppocire A, glycerogelatin, and polyethylene glycols. The formulae were evaluated in vitro using different pharmacotechnical methods such as visual, melting, weight and content uniformities, drug release, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and X-ray diffraction (XRD) analyses. In vivo bioavailability was also assessed in rabbits to compare the bioavailability of either raw sulpiride-incorporated or its SD-incorporated witepsol H15-based suppositories to its oral suspension (reference). Sulpiride SD-incorporated witepsol H15 formulation showed acceptable in vitro characteristics with a bioavailability of 117% relative to oral dosing, which excel that in humans (27% after dosing of oral product). In addition, the proposed formula not only passed the 6-month stability study but also proposed a promising scale-up approach. Hence, it showed a great potential for pediatric product development to manage TS in rural areas.

Development and optimization of buspirone oral osmotic pump tablet

PubMed Central

Derakhshandeh, K.; berenji, M. Ghasemnejad

2014-01-01

The aim of the current study was to design a porous osmotic pump–based drug delivery system for controlling the release of buspirone from the delivery system. The osmotic pump was successfully developed using symmetric membrane coating. The core of the tablets was prepared by direct compression technique and coated using dip-coating technique. Drug release from the osmotic system was studied using USP paddle type apparatus. The effect of various processing variables such as the amount of osmotic agent, the amount of swellable polymer, concentration of the core former, concentration of the plasticizer, membrane thickness, quantum of orifice on drug release from osmotic pump were evaluated. Different kinetic models (zero order, first order and Higuchi model) were applied to drug release data in order to establish the kinetics of drug release. It was found that the drug release was mostly affected by the amount of NaCl as osmotic agent, the swellable polymer; hydroxy propyl methyl cellulose (HPMC), the amount of PEG-400 and cellulose acetate in the coating solution and thickness of the semipermeable membrane. The optimized formulation released buspirone independent of pH and orifice quantum at the osmogen amount of 42%, hydrophilic polymer of 13% and pore size of 0.8 mm on the tablet surface. The drug release of osmotic formulation during 24 h showed zero order kinetics and could be suggested that this formulation as a once-daily regimen improves pharmacokinetic parameters of the drug and enhances patient compliance. PMID:25657794

Development and optimization of buspirone oral osmotic pump tablet.

PubMed

Derakhshandeh, K; Berenji, M Ghasemnejad

2014-01-01

The aim of the current study was to design a porous osmotic pump-based drug delivery system for controlling the release of buspirone from the delivery system. The osmotic pump was successfully developed using symmetric membrane coating. The core of the tablets was prepared by direct compression technique and coated using dip-coating technique. Drug release from the osmotic system was studied using USP paddle type apparatus. The effect of various processing variables such as the amount of osmotic agent, the amount of swellable polymer, concentration of the core former, concentration of the plasticizer, membrane thickness, quantum of orifice on drug release from osmotic pump were evaluated. Different kinetic models (zero order, first order and Higuchi model) were applied to drug release data in order to establish the kinetics of drug release. It was found that the drug release was mostly affected by the amount of NaCl as osmotic agent, the swellable polymer; hydroxy propyl methyl cellulose (HPMC), the amount of PEG-400 and cellulose acetate in the coating solution and thickness of the semipermeable membrane. The optimized formulation released buspirone independent of pH and orifice quantum at the osmogen amount of 42%, hydrophilic polymer of 13% and pore size of 0.8 mm on the tablet surface. The drug release of osmotic formulation during 24 h showed zero order kinetics and could be suggested that this formulation as a once-daily regimen improves pharmacokinetic parameters of the drug and enhances patient compliance.

Incorporation of the HIV-1 microbicide cyanovirin-N in a food product

PubMed Central

Li, Ming; Patton, Dorothy L.; Cosgrove-Sweeney, Yvonne; Ratner, Deena; Rohan, Lisa C.; Cole, Alexander M.; Tarwater, Patrick M.; Gupta, Phalguni; Ramratnam, Bharat

2012-01-01

An urgent need exists for HIV-1 microbicides. Here, we describe the in vivo testing of lactic acid bacteria bioengineered to secrete cyanovirin-N. We fed pigtail macaques a yogurt formulation that used bioengineered strains as a starter culture. Cyanovirin-N expression could be detected in the rectal vault during and immediately after feeding. Ex vivo viral challenge of rectal tissue biopsies revealed that peak viral burden was significantly lower in tissue obtained from experimental animals compared to control animals. Formulation of candidate compounds in lactic acid bacteria and their oral administration appears to be a feasible strategy for mucosal delivery of microbicides. PMID:21926631

Solid lipid nanoparticles as an efficient drug delivery system of olmesartan medoxomil for the treatment of hypertension.

PubMed

Pandya, Nilima T; Jani, Parva; Vanza, Jigar; Tandel, Hemal

2018-05-01

The aim of the current investigation was to develop solid lipid nanoparticles of olmesartan medoxomil using hot homogenization method to improve its oral bioavailability. Central composite design was applied to optimize the formulation variables; lipid X1 (Glyceryl monostearate) and surfactant X2 (Poloxamer: Tween 80). The particle sizes were in the nanometer range and spherical shaped for all prepared solid lipid nanoparticles formulations and the zeta potential absolute values were high, predicting good long-term stability. In vitro study of olmesartan loaded solid lipid nanoparticle exhibited controlled release profile for at least 24 h. The rate and extent of drug diffusion was studied using dialysis sac, rat's stomach and intestine tissues; study demonstrated that drug release from the solid lipid nanoparticles was significantly higher than drug suspension. In vivo pharmacokinetic study of olmesartan loaded solid lipid nanoparticles revealed higher Cmax of 1610 ng/mL, higher AUC of 15492.50 ng/mL and increased relative bioavailability by almost 2.3 folds compared to marketed formulation. These results clearly indicate that olmesartan loaded solid lipid nanoparticles are shown to have enhanced bioavailability and effective therapeutic result and thus would be an excellent way to treat hypertension. Hence, these solid lipid nanoparticles could represent as a great potential for a possible alternative to conventional oral formulation in the treatment of hypertension. Copyright © 2018 Elsevier B.V. All rights reserved.

Rapidly disintegrating tablets containing taste masked metoclopramide hydrochloride prepared by extrusion-precipitation method.

PubMed

Randale, Shivsagar Ashok; Dabhi, Chandu Somatbhai; Tekade, Avinash Ramrao; Belgamwar, Veena Shailendra; Gattani, Surendra Ganeshlal; Surana, Sanjay Javarilal

2010-04-01

The purpose of this study was to mask the intensely bitter taste of metoclopramide HCl and to formulate a rapid disintegrating tablet (RDT) of the taste-masked drug. Taste masking was done by complexing metoclopramide HCl with aminoalkyl methacrylate copolymer (Eudragit EPO) in different ratio by the extrusion-precipitation method. Drug-polymer complexes (DPCs) were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.8, taste evaluation in oral cavity and molecular property. The complex having drug-polymer ratio of 1 : 2 shows significant taste masking, confirmed by drug release in SSF and in-vivo taste evaluation; therefore, it was selected for further study. Taste evaluation of DPCs in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value (0.5) within 10 s, whereas, metoclopramide HCl was rated intensely bitter with a score of +3 for 10 s. Tablets were evaluated for various parameters like tensile strength, wetting time, water absorption ratio, in-vitro disintegration time, and disintegration in oral cavity. The effect of diluents, lubricants and sweetening agent (Xylisorb) on the disintegration time was also evaluated. Tablets of batch F3 containing mannitol and microcrystalline cellulose in the ratio 1 : 1 and 8% w/w crosspovidone showed faster disintegration (within 20 s) than the marketed formulation (180 s). Good correlation between in vitro disintegration behavior and in the oral cavity was recognized. Tablets of batch F3 also revealed rapid drug release (t(90), 90 s) in SGF compared with marketed formulation (t(90), 600 s).

A Randomized, Double-Blind, Double-Dummy Study to Evaluate the Intranasal Human Abuse Potential and Pharmacokinetics of a Novel Extended-Release Abuse-Deterrent Formulation of Oxycodone

PubMed Central

Kopecky, Ernest A.; Smith, Michael D.; Fleming, Alison B.

2016-01-01

Objective. Evaluate the human abuse potential (HAP) of an experimental, microsphere-in-capsule formulation of extended-release oxycodone (oxycodone DETERx®) (herein “DETERx”). Design. Randomized, double-blind, double-dummy, positive- and placebo-controlled, single-dose, four-phase, four-treatment, crossover study. Setting. Clinical research site. Subjects. There were 39 qualifying subjects (72% male, 85% white, mean age of 27 years) with 36 completing all four Double-blind Treatment Periods. Methods. The four phases encompassed: 1) Screening; 2) Drug Discrimination; 3) Double-blind Treatment; and 4) Follow-up. Drug Discrimination tests ensured that subjects could distinguish placebo from opioid. The four Double-blind Treatments compared DETERx—administered as either a crushed intranasal (IN) or an intact oral (PO) preparation—with immediate-release oxycodone IN (OXY-IR IN) and with an intact IN and PO placebo DETERx control. Results. For primary pharmacokinetic (PK) assessments, abuse quotient (Cmax/Tmax) was lower with DETERx IN than DETERx PO; both treatments were substantially lower than OXY-IR IN (6.24, 8.60, and 69.6 ng/mL/h, respectively). For drug liking, the primary subjective pharmacodynamic (PD) endpoint, both DETERx IN and DETERx PO produced significantly lower scores than OXY-IR IN (P ≤ 0.0001 for each); DETERx IN was less liked than DETERx PO (P ≤ 0.05), mirroring the PK relationships. Objectively assessed pupillometry corroborated the more rapid and significantly greater effect of OXY-IR IN than either DETERx IN or DETERx PO (P ≤ 0.007 for each). Overall safety profiles of DETERx and OXY-IR were comparable and both were well tolerated. Conclusions. Pharmacokinetic and pharmacodynamic outcomes suggest that DETERx IN has relatively low HAP; continued research in larger populations is suggested. PMID:26814256

Enalapril maleate orally disintegrating tablets: tableting and in vivo evaluation in hypertensive rats.

PubMed

Tawfeek, Hesham M; Faisal, Waleed; Soliman, Ghareb M

2018-06-01

The aim of this study was to develop orally disintegrating tablets (ODTs) for enalapril maleate (EnM) to facilitate its administration to the elderly or other patients having dysphagia. Compatibility between EnM and various excipients was studied using differential scanning calorimetry. ODTs of EnM were prepared by direct compression of EnM mixtures with various superdisintegrants. The tablets were evaluated for physical properties including drug content, hardness, friability, disintegration time, wetting time, and drug release. The antihypertensive effect of the optimum EnM ODTs was evaluated in vivo in hypertensive rats and compared with commercial EnM formulation. EnM ODTs had satisfactory results in terms of drug content and friability. Tablet wetting and disintegration were fast and dependent on the used superdisintegrant where croscarmellose showed the fastest wetting and disintegration time of ∼7 s. EnM release from the tablets was rapid where complete release was obtained in 10-15 min. Selected EnM ODTs rapidly and efficiently reduced the rat's blood pressure to its normal value within 1 h, compared with 4 h for EnM commercial formulation. These results confirm that EnM ODTs could find application in the management of hypertension in the elderly or other patients having dysphagia.

Characterization of natural polymers from jackfruit pulp, calendula flowers and tara seeds as mucoadhesive and controlled release components in buccal tablets.

PubMed

Sabale, Vidya; Paranjape, Archana; Patel, Vandana; Sabale, Prafulla

2017-02-01

Identification and physiochemical parameters such as solubility, loss on drying, viscosity, pH, swelling index, starch and gum constituents were determined in natural polymers and showed satisfactory results. Spectral studies established the compatibility of natural polymers. The drug release kinetics in preliminary trial batches showed that tablets containing natural mucilages and gum showed a prolonged drug release comparable to Carbopol 974P and Methocel K4M. Also, all tablets showed a satisfactory drug permeability flux. Acute toxicity studies confirmed the safety of natural polymers. Using response surface method supported by 2 3 factorial design, the optimized buccoadhesive tablets (C1) with drug release at 8h (R8h, %) of 53.48±0.048% showed controlled release over ≥8h and followed the Korsmeyer-Peppas model with anomalous (non-Fickian) diffusion mechanism. Mucoadhesive strength was found to be 42.71±0.49g. Comparative dissolution study between prepared and marketed formulation showed that there was no significant difference in drug release profile having similarity factor 82.97. In vivo study for optimized formulation of the buccoadhesive tablets showed the better absolute bioavailability (71.26%) against the oral solution (51.22%). Histological study confirmed non-irritant nature and stability study indicated stability of the formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system.

PubMed

Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

2012-01-01

Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor(®) EL:Transcutol(®) P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin.

The relationship between functional sciatic nerve block duration and the rate of release of lidocaine from a controlled-release matrix.

PubMed

Gerner, Peter; Wang, Chi-Fei; Lee, Byung-Sang; Suzuki, Suzuko; Degirolami, Umberto; Gandhi, Ankur; Knaack, David; Strichartz, Gary

2010-07-01

Nerve blocks of long duration are often desirable in perioperative and postoperative situations. The relationship between the duration of such blocks and the rate at which a local anesthetic is released is important to know for developing a localized drug delivery system that will optimize block duration. Lidocaine concentration was varied in 1 series of formulations (OSB-L) containing a constant amount of release rate modifier. In another series (OST-R), the release rate modifier was varied while the lidocaine content was held constant. Release kinetics were measured in vitro and correlated to the in vivo duration of antinociceptive and motor block effects when the formulation was implanted next to the rat sciatic nerve. In parallel studies, rats receiving different formulations of slow-release lidocaine were fixed by intracardiac perfusion with 4% paraformaldehyde and nerve-muscle tissue taken for histopathological analysis. In this study, we have demonstrated that the most important variable for effecting functional nerve block, i.e., the blockade of impulses in the relevant fibers of the sciatic nerve, is the rate of lidocaine release at that time. For the OSB-L formulations (lidocaine concentrations of 1.875%, 3.75%, 7.5%, and 15% at a constant release rate modifier of 5%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 0.91 +/- 0.28 and 1.75 +/- 0.61 mg/h, respectively. For the OST-R formulations (16% lidocaine with release rate modifier concentrations of 1.875%, 3.75%, 7.5%, and 15%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 2.33 +/- 1.39 and 4.34 +/- 1.09 mg/h, respectively. The OSB-L formulations showed a dose-dependent increase in block duration proportional to an increase in initial lidocaine concentration, whereas the OST-R formulations showed a nonmonotonic relationship between release rate modifier concentration and block duration. The histopathological studies at 24 hours, 3, 5, or 7 days, and 4 weeks after the implantation revealed inflammatory reactions with degrees correlated with lidocaine content, but limited to the connective tissue and muscle immediately surrounding the implanted material. Despite these observed inflammatory reactions, nociceptive and motor block function returned to normal, preimplantation values in all animals. Increasing initial lidocaine content proportionately increased the duration of functional sciatic nerve block. However, decreasing the release rate per se does not give a proportional increase in block duration. Instead, there seems to be an optimal, intermediate release rate for achieving the maximum duration of block.

Formulation of bi-layer matrix tablets of tramadol hydrochloride: Comparison of rate retarding ability of the incorporated hydrophilic polymers.

PubMed

Arif, Hasanul; Al-Masum, Abdullah; Sharmin, Florida; Reza, Selim; Sm Islam, Sm Ashraful

2015-05-01

Bi-layer tablets of tramadol hydrochloride were prepared by direct compression technique. Each tablet contains an instant release layer with a sustained release layer. The instant release layer was found to release the initial dose immediately within minutes. The instant release layer was combined with sustained release matrix made of varying quantity of Methocel K4M, Methocel K15MCR and Carbomer 974P. Bi-layer tablets were evaluated for various physical tests including weight variation, thickness and diameter, hardness and percent friability. Drug release from bi-layer tablet was studied in acidic medium and buffer medium for two and six hours respectively. Sustained release of tramadol hydrochloride was observed with a controlled fashion that was characteristic to the type and extent of polymer used. % Drug release from eight-hour dissolution study was fitted with several kinetic models. Mean dissolution time (MDT) and fractional dissolution values (T25%, T50% and T80%) were also calculated as well, to compare the retarding ability of the polymers. Methocel K15MCR was found to be the most effective in rate retardation of freely water-soluble tramadol hydrochloride compared to Methocel K4M and Capbomer 974P, when incorporated at equal ratio in the formulation.

Impact of abuse-deterrent OxyContin on prescription opioid utilization.

PubMed

Hwang, Catherine S; Chang, Hsien-Yen; Alexander, G Caleb

2015-02-01

We quantified the degree to which the August 2010 reformulation of abuse-deterrent OxyContin affected its use, as well as the use of alternative extended-release and immediate-release opioids. We used the IMS Health National Prescription Audit, a nationally representative source of prescription activity in the USA, to conduct a segmented time-series analysis of the use of OxyContin and other prescription opioids. Our primary time period of interest was 12 months prior to and following August 2010. We performed model checks and sensitivity analyses, such as adjusting for marketing and promotion, using alternative lag periods, and adding extra observation points. OxyContin sales were similar before and after the August 2010 reformulation, with approximately 550 000 monthly prescriptions. After adjusting for declines in the generic extended-release oxycodone market, the formulation change was associated with a reduction of approximately 18 000 OxyContin prescription sales per month (p = 0.02). This decline corresponded to a change in the annual growth rate of OxyContin use, from 4.9% prior to the reformulation to -23.8% during the year after the reformulation. There were no statistically significant changes associated with the sales of alternative extended-release (p = 0.42) or immediate-release (p = 0.70) opioids. Multiple sensitivity analyses supported these findings and their substantive interpretation. The market debut of abuse-deterrent OxyContin was associated with declines in its use after accounting for the simultaneous contraction of the generic extended-release oxycodone market. Further scrutiny into the effect of abuse-deterrent formulations on medication use and health outcomes is vital given their popularity in opioid drug development. Copyright © 2014 John Wiley & Sons, Ltd.

Stabilization challenges and formulation strategies associated with oral biologic drug delivery systems.

PubMed

Truong-Le, Vu; Lovalenti, Phillip M; Abdul-Fattah, Ahmad M

2015-10-01

Delivery of proteins to mucosal tissues of GI tract typically utilize formulations which protect against proteolysis and target the mucosal tissues. Using case studies from literature and the authors' own work, the in-process stability and solid state storage stability of biopharmaceuticals formulated in delivery systems designed for oral delivery to the GI tract will be reviewed. Among the range of delivery systems, biodegradable polymer systems for protection and controlled release of proteins have been the most studied; hence these systems will be covered in greater depth. These delivery systems include polymeric biodegradable microspheres or nanospheres that contain proteins or vaccines, which are designed to reduce the number of administrations/inoculations and the total protein dose required to achieve the desired biological effect. Specifically, this review will include a landscape survey of the systems that have been studied, the manufacturing processes involved, stability through the manufacturing process, key pharmaceutical formulation parameters that impact stability of the encased proteins, and storage stability of the encapsulated proteins in these delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Chronomodulated drug delivery system of urapidil for the treatment of hypertension

PubMed Central

Chaudhary, Sona S.; Patel, Hetal K.; Parejiya, Punit B.; Shelat, Pragna K.

2015-01-01

Introduction: Hypertension is a disease which shows circadian rhythm in the pattern of two peaks, one in the evening at about 7pm and other in the early morning between 4 am to 8 am. Conventional therapies are incapable to target those time points when actually the symptoms get worsened. To achieve drug release at two time points, chronomodulated delivery system may offer greater benefits. Materials and methods: The chronomodulated system comprised of dual approach; immediate release granules (IRG) and pulsatile release mini-tablets (PRM) filled in the hard gelatin capsule. The mini-tablets were coated using Eudragit S-100 which provided the lag time. To achieve the desired release, various parameters like coating duration and coat thickness were studied. The immediate release granules were evaluated for micromeritical properties and drug release, while mini-tablets were evaluated for various parameters such as hardness, thickness, friability, weight variation, drug content, and disintegration time and in-vitro drug release. Compatibility of drug-excipient was checked by fourier transform infrared spectroscopy and Differential scanning calorimetry studies and pellets morphology was done by Scanning electron microscopy studies. Results: The in-vitro release profile suggested that immediate release granules gives drug release within 20 min at the time of evening attack while the programmed pulsatile release was achieved from coated mini-tablets after a lag time of 9hrs, which was consistent with the demand of drug during early morning hour attack. Pellets found to be spherical in shape with smooth surface. Moreover compatibility studies illustrated no deleterious reaction between drug and polymers used in the study. Conclusions: The dual approach of developed chronomodulated formulation found to be satisfactory in the treatment of hypertension. PMID:25838996

In vitro models for the prediction of in vivo performance of oral dosage forms.

PubMed

Kostewicz, Edmund S; Abrahamsson, Bertil; Brewster, Marcus; Brouwers, Joachim; Butler, James; Carlert, Sara; Dickinson, Paul A; Dressman, Jennifer; Holm, René; Klein, Sandra; Mann, James; McAllister, Mark; Minekus, Mans; Muenster, Uwe; Müllertz, Anette; Verwei, Miriam; Vertzoni, Maria; Weitschies, Werner; Augustijns, Patrick

2014-06-16

Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is anticipated that the innovative in vitro biopharmaceutical tools arising from the OrBiTo project will lead to improved predictions for in vivo behavior of drug formulations in the GI tract. Copyright © 2013 Elsevier B.V. All rights reserved.

