High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation.

PubMed

Sakai, Kenichi; Obata, Kouki; Yoshikawa, Mayumi; Takano, Ryusuke; Shibata, Masaki; Maeda, Hiroyuki; Mizutani, Akihiko; Terada, Katsuhide

2012-10-01

To design a high drug loading formulation of self-microemulsifying/micelle system. A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400 = 8:2 was selected, and achieved the target loading level (200 mg/mL). The formulation formed fine emulsion/micelle (49.1 nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.

Neonates need tailored drug formulations.

PubMed

Allegaert, Karel

2013-02-08

Drugs are very strong tools used to improve outcome in neonates. Despite this fact and in contrast to tailored perfusion equipment, incubators or ventilators for neonates, we still commonly use drug formulations initially developed for adults. We would like to make the point that drug formulations given to neonates need to be tailored for this age group. Besides the obvious need to search for active compounds that take the pathophysiology of the newborn into account, this includes the dosage and formulation. The dosage or concentration should facilitate the administration of low amounts and be flexible since clearance is lower in neonates with additional extensive between-individual variability. Formulations need to be tailored for dosage variability in the low ranges and also to the clinical characteristics of neonates. A specific focus of interest during neonatal drug development therefore is a need to quantify and limit excipient exposure based on the available knowledge of their safety or toxicity. Until such tailored vials and formulations become available, compounding practices for drug formulations in neonates should be evaluated to guarantee the correct dosing, product stability and safety.

Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye.

PubMed

Loftsson, Thorsteinn; Stefánsson, Einar

2002-04-01

Cyclodextrins are cylindrical oligosaccharides with a lipophilic central cavity and hydrophilic outer surface. They can form water-soluble complexes with lipophilic drugs, which 'hide' in the cavity. Cyclodextrins can be used to form aqueous eye drop solutions with lipophilic drugs, such as steroids and some carbonic anhydrase inhibitors. The cyclodextrins increase the water solubility of the drug, enhance drug absorption into the eye, improve aqueous stability and reduce local irritation. Cyclodextrins are useful excipients in eye drop formulations of various drugs, including steroids of any kind, carbonic anhydrase inhibitors, pilocarpine, cyclosporins, etc. Their use in ophthalmology has already begun and is likely to expand the selection of drugs available as eye drops. In this paper we review the properties of cyclodextrins and their application in eye drop formulations, of which their use in the formulation of dexamethasone eye drops is an example. Cyclodextrins have been used to formulate eye drops containing corticosteroids, such as dexamethasone, with levels of concentration and ocular absorption which, according to human and animal studies, are many times those seen with presently available formulations. Cyclodextrin-based dexamethasone eye drops are well tolerated in the eye and seem to provide a higher degree of bioavailability and clinical efficiency than the steroid eye drop formulations presently available. Such formulations offer the possibility of once per day application of corticosteroid eye drops after eye surgery, and more intensive topical steroid treatment in severe inflammation. While cyclodextrins have been known for more than a century, their use in ophthalmology is just starting. Cyclodextrins are useful excipients in eye drop formulations for a variety of lipophilic drugs. They will facilitate eye drop formulations for drugs that otherwise might not be available for topical use, while improving absorption and stability and decreasing local irritation.

Studies on a novel doughnut-shaped minitablet for intraocular drug delivery.

PubMed

Choonara, Yahya E; Pillay, Viness; Carmichael, Trevor; Danckwerts, Michael P

2007-12-28

The objective of this study was to evaluate the effect of 2 independent formulation variables on the drug release from a novel doughnut-shaped minitablet (DSMT) in order to optimize formulations for intraocular drug delivery. Formulations were based on a 3(2) full-factorial design. The 2 independent variables were the concentration of Resomer (% wt/wt) and the type of Resomer grade (RG502, RG503, and RG504), respectively. The evaluated response was the drug release rate constant computed from a referenced marketed product and in vitro drug release data obtained at pH 7.4 in simulated vitreous humor. DSMT devices were prepared containing either of 2 model drugs, ganciclovir or foscarnet, using a Manesty F3 tableting press fitted with a novel central-rod, punch, and die setup. Dissolution data revealed biphasic drug release behavior with 55% to 60% drug released over 120 days. The inherent viscosity of the various Resomer grades and the concentration were significant to achieve optimum release rate constants. Using the resultant statistical relationships with the release rate constant as a response, the optimum formulation predicted for devices formulated with foscarnet was 70% wt/wt of Resomer RG504, while 92% wt/wt of Resomer RG503 was ideal for devices formulated with ganciclovir. The results of this study revealed that the full-factorial design was a suitable tool to predict an optimized formulation for prolonged intraocular drug delivery.

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.

Nanocrystal for ocular drug delivery: hope or hype.

PubMed

Sharma, Om Prakash; Patel, Viral; Mehta, Tejal

2016-08-01

The complexity of the structure and nature of the eye emanates a challenge for drug delivery to formulation scientists. Lower bioavailability concern of conventional ocular formulation provokes the interest of researchers in the development of novel drug delivery system. Nanotechnology-based formulations have been extensively investigated and found propitious in improving bioavailability of drugs by overcoming ocular barriers prevailing in the eye. The advent of nanocrystals helped in combating the problem of poorly soluble drugs specifically for oral and parenteral drug delivery and led to development of various marketed products. Nanocrystal-based formulations explored for ocular drug delivery have been found successful in achieving increase in retention time, bioavailability, and permeability of drugs across the corneal and conjunctival epithelium. In this review, we have highlighted the ocular physiology and barriers in drug delivery. A comparative analysis of various nanotechnology-based ocular formulations is done with their pros and cons. Consideration is also given to various methods of preparation of nanocrystals with their patented technology. This article highlights the success achieved in conquering various challenges of ocular delivery by the use of nanocrystals while emphasizing on its advantages and application for ocular formulation. The perspectives of nanocrystals as an emerging flipside to explore the frontiers of ocular drug delivery are discussed.

Extemporaneous drug formulations.

PubMed

Nahata, Milap C; Allen, Loyd V

2008-11-01

Access to a special dosage form of a medication is essential when administration to infants and children and selected other populations is required. Some drugs necessary for pediatric patients are not commercially available in dosage forms appropriate for use in this population. These drugs may be prepared extemporaneously for use in individual patients. Physical and chemical properties of drugs and excipients should be considered when preparing extemporaneous formulations. These formulations, however, may lack studies to document stability, bioavailability, pharmacokinetics, pharmacodynamics, efficacy, and tolerability. The goal of this article was to discuss factors involved in extemporaneous compounding of pediatric dosage forms. The proceedings from a Pediatric Formulation Initiative workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, held December 6 and 7, 2005, in Bethesda, Maryland, were used as a source of information for this article. A literature search of PubMed/ MEDLINE (1966-October 2008) was also conducted, using the search terms extemporaneous, drug formulations, and pediatric. Access to age-appropriate drug formulations is critical to provide effective and well-tolerated medications to patients. There continues to be a need for extemporaneous formulations of brand and generic drugs for neonates, infants, and children. Potential solutions to current limitations include the need to develop a prioritized list of essential formulations, increased funding of research, dissemination of data, and monitoring of clinical effectiveness and tolerability during use in various age groups of pediatric patients and the sharing of these clinical experiences. To achieve desired therapeutic outcomes in pediatric patients, access to age-appropriate, stable, effective, and well-tolerated drug formulations is essential.

Positively Charged Nanostructured Lipid Carriers and Their Effect on the Dissolution of Poorly Soluble Drugs.

PubMed

Choi, Kyeong-Ok; Choe, Jaehyeog; Suh, Seokjin; Ko, Sanghoon

2016-05-20

The objective of this study is to develop suitable formulations to improve the dissolution rate of poorly water soluble drugs. We selected lipid-based formulation as a drug carrier and modified the surface using positively charged chitosan derivative (HTCC) to increase its water solubility and bioavailability. Chitosan and HTCC-coated lipid particles had higher zeta-potential values than uncoated one over the whole pH ranges and improved encapsulation efficiency. In vitro drug release showed that all NLC formulations showed higher in vitro release efficiency than drug particle at pH 7.4. Furthermore, NLC formulation prepared with chitosan or HTCC represented good sustained release property. The results indicate that chitosan and HTCC can be excellent formulating excipients of lipid-based delivery carrier for improving poorly water soluble drug delivery.

Efficient Human Breast Cancer Xenograft Regression after a Single Treatment with a Novel Liposomal Formulation of Epirubicin Prepared Using the EDTA Ion Gradient Method

PubMed Central

Gubernator, Jerzy; Lipka, Dominik; Korycińska, Mariola; Kempińska, Katarzyna; Milczarek, Magdalena; Wietrzyk, Joanna; Hrynyk, Rafał; Barnert, Sabine; Süss, Regine; Kozubek, Arkadiusz

2014-01-01

Liposomes act as efficient drug carriers. Recently, epirubicin (EPI) formulation was developed using a novel EDTA ion gradient method for drug encapsulation. This formulation displayed very good stability and drug retention in vitro in a two-year long-term stability experiment. The cryo-TEM images show drug precipitate structures different than ones formed with ammonium sulfate method, which is usually used to encapsulate anthracyclines. Its pharmacokinetic properties and its efficacy in the human breast MDA-MB-231 cancer xenograft model were also determined. The liposomal EPI formulation is eliminated slowly with an AUC of 7.6487, while the free drug has an AUC of only 0.0097. The formulation also had a much higher overall antitumor efficacy than the free drug. PMID:24621591

Nanoparticle-Delivered Chemotherapy: Old Drugs in New Packages.

PubMed

Lee, Michael S; Dees, E Claire; Wang, Andrew Z

2017-03-15

Cytotoxic chemotherapies have a narrow therapeutic window, with high peaks and troughs of plasma concentration. Novel nanoparticle formulations of cytotoxic chemotherapy drugs can enhance pharmacokinetic characteristics and facilitate passive targeting of drugs to tumors via the enhanced permeability and retention effect, thus mitigating toxicity. Nanoparticle vehicles currently in clinical use or undergoing clinical investigation for anticancer therapies include liposomes, polymeric micelles, protein-drug nanoparticles, and dendrimers. Multiple nanoparticle formulations of existing cytotoxic chemotherapies are approved for use in several indications, with clinical data indeed showing optimization of pharmacokinetics and different toxicity profiles compared with their parent drugs. There are also many new nanoparticle drug formulations in development and undergoing early- and late-phase clinical trials, including several that utilize active targeting or triggered release based on environmental stimuli. Here, we review the rationale for nanoparticle formulations of existing or previously investigated cytotoxic drugs, describe currently approved nanoparticle formulations of drugs, and discuss some of the most promising clinical trials currently underway.

Drug carrier systems for solubility enhancement of BCS class II drugs: a critical review.

PubMed

Kumar, Sumit; Bhargava, Deepak; Thakkar, Arti; Arora, Saahil

2013-01-01

Poor aqueous solubility impedes a drug's bioavailability and challenges its pharmaceutical development. Pharmaceutical development of drugs with poor water solubility requires the establishment of a suitable formulation layout among various techniques. Various approaches have been investigated extensively to improve the aqueous solubility and poor dissolution rate of BCS class II and IV drugs. In this literature review, novel formulation options, particularly for class II drugs designed for applications such as micronization, self-emulsification, cyclodextrin complexation, co-crystallisation, super critical fluid technology, solubilisation by change in pH, salt formation, co-solvents, melt granulation, and solid dispersion, liposomal/niosomal formulations, are discussed in detail to introduce biopharmaceutical challenges and recent approaches to facilitate more efficient drug formulation and development.

Tissue compatibility and pharmacokinetics of three potential subcutaneous injectables for low-pH drug solutions.

PubMed

Wu, Zimei; Tucker, Ian G; Razzak, Majid; McSporran, Keith; Medlicott, Natalie J

2010-07-01

The aim of the study was to investigate the tissue tolerance and bioavailability of four formulations containing 5% ricobendazole solubilised at low pH, following subcutaneous injection in sheep. Formulations were: a water-in-oil emulsion, a microemulsion, a hydroxypropyl-beta-cyclodextrin (HP-beta-CD, 20%) drug solution, and a low-pH drug solution (reference). In-vitro cytotoxicity of the formulations was investigated in L929 fibroblasts using MTS viability and lactate dehydrogenase leakage assays. Each formulation and respective vehicle was injected into either side of the back of a sheep to investigate the tissue tolerance and pharmacokinetics. In-vitro studies suggested that both the emulsion and the microemulsion are unlikely to give a burst release of the low-pH drug solution in aqueous media. The microemulsion showed the greatest in-vitro cytotoxic effect but no significant difference was observed between the other formulations. In sheep, the three new formulations and vehicles caused little or no injection-site reactions compared with a marked response to the reference formulation. Bioavailabilities of HP-beta-CD formulation, emulsion and microemulsion formulations, relative to the reference formulation, were 194, 155 and 115%, respectively. The three new subcutaneous injectables showed promise for reducing irritation of low-pH solubilised ricobendazole. HP-beta-CD significantly enhanced the drug absorption. Controlling the burst release of the low-pH drug solution may improve tissue tolerance and minimise post-injection precipitation, and hence increase drug bioavailability. The in-vitro cytotoxicity studies did not predict the in-vivo irritation effects.

Formulation development of smart gel periodontal drug delivery system for local delivery of chemotherapeutic agents with application of experimental design.

PubMed

Dabhi, Mahesh R; Nagori, Stavan A; Gohel, Mukesh C; Parikh, Rajesh K; Sheth, Navin R

2010-01-01

Smart gel periodontal drug delivery systems (SGPDDS) containing gellan gum (0.1-0.8% w/v), lutrol F127 (14, 16, and 18% w/v), and ornidazole (1% w/v) were designed for the treatment of periodontal diseases. Each formulation was characterized in terms of in vitro gelling capacity, viscosity, rheology, content uniformity, in vitro drug release, and syringeability. In vitro gelation time and the nature of the gel formed in simulated saliva for prepared formulations showed polymeric concentration dependency. Drug release data from all formulations was fitted to different kinetic models and the Korsemeyer-Peppas model was the best fit model. Drug release was significantly decreased as the concentration of each polymer component was increased. Increasing the concentration of each polymeric component significantly increased viscosity, syringeability, and time for 50%, 70%, and 90% drug release. In conclusion, the formulations described offer a wide range of physical and drug release characteristics. The formulation containing 0.8% w/v of gellan gum and 16% w/v of lutrol F127 exhibited superior physical characteristics.

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.

A targeted liposome delivery system for combretastatin A4: formulation optimization through drug loading and in vitro release studies.

PubMed

Nallamothu, Ramakrishna; Wood, George C; Kiani, Mohammad F; Moore, Bob M; Horton, Frank P; Thoma, Laura A

2006-01-01

Efficient liposomal therapeutics require high drug loading and low leakage. The objective of this study is to develop a targeted liposome delivery system for combretastatin A4 (CA4), a novel antivascular agent, with high loading and stable drug encapsulation. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, and distearoyl phosphoethanolamine-PEG-2000 conjugate (DSPE-PEG) were prepared by the lipid film hydration and extrusion process. Cyclic arginine-glycine-aspartic acid (RGD) peptides with affinity for alphav beta3-integrins overexpressed on tumor vascular endothelial cells were coupled to the distal end of polyethylene glycol (PEG) on the liposomes sterically stabilized with PEG (non-targeted liposomes; LCLs). Effect of lipid concentration, drug-to-lipid ratio, cholesterol, and DSPE-PEG content in the formulation on CA4 loading and its release from the liposomes was studied. Total liposomal CA4 levels obtained increased with increasing lipid concentration in the formulation. As the drug-to-lipid ratio increased from 10:100 to 20:100, total drug in the liposome formulation increased from 1.05+/-0.11 mg/mL to 1.55+/-0.13 mg/mL, respectively. When the drug-to-lipid ratio was further raised to 40:100, the total drug in liposome formulation did not increase, but the amount of free drug increased significantly, thereby decreasing the percent of entrapped drug. Increasing cholesterol content in the formulation decreased drug loading. In vitro drug leakage from the liposomes increased with increase in drug-to-lipid ratio or DSPE-PEG content in the formulation; whereas increasing cholesterol content of the formulation up to 30 mol-percent, decreased CA4 leakage from the liposomes. Ligand coupling to the liposome surface increased drug leakage as a function of ligand density. Optimized liposome formulation with 100 mM lipid concentration, 20:100 drug-to-lipid ratio, 30 mol-percent cholesterol, 4 mol-percent DSPE-PEG, and 1 mol-percent DSPE-PEG-maleimide content yielded 1.77+/-0.14 mg/mL liposomal CA4 with 85.70+/-1.71% of this being entrapped in the liposomes. These liposomes, with measured size of 123.84+/-41.23 nm, released no significant amount of the encapsulated drug over 48 h at 37 degrees C.

Preparation of finasteride capsules-loaded drug nanoparticles: formulation, optimization, in vitro, and pharmacokinetic evaluation

PubMed Central

Ahmed, Tarek A

2016-01-01

In this study, optimized freeze-dried finasteride nanoparticles (NPs) were prepared from drug nanosuspension formulation that was developed using the bottom–up technique. The effects of four formulation and processing variables that affect the particle size and solubility enhancement of the NPs were explored using the response surface optimization design. The optimized formulation was morphologically characterized using transmission electron microscopy (TEM). Physicochemical interaction among the studied components was investigated. Crystalline change was investigated using X-ray powder diffraction (XRPD). Crystal growth of the freeze-dried NPs was compared to the corresponding aqueous drug nanosuspension. Freeze-dried NPs formulation was subsequently loaded into hard gelatin capsules that were examined for in vitro dissolution and pharmacokinetic behavior. Results revealed that in most of the studied variables, some of the quadratic and interaction effects had a significant effect on the studied responses. TEM image illustrated homogeneity and shape of the prepared NPs. No interaction among components was noticed. XRPD confirmed crystalline state change in the optimized NPs. An enhancement in the dissolution rate of more than 2.5 times from capsules filled with optimum drug NPs, when compared to capsules filled with pure drug, was obtained. Crystal growth, due to Ostwald ripening phenomenon and positive Gibbs free energy, was reduced following lyophilization of the nanosuspension formulation. Pharmacokinetic parameters from drug NPs were superior to that of pure drug and drug microparticles. In conclusion, freeze-dried NPs based on drug nanosuspension formulation is a successful technique in enhancing stability, solubility, and in vitro dissolution of poorly water-soluble drugs with possible impact on the drug bioavailability. PMID:26893559

Understanding the Different Effects of Inhaler Design on the Aerosol Performance of Drug-Only and Carrier-Based DPI Formulations. Part 1: Grid Structure.

PubMed

Leung, Cassandra Ming Shan; Tong, Zhenbo; Zhou, Qi Tony; Chan, John Gar Yan; Tang, Patricia; Sun, Siping; Yang, Runyu; Chan, Hak-Kim

2016-09-01

The design of a dry powder inhaler device has significant influence on aerosol performance; however, such influence may be different between the drug-only and carrier-based formulations. The present study aims to examine the potential difference on the dispersion between these distinct types of formulations, using Aerolizer(®) as a model inhaler with the original or modified (cross-grid) designs. A coupled CFD-discrete element method analysis was employed to determine the flow characteristics and particle impaction. Micronized salbutamol sulphate as a drug-only formulation and three lactose carrier-based formulations with various drug-to-carrier weight ratios 1:5, 1:10 and 1:100 were used. The in vitro aerosolization performance was assessed by a next-generation impactor operating at 100 L/min. Using the original device, FPFloaded was reduced from 47.5 ± 3.8% for the drug-only formulation to 31.8 ± 0.7%, 32.1 ± 0.7% and 12.9 ± 1.0% for the 1:5, 1:10 and 1:100 formulations, respectively. With the cross-grid design, powder-mouthpiece impaction was increased, which caused not only powder deagglomeration but also significant drug retention (doubling or more) in the mouthpiece, and the net result is a significant decrease in FPFloaded to 36.8 ± 1.2%, 20.9 ± 2.6% and 21.9 ± 1.5% for the drug-only, 1:5 and 1:10 formulations, respectively. In contrast, the FPFloaded of the 1:100 formulation remained the same at 12.1 ± 1.3%, indicating the increased mouthpiece drug retention was compensated by increased drug detachment from carriers caused by increased powder-mouthpiece impaction. In conclusion, this study has elucidated different effects and the mechanism on the aerosolization of varied dry powder inhaler formulations due to the grid design.

Comparative bioavailability of rifampicin and isoniazid in fixed-dose combinations and single-drug formulations.

PubMed

Hao, L-H; Guo, S-C; Liu, C-C; Zhu, H; Wang, B; Fu, L; Chen, M-T; Zhou, L; Chi, J-Y; Yang, W; Nie, W-J; Lu, Y

2014-12-01

The bioavailability of rifampicin (RMP) decreases by ∼30% on interaction with isoniazid (INH) in stomach acid conditions, which can result in the development of drug resistance and treatment failure. To compare the bioavailability in healthy volunteers of five anti-tuberculosis fixed-drug combinations (FDCs) used in China (formulations A-E) containing RMP and INH against single-drug formulations taken as reference. Two- or three-period, two- or three-sequence crossover study of drugs. Only RMP formulation E passed the bioequivalence criteria, with 90% confidence intervals for the log-transformed ratios of AUC₀₋₂₄, AUC₀₋∞, and Cmax of respectively 89.9-103.7, 89.6-102.2 and 87.7-107.9. For INH, formulations A, B, C and D passed the bioequivalence test, but not product E, where the 90%CIs of the log-transformed ratios of AUC₀₋₂₄, AUC₀₋∞, and Cmax were respectively 85.2-100.7, 85.2-100.7 and 73.8-100.9. According to the results of the bioequivalence analysis carried out in this study, RMP formulations A, B, C and D were not within the acceptable range and only formulation E passed the bioequivalence criteria of 80-125%. In comparison, four-test INH formulations (A, B, C and D) were bioequivalent to the corresponding single-drug formulation, while product E failed in the bioequivalence criteria.

Evaluating Suspension Formulations of Theophylline Cocrystals With Artificial Sweeteners.

PubMed

Aitipamula, Srinivasulu; Wong, Annie B H; Kanaujia, Parijat

2018-02-01

Pharmaceutical cocrystals have garnered significant interest as potential solids to address issues associated with formulation development of drug substances. However, studies concerning the understanding of formulation behavior of cocrystals are still at the nascent stage. We present results of our attempts to evaluate suspension formulations of cocrystals of an antiasthmatic drug, theophylline, with 2 artificial sweeteners. Stability, solubility, drug release, and taste of the suspension formulations were evaluated. Suspension that contained cocrystal with acesulfame showed higher drug release rate, while a cocrystal with saccharin showed a significant reduction in drug release rate. The cocrystal with saccharin was found stable in suspension for over 9 weeks at accelerated test condition; in contrast, the cocrystal with acesulfame was found unstable. Taste analysis using an electronic taste-sensing system revealed improved sweetness of the suspension formulations with cocrystals. Theophylline has a narrow therapeutic index with a short half-life which necessitates frequent dosing. This adversely impacts patient compliance and enhances risk of gastrointestinal and cardiovascular adverse effects. The greater thermodynamic stability, sweetness, and sustained drug release of the suspension formulation of theophylline-saccharin could offer an alternative solution to the short half-life of theophylline and make it a promising formulation for treating asthmatic pediatric and geriatric patients. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development-Industry Case Studies.

PubMed

Kesisoglou, Filippos; Chung, John; van Asperen, Judith; Heimbach, Tycho

2016-09-01

In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug-drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Development of Oral Flexible Tablet (OFT) Formulation for Pediatric and Geriatric Patients: a Novel Age-Appropriate Formulation Platform.

PubMed

Chandrasekaran, Prabagaran; Kandasamy, Ruckmani

2017-08-01

Development of palatable formulations for pediatric and geriatric patients involves various challenges. However, an innovative development with beneficial characteristics of marketed formulations in a single formulation platform was attempted. The goal of this research was to develop solid oral flexible tablets (OFTs) as a platform for pediatrics and geriatrics as oral delivery is the most convenient and widely used mode of drug administration. For this purpose, a flexible tablet formulation using cetirizine hydrochloride as model stability labile class 1 and 3 drug as per the Biopharmaceutical Classification System was developed. Betadex, Eudragit E100, and polacrilex resin were evaluated as taste masking agents. Development work focused on excipient selection, formulation processing, characterization methods, stability, and palatability testing. Formulation with a cetirizine-to-polacrilex ratio of 1:2 to 1:3 showed robust physical strength with friability of 0.1% (w/w), rapid in vitro dispersion within 30 s in 2-6 ml of water, and 0.2% of total organic and elemental impurities. Polacrilex resin formulation shows immediate drug release within 30 min in gastric media, better taste masking, and acceptable stability. Hence, it is concluded that ion exchange resins can be appropriately used to develop taste-masked, rapidly dispersible, and stable tablet formulations with tailored drug release suitable for pediatrics and geriatrics. Flexible formulations can be consumed as swallowable, orally disintegrating, chewable, and as dispersible tablets. Flexibility in dose administration would improve compliance in pediatrics and geriatrics. This drug development approach using ion exchange resins can be a platform for formulating solid oral flexible drug products with low to medium doses.

Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications.

PubMed

Kawabata, Yohei; Wada, Koichi; Nakatani, Manabu; Yamada, Shizuo; Onoue, Satomi

2011-11-25

The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Assessing bioequivalence of generic antiepilepsy drugs.

PubMed

Krauss, Gregory L; Caffo, Brian; Chang, Yi-Ting; Hendrix, Craig W; Chuang, Kelly

2011-08-01

Patients with epilepsy are often concerned that switching between brand-name and generic formulations of antiepilepsy drugs (AEDs) may cause clinically significant changes in plasma drug concentrations. We assessed bioequivalence (BE) studies for approved generic AEDs to evaluate US Food and Drug Administration claims that: (1) generic AEDs are accurate copies of reference formulations; (2) delivery of reference formulations may be as variable as generic AEDs and so provide no increased benefit; and (3) switches between generic AED formulations are safe and effective. We determined differences in 90% confidence interval limits for total drug exposure (AUC(0-t) ) and peak concentration (Cmax) ratios of generic and reference formulations during fasting and fed BE studies. We simulated BE between generic formulations after adjusting for reference values. AUC(0-t) values of approved reference and generic formulations differed by <15% in 99% of BE studies; Cmax differed by <15% in 89% of studies. Food affected variability of Cmax but not AUC(0-t) . Intersubject variability in Cmax and AUC(0-t) was small and similar for reference and generic products. In simulated switches between 595 pairs of generic AED formulations, estimated AUC(0-t) differed by >15% for 17% of pairs; estimated Cmax differed by >15% for 39%. AEDs with low bioavailability and solubility (eg, oxcarbazepine) had the greatest variability in BE. Most generic AED products provide total drug delivery (AUC) similar to reference products; differences in peak concentrations between formulations are more common. Switches between generic AED products may cause greater changes in plasma drug concentrations than generic substitutions of reference products. Copyright © 2011 American Neurological Association.

Poly (amidoamine) dendrimer-mediated hybrid formulation for combination therapy of ramipril and hydrochlorothiazide.

PubMed

Singh, Mayank Kumar; Pooja, Deep; Kulhari, Hitesh; Jain, Sanjay Kumar; Sistla, Ramakrishna; Chauhan, Abhay Singh

2017-01-01

We present a dendrimer-based hybrid formulation strategy to explore the potential of poly (amidoamine) PAMAM dendrimers to be used as drug carriers for combination therapy of an anti-hypertensive drug ramipril (RAPL) and a diuretic hydrochlorothiazide (HCTZ). The drug-dendrimer complexes were prepared by phase-equilibration method. The results showed that the solubility of RAPL and HCTZ was dependent on dendrimer concentration and pH of dendrimer solution. The solubility profile of both RAPL and HCTZ dendrimer complexes illustrated a non-linear relationship with dendrimer concentration. At 0.8% (w/v) dendrimer concentration, solubility of RAPL was increased 4.91 folds with amine-terminated while for HCTZ, solubility enhancement was highest (3.72 folds) with carboxy-terminated. The complexes were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance analysis and high performance liquid chromatography. In-vitro drug dissolution performance of pure drugs, individual drug loaded dendrimer formulations and hybrid formulations was studied in USP dissolution medium (pH7.0) and in simulated gastric fluid (pH1.2). Dendrimer mediated formulations showed faster and complete dissolution compared to pure RAPL or HCTZ. Surprisingly, similar pattern of dissolution profile was established with hybrid formulations as compared to individual drug loaded dendrimers. The dendrimer-based hybrid formulations were found to be stable at dark and refrigerated conditions up to 5weeks. Conclusively, the proposed formulation strategy establishes a novel multitasking platform using dendrimer for simultaneous loading and delivery of multiple drugs for pharmaceutical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Identification of Drugs in Parenteral Pharmaceutical Preparations from a Quality Assurance and a Diversion Program by Direct Analysis in Real-Time AccuTOFTM-Mass Spectrometry (DART-MS).

PubMed

Poklis, Justin L; Mohs, Amanda J; Wolf, Carl E; Poklis, Alphonse; Peace, Michelle R

2016-10-01

In healthcare settings drug diversion and impairment of physicians are major concerns requiring a rapid and efficient method for surveillance and detection. A Direct Analysis in Real Time ion source coupled to a JEOL AccuTOF TM time-of-flight mass spectrometer (DART-MS) method was developed to screen parenteral pharmaceutical formulations for potential drug diversion. Parenteral pharmaceutical formulations are also known as injectable formulations and are used with intravenous, subcutaneous, intramuscular and intra-articular administration. A library was created using the mass spectra data collected by a DART-MS operated in switching mode at 20, 60 and 90 V settings. This library contained 17 commonly encountered drugs in parenteral pharmaceutical formulations that included the surgical analgesic: fentanyl, hydromorphone and morphine; anesthetic: baclofen, bupivacaine, ketamine, midazolam, ropivacaine and succinylcholine; and a mixture of other drug classes: caffeine, clonidine, dexamethasone, ephedrine, heparin, methadone, oxytocin and phenylephrine. Randomly selected 200 de-identified parenteral pharmaceutical formulations containing one or more drugs were submitted for analysis to the FIRM Toxicology Laboratory at Virginia Commonwealth University Health and were screened using the DART-MS. The drug contents of the de-identified formulations were previously confirmed by a published high performance liquid chromatography (HPLC) method. The drugs in the formulations were rapidly and successfully identified using the generated library. The DART-MS and HPLC results were in complete agreement for all 200 parenteral pharmaceutical formulations. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ultrasonication-assisted preparation and characterization of emulsions and emulsion gels for topical drug delivery.