Development of a controlled release formulation by continuous twin screw granulation: Influence of process and formulation parameters.

PubMed

Vanhoorne, V; Vanbillemont, B; Vercruysse, J; De Leersnyder, F; Gomes, P; Beer, T De; Remon, J P; Vervaet, C

2016-05-30

The aim of this study was to evaluate the potential of twin screw granulation for the continuous production of controlled release formulations with hydroxypropylmethylcellulose as hydrophilic matrix former. Metoprolol tartrate was included in the formulation as very water soluble model drug. A premix of metoprolol tartrate, hydroxypropylmethylcellulose and filler (ratio 20/20/60, w/w) was granulated with demineralized water via twin screw granulation. After oven drying and milling, tablets were produced on a rotary Modul™ P tablet press. A D-optimal design (29 experiments) was used to assess the influence of process (screw speed, throughput, barrel temperature and screw design) and formulation parameters (starch content of the filler) on the process (torque), granule (size distribution, shape, friability, density) and tablet (hardness, friability and dissolution) critical quality attributes. The torque was dominated by the number of kneading elements and throughput, whereas screw speed and filling degree only showed a minor influence on torque. Addition of screw mixing elements after a block of kneading elements improved the yield of the process before milling as it resulted in less oversized granules and also after milling as less fines were present. Temperature was also an important parameter to optimize as a higher temperature yielded less fines and positively influenced the aspect ratio. The shape of hydroxypropylmethylcellulose granules was comparable to that of immediate release formulations. Tensile strength and friability of tablets were not dependent on the process parameters. The use of starch as filler was not beneficial with regard to granule and tablet properties. Complete drug release was obtained after 16-20h and was independent of the design's parameters. Copyright © 2016 Elsevier B.V. All rights reserved.

The in vivo fate of nanoparticles and nanoparticle-loaded microcapsules after oral administration in mice: Evaluation of their potential for colon-specific delivery.

PubMed

Ma, Yiming; Fuchs, Adrian V; Boase, Nathan R B; Rolfe, Barbara E; Coombes, Allan G A; Thurecht, Kristofer J

2015-08-01

Anti-cancer drug loaded-nanoparticles (NPs) or encapsulation of NPs in colon-targeted delivery systems shows potential for increasing the local drug concentration in the colon leading to improved treatment of colorectal cancer. To investigate the potential of the NP-based strategies for colon-specific delivery, two formulations, free Eudragit® NPs and enteric-coated NP-loaded chitosan-hypromellose microcapsules (MCs) were fluorescently-labelled and their tissue distribution in mice after oral administration was monitored by multispectral small animal imaging. The free NPs showed a shorter transit time throughout the mouse digestive tract than the MCs, with extensive excretion of NPs in faeces at 5h. Conversely, the MCs showed complete NP release in the lower region of the mouse small intestine at 8h post-administration. Overall, the encapsulation of NPs in MCs resulted in a higher colonic NP intensity from 8h to 24h post-administration compared to the free NPs, due to a NP 'guarding' effect of MCs during their transit along mouse gastrointestinal tract which decreased NP excretion in faeces. These imaging data revealed that this widely-utilised colon-targeting MC formulation lacked site-precision for releasing its NP load in the colon, but the increased residence time of the NPs in the lower gastrointestinal tract suggests that it is still useful for localised release of chemotherapeutics, compared to NP administration alone. In addition, both formulations resided in the stomach of mice at considerable concentrations over 24h. Thus, adhesion of NP- or MC-based oral delivery systems to gastric mucosa may be problematic for colon-specific delivery of the cargo to the colon and should be carefully investigated for a full evaluation of particulate delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Preparation and in vitro-in vivo evaluation of none gastric resident dipyridamole (DIP) sustained-release pellets with enhanced bioavailability.

PubMed

Xu, Lishuang; Luo, Yanfei; Feng, Jia; Xu, Ming; Tao, Xiaoguang; He, Haibing; Tang, Xing

2012-01-17

The objective of this study was to develop none gastric resident sustained-release pellets loaded with dipyridamole with a high bioavailability. Two different kinds of core pellets, one containing citric acid as a pH-modifier (CAP) and, the other without pH-modifier (NCAP) were prepared by extrusion-spheronization and then coated with mixtures of enteric soluble and insoluble polymers (referred to as CAP(1) and NCAP(1)) or insoluble polymer alone (referred to as CAP(2) and NCAP(2)). The relative bioavailability of the sustained-release pellets was studied in fasted beagle dogs after oral administration using a commercially available immediate release tablet (IRT) as a reference. The in vitro release, in vivo absorption and in vitro-in vivo correlation were also evaluated. Results revealed that the plasma drug concentrations after administration of CAP(2), NCAP(1) and NCAP(2) were undetectable, indicating that the drug release was almost zero from the preparations throughout the gastro-intestinal tract. The C(max), T(max) and AUC((0→24)) of CAP(1) were 0.78 ± 0.23 (μg/ml), 3.80 ± 0.30 (h), and 6.74 ± 0.47 (μg/mlh), respectively. While the corresponding values were 2.23 ± 0.32 (μg/ml), 3.00 ± 0.44 (h) and 9.42 ± 0.69 (μg/mlh) for IRT. The relative bioavailability of CAP(1) was 71.55% compared with IRT. By combined incorporation of a pH-modifier into the core of pellets to modify the inner micro-environment and employing mixtures of enteric soluble and insoluble polymers as a retarding layer, drugs with high solubility in stomach and limited solubility in small intestine, such as DIP, could be successfully formulated as sustained release preparations with no pH-dependence in drug release and enhanced bioavailability. Copyright © 2011 Elsevier B.V. All rights reserved.

Sustained-release liquisolid compact tablets containing artemether-lumefantrine as alternate-day regimen for malaria treatment to improve patient compliance.

PubMed

Nnamani, Petra Obioma; Ugwu, Agatha Adaora; Ibezim, Emmanuel Chinedu; Kenechukwu, Franklin Chimaobi; Akpa, Paul Achile; Ogbonna, John-Dike Nwabueze; Obitte, Nicholas Chinedu; Odo, Amelia Ngozi; Windbergs, Maike; Lehr, Claus-Michael; Attama, Anthony Amaechi

The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether-lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol ® ATO 5/Transcutol ® HP and tallow fat/Transcutol ® HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected with Plasmodium berghei berghei (NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol ® ATO 5/Transcutol ® HP batch, then 81% and 95% for tallow fat/Transcutol ® HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol ® ATO 5/Transcutol ® HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol ® HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem ® tablets (86%) and chloroquine phosphate tablets (66%). No significant difference ( P <0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms.

Sustained-release liquisolid compact tablets containing artemether–lumefantrine as alternate-day regimen for malaria treatment to improve patient compliance

PubMed Central

Nnamani, Petra Obioma; Ugwu, Agatha Adaora; Ibezim, Emmanuel Chinedu; Kenechukwu, Franklin Chimaobi; Akpa, Paul Achile; Ogbonna, John-Dike Nwabueze; Obitte, Nicholas Chinedu; Odo, Amelia Ngozi; Windbergs, Maike; Lehr, Claus-Michael; Attama, Anthony Amaechi

2016-01-01

The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether–lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol® ATO 5/Transcutol® HP and tallow fat/Transcutol® HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected with Plasmodium berghei berghei (NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol® ATO 5/Transcutol® HP batch, then 81% and 95% for tallow fat/Transcutol® HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol® ATO 5/Transcutol® HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol® HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem® tablets (86%) and chloroquine phosphate tablets (66%). No significant difference (P<0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms. PMID:27932882

Development of a Rapidly Dissolvable Oral Pediatric Formulation for Mefloquine Using Liposomes.

PubMed

Tang, Wei-Lun; Tang, Wei-Hsin; Chen, Weihsu Claire; Diako, Charles; Ross, Carolyn F; Li, Shyh-Dar

2017-06-05

Mefloquine (Mef), a poorly soluble and highly bitter drug, has been used for malaria prophylaxis and treatment. The dosage form for Mef is mostly available as adult tablets, and thus children under the age of 5 suffer from poor medication adherence. We have developed a stable, rapidly dissolvable, and palatable pediatric formulation for Mef using liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol with a mean diameter of ∼110 nm. Mef was actively loaded into the liposomes via an ammonium sulfate gradient using the solvent-assisted loading technology (SALT) developed in our lab. Complete loading of Mef inside the liposomal core was achieved at a high drug-to-lipid ratio (D/L) of 0.1-0.2 (w/w), and the final drug content in the formulation was ∼8 mg/mL, well above the solubility of Mef (<0.6 mg/mL in simulated fluids). The strong bitterness of Mef was masked by the liposomal encapsulation as measured by an electronic tongue. Incubating the Mef-liposomes (Mef-Lipo) in the simulated gastric fluid (pH 1.2) and the simulated intestinal fluid containing 3 mM sodium taurocholate (pH 6.8) induced changes in liposome size and the polydispersity, resulting in drug release (∼40% in 2 h). However, no drug release from the Mef-Lipo was measured in the bile salt-free intestinal fluid or simulated saliva (0% in 3 h). These data suggest that drug release from the Mef-Lipo was mediated by a low pH and the presence of a surfactant. Pancreatic lipase did not degrade DSPC in the Mef-Lipo after 8 h of incubation nor induce Mef release from the liposomes, indicating that lipid digestion played a minor role for drug release from the Mef-Lipo. In order to improve long-term room temperature storage, the Mef-Lipo was lyophilized to obtain a solid formulation, which was completely dissolvable in water in 10 s and displayed similar in vitro profiles of release as the liquid form. The lyophilized Mef-Lipo was stable at room temperature for >3 months. In mice, orally delivered liquid and lyophilized Mef-Lipo displayed comparable absorption with bioavailability (BA) of 81-86%, while the absorption of the standard Mef suspension was significantly lower with BA of 70% and 20% decreased maximal plasma concentration and area under the curve. Our data suggest that the Mef-Lipo was a stable, palatable, and bioavailable formulation that might be suitable for pediatric use.

Oral sustained-release suspension based on a lauryl sulfate salt/complex.

PubMed

Kasashima, Yuuki; Uchida, Shinya; Yoshihara, Keiichi; Yasuji, Takehiko; Sako, Kazuhiro; Namiki, Noriyuki

2016-12-30

The objective of this study was to evaluate the feasibility of lauryl sulfate (LS) salt/complex as a novel carrier in oral sustained-release suspensions. Mirabegron, which has a pH-dependent solubility, was selected as the model drug. Sodium lauryl sulfate (SLS) was bound to mirabegron in a stoichiometric manner to form an LS salt/complex. LS salt/complex formulation significantly reduced the solubility of mirabegron and helped mirabegron achieve sustained-release over a wide range of pH conditions. Microparticles containing the LS salt/complex were prepared by spray drying with the aqueous dispersion of ethylcellulose (Aquacoat ® ECD). The diameter of the microparticles was less than 200μm, which will help avoid a gritty taste. In vitro results indicated the microparticles had slower dissolution profiles than the LS salt/complex. The dissolution rate could be controlled flexibly by changing the amount of Aquacoat ® ECD. The microparticle suspension retained the desired sustained-release property and dissolution profile after being stored for 30days at 40°C. In addition, the suspension displayed sustained-release behavior in dogs without a pronounced C max peak, which will help prevent side effects. These results suggest that microparticles containing LS salt/complex may be useful as a novel sustained-release suspension for oral delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Oral bioavailability enhancement and hepatoprotective effects of thymoquinone by self-nanoemulsifying drug delivery system.

PubMed

Kalam, Mohd Abul; Raish, Mohammad; Ahmed, Ajaz; Alkharfy, Khalid M; Mohsin, Kazi; Alshamsan, Aws; Al-Jenoobi, Fahad I; Al-Mohizea, Abdullah M; Shakeel, Faiyaz

2017-07-01

Thymoquinone (TQ) is a poorly water soluble bioactive compound which shows poor oral bioavailability upon oral administration. Due to poor aqueous solubility and bioavailability of TQ, various self-nanoemulsifying drug delivery systems (SNEDDS) of TQ were developed and evaluated for enhancement of its hepatoprotective effects and oral bioavailability. Hepatoprotective and pharmacokinetic studies of TQ suspension and TQ-SNEDDS were carried out in rat models. Different SNEDDS formulations of TQ were developed and thermodynamically stable TQ-SNEDDS were characterized for physicochemical parameters and evaluated for drug release studies via dialysis membrane. Optimized SNEDDS formulation of TQ was selected for further evaluation of in vivo evaluation. In vivo hepatoprotective investigations showed significant hepatoprotective effects for optimized TQ-SNEDDS in comparison with TQ suspension. The oral administration of optimized SNEDDS showed significant improvement in in vivo absorption of TQ in comparison with TQ suspension. The relatively bioavailability of TQ was enhanced 3.87-fold by optimized SNEDDS in comparison with TQ suspension. The results of this research work indicated the potential of SNEDDS in enhancing relative bioavailability and therapeutic effects of natural bioactive compounds such as TQ. Copyright © 2017 Elsevier B.V. All rights reserved.

A bioequivalence study of gliclazide based on quantification by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry.

PubMed

Mendes, G D; Moreira, L D; Pereira, A dos S; Borges, A; Yui, F; Mendes, F D; de Nucci, G

2007-03-01

The aim of this study was to evaluate, in human volunteers, the performance of one gliclazide tablet formulation (gliclazide 80 mg tablet from EMS Indústria Farmacêutica Ltda.) against two reference gliclazide tablet formulations (Diamicron 80 mg tablet from Servier do Brazil Ltda. and Diamicron 80 mg tablet from Servier (Ireland) Industries Limited). The study had an open, randomized, three-period crossover design with a one-week washout interval between doses. The samples were obtained over a 48-h interval after each oral administration of gliclazide. The samples were extracted from plasma using diethylether : hexane (80 : 20, v/v) and the extracts were analyzed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/ MS). Chromatography was performed isocratically using a Jones Chromatography Genesis C8 120A 4u. The method had a chromatographic run-time of 2.5 min and a calibration curve of the range of 0.02- 10 microg x ml(-1) (r(2) > 0.9993). The limit of quantification was 0.02 microg x ml(-1). The geometric mean and 90% confidence intervals (CI) for the Gliclazide/Diamicron (Ireland) ratio were 588.68% (90% CI= 491.16, 705.58%) for AUClast, 423.50% (90% CI = 338.25, 530.23%) for AUCinf, and 1395.77% (90% CI= 1116.62, 1744.72%) for Cmax. The geometric mean and 90% confidence intervals (CI) for the Gliclazide/Diamicron (Brazil) ratio were 249.16% (90% CI = 207.96, 298.54%) for AUCiast, 249.16% (90% CI = 207.96 - 298.54%) for AUCinf, and 188.04% (90% CI - 151.72, 233.05%) for Cmax. Since the 90% CI for Cmax, AUClast and AUC(0-infinity) ratios were all outside the 125% interval proposed by the US Food and Drug Administration, we concluded that the gliclazide test formulation were not bioequivalent to either reference formulation. Interestingly, the pharmacokinetic parameters such as Cmax, AUClast of both reference formulations are compatible with neither the literature nor the profile of an immediate release formulation. In addition, both reference formulations were not bioequivalent in themselves, indicating significant differences in reference product formulation.

Pharmaceutical development and optimization of azithromycin suppository for paediatric use.

PubMed

Kauss, Tina; Gaubert, Alexandra; Boyer, Chantal; Ba, Boubakar B; Manse, Muriel; Massip, Stephane; Léger, Jean-Michel; Fawaz, Fawaz; Lembege, Martine; Boiron, Jean-Michel; Lafarge, Xavier; Lindegardh, Niklas; White, Nicholas J; Olliaro, Piero; Millet, Pascal; Gaudin, Karen

2013-01-30

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought. Copyright © 2012 Elsevier B.V. All rights reserved.

Pharmaceutical development and optimization of azithromycin suppository for paediatric use

PubMed Central

Kauss, Tina; Gaubert, Alexandra; Boyer, Chantal; Ba, Boubakar B.; Manse, Muriel; Massip, Stephane; Léger, Jean-Michel; Fawaz, Fawaz; Lembege, Martine; Boiron, Jean-Michel; Lafarge, Xavier; Lindegardh, Niklas; White, Nicholas J.; Olliaro, Piero; Millet, Pascal; Gaudin, Karen

2013-01-01

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought. PMID:23220079

Once daily 5-aminosalicylic acid for the treatment of ulcerative colitis; are we there yet?

PubMed

Lakatos, Peter Laszlo; Lakatos, Laszlo

2008-01-01

5-Aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents are commercially available, including azo-bond pro-drugs such as sulfasalazine, olsalazine and balsalazide, and delayed- and controlled-release forms of mesalazine. In addition, the effectiveness of oral therapy relies on good compliance, which may be adversely affected by frequent daily dosing and a large number of tablets. Furthermore, poor adherence has been shown to be an important barrier to successful management of patients with UC. Recently, new, once daily formulations of mesalazine including the unique multi-matrix delivery system and mesalazine granules were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of low pill burden and may contribute to increased long-term compliance and treatment success in clinical practice and might potentially further contribute to a decline in the risk for UC-associated colon cancers. In this systematic review, the authors summarize the available literature on the short- and medium-term efficacy and safety of the new once daily mesalazine formulations.

[Effectiveness of new, once-daily 5-aminosalicylic acid in the treatment of ulcerative colitis].

PubMed

Lakatos, Péter László; Lakatos, László

2009-03-01

5-aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents is commercially available, including azo-bond pro-drugs such as sulfasalazine, olsalazine and balsalazide, and delayed- and controlled-release forms of mesalazine. In addition, the effectiveness of oral therapy relies on good compliance, which may be adversely affected by frequent daily dosing and a large number of tablets. Furthermore, poor adherence has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine including the unique multi-matrix delivery system and mesalazine granules were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of low pill burden and may contribute to increased long-term compliance and treatment success in clinical practice and might potentially further contribute to a decline in the risk for UC-associated colon cancers. In this systematic review, the authors summarize the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.

Application of ICH Q9 Quality Risk Management Tools for Advanced Development of Hot Melt Coated Multiparticulate Systems.

PubMed

Stocker, Elena; Becker, Karin; Hate, Siddhi; Hohl, Roland; Schiemenz, Wolfgang; Sacher, Stephan; Zimmer, Andreas; Salar-Behzadi, Sharareh

2017-01-01

This study aimed to apply quality risk management based on the The International Conference on Harmonisation guideline Q9 for the early development stage of hot melt coated multiparticulate systems for oral administration. N-acetylcysteine crystals were coated with a formulation composing tripalmitin and polysorbate 65. The critical quality attributes (CQAs) were initially prioritized using failure mode and effects analysis. The CQAs of the coated material were defined as particle size, taste-masking efficiency, and immediate release profile. The hot melt coated process was characterized via a flowchart, based on the identified potential critical process parameters (CPPs) and their impact on the CQAs. These CPPs were prioritized using a process failure mode, effects, and criticality analysis and their critical impact on the CQAs was experimentally confirmed using a statistical design of experiments. Spray rate, atomization air pressure, and air flow rate were identified as CPPs. Coating amount and content of polysorbate 65 in the coating formulation were identified as critical material attributes. A hazard and critical control points analysis was applied to define control strategies at the critical process points. A fault tree analysis evaluated causes for potential process failures. We successfully demonstrated that a standardized quality risk management approach optimizes the product development sustainability and supports the regulatory aspects. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Inhaled Treprostinil-Prodrug Lipid Nanoparticle Formulations Provide Long-Acting Pulmonary Vasodilation.

PubMed

Leifer, Franziska G; Konicek, Donna M; Chen, Kuan-Ju; Plaunt, Adam J; Salvail, Dany; Laurent, Charles E; Corboz, Michel R; Li, Zhili; Chapman, Richard W; Perkins, Walter R; S Malinin, Vladimir

2018-05-23

Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]. To ameliorate these side effects and reduce dosing frequency we designed an inhaled slow-release TRE formulation. TRE was chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. Preclinical screening in a rat model of hypoxia-induced pulmonary vasoconstriction led to selection of a 16-carbon alkyl ester derivative of TRE. The TPD-LNP demonstrated approximately 10-fold lower TRE plasma C max compared to inhaled TRE solution while maintaining an extended vasodilatory effect. The favorable PK profile is attributed to gradual dissociation of TPD from the LNP and subsequent conversion to TRE. Together, this sustained presentation of TRE to the lungs and plasma is consistent with a once- or twice-daily dosing schedule in the absence of high C max -associated adverse events which could provide patients with an improved treprostinil therapy. © Georg Thieme Verlag KG Stuttgart · New York.

The administration of L-thyroxine as soft gel capsule or liquid solution.

PubMed

Vita, Roberto; Fallahi, Poupak; Antonelli, Alessandro; Benvenga, Salvatore

2014-07-01

Levothyroxine (l-T4) is the mainstay of treating hypothyroidism. The tablet is the traditional formulation of l-T4. Tablet l-T4 malabsorption results from either hindered gastric dissolution of the tablet or binding of l-T4 by sequestrants in the intestinal lumen. This review provides an overview of the pharmacokinetics of l-T4 formulations available in the market: the tablet, the soft gel capsule and the oral solution. We review literature on the new formulations and anticipate the areas of future research. Failure of l-T4 treatment to reach target serum thyroid-stimulating hormone levels generally prompts the physicians to increase l-T4 daily dose. In vitro studies have shown that the soft gel capsule releases the active ingredient more consistently at varying pH than the tablet. In addition, in vivo studies have confirmed the in vitro data and have demonstrated that both the soft gel capsule and the liquid formulation are capable to solve tablet l-T4 malabsorption caused by certain drugs, bariatric surgery or coffee. These new formulations may be attractive also for patients who cannot/do not want to change their (improper) habits of l-T4 ingestion. Finally, the oral solution l-T4 could be suitable for patients who cannot swallow the solid formulations.

Nanoencapsulation of dietary flavonoid fisetin: Formulation and in vitro antioxidant and α-glucosidase inhibition activities.

PubMed

Sechi, Mario; Syed, Deeba N; Pala, Nicolino; Mariani, Alberto; Marceddu, Salvatore; Brunetti, Antonio; Mukhtar, Hasan; Sanna, Vanna

2016-11-01

The bioactive flavonoid fisetin (FS) is a diet-derived antioxidant that is being increasingly investigated for its health-promoting effects. Unfortunately, the poor physicochemical and pharmacokinetic properties affect and limit the clinical application. In this study, novel polymeric nanoparticles (NPs), based on Poly-(ε-caprolactone) (PCL) and PLGA-PEG-COOH, encapsulating FS were formulated as suitable oral controlled release systems. Results showed NPs having a mean diameter of 140-200nm, and a percent loading of FS ranging from 70 to 82%. In vitro release studies revealed that NPs are able to protect and preserve the release of FS in gastric simulated conditions, also controlling the release in the intestinal medium. Moreover, the DPPH and ABTS scavenging capacity of FS, as well as α-glucosidase inhibition activity, that resulted about 20-fold higher than commercial Acarbose, were retained during nanoencapsulation process. In summary, our developed NPs can be proposed as an attractive delivery system to control the release of antioxidant and anti-hyperglycemic FS for nutraceutical and/or therapeutic application. Copyright © 2016 Elsevier B.V. All rights reserved.

Development of Self Emulsifying Formulations of Poorly Soluble Naproxen for Enhanced Drug Delivery.

PubMed

Penjuri, Subhash C B; Saritha, Damineni; Ravouru, Nagaraju; Poreddy, Srikanth R

2016-01-01

The objective of this investigation was to develop a self emulsifying drug delivery system (SEDDS) of naproxen, a poorly water soluble drug, which could improve its solubility and oral bioavailability. The recent patents on SEDDS of abiraterone acetate (WO2014/009434 A1) and tamoxifen (WO2013/0080083) helped in selecting the naproxen and excipients. Phase diagrams were constructed and the formulations were taken from the micro emulsion region. Formulations were subjected to thermodynamic stability, dispersibility and precipitation tests for optimization. Physico chemical characterization was carried out by FTIR and DSC studies. The selected SEDDS consisted of IPM+labrafac lipophile WL 1349, tween 80, PEG 400 and naproxen. The optimized formulation has globule size- 187.6 nm, zeta potential- -9.81 mv, viscosity- 1.772 cps and infinite dilution ability. In vitro drug release was 98.21% and was found to be significantly different from the marketed product and plain drug. After oral administration in rats the SEDDS of naproxen showed anti inflammatory activity (69.82%) which was much improved as compared to the marketed formulation. The Cmax, AUC0t of naproxen was boosted with SEDDS to 133.63 g/ml and 698.29 hr. g/ml respectively. The optimized formulation was found to be stable for 6 months during stability studies conducted according to the ICH Q1A (R2) guidelines. Thus this developed self emulsifying drug delivery system may be a useful tool to enhance the solubility of oral poorly water soluble drug naproxen. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Microparticulate drug delivery system containing tramadol hydrochloride for pain treatment.

PubMed

Ciurba, Adriana; Todoran, Nicoleta; Vari, C E; Lazăr, Luminita; Al Hussein, Stela; Hancu, G

2014-01-01

The current trend of replacing conventional pharmaceutical forms is justified because most substances administered in this form give fluctuations of therapeutic concentrations and often outside the therapeutic range. In addition, these formulations offer a reduction in the dose or the number of administrations, thus increasing patient compliance. In the experiment, we developed an appropriate technology for the preparation of gelatin microspheres containing tramadol hydrochloride by emulsification/cross-linking method. The formulated microspheres were characterized by product yield, size distribution, encapsulation efficiency and in vitro release of tramadol hydrochloride. Data obtained from in vitro release studies were fitted to various mathematical models to elucidate the transport mechanisms. The kinetic models used were zero-order, first-order, Higuchi Korsmeyer-Peppas and Hopfenberg. Spherical microspheres were obtained, with free-flowing properties. The entrapment efficiency of tramadol hydrochloride in microparticles was 79.91% and product yield -94.92%. As the microsphere size was increased, the entrapment efficiency increased. This was 67.56, 70.03, 79.91% for formulations MT80-250, MT8-500 and, MT250-500. High entrapment efficiency was observed for MT250-500 formulation. The gelatin microspheres had particle sizes ranging from 80 to 500 microm. The drug was released for a period of 12 hours with a maximum release of 96.02%. Of the three proposed formulations, MT250-500 presented desirable properties and optimal characteristics for the therapy of pain. Release of tramadol hydrochloridi was best fitted to Korsmeyer-Peppas equation because the Akaike Information Criterion had the lowest values for this kinetic model. These results suggest the opportunity to influence the therapeutic characteristics of gelatin microspheres to obtain a suitable drug delivery system for the oral administration of tramadol hydrochloride.

Design and statistical optimization of glipizide loaded lipospheres using response surface methodology.

PubMed

Shivakumar, Hagalavadi Nanjappa; Patel, Pragnesh Bharat; Desai, Bapusaheb Gangadhar; Ashok, Purnima; Arulmozhi, Sinnathambi

2007-09-01

A 32 factorial design was employed to produce glipizide lipospheres by the emulsification phase separation technique using paraffin wax and stearic acid as retardants. The effect of critical formulation variables, namely levels of paraffin wax (X1) and proportion of stearic acid in the wax (X2) on geometric mean diameter (dg), percent encapsulation efficiency (% EE), release at the end of 12 h (rel12) and time taken for 50% of drug release (t50), were evaluated using the F-test. Mathematical models containing only the significant terms were generated for each response parameter using the multiple linear regression analysis (MLRA) and analysis of variance (ANOVA). Both formulation variables studied exerted a significant influence (p < 0.05) on the response parameters. Numerical optimization using the desirability approach was employed to develop an optimized formulation by setting constraints on the dependent and independent variables. The experimental values of dg, % EE, rel12 and t50 values for the optimized formulation were found to be 57.54 +/- 1.38 mum, 86.28 +/- 1.32%, 77.23 +/- 2.78% and 5.60 +/- 0.32 h, respectively, which were in close agreement with those predicted by the mathematical models. The drug release from lipospheres followed first-order kinetics and was characterized by the Higuchi diffusion model. The optimized liposphere formulation developed was found to produce sustained anti-diabetic activity following oral administration in rats.

A comparative study of the effect of spray drying and hot-melt extrusion on the properties of amorphous solid dispersions containing felodipine.

PubMed

Mahmah, Osama; Tabbakh, Rami; Kelly, Adrian; Paradkar, Anant

2014-02-01

To compare the properties of solid dispersions of felodipine for oral bioavailability enhancement using two different polymers, polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), by hot-melt extrusion (HME) and spray drying. Felodipine solid dispersions were prepared by HME and spray drying techniques. PVP and HPMCAS were used as polymer matrices at different drug : polymer ratios (1 : 1, 1 : 2 and 1 : 3). Detailed characterization was performed using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and in-vitro dissolution testing. Dissolution profiles were evaluated in the presence of sodium dodecyl sulphate. Stability of different solid dispersions was studied under accelerated conditions (40°C/75% RH) over 8 weeks. Spray-dried formulations were found to release felodipine faster than melt extruded formulations for both polymer matrices. Solid dispersions containing HMPCAS exhibited higher drug release rates and better wettability than those produced with a PVP matrix. No significant differences in stability were observed except with HPMCAS at a 1 : 1 ratio, where crystallization was detected in spray-dried formulations. Solid dispersions of felodipine produced by spray drying exhibited more rapid drug release than corresponding melt extruded formulations, although in some cases improved stability was observed for melt extruded formulations. © 2013 Royal Pharmaceutical Society.

Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture design.

PubMed

Yeom, Dong Woo; Song, Ye Seul; Kim, Sung Rae; Lee, Sang Gon; Kang, Min Hyung; Lee, Sangkil; Choi, Young Wook

2015-01-01

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A D-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the D-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs.

Development and optimization of a self-microemulsifying drug delivery system for ator vastatin calcium by using d-optimal mixture design

PubMed Central

Yeom, Dong Woo; Song, Ye Seul; Kim, Sung Rae; Lee, Sang Gon; Kang, Min Hyung; Lee, Sangkil; Choi, Young Wook

2015-01-01

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A d-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the d-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs. PMID:26089663

Use of new once-daily 5-aminosalicylic acid preparations in the treatment of ulcerative colitis: Is there anything new under the sun?

PubMed Central

Lakatos, Peter Laszlo

2009-01-01

5-aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents are commercially available, including azobond pro-drugs, as well as delayed- and controlled-release forms of mesalazine. However, poor adherence due to frequent daily dosing and a large number of tablets has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine, including the unique multi-matrix delivery system and mesalazine granules, were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of a low pill burden and might contribute to increased long-term compliance and treatment success in clinical practice. This editorial summarizes the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations. PMID:19370774

Use of new once-daily 5-aminosalicylic acid preparations in the treatment of ulcerative colitis: Is there anything new under the sun?

PubMed

Lakatos, Peter Laszlo

2009-04-21

5-aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents are commercially available, including azobond pro-drugs, as well as delayed- and controlled-release forms of mesalazine. However, poor adherence due to frequent daily dosing and a large number of tablets has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine, including the unique multi-matrix delivery system and mesalazine granules, were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of a low pill burden and might contribute to increased long-term compliance and treatment success in clinical practice. This editorial summarizes the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.

Development and characterisation of sustained release solid dispersion oral tablets containing the poorly water soluble drug disulfiram.

PubMed

Shergill, Mandip; Patel, Mina; Khan, Siraj; Bashir, Ayesha; McConville, Christopher

2016-01-30

Administration of drugs via the oral route is the most common and preferred route due to its ease of administration, cost-effectiveness and flexibility in design. However, if the drug being administered has limited aqueous solubility it can result in poor bioavailability. Furthermore, the low pH of the stomach as well as enzymatic activity can result in drugs delivered via the oral route being rapidly metabolised and degraded. Here we demonstrate the development and characterisation of sustained release solid dispersion oral tablets, containing the poorly water-soluble drug disulfiram (DSF). The tablets, which are manufactured from two different polymers (Kolliphor(®) P 188 and P 237) specifically designed for the manufacture of solid dispersions and two different polymers (Kollidon(®) SR and HPMC) specifically designed to provide sustained release, can enhance the solubility of DSF, sustain its release, while protecting it from degradation in simulated gastric fluid (SGF). The paper demonstrates that when using the hot melt method at 80°C the DSF loading capacity of the Kolliphor(®) P 188 and P 237 polymers is approximately 43 and 46% respectively, with the DSF completely in an amorphous state. The addition of 80% Kollidon(®) SR to the formulation completely protected the DSF in SGF for up to 70 min with 16% degradation after 120 min, while 75% degradation occurred after 120 min with the addition of 80% HPMC. The release rate of DSF can be manipulated by both the loading and type of sustained release polymer used, with HPMC providing for a much faster release rate compared to Kollidon(®) SR. Copyright © 2015 Elsevier B.V. All rights reserved.

Methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder.

PubMed

Sugrue, David; Bogner, Robin; Ehret, Megan J

2014-07-15

Current literature on the safety and efficacy of various intermediate- and long-acting preparations of methylphenidate and dexmethylphenidate for pediatric attention-deficit/hyperactivity disorder (ADHD) is reviewed. The efficacy of methylphenidate in controlling ADHD symptoms is firmly established. Given the drug's relatively short half-life in pediatric patients (about 2.5 hours), a number of intermediate- and long-acting products have been developed; these extended-release methylphenidate products provide the same efficacy as immediate-release (IR) formulations, with the convenience of less frequent dosing. Intermediate-acting methylphenidate preparations have effects lasting as long as 8 hours, but peak concentrations are not attained for up to 5 hours, and many patients may require twice-daily dosing. Long-acting methylphenidate products developed to address these challenges include a controlled-release tablet and bimodal-delivery capsules containing mixtures of IR and extended-release beads (durations of effect, 8-12 hours). Options for patients with difficulty swallowing tablets or capsules include a once-daily transdermal delivery system and a once-daily liquid formulation. Dexmethylphenidate (the more pharmacologically active d-isomer of racemic methylphenidate) can provide efficacy comparable to that of IR methylphenidate at half the dose; an extended-release form of dexmethylphenidate can provide less fluctuation in peak and trough concentrations than the IR form. Methylphenidate and dexmethylphenidate products in capsule form can be opened and sprinkled on applesauce. The various formulations of IR and intermediate- and extended-release methylphenidate and dexmethylphenidate can be useful options in satisfying patients' individual needs in the management of ADHD. All are equally efficacious in controlling ADHD symptoms. Copyright © 2014 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Characterization, in Vivo and in Vitro Evaluation of Solid Dispersion of Curcumin Containing d-α-Tocopheryl Polyethylene Glycol 1000 Succinate and Mannitol.

PubMed

Song, Im-Sook; Cha, Jin-Sun; Choi, Min-Koo

2016-10-17

The aim of this study was to prepare a solid dispersion formulation of curcumin to enhance its solubility, dissolution rate, and oral bioavailability. The formulation was prepared with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and mannitol using solvent evaporation and freeze-drying methods, which yielded a solid dispersion composed of curcumin, TPGS, and mannitol at a ratio of 1:10:15 ( w / w / w ). The solubility and dissolution rate of the curcumin solid dispersion markedly improved compared with those of curcumin powder and a physical mixture of curcumin, TPGS, and mannitol. About 90% of the curcumin was released from the solid dispersion formulation within 10 min. After administering the formulation orally to rats, higher plasma concentrations of curcumin were observed, with increases in the maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) of 86- and 65-fold, respectively, compared with those of curcumin powder. The solid dispersion formulation effectively increased intestinal permeability and inhibited P-gp function. These effects increased the anti-proliferative effect of curcumin in MDA-MB-231 breast cancer cells. Moreover, 2 h incubation with curcumin powder, solid dispersion formulation, and its physical mixture resulted in differential cytotoxic effect of paclitaxel in P-gp overexpressed LLC-PK1-P-gp and MDA-MB-231 cells through the inhibition of P-gp-mediated paclitaxel efflux. In conclusion, compared with curcumin, a solid dispersion formulation of curcumin with TPGS and mannitol could be a promising option for enhancing the oral bioavailability and efficacy of curcumin through increased solubility, dissolution rate, cell permeability, and P-gp modulation.

Drug formulations intended for the global market should be tested for stability under tropical climatic conditions.

PubMed

Risha, P G; Vervaet, C; Vergote, G; Bortel, L Van; Remon, J P

2003-06-01

The quality of drugs imported into developing countries having a tropical climate may be adversely affected if their formulations have not been optimized for stability under these conditions. The present study investigated the influence of tropical climate conditions (class IV: 40 degrees C, 75% relative humidity) on the drug content, in vitro dissolution and oral bioavailability of different formulations of two essential drugs marketed in Tanzania: diclofenac sodium and ciprofloxacin tablets. Before and after 3 and 6 months storage under class IV conditions the drug content and in vitro dissolution were evaluated using United States Pharmacopoeia (USP) 24 methods. Following a randomized four-period cross-over study, the pharmacokinetic parameters of drug formulations stored for 3 months under class IV conditions were compared with those stored at ambient conditions. Drug content and drug release from all tested ciprofloxacin formulations were within USP-24 requirements and remained stable during storage at simulated tropical conditions. Oral bioavailability was also not influenced by tropical conditions. The dissolution rate of two diclofenac formulations (Diclo 50 manufactured by Camden and Dicloflame 50 manufactured by Intas) reduced significantly during storage under class IV conditions. After oral administration Camden tablets stored for 3 months under class IV conditions showed a reduction in C(max) (90% CI of C(max) ratio: 0.59 - 0.76). This reduction was smaller than expected based on the in vitro tests. Some drug formulations imported into Tanzania are not optimized for stability in a tropical climate. Manufacturers and regulatory authorities should pay more attention to the WHO recommendations for testing the stability of drugs under tropical climate conditions. Efforts should be made to improve the in vitro tests to better predict the bioavailability.

Comparative pharmacokinetics of a new oral long-acting formulation of doxycycline hyclate: A canine clinical trial.

PubMed

Arciniegas Ruiz, Sara Melisa; Gutiérrez Olvera, Lilia; Bernad Bernad, María Josefa; Caballero Chacón, Sara Del Carmen; Vargas Estrada, Dinorah

2015-12-01

Doxycicline is used in dogs as treatment of several bacterial infections, mycoplasma, chlamydia and rickettsial diseases. However, it requires long treatments and several doses to be effective. The aim of this study was to determine the pharmacokinetics of four formulations of doxycycline hyclate, administered orally, with different proportions of excipients, acrylic acid-polymethacrylate-based matrices, to obtain longer therapeutic levels than conventional formulation. Forty-eight dogs were randomly assigned in five groups to receive a single oral dose (20mg/kg) of doxycycline hyclate without excipients (control) or a long-acting formulation containing doxycycline, acrylic acid polymer, and polymethacrylate in one of the following four proportions: DOX1(1:0.25:0.0035), DOX2(1:0.5:0.0075), DOX3 (1:1:0.015), or DOX4(1:2:0.0225). Temporal profiles of serum concentrations were obtained at several intervals after each treatment. Therapeutic concentrations were observed for 60h for DOX1 and DOX4, 48h for DOX2 and DOX3 and only 24h for DOX-C. None of the pharmacokinetic parameter differed significantly between DOX1 and DOX2 or between DOX3 and DOX4; however, the findings for the control treatment were significantly different compared to all four long-acting formulations. Results indicated that DOX1 had the most adequate pharmacokinetic-pharmacodynamic relationships for a time-dependent drug and had longer release times than did doxycycline alone. However, all four formulations can be effective depend on the minimum effective serum doxycycline concentration of the microorganism being treated. These results suggest that the use of any of these formulations can reduce the frequency of administration, the patient's stress, occurrence of adverse effects and the cost of treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Better efficacy for the osmotic release oral system methylphenidate among poor adherents to immediate-release methylphenidate in the three ADHD subtypes.

PubMed

Chou, Wen-Jiun; Chou, Miao-Chun; Tzang, Ruu-Fen; Hsu, Ya-Chen; Gau, Susan Shur-Fen; Chen, Shin-Jaw; Wu, Yu-Yu; Huang, Ya-Fen; Liang, Hsin-Yi; Cheng, Helen

2009-04-01

To determine factors for switching to osmotic release oral system methylphenidate (OROS-MPH) among poor adherents to immediate-release methylphenidate (IR-MPH); and to compare the efficacy of OROS-MPH on the three attention-deficit/hyperactivity disorder (ADHD) subtypes in a multi-site prospective observational study in Taiwan. The sample included 240 children with ADHD, aged 6-16 years, who were poor adherents to IR-MPH, 137 of whom were switched to OROS-MPH. The child psychiatrists diagnosed the Diagnostic Statistical Manual of Mental Disorders (4th edition) ADHD subtypes and assessed the medical history, adherence, side-effects, global ADHD severity, and family/school effectiveness. Parents reported their child's behavioral symptoms. The determinants for an OROS-MPH switch were higher dosage, shorter treatment and thrice-daily administration of IR-MPH, and more severe inattention symptoms. Hyperactivity and oppositional symptoms were greater in the ADHD combined and hyperactive-impulsive subtypes than the inattentive subtype. Switching to OROS-MPH significantly improved behavioral symptoms and family/school measures, and this was most evident in the ADHD-combined group, followed by the ADHD-inattentive group. Inattention influenced not only academic performance, but also overall classroom behaviors and the parent-child relationship, with the latter two also influenced by oppositional symptoms. This study suggests better efficacy for the OROS-MPH among poor adherents to IR-MPH; however, its effectiveness varied across the three ADHD subtypes (ClinicalTrials.gov number NCT00460720).

Development of chitosan-based ondansetron buccal delivery system for the treatment of emesis.

PubMed

Park, Dong-Min; Song, Yun-Kyoung; Jee, Jun-Pil; Kim, Hyung Tae; Kim, Chong-Kook

2012-09-01

For the buccal drug delivery, chitosan (CS) can be used to improve drug absorption and reduce application frequency and drug amount. The aim of this study is to develop and evaluate mucoadhesive ondansetron buccal films for the treatment of emesis using CS as a mucoadhesive polymer. The film prepared by solvent casting method was comprised of ondansetron (approximately 65 μg)-loaded mucoadhesive gels containing 1, 2 or 3% CS and impermeable backing layer. Rheological property of the gels, physiochemical properties of the films (weight, thickness, drug content, swelling ratio, adhesion time and mucoadhesive force) and in vitro ondansetron release profile from the films were determined to evaluate the formulation. The films containing 3% CS (diameter: 0.5 cm; thickness: 170 μm) was selected as the novel formulation, and were used for the in vivo study. Comparative pharmacokinetic studies of ondansetron with this film and oral solution were performed at the same dose in hamsters. The mean values of T(max) and C(max) of the film and oral solution were similar. However, the half-life, mean residence time and AUC(0-24 h) of the film were about 1.7, 1.4 and 2.0-fold higher than those of the oral solution, respectively. The film showed enhanced bioavailability and prolonged efficacy compared to the oral solution. The mucoadhesive ondansetron buccal film may be a potential alternative to the marketed oral formulation, parenterals and solid suppositories with better patient compliance and higher bioavailability for the treatment of emesis.