PubMed

Singh, Vinay K; Behera, Baikuntha; Pramanik, Krishna; Pal, Kunal

2015-03-01

The current study describes the use of ultrasonication for the preparation of biphasic emulsions and emulsion gels for topical drug delivery. Sorbitan monostearate (SMS) was used as the surfactant for stabilizing the interface of sesame oil (apolar phase) and water (polar phase). Emulsions were formed at lower concentrations of SMS, whereas emulsion gels were formed at higher concentrations of SMS. The formulations were characterized by fluorescent microscopy, X-ray diffraction, viscosity, stress relaxation, spreadability, and differential scanning calorimetry studies. Fluorescence microscopy suggested formation of oil-in-water type of formulations. There was an increase in the viscosity, bulk resistance, and firmness of the formulations as the proportions of SMS was increased. The emulsion gels were viscoelastic in nature. Thermal studies suggested higher thermodynamic stability at higher proportions of either SMS or water. Metronidazole, a model antimicrobial drug, was incorporated within the formulations. The release of the drug from the formulations was found to be diffusion mediated. The drug-loaded formulations showed sufficient antimicrobial efficiency to be used as carriers for topical antimicrobial drug delivery. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

A new in vitro lipid digestion - in vivo absorption model to evaluate the mechanisms of drug absorption from lipid-based formulations.

PubMed

Crum, Matthew F; Trevaskis, Natalie L; Williams, Hywel D; Pouton, Colin W; Porter, Christopher J H

2016-04-01

In vitro lipid digestion models are commonly used to screen lipid-based formulations (LBF), but in vitro-in vivo correlations are in some cases unsuccessful. Here we enhance the scope of the lipid digestion test by incorporating an absorption 'sink' into the experimental model. An in vitro model of lipid digestion was coupled directly to a single pass in situ intestinal perfusion experiment in an anaesthetised rat. The model allowed simultaneous real-time analysis of the digestion and absorption of LBFs of fenofibrate and was employed to evaluate the influence of formulation digestion, supersaturation and precipitation on drug absorption. Formulations containing higher quantities of co-solvent and surfactant resulted in higher supersaturation and more rapid drug precipitation in vitro when compared to those containing higher quantities of lipid. In contrast, when the same formulations were examined using the coupled in vitro lipid digestion - in vivo absorption model, drug flux into the mesenteric vein was similar regardless of in vitro formulation performance. For some drugs, simple in vitro lipid digestion models may underestimate the potential for absorption from LBFs. Consistent with recent in vivo studies, drug absorption for rapidly absorbed drugs such as fenofibrate may occur even when drug precipitation is apparent during in vitro digestion.

Development and evaluation of Ketoprofen sustained release matrix tablet using Hibiscus rosa-sinensis leaves mucilage.

PubMed

Kaleemullah, M; Jiyauddin, K; Thiban, E; Rasha, S; Al-Dhalli, S; Budiasih, S; Gamal, O E; Fadli, A; Eddy, Y

2017-07-01

Currently, the use of natural gums and mucilage is of increasing importance in pharmaceutical formulations as valuable drug excipient. Natural plant-based materials are economic, free of side effects, biocompatible and biodegradable. Therefore, Ketoprofen matrix tablets were formulated by employing Hibiscus rosa-sinensis leaves mucilage as natural polymer and HPMC (K100M) as a synthetic polymer to sustain the drug release from matrix system. Direct compression method was used to develop sustained released matrix tablets. The formulated matrix tablets were evaluated in terms of physical appearance, weight variation, thickness, diameter, hardness, friability and in vitro drug release. The difference between the natural and synthetic polymers was investigated concurrently. Matrix tablets developed from each formulation passed all standard physical evaluation tests. The dissolution studies of formulated tablets revealed sustained drug release up to 24 h compared to the reference drug Apo Keto® SR tablets. The dissolution data later were fitted into kinetic models such as zero order equation, first order equation, Higuchi equation, Hixson Crowell equation and Korsmeyer-Peppas equation to study the release of drugs from each formulation. The best formulations were selected based on the similarity factor ( f 2 ) value of 50% and more. Through the research, it is found that by increasing the polymers concentration, the rate of drug release decreased for both natural and synthetic polymers. The best formulation was found to be F3 which contained 40% Hibiscus rosa-sinensis mucilage polymer and showed comparable dissolution profile to the reference drug with f 2 value of 78.03%. The release kinetics of this formulation has shown to follow non-Fickian type which involved both diffusion and erosion mechanism. Additionally, the statistical results indicated that there was no significant difference (p > 0.05) between the F3 and reference drug in terms of MDT and T50% with p-values of 1.00 and 0.995 respectively.

Ion-Responsive Drug Delivery Systems.

PubMed

Yoshida, Takayuki; Shakushiro, Kohsuke; Sako, Kazuhiro

2018-02-08

Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effect of squalane on mebendazole-loaded Compritol® nanoparticles.

PubMed

Graves, Richard A; Ledet, Grace A; Nation, Cedric A; Pramar, Yashoda V; Bostanian, Levon A; Mandal, Tarun K

2015-01-01

The objective of this study is to develop nanostructured lipid formulations of Compritol for the delivery of mebendazole. The formulations were prepared with Compritol 888 ATO, squalane, and Pluronic F68. Nine batches with different amounts of modifier, squalane, and drug were prepared. The formulations were characterized by evaluating particle size, morphology, and zeta potential. The thermal properties of the formulations were analyzed by differential scanning calorimetry (DSC). The encapsulation efficiency of each formulation and the drug release rates from each formulation were quantified by UPLC. The particles were spherical and had median particle sizes between 300 and 600 nm (50th percentile). A linear relationship was observed between Compritol/squalane composition and the melting point of the mixture. The DSC scans of the formulations revealed some recrystallization of the drug from the formulations, and the amount of recrystallization correlated with the amount of squalane in the formulation. Approximately, 70% efficiency of encapsulation was observed in the formulations with 30% (w/w) squalane, and these formulations also had faster dissolution rates compared to the other formulations. Overall, the formulations with 30% squalane are the preferred formulation for future testing.

Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications.

PubMed

Singh, Bhupinder; Bandopadhyay, Shantanu; Kapil, Rishi; Singh, Ramandeep; Katare, O

2009-01-01

Self-emulsifying drug delivery systems (SEDDS) possess unparalleled potential in improving oral bioavailability of poorly water-soluble drugs. Following their oral administration, these systems rapidly disperse in gastrointestinal fluids, yielding micro- or nanoemulsions containing the solubilized drug. Owing to its miniscule globule size, the micro/nanoemulsifed drug can easily be absorbed through lymphatic pathways, bypassing the hepatic first-pass effect. We present an exhaustive and updated account of numerous literature reports and patents on diverse types of self-emulsifying drug formulations, with emphasis on their formulation, characterization, and systematic optimization strategies. Recent advancements in various methodologies employed to characterize their globule size and shape, ability to encapsulate the drug, gastrointestinal and thermodynamic stability, rheological characteristics, and so forth, are discussed comprehensively to guide the formula-tor in preparing an effective and robust SEDDS formulation. Also, this exhaustive review offers an explicit discussion on vital applications of the SEDDS in bioavailability enhancement of various drugs, outlining an overview on myriad in vitro, in situ, and ex vivo techniques to assess the absorption and/ or permeation potential of drugs incorporated in the SEDDS in animal and cell line models, and the subsequent absorption pathways followed by them. In short, the current article furnishes an updated compilation of wide-ranging information on all the requisite vistas of the self-emulsifying formulations, thus paving the way for accelerated progress into the SEDDS application in pharmaceutical research.

A toxicity assessment of 30 pharmaceuticals using Aliivibrio fischeri: a comparison of the acute effects of different formulations.

PubMed

Jacob, Raquel Sampaio; Santos, Lucilaine Valéria de Souza; de Souza, Ana Flávia Rodrigues; Lange, Liséte Celina

2016-11-01

Considerable quantities of different classes of drugs are consumed annually worldwide. These drugs, once disposed, often remain stable, even after conventional or advanced treatments. Although there have been a number of studies on the potential harm caused by drugs when released into the environment, few studies have investigated the toxicity of pharmaceutical excipients. In the present study, the acute toxicity of 30 drugs was tested to Aliivibrio fischeri. Ten different active ingredients were investigated, each in three distinct formulations: generic, similar and reference (brand drug). The aim of the study was to evaluate the harmful potential of drugs frequently sold in drugstores and to assess the contribution of excipients towards the observed acute toxicity. Within the 10 drugs evaluated, only one, dexchlorpheniramine maleate, was not toxic in any formulation. The toxicities of the three formulations were often different, even though the active ingredient has been the same. For some drugs, such as diazepam, glibenclamide, metformin, nimesulide, hydrochlorothiazide and simvastatin, only one or two of the three formulations tested were toxic to A. fischeri. These results highlight the toxicological potential of drug excipients, but not exclusively the toxicity of the active ingredients.

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation.

PubMed

Suys, Estelle J A; Chalmers, David K; Pouton, Colin W; Porter, Christopher J H

2018-06-04

The ability of lipid-based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastrointestinal (GI) fluids has generated significant interest in the past decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs) to the formulation. In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid-soluble polymers Eudragit (EU) RL100 and poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water-soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure, and a good correlation was found between the degree of in vitro supersaturation and in vivo drug exposure. An improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.

Rapidly dissolving repaglinide powders produced by the ultra-rapid freezing process.

PubMed

Purvis, Troy; Mattucci, Michal E; Crisp, M Todd; Johnston, Keith P; Williams, Robert O

2007-07-20

The objective of the study was to produce rapidly dissolving formulations of the poorly water-soluble drug repaglinide using an innovative new technology, ultra-rapid freezing (URF), and to investigate the influence of excipient type on repaglinide stability. Repaglinide compositions containing different types and levels of excipients and different drug potencies (50%-86%) were produced by the URF technology. Repaglinide/excipient solutions were frozen on a cryogenic substrate, collected, and lyophilized to form a dry powder. Surfactants, including sodium dodecyl sulfate, and alkalizing agents such as diethanolamine (DEA) and tromethamine (TRIS) were incorporated into the compositions. Forced degradation of repaglinide was conducted under stressed conditions (eg, elevated temperature, exposure to peroxide) to determine the stability of the drug in such environments. The solubility of repaglinide increased as a function of increasing pH; therefore, incorporation of an alkalizing agent into the URF formulations increased the drug's solubility. Drug instability resulted when the drug was exposed to pH values above 9.0. URF formulations containing alkalizing agents showed no degradation or spontaneous recrystallization in the formulation, indicating that increased stability was afforded by processing. URF processing created nanostructured drug/excipient particles with higher dissolution rates than were achieved for unprocessed drug. Alkalizing agents such as TRIS and DEA, present at levels of 25% to 33% wt/wt in the formulations, did not cause degradation of the drug when processed using URF. URF processing, therefore, yielded fast-dissolving formulations that were physically and chemically stable, resistant to alkali degradation or spontaneous recrystallization in the formulation.

Formulation development and in vitro evaluation of solidified self-microemulsion in the form of tablet containing atorvastatin calcium.

PubMed

Ali, Kazi Asraf; Mukherjee, Biswajit; Bandyopadhyay, Amal Kumar

2013-11-01

The objective of our present study was to prepare solid self-microemulsion in the form of tablet of a poorly water soluble drug, Atorvastatin calcium (ATNC) to increase the solubility, dissolution rate, and minimize the hazards experienced from liquid emulsions. Self-microemulsifying ATNC tablet was formulated mainly by using self-emulsifying base, solidifying agent silicon dioxide and sodium starch glycolate as tablet disintegrant. Self-emulsifying base containing Transcutol P, Gelucire 44/14, and Lutrol F68 with their ratios in the formulation, were best selected by solubility study and ternary phase diagram in different vehicles. Particle size of microemulsion from tablet, physical parameters of the tablet and drug content has been checked. In vitro drug release rate has been carried out in phosphate buffer medium (pH 6.8). Physicochemical characterization of the drug in the optimized formulation has been performed to check drug-excipient incompatibility, if any. Average particle diameter of the emulsions formed from the tablet was found to be below 100 nm in case of formulation F4 and F5, which indicated microemulsions has been formed. In vitro drug release from the formulations F3, F4, and F5 was found to be >90%, indicated the enhancement of solubility of ATNC compared to parent drug. Differential thermal analysis (DTA), Powder X-ray Diffraction (X-RD) and Fourier transform infra red (FTIR) study proved the identity of the drug in the optimized formulation. The tablet form of self-microemulsifying (SME) drug delivery is good for solubility enhancement.

Formulation characteristics and in vitro release testing of cyclosporine ophthalmic ointments.

PubMed

Dong, Yixuan; Qu, Haiou; Pavurala, Naresh; Wang, Jiang; Sekar, Vasanthakumar; Martinez, Marilyn N; Fahmy, Raafat; Ashraf, Muhammad; Cruz, Celia N; Xu, Xiaoming

2018-06-10

The aim of the present study was to investigate the relationship between formulation/process variables versus the critical quality attributes (CQAs) of cyclosporine ophthalmic ointments and to explore the feasibility of using an in vitro approach to assess product sameness. A definitive screening design (DSD) was used to evaluate the impact of formulation and process variables. The formulation variables included drug percentage, percentage of corn oil and lanolin alcohol. The process variables studied were mixing temperature, mixing time and the method of mixing. The quality and performance attributes examined included drug assay, content uniformity, image analysis, rheology (storage modulus, shear viscosity) and in vitro drug release. Of the formulation variables evaluated, the percentage of the drug substance and the percentage of corn oil in the matrix were the most influential factors with respect to in vitro drug release. Conversely, the process parameters tested were observed to have minimal impact. An evaluation of the release mechanism of cyclosporine from the ointment revealed an interplay between formulation (e.g. physicochemical properties of the drug and ointment matrix type) and the release medium. These data provide a scientific basis to guide method development for in vitro drug release testing of ointment dosage forms. These results demonstrate that the in vitro methods used in this investigation were fit-for-purpose for detecting formulation and process changes and therefore amenable to assessment of product sameness. Published by Elsevier B.V.

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.

Mechanism for enhanced absorption of a solid dispersion formulation of LY2300559 using the artificial stomach duodenum model.

PubMed

Polster, Christopher S; Wu, Sy-Juen; Gueorguieva, Ivelina; Sperry, David C

2015-04-06

An artificial stomach duodenum (ASD) model has been used to demonstrate the performance difference between two formulations of LY2300559, a low-solubility acidic developmental drug. The two formulations investigated were a conventional high-shear wet granulation (HSWG) formulation and a solid dispersion formulation. A pharmacokinetic study in humans demonstrated the enhanced performance of the solid dispersion formulation relative to the HSWG formulation. The Cmax and AUC of the solid dispersion was 2.6 and 1.9 times greater, respectively, compared to the HSWG formulation. In the ASD, the solid dispersion formulation performance was characterized by three main phases: (1) rapid release in the stomach, creating a supersaturated concentration of drug, (2) precipitation in the stomach, and (3) rapid redissolution of the precipitate in the duodenum to concentration levels that are supersaturated relative to crystalline drug. A series of complementary experiments were employed to describe this performance behavior mechanistically. Imaging experiments with a pH indicating dye showed that local pH gradients from meglumine in the solid dispersion formulation were responsible for creating a high initial supersaturation concentration in the stomach. Upon dissipation of meglumine, the drug precipitated in the stomach as an amorphous solid. Because the precipitated drug is in an amorphous form, it can then rapidly redissolve as it transits to the more neutral environment of the duodenum. This unexpected sequence of physical state changes gives a mechanistic explanation for the enhanced in vivo performance of the solid dispersion formulation relative to the HSWG formulation.

Design, development and evaluation of clopidogrel bisulfate floating tablets.

PubMed

Rao, K Rama Koteswara; Lakshmi, K Rajya

2014-01-01

The objective of the present work was to formulate and to characterize a floating drug delivery system for clopidogrel bisulphate to improve bioavailability and to minimize the side effects of the drug such as gastric bleeding and drug resistance development. Clopidogrel floating tablets were prepared by direct compression technique by the use of three polymers xanthan gum, hydroxypropyl methylcellulose (HPMC) K15M and HPMC K4M in different concentrations (20%, 25% and 30% w/w). Sodium bicarbonate (15% w/w) and microcrystalline cellulose (30% w/w) were used as gas generating agent and diluent respectively. Studies were carried out on floating behavior and influence of type of polymer on drug release rate. All the formulations were subjected to various quality control and in-vitro dissolution studies in 0.1 N hydrochloric acid (1.2 pH) and corresponding dissolution data were fitted to popular release kinetic equations in order to evaluate release mechanisms and kinetics. All the clopidogrel floating formulations followed first order kinetics, Higuchi drug release kinetics with diffusion as the dominant mechanism of drug release. As per Korsmeyer-Peppas equation, the release exponent "n" ranged 0.452-0.654 indicating that drug release from all the formulations was by non-Fickian diffusion mechanism. The drug release rate of clopidogrel was found to be affected by the type and concentration of the polymer used in the formulation (P < 0.05). As the concentration of the polymer was increased, the drug release was found to be retarded. Based on the results, clopidogrel floating tablets prepared by employing xanthan gum at concentration 25% w/w (formulation F2) was the best formulation with desired in-vitro floating time and drug dissolution.

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.

Application of instrumental evaluation of color for the pre-formulation and formulation of rabeprazole.

PubMed

Rhee, Yun-Seok; Park, Chun-Woong; Shin, Yoon-Sub; Kam, Sung-Hoon; Lee, Kyu-Hyun; Park, Eun-Seok

2008-02-28

The aims of this study were to fast screen the compatibility of rabeprazole and excipients using a spectrocolorimeter and to examine the relationship between the color change value and drug contents/drug degradation products in solid dosage forms. The color change values of rabeprazole-excipient mixtures were measured using a spectrocolorimeter, with six tablet formulations compressed using a single-punch instrumental tablet press. The rabeprazole and degradation products contents in the tablets were analyzed using an HPLC method, with the color change values of the tablets measured using spectrocolorimetery for 4 weeks. These experiments indicated that the instrumental evaluation of color was a speedy, simple and useful tool in the determination of the interaction between the drug and excipients, as well as in the formulation of solid dosage forms. The relationships of the % reduced drug contents versus the color change value, and those of the % drug degradation products versus the color change value were exponentially increased in formulations containing zinc stearate. On stress testing, the color change value of rabeprazole was inconsistent with previous reports, as the degradation of rabeprazole can be greatly influenced by humidity as well as temperature. Consequently, these results highlight the potential of color formation in the application of pre-formulation and formulation of drugs.

Effects of formulation variables and post-compression curing on drug release from a new sustained-release matrix material: polyvinylacetate-povidone.

PubMed

Shao, Z J; Farooqi, M I; Diaz, S; Krishna, A K; Muhammad, N A

2001-01-01

A new commercially available sustained-release matrix material, Kollidon SR, composed of polyvinylacetate and povidone, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound, diphenhydramine HCl. Kollidon SR was found to provide a sustained-release effect for the model compound, with certain formulation and processing variables playing an important role in controlling its release kinetics. Formulation variables affecting the release include the level of the polymeric material in the matrix, excipient level, as well as the nature of the excipients (water soluble vs. water insoluble). Increasing the ratio of a water-insoluble excipient, Emcompress, to Kollidon SR enhanced drug release. The incorporation of a water-soluble excipient, lactose, accelerated its release rate in a more pronounced manner. Stability studies conducted at 40 degrees C/75% RH revealed a slow-down in dissolution rate for the drug-Kollidon SR formulation, as a result of polyvinylacetate relaxation. Further studies demonstrated that a post-compression curing step effectively stabilized the release pattern of formulations containing > or = 47% Kollidon SR. The release mechanism of Kollidon-drug and drug-Kollidon-Emcompress formulations appears to be diffusion controlled, while that of the drug-Kollidon-lactose formulation appears to be controlled predominantly by diffusion along with erosion.

Self-microemulsifying smaller molecular volume oil (Capmul MCM) using non-ionic surfactants: a delivery system for poorly water-soluble drug.

PubMed

Bandivadeka, Mithun Mohanraor; Pancholi, Shyam Sundar; Kaul-Ghanekar, Ruchika; Choudhari, Amit; Koppikar, Soumya

2012-07-01

The main purpose of this work is to formulate self-microemulsifying drug delivery system (SMEDDS) using smaller molecular oil with Atorvastatin calcium as a model drug. Solubility of the selected drug was accessed in oils and surfactants. Percent transmittance (%T) test study was performed to identify the efficient self-microemulsifying formulations. Those formulations which showed higher value for %T were evaluated for droplet size, polydispersity index, ζ potential, refractive index and cloud point measurement. Effect of drug loading on droplet size, increasing dilution in different media, thermodynamic stability and in vitro dissolution was performed to observe the performance of the selected formulation. Further cytotoxicity and permeation enhancement studies were carried out on Caco2 cell lines. Of all the oils accessed for drug solubility, Capmul MCM showed higher solubility capacity for Atorvastatin calcium. Capmul MCM was better microemulsified using combination of Tween 20 and Labrasol surfactant. Droplet size was as low as 86.93 nm with polydispersity index and ζ potential at 0.195 ± 0.011 and -7.27 ± 3.11 mV respectively. The selected undiluted formulation showed refractive index values ranging from 1.40 to 1.47 indicating the isotropicity of the formulation. The selected formulation was robust to dilution in different media and thermodynamically stable. Dissolution profile was enhanced for the selected drug as compared to marketed formulation with t85% and DE values at 10 min and 80.15 respectively. Also cytotoxicity measurement showed minimum effect with good permeation enhancing capacity. Thus our study demonstrates the use of smaller molecular oil (Capmul MCM) for developing self-microemulsifying drug delivery system for better in vitro and in vivo performance.

Calcipotriol delivery into the skin as emulgel for effective permeation.

PubMed

Naga Sravan Kumar Varma, V; Maheshwari, P V; Navya, M; Reddy, Sharath Chandra; Shivakumar, H G; Gowda, D V

2014-12-01

The objective of this work is to formulate and evaluate an emulgel containing calcipotriol for treatment of psoriasis. Emulgels have emerged as a promising drug delivery system for the delivery of hydrophobic drugs. Isopropyl alcohol and polyethylene glycol have been employed as permeation enhancers. Formulation chart is made with seven formulations, evaluated for physical parameters, drug content, viscosity, thixotropy, spreadability, extrudability, mucoadhesion, diffusion studies, skin irritation test along with short term stability studies. Carbopolis is reported to have a direct influence on appearance and viscosity of final formulation. The photomicroscopic evaluations showed the presence of spherical globules in size range of 10-15 μm. Rheograms revealed that all the formulations exhibited pseudoplastic flow. Optimized formulation (F6) had shown 86.42 ± 2.0% drug release at the end of 8 h study. The release rate through dialysis membrane and rat skin is higher when compared to commercial calcipotriol ointment. Hence it is concluded that calcipotriol can be delivered topically with enhanced penetration properties when formulated as emulgel.

Glycerogelatin-based ocular inserts of aceclofenac: physicochemical, drug release studies and efficacy against prostaglandin E₂-induced ocular inflammation.

PubMed

Mathurm, Manish; Gilhotra, Ritu Mehra

2011-01-01

An attempt has been made in the present study to formulate soluble ocular inserts of aceclofenac to facilitate the bioavailability of the drug into the eye, as no eye drop solution could be formulated. Glycero-gelatin ocular inserts/films were prepared and physicochemical parameters and drug release profiles of glycerol-gelatin films of aceclofenac were compared with surface cross-linked films of similar compositions. Ocular irritation of the developed formulation was also checked by HET-CAM test and efficacy of the developed formulation against prostaglandin-induced ocular inflammation in rabbit eye was determined. The non-cross-linked films showed poor mechanical, physicochemical properties, and very little potential of sustaining drug release, however cross-linking the films enhanced tensile strength by 70%, but elasticity decreased by 95%. The cross-linked ocular inserts showed less swelling than non-cross-linked. Formulation AF8 (20% gelatin and 70% glycerin, treated by cross-linker for 1 h) demonstrated the longest drug release for 24 h. As per the kinetic models all films showed a constant drug release with Higuchi diffusion mechanism. Formulation was found to be practically non-irritant. The optimized formulation was tested and compared with eye drops of aceclofenac for anti-inflammatory activity in rabbits against PGE₂-induced inflammation. In vivo studies with developed formulation indicated a significant inhibition of PGE₂-induced PMN migration as compared to eye drops. In conclusion, ocular inserts of aceclofenac was found promising as it achieved sustained drug release and better pharmacodynamic activity.

[Evaluation of Gastric Mucosal Injury Model Animals of Rebamipide Formulation--Study of Therapeutic Equivalence].

PubMed

Abe, Noriaki; Funato, Hiroki; Hirata, Ayumu; Nakai, Megumi; Iizuka, Michiro; Shiraishi, Hisashi; Jobu, Kohei; Yagi, Yusuke; Kadota, Aki; Ogi, Kyoko; Yokota, Junko; Miyamura, Mitsuhiko

2016-01-01

The introduction of generic drugs is promoted from the perspective of medical economics. In this context, we need to understand not only the bioequivalence of generic drugs specified in "the Guidelines for Bioequivalence Studies of Generic Products", but also formulation properties to consider their effect on pharmacological therapy. We evaluated the pharmaceutical characteristics of rebamipide formulations, a brand-name drug and two generic drugs, and their clinical functionality by using rat models of gastric mucosal injury induced by non-steroidal anti-inflammatory drugs (NSAIDs). Pharmaceutical evaluation showed significant differences in hardness. The inter-lot variation was small in all rebamipide formulations. In the clinical functionality study, biochemistry test values 7 d after the administration of rebamipide showed no differences among formulations. Higher levels of mucosal fluid secretion and antioxidative enzymes were observed in the groups administered rebamipide than in the control group. The levels of lipid peroxide were lower in the groups administered rebamipide than the control group. Multivariate analysis showed slight divergence between the brand-name and generic drugs. In future, it will be necessary to select generic drugs after careful consideration of bioequivalence, clinical functionality, and therapeutic equivalence by reviewing scientific evidence such as indication and formulation design, not to mention stable provision.

Application of the BCS biowaiver approach to assessing bioequivalence of orally disintegrating tablets with immediate release formulations.

PubMed

Ono, Asami; Sugano, Kiyohiko

2014-11-20

The aim of this study was to compare the dissolution profiles of oral disintegrating tablets (ODTs) and immediate release (IR) formulations in order to experimentally validate the regulatory biowaiver scheme (BWS) for biopharmaceutical classification system (BCS) class III drugs. We examined six drugs that show clinical bioequivalence between the ODTs and IR formulations: taltirelin, olopatadine, droxidopa, famotidine, fexofenadine, and hydrochlorothiazide. The dissolution profiles of these drugs were evaluated using the compendium paddle apparatus at pH 1.2 and 6.8. Taltirelin and olopatadine showed very rapid dissolution and met the dissolution criteria in the BWS, whereas droxidopa, famotidine, fexofenadine, and hydrochlorothiazide did not. Furthermore, in the case of famotidine, fexofenadine, and hydrochlorothiazide, the ODTs and IR formulations showed dissimilar dissolution profiles. The dose-to-solubility ratio (D:S) of these drugs was larger than that of the other drugs. The results of this study suggest that extension of the BCS-BWS to ODTs and IR formulations of BCS class III drugs is appropriate. Furthermore, for BCS class III drugs with relatively high D:S, clinical bioequivalence would be achievable even when two formulations showed different dissolution profiles in vitro. Copyright © 2014 Elsevier B.V. All rights reserved.

Influence of beta-cyclodextrin and chitosan in the formulation of a colon-specific drug delivery system.

PubMed

Rehman, K; Amin, M C I M; Muda, S

2013-12-01

The increase in diseases of the colon underscores the need to develop cost-effective site-directed therapies. We formulated a polysaccharide-based matrix system that could release ibuprofen under conditions simulating those in the colon by employing a wet granulation method. Tablets were prepared in a series of formulations containing a polysaccharide (beta-cyclodextrin and chitosan) matrix system along with ethylcellulose. We characterized physicochemical properties and performed an in vitro drug release assay in the absence and presence of digestive enzymes to assess the ability of the polysaccharides to function as a protective barrier against the upper gastrointestinal environment. Fourier transform infrared spectroscopy studies revealed no chemical interaction between ibuprofen and polysaccharides; however, spectrum analysis suggested the formation of an inclusion complex of beta-cyclodextrin with ibuprofen. The formulations contained 50% ethylcellulose and 50% beta-cyclodextrins (1:1) were proven to be the better formulation that slowly released the drug until 24 h (101.04 ± 0.65% maximum drug release in which 83.08 ± 0.89% drug was released in colonic medium) showed better drug release profiles than the formulations containing chitosan. We conclude that a beta-cyclodextrin drug carrier system may represent an effective approach for treatment of diseases of the colon. © Georg Thieme Verlag KG Stuttgart · New York.

Development and evaluation of 6-mercaptopurine and metoclopramide polypill formulation for oral administration: In-vitro and ex vivo studies

PubMed Central

Chowdhary, Rajani; Pai, Roopa S; Singh, Gurinder

2013-01-01

Introduction: The present investigation was to develop a polypill of 6-mercaptopurine and metoclopramide. A polypill with delayed release granules of an anticancer and immediate release mucoadhesive tablet of antiemetic may result in the reduction of emesis caused by oral chemotherapy. Materials and Methods: 6-Mercaptopurine granules were prepared by wet granulation process. Chitosan, hydroxypropyl methylcellulose, and ethylcellulose were used as individually as delayed release polymers. Seven granule formulations (F1-F7) were prepared and evaluated for flow properties and drug content. Immediate release mucoadhesive tablets of metoclopramide were prepared by direct compression technique using pectin and PVPK-40 as mucoadhesive polymers. Three formulations of pectin (L1-L3) and three formulations of PVPK40 (M1-M3) were prepared using lactose, magnesium stearate, and mannitol and talc as diluent and glidant, respectively. Tablets were evaluated for weight variation, hardness, friability, drug content, ex vivo mucoadhesion time, and in vitro dissolution studies. Results: Formulation F2, F4, F5, and F7 showed maximum drug content. Formulation F7 exhibited the drug release up to 2 h and was selected as the best delayed release formulation. All formulations of metoclopramide showed good drug content ranging from 97.6 % to 100.6%. Formulation M2 among tablets prepared with PVP exhibited desired mucoadhesion time of 15.33 min which prolongs the duration of drug release in gastric pouch of the male Wistar rats. Both the selected formulations F7 and M2 were filled into body of capsule size 0 and capsule was evaluated for technological properties. Conclusion: It may be concluded that polypill released the metoclopramide immediately prior to 6-mercaptopurine. PMID:24350042

European perspectives on pediatric formulations.