Development and optimization of enteric coated mucoadhesive microspheres of duloxetine hydrochloride using 32 full factorial design

PubMed Central

Setia, Anupama; Kansal, Sahil; Goyal, Naveen

2013-01-01

Background: Microspheres constitute an important part of oral drug delivery system by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at the site of absorption. Objective: The objective of the present study was to formulate and systematically evaluate in vitro performance of enteric coated mucoadhesive microspheres of duloxetine hydrochloride (DLX), an acid labile drug. Materials and Methods: DLX microspheres were prepared by simple emulsification phase separation technique using chitosan as carrier and glutaraldehyde as a cross-linking agent. Microspheres prepared were coated with eudragit L-100 using an oil-in-oil solvent evaporation method. Eudragit L-100was used as enteric coating polymer with the aim to release the drug in small intestine The microspheres prepared were characterized by particle size, entrapment efficiency, swelling index (SI), mucoadhesion time, in vitro drug release and surface morphology. A 32 full factorial design was employed to study the effect of independent variables polymer-to-drug ratio (X1) and stirring speed (X2) on dependent variables, particle size, entrapment efficiency, SI, in vitro mucoadhesion and drug release up to 24 h (t24). Results: Microspheres formed were discrete, spherical and free flowing. The microspheres exhibited good mucoadhesive property and also showed high percentage entrapment efficiency. The microspheres were able to sustain the drug release up to 24 h. Conclusion: Thus, the prepared enteric coated mucoadhesive microspheres may prove to be a potential controlled release formulation of DLX for oral administration. PMID:24167786

Formulation of Saudi Propolis into Biodegradable Chitosan Chips for Vital Pulpotomy.

PubMed

Balata, Gihan F; Abdelhady, Mohamed I S; Mahmoud, Ghada M; Matar, Moustafa A; Abd El-Latif, Amani N

2018-01-01

Propolis has been widely used to treat oral cavity disorders, such as endodontal and periodontal diseases and microbial infections. The study aimed at the formulation of commercial Saudi propolis into biodegradable chitosan chips and evaluation of its effectiveness as a pulpotomy agent. The standardization of 80% ethanolic propolis extract was performed regarding its total phenolic content, total flavonoid content, quantitative estimation of main polyphenolic constituents and antioxidant activity. Chitosan chips containing propolis extract were prepared by the solvent/ casting method. The investigated variables were % of chitosan polymer (2, 2.5 and 3%), % of plasticizer (1, 5 and 10%) and incorporation of different concentrations of hydroxypropyl methylcellulose (5, 10 and 20% of polymer weight). The chips were characterized for weight and thickness uniformity, content uniformity, pH, percentage moisture loss, swelling index, tensile strength and in vitro propolis release. The optimal propolis chip formulation was further investigated in dogs regarding the short term response of primary dental pulp to propolis chips compared with the most commonly used formocresol preparation. The prepared films were flexible and demonstrated satisfactory physicochemical characteristics. The optimal formulation showed an initial release of about 41.7% of the loaded propolis followed by a sustained release extended up to 7 days. The kinetics study demonstrated that propolis release was controlled by Fick´s diffusion. The optimal propolis chip formulation resulted in less pulpal inflammation compared to formocresol, and produced hard tissue formation in all specimens. Formulation of commercial Saudi propolis as a biodegradable chitosan chip is an effective alternative to the commercially available chemical agents for the treatment of vital pulpotomy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets.

PubMed

Sadia, Muzna; Arafat, Basel; Ahmed, Waqar; Forbes, Robert T; Alhnan, Mohamed A

2018-01-10

Conventional immediate release dosage forms involve compressing the powder with a disintegrating agent that enables rapid disintegration and dissolution upon oral ingestion. Among 3D printing technologies, the fused deposition modelling (FDM) 3D printing technique has a considerable potential for patient-specific dosage forms. However, the use of FDM 3D printing in tablet manufacturing requires a large portion of polymer, which slows down drug release through erosion and diffusion mechanisms. In this study, we demonstrate for the first time the use of a novel design approach of caplets with perforated channels to accelerate drug release from 3D printed tablets. This strategy has been implemented using a caplet design with perforating channels of increasing width (0.2, 0.4, 0.6, 0.8 or 1.0mm) and variable length, and alignment (parallel or at right angle to tablet long axis). Hydrochlorothiazide (BCS class IV drug) was chosen as the model drug as enhanced dissolution rate is vital to guarantee oral bioavailability. The inclusion of channels exhibited an increase in the surface area/volume ratio, however, the release pattern was also influenced by the width and the length of the channel. A channel width was ≥0.6mm deemed critical to meet the USP criteria of immediate release products. Shorter multiple channels (8.6mm) were more efficient at accelerating drug release than longer channels (18.2mm) despite having comparable surface area/mass ratio. This behaviour may be linked to the reduced flow resistance within the channels and the faster fragmentation during dissolution of these tablets. In conclusion, the width and length of the channel should be carefully considered in addition to surface area/mass when optimizing drug release from 3D printed designs. The incorporation of short channels can be adopted in the designs of dosage forms, implants or stents to enhance the release rate of eluting drug from polymer-rich structures. Copyright © 2017 Elsevier B.V. All rights reserved.

Curcumin loaded nano globules for solubility enhancement: preparation, characterization and ex vivo release study.

PubMed

Kumar, Anil; Ahuja, Alka; Ali, Javed; Baboota, Sanjula

2012-11-01

Curcumin in spite of being an effective chemotherapeutic agent against different type of cancer, suffer from the problem of low systemic bioavailability due to low aqueous solubility, extensive intestinal metabolism and first-pass metabolism when administered via the oral route. The aim of present investigation was to evaluate the potential of nano globules based nanoemulsion formulation for the solubility enhancement of curcumin. The nano globules based formulation was developed using Labrafac Lipophile WL 1349, Unitop FFT 40, PEG 400 and distilled water as an oil, surfactant, co-surfactant and aqueous phase respectively using aqueous titration method. Furthermore, different formulations were subjected to physical stability and consequently evaluated for ex vivo permeation using small intestine. The optimized formulation had small average globule diameter of 58 nm with zeta potential of -32 mv which indicated long-term dispersion stability. The globules were spherical in shape as observed by Transmission electron microscopy. During ex vivo study, the release of curcumin from nanoemulsion was 96.21% and 98.1% in 6 h and 12 h respectively whereas CU suspension was release up to 28.2% at the end of 12 h. This indicated the enhancement of solubility of curcumin in aqueous solution which is the rate limiting step in the absorption of curcumin in the intestine.

Efficacy of a Methylphenidate Transdermal System versus t.i.d. Methylphenidate in a Laboratory Setting

ERIC Educational Resources Information Center

Pelham, William E.; Waxmonsky, James G.; Schentag, Jerome; Ballow, Charles H.; Panahon, Carlos J.; Gnagy, Elizabeth M.; Hoffman, Martin T.; Burrows-MacLean, Lisa; Meichenbaum, David L.; Forehand, Gregory L.; Fabiano, Gregory A.; Tresco, Katy E.; Lopez-Williams, Andy; Coles, Erika K.; Gonzalez, Mario A.

2011-01-01

Objective: To test the efficacy and tolerability of the methylphenidate transdermal formulation (MTS) against immediate-release methylphenidate (IR MPH) and placebo in a 12-hr analog classroom setting. Method: A total of nine boys ages 6 to 9 years, medicated with MPH for ADHD, complete a within-subject, double-blind study. For the purpose of the…

Indinavir-loaded pH-sensitive microparticles for taste masking: toward extemporaneous pediatric anti-HIV/AIDS liquid formulations with improved patient compliance.

PubMed

Chiappetta, Diego A; Carcaboso, Angel M; Bregni, Carlos; Rubio, Modesto; Bramuglia, Guillermo; Sosnik, Alejandro

2009-01-01

The aim of this work was to develop indinavir pediatric anti-HIV/AIDS formulations enabling convenient dose adjustment, ease of oral administration, and improved organoleptic properties by means of the generation of drug-loaded microparticles made of a polymer that is insoluble under intake conditions and dissolves fast in the stomach in order to completely release the active agent. Indinavir-loaded microparticles made of a pH-dependent polymeric excipient soluble at pH < 5, Eudragit E100, were prepared using a double emulsion solvent diffusion technique and the in vitro release profiles characterized. Finally, taste masking properties were evaluated in blind randomized sensory experiments by ten healthy human volunteers. The use of a w/o/o emulsion system resulted in indinavir loads around 90%. Thermal analysis of the microparticles by differential scanning calorimetry revealed that indinavir appeared mainly dispersed at the molecular level. Concentrations of residual organic solvents as determined by gas chromatography were below the upper limits specified by the European Pharmacopeia for pharmaceutical oral formulations. Then, the behavior of drug-containing microparticles in aqueous media at different pH values was assessed. While they selectively dissolved in gastric-like medium, in tap water (intake conditions), the matrix remained almost unchanged and efficiently prevented drug dissolution. Finally, sensoring taste tests performed by volunteers indicated that systems with indinavir loads approximately 15% displayed acceptable taste. This work explored the production of indinavir-containing microparticles based on a common pharmaceutical excipient as a means for the improvement of medicines of drugs involved in the treatment of HIV/AIDS. For systems containing about 15% drug, taste studies confirmed the acceptability of the formulation. In pediatric regimes, this composition would require an acceptable amount of formulation (0.7-1.5 g).

Oral fast-dissolving films containing lutein nanocrystals for improved bioavailability: formulation development, in vitro and in vivo evaluation.

PubMed

Liu, Chen; Chang, Daoxiao; Zhang, Xinhui; Sui, Hong; Kong, Yindi; Zhu, Rongyue; Wang, Wenping

2017-11-01

Lutein is widely used as diet supplement for prevention of age-related macular degeneration. However, the application and efficacy of lutein in food and nutritional products has been hampered due to its poor solubility and low oral bioavailability. This study aimed to develop and evaluate the formulation of oral fast-dissolving film (OFDF) containing lutein nanocrystals for enhanced bioavailability and compliance. Lutein nanocrystals were prepared by anti-solvent precipitation method and then encapsulated into the films by solvent casting method. The formulation of OFDF was optimized by Box-Behnken Design (BBD) as follows: HPMC 2.05% (w/v), PEG 400 1.03% (w/v), Cremophor EL 0.43% (w/v). The obtained films exhibited uniform thickness of 35.64 ± 1.64 μm and drug content of 0.230 ± 0.003 mg/cm 2 and disintegrated rapidly in 29 ± 8 s. The nanocrystal-loaded films with reconstituted particle size of 377.9 nm showed better folding endurance and faster release rate in vitro than the conventional OFDFs with raw lutein. The microscope images, thermograms, and diffractograms indicated that lutein nanocrystals were highly dispersed into the films. After administrated to SD rats, t max was decreased from 3 h for oral solution formulation to less than 0.8 h for OFDF formulations, and C max increased from 150 ng/mL for solution to 350 ng/mL for conventional OFDF or 830 ng/mL for nanocrystal OFDF. The AUC 0-24h of conventional or nanocrystal OFDF was 1.37 or 2.08-fold higher than that of the oral solution, respectively. These results suggested that drug nanocrystal-loaded OFDF can be applied as a promising approach for enhanced bioavailability of poor soluble drugs like lutein.

A study on maize proteins as a potential new tablet excipient.

PubMed

Georget, Dominique M R; Barker, Susan A; Belton, Peter S

2008-06-01

This investigation has examined the use of zein proteins from maize as the major component in oral controlled-release tablets, such formulations often being required to improve patient compliance. Tablets containing ground zein proteins, calcium hydrogen orthophosphate, polyvinyl pyrrolidone, theophylline and magnesium stearate were produced by wet granulation and compression on a single station tablet press and were compared to directly compressed tablets based on zein proteins, calcium hydrogen orthophosphate and theophylline. Non invasive techniques such as Fourier Transform infrared spectroscopy and Fourier Transform Raman spectroscopy were employed to investigate any changes in the secondary structure of zein proteins during tablet production. Random coils, alpha helices and beta sheets predominated and their relative content remained unaffected during grinding, wet granulation and compression, indicating that formulations based on zeins will be robust, i.e. insensitive to minor changes in the production conditions. Drug release from the tablets was studied using a standard pharmacopoeial dissolution test. Dissolution profiles in water, 0.1M HCl (pH=1) and phosphate buffer (pH=6.8) show that only a limited amount of theophylline was released after 4.5h, suggesting that zein proteins could act as a potential vehicle for oral controlled drug release. Analysis of the theophylline release profiles using the Peppas and Sahlin model reveals that diffusion and polymer relaxation occurred in acidic (pH=1) and buffered (pH=6.8) conditions for wet granulated tablets, whereas diffusion was predominant in directly compressed tablets. In conclusion, the present study has shown that zeins can be successfully used as a pharmaceutical excipient, and in particular as a matrix in monolithic controlled release tablets.

In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.

PubMed

Jinno, Jun-ichi; Kamada, Naoki; Miyake, Masateru; Yamada, Keigo; Mukai, Tadashi; Odomi, Masaaki; Toguchi, Hajime; Liversidge, Gary G; Higaki, Kazutaka; Kimura, Toshikiro

2008-08-25

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.

Pharmacokinetics and anti-hypertensive effect of metoprolol tartrate rectal delivery system.

PubMed

Abou el Ela, Amal El Sayeh F; Allam, Ayat A; Ibrahim, Ehsan H

2016-01-01

The main aim of this work was to develop rectal suppositories for better delivery of metoprolol tartrate (MT). The various bases used were fatty, water soluble and emulsion bases. The physical properties of the prepared suppositories were characterized such as weight variation, hardness, disintegration time, melting range and the drug content uniformity. The in vitro release of MT from the prepared suppositories was carried out. The evaluation of the pharmacological effects of MT on the blood pressure and heart rate of the healthy rabbits after the rectal administration compared to the oral tablets was studied. Moreover, the formulation with the highest in vitro release and the highest pharmacological effects would be selected for a further pharmacokinetics study compared to the oral tablets. The results revealed that the emulsion bases gave the highest rate of the drug release than the other bases used. The reduction effect of the emulsion MT suppository base on the blood pressure and heart rate was found to be faster and greater than that administered orally. The selected emulsion suppository base (F11) showed a significant increase in the AUC (1.88-fold) in rabbits as compared to the oral tablets. From the above results we can conclude that rectal route can serve as an efficient alternative route to the oral one for systemic delivery of MT which may be due to the avoidance of first-pass effect in the liver.

Formulation and evaluation of antihyperglycemic leaf extracts of Zizyphus spina-christi (L.) Willd.

PubMed

Nesseem, D I; Michel, C G; Sleem, A A; El-Alfy, T S

2009-02-01

This study deals with the formulation of antihyperglycemic leaf extracts of Zizyphus spina-christi (L.) Willd. A bioactivity guided fractionation of different leaf extracts [defatted ethanol 70% (a), butanol (b), ethanol 70% (c), ethyl acetate (d) and petroleum ether (e) extracts] revealed that extract (c) possessed the highest antihyperglycemic activity followed by (b) and (a). HPLC was adopted for standardization of the extract (c) based on evaluation of the major saponin christinin-A which was used as marker. The detection limit was 9.45 mg/ml for Christinin-A. Extracts (a), (b) and (c) were separately formulated in soft (S) and hard (H) gelatin capsules. Two different formulations (F1 and F2) were tried using different excipients suitable for oral drug delivery. Formula 1, used for soft gelatin capsules [(F1) Sa, Sb, Sc] Formula 2, used for hard gelatin capsules [(F2) - Ha, Hb, Hc]. The recovery rates of the samples of saponin were in the range 99.43-101.86% at 200, 800 microg/ml and 1200 microg/ml. Saponin release rates from different formulae were carried out using dissolution tester USP XXIV. The highest release was obtained from formulation Sc. The release of the extracts followed diffusion mechanism. The selected formula Sc exhibited highest anti-diabetic activity (P < 0.01) on acute and long-term administration and highest saponin release. This formula (Sc) contained poly-oxyethylene (20) cetyl ether (BC-20TX), PEG 400, PEG 6000, purified water, meglyol 810, ascorbic acid and 200 mg of extract (c).

Changes in the dispensing of opioid medications in Canada following the introduction of a tamper-deterrent formulation of long-acting oxycodone: a time series analysis.

PubMed

Gomes, Tara; Mastorakos, Andrea; Paterson, J Michael; Sketris, Ingrid; Caetano, Patricia; Greaves, Simon; Henry, David

2017-11-22

In February 2012, a reformulated tamper-deterrent form of long-acting oxycodone, OxyNeo, was introduced in Canada. We investigated the impact of the introduction of OxyNeo on patterns of opioid prescribing. We conducted population-based, cross-sectional analyses of opioid dispensing in Canada between 2008 and 2016. We estimated monthly community pharmacy dispensing of oral formulations of codeine, morphine, hydromorphone and oxycodone, and a transdermal formulation of fentanyl, and converted quantities to milligrams of morphine equivalents (MMEs) per 1000 population. We used time series analysis to evaluate the effect of the introduction of OxyNeo on these trends. National dispensing of long-acting opioids fell by 14.9% between February 2012 and April 2016, from 36 098 MMEs to 30 716 MMEs per 1000 population ( p < 0.01). This effect varied across Canada and was largest in Ontario (reduction of 22.8%) ( p = 0.01) and British Columbia (reduction of 30.0%) ( p = 0.01). The national rate of oxycodone dispensing fell by 46.4% after the introduction of OxyNeo ( p < 0.001); this was partially offset by an increase of 47.8% in hydromorphone dispensing ( p < 0.001). Although dispensing of immediate-release opioids was a substantial contributor to overall population opioid exposure across Canada, it was unaffected by the introduction of OxyNeo ( p > 0.05 in all provinces). The findings suggest that the introduction of a tamper-deterrent formulation of long-acting oxycodone in Canada, against a background of changing public drug benefits, was associated with sustained changes in selection of long-acting opioids but only small changes in the quantity of long-acting opioids dispensed. This illustrates the limited effect a tamper-deterrent formulation and associated coverage policy can have when other, non-tamper-deterrent alternatives are readily available. Copyright 2017, Joule Inc. or its licensors.

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

PubMed

Mizuno, Yoshikuni; Yamamoto, Mitsutoshi; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Kagimura, Tatsuro; Sarashina, Akiko; Rascol, Olivier; Schapira, Anthony H V; Barone, Paolo; Hauser, Robert A; Poewe, Werner

2012-01-01

To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Study of controlled-release floating tablets of dipyridamole using the dry-coated method.

PubMed

Chen, Kai; Wen, Haoyang; Yang, Feifei; Yu, Yibin; Gai, Xiumei; Wang, Haiying; Li, Pingfei; Pan, Weisan; Yang, Xinggang

2018-01-01

Dipyridamole (DIP), having a short biological half-life, has a narrow absorption window and is primarily absorbed in the stomach. So, the purpose of this study was to prepare controlled-release floating (CRF) tablets of dipyridamole by the dry-coated method. The influence of agents with different viscosity, hydroxypropylmethylcellulose (HPMC) and polyvinylpyrollidon K30 (PVP K30) in the core tablet and low-viscosity HPMC and PVP K30 in the coating layer on drug release, were investigated. Then, a study with a three-factor, three-level orthogonal experimental design was used to optimize the formulation of the CRF tablets. After data processing, the optimized formulation was found to be: 80 mg HPMC K4M in the core tablet, 80 mg HPMC E15 in core tablet and 40 mg PVP K30 in the coating layer. Moreover, an in vitro buoyancy study showed that the optimized formulation had an excellent floating ability and could immediately float without a lag time and this lasted more than 12 h. Furthermore, an in vivo gamma scintigraphic study showed that the gastric residence time of the CRF tablet was about 8 h.

Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery.

PubMed

Patel, Viral; Sharma, Om Prakash; Mehta, Tejal

2018-04-01

Skin is an important route of drug delivery for the treatment of various dermatological conditions. The advent of nanotechnology is paving the roadmaps for topical drug delivery by providing sustained release as well as maintaining a localized effect, outweighing the toxicity concern. Area covered: This review highlighted the morphology of skin, its barrier nature as well as drug penetration pathways after topical application of formulations. The existing methods to improve topical drug delivery, by infringing or permeating the skin barriers, are discussed. This context concretes the foundation to accentuate the need for the development of nanocrystal-based topical formulation. The mechanism of drug release, immediate as well as sustained release, after topical administration of drug nanocrystals is also elaborated. The special emphasis is given on the breakthrough achieved, in topical drug delivery using drug nanocrystals, so far in the plethora of literature, patents, and products, under clinical trial as well as in the market. Expert opinion: The current research on nanocrystals for topical drug delivery is highlighting the breakthroughs achieved so far. The output of these research envisages that topical nanocrystals based formulations can be a novel strategy for the drugs which are facing solubility, bioavailability and toxicity concerns.