PubMed

Breitkreutz, Jörg

2008-11-01

The 2007 European Union (EU) regulation on medicinal products for pediatric use may change the present unsatisfying situation in the EU by stimulating research and development of medicines for use in children through rewards and incentives. This commentary reflects on the new EU regulations and guidelines, with special attention paid to the impact on pediatric formulation science. The focus of this article is on the EU perspective for pediatric formulations and highlights the differences compared with the pediatric drug formulation situation in the United States. Materials for this article were gathered during a literature search of MEDLINE and Chemical Abstracts (1970-October 2008) using the following terms: paediatric/pediatric drug formulations, age-appropriate dosage forms, child-appropriate medicines, and paediatric/pediatric regulation. Since the EU legislation on medicines for children came into force in 2007, a great emphasis has been placed on creating new organizations, scientific networks, and programs dealing with pediatric medicines and child-appropriate drug formulations. Although the US legislation was an appropriate model, the EU introduced some novel measures to improve the current situation, such as the Paediatric Investigation Plan and the Paediatric Use Marketing Authorisation. For globally operating pharmaceutical companies, the peculiarities of the European market have a strong impact on their product development strategies. Because the European approach demands early investigations into drug formulations for children, various issues must be resolved, including the following: choosing formulations for each age group, determining which excipients may be used in the formulation and which delivery device is appropriate, and predicting the taste sensation of an oral formulation. Numerous initiatives and networks are evolving in Europe. An important future task will be the coordination of these activities and the linking to other groups working on pediatric formulations outside the EU. Similar to the research in pediatric drug formulations that was stimulated by the US legislation and incentives of the last decade, the 2007 EU legislation promises improvements in the availability of child-appropriate drugs in Europe.

The solubility-permeability interplay and oral drug formulation design: Two heads are better than one.

PubMed

Dahan, Arik; Beig, Avital; Lindley, David; Miller, Jonathan M

2016-06-01

Poor aqueous solubility is a major challenge in today's biopharmaceutics. While solubility-enabling formulations can significantly increase the apparent solubility of the drug, the concomitant effect on the drug's apparent permeability has been largely overlooked. The mathematical equation to describe the membrane permeability of a drug comprises the membrane/aqueous partition coefficient, which in turn is dependent on the drug's apparent solubility in the GI milieu, suggesting that the solubility and the permeability are closely related, exhibit a certain interplay between them, and treating the one irrespectively of the other may be insufficient. In this article, an overview of this solubility-permeability interplay is provided, and the available data is analyzed in the context of the effort to maximize the overall drug exposure. Overall, depending on the type of solubility-permeability interplay, the permeability may decrease, remain unchanged, and even increase, in a way that may critically affect the formulation capability to improve the overall absorption. Therefore, an intelligent design of solubility-enabling formulation needs to consider both the solubility afforded by the formulation and the permeability in the new luminal environment resulting from the formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Microemulsion-Based Topical Hydrogels of Tenoxicam for Treatment of Arthritis.

PubMed

Goindi, Shishu; Narula, Manleen; Kalra, Atin

2016-06-01

Tenoxicam (TNX) is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, backache and pain. However, prolonged oral use of this drug is associated with gastrointestinal adverse events like peptic ulceration, thus necessitating its development as topical formulation that could obviate the adverse effects and improve patient compliance. The present study was aimed at development of microemulsion-based formulations of TNX for topical delivery at the affected site. The pseudoternary phase diagrams were developed and microemulsion formulations were prepared using Captex 300/oleic acid as oil, Tween 80 as surfactant and n-butanol/ethanol as co-surfactant. Optimized microemulsions were characterized for drug content, droplet size, viscosity, pH and zeta potential. The ex vivo permeation studies through Laca mice skin were performed using Franz diffusion cell assembly, and the permeation profile of the microemulsion formulation was compared with aqueous suspension of drug and drug incorporated in conventional cream. Microemulsion formulations of TNX showed significantly higher (p < 0.001) mean cumulative percent permeation values in comparison to conventional cream and suspension of drug. In vivo anti-arthritic and anti-inflammatory activity of the developed TNX formulations was evaluated using various inflammatory models such as air pouch model, xylene-induced ear edema, cotton pellet granuloma and carrageenan-induced inflammation. Microemulsion formulations were found to be superior in controlling inflammation as compared to conventional topical dosage forms and showed efficacy equivalent to oral formulation. Results suggest that the developed microemulsion formulations may be used for effective topical delivery of TNX to treat various inflammatory conditions.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals.

PubMed

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals

PubMed Central

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations. PMID:28243062

Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes.

PubMed

Loftsson, Thorsteinn; Brewster, Marcus E

2011-09-01

Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories.   Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in cyclodextrins. A second related critical success factor in the formulation of cyclodextrin-based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug-to-cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation 'push' and may reduce the bioavailability of the system. A mechanism-based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Effect of aminoalkyl methacrylate copolymer E/HCl on in vivo absorption of poorly water-soluble drug.

PubMed

Yoshida, Takatsune; Kurimoto, Ippei; Yoshihara, Keiichi; Umejima, Hiroyuki; Ito, Naoki; Watanabe, Shunsuke; Sako, Kazuhiro; Kikuchi, Akihiko

2013-11-01

This study aimed to investigate in vivo absorption of tacrolimus formulated as a solid dispersion using Eudragit E®/HCl (E-SD). E-SD is an aminoalkyl methacrylate copolymer that can be dissolved under neutral pH conditions. E-SD was used alone as a solid dispersion carrier and/or was mixed with tacrolimus primarily dispersed with hydroxypropylmethylcellulose (HPMC). Tacrolimus was formulated with E-SD at several different ratios. Formulations with tacrolimus/E-SD ratio of 1/3 showed higher in vivo absorption, compared to tacrolimus dispersed in the excipients (primarily HPMC) found in commercially available tacrolimus capsules, using a rat in situ closed loop method. Good correlation was observed between in vitro drug solubility and in vivo drug absorption. In vitro solubility tests and rat oral absorption studies of tacrolimus/HPMC solid dispersion formulations were also conducted after mixing the HPMC dispersion with several ratios of E-SD. E-SD/tacrolimus/HPMC formulations yielded high in vitro drug solubility but comparatively low in vivo absorption. Dog oral absorption studies were conducted using capsules containing a formulation of tacrolimus/E-SD at a ratio of 1/5. The E-SD formulation-containing capsule showed higher in vivo drug absorption than tacrolimus dispersed in the standard HPMC capsule. These studies report enhancement of the in vivo absorption of a poorly water-soluble drug following dispersion with E-SD when compared to formulation in HPMC.

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.

Formulation and evaluation of voriconazole ophthalmic solid lipid nanoparticles in situ gel.

PubMed

Pandurangan, Dinesh Kumar; Bodagala, Prathima; Palanirajan, Vijayaraj Kumar; Govindaraj, Saravanan

2016-01-01

In the present investigation, solid lipid nanoparticles (SLNs)-loaded in situ gel with voriconazole drug was formulated. Further, the formulation was characterized for pH, gelling capacity, entrapment efficiency, in vitro drug release, drug content, and viscosity. Voriconazole is an antifungal drug used to treat various infections caused by yeast or other types of fungi. Film hydration technique was used to prepared SLNs from lecithin and cholesterol. Based on the entrapment efficiency 67.2-97.3% and drug release, the optimized formulation NF1 of SLNs was incorporated into in situ gels. The in situ gels were prepared using viscosity-enhancing polymers such as Carbopol and (hydroxypropyl)methyl cellulose (HPMC). Formulated SLN in situ gel formulations were characterized, which showed pH 4.9-7.1, drug content 65.69-96.3%, and viscosity (100 rpm) 120-620 cps. From the characterizations given above, F6 was optimized and evaluated for microbial assay and ocular irritation studies. Microbial assay was conducted by the cup-plate method using Candida albicans as the test organism. An ocular irritation study was conducted on albino rabbits. The results revealed that there was no ocular damage to the cornea, conjunctiva, or iris. Stability studies were carried out on the F6 formulation for 3 months, which showed that the formulation had good stability. These results indicate that the studied SLNs-loaded in situ gel is a promising vehicle for ocular delivery.

Inventory of oral anticancer agents: Pharmaceutical formulation aspects with focus on the solid dispersion technique.

PubMed

Sawicki, E; Schellens, J H M; Beijnen, J H; Nuijen, B

2016-11-01

Dissolution from the pharmaceutical formulation is a prerequisite for complete and consistent absorption of any orally administered drug, including anticancer agents (oncolytics). Poor dissolution of an oncolytic can result in low oral bioavailability, high variability in blood concentrations and with that suboptimal or even failing therapy. This review discusses pharmaceutical formulation aspects and absorption pharmacokinetics of currently licensed orally administered oncolytics. In nearly half of orally dosed oncolytics poor dissolution is likely to play a major role in low and unpredictable absorption. Dissolution-limited drug absorption can be improved with a solid dispersion which is a formulation method that induces super-saturated drug dissolution and with that it enhances in vivo absorption. This review discusses formulation principles with focus on the solid dispersion technology and how it works to enhance drug absorption. There are currently three licensed orally dosed oncolytics formulated as a solid dispersion (everolimus, vemurafenib and regorafenib) and these formulations result in remarkably improved dissolution and absorption compared to what can be achieved with conventional formulations of the respective oncolytics. Because of the successful implementation of these three solid dispersion formulations, we encourage the application of this formulation method for poorly soluble oral oncolytics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development of liposomal and microemulsion formulations for transdermal delivery of clonazepam: effect of randomly methylated β-cyclodextrin.

PubMed

Mura, Paola; Bragagni, Marco; Mennini, Natascia; Cirri, Marzia; Maestrelli, Francesca

2014-11-20

Transdermal administration of clonazepam, a poorly water-soluble benzodiazepine, is an interesting strategy for overcoming the drawbacks of its oral administration. With this aim, two nano-carrier formulations, based on ultra-deformable liposomes and microemulsions, have been developed to favour clonazepam transdermal delivery. Considering the solubilizing power of methyl-βcyclodextrin (Me-βCD) toward clonazepam and its potential positive influence on transdermal drug delivery, the effect of its addition to these formulations was investigated. Artificial lipophilic membranes simulating the skin allowed a rapid evaluation of the drug permeation properties from the systems, compared with those from an aqueous drug suspension, with or without Me-βCD. The best formulations were further characterized by permeation through excised rabbit ear skin. All the formulations increased drug permeability, ranging from 2-fold (liposomes without Me-βCD), up to over 4-fold (microemulsions containing Me-βCD). The different formulations allowed for pointing out different possible permeation enhancing mechanisms of Me-βCD: increase in drug solubility and thermodynamic activity in the vehicle, when added to the drug aqueous suspension; interactions with the vesicle bilayer, in case of liposomal formulations; interactions with the skin membrane lipids, as evidenced in experiments with excised rabbit ear for microemulsions containing Me-βCD, that were then selected for further in vivo studies. Copyright © 2014. Published by Elsevier B.V.

Phototoxicity free quantum dot-based niosome formulation for controlled drug release and its monitoring

NASA Astrophysics Data System (ADS)

Kumar, Sunil; Kang, T. W.; Bala, Suman; Kamboj, Sunil; Jeon, H. C.

2018-04-01

A novel niosomes-based system composed of Hypromellose (HPMC) functionalized fluorescent, biocompatible ZnS:Mn quantum dots (QDs), and anti-HIV drug Tenofovir disoproxil fumarate (TDF) was designed. An appropriate ratio of surfactant Sorbitan Monostearate (SPAN-60) and cholesterol was used to obtain an optimal entrapment efficiency. Initially, after observing the successful interaction of HPMC with SPAN-60, the noisome formulation including (QDs + drug) and HPMC-coated QDs was synthesized by a wet chemical route and characterized by X-ray diffraction (XRD), Transmission electron microscope (TEM) and Selected Electron Diffraction (SAED). Secondly, (QDs + drug) loaded niosome formulations were studied by varying the ratio of SPAN-60 and cholesterol. Multiple studies were done to characterize the shape, size, viscosity, colloidal stability, and entrapment efficiency of (QDs + drug) loaded niosomes. Lastly, pH-dependent (QDs + drug) release profiles were studied by a spectroscopic technique considering the pH of the human gastrointestinal region to obtain the formulation stability of (QDs + drug) release from the niosome vesicles. These studies also include pH-dependent photo-stability measurements based on laser-induced multiphoton excitation technique in the Infrared region. The multiphoton time-resolved studies were completed to avoid the UV induced phototoxicity in the drug delivery modules. Current studies on the formulation of niosomes-based (QDs + drug) system laid a foundation to make a complete phototoxicity free system for tracking controlled drug release and its imaging.

Physical stabilization of low-molecular-weight amorphous drugs in the solid state: a material science approach.

PubMed

Qi, Sheng; McAuley, William J; Yang, Ziyi; Tipduangta, Pratchaya

2014-07-01

Use of the amorphous state is considered to be one of the most effective approaches for improving the dissolution and subsequent oral bioavailability of poorly water-soluble drugs. However as the amorphous state has much higher physical instability in comparison with its crystalline counterpart, stabilization of amorphous drugs in a solid-dosage form presents a major challenge to formulators. The currently used approaches for stabilizing amorphous drug are discussed in this article with respect to their preparation, mechanism of stabilization and limitations. In order to realize the potential of amorphous formulations, significant efforts are required to enable the prediction of formulation performance. This will facilitate the development of computational tools that can inform a rapid and rational formulation development process for amorphous drugs.

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery.

PubMed

Pozzoli, Michele; Traini, Daniela; Young, Paul M; Sukkar, Maria B; Sonvico, Fabio

2017-09-01

The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus ® (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route. The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray. The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus-BUD formulation. The freeze-dried Soluplus-BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334 ± 0.0178 m 2 /g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension. Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.

Effect of formulation pH on transdermal penetration of antiemetics formulated in poloxamer lecithin organogel.

PubMed

Woodall, Rachel; Arnold, John J; McKay, Doug; Asbill, C Scott

2013-01-01

The purpose of this study was to assess the impact of altering formulation pH on the transdermal penetration of several commonly used antiemetic, weakly basic drugs incorporated into poloxamer lecithin organogel vehicle. Poloxamer lecithin organogel formulations containing promethazine hydrochloride (25 mg/mL), metoclopramide hydrochloride (10 mg/mL), and ondansetron hydrochloride (8 mg/mL) were examined for both drug release and transdermal penetration across porcine skin in modified Franz diffusion cells for a period of 24 hours. For the transdermal studies, each antiemetic drug was formulated at a pH above and below their acid dissociation constant (pKa) in an attempt to assure that the drug would be primarily in their respective ionized or non-ionized states. In addition, drug content in skin was assessed at the end of the 24-hour experiment. Drug content analysis was determined via high-performance liquid chromatography. As a percent of total drug release from the poloxamer lecithin organogel vehicle, promethazine hydrochloride demonstrated the most transdermal drug penetration after 24 hours (30.2% +/- 20.2%), followed by ondansetron hydrochloride (2.7% +/- 1.1%) and metoclopramide hydrochloride (1.8% +/- 1.6%). Subsequently, the pH of the Pluronic F-127 gel was adjusted in order to ensure that each antiemetic drug would be primarily in its unionized state. The transdermal permeation of each antiemetic drug primarily in its unionized state increased over that observed with the drug primarily in its ionized state after 24 hours (promethazine: 1.6-fold increase; metoclopramide: 1.3-fold increase; ondansetron: 1.8-fold increase). A similar trend was noted in the amount of each drug found in the skin after 24 hours (promethazine: 1.2-fold increase; metoclopramide: 2.4-fold increase; ondansetron: 3.0-fold increase). These results suggest that proper optimization of drug ionization state may be a useful strategy for compounding pharmacists to increase the efficacy of drugs intended for inclusion in transdermal formulations.

Current and emerging formulation strategies for the effective transdermal delivery of HIV inhibitors.

PubMed

Ham, Anthony S; Buckheit, Robert W

2015-02-01

Current and emerging formulation strategies for skin permeation are poised to open the transdermal drug delivery to a broader range of small molecule compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Transdermal drug delivery offers several distinct advantages over traditional dosage forms. Current antiretroviral drugs used for the treatment of HIV infection include a variety of highly active small molecule compounds with significantly limited skin permeability, and thus new and novel means of enhancing transport through the skin are needed. Current and emerging formulation strategies are poised to open the transdermal drug delivery to a broader range of compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Thus, with continuing research into skin permeability and patch formulation strategies, there is a large potential for antiretroviral transdermal drug delivery.

Current and emerging formulation strategies for the effective transdermal delivery of HIV inhibitors

PubMed Central

Ham, Anthony S; Buckheit, Robert W

2015-01-01

Current and emerging formulation strategies for skin permeation are poised to open the transdermal drug delivery to a broader range of small molecule compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Transdermal drug delivery offers several distinct advantages over traditional dosage forms. Current antiretroviral drugs used for the treatment of HIV infection include a variety of highly active small molecule compounds with significantly limited skin permeability, and thus new and novel means of enhancing transport through the skin are needed. Current and emerging formulation strategies are poised to open the transdermal drug delivery to a broader range of compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Thus, with continuing research into skin permeability and patch formulation strategies, there is a large potential for antiretroviral transdermal drug delivery. PMID:25690088

Computational prediction of formulation strategies for beyond-rule-of-5 compounds.

PubMed

Bergström, Christel A S; Charman, William N; Porter, Christopher J H

2016-06-01

The physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of 'formulate-ability' during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Oral formulation strategies to improve solubility of poorly water-soluble drugs.

PubMed

Singh, Abhishek; Worku, Zelalem Ayenew; Van den Mooter, Guy

2011-10-01

In the past two decades, there has been a spiraling increase in the complexity and specificity of drug-receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends. Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends. Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.

Comparative drug release measurements in limited amounts of liquid: a suppository formulation study.

PubMed

Welch, Ken; Ek, Ragnar; Strømme, Maria

2006-07-01

A novel method for the investigation of drug formulations in limited liquid volumes is presented. The experimental setup consists of a measurement cell containing an absorbent sponge cloth placed between two parallel electrodes. Conductivity measurements are used to monitor the drug release from the dosage form. By varying the amount of water contained in the absorbent cloth surrounding the dosage form, it is possible to measure the drug release performance of the dosage form in very limited amounts of water. The method was employed to test four different tablet formulations consisting of the model drug NaCl incorporated in excipient matrices of hard fat, polyethylene glycol, microcrystalline cellulose and a mixture of microcrystalline cellulose and croscarmellose sodium (Ac-Di-Sol). The drug release rates of the different formulations in limited water volumes differed markedly from the release rates in an excess of water. Whereas the release rates from all tablet types in an excess of water showed only minor differences among the tablet types, the release rates from the tablets formulated with disintegrating excipients were clearly superior in limited water volumes. The developed method for drug release in limited volumes of liquid should be suitable for evaluation of rectal dosage forms.

Nanoengineered drug delivery systems for enhancing antibiotic therapy.

PubMed

Kalhapure, Rahul S; Suleman, Nadia; Mocktar, Chunderika; Seedat, Nasreen; Govender, Thirumala

2015-03-01

Formulation scientists are recognizing nanoengineered drug delivery systems as an effective strategy to overcome limitations associated with antibiotic drug therapy. Antibiotics encapsulated into nanodelivery systems will contribute to improved management of patients with various infectious diseases and to overcoming the serious global burden of antibiotic resistance. An extensive review of several antibiotic-loaded nanocarriers that have been formulated to target drugs to infectious sites, achieve controlled drug release profiles, and address formulation challenges, such as low-drug entrapment efficiencies, poor solubility and stability is presented in this paper. The physicochemical properties and the in vitro/in vivo performances of various antibiotic-loaded delivery systems, such as polymeric nanoparticles, micelles, dendrimers, liposomes, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanohybirds, nanofibers/scaffolds, nanosheets, nanoplexes, and nanotubes/horn/rods and nanoemulsions, are highlighted and evaluated. Future studies that will be essential to optimize formulation and commercialization of these antibiotic-loaded nanosystems are also identified. The review presented emphasizes the significant formulation progress achieved and potential that novel nanoengineered antibiotic drug delivery systems have for enhancing the treatment of patients with a range of infections. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Statistical optimization of tretinoin-loaded penetration-enhancer vesicles (PEV) for topical delivery.

PubMed

Bavarsad, Neda; Akhgari, Abbas; Seifmanesh, Somayeh; Salimi, Anayatollah; Rezaie, Annahita

2016-02-29

The aim of this study was to develop and optimize deformable liposome for topical delivery of tretinoin. Liposomal formulations were designed based on the full factorial design and prepared by fusion method. The influence of different ratio of soy phosphatidylcholine and transcutol (independent variables) on incorporation efficiency and drug release in 15 min and 24 h (responses) from liposomal formulations was evaluated. Liposomes were characterized for their vesicle size and Differential Scanning Calorimetry (DSC) was used to investigate changes in their thermal behavior. The penetration and retention of drug was determined using mouse skin. Also skin histology study was performed. Particle size of all formulations was smaller than 20 nm. Incorporation efficiency of liposomes was 79-93 %. Formulation F7 (25:5) showed maximum drug release. Optimum formulations were selected based on the contour plots resulted by statistical equations of drug release in 15 min and 24 h. Solubility properties of transcutol led to higher skin penetration for optimum formulations compared to tretinoin cream. There was no significant difference between the amount of drug retained in the skin by applying optimum formulations and cream. Histopatological investigation suggested optimum formulations could decrease the adverse effect of tretinoin in liposome compared to conventional cream. According to the results of the study, it is concluded that deformable liposome containing transcutol may be successfully used for dermal delivery of tretinoin.

Development of gellan gum containing formulations for transdermal drug delivery: Component evaluation and controlled drug release using temperature responsive nanogels.

PubMed

Carmona-Moran, Carlos A; Zavgorodnya, Oleksandra; Penman, Andrew D; Kharlampieva, Eugenia; Bridges, S Louis; Hergenrother, Robert W; Singh, Jasvinder A; Wick, Timothy M

2016-07-25

Enhancing skin permeation is important for development of new transdermal drug delivery formulations. This is particularly relevant for non-steroidal anti-inflammatory drugs (NSAIDs). To address this, semisolid gel and solid hydrogel film formulations containing gellan gum as a gelling agent were developed and the effects of penetration enhancers (dimethyl sulfoxide, isopropyl alcohol and propylene glycol) on transport of the NSAID diclofenac sodium was quantified. A transwell diffusion system was used to accelerate formulation development. After 4h, diclofenac flux from a superior formulation of the semisolid gel or the solid hydrogel film was 130±11μg/cm(2)h and 108±7μg/cm(2)h, respectively, and significantly greater than that measured for a currently available diclofenac sodium topical gel (30±4μg/cm(2)h, p<0.05) or solution formulation (44±6μg/cm(2)h, p<0.05) under identical conditions. Over 24h diclofenac transport from the solid hydrogel film was greater than that measured for any new or commercial diclofenac formulation. Entrapment of temperature-responsive nanogels within the solid hydrogel film provides temperature-activated prolonged release of diclofenac. Diclofenac transport was minimal at 22°C, when diclofenac is entrapped within temperature-responsive nanogels incorporated into the solid hydrogel film, but increased 6-fold when the temperature was increased to skin surface temperature of 32°C. These results demonstrate the feasibility of the semisolid gel and solid hydrogel film formulations that can include thermo-responsive nanogels for development of transdermal drug formulations with adjustable drug transport kinetics. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis and evaluation of mesoporous carbon/lipid bilayer nanocomposites for improved oral delivery of the poorly water-soluble drug, nimodipine.

PubMed

Zhang, Yanzhuo; Zhao, Qinfu; Zhu, Wufu; Zhang, Lihua; Han, Jin; Lin, Qisi; Ai, Fengwei

2015-07-01

A novel mesoporous carbon/lipid bilayer nanocomposite (MCLN) with a core-shell structure was synthesized and characterized as an oral drug delivery system for poorly water-soluble drugs. The objective of this study was to investigate the potential of MCLN-based formulation to modulate the in vitro release and in vivo absorption of a model drug, nimodipine (NIM). NIM-loaded MCLN was prepared by a procedure involving a combination of thin-film hydration and lyophilization. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), specific surface area analysis, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were employed to characterize the NIM-loaded MCLN formulation. The effect of MCLN on cell viability was assessed using the MTT assay. In addition, the oral bioavailability of NIM-loaded MCLN in beagle dogs was compared with that of the immediate-release formulation, Nimotop®. Our results demonstrate that the NIM-loaded MCLN formulation exhibited a typical sustained release pattern. The NIM-loaded MCLN formulation achieved a greater degree of absorption and longer lasting plasma drug levels compared with the commercial formulation. The relative bioavailability of NIM for NIM-loaded MCLN was 214%. MCLN exhibited negligible toxicity. The data reported herein suggest that the MCLN matrix is a promising carrier for controlling the drug release rate and improving the oral absorption of poorly water-soluble drugs.

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.

Calcipotriol delivery into the skin as emulgel for effective permeation

PubMed Central

Naga Sravan Kumar Varma, V.; Maheshwari, P.V.; Navya, M.; Reddy, Sharath Chandra; Shivakumar, H.G.; Gowda, D.V.

2014-01-01

The objective of this work is to formulate and evaluate an emulgel containing calcipotriol for treatment of psoriasis. Emulgels have emerged as a promising drug delivery system for the delivery of hydrophobic drugs. Isopropyl alcohol and polyethylene glycol have been employed as permeation enhancers. Formulation chart is made with seven formulations, evaluated for physical parameters, drug content, viscosity, thixotropy, spreadability, extrudability, mucoadhesion, diffusion studies, skin irritation test along with short term stability studies. Carbopolis is reported to have a direct influence on appearance and viscosity of final formulation. The photomicroscopic evaluations showed the presence of spherical globules in size range of 10–15 μm. Rheograms revealed that all the formulations exhibited pseudoplastic flow. Optimized formulation (F6) had shown 86.42 ± 2.0% drug release at the end of 8 h study. The release rate through dialysis membrane and rat skin is higher when compared to commercial calcipotriol ointment. Hence it is concluded that calcipotriol can be delivered topically with enhanced penetration properties when formulated as emulgel. PMID:25561873

Effects of drug-carrier interactions on drug dissolution from binary and ternary matrices

NASA Astrophysics Data System (ADS)

Iqbal, Zafar

For nearly five decades, pharmaceutical researchers have studied solid solutions of drugs in polymers as a potential means to enhance the dissolution of drugs with poor aqueous solubility. This has become of greater importance in recent years because most new potential drug compounds (new chemical entities) exhibit poor water solubility and present great challenges to scientists who must design dosage forms from which the drugs are bioavailable. During the formulation of a solid solution, the drug undergoes physical but not chemical alterations that increase its chemical potential in the formulation relative to that of the pure drug in its stable form. This increased chemical potential is responsible for enhanced dissolution as well as physical instabilities, such as amorphous to crystalline conversions and precipitation within the solid state. The chemical potential is derived from the Gibbs free energy, so it is reasonable to explain the behavior of solid solution systems in terms of thermodynamics. Solid solutions and dispersions have been extensively studied by pharmaceutical scientists, both with regard to manufacturing aspects and the proposal of various models in attempts to explain the physical bases for how these systems work. Recently, Dave and Bellantone proposed a model based on the thermodynamic changes resulting from the formulation of binary solid solutions of a drug in the polymer PVP. Their model introduced a modification of the F-H theory, which was used to quantify the drug-polymer interaction energies and calculate the entropy of mixing of the drug and polymer. In this work, the model of Dave and Bellantone was extended to include three-component systems, consisting of one drug mixed in a carrier matrix consisting of mixture of two polymers or a polymer and a surfactant. For this research, solid solutions were formed using various drug weight fractions in the formulations. The study focused on the following points: (1) Prepare solid solution formulations and perform appropriate physical characterizations. (2) Characterize the increase in drug dissolution rates resulting from solid solution formulations. (3) Relate the initial dissolution rates to the drug solubility. (4) Explain the solubility enhancement from solid solution dosage in terms of the drug polymer interactions using the extended thermodynamic model. Two poorly water soluble drugs, levonorgestrel (LEVO) and ethinyl estradiol (EE) were formulated in seven solid solution preparations comprised of four carrier systems. Materials used as carriers included various combinations of the polymers PVP K-30, Copovidone (COP), Poloxamer 182, and the surfactant TweenRTM 20. Additionally, ibuprofen (IBU) was used in three formulations consisting of various combinations of PVP K-30, Copovidone and TweenRTM 20. Formulations with various drug weight fractions (0.5%--30%) were prepared using the solvent evaporation technique. Each formulation was tested for dissolution using intrinsic dissolution apparatus (USP). The solid solutions were compressed into tablets into the sample die that maintained a constant surface area during the dissolution process. DSC, XRD and NIRS scans identified that the crystalline peaks of the drug disappeared with the addition of the polymer for all ratios of EE, indicating the formation of solid solutions (to within the limits of detection of the equipment). This was also observed for the LEVO dispersions up to 10% drug loading. At higher drug loading, solutions were formed but some small degree crystallinity was also present. For each experiment, the initial dissolution rates were obtained from the slope of the mass dissolved vs. time plots taken at early times, and volume normalized initial dissolution rates RV were calculated by dividing the initial dissolution rate by the volume fraction of the drug in the formulation. Comparison of the RV values for the various formulations with a reference RV (typically that of the pure drug or of the formulation with the highest polymer content) allowed calculation of relative volume normalized dissolution rates (RNV). The various RNV were used in the thermodynamic model for data analyses and to determine the interactions between the drug and carrier molecules. It was generally seen that RNV increased with decreased drug fraction, and was adequately modeled by the equations derived from the extended thermodynamic model. It was concluded that the model proposed for the binary and ternary systems successfully represented the mechanism of drug-polymer interaction and the energy changes taken place within the dispersion systems. The dissolution data analysis and subsequent understanding of physical modifications in the dispersion systems characterized by XRD, NIRS and DSC further substantiated the findings. The understanding of the fundamental physical might help scientists to predict the effects of mixing various drugs and polymers, and the effects of varying ratios.

Assessment of formulated amodiaquine microparticles in Leishmania donovani infected rats.

PubMed

Nettey, Henry; Allotey-Babington, Grace Lovia; Somuah, Isaac; Banga, N'guessan Benoit; Afrane, Barima; Amponsah, Seth Kwabena; Annor, Henrietta; Darko, Henry; Hanson, Kwame; Aidoo, Anoa; Broni, Marisa Nyarkoa; Sasu, Clement; Nyarko, Alexander

2017-02-01

The aim of this study was to formulate, characterise and evaluate the activity of amodiaquine microparticles against Leishmania donovani. Microparticles were formulated by encapsulating the drug in bovine serum albumin using the spray-dryer method. The microparticles were evaluated for size, zeta potential, drug content, encapsulation efficiency and in vitro release profile. The size range of the microparticles formulated was between 1.9 and 10 μm with an average zeta potential of -25.5 mV. Of the expected 20% drug loading, an average of 18.27% was obtained giving an encapsulation efficiency of 91.35%. Pharmacokinetic profile of amodiaquine improved with microencapsulation of the drug with C max , AUC 0→48 and t 1//2 all significantly higher than amodiaquine solution. Amodiaquine microparticles showed an overall higher bioavailability and hence were more effective in eliminating intra-tissue parasites than the drug solution. It would therefore be expected that the formulated microparticles will be more effective in treating visceral leishmaniasis.

Transdermal glimepiride delivery system based on optimized ethosomal nano-vesicles: Preparation, characterization, in vitro, ex vivo and clinical evaluation.

PubMed

Ahmed, Tarek A; El-Say, Khalid M; Aljaeid, Bader M; Fahmy, Usama A; Abd-Allah, Fathy I

2016-03-16

This work aimed to develop an optimized ethosomal formulation of glimepiride then loading into transdermal films to offer lower drug side effect, extended release behavior and avoid first pass effect. Four formulation factors were optimized for their effects on vesicle size (Y1), entrapment efficiency (Y2) and vesicle flexibility (Y3). Optimum desirability was identified and, an optimized formulation was prepared, characterized and loaded into transdermal films. Ex-vivo permeation study for the prepared films was conducted and, the permeation parameters and drug permeation mechanism were identified. Penetration through rat skin was studied using confocal laser microscope. In-vivo study was performed following transdermal application on human volunteers. The percent of alcohol was significantly affecting all the studied responses while the other factors and their interaction effects were varied on their effects on each response. The optimized ethosomal formulation showed observed values for Y1, Y2 and Y3 of 61 nm, 97.12% and 54.03, respectively. Ex-vivo permeation of films loaded with optimized ethosomal formulation was superior to that of the corresponding pure drug transdermal films and this finding was also confirmed after confocal laser microscope study. Permeation of glimepiride from the prepared films was in favor of Higushi-diffusion model and exhibited non-Fickian or anomalous release mechanism. In-vivo study revealed extended drug release behavior and lower maximum drug plasma level from transdermal films loaded with drug ethosomal formulation. So, the ethosomal formulation could be considered a suitable drug delivery system especially when loaded into transdermal vehicle with possible reduction in side effects and controlling the drug release. Copyright © 2016 Elsevier B.V. All rights reserved.

Enhanced in vivo absorption of CB-1 antagonist in rats via solid solutions prepared by hot-melt extrusion.

PubMed

Ranzani, L S; Font, J; Galimany, F; Santanach, A; Gomez-Gomar, A M; Casadevall, G; Gryczke, A

2011-06-01

The aim of the present work was to investigate in vitro dissolution properties of three binary solid solutions prepared by a hot-melt extrusion (HME) process with vinyl pirrolidone--vinyl acetate copolymer (Kollidon VA 64), ethyl acrylate, methyl methacrylate polymer (Eudragit E) polyetilenglicol 8000 (PEG 8000) with a cannabinoid type 1 (CB-1) antagonist. Hansen solubility parameters were calculated from the chemical structures of the drug and the individual polymers in order to predict miscibility. Solid state characterizations of drug substance, physical blends and HME formulations were performed with differential scanning calorimetry. The dissolution testing conducted under sink conditions revealed that the dissolution rate of HME formulations improved around 1.8-fold vs drug substance. Supersaturation dissolution study demonstrated that HME formulations composed by Eudragit E and Kollidon VA64 increased drug solubility between 30- and 35-fold, respectively comparing to the drug substance. Physical and chemical stability of formulations were studied at 40°C/75%HR with open dish during 15 days. The formulation composed by the drug and Eudragit E at 10:90 was evaluated for in vivo drug absorption in male Wistar-Hannover rats and it was found to increase CB-1 absorption threefold greater than pure drug oral suspension.

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.

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.

Formulation and optimization of zinc-pectinate beads for the controlled delivery of resveratrol.

PubMed

Das, Surajit; Ng, Ka-Yun; Ho, Paul C

2010-06-01

Preventive and therapeutic efficacies of resveratrol on several lower gastrointestinal (GI) diseases (e.g., colorectal cancer, colitis) are well documented. To overcome the problems due to its rapid absorption and metabolism at the upper GI tract, a delayed release formulation of resveratrol was designed to treat these lower GI diseases. The current study aimed to develop a delayed release formulation of resveratrol as multiparticulate pectinate beads by varying different formulation parameters. Zinc-pectinate (Zn-pectinate) beads exhibited better delayed drug release pattern than calcium-pectinate (Ca-pectinate) beads. The effects of the formulation parameters were investigated on shape, size, Zn content, moisture content, drug encapsulation efficiency, swelling-erosion, and resveratrol retention pattern of the formulated beads. Upon optimization of the formulation parameters in relative to the drug release profiles, the optimized beads were further subjected to morphological, chemical interaction, enzymatic degradation, and stability studies. Almost all prepared beads were spherical with approximately 1 mm diameter and efficiently encapsulated resveratrol. The formulation parameters revealed great influence on resveratrol retention and swelling-erosion behavior. In most of the cases, the drug release data more appropriately fitted with zero-order equation. This study demonstrates that the optimized Zn-pectinate beads can encapsulate very high amount of resveratrol and can be used as delayed release formulation of resveratrol.

Swelling, erosion and drug release characteristics of salbutamol sulfate from hydroxypropyl methylcellulose-based matrix tablets.

PubMed

Chaibva, Faith A; Khamanga, Sandile M M; Walker, Roderick B

2010-12-01

Hydrophilic matrix formulations are important and simple technologies that are used to manufacture sustained release dosage forms. Hydroxypropyl methylcellulose-based matrix tablets, with and without additives, were manufactured to investigate the rate of hydration, rate of erosion, and rate and mechanism of drug release. Scanning electron microscopy was used to assess changes in the microstructure of the tablets during drug release testing and whether these changes could be related to the rate of drug release from the formulations. The results revealed that the rate of hydration and erosion was dependent on the polymer combination(s) used, which in turn affected the rate and mechanism of drug release from these formulations. It was also apparent that changes in the microstructure of matrix tablets could be related to the different rates of drug release that were observed from the test formulations. The use of scanning electron microscopy provides useful information to further understand drug release mechanisms from matrix tablets.

Induction of oxidative stress by Taxol® vehicle Cremophor-EL triggers production of interleukin-8 by peripheral blood mononuclear cells through the mechanism not requiring de novo synthesis of mRNA.

PubMed

Ilinskaya, Anna N; Clogston, Jeffrey D; McNeil, Scott E; Dobrovolskaia, Marina A

2015-11-01

Understanding the ability of cytotoxic oncology drugs, and their carriers and formulation excipients, to induce pro-inflammatory responses is important for establishing safe and efficacious formulations. Literature data about cytokine response induction by the traditional formulation of paclitaxel, Taxol®, are controversial, and no data are available about the pro-inflammatory profile of the nano-albumin formulation of this drug, Abraxane®. Herein, we demonstrate and explain the difference in the cytokine induction profile between Taxol® and Abraxane®, and describe a novel mechanism of cytokine induction by a nanosized excipient, Cremophor EL, which is not unique to Taxol® and is commonly used in the pharmaceutical industry for delivery of a wide variety of small molecular drugs. Advances in nanotechnology have enabled the production of many nano-formulation drugs. The cellular response to drugs has been reported to be different between traditional and nano-formulations. In this article, the authors investigated and compared cytokine response induction profiles between Taxol® and Abraxane®. The findings here provided further understanding to create drugs with better safety profiles. Copyright © 2015 Elsevier Inc. All rights reserved.

Drug Release and Skin Permeation from Lipid Liquid Crystalline Phases

NASA Astrophysics Data System (ADS)

Costa-Balogh, F. O.; Sparr, E.; Sousa, J. J. S.; Pais, A. A. C. C.

We have studied drug release and skin permeation from several different liquid crystalline lipid formulations that may be used to control the respective release rates. We have studied the release and permeation through human skin of a water-soluble and amphiphilic drug, propranolol hydrochloride, from several formulations prepared with monoolein and phytantriol as permeation enhancers and controlled release excipients. Diolein and cineol were added to selected formulations. We observed that viscosity decreases with drug load, wich is compatible with the occurrence of phase changes. Diolein stabilizes the bicontinuous cubic phases leading to an increase in viscosity and sustained release of the drug. The slowest release was found for the cubic phases with higher viscosity. Studies on skin permeation showed that these latter formulations also presented lower permeability than the less viscous monoolein lamellar phases. Formulations containing cineol originated higher permeability with higher enhancement ratios. Thus, the various formulations are adapted to different circumstances and delivery routes. While a slow release is usually desired for drug sustained delivery, the transdermal route may require a faster release. Lamellar phases, which are less viscous, are more adapted to transdermal applications. Thus, systems involving lamellar phases of monoolein and cineol are good candidates to be used as skin permeation enhancers for propranolol hydrochloride.

Optimization of Primary Drying in Lyophilization during Early Phase Drug Development using a Definitive Screening Design with Formulation and Process Factors.

PubMed

Goldman, Johnathan M; More, Haresh T; Yee, Olga; Borgeson, Elizabeth; Remy, Brenda; Rowe, Jasmine; Sadineni, Vikram

2018-06-08

Development of optimal drug product lyophilization cycles is typically accomplished via multiple engineering runs to determine appropriate process parameters. These runs require significant time and product investments, which are especially costly during early phase development when the drug product formulation and lyophilization process are often defined simultaneously. Even small changes in the formulation may require a new set of engineering runs to define lyophilization process parameters. In order to overcome these development difficulties, an eight factor definitive screening design (DSD), including both formulation and process parameters, was executed on a fully human monoclonal antibody (mAb) drug product. The DSD enables evaluation of several interdependent factors to define critical parameters that affect primary drying time and product temperature. From these parameters, a lyophilization development model is defined where near optimal process parameters can be derived for many different drug product formulations. This concept is demonstrated on a mAb drug product where statistically predicted cycle responses agree well with those measured experimentally. This design of experiments (DoE) approach for early phase lyophilization cycle development offers a workflow that significantly decreases the development time of clinically and potentially commercially viable lyophilization cycles for a platform formulation that still has variable range of compositions. Copyright © 2018. Published by Elsevier Inc.

Formulation and evaluation of controlled release antibiotic biodegradable implants for post operative site delivery.

PubMed

Mathur, Vijay; Mudnaik, Rajesh; Barde, Laxmikant; Roy, Arghya; Shivhare, Umesh; Bhusari, Kishore

2010-03-01

Biodegradable implants of ciprofloxacin hydrochloride for post operative site delivery were prepared using glyceryl monostearate and different concentrations of polyethylene glycol (PEG 6000), glycerol and Tween 80 as erosion enhancers by compression and molding technique. Formulations were subjected to in vitro drug release by the USP dissolution method, while promising formulations were subjected to in vitro drug release by the agar gel method and also to stability studies. It was observed that glyceryl monostearate formed hydrophobic matrix and delayed the drug delivery. Antibiotic release profile was controlled by using different combinations of erosion enhancers. The formulation prepared by the compression method showed more delayed release compared to formulations prepared by the molding method.

Biowaiver extension potential and IVIVC for BCS Class II drugs by formulation design: Case study for cyclosporine self-microemulsifying formulation.

PubMed

Yang, Su-Geun

2010-11-01

The objective of this work was to suggest the biowaiver potential of biopharmaceutical classification system (BCS) Class II drugs in self-microemulsifying drug delivery systems (SMEDDS) which are known to increase the solubility, dissolution and oral absorption of water-insoluble drugs. Cyclosporine was selected as a representative BCS Class II drug. New generic candidate of cyclosporine SMEDDS (test) was applied for the study with brand SMEDDS (reference I) and cyclosporine self-emulsifying drug delivery systems (SEDDS, reference II). Solubility and dissolution of cyclosporine from SMEDDS were critically enhanced, which were the similar behaviors with BCS class I drug. The test showed the identical dissolution rate and the equivalent bioavailability (0.34, 0.42 and 0.68 of p values for AUC₀(→)₂₄(h), C(max) and T(max), respectively) with the reference I. Based on the results, level A in vitro-in vivo correlation (IVIVC) was established from these two SMEDDS formulations. This study serves as a good example for speculating the biowaiver extension potential of BCS Class II drugs specifically in solubilizing formulation such as SMEDDS.

Enhancement of oral bioavailability of atorvastatin calcium by self-emulsifying drug delivery systems (SEDDS).

PubMed

Kadu, Pawan J; Kushare, Sachin S; Thacker, Dhaval D; Gattani, Surendra G

2011-02-01

The aim of the present study was to formulate a self-emulsifying drug delivery system of atorvastatin calcium and its characterization including in vitro and in vivo potential. The solubility of atorvastatin calcium was determined in various vehicles such as Captex 355, Captex 355 EP/NF, Ethyl oleate, Capmul MCM, Capmul PG-8, Gelucire 44/14, Tween 80, Tween 20, and PEG 400. Pseudoternary phase diagrams were plotted on the basis of solubility data of drug in various components to evaluate the microemulsification region. Formulation development and screening was carried out based on results obtained from phase diagrams and characteristics of resultant microemulsion. Prepared formulations were tested for microemulsifying properties and evaluated for clarity, precipitation, viscosity determination, drug content and in vitro dissolution. The optimized formulation further evaluated for particle size distribution, zeta potential, stability studies and in vivo potential. In vivo performance of the optimized formulation was evaluated using a Triton-induced hypercholesterolemia model in male Albino Wistar rats. The formulation significantly reduced serum lipid levels as compared with atorvastatin calcium. Thus studies illustrated the potential use for the delivery of hydrophobic drug such as atorvastatin calcium by oral route.

Formulation and Characterization of Benzoyl Peroxide Gellified Emulsions

PubMed Central

Thakur, Naresh Kumar; Bharti, Pratibha; Mahant, Sheefali; Rao, Rekha

2012-01-01

The present investigation was carried out with the objective of formulating a gellified emulsion of benzoyl peroxide, an anti-acne agent. The formulations were prepared using four different vegetable oils, viz. almond oil, jojoba oil, sesame oil, and wheat germ oil, owing to their emollient properties. The idea was to overcome the skin irritation and dryness caused by benzoyl peroxide, making the formulation more tolerable. The gellified emulsions were characterized for their homogeneity, rheology, spreadability, drug content, and stability. In vitro permeation studies were performed to check the drug permeation through rat skin. The formulations were evaluated for their antimicrobial activity, as well as their acute skin irritation potential. The results were compared with those obtained for the marketed formulation. Later, the histopathological examination of the skin treated with various formulations was carried out. Formulation F3 was found to have caused a very mild dysplastic change to the epidermis. On the other hand, the marketed formulation led to the greatest dysplastic change. Hence, it was concluded that formulation F3, containing sesame oil (6%w/w), was the optimized formulation. It exhibited the maximum drug release and anti-microbial activity, in addition to the least skin irritation potential. PMID:23264949

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.

Single processing step toward injectable sustained-release formulations of Triptorelin based on a novel degradable semi-solid polymer.

PubMed

Asmus, Lutz R; Kaufmann, Béatrice; Melander, Louise; Weiss, Torsten; Schwach, Grégoire; Gurny, Robert; Möller, Michael

2012-08-01

Poly(lactic acid) is a widely used polymer for parenteral sustained-release formulations. But its solid state at room-temperature complicates the formulation process, and elaborate formulation systems like microparticles and self-precipitating implants are required for administration. In contrast, hexylsubstituted poly(lactic acid) (hexPLA) is a viscous, biodegradable liquid, which can simply be mixed with the active compound. In this study, the feasibility to prepare injectable suspension formulations with peptides was addressed on the example of the GnRH-agonist Triptorelin. Two formulation procedures, of which one was a straight forward one-step cryo-milling-mixing process, were compared regarding the particle size of the peptide in the polymer matrix, distribution, and drug release. This beneficial method resulted in a homogeneous formulation with an average particle diameter of the incorporated Triptorelin of only 4.1 μm. The rheological behavior of the Triptorelin-hexPLA formulations was assessed and showed thixotropic and shear-thinning behavior. Viscosity and injectability were highly dependent on the drug loading, polymer molecular weight, and temperature. Nine formulations with drug loadings from 2.5% to 10% and hexPLA molecular weights between 1500 and 5000 g/mol were investigated in release experiments, and all displayed a long-term release for over 3 months. Formulations with hexPLA of 1500 g/mol showed a viscosity-dependent release and hexPLA-Triptorelin formulations of over 2500 g/mol a molecular weight-dependent release profile. In consequence, the burst release and rate of release were controllable by adapting the drug loading and the molecular weight of the hexPLA. The degradation characteristics of the hexPLA polymer during the in vitro release experiment were studied by following the molecular weight decrease and weight loss. Triptorelin-hexPLA formulations had interesting sustained-release characteristics justifying further investigations in the drug-polymer interactions and the in vivo behavior. Copyright © 2012 Elsevier B.V. All rights reserved.

Development and evaluation of in situ gel of pregabalin

PubMed Central

Madan, Jyotsana R; Adokar, Bhushan R; Dua, Kamal

2015-01-01

Aim and Background: Pregabalin (PRG), an analog of gamma-aminobutyric acid, reduces the release of many neurotransmitters, including glutamate, and noradrenaline. It is used for the treatment of epilepsy; simple and complex partial convulsion. The present research work aims to ensure a high drug absorption by retarding the advancement of PRG formulation through the gastrointestinal tract. The work aims to design a controlled release PRG formulation which is administered as liquid and further gels in the stomach and floats in gastric juice. Materials and Methods: In situ gelling formulations were prepared using sodium alginate, calcium chloride, sodium citrate, hydroxypropyl methylcellulose (HPMC) K100M, and sodium bicarbonate. The prepared formulations were evaluated for solution viscosity, drug content, in vitro gelling studies, gel strength, and in vitro drug release. The final formulation was optimized using a 32 full factorial design. Results: The formulation containing 2.5% w/v sodium alginate and 0.2% w/v calcium chloride were considered optimum since it showed minimum floating lag time (18 s), optimum viscosity (287.3 cps), and gel strength (4087.17 dyne/cm2). The optimized formulation follows Korsmeyer-Peppas kinetic model with n value 0.3767 representing Fickian diffusion mechanism of drug release. Conclusion: Floating in situ gelling system of PRG can be formulated using sodium alginate as a gelling polymer and calcium chloride as a complexing agent to control the drug release for about 12 h for the treatment of epilepsy. PMID:26682193

High drug load, stable, manufacturable and bioavailable fenofibrate formulations in mesoporous silica: a comparison of spray drying versus solvent impregnation methods.

PubMed

Hong, Shiqi; Shen, Shoucang; Tan, David Cheng Thiam; Ng, Wai Kiong; Liu, Xueming; Chia, Leonard S O; Irwan, Anastasia W; Tan, Reginald; Nowak, Steven A; Marsh, Kennan; Gokhale, Rajeev

2016-01-01

Encapsulation of drugs in mesoporous silica using co-spray drying process has been recently explored as potential industrial method. However, the impact of spray drying on manufacturability, physiochemical stability and bioavailability in relation to conventional drug load processes are yet to be fully investigated. Using a 2(3) factorial design, this study aims to investigate the effect of drug-loading process (co-spray drying and solvent impregnation), mesoporous silica pore size (SBA-15, 6.5 nm and MCM-41, 2.5 nm) and percentage drug load (30% w/w and 50% w/w) on material properties, crystallinity, physicochemical stability, release profiles and bioavailability of fenofibrate (FEN) loaded into mesoporous silica. From the scanning electronic microscopy (SEM) images, powder X-ray diffraction and Differential scanning calorimetry measurements, it is indicated that the co-spray drying process was able to load up to 50% (w/w) FEN in amorphous form onto the mesoporous silica as compared to the 30% (w/w) for solvent impregnation. The in vitro dissolution rate of the co-spray dried formulations was also significantly (p = 0.044) better than solvent impregnated formulations at the same drug loading. Six-month accelerated stability test at 40 °C/75 RH in open dish indicated excellent physical and chemical stability of formulations prepared by both methods. The amorphous state of FEN and the enhanced dissolution profiles were well preserved, and very low levels of degradation were detected after storage. The dog data for the three selected co-spray-dried formulations revealed multiple fold increment in FEN bioavailability compared to the reference crystalline FEN. These results validate the viability of co-spray-dried mesoporous silica formulations with high amorphous drug load as potential drug delivery systems for poorly water soluble drugs.

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.

Drug nanosuspensions: a ZIP tool between traditional and innovative pharmaceutical formulations.

PubMed

Leone, Federica; Cavalli, Roberta

2015-01-01

A nanosuspension or nanocrystal suspension is a versatile formulation combining conventional and innovative features. It comprises 100% pure drug nanoparticles with sizes in the nano-scale range, generally stabilized by surfactants or polymers. Nanosuspensions are usually obtained in liquid media with bottom-up and top-down methods or by their combination. They have been designed to enhance the solubility, the dissolution rate and the bioavailability of drugs via various administration routes. Due to their small sizes, nanosuspensions can be also considered a drug delivery nanotechnology for the preparation of nanomedicine products. This review focuses on the state of the art of the nanocrystal-based formulation. It describes theory characteristics, design parameters, preparation methods, stability issues, as well as specific in vivo applications. Innovative strategies proposed to obtain nanomedicine formulation using nanocrystals are also reported. Many drug nanodelivery systems have been developed to increase the bioavailability of drugs and to decrease adverse side effects, but few can be industrially manufactured. Nanocrystals can close this gap by combining traditional and innovative drug formulations. Indeed, they can be used in many pharmaceutical dosage forms as such, or developed as new nano-scaled products. Engineered surface nanocrystals have recently been proposed as a dual strategy for stability enhancement and targeting delivery of nanocrystals.

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.

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

Implications of formulation design on lipid-based nanostructured carrier system for drug delivery to brain.

PubMed

Salunkhe, Sachin S; Bhatia, Neela M; Bhatia, Manish S

2016-05-01

The aim of present investigation was to formulate and develop lipid-based nanostructured carriers (NLCs) containing Idebenone (IDE) for delivery to brain. Attempts have been made to evaluate IDE NLCs for its pharmacokinetic and pharmacodynamic profile through the objective of enhancement in bioavailability and effectivity of drug. Nanoprecipitation technique was used for development of drug loaded NLCs. The components solid lipid Precirol ATO 5, oil Miglyol 840, surfactants Tween 80 and Labrasol have been screened out for formulation development by consideration of preformulation parameters including solubility, Required Hydrophilic lipophilic balance (HLB) of lipids and stability study. Developed IDE NLCs were subjected for particle size, zeta potential, entrapment efficiency (%EE), crystallographic investigation, transmission electron microscopy, in vitro drug release, pharmacokinetics, in vivo and stability study. Formulation under investigation has particle size 174.1 ± 2.6 nm, zeta potential -18.65 ± 1.13 mV and% EE 90.68 ± 2.90. Crystallographic studies exemplified for partial amorphization of IDE by molecularly dispersion within lipid crust. IDE NLCs showed drug release 93.56 ± 0.39% at end of 24 h by following Higuchi model which necessitates for appropriate drug delivery with enhancement in bioavailability of drug by 4.6-fold in plasma and 2.8-fold in brain over plain drug loaded aqueous dispersions. In vivo studies revealed that effect of drug was enhanced by prepared lipid nanocarriers. IDE lipid-based nanostructured carriers could have potential for efficient drug delivery to brain with enhancement in bioavailability of drug over the conventional formulations.

Development and characterization of minoxidil-loaded liposomal system for delivery to pilosebaceous units.

PubMed

Jain, Bhawna; Singh, Bhupinder; Katare, Om Prakash; Vyas, Suresh Prashad

2010-06-01

The current study aimed to deliver minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide; MXD), a potent hypertrichotic agent, into the pilosebaceous units, exploring the potential of the liposomal system. MXD-loaded liposomes of different compositions were prepared by a thin-film hydration technique and subsequently characterized for various vesicle-specific attributes (i.e., size, shape, lamellarity, and entrapment efficiency). Comparative analysis among these compositions was conducted with reference to their vesicle-specific parameters, drug deposition, and drug-delivery mechanism toward pilosebaceous units. The latter may bring about a distinct change in MXD therapy for various ailments related to pilosebaceous units, such as alopecia. The in vitro drug release, ex vivo skin permeation, and drug-retention behavior of the prepared formulation were evaluated by employing rat skin (normal as well as pilosebaceous free) and semipermeable membrane. The results revealed that the neutral liposomes (mean vesicle size, 3.83 +/- 0.18 microm) showed maximum drug deposition in the pilosebaceous units among all the other tested formulations. A quantitative estimation of pilosebaceous delivery revealed that the concentration of MXD in each pilosebaceous unit decreased in the following order: neutral liposomal formulation (5.8 x 10(3) to 7.25 x 10(3) microg) > positively charged liposomal formulation (4.7 x 10(3) to 5.87 x 10(3) microg) > negatively charged liposomal formulation (4.2 x 10(3) to 5.25 x 10(3) microg) > nonliposomal formulation (1.6 x 10(3) to 2.0 x 10(3) microg). Stability studies construed the need to store the liposomal formulation at lower temperatures. The results of the current work indicate that the neutral liposomes can deliver the drug molecules into pilosebaceous units more effectively than the other studied formulations.

Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug.

PubMed

Mitra, Amitava; Li, Li; Marsac, Patrick; Marks, Brian; Liu, Zhen; Brown, Chad

2016-05-30

Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility=1μg/mL). The poor solubility of the compound and high dose (300mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life. Copyright © 2016 Elsevier B.V. All rights reserved.

Dissolution properties of co-amorphous drug-amino acid formulations in buffer and biorelevant media.

PubMed

Heikkinen, A T; DeClerck, L; Löbmann, K; Grohganz, H; Rades, T; Laitinen, R

2015-07-01

Co-amorphous formulations, particularly binary drug-amino acid mixtures, have been shown to provide enhanced dissolution for poorly-soluble drugs and improved physical stability of the amorphous state. However, to date the dissolution properties (mainly intrinsic dissolution rate) of the co-amorphous formulations have been tested only in buffers and their supersaturation ability remain unexplored. Consequently, dissolution studies in simulated intestinal fluids need to be conducted in order to better evaluate the potential of these systems in increasing the oral bioavailability of biopharmaceutics classification system class II drugs. In this study, solubility and dissolution properties of the co-amorphous simvastatin-lysine, gibenclamide-serine, glibenclamide-threonine and glibenclamide-serine-threonine were studied in phosphate buffer pH 7.2 and biorelevant media (fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, respectively)). The co-amorphous formulations were found to provide a long-lasting supersaturation and improve the dissolution of the drugs compared to the crystalline and amorphous drugs alone in buffer. Similar improvement, but in lesser extent, was observed in biorelevant media suggesting that a dissolution advantage observed in aqueous buffers may overestimate the advantage in vivo. However, the results show that, in addition to stability advantage shown earlier, co-amorphous drug-amino acid formulations provide dissolution advantage over crystalline drugs in both aqueous and biorelevant conditions.

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.

Spray-dried high-amylose sodium carboxymethyl starch: impact of α-amylase on drug-release profile.

PubMed

Nabais, Teresa; Zaraa, Sarra; Leclair, Grégoire

2016-11-01

Spray-dried high-amylose sodium carboxymethyl starch (SD HASCA) is a promising pharmaceutical excipient for sustained-release (SR) matrix tablets produced by direct compression. The presence of α-amylase in the gastrointestinal tract and the variations of the gastric residence time of non-disintegrating dosage forms may affect the presystemic metabolism of this excipient and, consequently, the drug-release profile from formulations produced with SD HASCA. In this study, the influence of α-amylase and the residence time in acidic conditions on the drug-release profile was evaluated for a once-daily acetaminophen formulation (Acetaminophen SR) and a once-daily tramadol hydrochloride formulation (Tramadol SR). Both formulations were based on SD HASCA. α-Amylase concentrations ranging from 0 IU/L to 20000 IU/L did not significantly affect the drug-release profiles of acetaminophen and tramadol hydrochloride from SD HASCA tablets (f2 > 50) for all but only one of the studied conditions (f2 = 47). Moreover, the drug-release properties from both SD HASCA formulations were not significantly different when the residence time in acidic medium was 1 h or 3 h. An increase in α-amylase concentration led to an increase in the importance of polymer erosion as the main mechanism of drug-release instead of drug diffusion, for both formulations and both residence times, even if release profiles remained comparable. As such, it is expected that α-amylase concentration and residence time in the stomach will not clinically affect the performance of both SD HASCA SR formulations, even if the mechanism of release itself may be affected.