Layered nanoemulsions as mucoadhesive buccal systems for controlled delivery of oral cancer therapeutics

PubMed Central

Gavin, Amy; Pham, Jimmy TH; Wang, Dawei; Brownlow, Bill; Elbayoumi, Tamer A

2015-01-01

Oral cavity and oropharyngeal cancers are considered the eighth most common cancer worldwide, with relatively poor prognosis (62% of patients surviving 5 years, after diagnosis). The aim of this study was to develop a proof-of-concept mucoadhesive lozenge/buccal tablet, as a potential platform for direct sustained delivery of therapeutic antimitotic nanomedicines. Our system would serve as an adjuvant therapy for oral cancer patients undergoing full-scale diagnostic and operative treatment plans. We utilized lipid-based nanocarriers, namely nanoemulsions (NEs), containing mixed-polyethoxylated emulsifiers and a tocopheryl moiety–enriched oil phase. Prototype NEs, loaded with the proapoptotic lipophilic drug genistein (Gen), were further processed into buccal tablet formulations. The chitosan polyelectrolyte solution overcoat rendered NE droplets cationic, by acting as a mucoadhesive interfacial NE layer. With approximate size of 110 nm, the positively charged chitosan-layered NE (+25 mV) vs negatively charged chitosan-free/primary aqueous NE (−28 mV) exhibited a controlled-release profile and effective mucoadhesion for liquid oral spray prototypes. When punch-pressed, porous NE-based buccal tablets were physically evaluated for hardness, friability, and swelling in addition to ex vivo tissue mucoadhesion force and retention time measurements. Chitosan-containing NE tablets were found equivalent to primary NE and placebo tablets in compression tests, yet significantly superior in all ex vivo adhesion and in vitro release assays (P≤0.05). Following biocompatibility screening of prototype chitosan-layered NEs, substantial anticancer activity of selected cationic Gen-loaded NE formulations, against two oropahryngeal carcinomas, was observed. The data strongly indicate the potential of such nanomucoadhesive systems as maintenance therapy for oral cancer patients awaiting surgical removal, or postresection of identified cancerous lesions. PMID:25759580

Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy.

PubMed

Cao, Shi-lei; Zhang, Qi-zhi; Jiang, Xin-guo

2007-04-01

To develop a novel, in situ gel system for nasal delivery of scopolamine hydrobromide (SCOP) and study its efficacy on motion sickness. SCOP in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of viscosity, in vitro release, and nasal ciliotoxicity. Single photon emission computing tomography technique was used to evaluate the nasal residence time of gel containing (99m)Tc tracer. The antimotion sickness efficacy produced by the in situ gel formulation was investigated in rats and compared with those achieved after subcutaneous and oral administration. The viscosity of the gellan gum formulations either in solution or in gel increased with increasing concentrations of gellan gum. Its release in vitro was moderate in artificial nasal fluid. The micrographic results showed that in situ gels were safe, without nasal ciliotoxicity. In comparison with phosphate buffer saline, a prolonged radioactivity of (99m)Tc in the rabbit nasal cavity was observed after administration of the gellan gum formulation. Intranasal SCOP in situ gel at a dose of 100 microg/kg decreased symptoms of motion sickness significantly in comparison with subcutaneous and oral administration (P<0.01). SCOP nasal in situ gel is a safe and promising therapeutic alternative to existing medications for motion sickness.

Pharmacokinetics of ivermectin in llamas (Lama glama).

PubMed

Jarvinen, J A; Miller, J A; Oehler, D D

2002-03-16

The pharmacokinetic behaviour of ivermectin was investigated in adult llamas (Lama glama) by using high performance liquid chromatography with a lower limit of quantification of 2 ng/ml to measure its concentration in serum. Llamas were treated with one of three commercial formulations (injectable, pour-on or oral paste) at dosages recommended by the manufacturer, or with an experimental injectable sustained-release formulation. In five llamas given 1 per cent ivermectin subcutaneously at 200 microg/kg, the median peak serum concentration (Cmax) was 3 ng/ml and the area under the serum concentration-time curve (AUC) was 13.5 ng x day/ml. In six llamas treated topically with 0.5 per cent ivermedin pour-on at 500 microg/kg, Cmax was 2.5 ng/ml or less and the AUC was 7.75 ng x day/ml or less. In seven llamas with measurable concentrations of ivermedin, the median times to peak serum concentration (tmax) were six days after subcutaneous injection and seven days after treatment with the pour-on formulation. In six llamas, the serum concentration of ivermectin remained less than 2 ng/ml for 124 hours after treatment with a 1.87 per cent oral paste at 200 microg/kg. In five llamas treated subcutaneously with 25 per cent ivermectin sustained-release microspheres at 1500 microg/kg, the median Cmax was 5 ng/ml and the median AUC was 224 ng x day/ml.

Preparation and Optimization of Immediate Release/Sustained Release Bilayered Tablets of Loxoprofen Using Box-Behnken Design.

PubMed

Tak, Jin Wook; Gupta, Biki; Thapa, Raj Kumar; Woo, Kyu Bong; Kim, Sung Yub; Go, Toe Gyeong; Choi, Yongjoo; Choi, Ju Yeon; Jeong, Jee-Heon; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

2017-05-01

The aim of our current study was to characterize and optimize loxoprofen immediate release (IR)/sustained release (SR) tablet utilizing a three-factor, three-level Box-Behnken design (BBD) combined with a desirability function. The independent factors included ratio of drug in the IR layer to total drug (X 1 ), ratio of HPMC to drug in the SR layer (X 2 ), and ratio of Eudragit RL PO to drug in the SR layer (X 3 ). The dependent variables assessed were % drug released in distilled water at 30 min (Y 1 ), % drug released in pH 1.2 at 2 h (Y 2 ), and % drug released in pH 6.8 at 12 h (Y 3 ). The responses were fitted to suitable models and statistical validation was performed using analysis of variance. In addition, response surface graphs and contour plots were constructed to determine the effects of different factor level combinations on the responses. The optimized loxoprofen IR/SR tablets were successfully prepared with the determined amounts of ingredients that showed close agreement in the predicted and experimental values of tablet characterization and drug dissolution profile. Therefore, BBD can be utilized for successful optimization of loxoprofen IR/SR tablet, which can be regarded as a suitable substitute for the current marketed formulations.

In Vitro Release and Bioavailability of Silybin from Micelle-Templated Porous Calcium Phosphate Microparticles.

PubMed

Zhu, Yuan; Wang, Miaomiao; Zhang, Ya; Zeng, Jin; Omari-Siaw, E; Yu, Jiangnan; Xu, Ximing

2016-10-01

Developing a promising carrier for the delivery of poorly water-soluble drugs, such as silybin, to improve oral absorption has become a very worthy of consideration. The goal of this study was to prepare a novel porous calcium phosphate microparticle using povidone-mixed micelles as template while evaluating its in vitro and in vivo properties with silybin as a model drug. The particle characterization, in vitro drug release behavior, and pharmacokinetic parameters of the prepared silybin-loaded calcium phosphate microparticle were investigated. The mean particle size was found to be 3.54 ± 0.32 μm with a rough surface porous structure. Additionally, the silybin-loaded calcium phosphate microparticle compared with the free silybin showed a prolonged 72-h release in vitro and a higher C max (418.5 ± 23.7 ng mL(-1)) with 167.5% oral relative bioavailability. A level A in vitro-in vivo correlation (IVIVC), established for the first time, demonstrated an excellent IVIVC of the formulated silybin in oral administration. In conclusion, this povidone-mixed micelle-based microparticle was successfully prepared to enhance the oral bioavailability of silybin. Therefore, application of this novel porous calcium phosphate microparticle holds a significant potential for the development of poorly water-soluble drugs.

Controlled-release systemic delivery - a new concept in cancer chemoprevention

PubMed Central

2012-01-01

Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo. PMID:22696595

Montmorillonite nanodevices for the colon metronidazole delivery.

PubMed

Calabrese, Ilaria; Cavallaro, Gennara; Scialabba, Cinzia; Licciardi, Mariano; Merli, Marcello; Sciascia, Luciana; Turco Liveri, Maria Liria

2013-11-30

The adsorption profiles of the antibiotic metronidazole (MNE) into the K10-montmorillonite (MMT-K10) clay and the subsequent release have been investigated as a function of pH and MNE/MMT-K10 ratio, in order to evaluate the potential of the MNE/MMT-K10 hybrids as controlled drug delivery system. The adsorption mechanism has been first elucidated by performing complementary equilibrium and kinetic studies and through the X-ray diffractometry (XRD) characterization of the obtained composite materials. The gathered results allowed us to propose a mechanism consisting of a multi-step pathway involving the neutral and the cationic form of the drug, which interact with different sites of the clay surfaces, i.e. the interlayer region and the faces of the lamella. In a second step the drug release kinetics has been studied under physiological pH mimicking conditions simulating the oral drug administration and delivery. For the sake of comparison the commercial formulation has also been employed for the release studies. The investigation of the release profiles and the comparison with the commercial formulation of the drug reveal that the new-tailor made formulation could be fruitful exploited for successfully prolonged the action of drug in the desired site. Copyright © 2013 Elsevier B.V. All rights reserved.

Characterization of particulate drug delivery systems for oral delivery of Peptide and protein drugs.

PubMed

Christophersen, Philip Carsten; Fano, Mathias; Saaby, Lasse; Yang, Mingshi; Nielsen, Hanne Mørck; Mu, Huiling

2015-01-01

Oral drug delivery is a preferred route because of good patient compliance. However, most peptide/ protein drugs are delivered via parenteral routes because of the absorption barriers in the gastrointestinal (GI) tract such as enzymatic degradation by proteases and low permeability acrossthe biological membranes. To overcome these barriers, different formulation strategies for oral delivery of biomacromolecules have been proposed, including lipid based formulations and polymer-based particulate drug delivery systems (DDS). The aim of this review is to summarize the existing knowledge about oral delivery of peptide/protein drugs and to provide an overview of formulationand characterization strategies. For a better understanding of the challenges in oral delivery of peptide/protein drugs, the composition of GI fluids and the digestion processes of different kinds of excipients in the GI tract are summarized. Additionally, the paper provides an overview of recent studies on characterization of solid drug carriers for peptide/protein drugs, drug distribution in particles, drug release and stability in simulated GI fluids, as well as the absorption of peptide/protein drugs in cell-based models. The use of biorelevant media when applicable can increase the knowledge about the quality of DDS for oral protein delivery. Hopefully, the knowledge provided in this review will aid the establishment of improved biorelevant models capable of forecasting the performance of particulate DDS for oral peptide/protein delivery.

Preparation and Evaluation of Montelukast Sodium Loaded Solid Lipid Nanoparticles

PubMed Central

Priyanka, K; Sathali, A Abdul Hasan

2012-01-01

Solid lipid nanoparticles (SLNs) are an alternative carrier system used to load the drug for targeting, to improve the bioavailability by increasing its solubility, and protecting the drug from presystemic metabolism. The avoidance of presystemic metabolism is due to the nano-metric size range, so that the liver cannot uptake the drug from the delivery system and is not metabolized by the liver. Montelukast sodium is an anti-asthmatic drug, because of its poor oral bioavailability, presystemic metabolism, and decreased half-life; it was chosen to formulate as the solid lipid nanoparticle (SLN) system by hot homogenization followed by an ultrasonication method, to overcome the above. Compritol ATO 888, stearic acid, and glyceryl monostearate were used as a lipid matrix and polyvinyl alcohol as a surfactant. The prepared formulations have been evaluated for entrapment efficiency, drug content, in vitro drug release, particle size analysis, scanning electron microscopy, Fourier transform-infrared studies (FT-IR), differential scanning calorimetry (DSC), and stability. Particle size analysis revealed that the SLN prepared from the higher melting point lipid showed a larger particle size and with increased carbon chain length of the fatty acids. Entrapment efficiency (EE) was ranging from 42% to 92%. In vitro release studies showed maximum cumulative drug release was obtained for F 1 (59.1%) containing stearic acid, and the lowest was observed for F 18 (28.1%) containing compritol ATO 888 after 12 h and all the formulations followed first-order release kinetics. FT-IR and DSC studies revealed no interaction between drug and lipids. Studies showed that increase in lipid concentration, increased particle size, EE, and maintained the sustained release of drug. Among all, compritol ATO 888 was chosen as the best lipid for formulating SLN because it had high EE and sustained the drug release. PMID:23112531

Abuse and Diversion of Immediate Release Opioid Analgesics as Compared to Extended Release Formulations in the United States

PubMed Central

Iwanicki, Janetta L.; Severtson, S. Geoff; McDaniel, Heather; Rosenblum, Andrew; Fong, Chunki; Cicero, Theodore J.; Ellis, Matthew S.; Kurtz, Steven P.; Buttram, Mance E.; Dart, Richard C.

2016-01-01

Background Therapeutic use and abuse of prescription opioids in the United States increased substantially between 1990 and 2010. The Centers for Disease Control estimated deaths related to pharmaceutical opioids reached nearly 19,000 in 2014. Of prescription opioids sold, 10% are extended release (ER) and 90% immediate release (IR). However, most regulations and interventions have focused on decreasing ER abuse. Our objective was to compare rates of abuse and diversion of ER and IR opioid analgesics over time using multiple surveillance programs. Methods Rates of abuse and diversion of ER and IR opioid formulations were compared using data from four surveillance programs in the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS®) System. Data were evaluated from 2009 through 2015, and Poisson regression used to compare IR and ER opioid cases over time. Results From 2009 to 2015, IR opioids were prescribed at a rate 12 to 16 times higher than ER. In the Poison Center Program, population-adjusted rates of Intentional Abuse for IR were 4.6 fold higher than ER opioids (p<0.001). In the Drug Diversion Program, population-adjusted rates of diversion were 6.1 fold higher for IR than ER opioids (p<0.001). In the Opioid Treatment Program, population-adjusted rates of endorsements for abuse were 1.6 fold higher for IR opioids than ER (p = 0.002). In the Survey of Key Informants' Patients Program, population-adjusted rates of endorsements for abuse were 1.5 fold higher for IR opioids than ER (p<0.001). Conclusions Between 2009 and 2015, IR opioids were prescribed at a much higher rate than ER opioids. Results from four surveillance programs show population-adjusted rates of prescription opioid abuse were markedly higher for IR than ER medications. For the greatest public health benefit, future interventions to decrease prescription opioid abuse should focus on both IR and ER formulations. PMID:27936038

Abuse and Diversion of Immediate Release Opioid Analgesics as Compared to Extended Release Formulations in the United States.

PubMed

Iwanicki, Janetta L; Severtson, S Geoff; McDaniel, Heather; Rosenblum, Andrew; Fong, Chunki; Cicero, Theodore J; Ellis, Matthew S; Kurtz, Steven P; Buttram, Mance E; Dart, Richard C

2016-01-01

Therapeutic use and abuse of prescription opioids in the United States increased substantially between 1990 and 2010. The Centers for Disease Control estimated deaths related to pharmaceutical opioids reached nearly 19,000 in 2014. Of prescription opioids sold, 10% are extended release (ER) and 90% immediate release (IR). However, most regulations and interventions have focused on decreasing ER abuse. Our objective was to compare rates of abuse and diversion of ER and IR opioid analgesics over time using multiple surveillance programs. Rates of abuse and diversion of ER and IR opioid formulations were compared using data from four surveillance programs in the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS®) System. Data were evaluated from 2009 through 2015, and Poisson regression used to compare IR and ER opioid cases over time. From 2009 to 2015, IR opioids were prescribed at a rate 12 to 16 times higher than ER. In the Poison Center Program, population-adjusted rates of Intentional Abuse for IR were 4.6 fold higher than ER opioids (p<0.001). In the Drug Diversion Program, population-adjusted rates of diversion were 6.1 fold higher for IR than ER opioids (p<0.001). In the Opioid Treatment Program, population-adjusted rates of endorsements for abuse were 1.6 fold higher for IR opioids than ER (p = 0.002). In the Survey of Key Informants' Patients Program, population-adjusted rates of endorsements for abuse were 1.5 fold higher for IR opioids than ER (p<0.001). Between 2009 and 2015, IR opioids were prescribed at a much higher rate than ER opioids. Results from four surveillance programs show population-adjusted rates of prescription opioid abuse were markedly higher for IR than ER medications. For the greatest public health benefit, future interventions to decrease prescription opioid abuse should focus on both IR and ER formulations.

Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system

PubMed Central

Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

2012-01-01

Background Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. Methods A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. Results The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor® EL:Transcutol® P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. Conclusion The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin. PMID:22403491

Formulation strategy towards minimizing viscosity mediated negative food effect on disintegration and dissolution of immediate release tablets.

PubMed

Zaheer, Kamran; Langguth, Peter

2018-03-01

Food induced viscosity can delay disintegration and subsequent release of API from solid dosage form which may lead to severe reduction in the bioavailability of BCS type III compounds. Formulations of such tablets need to be optimized in view of this postprandial viscosity factor. In this study, three super disintegrants, croscarmellose sodium (CCS), cross-linked polyvinylpolypyrrolidone (CPD), and sodium starch glycolate (SSG) were assessed for their efficiency under simulated fed state. Tablets containing these disintegrants were compressed at 10 and 30 KN, while taking lactose as a soluble filler. In addition to other compendial tests, disintegration force of these formulations was measured by texture analysis. Comparison of parameters derived from force - time curves revealed a direct relation of maximum disintegration force (F max ) and disintegration force development rate (DFDR) with compressional force in fasted state, whereas an inverse relationship of F max and DFDR with compressional force was observed in fed state. The gelling tendency of disintegrants influenced the rate of release of API in simulated fed and fasted states when compressional force was changed. These observations recommend the evaluation of formulations in simulated fed state, in the development stage, with an objective of minimizing the negative impact of food induced viscosity on disintegration. Use of disintegrants that act without gelling or can counteract the effect of gelling is recommended for tablet formulations with reduced disintegration time (DT) and mean dissolution time (MDT) in fed state, respectively.

Enteric protection of naproxen in a fixed-dose combination product produced by hot-melt co-extrusion.

PubMed

Vynckier, A-K; De Beer, M; Monteyne, T; Voorspoels, J; De Beer, T; Remon, J P; Vervaet, C

2015-08-01

In this study hot-melt co-extrusion is used as processing technique to manufacture a fixed-dose combination product providing enteric protection to naproxen incorporated in the core and immediate release to esomeprazole magnesium embedded in the coat. The plasticizing effect of naproxen and triethyl citrate (TEC) was tested on the enteric polymers investigated (Eudragit(®) L100-55, HPMC-AS-LF and HPMCP-HP-50). Core matrix formulations containing HPMC-AS-LF, TEC and a naproxen load of 15, 30 and 50% were processed and characterized. The in vitro naproxen release in 0.1N HCl was prevented for 2h for all formulations. The physicochemical state of the drug in the extrudates was determined and a stability study was performed. Intermolecular interactions between naproxen and polymer were identified using attenuated total reflection Fourier-transform infrared (ATR FT-IR) spectroscopy. When esomeprazole magnesium was formulated in a polyethylene oxide 100K:polyethylene glycol 4K (1:1) matrix, separated from the naproxen-containing layer, the formulation could be easily processed and complete in vitro drug release was observed after 45 min. When co-extruding the core/coat dosage form it was observed that a third layer of polymer, separating the naproxen loaded enteric formulation in the core from the coat, is required to prevent degradation of the acid-labile esomeprazole magnesium at the core/coat interface. Copyright © 2015 Elsevier B.V. All rights reserved.

Oral bioavailability enhancement of raloxifene by developing microemulsion using D-optimal mixture design: optimization and in-vivo pharmacokinetic study.

PubMed

Shah, Nirmal; Seth, Avinashkumar; Balaraman, R; Sailor, Girish; Javia, Ankur; Gohil, Dipti

2018-04-01

The objective of this work was to utilize a potential of microemulsion for the improvement in oral bioavailability of raloxifene hydrochloride, a BCS class-II drug with 2% bioavailability. Drug-loaded microemulsion was prepared by water titration method using Capmul MCM C8, Tween 20, and Polyethylene glycol 400 as oil, surfactant, and co-surfactant respectively. The pseudo-ternary phase diagram was constructed between oil and surfactants mixture to obtain appropriate components and their concentration ranges that result in large existence area of microemulsion. D-optimal mixture design was utilized as a statistical tool for optimization of microemulsion considering oil, S mix , and water as independent variables with percentage transmittance and globule size as dependent variables. The optimized formulation showed 100 ± 0.1% transmittance and 17.85 ± 2.78 nm globule size which was identically equal with the predicted values of dependent variables given by the design expert software. The optimized microemulsion showed pronounced enhancement in release rate compared to plain drug suspension following diffusion controlled release mechanism by the Higuchi model. The formulation showed zeta potential of value -5.88 ± 1.14 mV that imparts good stability to drug loaded microemulsion dispersion. Surface morphology study with transmission electron microscope showed discrete spherical nano sized globules with smooth surface. In-vivo pharmacokinetic study of optimized microemulsion formulation in Wistar rats showed 4.29-fold enhancements in bioavailability. Stability study showed adequate results for various parameters checked up to six months. These results reveal the potential of microemulsion for significant improvement in oral bioavailability of poorly soluble raloxifene hydrochloride.

Controlled release systems containing solid dispersions: strategies and mechanisms.

PubMed

Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Park, Jun Bom; Lee, Beom-Jin

2011-10-01

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.

Novel Pharmacokinetic-Pharmacodynamic Model for Prediction of Outcomes with an Extended-Release Formulation of Ciprofloxacin

PubMed Central

Meagher, Alison K.; Forrest, Alan; Dalhoff, Axel; Stass, Heino; Schentag, Jerome J.