Formulation and characterization of sustained release dosage form of moisture sensitive drug

PubMed Central

Patel, Priya; Dave, Abhishek; Vasava, Amit; Patel, Paresh

2015-01-01

Objective: The purpose of this study was to prepare sustained release tablet of moisture sensitive drug like Ranitidine Hydrochloride for treatment of gastroesophageal reflux disease along with the improvement of moisture stability to get better therapeutic efficacy. Materials and Methods: Pan coating technique was used for coating of the tablet. Film coating was done using Eudragit RLPO and Eugragit EPO as coating polymer. 32 full factorial design was applied for optimization purpose, and 9 runs were conducted. In that Eudragit RLPO and Eudragit EPO taken as an independent variables and moisture gain and Cummulative Drug Release (CDR) were taken as dependent variables. Drug and excipient compatibility was done using differential scanning calorimetry and Fourier transform infrared spectroscopy study. The tablet was evaluated for precompression parameter and all postcompression parameter. Stability study was carried out at room temperature (30°C ± 2°C/65% ± 5% relative humidity). Final formulation was compared with marketed formulation RANTEC 300. Result: Tablets were passing out all precompression parameter along with postcompression parameter. Stability study shows that the parameter such as hardness, friability, and dissolution are in the range. Hence, there is no significant change shown after stability study. Our final formulation was compared with marketed formulation RANTEC 300 and result demonstrates that our final formulation have less moisture gain and give release up to 12 h. Conclusion: The result of present study demonstrates that final formulation has less moisture gain and getting desired CDR for sustained release of drug. On the basis of all study, it was concluded that the tablet was coated by combination of Eudragit RLPO 10% and Eudragit EPO 10% give better result. This formation provided promising approach for the drug release up to 12 h for moisture sensitive drug like ranitidine hydrochloride. PMID:25838994

Can formulation and drug delivery reduce attrition during drug discovery and development—review of feasibility, benefits and challenges

PubMed Central

Basavaraj, S; Betageri, Guru V.

2014-01-01

Drug discovery and development has become longer and costlier process. The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards “me too” drugs and improved generics (505(b) (2)) fillings. The discontinuance of molecules at late stage clinical trials is common these years. The molecules are withdrawn at various stages of discovery and development process for reasons such as poor ADME properties, lack of efficacy and safety reasons. Hence this review focuses on possible applications of formulation and drug delivery to salvage molecules and improve the drugability. The formulation and drug delivery technologies are suitable for addressing various issues contributing to attrition are discussed in detail. PMID:26579359

Solid effervescent formulations as new approach for topical minoxidil delivery.

PubMed

Pereira, Maíra N; Schulte, Heidi L; Duarte, Natane; Lima, Eliana M; Sá-Barreto, Livia L; Gratieri, Tais; Gelfuso, Guilherme M; Cunha-Filho, Marcilio S S

2017-01-01

Currently marketed minoxidil formulations present inconveniences that range from a grease hard aspect they leave on the hair to more serious adverse reactions as scalp dryness and irritation. In this paper we propose a novel approach for minoxidil sulphate (MXS) delivery based on a solid effervescent formulation. The aim was to investigate whether the particle mechanical movement triggered by effervescence would lead to higher follicle accumulation. Preformulation studies using thermal, spectroscopic and morphological analysis demonstrated the compatibility between effervescent salts and the drug. The effervescent formulation demonstrated a 2.7-fold increase on MXS accumulation into hair follicles casts compared to the MXS solution (22.0±9.7μg/cm 2 versus 8.3±4.0μg/cm 2 ) and a significant drug increase (around 4-fold) in remaining skin (97.1±29.2μg/cm 2 ) compared to the drug solution (23.5±6.1μg/cm 2 ). The effervescent formulations demonstrated a prominent increase of drug permeation highly dependent on the effervescent mixture concentration in the formulation, confirming the hypothesis of effervescent reaction favoring drug penetration. Clinically, therapy effectiveness could be improved, increasing the administration interval, hence, patient compliance. More studies to investigate the follicular targeting potential and safety of new formulations are needed. Copyright © 2016 Elsevier B.V. All rights reserved.

Availability of pediatric-evaluated formulations in Serbia.

PubMed

Božić, Bojana; Stupar, Sanja; Stupar, Duško; Babić, Uroš; Bajčetić, Milica

2017-01-01

The aim of this study is to analyze the availability and coverage by health insurance reimbursement of pediatric formulations labeled for children up to the age of 12 in Serbia. To provide good insight in general availability of pediatric medicines, results were compared with the World Health Organization's (WHO) "Model List of Essential Medicines for Children" and with published evidence. Sources of information about medicines are the Summary of Product Characteristics, National Health Insurance Fund (NHIF) Drug Lists, WHO Model Lists of Essential Medicines for Children, and Serbia's official drug registry (2013). Out of total number of medicines in Serbia, only 49% (496) were available for children. Of all available drugs for children, 66% were with license and majority were parenteral formulation (57%), followed by drugs for local use (28%) and formulations for oral use (23%). The lowest availability of medicines was for children 0-27 days. From the total number of licensed medicines for children up to 12 years old, NHIF covers 64% of drugs. The availability of the WHO essential medicines for children in Serbia was 51%, from which 92% were licensed for pediatric use. Our results demonstrated the alarming lack of pediatric suitable formulations in Serbia. Significant differences in the availability of drugs suitable for children exist worldwide. From global health point of view, the differences in the access to children formulations should, therefore, be of the highest priority.

Effect of Formulation Variables on Preparation of Celecoxib Loaded Polylactide-Co-Glycolide Nanoparticles

PubMed Central

Cooper, Dustin L.; Harirforoosh, Sam

2014-01-01

Polymer based nanoparticle formulations have been shown to increase drug bioavailability and/or reduce drug adverse effects. Nonsteroidal anti-inflammatory drugs (e.g. celecoxib) reduce prostaglandin synthesis and cause side effects such as gastrointestinal and renal complications. The aim of this study was to formulate celecoxib entrapped poly lactide-co-glycolide based nanoparticles through a solvent evaporation process using didodecyldimethylammonium bromide or poly vinyl alcohol as stabilizer. Nanoparticles were characterized for zeta potential, particle size, entrapment efficiency, and morphology. Effects of stabilizer concentration (0.1, 0.25, 0.5, and 1% w/v), drug amount (5, 10, 15, and 20 mg), and emulsifier (lecithin) on nanoparticle characterization were examined for formula optimization. The use of 0.1, 0.25, and 0.5% w/v didodecyldimethylammonium bromide resulted in a more than 5-fold increase in zeta potential and a more than 1.5-fold increase in entrapment efficiency with a reduction in particle size over 35%, when compared to stabilizer free formulation. Nanoparticle formulations were also highly influenced by emulsifier and drug amount. Using 0.25% w/v didodecyldimethylammonium bromide NP formulations, peak zeta potential was achieved using 15 mg celecoxib with emulsifier (17.15±0.36 mV) and 20 mg celecoxib without emulsifier (25.00±0.18 mV). Peak NP size reduction and entrapment efficiency was achieved using 5 mg celecoxib formulations with (70.87±1.24 nm and 95.55±0.66%, respectively) and without (92.97±0.51 nm and 95.93±0.27%, respectively) emulsifier. In conclusion, formulations using 5 mg celecoxib with 0.25% w/v didodecyldimethylammonium bromide concentrations produced nanoparticles exhibiting enhanced size reduction and entrapment efficiency. Furthermore, emulsifier free formulations demonstrated improved zeta potential when compared to formulations containing emulsifier (p<0.01). Therefore, our results suggest the use of emulsifier free 5 mg celecoxib drug formulations containing 0.25% w/v didodecyldimethylammonium bromide for production of polymeric NPs that demonstrate enhanced zeta potential, small particle size, and high entrapment efficiency. PMID:25502102

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

Influence of administration vehicles and drug formulations on the pharmacokinetic profile of lamotrigine in rats.

PubMed

Castel-Branco, M M; Figueiredo, I V; Falcão, A C; Macedo, T R A; Caramona, M M

2002-10-01

Given that administration vehicles and drug formulations can affect drug bioavailability, their influence on the pharmacokinetic profile of lamotrigine (LTG), a new-generation anti-epileptic drug, was studied in rats. Three different formulations administered intraperitoneally at a dose of 10 mg/kg were used: (1) LTG suspended in a 0.25% methylcelulose solution, (2) LTG dissolved in a 50% propylene glycol solution, and (3) LTG isethionate dissolved in distilled water. Plasma and brain homogenate levels were determined in order to evaluate vehicle-dependent drug absorption. The results demonstrated rapid absorption of LTG when it was administered as an aqueous solution, in contrast to a slower and more erratic absorption after the injection of either the lipophilic solution or the suspension. A plasma peak was achieved 15 min post-dose with the aqueous solution, with a brain peak being achieved 15 min later, while with the other formulations both plasma and brain homogenate peaks were reached 2 h after LTG administration. This study suggests that LTG isethionate dissolved in distilled water is the most suitable formulation for successful LTG pharmacokinetic studies in rats.

Effect of gellan gum on the thermogelation property and drug release profile of Poloxamer 407 based ophthalmic formulation.

PubMed

Dewan, Mitali; Sarkar, Gunjan; Bhowmik, Manas; Das, Beauty; Chattoapadhyay, Atis Kumar; Rana, Dipak; Chattopadhyay, Dipankar

2017-09-01

The effect of gellan gum on the gelation behavior and in-vitro release of a specific drug named pilocarpine hydrochloride from different ophthalmic formulations based on poloxamer 407 is examined. The mixture of 0.3wt% gellan gum and 18wt% poloxamer (PM) solutions show a considerable increase in gel strength in physiological condition. Gel dissolution rate from PM based formulation is significantly decreased due to the addition of gellan gum. FTIR spectra analysis witnesses an interaction in between OH groups of two polymers which accounts for lowering in gelation temperature of PM-gellan gum based formulations. It is also observed from the cryo-SEM study that the pore size of PM gel decreases with an addition of gellan gum and in-vitro release studies indicate that PM-gellan gum based formulation retain drug better than the PM solution alone. Therefore, the developed formulation has the potential to be utilized as an in-situ ophthalmic drug carrier. Copyright © 2017 Elsevier B.V. All rights reserved.

Formulations for children: problems and solutions

PubMed Central

Batchelor, Hannah K; Marriott, John F

2015-01-01

Paediatric formulation design is complex as there is a need to understand the developmental physiological changes that occur during childhood and their impact on the absorption of drugs. Paediatric dose adjustments are usually based on achieving pharmacokinetic or pharmacodynamic profiles equivalent to those achieved in adult populations. However, differences in the way in which children handle adult products or the use of bespoke paediatric formulations can result in unexpected pharmacokinetic drug profiles with altered clinical efficacy. Differences in drug formulations need to be understood by healthcare professionals involved in the prescribing, administration or dispensing of drugs to children such that appropriate advice is given to ensure that therapeutic outcomes are achieved. This issue is not confined to oral medicines but is applicable for all routes of administration encountered in paediatric therapy. PMID:25855822

Nano-sized crystalline drug production by milling technology.

PubMed

Moribe, Kunikazu; Ueda, Keisuke; Limwikrant, Waree; Higashi, Kenjirou; Yamamoto, Keiji

2013-01-01

Nano-formulation of poorly water-soluble drugs has been developed to enhance drug dissolution. In this review, we introduce nano-milling technology described in recently published papers. Factors affecting the size of drug crystals are compared based on the preparation methods and drug and excipient types. A top-down approach using the comminution process is a method conventionally used to prepare crystalline drug nanoparticles. Wet milling using media is well studied and several wet-milled drug formulations are now on the market. Several trials on drug nanosuspension preparation using different apparatuses, materials, and conditions have been reported. Wet milling using a high-pressure homogenizer is another alternative to preparing production-scale drug nanosuspensions. Dry milling is a simple method of preparing a solid-state drug nano-formulation. The effect of size on the dissolution of a drug from nanoparticles is an area of fundamental research, but it is sometimes incorrectly evaluated. Here, we discuss evaluation procedures and the associated problems. Lastly, the importance of quality control, process optimization, and physicochemical characterization are briefly discussed.

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

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

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.

Formulation and clinical evaluation of silymarin pluronic-lecithin organogels for treatment of atopic dermatitis

PubMed Central

Mady, Fatma M; Essa, Hanaa; El-Ammawi, Tarek; Abdelkader, Hamdy; Hussein, Amal K

2016-01-01

Silymarin is a naturally occurring flavonoid drug; evidence from recent research has highlighted its use as a potential treatment for atopic dermatitis (AD). Both poor water solubility and drug permeability have hindered the percutaneous absorption of silymarin. Formulation of silymarin into pluronic-lecithin organogel (PLO) basis for topical skin delivery is the main aim of this work. Six different PLO formulations were prepared containing various pluronic to lecithin ratios using two cosolvent systems of ethyl alcohol and dimethyl sulfoxide. Formulation 2 (20% pluronic and 3% lecithin) was found to be the optimal base for topical delivery of silymarin as it showed optimum pH, viscosity, drug content, and satisfactory in vitro silymarin permeation. The silymarin PLO formulation significantly relieved inflammatory symptoms of AD such as redness, swelling, and inflammation. These findings warrant the ability for application of these novel silymarin PLO formulations as a novel treatment for AD. PMID:27022248

Formulation and clinical evaluation of silymarin pluronic-lecithin organogels for treatment of atopic dermatitis.

PubMed

Mady, Fatma M; Essa, Hanaa; El-Ammawi, Tarek; Abdelkader, Hamdy; Hussein, Amal K

2016-01-01

Silymarin is a naturally occurring flavonoid drug; evidence from recent research has highlighted its use as a potential treatment for atopic dermatitis (AD). Both poor water solubility and drug permeability have hindered the percutaneous absorption of silymarin. Formulation of silymarin into pluronic-lecithin organogel (PLO) basis for topical skin delivery is the main aim of this work. Six different PLO formulations were prepared containing various pluronic to lecithin ratios using two cosolvent systems of ethyl alcohol and dimethyl sulfoxide. Formulation 2 (20% pluronic and 3% lecithin) was found to be the optimal base for topical delivery of silymarin as it showed optimum pH, viscosity, drug content, and satisfactory in vitro silymarin permeation. The silymarin PLO formulation significantly relieved inflammatory symptoms of AD such as redness, swelling, and inflammation. These findings warrant the ability for application of these novel silymarin PLO formulations as a novel treatment for AD.

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.

Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.

PubMed

Katare, Yogesh K; Daya, Ritesh P; Sookram Gray, Christal; Luckham, Roger E; Bhandari, Jayant; Chauhan, Abhay S; Mishra, Ram K

2015-09-08

Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain.

Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid.

PubMed

Jhawat, Vikas; Gupta, Sumeet; Saini, Vipin

2016-11-01

In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56-5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2 > F3 > F10 > F4 > F1 > F9 > F8 > F5 > F7 > F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti-inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant.

Nanosized ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery against vitiligo: formulation optimization, in vitro evaluation and preclinical assessment.

PubMed

Garg, Bhawna Jain; Garg, Neeraj K; Beg, Sarwar; Singh, Bhupinder; Katare, Om Prakash

2016-01-01

The present investigation aimed for the development and characterization of ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery and effective treatment against vitiligo. The ethosomes were prepared by central composite design (CCD) and characterized for various quality attributes like vesicle shape, size, zeta potential, lamellarity, drug entrapment and drug leaching. The optimized ethosomes were subsequently incorporated int Carbopol® 934 gel and characterized for drug content, rheological behavior, texture profile, in vitro release, ex vivo skin permeation and retention, skin photosensitization and histopathological examination. Ethosomes were found to be spherical and multilamellar in structures having nanometric size range with narrow size distribution, and high encapsulation efficiency. Ethosomal formulations showed significant skin permeation and accumulation in the epidermal and dermal layers. The fluorescence microscopy study using 123 Rhodamine exhibited enhanced permeation of the drug-loaded ethosomes in the deeper layers of skin. Also, the developed formulation showed insignificant phototoxicity and erythema vis-à-vis the conventional cream. The results were cross-validated using histopathological examination of skin segments. In a nutshell, the ethosomes-based hydrogel formulation was found to be a promising drug delivery system demonstrating enhanced percutaneous penetration of methoxsalen with reduced phototoxicity and erythema, thus leading to improved patient compliance for the treatment against vitiligo.

Multiple response optimization of processing and formulation parameters of Eudragit RL/RS-based matrix tablets for sustained delivery of diclofenac.

PubMed

Elzayat, Ehab M; Abdel-Rahman, Ali A; Ahmed, Sayed M; Alanazi, Fars K; Habib, Walid A; Sakr, Adel

2017-11-01

Multiple response optimization is an efficient technique to develop sustained release formulation while decreasing the number of experiments based on trial and error approach. Diclofenac matrix tablets were optimized to achieve a release profile conforming to USP monograph, matching Voltaren ® SR and withstand formulation variables. The percent of drug released at predetermined multiple time points were the response variables in the design. Statistical models were obtained with relative contour diagrams being overlaid to predict process and formulation parameters expected to produce the target release profile. Tablets were prepared by wet granulation using mixture of equivalent quantities of Eudragit RL/RS at overall polymer concentration of 10-30%w/w and compressed at 5-15KN. Drug release from the optimized formulation E4 (15%w/w, 15KN) was similar to Voltaren, conformed to USP monograph and found to be stable. Substituting lactose with mannitol, reversing the ratio between lactose and microcrystalline cellulose or increasing drug load showed no significant difference in drug release. Using dextromethorphan hydrobromide as a model soluble drug showed burst release due to higher solubility and formation of micro cavities. A numerical optimization technique was employed to develop a stable consistent promising formulation for sustained delivery of diclofenac.

[Efficacy of a new fenbendazole formulation produced by nanotechnology-based drug delivery system against nematodosis].

PubMed

Varlamova, A I; Arkhipov, I A; Odoevskaia, I M; Danilevskaia, N V; Khalikov, S S; Chistiachenko, Iu S; Dushkin, A V

2014-01-01

The efficacy of a new fenbendazile formulation produced by nanotechnology-based drug delivery system was investigated in45 sheep naturally infected with gastrointestinal nematodes. The formulation showed 95.6% efficacy against Nematodes spp. at a dose of 1.0 mg/kg dw of its active ingredient and 100% efficacy against other species of gastrointestinal nematodes. Given at a dose of 10 mg/kg dw, the basic drug--fenbendazole (substance) displayed 96.39 and 100% efficacy, respectively.

Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.

PubMed

Williams, Hywel D; Anby, Mette U; Sassene, Philip; Kleberg, Karen; Bakala-N'Goma, Jean-Claude; Calderone, Marilyn; Jannin, Vincent; Igonin, Annabel; Partheil, Anette; Marchaud, Delphine; Jule, Eduardo; Vertommen, Jan; Maio, Mario; Blundell, Ross; Benameur, Hassan; Carrière, Frédéric; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H

2012-11-05

The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a threshold value for SR(M) was evident, regardless of formulation composition and drug solubilization reduced markedly above SR(M) > 2.5. The threshold SR(M) may prove to be an effective tool in discriminating between LBFs based on performance.

Preparation and characterization of cefditoren pivoxil-loaded liposomes for controlled in vitro and in vivo drug release

PubMed Central

Venugopalarao, Gojjala; Lakshmipathy, Rajasekhar; Sarada, Nallani Chakravarthula

2015-01-01

Background The application of antibiotics has been limited due to weak biodistribution and pharmacokinetics. Encapsulation of these drugs in lipid vesicles might be a good solution for obtaining the required properties. Liposomes are one of the most suitable drug-delivery systems to deliver the drug to the target organ and minimize the distribution of the drug to non-target tissues. Objective The study reported here aimed to develop cefditoren pivoxil liposomes by thin-film hydration, characterize them in terms of physical interactions, and undertake in vitro and in vivo release studies. Methodology The pre-formulation studies were carried out using Fourier-transform infrared spectroscopy and differential scanning calorimetry. Cefditoren pivoxil liposomal formulations were formulated by thin-film hydration using biomaterials ie, soya lecithin and cholesterol in different molar ratios. The best molar ratio was determined by in vitro studies such as entrapment efficacy, particle size distribution, and diffusion. Results From the in vitro release studies, it was found that the formulation that contained soya lecithin and cholesterol in a 1.0:0.6 molar ratio gave good entrapment of 72.33% and drug release of 92.5% at 36 hours. Further, the formulation’s zeta potential and surface morphology were examined and stability and in vivo studies were undertaken evaluating the pharmacokinetic parameters, which showed promising results. Conclusion Formulation CPL VI showed the maximum drug-loading capacity of 72.3% with good controlled release and acceptable stability when compared with the other formulations. In vivo studies in rabbits showed that the drug release from the liposomes was successfully retarded with good controlled release behavior which can be used to treat many bacterial infections with a minimal dose. PMID:26491316

Preparation and evaluation of niosome gel containing acyclovir for enhanced dermal deposition.

PubMed

Jacob, Shery; Nair, Anroop B; Al-Dhubiab, Bandar E

2017-12-01

Niosomes suggest a versatile vesicle delivery system with possible transport of drugs via topical route for skin delivery. The aim of the present research was to optimize niosome gel formulation of acyclovir and to evaluate in both in vitro and in vivo rabbit model. Niosome formulations were formulated by coacervation phase separation technique with different ratios of nonionic surfactants, phospholipids and cholesterol using 3 2 factorial design. Altering the surfactant concentration has influenced the drug entrapment, but not vesicle size. At high surfactant combinations, the acyclovir release from niosomes was strongly influenced by cholesterol:lecithin ratio. Ex vivo drug permeation data indicate substantial difference in flux values and was influenced by the niosome composition. Ex vivo studies using formulation (B 8 ) for drug deposition indicate greater amount of niosome being diffused into the skin layers and formed a depot, compared to commercial acyclovir cream (control). Two distinct dermatopharmacokinetic profiles were observed, in vivo, for niosome gel formulation (B 8 ) and control, which were analog to the profiles observed with ex vivo deposition studies. In vivo plasma drug level suggests low systemic exposure of acyclovir (C max : 9.44 ± 2.27 ng/mL and 14.54 ± 3.11 ng/mL for niosome formulation and control, respectively). Comparison of kinetic data of acyclovir in the stratum corneum and plasma signifies that the niosome formulation forms a depot in the epidermis or dermis region. This study concludes that the niosome gel formulation (B 8 ) could be a viable vesicular system for an impressive transdermal delivery of acyclovir by topical application.

[Effect of concomitant use of dental drug on the properties of recombinant human basic fibroblast growth factor formulation for periodontal disease].

PubMed

Sato, Yasuhiko; Oba, Takuma; Danjo, Kazumi

2013-01-01

We have discussed the essential property for periodontal disease medication using protein, such as recombinant human basic fibroblast growth factor (rhbFGF). In our previous study, the criteria of thickener for the medication, viscosity, flowability etc., were set. The aim of this study was to evaluate the physical and chemical effect of concomitant use of general dental drug or device on thickener properties for the clinical use of viscous rhbFGF formulation. Viscous formulation was prepared with six cellulose derivatives, two types hydroxy propyl cellulose (HPC), three types hydroxy ethyl cellulose (HEC) and methyl cellulose (MC). Antibiotic ointment, local anesthetic, bone graft substitute, agent for gargle and mouthwashes, were chosen as general dental drug and device. These drugs and device were mixed with the viscous formulations and the change of viscosity and flowability, the remaining ratio of rhbFGF were evaluated. When the various thickener solutions were mixed with the liquid drugs, viscosity and flowability did not changed much. However, in the case of MC solution, viscous property declined greatly when MC solution was mixed with cationic surfactant for gargle. The flowabilities of thickener solutions were declined with insoluble bone graft. The stabilities of rhbFGF in thickener solutions were no problem for 24 hours even in the case of mixing with dental drug or device. Our findings suggested that the viscous rhbFGF formulations prepared in this research were not substantially affected by the concomitant use of dental drug or device, especially the formulation with HPC or HEC was useful.

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.

Formulation and evaluation of Ketoconazole niosomal gel drug delivery system

PubMed Central

Shirsand, SB; Para, MS; Nagendrakumar, D; Kanani, KM; Keerthy, D

2012-01-01

Purpose: Niosomes play an increasingly important role in drug delivery as they can reduce toxicity and modify pharmacokinetic and bio-availability. Topically applied niosomes can increase the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug. It can act as drug containing reservoirs and the modification of the vesicular compositions or surface properties can adjust the drug release rate and the affinity for the target site. Ketoconazole is a broad spectrum Imidazole derivative useful in the treatment of superficial and systemic fungal infections. Materials and Methods: In order to improve the low skin penetration and to minimize the side effects associated with topical conventional drug administration, Ketoconazole niosomes were prepared by a thin film hydration method using different ratios of non-ionic surfactants (Span 40, 60 and Tween 60) along with cholesterol (CHO). The formulations were evaluated for size, shape, entrapment efficiency and in vitro drug release. Results: Niosomes appeared spherical in shape and size range was found to be 4.86 ± 1.24-7.38 ± 3.64 μm. The entrapment efficiency was found in the range of 55.14 ± 2.29-78.63 ± 0.91% and in vitro drug release in the range of 46.63 ± 0.95-72.37 ± 0.59% in 24 h. Ketoconazole niosomes formulated with Span 60 and CHO in the ratio of 1:0.2 were found to be promising and were incorporated into 1% Carbopol gel. The formulated gel was evaluated for various physicochemical parameters and antifungal activity. The in vitro drug release study was carried out using phosphate buffer saline pH 7.4 and was found to be 36.18 ± 1.50% in 12 h. Conclusion: Gel formulation containing niosomes loaded with Ketoconazole showed prolonged action than formulations containing Ketoconazole in non-niosomal form and it can be developed successfully to improve the antifungal activity. PMID:23580936

Formulation Development and Evaluation of the Therapeutic Efficacy of Brinzolamide Containing Nanoemulsions

PubMed Central

Mahboobian, Mohammad Mehdi; Seyfoddin, Ali; Rupenthal, Ilva D.; Aboofazeli, Reza; Foroutan, Seyed Mohsen

2017-01-01

Brinzolamide (BZ) is an intraocular pressure reducing agent with low bioavailability. The purpose of the present study was to overcome this issue by development of BZ containing nanoemulsions (NEs) as an ocular drug delivery system with desirable therapeutic efficacy. Brinzolamide NEs were prepared by the spontaneous emulsification method. Based on initial release studies, twelve formulations with the slowest release characteristics were subjected to further physicochemical investigations such as particle size, polydispersity index, pH, refractive index, osmolality and viscosity. The therapeutic efficacy of these formulations was assessed by measuring the intraocular pressure after instillation of the prepared NEs in normotensive albino rabbit eyes. Nanoemulsions with suitable physicochemical properties exhibited high formulation stability under different conditions. more over biological evaluations indicated that using lower drug concentrations in NE formulations (0.4%) had a similar or even better pharmacodynamic effect compared to the commercial suspension with a higher drug concentration (1%). Our findings suggest that NEs could be effectively used as carriers for enhancing the bioavailability of topically applied ophthalmic drugs. PMID:29201076

In vitro evaluation of suspoemulsions for in situ-forming polymeric microspheres and controlled release of progesterone.

PubMed

Turino, Ludmila N; Mariano, Rodolfo N; Mengatto, Luciano N; Luna, Julio A

2015-01-01

One possibility to obtain a higher dose of drug in a lower formulation volume can be by using of saturated quantity of drug in one of the phases of an emulsion. These formulations are called suspoemulsions (S/O/W). When a hydrophobic polymer is added to the organic phase of suspoemulsions, these formulations can be used to entrap the drug inside microspheres after in situ precipitation of the polymer-drug-excipients mix. In this work, performance and stability of progesterone suspensions in triacetin as organic phase of suspoemulsions were evaluated. These formulations were compared with O/W emulsions. Mathematical models were used to study in vitro release profiles. The results confirmed that S/O/W systems could be an attractive alternative to O/W formulations for the entrapment of progesterone inside poly(d,l-lactide-co-glycolide) microspheres. Diffusive-based models fit the in vitro release of progesterone from in situ-formed microspheres. For longer release periods, a time-dependent diffusion coefficient was successfully estimated.

Development and evaluation of transdermal organogels containing nicorandil.

PubMed

Madan, J R; Sagar, Banode; Chellappan, Dinesh K; Dua, Kamal

2013-01-01

The objective of the study was to formulate a transdermal product containing Nicorandil as a model drug, because it has been first drug of choice to treat angina and hypertension. A further objective was to reduce its side effects. The transdermal product was prepared using various synthetic and natural gelling agents such as Carbopol 934p, Carbopol 974p, HPMC K15M and HPMC K100M. Various penetration enhancers were incorporated to enhance the diffusion across the rat skin. A further objective was to formulate organogels and minimize the concentration of penetration enhancer to 50% of the concentration used in gels and yet to achieve the maximum drug release. The prepared formulations were evaluated for their physical appearance, viscosity, spreadability, drug content and freeze thaw cycle. Based on in vitro studies across rat skin and human cadaver skin it was concluded that Nicrorandil transdermal organogel formulation using HPMC K100M with 2% w/w Transcutol-P shows increase in cumulative diffusion of Nicorandil amongst all other formulations.

Establishing "abuse-deterrence equivalence" for generic abuse-deterrent opioid formulations: A proposed development framework.

PubMed

Setnik, Beatrice; Cone, Edward J

2016-01-01

Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent formulations of novel drugs and formulations; however, they do not address "abuse-deterrence equivalence" for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.

Influence of Molecular Weight of Carriers and Processing Parameters on the Extrudability, Drug Release, and Stability of Fenofibrate Formulations Processed by Hot-Melt Extrusion.

PubMed

Alsulays, Bader B; Park, Jun-Bom; Alshehri, Sultan M; Morott, Joseph T; Alshahrani, Saad M; Tiwari, Roshan V; Alshetaili, Abdullah S; Majumdar, Soumyajit; Langley, Nigel; Kolter, Karl; Gryczke, Andreas; Repka, Michael A

2015-10-01

The objective of this study was to investigate the extrudability, drug release, and stability of fenofibrate (FF) formulations utilizing various hot-melt extrusion processing parameters and polyvinylpyrrolidone (PVP) polymers of various molecular weights. The different PVP grades selected for this study were Kollidon ® 12 PF (K12), Kollidon ® 30 (K30), and Kollidon ® 90 F (K90). FF was extruded with these polymers at three drug loadings (15%, 25%, and 35% w/w). Additionally, for FF combined with each of the successfully extruded PVP grades (K12 and K30), the effects of two levels of processing parameters for screw design, screw speed, and barrel temperature were assessed. It was found that the FF with (K90) was not extrudable up to 35% drug loading. With low drug loading, the polymer viscosity significantly influenced the release of FF. The crystallinity remaining was vital in the highest drug-loaded formulation dissolution profile, and the glass transition temperature of the polymer significantly affected its stability. Modifying the screw configuration resulted in more than 95% post-extrusion drug content of the FF-K30 formulations. In contrast to FF-K30 formulations, FF release and stability with K12 were significantly influenced by the extrusion temperature and screw speed.