2004-01-01

The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared to that of the immediate-release (IR) product in healthy volunteers. The only significant difference in pharmacokinetic parameters between the two formulations was seen in the rate constant of absorption, which was approximately 50% greater with the IR formulation. The geometric mean plasma ciprofloxacin concentrations were applied to an in vitro pharmacokinetic-pharmacodynamic model exposing three different clinical strains of Escherichia coli (MICs, 0.03, 0.5, and 2.0 mg/liter) to 24 h of simulated concentrations in plasma. A novel mathematical model was derived to describe the time course of bacterial CFU, including capacity-limited replication and first-order rate of bacterial clearance, and to model the effects of ciprofloxacin concentrations on these processes. A “mixture model” was employed which allowed as many as three bacterial subpopulations to describe the total bacterial load at any moment. Comparing the two formulations at equivalent daily doses, the rates and extents of bacterial killing were similar with the IR and XR formulations at MICs of 0.03 and 2.0 mg/liter. At an MIC of 0.5 mg/liter, however, the 1,000-mg/day XR formulation showed a moderate advantage in antibacterial effect: the area under the CFU-time curve was 45% higher for the IR regimen; the nadir log CFU and 24-h log CFU values for the IR regimen were 3.75 and 2.49, respectively; and those for XR were 4.54 and 3.13, respectively. The mathematical model explained the differences in bacterial killing rate for two regimens with identical AUC/MIC ratios. PMID:15155200

Salbutamol sulfate suppositories: influence of formulation on physical parameters and stability.

PubMed

Taha, Ehab I; Zaghloul, Abdel-Azim A; Kassem, Alaa A; Khan, Mansoor A

2003-01-01

To prepare and evaluate a suppository dosage form of salbutamol sulfate. The prepared formulae with and without different concentrations of gels were tested for hardness, melting time, content uniformity, and drug release. The stability of some of the selected formulae was assessed. Salbutamol sulfate was formulated as a rectal suppository with emulsifying fatty bases (suppocire and witepsol) and water-soluble bases (PEG) adopting the molding from a melt technique. Physical characteristics and dissolution profiles of the prepared formulations were determined as the responses. The effects of adding gels, methyl cellulose (MC), and Eudispert (Eud) and their concentrations (1, 3, and 6%) on these responses were also investigated. Formulations showing high rank order were scaled up for shelf-life stability study for one year. The results showed that all the investigated formulae have acceptable physical characteristics with respect to hardness, melting time (except F7), and uniformity of drug content. The amount of drug dissolved in 100 min of dissolution time was inversely affected by the melting point of the fatty base. The release from PEG bases was found to be molecular weight dependent. Addition of 1% MC or Eud gel increased the release from all the investigated formulae. Increasing gel concentration to 3% then to 6% showed different effects on the release. The degradation of salbutamol sulfate in the investigated formulae was found to be a first-order reaction. Rectal suppository of salbutamol sulfate could be prepared as an alternative to the oral dosage form to circumvent the first-pass metabolism.

Plasma concentrations of remoxipride and the gastrointestinal transit of 111In-marked extended-release coated spheres

DOE Office of Scientific and Technical Information (OSTI.GOV)

Graffner, C.; Wagner, Z.; Nilsson, M.I.

1990-01-01

To explore the oral absorption of remoxipride, spheres of remoxipride were labeled with indium-111 colloid before coating with a release-controlling ethylcellulose membrane. Since the labeling remained inside the coating, it was suitable as a marker. Eight healthy volunteers were given a single dose of 100 mg remoxipride in 111In-marked spheres as a multiple-unit capsule. The radioactivity and the position of the spheres (microcapsules) were followed externally for 30 hr by gamma scintigraphy. Parallel to this, plasma concentrations were drawn for 48 hr to confirm the extended dissolution and absorption of remoxipride. The hard gelatin, multiple-unit capsule released the microcapsules withinmore » the stomach. These were then rapidly emptied into the small intestine, within 0.5-1 hr. There was then an immediate distribution in the upper small intestine before collection in the lower portion, within 2-5 hr. After passing into the large intestine, there was again extended distribution of the microcapsules. A mean Cmax of 2.7 microM remoxipride was achieved 4 hr after drug administration and a mean AUC of 26.1 mumol.L-1.hr was achieved. Judging from the absorption versus time profile, calculated according to the Wagner-Nelson method, and the scintigraphic images, it is concluded that the main absorption occurs from the small intestine. Data from four volunteers, however, indicated a comparatively good absorption also from the large intestine. Due to the good absorption properties, it is reasonable to expect a low variation in the extent of bioavailability of remoxipride after administration in an extended-release, multiple-unit capsule formulation.« less

Bifunctional capsular dosage form: novel fanicular cylindrical gastroretentive system of clarithromycin and immediate release granules of ranitidine HCl for simultaneous delivery.

PubMed

Rajput, Pallavi; Singh, Deshvir; Pathak, Kamla

2014-01-30

The study was aimed to develop a bifunctional single unit capsular system containing gastroretentive funicular cylindrical system (FCS) for controlled local delivery of clarithromycin and immediate release of ranitidine HCl. A 2(3) full factorial design was used to prepare gastroretentive FCS of clarithromycin using polyacrylamide (PAM), HPMC E15LV and Carbopol 934 P. The FCSs were evaluated for % cumulative drug release, floating time and in vitro detachment stress. Among the eight formulations, FCS5 (containing PAM and Carbopol 934 P at high and HPMC E15LV at low levels) showed % cumulative drug release of 97.09±1.14% in 8 h, floating time of 3 h and detachment stress of 8303.64±0.34 dynes/cm(2). Evaluation of optimized FCS by novel dynamic in vitro test proved superior bioadhesivity than cylindrical system under aggressive simulated peristaltic activity. Magnetic resonance imaging elucidated zero order release via constant swelling and erosion of FCS5. In vitro permeability across gastric mucin ensured its potential for effective eradication of deep seated Helicobactor pylori in gastric linings. The optimized FCS was combined with immediate release granules of rantidine HCl to get a bifunctional capsular dosage form. In vitro simultaneous drug release of clarithromycin and rantidine estimated by Vierordt's method exhibited a controlled drug release of 97.72±0.4% in 8 h for clarithromycin through FCS5 and 98.8±1.2% in 60 min from IR granules of ranitidine HCl. The novel system thus established its capability of simultaneous variable delivery of acid suppression agent and macrolide antibiotic that can be advantageous in clinical setting. Copyright © 2013 Elsevier B.V. All rights reserved.

Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets.

PubMed

Arafat, Basel; Wojsz, Magdalena; Isreb, Abdullah; Forbes, Robert T; Isreb, Mohammad; Ahmed, Waqar; Arafat, Tawfiq; Alhnan, Mohamed A

2018-06-15

Fused deposition modelling (FDM) 3D printing has shown the most immediate potential for on-demand dose personalisation to suit particular patient's needs. However, FDM 3D printing often involves employing a relatively large molecular weight thermoplastic polymer and results in extended release pattern. It is therefore essential to fast-track drug release from the 3D printed objects. This work employed an innovative design approach of tablets with unique built-in gaps (Gaplets) with the aim of accelerating drug release. The novel tablet design is composed of 9 repeating units (blocks) connected with 3 bridges to allow the generation of 8 gaps. The impact of size of the block, the number of bridges and the spacing between different blocks was investigated. Increasing the inter-block space reduced mechanical resistance of the unit, however, tablets continued to meet pharmacopeial standards for friability. Upon introduction into gastric medium, the 1 mm spaces gaplet broke into mini-structures within 4 min and met the USP criteria of immediate release products (86.7% drug release at 30 min). Real-time ultraviolet (UV) imaging indicated that the cellulosic matrix expanded due to swelling of hydroxypropyl cellulose (HPC) upon introduction to the dissolution medium. This was followed by a steady erosion of the polymeric matrix at a rate of 8 μm/min. The design approach was more efficient than a comparison conventional formulation approach of adding disintegrants to accelerate tablet disintegration and drug release. This work provides a novel example where computer-aided design was instrumental at modifying the performance of solid dosage forms. Such an example may serve as the foundation for a new generation of dosage forms with complicated geometric structures to achieve functionality that is usually achieved by a sophisticated formulation approach. Copyright © 2018 Elsevier B.V. All rights reserved.

Ganciclovir. A pharmacoeconomic review of its use as intravenous or oral maintenance therapy in the management of cytomegalovirus retinitis in patients with AIDS.

PubMed

Perry, C M; Davis, R

1997-08-01

Cytomegalovirus retinitis, an opportunistic infection caused by the herpesvirus cytomegalovirus, is a major cause of illness in patients with advanced AIDS. As infected patients require long term drug treatment to delay disease progression and minimise loss of vision, the disease is associated with substantial treatment costs which considerably increase overall expenditure on AIDS-related health care. During the last decade, intravenous ganciclovir has been a mainstay of treatment for patients with cytomegalovirus retinitis. However, notwithstanding its demonstrated efficacy as maintenance therapy for this condition, long term intravenous drug administration is both inconvenient and uncomfortable for many patients. Moreover, neutropenia and catheter-related infections have been reported commonly in patients receiving ganciclovir via the intravenous route. To overcome the limitations of intravenous ganciclovir, an oral formulation of the drug has been developed for use as maintenance therapy. In comparative clinical trials, both intravenous and oral ganciclovir maintenance therapy slowed disease progression and preserved visual acuity in patients with stabilised cytomegalo-virus retinitis, although there was evidence that the intravenous formulation was more effective in terms of delaying recurrence of active disease. This suggests that oral ganciclovir use should be limited to the treatment of patients without evidence of immediately sight-threatening cytomegalovirus retinitis. Three published cost analyses, which were based on efficacy and tolerability data derived from 2 randomised, comparative clinical trials, have shown that oral ganciclovir maintenance therapy offers cost advantages over intravenous maintenance therapy, despite the higher acquisition cost of the oral formulation. The higher overall costs of intravenous maintenance treatment, compared with oral therapy, were attributed to higher drug administration and adverse event treatment costs. In one analysis, estimated lifetime treatment costs of oral maintenance therapy were 25.2% lower than those of intravenous maintenance treatment. As yet, no formal cost-effectiveness evaluations of oral and intravenous ganciclovir have been published. Few published data are available regarding the relative effects of intravenous and oral ganciclovir on quality of life. However, in a health state utility analysis, there was a large overall preference among HIV-infected individuals for oral over intravenous maintenance treatment. In conclusion, oral ganciclovir appears to be a cost-saving and patient-preferred alternative to its intravenous counterpart for the maintenance therapy of AIDS patients with stabilised cytomegalovirus retinitis in whom there is no evidence of sight-threatening disease.

Formulation, optimization and characterization of cationic polymeric nanoparticles of mast cell stabilizing agent using the Box-Behnken experimental design.

PubMed

Gajra, Balaram; Patel, Ravi R; Dalwadi, Chintan

2016-01-01

The present research work was intended to develop and optimize sustained release of biodegradable chitosan nanoparticles (CSNPs) as delivery vehicle for sodium cromoglicate (SCG) using the circumscribed Box-Behnken experimental design (BBD) and evaluate its potential for oral permeability enhancement. The 3-factor, 3-level BBD was employed to investigate the combined influence of formulation variables on particle size and entrapment efficiency (%EE) of SCG-CSNPs prepared by ionic gelation method. The generated polynomial equation was validated and desirability function was utilized for optimization. Optimized SCG-CSNPs were evaluated for physicochemical, morphological, in-vitro characterizations and permeability enhancement potential by ex-vivo and uptake study using CLSM. SCG-CSNPs exhibited particle size of 200.4 ± 4.06 nm and %EE of 62.68 ± 2.4% with unimodal size distribution having cationic, spherical, smooth surface. Physicochemical and in-vitro characterization revealed existence of SCG in amorphous form inside CSNPs without interaction and showed sustained release profile. Ex-vivo and uptake study showed the permeability enhancement potential of CSNPs. The developed SCG-CSNPs can be considered as promising delivery strategy with respect to improved permeability and sustained drug release, proving importance of CSNPs as potential oral delivery system for treatment of allergic rhinitis. Hence, further studies should be performed for establishing the pharmacokinetic potential of the CSNPs.

Chitosan-based nano-in-microparticle carriers for enhanced oral delivery and anticancer activity of propolis.

PubMed

Elbaz, Nancy M; Khalil, Islam A; Abd-Rabou, Ahmed A; El-Sherbiny, Ibrahim M

2016-11-01

This study reports a promising approach to enhance the oral delivery of propolis, improve its aqueous solubility and bioavailability, and allow its controlled release as well as enhancing its anticancer activity. Propolis was standardized then its solubility was improved via formulation into optimized solid dispersion (SD) matrices, and its release was controlled through incorporation into nanoparticles (NPs) of optimized composition followed by further inclusion into chitosan (Cs) microparticles. The anticancer activity of the newly developed propolis-loaded nano-in-microparticles (NIMs) was evaluated against human liver cancer (HepG2) and human colorectal cancer (HCT 116) cells. The prepared SDs, NPs and NIMs were characterized using SEM, TEM, DLS, FTIR, DSC and UV-vis spectrophotometry. The therapeutic efficiency of formulated propolis was bio-assessed via cytotoxicity measurements, mitochondrial dysfunction, apoptosis-induced cell death and cell cycle arrest. The results demonstrated a considerable enhancement in propolis solubility with a controlled release profile in different GIT environments. In-vitro cytotoxicity studies showed that the propolis-loaded NIMs induce more cytotoxic effect on HepG2 cells than HCT-116 cells and mediated three-fold higher therapeutic efficiency than free propolis. The apoptosis assay indicated that the propolis-loaded NIMs induce apoptosis of HepG2 cells and significantly decrease their number in the proliferative G0/G1, S and G2/M phases. Copyright © 2016 Elsevier B.V. All rights reserved.

Chitosan-doxycycline hydrogel: An MMP inhibitor/sclerosing embolizing agent as a new approach to endoleak prevention and treatment after endovascular aneurysm repair.

PubMed

Zehtabi, Fatemeh; Ispas-Szabo, Pompilia; Djerir, Djahida; Sivakumaran, Lojan; Annabi, Borhane; Soulez, Gilles; Mateescu, Mircea Alexandru; Lerouge, Sophie

2017-12-01

The success of endovascular repair of abdominal aortic aneurysms remains limited due to the development of endoleaks. Sac embolization has been proposed to manage endoleaks, but current embolizing materials are associated with frequent recurrence. An injectable agent that combines vascular occlusion and sclerosing properties has demonstrated promise for the treatment of endoleaks. Moreover, the inhibition of aneurysmal wall degradation via matrix metalloproteinases (MMPs) may further prevent aneurysm progression. Thus, an embolization agent that promotes occlusion, MMP inhibition and endothelial ablation was hypothesized to provide a multi-faceted approach for endoleak treatment. In this study, an injectable, occlusive chitosan (CH) hydrogel containing doxycycline (DOX)-a sclerosant and MMP inhibitor-was developed. Several CH-DOX hydrogel formulations were characterized for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo. All formulations were injectable and gelled rapidly at body temperature. Only hydrogels prepared with 0.075M sodium bicarbonate and 0.08M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel was in a two-stage pattern: a burst release followed by a slow continuous release. Released DOX was bioactive and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appear to be promising new multifunctional embolic agents for the treatment of endoleaks. An injectable embolizing chitosan hydrogel releasing doxycycline (DOX) was developed as the first multi-faceted approach for the occlusion of blood vessels. It combines occlusive properties with DOX sclerosing and MMP inhibition properties, respectively known to prevent recanalization process and to counteract the underlying pathophysiology of vessel wall degradation and aneurysm progression. After drug release, the biocompatible scaffold can be invaded by cells and slowly degrade. Local DOX delivery requires lower drug amount and decreases risks of side effects compared to systemic administration. This new gel could be used for the prevention or treatment of endoleaks after endovascular aneurysm repair, but also for the embolization of other blood vessels such as venous or vascular malformations. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Generic products of antiepileptic drugs: a perspective on bioequivalence, bioavailability, and formulation switches using Monte Carlo simulations.

PubMed

Karalis, Vangelis; Macheras, Panos; Bialer, Meir

2014-01-01

Generic products of antiepileptic drugs (AEDs) are currently a controversial topic as neurologists and patients are reluctant to switch from brand products to generics and to switch between generics. The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products. Monte Carlo simulations of the classic 2 × 2 BE studies were performed to study the effect of sample size, within-subject variability, and the true difference in pharmacokinetic values of the products under comparison on BE acceptance of generic AED products. Simulations were extended to study the comparative performance of two generic AED products against the same innovative product. The simulated results are compared with literature data on AEDs. The question with regard to bioavailability (BA) is whether two formulations are different, while for BE the question is whether two formulations are sufficiently similar in terms of extent and rate of absorption. Therefore, the criteria for BA and BE and the statistical analysis involved in their analysis are different. Two generic formulations that meet regulatory approval requirements for generics by being bioequivalent to the same innovative AED may not be bioequivalent to one another and therefore should not be regarded as equal or as therapeutically equivalent products. A switch from a standard or an immediate-release formulation to a modified-release product, which comprises extended-release or delayed-release formulations, should not be regarded as a switch between generics, but rather as a switch between different formulation types. Switches between bioequivalent generic AED products could potentially lead to larger changes in plasma levels and exposure than the brand-to-generic switch. The simulation work verified the clinical findings that not all generic AED products bioequivalent to the same innovative product are bioequivalent to one another. Two generic formulations that meet regulatory approval requirements for generics, by being bioequivalent to the innovative AED, may not be bioequivalent to one another. Additional BE criteria are needed for a formulation switch, particularly in epilepsy, where a breakthrough seizure may change a patient's status from seizure-free to refractory.

Enhanced Oral Bioavailability of Efavirenz by Solid Lipid Nanoparticles: In Vitro Drug Release and Pharmacokinetics Studies

PubMed Central

Gaur, Praveen Kumar; Mishra, Shikha; Bajpai, Meenakshi; Mishra, Anushika

2014-01-01

Solid lipid nanoparticle is an efficient lipid based drug delivery system which can enhance the bioavailability of poorly water soluble drugs. Efavirenz is a highly lipophilic drug from nonnucleoside inhibitor category for treatment of HIV. Present work illustrates development of an SLN formulation for Efavirenz with increased bioavailability. At first, suitable lipid component and surfactant were chosen. SLNs were prepared and analyzed for physical parameters, stability, and pharmacokinetic profile. Efavirenz loaded SLNs were formulated using Glyceryl monostearate as main lipid and Tween 80 as surfactant. ESLN-3 has shown mean particle size of 124.5 ± 3.2 nm with a PDI value of 0.234, negative zeta potential, and 86% drug entrapment. In vitro drug release study has shown 60.6–98.22% drug release in 24 h by various SLN formulations. Optimized SLNs have shown good stability at 40°C ± 2°C and 75 ± 5% relative humidity (RH) for 180 days. ESLN-3 exhibited 5.32-fold increase in peak plasma concentration (C max⁡) and 10.98-fold increase in AUC in comparison to Efavirenz suspension (ES). PMID:24967360

Concanavalin A conjugated biodegradable nanoparticles for oral insulin delivery

NASA Astrophysics Data System (ADS)

Hurkat, Pooja; Jain, Aviral; Jain, Ashish; Shilpi, Satish; Gulbake, Arvind; Jain, Sanjay K.

2012-11-01

Major research issues in oral protein delivery include the stabilization of protein in delivery devices which could increase its oral bioavailability. The study deals with development of oral insulin delivery system utilizing biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and modifying its surface with Concanavalin A to increase lymphatic uptake. Surface-modified PLGA nanoparticles were characterized for conjugation efficiency of ligand, shape and surface morphology, particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro drug release. Stability of insulin in the developed formulation was confirmed by SDS-PAGE, and integrity of entrapped insulin was assessed using circular dichroism spectrum. Ex vivo study was performed on Wistar rats, which exhibited the higher intestinal uptake of Con A conjugated nanoparticles. In vivo study performed on streptozotocin-induced diabetic rats which indicate that a surface-modified nanoparticle reduces blood glucose level effectively within 4 h of its oral administration. In conclusion, the present work resulted in successful production of Con A NPs bearing insulin with sustained release profile, and better absorption and stability. The Con A NPs showed high insulin uptake, due to its relative high affinity for non-reducing carbohydrate residues i.e., fucose present on M cells and have the potential for oral insulin delivery in effective management of Type 1 diabetes condition.

Innovation of natural essential oil-loaded Orabase for local treatment of oral candidiasis

PubMed Central

Labib, Gihan S; Aldawsari, Hibah

2015-01-01

Purpose Oral candidiasis may be manifested in the oral cavity as either mild or severe oral fungal infection. This infection results from the overgrowth of Candida species normally existing in the oral cavity in minute amounts based on many predisposing factors. Several aspects have spurred the search for new strategies in the treatment of oral candidiasis, among which are the limited numbers of new antifungal drugs developed in recent years. Previous studies have shown that thyme and clove oils have antimycotic activities and have suggested their incorporation into pharmaceutical preparations. This study aimed to investigate the possibility of the incorporation and characterization of essential oils or their extracted active ingredients in Orabase formulations. Methods Orabase loaded with clove oil, thyme oil, eugenol, and thymol were prepared and evaluated for their antifungal activities, pH, viscosity, erosion and water uptake characteristics, mechanical properties, in vitro release behavior, and ex vivo mucoadhesion properties. Results All prepared bases showed considerable antifungal activity and acceptable physical characteristics. The release pattern from loaded bases was considerably slow for all oils and active ingredients. All bases showed appreciable adhesion in the in vitro and ex vivo studies. Conclusion The incorporation of essential oils in Orabase could help in future drug delivery design, with promising outcomes on patients’ well-being. PMID:26170621

Innovation of natural essential oil-loaded Orabase for local treatment of oral candidiasis.

PubMed

Labib, Gihan S; Aldawsari, Hibah

2015-01-01

Oral candidiasis may be manifested in the oral cavity as either mild or severe oral fungal infection. This infection results from the overgrowth of Candida species normally existing in the oral cavity in minute amounts based on many predisposing factors. Several aspects have spurred the search for new strategies in the treatment of oral candidiasis, among which are the limited numbers of new antifungal drugs developed in recent years. Previous studies have shown that thyme and clove oils have antimycotic activities and have suggested their incorporation into pharmaceutical preparations. This study aimed to investigate the possibility of the incorporation and characterization of essential oils or their extracted active ingredients in Orabase formulations. Orabase loaded with clove oil, thyme oil, eugenol, and thymol were prepared and evaluated for their antifungal activities, pH, viscosity, erosion and water uptake characteristics, mechanical properties, in vitro release behavior, and ex vivo mucoadhesion properties. All prepared bases showed considerable antifungal activity and acceptable physical characteristics. The release pattern from loaded bases was considerably slow for all oils and active ingredients. All bases showed appreciable adhesion in the in vitro and ex vivo studies. The incorporation of essential oils in Orabase could help in future drug delivery design, with promising outcomes on patients' well-being.

Evaluation of a novel vaginal bromocriptine mesylate formulation: a pilot study.

PubMed

Darwish, Atef M; Hafez, Ehsan; El-Gebali, Ibraheem; Hassan, Saher B

2005-04-01

Because of the frequent side effects found with oral bromocriptine, we created two formulas of vaginal bromocriptine suppositories to compare with vaginal application of bromocriptine tablets. The formula containing bromocriptine and a releasing agent (Pluronic F127) showed an increased dissolution rate, 39-fold greater than that of the pure drug alone, and subsequently was effective in lowering serum prolactin.

Progressive cholinergic decline in Alzheimer's Disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology.

PubMed

Sabbagh, Marwan; Cummings, Jeffrey

2011-02-07

Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d) donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) versus the immediate-release formulation (3 hours), and higher daily concentrations. Herein, we review (1) the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2) the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3) recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease.

Influence of dissolution media pH and USP1 basket speed on erosion and disintegration characteristics of immediate release metformin hydrochloride tablets.

PubMed

Desai, Divyakant; Wong, Benjamin; Huang, Yande; Tang, Dan; Hemenway, Jeffrey; Paruchuri, Srinivasa; Guo, Hang; Hsieh, Daniel; Timmins, Peter

2015-01-01

To investigate the influence of the pH of the dissolution medium on immediate release 850 mg metformin hydrochloride tablets. A traditional wet granulation method was used to manufacture metformin hydrochloride tablets with or without a disintegrant. Tablet dissolution was conducted using the USP apparatus I at 100 rpm. In spite of its pH-independent high solubility, metformin hydrochloride tablets dissolved significantly slower in 0.1 N HCl (pH 1.2) and 50 mM pH 4.5 acetate buffer compared with 50 mM pH 6.8 phosphate buffer, the dissolution medium in the USP. Metformin hydrochloride API compressed into a round 1200 mg disk showed a similar trend. When basket rotation speed was increased from 100 to 250 rpm, the dissolution of metformin hydrochloride tablets was similar in all three media. Incorporation of 2% w/w crospovidone in the tablet formulation improved the dissolution although the pH-dependent trend was still evident, but incorporation of 2% w/w croscarmellose sodium resulted in rapid pH-independent tablet dissolution. In absence of a disintegrant in the tablet formulation, the dissolution was governed by the erosion-diffusion process. Even for a highly soluble drug, a super-disintegrant was needed in the formulation to overcome the diffusion layer limitation and change the dissolution mechanism from erosion-diffusion to disintegration.

Duloxetine loaded-microemulsion system to improve behavioral activities by upregulating serotonin and norepinephrine in brain for the treatment of depression.

PubMed

Sindhu, Pardeep; Kumar, Shobhit; Iqbal, Babar; Ali, Javed; Baboota, Sanjula

2018-04-01

Duloxetine is a well-known antidepressant molecule which is used in the treatment of depression but due to poor solubility it suffers with the drawback of low oral bioavailability. The objective of present work was to formulate and characterize duloxetine loaded microemulsion to enhance the oral bioavailability. Prepared microemulsion was studied for droplet size, zeta potential, refractive index, polydispersity index (PDI), percentage transmittance, viscosity and in vitro release study. Optimized microemulsion (D1) showed spherical droplets with mean diameter of 35.40 ± 3.11 nm, PDI of 0.170 and zeta potential values of -25.8 mV. Formulation showed good transmittance (greater than 99%), viscosity (0.205 Pa s) and refractive index (1.43 ± 0.01). Increased duloxetine release was obtained with microemulsion in comparison to drug suspension. Behavioral tests like mobility test, tail suspension test and forced swimming test performed in depressed and treated rats with duloxetine microemulsion significantly improved the behavioral activities in comparison to duloxetine suspension. Pharmacokinetic studies showed that microemulsion exhibited 1.8 times increment in bioavailability in comparison to duloxetine suspension. Copyright © 2018 Elsevier Ltd. All rights reserved.

Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations.

PubMed

Sferrazza, Gianluca; Siviero, Paolo D; Nicotera, Giuseppe; Turella, Paola; Serafino, Annalucia; Blandizzi, Corrado; Pierimarchi, Pasquale

2017-09-01

Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice. Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence. Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs.

Relative bioavailability of single doses of prolonged-release tacrolimus administered as a suspension, orally or via a nasogastric tube, compared with intact capsules: a phase 1 study in healthy participants.

PubMed

Undre, Nasrullah; Dickinson, James

2017-04-04

Tacrolimus, an immunosuppressant widely used in solid organ transplantation, is available as a prolonged-release capsule for once-daily oral administration. In the immediate postsurgical period, if patients cannot take intact capsules orally, tacrolimus therapy is often initiated as a suspension of the capsule contents, delivered orally or via a nasogastric tube. This study evaluated the relative bioavailability of prolonged-release tacrolimus suspension versus intact capsules in healthy participants. A phase 1, open-label, single-dose, cross-over study. A single clinical research unit. In total, 20 male participants, 18-55 years old, entered and completed the study. All participants received nasogastric administration of tacrolimus 10 mg suspension in treatment period 1, with randomisation to oral administration of suspension or intact capsules in periods 2 and 3. Blood concentration-time profile over 144 hours was used to estimate pharmacokinetic parameters. Primary end point: relative bioavailability of prolonged-release intact capsule versus oral or nasogastric administration of prolonged-release tacrolimus suspension (area under the concentration-time curve (AUC) from time 0 to infinity post-tacrolimus dose (AUC 0-∞ ); AUC measured until the last quantifiable concentration (AUC 0-tz ); maximum observed concentration (C max ); time to C max (T max )). Tolerability was assessed throughout the study. Relative bioavailability of prolonged-release tacrolimus suspension administered orally was similar to intact capsules, with a ratio of least-square means for AUC 0-tz and AUC 0-∞ of 1.05 (90% CI 0.96 to 1.14). Bioavailability was lower with suspension administered via a nasogastric tube versus intact capsules (17%; ratio 0.83; CI 0.76 to 0.92). C max was higher for oral and nasogastric suspension (30% and 28%, respectively), and median T max was shorter (difference 1.0 and 1.5 hours postdose, respectively) versus intact capsules (2.0 hours). Single 10 mg doses of tacrolimus were well tolerated. Compared with intact capsules, the rate of absorption of prolonged-release tacrolimus from suspension was faster, leading to higher peak blood concentrations and shorter time to peak; relative bioavailability was similar with suspension administered orally. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Sustained release biodegradable solid lipid microparticles: Formulation, evaluation and statistical optimization by response surface methodology.

PubMed

Hanif, Muhammad; Khan, Hafeez Ullah; Afzal, Samina; Mahmood, Asif; Maheen, Safirah; Afzal, Khurram; Iqbal, Nabila; Andleeb, Mehwish; Abbas, Nazar

2017-12-20

For preparing nebivolol loaded solid lipid microparticles (SLMs) by the solvent evaporation microencapsulation process from carnauba wax and glyceryl monostearate, central composite design was used to study the impact of independent variables on yield (Y1), entrapment efficiency (Y2) and drug release (Y3). SLMs having a 10-40 μm size range, with good rheological behavior and spherical smooth surfaces, were produced. Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffractometry pointed to compatibility between formulation components and the zeta-potential study confirmed better stability due to the presence of negative charge (-20 to -40 mV). The obtained outcomes for Y1 (29-86 %), Y2 (45-83 %) and Y3 (49-86 %) were analyzed by polynomial equations and the suggested quadratic model were validated. Nebivolol release from SLMs at pH 1.2 and 6.8 was significantly (p < 0.05) affected by lipid concentration. The release mechanism followed Higuchi and zero order models, while n > 0.85 value (Korsmeyer- Peppas) suggested slow erosion along with diffusion. The optimized SLMs have the potential to improve nebivolol oral bioavailability.

Safety and clinical effectiveness of a compounded sustained-release formulation of buprenorphine for postoperative analgesia in New Zealand White rabbits.

PubMed

DiVincenti, Louis; Meirelles, Luiz A D; Westcott, Robin A

2016-04-01

To determine the clinical effectiveness and safety of a compounded sustained-release formulation of buprenorphine, compared with effects of regular buprenorphine, for postoperative analgesia in rabbits. Blinded randomized controlled clinical trial. 24 purpose-bred adult male New Zealand White rabbits. Rabbits received titanium implants in each tibia as part of another study. Immediately prior to surgery, each rabbit received regular buprenorphine hydrochloride (0.02 mg/kg [0.009 mg/lb], SC, q 12 h for 3 days) or 1 dose of a compounded sustained-release formulation of buprenorphine (0.12 mg/kg [0.055 mg/lb], SC) followed by an equal volume of saline (0.9% NaCl) solution (SC, q 12 h for 3 days) after surgery. For 7 days after surgery, rabbits were evaluated for signs of pain by means of rabbit grimace and activity scoring and for adverse effects. No significant differences were identified between treatment groups in grimace and activity scores at any point. No major adverse effects were detected for either drug. However, 3 rabbits that received regular buprenorphine had pain scores suggestive of moderate to severe pain by the time dose administration was due (ie, within the 12-hour administration interval). No clinically important differences were detected in intraoperative anesthetic or postoperative recovery variables. Sustained-release buprenorphine administered SC at 0.12 mg/kg was at least as effective as regular buprenorphine in providing analgesia for rabbits following orthopedic surgery without any major adverse effects. This sustained-release formulation represents an important alternative for rabbit analgesia with potential to improve rabbit welfare over existing analgesic standards.

Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery systems (SMEDDSs) for oral delivery of aciclovir.

PubMed

Janković, Jovana; Djekic, Ljiljana; Dobričić, Vladimir; Primorac, Marija

2016-01-30

The study investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides) (10%), surfactant (Labrasol(®), polysorbate 20, or Kolliphor(®) RH40), cosurfactant (Plurol(®) Oleique CC 497) (q.s. ad 100%), and cosolvent (glycerol or macrogol 400) (20% or 30%), and evaluate their potential as carriers for oral delivery of a poorly permeable antivirotic aciclovir (acyclovir). The drug loading capacity of the prepared formulations ranged from 0.18-31.66 mg/ml. Among a total of 60 formulations, three formulations meet the limits for average droplet size (Z-ave) and polydispersity index (PdI) that have been set for SMEDDSs (Z-ave≤100nm, PdI<0.250) upon spontaneous dispersion in 0.1M HCl and phosphate buffer pH 7.2. SMEDDSs with the highest aciclovir loading capacity (24.06 mg/ml and 21.12 mg/ml) provided the in vitro drug release rates of 0.325 mg cm(-2)min(-1) and 0.323 mg cm(-2)min(-1), respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. The results revealed that development of SMEDDSs with enhanced drug loading capacity and oral delivery potential, required optimization of hydrophilic ingredients, in terms of size of hydrophilic moiety of the surfactant, surfactant-to-cosurfactant mass ratio (Km), and log P of the cosolvent. Copyright © 2015 Elsevier B.V. All rights reserved.

Influence of surfactants in self-microemulsifying formulations on enhancing oral bioavailability of oxyresveratrol: Studies in Caco-2 cells and in vivo.

PubMed

Sangsen, Yaowaporn; Wiwattanawongsa, Kamonthip; Likhitwitayawuid, Kittisak; Sritularak, Boonchoo; Graidist, Potchanapond; Wiwattanapatapee, Ruedeekorn

2016-02-10

Self-microemulsifying drug delivery systems (SMEDDS) containing two types (Tween80 and Labrasol) and two levels (low; 5% and high; 15%) of co-surfactants were formulated to evaluate the impact of surfactant phase on physical properties and oral absorption of oxyresveratrol (OXY). All formulations showed a very rapid release in the simulated gastric fluid (SGF) pH 1.2. After dilution with different media, the microemulsion droplet sizes of the Tween80-based (∼26 to 36 nm) were smaller than that of the Labrasol-based systems (∼34 to 45 nm). Both systems with high levels of surfactant increased the Caco-2 cells permeability of OXY compared to those with low levels of surfactant (1.4-1.7 folds) and the unformulated OXY (1.9-2.0 folds). It was of interest, that there was a reduction (4.4-5.3 folds) in the efflux transport of OXY from both systems compared to the unformulated OXY. The results were in good agreement with the in vivo absorption studies of such OXY-formulations in rats. Significantly greater values of Cmax and AUC(0-10h) (p<0.05) were obtained from the high levels of Tween80-based (F(r,0-10h) 786.32%) compared to those from the Labrasol-based system (F(r,0-10h) 218.32%). These finding indicate the importance of formulation variables such as type and quantity of surfactant in the SMEDDS to enhance oral drug bioavailability. Copyright © 2015 Elsevier B.V. All rights reserved.

The increasing role of monoamine oxidase type B inhibitors in Parkinson's disease therapy.

PubMed

Elmer, Lawrence W; Bertoni, John M

2008-11-01

The role of monoamine oxidase type B inhibitors in the treatment of Parkinson's disease has expanded with the new monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets. As primary therapy in early disease monoamine oxidase B inhibitors reduce motor disability and delay the need for levodopa. In more advanced disease requiring levodopa, adjunctive monoamine oxidase B inhibitors reduce 'off' time and may improve gait and freezing. Rasagiline and selegiline oral disintegrating tablets may reduce the safety risks associated with the amfetamine and methamfetamine metabolites of conventional oral selegiline while retaining or improving therapeutic efficacy. Articles were identified by searches of PubMed and searches on the Internet and reviewed. All articles and other referenced materials were retrieved using the keywords 'Parkinson's disease', 'treatment' and 'monoamine oxidase B inhibitor' and were published between 1960 and 2007, with older references selected for historical significance. Only papers published in English were reviewed. Accumulating data support the use of monoamine oxidase B inhibitors as monotherapy for early and mild Parkinson's disease and as adjunctive therapy for more advanced Parkinson's disease with levodopa-associated motor fluctuations. The recently released monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets, have potential advantages over conventional oral selegiline.

Formulation of medicines for children

PubMed Central

Nunn, Tony; Williams, Julie

2005-01-01

The development of age-adapted dosage forms and taste-masking of bitter-tasting drugs administered orally for children, are formidable challenges for formulation scientists. Childhood is a period of maturation requiring knowledge of developmental pharmacology to establish dose but the ability of the child to manage different dosage forms and devices also changes. Paediatric formulations must allow accurate administration of the dose to children of widely varying age and weight. Whilst the oral route will be preferred for long term use and the intravenous route for the acutely ill, many of the dosage forms designed for adults, such as oro-dispersible tablets, buccal gels and transdermal patches, would also benefit children if they contained an appropriate paediatric dose. The age at which children can swallow conventional tablets is of great importance for their safety. Liquid medicines are usually recommended for infants and younger dhildren so the ability to mask unpleasant taste with sweeteners and flavours is crucial. More sophisticated formulations such as granules and oro-dispersible tablets may be required but there will be limitations on choice and concentration of excipients. There are many gaps in our knowledge about paediatric formulations and many challenges for the industry if suitable preparations are to be available for all ranges. A CHMP points to consider document is soon to be released. More research and clinical feedback are important because a formulation with poor acceptability may affect compliance, prescribing practice and ultimately commercial viability. PMID:15948931

Histamine release inhibitory activity of Piper nigrum leaf.

PubMed

Hirata, Noriko; Naruto, Shunsuke; Inaba, Kazunori; Itoh, Kimihisa; Tokunaga, Masashi; Iinuma, Munekazu; Matsuda, Hideaki

2008-10-01

Oral administration of a methanolic extract of Piper nigrum leaf (PN-ext, 50, 200 and 500 mg/kg) showed a potent dose-dependent inhibition of dinitrofluorobenzene (DNFB)-induced cutaneous reaction at 1 h [immediate phase response (IPR)] after and 24 h [late phase response (LPR)] after DNFB challenge in mice which were passively sensitized with anti-dinitrophenyl (DNP) IgE antibody. Ear swelling inhibitory effect of PN-ext (50, 200 and 500 mg/kg, per os (p.o.)) on very late phase response (vLPR) in the model mice was significant but weaker than that on IPR. Oral administration of PN-ext (50, 200 and 500 mg/kg for 7 d) inhibited picryl chloride (PC)-induced ear swelling in PC sensitized mice. PN-ext exhibited in vitro inhibitory effect on compound 48/80-induced histamine release from rat peritoneal mast cells. Two lignans of PN-ext, (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2), were identified as major active principles having histamine release inhibitory activity.

Oral delivery system prolongs blood circulation of docetaxel nanocapsules via lymphatic absorption

PubMed Central

Attili-Qadri, Suha; Karra, Nour; Nemirovski, Alina; Schwob, Ouri; Talmon, Yeshayahu; Nassar, Taher; Benita, Simon

2013-01-01

An original oral formulation of docetaxel nanocapsules (NCs) embedded in microparticles elicited in rats a higher bioavailability compared with the i.v. administration of the commercial docetaxel solution, Taxotere. In the present study, various animal studies were designed to elucidate the absorption process of docetaxel from such a delivery system. Again, the docetaxel NC formulation elicited a marked enhanced absorption compared with oral Taxotere in minipigs, resulting in relative bioavailability and Cmax values 10- and 8.4-fold higher, respectively, confirming the previous rat study results. It was revealed that orally absorbed NCs altered the elimination and distribution of docetaxel, as shown in the organ biodistribution rat study, due to their reinforced coating, while transiting through the enterocytes by surface adsorption of apoproteins and phospholipids. These findings were demonstrated by the cryogenic-temperature transmission electron microscopy results and confirmed by the use of a chylomicron flow blocker, cycloheximide, that prevented the oral absorption of docetaxel from the NC formulation in an independent pharmacokinetic study. The lipoproteinated NCs reduced the docetaxel release in plasma and its distribution among the organs. The improved anticancer activity compared with i.v. Taxotere, observed in the metastatic lung cancer model in Severe Combined Immune Deficiency-beige (SCID-bg) mice, should be attributed to the extravasation effect, leading to the lipoproteinated NC accumulation in lung tumors, where they exert a significant therapeutic action. To the best of our knowledge, no study has reported that the absorption of NCs was mediated by a lymphatic process and reinforced during their transit. PMID:24101508

Liposomal lidocaine gel for topical use at the oral mucosa: characterization, in vitro assays and in vivo anesthetic efficacy in humans.

PubMed

Franz-Montan, Michelle; Baroni, Daniela; Brunetto, Giovana; Sobral, Viviane Roberta Vieira; da Silva, Camila Morais Gonçalves; Venâncio, Paulo; Zago, Patricia Wiziack; Cereda, Cintia Maria Saia; Volpato, Maria Cristina; de Araújo, Daniele Ribeiro; de Paula, Eneida; Groppo, Francisco Carlos

2015-03-01

To characterize liposomal-lidocaine formulations for topical use on oral mucosa and to compare their in vitro permeation and in vivo anesthetic efficacy with commercially available lidocaine formulations. Large unilamellar liposomes (400 nm) containing lidocaine were prepared using phosphatidylcholine, cholesterol, and α-tocoferol (4:3:0.07, w:w:w) and were characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and in vitro release. In vitro permeation across pig palatal mucosa and in vivo topical anesthetic efficacy on the palatal mucosa in healthy volunteers (double-blinded cross-over, placebo controlled study) were performed. The following formulations were tested: liposome-encapsulated 5% lidocaine (Liposome-Lido5); liposome-encapsulated 2.5% lidocaine (Liposome-Lido2.5); 5% lidocaine ointment (Xylocaina®), and eutectic mixture of lidocaine and prilocaine 2.5% (EMLA®). The Liposome-Lido5 and EMLA showed the best in vitro permeation parameters (flux and permeability coefficient) in comparison with Xylocaina and placebo groups, as well as the best in vivo topical anesthetic efficacy. We successfully developed and characterized a liposome encapsulated 5% lidocaine gel. It could be considered an option to other topical anesthetic agents for oral mucosa.