Formulation Strategies to Improve the Bioavailability of Poorly Absorbed Drugs with Special Emphasis on Self-Emulsifying Systems

PubMed Central

Gupta, Shweta; Kesarla, Rajesh

2013-01-01

Poorly water-soluble drug candidates are becoming more prevalent. It has been estimated that approximately 60–70% of the drug molecules are insufficiently soluble in aqueous media and/or have very low permeability to allow for their adequate and reproducible absorption from the gastrointestinal tract (GIT) following oral administration. Formulation scientists have to adopt various strategies to enhance their absorption. Lipidic formulations are found to be a promising approach to combat the challenges. In this review article, potential advantages and drawbacks of various conventional techniques and the newer approaches specifically the self-emulsifying systems are discussed. Various components of the self-emulsifying systems and their selection criteria are critically reviewed. The attempts of various scientists to transform the liquid self-emulsifying drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray drying, lyophilization, melt granulation, extrusion, and so forth to formulate various dosage forms like self emulsifying capsules, tablets, controlled release pellets, beads, microspheres, nanoparticles, suppositories, implants, and so forth have also been included. Formulation of SEDDS is a potential strategy to deliver new drug molecules with enhanced bioavailability mostly exhibiting poor aqueous solubility. The self-emulsifying system offers various advantages over other drug delivery systems having potential to solve various problems associated with drugs of all the classes of biopharmaceutical classification system (BCS). PMID:24459591

Formulation and process factors influencing product quality and in vitro performance of ophthalmic ointments.

PubMed

Xu, Xiaoming; Al-Ghabeish, Manar; Rahman, Ziyaur; Krishnaiah, Yellela S R; Yerlikaya, Firat; Yang, Yang; Manda, Prashanth; Hunt, Robert L; Khan, Mansoor A

2015-09-30

Owing to its unique anatomical and physiological functions, ocular surface presents special challenges for both design and performance evaluation of the ophthalmic ointment drug products formulated with a variety of bases. The current investigation was carried out to understand and identify the appropriate in vitro methods suitable for quality and performance evaluation of ophthalmic ointment, and to study the effect of formulation and process variables on its critical quality attributes (CQA). The evaluated critical formulation variables include API initial size, drug percentage, and mineral oil percentage while the critical process parameters include mixing rate, temperature, time and cooling rate. The investigated quality and performance attributes include drug assay, content uniformity, API particle size in ointment, rheological characteristics, in vitro drug release and in vitro transcorneal drug permeation. Using design of experiments (DoE) as well as a novel principle component analysis approach, five of the quality and performance attributes (API particle size, storage modulus of ointment, high shear viscosity of ointment, in vitro drug release constant and in vitro transcorneal drug permeation rate constant) were found to be highly influenced by the formulation, in particular the strength of API, and to a lesser degree by processing variables. Correlating the ocular physiology with the physicochemical characteristics of acyclovir ophthalmic ointment suggested that in vitro quality metrics could be a valuable predictor of its in vivo performance. Published by Elsevier B.V.

[Strategy and collaboration between medicinal chemists and pharmaceutical scientists for drug delivery systems].

PubMed

Mano, Takashi

2013-01-01

In order to successfully apply drug delivery systems (DDS) to new chemical entities (NCEs), collaboration between medicinal chemists and formulation scientists is critical for efficient drug discovery. Formulation scientists have to use 'language' that medicinal chemists understand to help promote mutual understanding, and medicinal chemists and formulation scientists have to set up strategies to use suitable DDS technologies at the discovery phase of the programmes to ensure successful transfer into the development phase. In this review, strategies of solubilisation formulation for oral delivery, inhalation delivery, nasal delivery and bioconjugation are all discussed. For example, for oral drug delivery, multiple initiatives can be proposed to improve the process to select an optimal delivery option for an NCE. From a technical perspective, formulation scientists have to explain the scope and limitations of formulations as some DDS technologies might be applicable only to limited chemical spaces. Other limitations could be the administered dose and, cost, time and resources for formulation development and manufacturing. Since DDS selection is best placed as part of lead-optimisation, formulation scientists need to be involved in discovery projects at lead selection and optimisation stages. The key to success in their collaboration is to facilitate communication between these two areas of expertise at both a strategic and scientific level. Also, it would be beneficial for medicinal chemists and formulation scientists to set common goals to improve the process of collaboration and build long term partnerships to improve DDS.

Understanding effect of formulation and manufacturing variables on the critical quality attributes of warfarin sodium product.

PubMed

Rahman, Ziyaur; Korang-Yeboah, Maxwell; Siddiqui, Akhtar; Mohammad, Adil; Khan, Mansoor A

2015-11-10

Warfarin sodium (WS) is a narrow therapeutic index drug and its product quality should be thoroughly understood and monitored in order to avoid clinical performance issues. This study was focused on understanding the effect of manufacturing and formulation variables on WS product critical quality attributes (CQAs). Eight formulations were developed with lactose monohydrate (LM) or lactose anhydrous (LA), and were either wet granulated or directly compressed. Formulations were granulated either with ethanol, isopropyl alcohol (IPA) and IPA-water mixture (50:50). Formulations were characterized for IPA, water content, hardness, disintegration time (DT), assay, dissolution and drug physical forms (scanning electron microscopy (SEM), near infrared chemical imaging (NIR-CI), X-ray powder diffraction (XRPD) and solid state nuclear magnetic resonance (ssNMR)), and performed accelerated stability studies at 40°C/75% RH for three days. The DT and dissolution of directly compressed formulations were faster than wet granulated formulations. This was due to phase transformation of crystalline drug into its amorphous form as indicated by SEM, NIR-CI, XRPD and ssNMR data which itself act as a binder. Similarly, LM showed faster disintegration and dissolution than LA containing formulations. Stability results indicated an increase in hardness and DT, and a decrease in dissolution rate and extent. This was due to phase transformation of the drug and consolidation with particles' bonding. In conclusion, the CQAs of WS product were significantly affected by manufacturing and formulation variables. Published by Elsevier B.V.

Formulation and Characterization of Aceclofenac -Aloe vera Transemulgel.

PubMed

Raju, Y Prasanna; Haritha, K; Satyanarayana, Rao P; Vandana, K R; Bindu, D Thushara; Vinesha, V; Chowdary, V Harini

2015-01-01

The present research was aimed to formulate aceclofenac transemulgel using Aloe vera as gel base. The prepared formulations were subjected to physical characterization, in-vitro and in-vivo assessment. Aceclofenac, a hydrophobic potential non steroidal anti inflammatory drug, causes ulceration upon chronic oral administration, could be formulated into transemulgel to enhance therapeutic efficacy and to lower the unwanted side effects. The transemulgel was prepared from aqueous Aloe vera gel and aceclofenac emulsion. The prepared transemulgel was evaluated for its pH, viscosity, drug content, skin irritation, in-vitro diffusion and accelerated stability studies. The prepared aceclofenac-Aloe vera tranemulgel and commercial aceclofenac gel were subjected to pharmacodynamic studies in albino rats of Wistar strain employing carrageenan induced left hind paw edema method to assess the anti-inflammatory effect. The transemulgel showed a pH of 6.78 and viscosity of 18 cps. In-vitro diffusion data revealed better permeation characteristics. Topical application of formulation found no skin irritation. Stability study has proved the integrity of the formulation. The prepared aceclofenac Aloe vera transemulgel showed better in-vitro drug release when compared with the commercial aceclofenac gel formulation. Anti-inflammatory activity in treated rats showed the significant paw volume reduction at p<0.05 compared with that of control. Thus, it is concluded that aceclofenac, a potential non steroidal anti inflammatory drug, showed high therapeutic efficiency when formulated into transemulgel using aqueous Aloe vera as gel base.

Optimization of drug loading to improve physical stability of paclitaxel-loaded long-circulating liposomes.

PubMed

Kannan, Vinayagam; Balabathula, Pavan; Divi, Murali K; Thoma, Laura A; Wood, George C

2015-01-01

The effect of formulation and process parameters on drug loading and physical stability of paclitaxel-loaded long-circulating liposomes was evaluated. The liposomes were prepared by hydration-extrusion method. The formulation parameters such as total lipid content, cholesterol content, saturated-unsaturated lipid ratio, drug-lipid ratio and process parameters such as extrusion pressure and number of extrusion cycles were studied and their impact on drug loading and physical stability was evaluated. A proportionate increase in drug loading was observed with increase in the total phospholipid content. Cholesterol content and saturated lipid content in the bilayer showed a negative influence on drug loading. The short-term stability evaluation of liposomes prepared with different drug-lipid ratios demonstrated that 1:60 as the optimum drug-lipid ratio to achieve a loading of 1-1.3 mg/mL without the risk of physical instability. The vesicle size decreased with an increase in the extrusion pressure and number of extrusion cycles, but no significant trends were observed for drug loading with changes in process pressure or number of cycles. The optimization of formulation and process parameters led to a physically stable formulation of paclitaxel-loaded long-circulating liposomes that maintain size, charge and integrity during storage.

Microstructured bicontinuous phase formulations: their characterization and application in dermal and transdermal drug delivery.

PubMed

Lapteva, Maria; Kalia, Yogeshvar N

2013-08-01

The development of approaches to increase drug solubility and partitioning into the skin is an active area of research in topical and transdermal delivery. In addition to forming spherical aggregates, e.g., conventional oil in water or water in oil microemulsions, the combination of an oil, surfactant and water can create bicontinuous structures where the self-assembly properties of surfactants mean that the boundaries between oil and water are no longer random. This leads to the formation of specific microstructures whose intrinsic properties and interactions with the drug will determine the ability to formulate a given drug, its stability once formulated and its subsequent delivery. The review explores the relationship between the microstructure of biphasic formulations, present in microemulsions and liquid crystalline phases, and drug delivery into the skin. An overview of possible internal microstructures is followed by a summary of the methods used for structure characterization. The final section presents the work to-date and discusses the efficacy of such vehicles in enhancing dermal and transdermal delivery. The combination of water, surface agent and oil generates a broad range of three dimensional structures differing in both chemical and physical proprieties. Knowledge of the microstructure is important in understanding the behavior of a formulation and its effect on drug delivery into the skin. Microstructure complexity, interactions between the drug and the vehicle (i.e., location and mobility) and those between the vehicle and the skin are key determinants of drug delivery.

Analysis of Non-Pivotal Bioequivalence Studies Submitted in Abbreviated New Drug Submissions for Delayed-Release Drug Products.

PubMed

Kaur, Paramjeet; Jiang, Xiaojian; Stier, Ethan

2017-01-01

The US FDA's rule on "Requirements for Submission of Bioequivalence Data" requiring submission of all bioequivalence (BE) studies conducted on the same formulation of the drug product submitted for approval was published in Federal Register in January 2009. With the publication of this rule, we evaluated the impact of data from non-pivotal BE studies in assessing BE and identified the reasons for failed in vivo BE studies for generic oral delayed-release (DR) drug products only. We searched the Agency databases from January 2009 toDecember 2016 to identify Abbreviated New Drug Applications (ANDAs) submitted for DR drug products containing non-pivotal BE studies. Out of 202 ANDAs, 43 ANDAs contained 102 non-pivotal BE studies. Forty-nine non-pivotal BE studies were conducted on the to-be-marketed (TBM) formulation and 53 were conducted on formulations different from the TBM formulation. These experimental formulations primarily differed in the ratio of components of the enteric coating layer and/or amount (i.e., %w/w) of enteric coating layer. Of the 49 non-pivotal BE studies conducted on the TBM formulation, 41 failed to meet the BE acceptance criteria. The majority of failed non-pivotal BE studies on the TBM DR generic products had insufficient power, which was expected as these studies are exploratory in nature and not designed to have adequate power to pass the BE statistical criteria. In addition, among the failed non-pivotal BE studies on the TBM DR generic products, the most commonly failing pharmacokinetic parameter was Cmax. The data from these non-pivotal BE studies indicate that inadequate BE study design can lead to failure of the BE on the same formulation. Also, the non-pivotal BE studies on formulations different from the TBM formulation help us link the formulation design to the product performance in vivo. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Drug Delivery Research: The Invention Cycle.

PubMed

Park, Kinam

2016-07-05

Controlled drug delivery systems have been successful in introducing improved formulations for better use of existing drugs and novel delivery of biologicals. The initial success of producing many oral products and some injectable depot formulations, however, reached a plateau, and the progress over the past three decades has been slow. This is likely due to the difficulties of formulating hydrophilic, high molecular weight drugs, such as proteins and nucleic acids, for targeting specific cells, month-long sustained delivery, and pulsatile release. Since the approaches that have served well for delivery of small molecules are not applicable to large molecules, it is time to develop new methods for biologicals. The process of developing future drug delivery systems, termed as the invention cycle, is proposed, and it starts with clearly defining the problems for developing certain formulations. Once the problems are well-defined, creative imagination examines all potential options and selects the best answer and alternatives. Then, innovation takes over to generate unique solutions for developing new formulations that resolve the previously identified problems. Ultimately, the new delivery systems will have to go through a translational process to produce the final formulations for clinical use. The invention cycle also emphasizes examining the reasons for success of certain formulations, not just the reasons for failure of many systems. Implementation of the new invention cycle requires new mechanisms of funding the younger generation of scientists and a new way of identifying their achievements, thereby releasing them from the burden of short-termism.

Multi-functional Magnetic Nanoparticles for Magnetic Resonance Imaging and Cancer Therapy

PubMed Central

Yallapu, Murali M.; Othman, Shadi F.; Curtis, Evan T.; Gupta, Brij K.; Jaggi, Meena; Chauhan, Subhash C.

2010-01-01

We have developed a multi-layer approach for the synthesis of water-dispersible superparamagnetic iron oxide nanoparticles for hyperthermia, magnetic resonance imaging (MRI) and drug delivery applications. In this approach, iron oxide core nanoparticles were obtained by precipitation of iron salts in the presence of ammonia and provided β-cyclodextrin and pluronic polymer (F127) coatings. This formulation (F127250) was highly water dispersible which allowed encapsulation of the anti-cancer drug(s) in β-cyclodextrin and pluronic polymer for sustained drug release. The F127250 formulation has exhibited superior hyperthermia effects over time under alternating magnetic field compared to pure magnetic nanoparticles (MNP) and β-cyclodextrin coated nanoparticles (CD200). Additionally, the improved MRI characteristics were also observed for the F127250 formulation in agar gel and in cisplatin resistant ovarian cancer cells (A12780CP) compared to MNP and CD200 formulations. Furthermore, the drug loaded formulation of F127250 exhibited many folds of imaging contrast properties. Due to the internalization capacity of the F127250 formulation, its curcumin loaded formulation (F127250-CUR) exhibited almost equivalent inhibition effects on A2780CP (ovarian), MDA-MB-231 (breast), and PC3 (prostate) cancer cells even though curcumin release was only 40%. The improved therapeutic effects were verified by examining molecular effects using Western blotting and transmission electron microscopic (TEM) studies. F127250-CUR also exhibited haemocompatibility, suggesting a nanochemo-therapuetic agent for cancer therapy. PMID:21167595

Multi-functional magnetic nanoparticles for magnetic resonance imaging and cancer therapy.

PubMed

Yallapu, Murali M; Othman, Shadi F; Curtis, Evan T; Gupta, Brij K; Jaggi, Meena; Chauhan, Subhash C

2011-03-01

We have developed a multi-layer approach for the synthesis of water-dispersible superparamagnetic iron oxide nanoparticles for hyperthermia, magnetic resonance imaging (MRI) and drug delivery applications. In this approach, iron oxide core nanoparticles were obtained by precipitation of iron salts in the presence of ammonia and provided β-cyclodextrin and pluronic polymer (F127) coatings. This formulation (F127250) was highly water dispersible which allowed encapsulation of the anti-cancer drug(s) in β-cyclodextrin and pluronic polymer for sustained drug release. The F127250 formulation has exhibited superior hyperthermia effects over time under alternating magnetic field compared to pure magnetic nanoparticles (MNP) and β-cyclodextrin coated nanoparticles (CD200). Additionally, the improved MRI characteristics were also observed for the F127250 formulation in agar gel and in cisplatin resistant ovarian cancer cells (A12780CP) compared to MNP and CD200 formulations. Furthermore, the drug-loaded formulation of F127250 exhibited many folds of imaging contrast properties. Due to the internalization capacity of the F127250 formulation, its curcumin-loaded formulation (F127250-CUR) exhibited almost equivalent inhibition effects on A2780CP (ovarian), MDA-MB-231 (breast), and PC-3 (prostate) cancer cells even though curcumin release was only 40%. The improved therapeutic effects were verified by examining molecular effects using Western blotting and transmission electron microscopic (TEM) studies. F127250-CUR also exhibited haemocompatibility, suggesting a nanochemo-therapeutic agent for cancer therapy. Copyright © 2010 Elsevier Ltd. All rights reserved.

Mucoadhesive and thermogelling systems for vaginal drug delivery.

PubMed

Caramella, Carla M; Rossi, Silvia; Ferrari, Franca; Bonferoni, Maria Cristina; Sandri, Giuseppina

2015-09-15

This review focuses on two formulation approaches, mucoadhesion and thermogelling, intended for prolonging residence time on vaginal mucosa of medical devices or drug delivery systems, thus improving their efficacy. The review, after a brief description of the vaginal environment and, in particular, of the vaginal secretions that strongly affect in vivo performance of vaginal formulations, deals with the above delivery systems. As for mucoadhesive systems, conventional formulations (gels, tablets, suppositories and emulsions) and novel drug delivery systems (micro-, nano-particles) intended for vaginal administration to achieve either local or systemic effect are reviewed. As for thermogelling systems, poly(ethylene oxide-propylene oxide-ethylene oxide) copolymer-based and chitosan-based formulations are discussed as thermogelling systems. The methods employed for functional characterization of both mucoadhesive and thermogelling drug delivery systems are also briefly described. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Availability of pediatric-evaluated formulations in Serbia

PubMed Central

Božić, Bojana; Stupar, Sanja; Stupar, Duško; Babić, Uroš; Bajčetić, Milica

2017-01-01

OBJECTIVES: The aim of this study is to analyze the availability and coverage by health insurance reimbursement of pediatric formulations labeled for children up to the age of 12 in Serbia. To provide good insight in general availability of pediatric medicines, results were compared with the World Health Organization's (WHO) “Model List of Essential Medicines for Children” and with published evidence. MATERIALS AND METHODS: Sources of information about medicines are the Summary of Product Characteristics, National Health Insurance Fund (NHIF) Drug Lists, WHO Model Lists of Essential Medicines for Children, and Serbia's official drug registry (2013). RESULTS: Out of total number of medicines in Serbia, only 49% (496) were available for children. Of all available drugs for children, 66% were with license and majority were parenteral formulation (57%), followed by drugs for local use (28%) and formulations for oral use (23%). The lowest availability of medicines was for children 0–27 days. From the total number of licensed medicines for children up to 12 years old, NHIF covers 64% of drugs. The availability of the WHO essential medicines for children in Serbia was 51%, from which 92% were licensed for pediatric use. CONCLUSIONS: Our results demonstrated the alarming lack of pediatric suitable formulations in Serbia. Significant differences in the availability of drugs suitable for children exist worldwide. From global health point of view, the differences in the access to children formulations should, therefore, be of the highest priority. PMID:28706333

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

Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

PubMed

O'Shea, Joseph P; Nagarsekar, Kalpa; Wieber, Alena; Witt, Vanessa; Herbert, Elisabeth; O'Driscoll, Caitriona M; Saal, Christoph; Lubda, Dieter; Griffin, Brendan T; Dressman, Jennifer B

2017-10-01

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation. © 2017 Royal Pharmaceutical Society.

Phospholipid-based solid drug formulations for oral bioavailability enhancement: A meta-analysis.

PubMed

Fong, Sophia Yui Kau; Brandl, Martin; Bauer-Brandl, Annette

2015-12-01

Low bioavailability nowadays often represents a challenge in oral dosage form development. Solid formulations composed of drug and phospholipid (PL), which, upon contact with water, eventually form multilamellar liposomes (i.e. 'proliposomes'), are an emerging approach to solve such issue. Regarded as an 'improved' version of liposomes concerning storage stability, the potential and versatility of a range of such formulations for oral drug delivery have been extensively discussed. However, a systematic and quantitative analysis of the studies that applied solid PL for oral bioavailability enhancement is currently lacking. Such analysis is necessary for providing an overview of the research progress and addressing the question on how promising this approach can be on bioavailability enhancement. The current review performed a systematic search of references in three evidence-based English databases, Medline, Embase, and SciFinder, from the year of 1985 up till March 2015. A total of 112 research articles and 82 patents that involved solid PL-based formulations were identified. The majority of such formulations was intended for oral drug delivery (55%) and was developed to address low bioavailability issues (49%). A final of 54 studies that applied such formulations for bioavailability enhancement of 43 different drugs with poor water solubility and/or permeability were identified. These proof-of-concept studies with in vitro (n=31) and/or animal (n=23) evidences have been systematically summarized. Meta-analyses were conducted to measure the overall enhancement power (percent increase compared to control group) of solid PL formulations on drugs' solubility, permeability and oral bioavailability, which were found to be 127.4% (95% CI [86.1, 168.7]), 59.6% (95% CI [30.1, 89.0]), and 18.5% (95% CI [10.1, 26.9]) respectively. Correlations between the enhancement factors and in silico physiochemical properties of drugs were also performed to check if such approach can be used to identify the best candidates for oral solid PL formulation. In addition to scientific literature, 13 solid PL formulation-related patents that addressed the issue of low oral bioavailability have been identified and summarized; whereas no clinical study was identified from the current search. By providing systematic information and meta-analysis on studies that applied the principle of 'proliposomes' for oral bioavailability enhancement, the current review should be insightful for formulation scientists who wish to adopt the PL based approach to overcome the solubility, permeability and bioavailability issues of orally delivered drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.

PubMed

Joshi, Hemant N; Tejwani, Ravindra W; Davidovich, Martha; Sahasrabudhe, Vaishali P; Jemal, Mohammed; Bathala, Mohinder S; Varia, Sailesh A; Serajuddin, Abu T M

2004-01-09

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.

Safety and efficacy of generic drugs with respect to brand formulation.

PubMed

Gallelli, Luca; Palleria, Caterina; De Vuono, Antonio; Mumoli, Laura; Vasapollo, Piero; Piro, Brunella; Russo, Emilio

2013-12-01

Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to generic formulations. In conclusion, the use of generic drugs could be related with an increased days of disease (time to relapse) or might lead to a therapeutic failure; on the other hand, a higher drug concentration might expose patients to an increased risk of dose-dependent side-effects.

Influence of cellulose derivative and ethylene glycol on optimization of lornoxicam transdermal formulation.

PubMed

Shahzad, Yasser; Khan, Qalandar; Hussain, Talib; Shah, Syed Nisar Hussain

2013-10-01

Lornoxicam containing topically applied lotions were formulated and optimized with the aim to deliver it transdermally. The formulated lotions were evaluated for pH, viscosity and in vitro permeation studies through silicone membrane using Franz diffusion cells. Data were fitted to linear, quadratic and cubic models and best fit model was selected to investigate the influence of variables, namely hydroxypropyl methylcellulose (HPMC) and ethylene glycol (EG) on permeation of lornoxicam from topically applied lotion formulations. The best fit quadratic model revealed that low level of HPMC and intermediate level of EG in the formulation was optimum for enhancing the drug flux across silicone membrane. FT-IR analysis confirmed absence of drug-polymer interactions. Selected optimized lotion formulation was then subjected to accelerated stability testing, sensatory perception testing and in vitro permeation across rabbit skin. The drug flux from the optimized lotion across rabbit skin was significantly better that that from the control formulation. Furthermore, sensatory perception test rated a higher acceptability while lotion was stable over stability testing period. Therefore, use of Box-Wilson statistical design successfully elaborated the influence of formulation variables on permeation of lornoxicam form topical formulations, thus, helped in optimization of the lotion formulation. Copyright © 2013 Elsevier B.V. All rights reserved.

Development, characterization and in vivo evaluation of benzocaine-loaded liposomes.

PubMed

Mura, Paola; Maestrelli, Francesca; González-Rodríguez, Maria Luisa; Michelacci, Ilaria; Ghelardini, Carla; Rabasco, Antonio M

2007-08-01

This study reports the development and in vivo evaluation of a liposomal formulation of the local anaesthetic benzocaine. Multi-lamellar (MLV) and small uni-lamellar (SUV) vesicles entrapping benzocaine were prepared using 50:50 w/w phosphatidylcholine-cholesterol as lipophilic phase and 50:50 v/v ethanol-water as hydrophilic phase. Liposome size, Zeta-potential, encapsulation efficiency and skin penetration properties were determined. Drug permeation from liposomal dispersions, as such or formulated in Carbopol gel, was evaluated through artificial lipophilic membranes and excised abdominal rat skin, whereas in vivo anaesthetic effect was tested on rabbits. Interestingly, addition of the drug into the hydrophilic phase, rather than into the lipophilic one, during liposome preparation enabled an improvement of the MLV's entrapment efficiency from 29.7% to 82.3%. On the other hand, sonication conditions to obtain SUV influenced size and polydispersity index of the vesicles and reduced the entrapment efficiency by about 30%. All liposomal-benzocaine formulations showed sustained release properties and a more intense anaesthetic effect than plain drug. Permeation experiments from drug solutions in gel containing the same amount of ethanol as in the liposomal formulations made it possible to exclude a possible enhancer effect of this solvent, at least when not used in liposomal formulations. MLV with the drug added into the hydrophilic phase gave the most effective formulation, showing a permeability coefficient value 2.5 times higher than that of the plain drug and allowing a significant improvement (P<0.01) not only of intensity but also of duration of anaesthetic effect of benzocaine. These results suggest that a suitably developed liposomal formulation of benzocaine can be of actual value for improving its clinical effectiveness in topical anaesthesia.

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.

Formulation and Optimization of Multiparticulate Drug Delivery System Approach for High Drug Loading.

PubMed

Shah, Neha; Mehta, Tejal; Gohel, Mukesh

2017-08-01

The aim of the present work was to develop and optimize multiparticulate formulation viz. pellets of naproxen by employing QbD and risk assessment approach. Mixture design with extreme vertices was applied to the formulation with high loading of drug (about 90%) and extrusion-spheronization as a process for manufacturing pellets. Independent variables chosen were level of microcrystalline cellulose (MCC)-X 1 , polyvinylpyrrolidone K-90 (PVP K-90)-X 2 , croscarmellose sodium (CCS)-X 3 , and polacrilin potassium (PP)-X 4 . Dependent variables considered were disintegration time (DT)-Y 1 , sphericity-Y 2 , and percent drug release-Y 3 . The formulation was optimized based on the batches generated by MiniTab 17 software. The batch with maximum composite desirability (0.98) proved to be optimum. From the evaluation of design batches, it was observed that, even in low variation, the excipients affect the pelletization property of the blend and also the final drug release. In conclusion, pellets with high drug loading can be effectively manufactured and optimized systematically using QbD approach.

Comparison of Clobetasol Propionate Generics Using Simplified in Vitro Bioequivalence Method for Topical Drug Products.

PubMed

Soares, Kelen Carine Costa; de Souza, Weidson Carlos; de Souza Texeira, Leonardo; da Cunha-Filho, Marcilio Sergio Soares; Gelfuso, Guilherme Martins; Gratieri, Tais

2017-11-20

The aim of this paper is to propose a simple in vitro skin penetration experiment in which the drug is extracted from the whole skin piece as a test valid for formulation screening and optimization during development process, equivalence assessment during quality control or post-approval after changes to the product. Twelve clobetasol propionate (CP) formulations (six creams and six ointments) from the local market were used as a model to challenge the proposed methodology in comparison to in vitro skin penetration following tape-stripping for drug extraction. To support the results, physicochemical tests for pH, viscosity, density and assay, as well as in vitro release were performed. Both protocols, extracting the drug from the skin using the tape-stripping technique or extracting from the full skin were capable of differentiating CP formulations. Only one formulation did not present statistical difference from the reference drug product in penetration tests and only other two oitments presented equivalent release to the reference. The proposed protocol is straightforward and reproducible. Results suggest the bioinequavalence of tested CP formulations reinforcing the necessity of such evaluations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Bioequivalence of isoniazid in a two drug fixed dose combination and in a single drug dosage form.

PubMed

Agrawal, S; Kaul, C L; Panchagnula, R

2001-08-01

To increase the patient compliance and reduce the risk of drug resistant strains, WHO and IUATLD recommend the use of Fixed Dose Combination (FDC) tablets as a routine therapeutic regimen in Directly Observed Treatment Shortcourse (DOTS). But the main issue in the use of FDC is the quality of the formulation. At present WHO and IUATLD suggest the bioequivalence assessment of only rifampicin from FDC compared to separate formulations. For the therapeutic effectiveness all the components of the FDCs should be bioavailable at tissue site. Also, the primary and acquired resistance rate of isoniazid is much higher compared to other anti-tubercular drugs. Hence, a comparative bioavailability study of isoniazid from a two drugs FDC compared to a separate formulation was carried out on a group of 12 healthy volunteers. When evaluated by normal or log transformed confidence interval, Two Way ANOVA and Hauschke analysis, the bioequivalence limits for AUC0-8 and AUC0-24 were within 0.8-1.25. For Cmax and Tmax, these limits were within 0.7-1.43. Hence, isoniazid from a FDC formulation was found to be bioequivalent to a separate formulation at same dose levels.

Process evaluation and in vitro selectivity analysis of aptamer-drug polymeric formulation for targeted pharmaceutical delivery.