Bioequivalence of Oral Products and the Biopharmaceutics Classification System: Science, Regulation, and Public Policy

PubMed Central

Amidon, KS; Langguth, P; Lennernäs, H; Yu, L; Amidon, GL

2011-01-01

The demonstration of bioequivalence (BE) is an essential requirement for ensuring that patients receive a product that performs as indicated by the label. The BE standard for a particular product is set by its innovator, and this standard must subsequently be matched by generic drug products. The Biopharmaceutics Classification System (BCS) sets a scientific basis for an improved BE standard for immediate-release solid oral dosage forms. In this paper, we discuss BE and the BCS, as well as the issues that are currently relevant to BE as a pharmaceutical product standard. PMID:21775984

3D-micro-patterned fibrous dosage forms for immediate drug release.

PubMed

Blaesi, Aron H; Saka, Nannaji

2018-03-01

At present, the most prevalent pharmaceutical dosage forms, the orally-delivered immediate-release tablets and capsules, are porous, granular solids. They disintegrate into their constituent particulates upon ingestion to release drug rapidly. The design, development, and manufacture of such granular solids, however, is inefficient due to difficulties associated with the unpredictable inter-particle interactions. Therefore, to achieve more predictable dosage form properties and processing, we have recently introduced melt-processed polymeric cellular dosage forms. The cellular forms disintegrated and released drug rapidly if the cells were predominantly interconnected. Preparation of interconnected cells, however, relies on the coalescence of gas bubbles in the melt, which is unpredictable. In the present work, therefore, new melt-processed fibrous dosage forms with contiguous void space are presented. The dosage forms are prepared by melt extrusion of the drug-excipient mixture followed by patterning the fibrous extrudate on a moving surface. It is demonstrated that the resulting fibrous structures are fully predictable by the extruder nozzle diameter and the motion of the surface. Furthermore, drug release experiments show that the disintegration time of the fibrous forms prepared in this work is of the order of that of the corresponding single fibers. The thin fibers of polyethylene glycol (excipient) and acetaminophen (drug) in turn disintegrate in a time proportional to the fiber radius and well within immediate-release specification. Finally, models of dosage form disintegration and drug release by single fibers and fibrous dosage forms are developed. It is found that drug release from fibrous forms is predictable by the physico-chemical properties of the excipient and such microstructural parameters as the fiber radius, the inter-fiber spacing, and the volume fraction of water-soluble excipient in the fibers. Copyright © 2017 Elsevier B.V. All rights reserved.

Synchronous delivery of felodipine and metoprolol tartrate using monolithic osmotic pump technology.

PubMed

Zhao, Shiqing; Yu, Fanglin; Liu, Nan; Di, Zhong; Yan, Kun; Liu, Yan; Li, Ying; Zhang, Hui; Yang, Yang; Yang, Zhenbo; Li, Zhiping; Mei, Xingguo

2016-11-01

The synchronous sustained-release of two drugs was desired urgently for patients needing combination therapy in long term. However, sophisticated technologies were used generally to realize the simultaneous delivery of two drugs especially those with different physico-chemical properties. The purpose of this study was to obtain the concurrent release of felodipine and metoprolol tartrate, two drugs with completely different solubilities, in a simple monolithic osmotic pump system (FMOP). Two types of blocking agents were used in monolithic osmotic pump tablets and the synchronous sustained-release of FMOP was acquired in vitro. The tablets were also administered to beagle dogs and the plasma levels of FMOP were determined by HPLC-MS/MS. The pharmacokinetic parameters were calculated using a non-compartmental model. Cmax of both felodipine and metoprolol from the osmotic pump tablets were lower, tmax and mean residence time of both felodipine and metoprolol from the osmotic pump tablets were longer significantly than those from immediate release tablets. These results verified prolonged release of felodipine and metoprolol tartrate from osmotic pump formulations. The similar absorption rate between felodipine and metoprolol in beagles was also obtained by this osmotic pump formulation. Therefore, it could be supposed that the accordant release of two drugs with completely different solubilities may be realized just by using monolithic osmotic pump technology.

Pharmacokinetics of colon-specific pH and time-dependent flurbiprofen tablets.

PubMed

Vemula, Sateesh Kumar; Veerareddy, Prabhakar Reddy; Devadasu, Venkat Ratnam

2015-09-01

Present research deals with the development of compression-coated flurbiprofen colon-targeted tablets to retard the drug release in the upper gastro intestinal system, but progressively release the drug in the colon. Flurbiprofen core tablets were prepared by direct compression method and were compression coated using sodium alginate and Eudragit S100. The formulation is optimized based on the in vitro drug release study and further evaluated by X-ray imaging and pharmacokinetic studies in healthy humans for colonic delivery. The optimized formulation showed negligible drug release (4.33 ± 0.06 %) in the initial lag period followed by progressive release (100.78 ± 0.64 %) for 24 h. The X-ray imaging in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. The C max of colon-targeted tablets was 12,374.67 ng/ml at T max 10 h, where as in case of immediate release tablets the C max was 15,677.52 ng/ml at T max 3 h, that signifies the ability of compression-coated tablets to target the colon. Development of compression-coated tablets using combination of time-dependent and pH-sensitive approaches was suitable to target the flurbiprofen to colon.

Poly(2-ethyl-2-oxazoline) as matrix excipient for drug formulation by hot melt extrusion and injection molding.

PubMed

Claeys, Bart; Vervaeck, Anouk; Vervaet, Chris; Remon, Jean Paul; Hoogenboom, Richard; De Geest, Bruno G

2012-10-15

Here we evaluate poly(2-ethyl-2-oxazoline)s (PEtOx) as a matrix excipient for the production of oral solid dosage forms by hot melt extrusion (HME) followed by injection molding (IM). Using metoprolol tartrate as a good water-soluble model drug we demonstrate that drug release can be delayed by HME/IM, with the release rate controlled by the molecular weight of the PEtOx. Using fenofibrate as a lipophilic model drug we demonstrate that relative to the pure drug the dissolution rate is strongly enhanced by formulation in HME/IM tablets. For both drug molecules we find that solid solutions, i.e. molecularly dissolved drug in a polymeric matrix, are obtained by HME/IM. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Formulation design of an HPMC-based sustained release tablet for pyridostigmine bromide as a highly hygroscopic model drug and its in vivo/in vitro dissolution properties.

PubMed

Huang, Yuh-Tyng; Tsai, Tong-Rong; Cheng, Chun-Jen; Cham, Thau-Ming; Lai, Tsun-Fwu; Chuo, Wen-Ho

2007-11-01

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2(3) full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T(max) was prolonged (from 0.65 +/- 0.082 hr to 4.83 +/- 1.60 hr) and AUC(0-t) (from 734.88 +/- 230.68 ng/ml.hr to 1153.34 +/- 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.

Formulation, development, and evaluation of floating pulsatile drug delivery system of atenolol.

PubMed

Jagdale, Swati C; Sali, Monali S; Barhate, Ajay L; Kuchekar, Bhanudas S; Chabukswar, Aniruddha R

2013-01-01

The objective of this work was to develop and evaluate a floating-pulsatile drug delivery of atenolol. The floating-pulsatile concept was applied to increase the gastric residence of the dosage form by having lag phase followed by a burst release. The system was generated which consisted of three different parts: a core tablet, containing the active ingredient; an erodible outer shell; and a top cover buoyant layer. The dry, coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with hydroxypropyl methylcellulose (HPMC) K100 M, citric acid, and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their physical properties in vitro release as well as in vivo behavior. The results showed that K3 (180 mg of HPMC K4 M) and K6 (290 mg of HPMC E15 LV) with a buoyant layer were the best formulation, with lag times of 5.2 ± 0.1 h and 4.1 ± 0.2 h, respectively. Floating time was controlled by the quantity and composition of the buoyant layer. In-vitro results point out the capability of the system with its prolonged residence of the tablets in the stomach and release of drug after a programmed lag time. This was confirmed by in vivo x-ray technique. The objective of the present work was to develop a floating-pulsatile oral drug delivery system of atenolol with addition of hydroxylpropyl methylcellulose (HPMC) K100 M, HPMC K4 M, and HPMC E15 LV in different ratios with citric acid and sodium bicarbonate as gas-forming agents. The system consist of three different parts: a core tablet, containing the active ingredient; a bottom layer that erodes; and a top cover floating layer. Atenolol, a β-blocker, is prescribed widely in diverse cardiovascular diseases, for example, hypertension, angina pectoris, arrhythmias, and myocardial infarction. Developed formulations were evaluated for their physical properties and vitro release as well as in vivo behavior. The results showed that K3 (180 mg HPMC K4 M) and K6 (290 mg of HPMC E15 LV) with a buoyant layer were the best formulations with the lag times of 5.2 ± 0.1 h and 4.1 ± 0.2 h, respectively, and were found to be the best choice for manufacturing tablets.

Dual-coating of liposomes as encapsulating matrix of antimicrobial peptides: Development and characterization

NASA Astrophysics Data System (ADS)

Gomaa, Ahmed I.; Martinent, Cynthia; Hammami, Riadh; Fliss, Ismail; Subirade, Muriel

2017-11-01

Abstract Antimicrobial peptides have been proposed as a potential biopreservatives in pharmaceutical research and agribusiness. However, many limitations hinder their utilization, such as their vulnerability to proteolytic digestion and their potential interaction with other food ingredients in complex food systems. One approach to overcome such problems is developing formulations entrapping and thereby protecting the antimicrobial peptides. Liposome encapsulation is a strategy that could be implemented to combine protection of the antimicrobial activity of the peptides from proteolytic enzymes and the controlled release of the encapsulated active ingredients. The objective of this study was to develop dual-coated food grade liposome formulations for oral administration of bacteriocins. The formulations were developed from anionic and cationic phospholipids as models of negatively and positively charged liposomes, respectively. Liposomes were prepared by the hydration of lipid films. Subsequently, the liposomes were coated with two layers comprising a biopolymer network (pectin) and whey proteins (WPI) in order to further improve their stability and enable the gradual release of the developed liposomes. Liposomes were characterized for their size, charge, molecular structure, morphology, encapsulation efficiency and release. The results of FTIR, zeta potential, size distribution and transmission electron microscopy confirmed that the liposomes were efficiently coated. Ionic interactions were involved in the stabilization of the positively charged liposome formulations. Negatively charge liposome formulations were stabilized through weak interactions. The release study proved the efficiency of dual coating on the protection of liposomes against gastrointestinal digestion. This work is the first to study the encapsulation of antimicrobial peptides in dual-coated liposomes. Furthermore, the work successfully encapsulated MccJ25 in both negative and positive liposome models.

Dissolution enhancement of atorvastatin calcium by co-grinding technique.

PubMed

Prabhu, Priyanka; Patravale, Vandana

2016-08-01

Atorvastatin calcium (AC) is a BCS class II drug which shows poor bioavailability due to inadequate dissolution. Solid dispersions present a promising option to enhance the solubility of poorly soluble drugs. Co-grinding with hydrophilic excipients is an easy and economical technique to improve the solubility of poorly soluble drugs and is free from usage of organic solvents. The aim of the present study was to explore novel carrier VBP-1 (organosulphur compound) for formulating a solid dispersion by using a simple, commercially viable co-grinding technique to enhance the dissolution of AC and to develop an oral formulation of the same. Composition of the solid dispersion was optimized based on the release profile in pH 1.2 buffer. The optimized solid dispersion was further characterized for flow properties, DSC, FTIR spectroscopy, XRD, contact angle, SEM studies and release profile in phosphate buffer pH 6.8. The developed solid dispersion gave similar release profile as the innovator formulation (Lipitor® tablets) in both pH 1.2 buffer and phosphate buffer pH 6.8. The developed solid dispersion was formulated into hard gelatin capsules (size 3). The developed capsules were found to give similar release as the innovator formulation in both pH 1.2 buffer and phosphate buffer pH 6.8. The developed capsules were found to be stable for a period of 6 months. Anti-hyperlipidemic efficacy studies in rats showed higher reduction in cholesterol and triglyceride levels by the developed capsules in comparison to pure AC. In conclusion, novel carrier VBP-1 was successfully employed to enhance the dissolution of AC using co-grinding technique.

Gastroretentive Ranitidine Hydrochloride Tablets with Combined Floating and Bioadhesive Properties: Factorial Design Analysis, In Vitro Evaluation and In Vivo Abdominal X-Ray Imaging.

PubMed

Abduljabbar, Hana N; Badr-Eldin, Shaimaa M; Aldawsari, Hibah M

2015-01-01

Ranitidine HCl is an H2-antagonist that suffers from low oral bioavailability of 50%. The site-specific absorption from the upper part of the small intestine and the colonic metabolism of the drug could partially contribute to its reduced bioavailability. To surmount these drawbacks, this work aimed at the formulation of Ranitidine HCl gastroretentive floating-biaodhesive tablets. A 3(2) factorial design was applied to assess the effects of matrix former (HPMC K100M): drug ratio, and the release retardant (Carbopol 971) amount on the characteristics of the tablets prepared using direct compression technique. The prepared tablets were thoroughly evaluated for physical properties, floating, swelling, bioadhesive and in vitro release behaviors. Statistical analysis of the results revealed significant effects for both formulation variables on the swelling index, maximum detachment force and cumulative percent drug released after 6 hours. In addition, the matrix- former: drug ratio showed a statistically significant effect on the floating lag time. Kinetic analysis of the release data indicated Higuchi diffusion kinetics and anomalous transport mechanism for all formulations. Scanning electron micrographs of the selected tablet formulation; F8, revealed intact surface without any perforations or channels in the dry state, while polymer expansion (relaxation) with some perforated areas were observed on the surface of the tablets after 12 hours dissolution in 0.1 N HCl. Furthermore, in vivo abdominal x-ray imaging showed good floating behavior of the selected formulation; F8, for up to 6 hours with appropriate bioadhesive property. In conclusion, the selected ranitidine HCl floating-bioadhesive tablets could be regarded as a promising gastroretentive drug delivery system that could deliver the drug at a controlled rate.

Formulation Optimization of Human Insulin Loaded Microspheres for Controlled Oral Delivery Using Response Surface Methodology.

PubMed

Agrawal, Gauravkuma; Wakte, Pravin; Shelke, Santosh

2017-01-01

The objectives of the present investigation were to prepare recombinant human insulin entrapped Eudragit-S100 microspheres containing protease inhibitors and to precisely analyze the outcome of different formulation variables on the microspheres properties using a response surface methodology to develop an optimized formulation with desirable features. A central composite design was employed to produce microspheres of therapeutic protein by w/o/w multiple emulsion solvent evaporation technique using Eudragit S-100 as coating material and polyvinyl alcohol as a stabilizer. The effect of formulation variables (independent variables) that is levels of Eudragit S-100 (X1), therapeutic protein (X2), volumes of inner aqueous phase (X3) and external aqueous phase (X4) on dependant variables, that are encapsulation efficiency (Y1), drug release at pH 1.2 after 2 h (Y2) and drug release at pH 7.4 after of 2 h (Y3) were evaluated. The significant terms in the mathematical models were generated for each response parameter using multiple linear regression analysis and analysis of variance. All the formulation variables except the volume of external aqueous phase (X4) exerted a significant effect (P <0.05) on drug encapsulation efficiency (Y1) whereas first two variables, namely the levels of Eudragit S-100 (X1) and therapeutic protein (X2) materialized as the determining factors which significantly influenced drug release at pH 1.2 after 2 h (Y2) and drug release at pH 7.4 after of 2 h (Y3). The formulation was numerically optimized by framing the constraints on the dependent and independent variables using the desirability approach. The experimental values for Y1 and Y2 of optimized formulation were found to be 77.65% and 3.64%, respectively which were quite closer to results suggested by software. The results recorded indicate that the recombinant human insulin loaded Eudragit S-100 microspheres containing aprotinin have the benefits of higher loading efficiency, pH responsive and prolonged release characteristics, which may help to carry insulin to the optimum site of absorption. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

BPA qualtitative and quantitative assessment associated with orthodontic bonding in vivo.

PubMed

Kloukos, Dimitrios; Sifakakis, Iosif; Voutsa, Dimitra; Doulis, Ioannis; Eliades, George; Katsaros, Christos; Eliades, Theodore

2015-08-01

To assess the in vivo amount of BPA released from a visible light-cured orthodontic adhesive, immediately after bracket bonding. 20 orthodontic patients were recruited after obtaining informed consent. All patients received 24 orthodontic brackets in both dental arches. In Group A (11 patients), 25 ml of tap water were used for mouth rinsing, whereas in Group B (9 patients) a simulated mouth rinse formulation was used: a mixture of 20 ml de-ionized water plus 5 ml absolute ethanol. Rinsing solutions were collected before, immediately after placing the orthodontic appliances and after washing out the oral cavity and were then stored in glass tubes. Rinsing was performed in a single phase for 60s with the entire volume of each liquid. The BPA analysis was performed by gas chromatography-mass spectrometry. An increase in BPA concentration immediately after the 1st post-bonding rinse was observed, for both rinsing media, which was reduced after the 2nd post-bonding rinse. Water exhibited higher levels of BPA concentration than water/ethanol after 1st and 2nd post-bonding rinses. Two-way mixed Repeated Measures ANOVA showed that the primary null hypothesis declaring mean BPA concentration to be equal across rinsing medium and rinsing status was rejected (p-value <0.001). The main effects of the rinsing medium and status, as well as their interaction were found to be statistically significant (p-values 0.048, <0.001 and 0.011 respectively). A significant pattern of increase of BPA concentration, followed by a decrease that reached the initial values was observed. The amount of BPA was relatively low and far below the reference limits of tolerable daily intake. Copyright © 2015. Published by Elsevier Ltd.

Do nitrates differ?

PubMed Central

Fung, H.-L.

1992-01-01

1 The organic nitrates all share a common biochemical and physiological mechanism of action. 2 The organic nitrates differ substantially in their pharmacologic potency and pharmacokinetics. In vitro potency differences appear larger than the corresponding in vivo activities. 3 The duration of action of organic nitrates, after a single immediate-release dose, is governed by the pharmacokinetics of the drug. However, the duration of action of available sustained-release preparations, whatever the nitrate or formulation, is limited to about 12 h, due to the development of pharmacologic tolerance. 4 Nitrates do not appear to differ in their production of undesirable effects. PMID:1633079

Drug release and swelling kinetics of directly compressed glipizide sustained-release matrices: establishment of level A IVIVC.

PubMed

Sankalia, Jolly M; Sankalia, Mayur G; Mashru, Rajashree C

2008-07-02

The purpose of this study was to examine a level A in vitro-in vivo correlation (IVIVC) for glipizide hydrophilic sustained-release matrices, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. The effect of polymeric blends of ethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500, and lactose on in vitro release profiles was studied and fitted to various release kinetics models. Water uptake kinetics with scanning electron microscopy (SEM) was carried out to support the drug release mechanism. An IVIVC was established by comparing the pharmacokinetic parameters of optimized (M-24) and marketed (Glytop-2.5 SR) formulations after single oral dose studies on white albino rabbits. The matrix M-19 (xanthan:MCC PH301 at 70:40) and M-24 (xanthan:HPMC K4M:Starch 1500 at 70:25:15) showed the glipizide release within the predetermined constraints at all time points with Korsmeyer-Peppas' and zero-order release mechanism, respectively. Kopcha model revealed that the xanthan gum is the major excipient responsible for the diffusional release profile and was further supported by SEM and swelling studies. A significant level A IVIVC with acceptable limits of prediction errors (below 15%) enables the prediction of in vivo performance from their in vitro release profile. It was concluded that proper selection of rate-controlling polymers with release rate modifier excipients will determine overall release profile, duration and mechanism from directly compressed matrices.

Development of Bilayer Tablets with Modified Release of Selected Incompatible Drugs.

PubMed

Dhiman, Neha; Awasthi, Rajendra; Jindal, Shammy; Khatri, Smriti; Dua, Kamal

2016-01-01

The oral route is considered to be the most convenient and commonly-employed route for drug delivery. When two incompatible drugs need to be administered at the same time and in a single formulation, bilayer tablets are the most appropriate dosage form to administer such incompatible drugs in a single dose. The aim of the present investigation was to develop bilayered tablets of two incompatible drugs; telmisartan and simvastatin. The bilayer tablets were prepared containing telmisartan in a conventional release layer using croscarmellose sodium as a super disintegrant and simvastatin in a slow-release layer using HPMC K15M, Carbopol 934P and PVP K 30 as matrix forming polymers. The tablets were evaluated for various physical properties, drug-excipient interactions using FTIR spectroscopy and in vitro drug release using 0.1M HCl (pH 1.2) for the first hour and phosphate buffer (pH 6.8) for the remaining period of time. The release kinetics of simvastatin from the slow release layer were evaluated using the zero order, first order, Higuchi equation and Peppas equation. All the physical parameters (such as hardness, thickness, disintegration, friability and layer separation tests) were found to be satisfactory. The FTIR studies indicated the absence of interactions between the components within the individual layers, suggesting drug-excipient compatibility in all the formulations. No drug release from the slow-release layer was observed during the first hour of the dissolution study in 0.1M HCl. The release-controlling polymers had a significant effect on the release of simvastatin from the slow-release layer. Thus, the formulated bilayer tablets avoided incompatibility issues and proved the conventional release of telmisartan (85% in 45 min) and slow release of simvastatin (80% in 8 h). Stable and compatible bilayer tablets containing telmisartan and simvastatin were developed with better patient compliance as an alternative to existing conventional dosage forms.