PubMed

Tan, Kei X; Lau, Sie Yon; Danquah, Michael K

2018-05-01

Targeted drug delivery is a promising strategy to promote effective delivery of conventional and emerging pharmaceuticals. The emergence of aptamers as superior targeting ligands to direct active drug molecules specifically to desired malignant cells has created new opportunities to enhance disease therapies. The application of biodegradable polymers as delivery carriers to develop aptamer-navigated drug delivery system is a promising approach to effectively deliver desired drug dosages to target cells. This study reports the development of a layer-by-layer aptamer-mediated drug delivery system (DPAP) via a w/o/w double emulsion technique homogenized by ultrasonication or magnetic stirring. Experimental results showed no significant differences in the biophysical characteristics of DPAP nanoparticles generated using the two homogenization techniques. The DPAP formulation demonstrated a strong targeting performance and selectivity towards its target receptor molecules in the presence of non-targets. The DPAP formulation demonstrated a controlled and sustained drug release profile under the conditions of pH 7 and temperature 37 °C. Also, the drug release rate of DPAP formulation was successfully accelerated under an endosomal acidic condition of ∼pH 5.5, indicating the potential to enhance drug delivery within the endosomal micro-environment. The findings from this work are useful to understanding polymer-aptamer-drug relationship and their impact on developing effective targeted delivery systems. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

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.

Dorzolamide Loaded Niosomal Vesicles: Comparison of Passive and Remote Loading Methods.

PubMed

Hashemi Dehaghi, Mohadeseh; Haeri, Azadeh; Keshvari, Hamid; Abbasian, Zahra; Dadashzadeh, Simin

2017-01-01

Glaucoma is a common progressive eye disorder and the treatment strategies will benefit from nanoparticulate delivery systems with high drug loading and sustained delivery of intraocular pressure lowering agents. Niosomes have been reported as a novel approach to improve drug low corneal penetration and bioavailability characteristics. Along with this, poor entrapment efficiency of hydrophilic drug in niosomal formulation remains as a major formulation challenge. Taking this perspective into consideration, dorzolamide niosomes were prepared employing two different loading methodologies (passive and remote loading methods) and the effects of various formulation variables (lipid to drug ratio, cholesterol percentage, drug concentration, freeze/thaw cycles, TPGS content, and external and internal buffer molarity and pH) on encapsulation efficiency were assessed. Encapsulation of dorzolamide within niosomes increased remarkably by the incorporation of higher cholesterol percentage as well as increasing the total lipid concentration. Remote loading method showed higher efficacy for drug entrapment compared to passive loading technique. Incorporation of TPGS in bilayer led to decrease in EE; however, retarded drug release rate. Scanning electron microscopy (SEM) studies confirmed homogeneous particle distribution, and spherical shape with smooth surface. In conclusion, the highest encapsulation can be obtained using phosphate gradient method and 50% cholesterol in Span 60 niosomal formulation.

When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

PubMed Central

Stern, Stephan T.; Stevens, David M.

2016-01-01

Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation. PMID:27670412

Design of an expert system for the development and formulation of push-pull osmotic pump tablets containing poorly water-soluble drugs.

PubMed

Zhang, Zhi-hong; Dong, Hong-ye; Peng, Bo; Liu, Hong-fei; Li, Chun-lei; Liang, Min; Pan, Wei-san

2011-05-30

The purpose of this article was to build an expert system for the development and formulation of push-pull osmotic pump tablets (PPOP). Hundreds of PPOP formulations were studied according to different poorly water-soluble drugs and pharmaceutical acceptable excipients. The knowledge base including database and rule base was built based on the reported results of hundreds of PPOP formulations containing different poorly water-soluble drugs and pharmaceutical excipients and the experiences available from other researchers. The prediction model of release behavior was built using back propagation (BP) neural network, which is good at nonlinear mapping and learning function. Formulation design model was established based on the prediction model of release behavior, which was the nucleus of the inference engine. Finally, the expert system program was constructed by VB.NET associating with SQL Server. Expert system is one of the most popular aspects in artificial intelligence. To date there is no expert system available for the formulation of controlled release dosage forms yet. Moreover, osmotic pump technology (OPT) is gradually getting consummate all over the world. It is meaningful to apply expert system on OPT. Famotidine, a water insoluble drug was chosen as the model drug to validate the applicability of the developed expert system. Copyright © 2011 Elsevier B.V. All rights reserved.

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

Cocktail of Superoxide Dismutase and Fasudil Encapsulated in Targeted Liposomes Slows PAH Progression at a Reduced Dosing Frequency.

PubMed

Gupta, Nilesh; Rashid, Jahidur; Nozik-Grayck, Eva; McMurtry, Ivan F; Stenmark, Kurt R; Ahsan, Fakhrul

2017-03-06

Currently, two or more pulmonary vasodilators are used to treat pulmonary arterial hypertension (PAH), but conventional vasodilators alone cannot reverse disease progression. In this study, we tested the hypothesis that a combination therapy comprising a vasodilator plus a therapeutic agent that slows pulmonary arterial remodeling and right heart hypertrophy is an efficacious alternative to current vasodilator-based PAH therapy. Thus, we encapsulated a cocktail of superoxide dismutase (SOD), a superoxide scavenger, and fasudil, a specific rho-kinase inhibitor, into a liposomal formulation equipped with a homing peptide, CAR. We evaluated the effect of the formulations on pulmonary hemodynamics in monocrotaline-induced PAH rats (MCT-induced PAH) and assessed the formulation's efficacy in slowing the disease progression in Sugen-5416/hypoxia-induced PAH rats (SU/hypoxia-induced PAH). For acute studies, we monitored both mean pulmonary and systemic arterial pressures (mPAP and mSAP) for 2 to 6 h after a single dose of the plain drugs or formulations. In chronic studies, PAH rats received plain drugs every 48 h and the formulations every 72 h for 21 days. In MCT-induced PAH rats, CAR-modified liposomes containing fasudil plus SOD elicited a more pronounced, prolonged, and selective reduction in mPAP than unmodified liposomes and plain drugs did. In SU/hypoxia-induced PAH rats, the formulation produced a >50% reduction in mPAP and slowed right ventricular hypertrophy. When compared with individual plain drugs or combination, CAR-modified-liposomes containing both drugs reduced the extent of collagen deposition, muscularization of arteries, increased SOD levels in the lungs, and decreased the expression of pSTAT-3 and p-MYPT1. Overall, CAR-modified-liposomes of SOD plus fasudil, given every 72 h, was as efficacious as plain drugs, given every 48 h, suggesting that the formulation can reduce the total drug intake, systemic exposures, and dosing frequency.

Formulation and transport properties of tenofovir loaded liposomes through Caco-2 cell model.

PubMed

Zidan, Ahmed S; Spinks, Crystal B; Habib, Muhammad J; Khan, Mansoor A

2013-12-01

The aim was to investigate the potential of proliposomes to improve the permeability of tenofovir, anti-HIV, for oral delivery. Tenofovir was incorporated into phosphatidylcholine proliposomes and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using aqueous drug solutions as reference. Five batches of proliposomes were prepared with different stearylamine levels and characterized in terms of vesicular morphology, drug encapsulation efficiency (EEF), drug leakage, vesicular sizing and surface charges. Cytotoxicity of the reconstituted liposomes was evaluated by the MTT assay. The obtained results showed that increasing the incorporated percentage of stearylamine led to an increase in drug encapsulation, a slower drug leakage and larger liposomes formed. Compared to the drug solutions at corresponding concentrations, the proposed formulations showed a positive relationship (R²= 0.9756) for the influence of increasing the stearylamine percentage on reduction of mitochondrial activity. Regarding the drug permeability, enhancements of apparent permeability by 16.5- and 5.2-folds were observed for proliposomes formulations with 5% and 15% stearylamine, respectively. A good correlation was observed between the Caco-2 and dialysis models that might indicate passive diffusion as well as paracellular transport as suggested mechanisms for drug absorption. Cationic proliposomes offered a potential formulation to improve the permeation of tenofovir.

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.

Development of performance matrix for generic product equivalence of acyclovir topical creams.

PubMed

Krishnaiah, Yellela S R; Xu, Xiaoming; Rahman, Ziyaur; Yang, Yang; Katragadda, Usha; Lionberger, Robert; Peters, John R; Uhl, Kathleen; Khan, Mansoor A

2014-11-20

The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax®). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted. The formulations were subjected to physicochemical characterization (drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase) and in vitro drug release studies against RLD. The results demonstrated that DOE formulations were structurally and functionally (e.g., drug release) similar (Q3) to RLD. Moreover, in vitro drug permeation studies showed that extent of drug bioavailability/retention in human epidermis from F-12-F-14 were similar to RLD, although differed in rate of permeation. The results suggested generic acyclovir creams can be manufactured to obtain identical performance as that of RLD with Q1/Q2/Q3. Published by Elsevier B.V.

Formulation and evaluation of different floating tablets containing metronidazole to target stomach.

PubMed

Loh, Zhiao C; Elkordy, Amal A

2015-01-01

The purpose of this study is to formulate and develop tablets dosage form containing Metronidazole which has swelling and floating properties as a gastroretentive controlled-release drug delivery system to improve drug bioavailability. Fifteen different formulations of effervescence-forming floating systems were designed using HPMC K15M, xanthan gum, co-povidone, Eudragit® RL PO, pluronic® F-127 and/or polypropylene foam powder as swelling agents and sodium bicarbonate with/ without citric acid as gas-forming agents at different compositions. Six out of these 15 formulations which have satisfactory tablet floating behaviour were further studied with the incorporation of Metronidazole. The tablets were evaluated based on tablet physicochemical properties, floating behaviour, swelling ability and drug dissolution studies which were carried out using 0.1M HCl at 37°C for 8 hours. Furthermore, evaluation of the powder mixtures using Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) were investigated. Most of the tablets show good physicochemical properties except for F11 which contains pluronic® F-127 as its release-retarding matrix-forming polymer. Other formulations show high swelling capacity, ability to float for at least 8 hours in vitro and have sustained drug release characteristics. Data obtained indicated that F3 which contains HPMC (12.5%w/w), xanthan gum (25%w/w), co-povidone (12.5%w/w) and sodium bicarbonate (31.7%w/w) is a suitable formulation with short floating lag time, good floating behaviour and sustained drug release for at least 8 hours in vitro with a zero order kinetic. Combinations of HPMC K15M and xanthan gum as swelling agents show synergistic effect in retarding drug release and are suitable in providing the most sustained drug release system.

Dissolution enhancement of glibenclamide by solid dispersion: solvent evaporation versus a supercritical fluid-based solvent -antisolvent technique

PubMed Central

Tabbakhian, M.; Hasanzadeh, F.; Tavakoli, N.; Jamshidian, Z.

2014-01-01

Glibenclamide (GLIB) is a poorly soluble drug with formulation-dependent bioavailability. Therefore, we attempted in this study to improve GLIB dissolution rate by preparing drug solid dispersions by solvent evaporation (SE) and supercritical fluid solvent-antisolvent techniques (SCF-SAS). A D-optimal mixture design was used to investigate the effects of different ratios of HPMCE5 (50-100%), PEG6000 (0-40%), and Poloxamer407 (0-20%) on drug dissolution from different solid dispersion (SD) formulations prepared by SE. The ratios of carriers used in SCF-SAS method were HPMCE5 (fixed at 60%), PEG6000 (20-40%), and Poloxamer407 (0-20%). A constant drug: carrier weight ratio of 1:10 was used in all experiments. The SDs obtained were physically characterized and subjected to the dissolution study. The major GLIB bands in FTIR spectra were indicative of drug integrity. The reduced intensity and the fewer number of peaks observed in X-ray diffractograms (XRD) of GLIB formulations was the indicative of at least partial transformation of crystalline to amorphous GLIB. This change and/or dilution of drug in much higher amounts of carriers present caused disappearance of distinctive endothermic peaks in differential scanning calorimetry thermograms of GLIB formulations. The model generated according to the results of the D-optimal mixture design indicated that GLIB formulations comprising HPMC (50%-60%), PEG (34-40%), and poloxamer (6-10%) had enhanced dissolution performances. As compared to SE method, the SCF-SAS technique produced formulations of higher dissolution performances, likely due to the effects of solution and the supercritical CO2 (SC-CO2) on enhanced plasticization of polymers and thus increased diffusion of the drug into the polymer matrix. PMID:25657806

Solid state properties and drug release behavior of co-amorphous indomethacin-arginine tablets coated with Kollicoat® Protect.

PubMed

Petry, Ina; Löbmann, Korbinian; Grohganz, Holger; Rades, Thomas; Leopold, Claudia S

2017-10-01

A promising approach to improve the solubility of poorly water-soluble drugs and to overcome the stability issues related to the plain amorphous form of the drugs, is the formulation of drugs as co-amorphous systems. Although polymer coatings have been proven very useful with regard to tablet stability and modifying drug release, there is little known on coating co-amorphous formulations. Hence, the aim of the present study was to investigate whether polymer coating of co-amorphous formulations is possible without inducing recrystallization. Tablets containing either a physical mixture of crystalline indomethacin and arginine or co-amorphous indomethacin-arginine were coated with a water soluble polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® Protect) and stored at 23°C/0% RH and 23°C/75% RH. The solid state properties of the coated tablets were analyzed by XRPD and FTIR and the drug release behavior was tested for up to 4h in phosphate buffer pH 4.5. The results showed that the co-amorphous formulation did not recrystallize during the coating process or during storage at both storage conditions for up to three months, which confirmed the high physical stability of this co-amorphous system. Furthermore, the applied coating could partially inhibit recrystallization of indomethacin during drug release testing, as coated tablets reached a higher level of supersaturation compared to the respective uncoated formulations and showed a lower decrease of the dissolved indomethacin concentration upon precipitation. Thus, the applied coating enhanced the AUC of the dissolution curve of the co-amorphous tablets by about 30%. In conclusion, coatings might improve the bioavailability of co-amorphous formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Reducing medication errors in critical care: a multimodal approach

PubMed Central

Kruer, Rachel M; Jarrell, Andrew S; Latif, Asad

2014-01-01

The Institute of Medicine has reported that medication errors are the single most common type of error in health care, representing 19% of all adverse events, while accounting for over 7,000 deaths annually. The frequency of medication errors in adult intensive care units can be as high as 947 per 1,000 patient-days, with a median of 105.9 per 1,000 patient-days. The formulation of drugs is a potential contributor to medication errors. Challenges related to drug formulation are specific to the various routes of medication administration, though errors associated with medication appearance and labeling occur among all drug formulations and routes of administration. Addressing these multifaceted challenges requires a multimodal approach. Changes in technology, training, systems, and safety culture are all strategies to potentially reduce medication errors related to drug formulation in the intensive care unit. PMID:25210478

The colorimetric analysis of anti-tuberculosis fixed-dose combination tablets and capsules.

PubMed

Ellard, G A

1999-11-01

The perceived need to demonstrate whether or not the actual amounts of rifampicin, isoniazid and pyrazinamide in fixed-dose combination tablets or capsules correspond to their stated drug contents. To adapt specific, robust and simple colorimetric methods that have been previously applied to measuring plasma and urinary rifampicin, isoniazid, pyrazinamide and ethambutol concentrations to estimate tablet and capsule drug contents. The methods were applied to the analysis of 14 commercially manufactured fixed-dose combinations: two capsule and three tablet formulations containing rifampicin and isoniazid; seven tablet formulations containing rifampicin, isoniazid and pyrazinamide; and two tablet formulations containing rifampicin, isoniazid, pyrazinamide and ethambutol. All the combined formulations contained near to their stated drug contents. Replicate analyses confirmed the excellent precision of the drug analyses. Such methods are not only rapid to perform but should be practical in many Third World situations with relatively modest laboratory facilities.

Are in situ formulations the keys for the therapeutic future of S-nitrosothiols?

PubMed

Parent, Marianne; Boudier, Ariane; Dupuis, François; Nouvel, Cécile; Sapin, Anne; Lartaud, Isabelle; Six, Jean-Luc; Leroy, Pierre; Maincent, Philippe

2013-11-01

S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP) were formulated into in situ forming implants (ISI) and microparticles (ISM) using PLGA and either N-methyl-2-pyrrolidone (NMP) or triacetin. Physicochemical characterization was carried out, including the study of matrix structure and degradation. A strong correlation between drug hydrophobicity and the in vitro release profiles was observed: whatever the formulation, GSNO and SNAP were completely released after ca. 1 day and 1 week, respectively. Then, selected formulations (i.e., SNAP-loaded NMP formulations) demonstrated the ability to sustain the vasodilation effect of SNAP, as shown by monitoring the arterial pressure (telemetry) of Wistar rats after subcutaneous injection. Both ISI and ISM injections resulted in a 3-fold extended decrease in pulse arterial pressure compared with the unloaded drug, without significant decrease in the mean arterial pressure. Hence, the results emphasize the suitability of these formulations as drug delivery systems for S-nitrosothiols, widening their therapeutic potential. Copyright © 2013 Elsevier B.V. All rights reserved.

Applications of lipid based formulation technologies in the delivery of biotechnology-based therapeutics.

PubMed

du Plessis, Lissinda H; Marais, Etienne B; Mohammed, Faruq; Kotzé, Awie F

2014-01-01

In the last decades several new biotechnologically-based therapeutics have been developed due to progress in genetic engineering. A growing challenge facing pharmaceutical scientists is formulating these compounds into oral dosage forms with adequate bioavailability. An increasingly popular approach to formulate biotechnology-based therapeutics is the use of lipid based formulation technologies. This review highlights the importance of lipid based drug delivery systems in the formulation of oral biotechnology based therapeutics including peptides, proteins, DNA, siRNA and vaccines. The different production procedures used to achieve high encapsulation efficiencies of the bioactives are discussed, as well as the factors influencing the choice of excipient. Lipid based colloidal drug delivery systems including liposomes and solid lipid nanoparticles are reviewed with a focus on recent advances and updates. We further describe microemulsions and self-emulsifying drug delivery systems and recent findings on bioactive delivery. We conclude the review with a few examples on novel lipid based formulation technologies.

Formulation and evaluation of polyelectrolyte complex-based matrix tablet of Isosorbide Mononitrate

PubMed Central

Syed, Iizhar Ahmed; Niveditha, P.; Ahmad, Ismail

2014-01-01

Introduction: The polyelectrolyte Complexes (PECs) are based on ionic cross-linking. They have been employed to prepare a sustained release matrix tablets. These systems are based upon the fact that their structure can entrap the drug within them. Isosorbide Mononitrate (ISMN) is an anti-anginal organic nitrate vasodilator used in the treatment of various cardiovascular disorders and prophylaxis of angina Pectoris, which is poorly absorbed from the upper GIT, hence CR formulation is desirable. Materials and Methods: Chitosan (CH)/Sodium alginate (SA), Guar gum (GG), and Xanthan gum (XG) were used as PECs, and were prepared using different proportions i.e., in 1:1 and 1:2 ratio. The optimum ratio of CH: SA, CH: GG and CH: XG was in the ratio was 1:2; these are formed due to electrostatic interaction between oppositely charged poly ions. These normally employ a hydrophilic matrix system. Matrix tablet of ISMN was formulated by using PECs as matrix forming agent by wet granulation technique. Results: The tablets were evaluated for hardness, wt variation, drug content, and in-vitro dissolution studies and found to be within limits. Release kinetics data indicated that ISMN released from the PECs-based matrix tablets of CH-SA, CH-GG and CH-XG CP in 1:1 and 1:2 ratio, followed Fickian and non-Fickian diffusion mechanism respectively. Thus, the drug release rate was extended for over a period of more than 12 h stability studies. There is no significant difference in the mean % drug released from formulation CH-X2 after storing for 3 months at 40°C/75% RH. The FT-IR spectra revealed that there was no interaction between polymers and drug, Statistical analysis showed a significant differences (P < 0.05) for the amount of ISMN released from the formulations (MXG) and formulations (CH-X2). Conclusion: Formulation CH-XG2 (1:2) showed better sustained release of highly water-soluble ISMN with the desired release rate. Thus, the formulated PECs-based matrix tablets seems to be a potential candidate for sustained drug delivery of highly soluble drug ISMN in the symptomatic therapy of angina pectoris. PMID:24678461

Tailoring the mucoadhesive and sustained release characteristics of mesalamine loaded formulations for local treatment of distal forms of ulcerative colitis.

PubMed

Ali, Hany S M; Hanafy, Ahmed F; El Achy, Samar N

2016-10-10

Direct delivery of sustained therapeutic levels of mesalamine (MS) via rectal systems to manage distal forms of ulcerative colitis was studied. The High molecular weight hydroxypropyl methylcellulose (HPMC K4M) polymer was combined with hydrophilic surfactants to control polymer hydration process allowing optimization of the mucoadhesive and controlled drug release properties for the rectal systems. Physical mixtures and granules of MS and HPMC K4M were prepared and in vitro characterized using scanning electron microscope, differential scanning calorimetry and X-ray diffraction techniques. Rectal formulations were prepared utilizing MS-HPMC K4M mixtures in different polyethylene glycol (PEG) combination bases. The developed rectal formulations were investigated for physical, mucoadhesion, in-vitro drug release and swelling characteristics. Results revealed acceptable physical characteristics of the prepared formulations with good content uniformity and minimum weight variation. Sustained release patterns of MS form HPMC K4M based formulations were observed. Formulations prepared using high proportions of the polymer or PEG 400 showed higher extent of mucoadhesion, swelling and greatly extended drug release time. Efficacy of an optimized formulation was assessed using the acetic acid induced colitis model in rats and compared to a reference polymer-free formulation of the drug. Clinical evaluation included bleeding from rectum, consistency of animal stool and colon/body weight ratio. Furthermore, histopathological analysis was carried out to evaluate the degree of inflammation and mucosal damage. Overall results showed a significant enhancement in the clinical pictures and colon histopathology of animals treated by the sustained release mucoadhesive formulation compared to the reference polymer free formulation and the non-treated colitis group. Copyright © 2016 Elsevier B.V. All rights reserved.

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations.

PubMed

Williams, Hywel D; Sassene, Philip; Kleberg, Karen; Calderone, Marilyn; Igonin, Annabel; Jule, Eduardo; Vertommen, Jan; Blundell, Ross; Benameur, Hassan; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H

2013-12-01

Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs. Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases. Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol. The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

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.

Pharmaceutical applications of cyclodextrins: basic science and product development.

PubMed

Loftsson, Thorsteinn; Brewster, Marcus E

2010-11-01

Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations. There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes. We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing. © 2010 The Authors. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.

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.

Formulation and advantages of furazolidone in liposomal drug delivery systems.

PubMed

Alam, Muhammad Irfan; Paget, Timothy; Elkordy, Amal Ali

2016-03-10

Furazolidone has proven to have antiprotozoal and antibacterial activity. A number of literature supported its use against Helicobacter pylori. This potential application opens new prospects of its use in clinical settings in triple therapy. In order to avoid side effects associated with this drug, liposomal mucoadhesive drug delivery that can work locally in stomach is considered as an appropriate approach. This study is a focus on formulations and in vitro characterization of liposomes containing furazolidone. Therefore, the effects of variable amounts of drug and cholesterol on encapsulation efficacy and in vitro drug release were evaluated for different liposomal formulations. Mucoadhesive behavior of chitosan coated liposomal at two different pHs was also evaluated and increase in pH from 1.3 to 4.5 increased mucoadhesion from 42% to 60% respectively. Increasing the amount of drug from 4mg to 5mg increased encapsulation activity however, increasing the drug any further decreased encapsulation activity. In contrast, by increasing the amount of cholesterol decrease in encapsulation activity was observed. The optimized formulation with 5mg of drug and 53mg of cholesterol in formulation gave 57% drug release at pH 1.3 but release was increased up to 71% by increasing pH to 4.5 for same amount of drug. However, by using 10.6mg of cholesterol and 5mg of drug the overall release was increased at both pH conditions, at pH 1.3 release was 69% as compared to 77% at pH 4.5. This trend of drug release profile and mucoadhesion that favors pH 4.5 is documented as useful in targeting H. pylori as normal pH of stomach is expected to be higher by the influence of this microbe. Hence, the results of this research can be taken further into a future in vivo study. Copyright © 2016 Elsevier B.V. All rights reserved.

Safety and efficacy of generic drugs with respect to brand formulation

PubMed Central

Gallelli, Luca; Palleria, Caterina; De Vuono, Antonio; Mumoli, Laura; Vasapollo, Piero; Piro, Brunella; Russo, Emilio

2013-01-01

Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to generic formulations. In conclusion, the use of generic drugs could be related with an increased days of disease (time to relapse) or might lead to a therapeutic failure; on the other hand, a higher drug concentration might expose patients to an increased risk of dose-dependent side-effects. PMID:24347975

Optimization of carboxylate-terminated poly(amidoamine) dendrimer-mediated cisplatin formulation.

PubMed

Kulhari, Hitesh; Pooja, Deep; Singh, Mayank K; Chauhan, Abhay S

2015-02-01

Abstract Cisplatin is mainly used in the treatment of ovarian, head and neck and testicular cancer. Poor solubility and non-specific interactions causes hurdles in the development of successful cisplatin formulation. There were few reports on poly(amidoamine) (PAMAM) dendrimer-cisplatin complexes for anticancer treatment. But the earlier research was mainly focused on therapeutic effect of PAMAM dendrimer-cisplatin complex, with less attention paid on the formulation development of these complexes. Objective of the present study is to optimize and validate the carboxylate-terminated, EDA core PAMAM dendrimer-based cisplatin formulation with respect to various variables such as dendrimer core, generation, drug entrapment, purification, yield, reproducibility, stability, storage and in-vitro release. Dendrimer-cisplatin complex was prepared by an efficient method which significantly increases the % platinum (Pt) content along with the product yield. Dendrimers showed reproducible (∼27%) platinum loading by weight. Variation in core and generations does not produce significant change in the % Pt content. Percentage Pt content of dendrimeric formulation increases with increase in drug/dendrimer mole ratio. Formulation with low drug/dendrimer mole ratio showed delayed release compared to the higher drug/dendrimer mole ratio; these dendrimer formulations are stable in room temperature. In vitro release profiles of the stored dendrimer-cisplatin samples showed comparatively slow release of cisplatin, which may be due to formation of strong bond between cisplatin and dendrimer. This study will contribute to create a fine print for the formulation development of PAMAM dendrimer-cisplatin complexes.

A comparative study of vitamin E TPGS/HPMC supersaturated system and other solubilizer/polymer combinations to enhance the permeability of a poorly soluble drug through the skin.

PubMed

Ghosh, Indrajit; Michniak-Kohn, Bozena

2012-11-01

In transdermal drug delivery systems (TDDS), it is a challenge to achieve stable and prolonged high permeation rates across skin, because the concentration of the drug dissolved in the matrix has to be high in order to maintain zero order release kinetics of the drug. In case of poorly soluble drugs, due to thermodynamic challenges, there is a high tendency for the drug to nucleate immediately after formulating or even during storage. The present study focuses on the efficiency of vitamin E TPGS/HPMC supersaturated solution and other solubilizer/polymer systems to improve the solubility of the drug and inhibit crystal growth in the transdermal formulation. Effect of several solubilizers, for example, Pluronic F-127, vitamin E TPGS and co-solvent, for example, propylene glycol (PG) were studied on the supersaturated systems of ibuprofen as model drug. Various stabilizers such as hydroxylpropyl methylcellulose (HPMC 3 cps) and polyvinylpyrrolidone (PVP K-30) were examined to evaluate their crystal inhibitory effects. Different analytical tools were used in this study to detect the growth of crystals in the systems. Vitamin E TPGS and HPMC 3 cps formulation produced the highest permeation rate of the drug as compared to other systems. In addition, the onset of crystallization time was shown to be longer with this formulation as compared to other solubilizer/polymer combinations.

Formulation and characterization of modified release tablets containing isoniazid using swellable polymers.

PubMed

Akhtar, M F; Rabbani, M; Sharif, A; Akhtar, B; Saleem, A; Murtaza, G

2011-01-01

The aim of this work was to develop swellable modified release (MR) isoniazid tablets using different combinations of polyvinyl acetate (PVAc) and sodium-carboxymethylcellulose (Na-CMC). Granules were prepared by moist granulation technique and then compressed into tablets. In vitro release studies for 12 hr were carried out in dissolution media of varying pH i.e. pH 1.2, 4.5, 7.0 and 7.5. Tablets of all formulations were found to be of good physical quality with respect to appearance (width and thickness), content uniformity, hardness, weight variation and friability. In vitro release data showed that increasing total polymer content resulted in more retarding effect. Formulation with 35% polymer content exhibited zero order release profile and it released 35% of the drug in first hr, later on, controlled drug release was observed upto the 12(th) hour. Formulations with PVAc to Na-CMC ratio 20:80 exhibited zero order release pattern at levels of studied concentrations, which suggested that this combination can be used to formulate zero order release tablets of water soluble drugs like isoniazid. Korsmeyer-Peppas modeling of drug release showed that non-Fickian transport is the primary mechanism of isoniazid release from PVAc and Na-CMC based tablets. The value of mean dissolution time decreased with the increase in the release rate of drug clearly showing the retarding behavior of the swellable polymers. The application of a mixture of PVAc to Na-CMC in a specific ratio may be feasible to formulate zero order release tablets of water soluble drugs like isoniazid.

Formulation approaches to pediatric oral drug delivery: benefits and limitations of current platforms

PubMed Central

Lopez, Felipe L; Ernest, Terry B; Tuleu, Catherine; Gul, Mine Orlu

2015-01-01

Introduction: Most conventional drug delivery systems are not acceptable for pediatric patients as they differ in their developmental status and dosing requirements from other subsets of the population. Technology platforms are required to aid the development of age-appropriate medicines to maximize patient acceptability while maintaining safety, efficacy, accessibility and affordability. Areas covered: The current approaches and novel developments in the field of age-appropriate drug delivery for pediatric patients are critically discussed including patient-centric formulations, administration devices and packaging systems. Expert opinion: Despite the incentives provided by recent regulatory modifications and the efforts of formulation scientists, there is still a need for implementation of pharmaceutical technologies that enable the manufacture of licensed age-appropriate formulations. Harmonization of endeavors from regulators, industry and academia by sharing learning associated with data obtained from pediatric investigation plans, product development pathways and scientific projects would be the way forward to speed up bench-to-market age appropriate formulation development. A collaborative approach will benefit not only pediatrics, but other patient populations such as geriatrics would also benefit from an accelerated patient-centric approach to drug delivery. PMID:26165848

Anacardic acid enhances the anticancer activity of liposomal mitoxantrone towards melanoma cell lines – in vitro studies

PubMed Central

Legut, Mateusz; Lipka, Dominik; Filipczak, Nina; Piwoni, Adriana; Kozubek, Arkadiusz; Gubernator, Jerzy

2014-01-01

This paper describes a novel formulation of antineoplastic drug: mitoxantrone loaded into liposomal carriers enriched with encapsulated anacardic acid in the liposomal bilayer using a vitamin C gradient. Anacardic acid is a potent epigenetic agent with anticancer activity. This is the first liposomal formulation to combine an actively encapsulated drug and anacardic acid. The liposomes were characterized in terms of basic parameters, such as size, zeta potential, optimal drug-to-lipid ratio, loading time and temperature, and stability at 4°C and in human plasma in vitro. The formulation was found to be stable, and the loading process was rapid and efficient (drug-to-lipid ratio of up to 0.3 with over 90% efficiency in 5 minutes). The cytotoxicity of these formulations was assessed using the human melanoma cell lines A375 and Hs294T and the normal human dermal fibroblast line. The results showed that anacardic acid and to a smaller extent vitamin C significantly increased the cytotoxicity of the drug towards melanoma compared to ammonium sulfate liposomes. On the other hand, vitamin C and anacardic acid both protected normal cells from damage caused by the drug. The formulation combining anacardic acid, vitamin C, and mitoxantrone showed promising results in terms of cytotoxicity and cytoprotection. Therefore, it has potential for anticancer treatment. PMID:24489469

Topical Vehicle Formulations in the Treatment of Acne.

PubMed

Hoffman, Lauren K; Bhatia, Neal; Zeichner, Joshua; Kircik, Leon H

2018-06-01

Topical treatment is the mainstay of acne therapy. The most commonly prescribed topical medications for acne include benzoyl peroxide, clindamycin, and retinoids. Despite their effectiveness in treating mild to moderate acne vulgaris, these topical medications are found to be irritating, and are historically associated with poor tolerability and diminished patient adherence. Thus, choosing the right formulation that will be effective and well tolerated is essential. Novel formulations that optimize drug concentration and utilize improved delivery vehicles have helped to enhance the tolerability and efficacy, and allow for less frequent application or co-application of drugs that were previously considered incompatible. This article will review the goals of topical therapy for the treatment of acne, in addition to common therapies and their challenges. Advanced formulations and combination formulations of benzoyl peroxide, clindamycin, and tretinoin will also be discussed. J Drugs Dermatol. 2018;17(6 Suppl):s6-10.

Formulation and Evaluation of Guggul Lipid Nanovesicles for Transdermal Delivery of Aceclofenac

PubMed Central

Gaur, Praveen Kumar; Mishra, Shikha; Aeri, Vidhu

2014-01-01

Context. Most new drugs have low water solubility and liposome is an important formulation to administer such drugs; however, it is quite unstable and has negligible systemic absorption. Objective. Aceclofenac nanovesicles were made using guggul lipid for formulating stable transdermal formulation. Materials and Methods. Guggul lipid was formulated into vesicles along with cholesterol and dicetyl phosphate using film hydration method. The formulations were analyzed for physicochemical properties and stability. Then its skin permeation and anti-inflammatory activity were determined. Results. Both categories of vesicles (PC and GL) showed optimum physicochemical properties; however, accelerated stability study showed considerable differences. GL-1 was appreciably stable for over 6 months at 4°C. Corresponding gels (PCG-1 and GLG-1) showed C max values at 4.98 and 7.32 μg/mL along with the T max values at 4 and 8 hours, respectively. GLG-1 inhibited edema production by 90.81% in 6 hours. Discussion. PC liposomes are unstable at higher temperature and upon longer storage. The formulation with higher lipid content (GL-1) showed good drug retention after 24 hours and appreciable stability both at higher temperature and for longer duration. Guggul lipid being a planar molecule might be stacked in vesicle wall with cholesterol. Conclusion. The composition of the nanovesicle played an important role in stability and drug permeation. Guggul lipid is suitable for producing stable vesicles. PMID:24672328

PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin.

PubMed

Ryan, Gemma M; Kaminskas, Lisa M; Bulitta, Jürgen B; McIntosh, Michelle P; Owen, David J; Porter, Christopher J H

2013-11-28

Improved delivery of chemotherapeutic drugs to the lymphatic system has the potential to augment outcomes for cancer therapy by enhancing activity against lymph node metastases. Uptake of small molecule chemotherapeutics into the lymphatic system, however, is limited. Nano-sized drug carriers have the potential to promote access to the lymphatics, but to this point, this has not been examined in detail. The current study therefore evaluated the lymphatic exposure of doxorubicin after subcutaneous and intravenous administration as a simple solution formulation or when formulated as a doxorubicin loaded PEGylated poly-lysine dendrimer (hydrodynamic diameter 12 nm), a PEGylated liposome (100 nm) and various pluronic micellar formulations (~5 nm) to thoracic lymph duct cannulated rats. Plasma and lymph pharmacokinetics were analysed by compartmental pharmacokinetic modelling in S-ADAPT, and Berkeley Madonna software was used to predict the lymphatic exposure of doxorubicin over an extended period of time. The micelle formulations displayed poor in vivo stability, resulting in doxorubicin profiles that were similar to that observed after administration of the doxorubicin solution formulation. In contrast, the dendrimer formulation significantly increased the recovery of doxorubicin in the thoracic lymph after both intravenous and subcutaneous dosing when compared to the solution or micellar formulation. Dendrimer-doxorubicin also resulted in increases in lymphatic doxorubicin concentrations when compared to the liposome formulation, although liposomal doxorubicin did increase lymphatic transport when compared to the solution formulation. Specifically, the dendrimer formulation increased the recovery of doxorubicin in the lymph up to 30 h post dose by up to 685 fold and 3.7 fold when compared to the solution and liposomal formulations respectively. Using the compartmental model to predict lymphatic exposure to longer time periods suggested that doxorubicin exposure to the lymphatic system would ultimately be 9796 times and 6.1 times greater after administration of dendrimer doxorubicin when compared to the solution and liposome formulations respectively. The recovery of doxorubicin in the sentinel lymph nodes draining the subcutaneous injection site was also quantified directly, and consistent with the lymph pharmacokinetic data, lymph node recovery was greatest for the dendrimer formulation (12% of dosed doxorubicin/g node) when compared to the liposome (1.4%/g node) and solution (<1%/g node) formulations. The data suggest that dendrimer-based drug delivery systems have the potential to enhance drug exposure to lymph-based drug targets such as lymphatic metastases. © 2013.

Novel strategies for the formulation and processing of poorly water-soluble drugs.

PubMed

Göke, Katrin; Lorenz, Thomas; Repanas, Alexandros; Schneider, Frederic; Steiner, Denise; Baumann, Knut; Bunjes, Heike; Dietzel, Andreas; Finke, Jan H; Glasmacher, Birgit; Kwade, Arno

2018-05-01

Low aqueous solubility of active pharmaceutical ingredients presents a serious challenge in the development process of new drug products. This article provides an overview on some of the current approaches for the formulation of poorly water-soluble drugs with a special focus on strategies pursued at the Center of Pharmaceutical Engineering of the TU Braunschweig. These comprise formulation in lipid-based colloidal drug delivery systems and experimental as well as computational approaches towards the efficient identification of the most suitable carrier systems. For less lipophilic substances the preparation of drug nanoparticles by milling and precipitation is investigated for instance by means of microsystem-based manufacturing techniques and with special regard to the preparation of individualized dosage forms. Another option to overcome issues with poor drug solubility is the incorporation into nanospun fibers. Copyright © 2017 Elsevier B.V. All rights reserved.

Formulation and In-vitro Characterization of Sustained Release Matrix Type Ocular Timolol Maleate Mini-Tablet

PubMed Central

Mortazavi, Seyed Alireza; Jafariazar, Zahra; Ghadjahani, Yasaman; Mahmoodi, Hoda; Mehtarpour, Farzaneh

2014-01-01

The purpose of this study was preparation and evaluation of sustained release matrix type ocular mini-tablets of timolol maleate, as a potential formulation for the treatment of glaucoma. Following the initial studies on timolol maleate powder, it was formulated into ocular mini-tablets. The polymers investigated in this study included cellulose derivatives (HEC, CMC, EC) and Carbopol 971P. Mannitol was used as the solubilizing agent and magnesium stearate as the lubricant. Mini-tablets were prepared by through mixing of the ingredients, followed by direct compression. All the prepared formulations were evaluated in terms of physicochemical tests, including uniformity of weight, thickness, crushing strength, friability and in-vitro drug release. Four groups of formulations were prepared. The presence of different amounts of cellulose derivatives or Carbopol 971P, alone, was studied in group A formulations. In group B formulations, the effect of adding Carbopol 971P alongside different cellulose derivatives was investigated. Group C formulations were made by including mannitol as the solubilizing agent, alongside Carbopol 971P and a cellulose derivative. In group D formulations, mini-tablets were made using Carbopol 971P, alongside two different cellulose derivative. The selected formulation (C1) contained ethyl cellulose, Carbopol 971P, mannitol and magnesium stearate, which showed almost 100% drug release over 5 h. Based on kinetic studies, this formulation was found to best fit the zero-order model of drug release. However, the Higuchi and Hixson -Crowell models also showed a good fit. Hence, overall, formulation C1 was chosen as the best formulation. PMID:24734053

The influence of initial atomized droplet size on residual particle size from pressurized metered dose inhalers.

PubMed

Sheth, Poonam; Stein, Stephen W; Myrdal, Paul B

2013-10-15

Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of diseases of the lung, including asthma and chronic obstructive pulmonary disease. The mass median aerodynamic diameter of the residual particles (MMADR) delivered from a pMDI plays a key role in determining the amount and location of drug deposition in the lung and thereby the efficacy of the inhaler. The mass median diameter of the initial droplets (MMDI), upon atomization of a formulation, is a significant factor influencing the final particle size. The purpose of this study was to evaluate the extent that MMDI and initial droplet geometric standard deviation (GSD) influence the residual aerodynamic particle size distribution (APSDR) of solution and suspension formulations. From 48 solution pMDI configurations with varying ethanol concentrations, valve sizes and actuator orifice diameters, it was experimentally found that the effective MMDI ranged from 7.8 to 13.3 μm. Subsequently, computational methods were utilized to determine the influence of MMDI on MMADR, by modulating the MMDI for solution and suspension pMDIs. For solution HFA-134a formulations of 0.5% drug in 10% ethanol, varying the MMDI from 7.5 to 13.5 μm increased the MMADR from 1.4 to 2.5 μm. For a suspension formulation with a representative particle size distribution of micronized drug (MMAD=2.5 μm, GSD=1.8), the same increase in MMDI resulted in an increase in the MMADR from 2.7 to only 3.3 μm. Hence, the same increase in MMDI resulted in a 79% increase in MMADR for the solution formulation compared to only a 22% increase for the suspension formulation. Similar trends were obtained for a range of drug concentrations and input micronized drug sizes. Thus, APSDR is more sensitive to changes in MMDI for solution formulations than suspension formulations; however, there are situations in which hypothetically small micronized drug in suspension (e.g. 500 nm MMAD) could resemble trends observed for solution formulations. Furthermore, the relationship between APSDR and drug concentration and MMDI is predictable for solution pMDIs, but this is not as straightforward for suspension formulations. In addition, the MMADR was relatively insensitive to changes in initial droplet GSD (from 1.6 to 2.0) and the solution and suspension pMDI residual particle GSDs were essentially identical to the initial droplet GSDs. Copyright © 2013 Elsevier B.V. All rights reserved.

Pharmaceutical Dispersion Techniques for Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs.

PubMed

Zhang, Xingwang; Xing, Huijie; Zhao, Yue; Ma, Zhiguo

2018-06-23

Over the past decades, a large number of drugs as well as drug candidates with poor dissolution characteristics have been witnessed, which invokes great interest in enabling formulation of these active ingredients. Poorly water-soluble drugs, especially biopharmaceutical classification system (BCS) II ones, are preferably designed as oral dosage forms if the dissolution limit can be broken through. Minimizing a drug’s size is an effective means to increase its dissolution and hence the bioavailability, which can be achieved by specialized dispersion techniques. This article reviews the most commonly used dispersion techniques for pharmaceutical processing that can practically enhance the dissolution and bioavailability of poorly water-soluble drugs. Major interests focus on solid dispersion, lipid-based dispersion (nanoencapsulation), and liquisolid dispersion (drug solubilized in a non-volatile solvent and dispersed in suitable solid excipients for tableting or capsulizing), covering the formulation development, preparative technique and potential applications for oral drug delivery. Otherwise, some other techniques that can increase the dispersibility of a drug such as co-precipitation, concomitant crystallization and inclusion complexation are also discussed. Various dispersion techniques provide a productive platform for addressing the formulation challenge of poorly water-soluble drugs. Solid dispersion and liquisolid dispersion are most likely to be successful in developing oral dosage forms. Lipid-based dispersion represents a promising approach to surmounting the bioavailability of low-permeable drugs, though the technique needs to traverse the obstacle from liquid to solid transformation. Novel dispersion techniques are highly encouraged to develop for formulation of poorly water-soluble drugs.

Celecoxib Encapsulation in β-Casein Micelles: Structure, Interactions, and Conformation.

PubMed

Turovsky, Tanya; Khalfin, Rafail; Kababya, Shifi; Schmidt, Asher; Barenholz, Yechezkel; Danino, Dganit

2015-07-07

β-Casein is a 24 kDa natural protein that has an open conformation and almost no folded or secondary structure, and thus is classified as an intrinsically unstructured protein. At neutral pH, β-casein has an amphiphilic character. Therefore, in contrast to most unstructured proteins that remain monomeric in solution, β-casein self-assembles into well-defined core-shell micelles. We recently developed these micelles as potential carriers for oral administration of poorly water-soluble pharmaceuticals, using celecoxib as a model drug. Herein we present deep and precise insight into the physicochemical characteristics of the protein-drug formulation, both in bulk solution and in dry form, emphasizing drug conformation, packing properties and aggregation state. In addition, the formulation is extensively studied in terms of structure and morphology, protein/drug interactions and physical stability. Particularly, NMR measurements indicated strong drug-protein interactions and noncrystalline drug conformation, which is expected to improve drug solubility and bioavailability. Small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were combined for nanostructural characterization, proving that drug-protein interactions lead to well-defined spheroidal micelles that become puffier and denser upon drug loading. Dynamice light scattering (DLS), turbidity measurements, and visual observations complemented the analysis for determining formulation structure, interactions, and stability. Additionally, it was shown that the loaded micelles retain their properties through freeze-drying and rehydration, providing long-term physical and chemical stability. Altogether, the formulation seems greatly promising for oral drug delivery.

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.

Preparation and Evaluation of Herbal Shampoo Powder

PubMed Central

Dubey, Sachin; Nema, Neelesh; Nayak, S.

2004-01-01

Two preparations of herbal shampoo powder were formulated using some common traditional drugs used by folk and traditional people of Bundelkhand region (M.P) India, for hair care. The preparations were formulated using bahera, amla, neem tulsi, shikakai henna & brahmi evaluated for organoleptic, powder charecterestics, foam test and physical evaluation. As the selected drugs being used since long time as single drug or in combination, present investigations will further help to establish a standard formulation and evaluation parameters, which will certainly help in the standardization for quality and purity of such type of herbal powder shampoos. PMID:22557149

Ibuprofen transport into and through skin from topical formulations: in vitro-in vivo comparison.

PubMed

Herkenne, Christophe; Naik, Aarti; Kalia, Yogeshvar N; Hadgraft, Jonathan; Guy, Richard H

2007-01-01

The goal was to compare ibuprofen transport into and through skin in vivo in man and in vitro (across silicone membranes and freshly excised pig skin) from four marketed formulations. Ibuprofen gels were administered in vivo for 30 minutes. The stratum corneum (SC) at the application site was then tape-stripped, quantified gravimetrically, and extracted for drug analysis. Together with concomitant transepidermal water loss measurements, SC drug concentration-depth profiles were reproducibly determined and fitted mathematically to obtain a partition coefficient, a first-order rate constant related to ibuprofen diffusivity, and the total drug amount in the SC at the end of the application. All derived parameters were consistent across formulations. Ibuprofen permeation data through both silicone membrane and pig ear skin were also fitted to yield partitioning and diffusion parameters. The former revealed that ibuprofen partitioned differently from the gels into this model barrier. Across pig skin, however, better correlation with in vivo results was found. The dermatopharmacokinetic approach, using SC tape-stripping, offers a valid method to assess equivalency between topical drug formulations. In vitro experiments must be extrapolated cautiously to the clinic, especially when complex interactions between real formulations, which deliver both drug and excipients, and the skin occur.

Microphase separation in solid lipid dosage forms as the cause of drug release instability.

PubMed

Lopes, Diogo Gomes; Koutsamanis, Ioannis; Becker, Karin; Scheibelhofer, Otto; Laggner, Peter; Haack, Detlev; Stehr, Michael; Zimmer, Andreas; Salar-Behzadi, Sharareh

2017-01-30

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and characterization of a novel drug nanocarrier for oral delivery, based on self-assembled β-casein micelles.

PubMed

Bachar, Michal; Mandelbaum, Amitai; Portnaya, Irina; Perlstein, Hadas; Even-Chen, Simcha; Barenholz, Yechezkel; Danino, Dganit

2012-06-10

β-casein is an amphiphilic protein that self-organizes into well-defined core-shell micelles. We developed these micelles as efficient nanocarriers for oral drug delivery. Our model drug is celecoxib, an anti-inflammatory hydrophobic drug utilized for treatment of rheumatoid arthritis and osteoarthritis, now also evaluated as a potent anticancer drug. This system is unique as it enables encapsulation loads >100-fold higher than other β-casein/drug formulations, and does not require additives as do other formulations that have high loadings. This is combined with the ability to lyophilize the formulation without a cryoprotectant, long-term physical and chemical stability of the resulting powder, and fully reversible reconstitution of the structures by rehydration. The dry dosage form, in which >95% of the drug is encapsulated, meets the daily dose. Cryo-TEM and DLS prove that drug encapsulation results in micelle swelling, and X-ray diffraction shows that the encapsulated drug is amorphous. Altogether, our novel dosage form is highly advantageous for oral administration. Copyright © 2012 Elsevier B.V. All rights reserved.

Tailored nanostructured platforms for boosting transcorneal permeation: Box–Behnken statistical optimization, comprehensive in vitro, ex vivo and in vivo characterization

PubMed Central

Elsayed, Ibrahim; Sayed, Sinar

2017-01-01

Ocular drug delivery systems suffer from rapid drainage, intractable corneal permeation and short dosing intervals. Transcorneal drug permeation could increase the drug availability and efficiency in the aqueous humor. The aim of this study was to develop and optimize nanostructured formulations to provide accurate doses, long contact time and enhanced drug permeation. Nanovesicles were designed based on Box–Behnken model and prepared using the thin film hydration technique. The formed nanodispersions were evaluated by measuring the particle size, polydispersity index, zeta potential, entrapment efficiency and gelation temperature. The obtained desirability values were utilized to develop an optimized nanostructured in situ gel and insert. The optimized formulations were imaged by transmission and scanning electron microscopes. In addition, rheological characters, in vitro drug diffusion, ex vivo and in vivo permeation and safety of the optimized formulation were investigated. The optimized insert formulation was found to have a relatively lower viscosity, higher diffusion, ex vivo and in vivo permeation, when compared to the optimized in situ gel. So, the lyophilized nanostructured insert could be considered as a promising carrier and transporter for drugs across the cornea with high biocompatibility and effectiveness. PMID:29133980

Compressibility of binary powder formulations: investigation and evaluation with compaction equations.

PubMed

Gentis, Nicolaos D; Betz, Gabriele

2012-02-01

The purpose of this work was to investigate and evaluate the powder compressibility of binary mixtures containing a well-compressible compound (microcrystalline cellulose) and a brittle active drug (paracetamol and mefenamic acid) and its progression after a drug load increase. Drug concentration range was 0%-100% (m/m) with 10% intervals. The powder formulations were compacted to several relative densities with the Zwick material tester. The compaction force and tensile strength were fitted to several mathematical models that give representative factors for the powder compressibility. The factors k and C (Heckel and modified Heckel equation) showed mostly a nonlinear correlation with increasing drug load. The biggest drop in both factors occurred at far regions and drug load ranges. This outcome is crucial because in binary mixtures the drug load regions with higher changeover of plotted factors could be a hint for an existing percolation threshold. The susceptibility value (Leuenberger equation) showed varying values for each formulation without the expected trend of decrease for higher drug loads. The outcomes of this study showed the main challenges for good formulation design. Thus, we conclude that such mathematical plots are mandatory for a scientific evaluation and prediction of the powder compaction process. Copyright © 2011 Wiley Periodicals, Inc.

Efficient co-delivery of immiscible hydrophilic/hydrophobic chemotherapeutics by lipid emulsions for improved treatment of cancer.

PubMed

Zhang, Bo; Song, Yunmei; Wang, Tianqi; Yang, Shaomei; Zhang, Jing; Liu, Yongjun; Zhang, Na; Garg, Sanjay

2017-01-01

Combinational nanomedicine is becoming a topic of much interest in cancer therapy, although its translation into the clinic remains extremely challenging. One of the main obstacles lies in the difficulty to efficiently co-deliver immiscible hydrophilic/hydrophobic drugs into tumor sites. The aim of this study was to develop co-loaded lipid emulsions (LEs) to co-deliver immiscible hydrophilic/hydrophobic drugs to improve cancer therapy and to explore the co-delivery abilities between co-loaded LEs and mixture formulation. Multiple oxaliplatin/irinotecan drug-phospholipid complexes (DPCs) were formulated. Co-loaded LEs were prepared using DPC technique to efficiently encapsulate both drugs. Co-loaded LEs exhibited uniform particle size distribution, desired stability and synchronous release profiles in both drugs. Co-loaded LEs demonstrated superior anti-tumor activity compared with the simple solution mixture and the mixture of single-loaded LEs. Furthermore, co-loaded nanocarriers could co-deliver both drugs into the same cells more efficiently and exhibited the optimized synergistic effect. These results indicate that co-loaded LEs could be a desired formulation for enhanced cancer therapy with potential application prospects. The comparison between co-loaded LEs and mixture formulation is significant for pharmaceutical designs aimed at co-delivery of multiple drugs.

Preparation and Characterization of Liquisolid Compacts for Improved Dissolution of Telmisartan

PubMed Central

Narra, Nataraj; Rama Rao, Tadikonda

2014-01-01

The objective of the present work was to obtain pH independent and improved dissolution profile for a poorly soluble drug, telmisartan using liquisolid compacts. Liquisolid compacts were prepared using Transcutol HP as vehicle, Avicel PH102 as carrier, and Aerosil 200 as a coating material. The formulations were evaluated for drug excipient interactions, change in crystallinity of drug, flow properties, and general quality control tests of tablets using Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), angle of repose, and various pharmacopoeial tests. In vitro dissolution studies were performed at three pH conditions (1.2, 4.5 and 7.4). Stability studies were performed at 40°C and 75% RH for three months. The formulation was found to comply with Indian pharmacopoeial limits for tablets. FTIR studies confirmed no interaction between drug and excipients. XRD and DSC studies indicate change/reduction in crystallinity of drug. Dissolution media were selected based on the solubility studies. The optimized formulation showed pH independent release profile with significant improvement (P < 0.005) in dissolution compared to plain drug and conventional marketed formulation. No significant difference was seen in the tablet properties, and drug release profile after storage for 3 months. PMID:25371826

Dorzolamide Loaded Niosomal Vesicles: Comparison of Passive and Remote Loading Methods

PubMed Central

Hashemi Dehaghi, Mohadeseh; Haeri, Azadeh; Keshvari, Hamid; Abbasian, Zahra; Dadashzadeh, Simin

2017-01-01

Glaucoma is a common progressive eye disorder and the treatment strategies will benefit from nanoparticulate delivery systems with high drug loading and sustained delivery of intraocular pressure lowering agents. Niosomes have been reported as a novel approach to improve drug low corneal penetration and bioavailability characteristics. Along with this, poor entrapment efficiency of hydrophilic drug in niosomal formulation remains as a major formulation challenge. Taking this perspective into consideration, dorzolamide niosomes were prepared employing two different loading methodologies (passive and remote loading methods) and the effects of various formulation variables (lipid to drug ratio, cholesterol percentage, drug concentration, freeze/thaw cycles, TPGS content, and external and internal buffer molarity and pH) on encapsulation efficiency were assessed. Encapsulation of dorzolamide within niosomes increased remarkably by the incorporation of higher cholesterol percentage as well as increasing the total lipid concentration. Remote loading method showed higher efficacy for drug entrapment compared to passive loading technique. Incorporation of TPGS in bilayer led to decrease in EE; however, retarded drug release rate. Scanning electron microscopy (SEM) studies confirmed homogeneous particle distribution, and spherical shape with smooth surface. In conclusion, the highest encapsulation can be obtained using phosphate gradient method and 50% cholesterol in Span 60 niosomal formulation. PMID:28979296

Availability of Oral Formulations Labeled for Use in Young Children in Serbia, Germany and the USA.

PubMed

Bajcetic, Milica; Kearns, Gregory L; Jovanovic, Ida; Brajovic, Milan; van den Anker, John N

2015-01-01

The paucity of marketed drug products that have been adequately studied in infants and children and subsequently, licensed (or labeled) for pediatric use has caused abundant use of off-label and unauthorized products in this patient population. In those instances where insufficient pharmacologic or therapeutic information exists for children, the potential for off-label use of medicines to result in therapeutic misadventure does as well. In the USA, a series of regulatory measures have been introduced since 1997 which have increased both the number and scope of pediatric drug trials and also, fostered the development of ageappropriate drug formulations by pharmaceutical companies. Provisions of these regulations for previously marketed drugs include the potential for a company to be granted 6 months of marketing exclusivity, thereby providing them with a financial incentive. For new drugs being developed that have potential pediatric use, the regulations mandate the inclusion of children in the drug development process. In the EU comparable measures have been very recently (Jan 2007) signed into European law to overcome the therapeutic orphan status of the infants and children of Europe. The aims of this study was to compare the availability of age-appropriate oral formulations labeled for use in children less than 12 years of age in Serbia, Germany and USA in 2007, and to investigate if certain drug groups of therapeutic importance to children had fewer medicines appropriately labeled for pediatric patients available. The primary sources of information for determining the ageappropriate oral dosage forms, and their licensing and labeling status were the official manuals on drug information and national formularies in 2007. The general availability of oral drugs was the highest in the USA (304), followed by Germany (235) and Serbia (156). From all these oral drugs the availability of labeled age-appropriate pediatric dosage formulations was only between 21.2% and 47.7%. Moreover, there were striking differences between the three countries in the availability of labeled age-appropriate formulations for certain drug groups such as cardiovascular (absent in Serbia) and antiparasitic drugs (absent in Serbia and Germany). Our data suggest that significant country-to-country differences continue to exist in both the number and type of oral drug formulations that have pediatric labeling. Potential contributing factors include country-specific differences in the drug regulatory process, capacity for pharmaceutical development and the regulatory lag time associated with the implementation of drug regulation specifically addressing pediatric product development and labeling. We hypothesize that the new European regulation concerning medicines and children will improve the current unacceptable situation.

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.

Recommendations of the Oligonucleotide Safety Working Group's Formulated Oligonucleotide Subcommittee for the Safety Assessment of Formulated Oligonucleotide-Based Therapeutics.

PubMed

Marlowe, Jennifer L; Akopian, Violetta; Karmali, Priya; Kornbrust, Douglas; Lockridge, Jennifer; Semple, Sean

2017-08-01

The use of lipid formulations has greatly improved the ability to effectively deliver oligonucleotides and has been instrumental in the rapid expansion of therapeutic development programs using oligonucleotide drugs. However, the development of such complex multicomponent therapeutics requires the implementation of unique, scientifically sound approaches to the nonclinical development of these drugs, based upon a hybrid of knowledge and experiences drawn from small molecule, protein, and oligonucleotide therapeutic drug development. The relative paucity of directly applicable regulatory guidance documents for oligonucleotide therapeutics in general has resulted in the generation of multiple white papers from oligonucleotide drug development experts and members of the Oligonucleotide Safety Working Group (OSWG). The members of the Formulated Oligonucleotide Subcommittee of the OSWG have utilized their collective experience working with a variety of formulations and their associated oligonucleotide payloads, as well as their insights into regulatory considerations and expectations, to generate a series of consensus recommendations for the pharmacokinetic characterization and nonclinical safety assessment of this unique class of therapeutics. It should be noted that the focus of Subcommittee discussions was on lipid nanoparticle and other types of particulate formulations of therapeutic oligonucleotides and not on conjugates or other types of modifications of oligonucleotide structure intended to facilitate delivery.

Development of rectal self-emulsifying suspension of a moisture-labile water-soluble drug.

PubMed

Kauss, Tina; Gaubert, Alexandra; Tabaran, Luc; Tonelli, Giovanni; Phoeung, Thida; Langlois, Marie-Hélène; White, Nick; Cartwright, Anthony; Gomes, Melba; Gaudin, Karen

2018-01-30

Self-emulsifying drug delivery systems, commonly used for oral delivery of poorly soluble compounds, were used to formulate water soluble but moisture labile compounds for rectal application. The objective was to use the oily phase of the system to formulate a liquid, non-aqueous product while obtaining the advantages of self-emulsification, rapid contact with the rectal mucosa and rapid absorption post-administration. Ceftriaxone was used as a model drug and the human bile salt sodium chenodeoxycholate was used as an absorption enhancer. After preliminary screening of 23 excipients, based on their emulsification ability and emulsion fineness in binary and ternary mixtures, a full factorial design was used to screen different formulations of three preselected excipients. The optimal formulation contained 60% of excipients, namely Capryol 90, Kolliphor EL and Kolliphor PS20 in 4 : 6 : 6 ratio and 40% of a powder blend that included 500 mg of ceftriaxone. Characterization of the system showed that it complied with the requirements for rectal administration, in particular rapid emulsification in a small quantity of liquid. Rabbit bioavailability showed rapid absorption of ceftriaxone, achieving 128% bioavailability compared to powder control formulation. These results demonstrated the potential of self-emulsifying formulations for rectal administration of Class 3 BCS drugs. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

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.

Press-coated tablets for time-programmed release of drugs.

PubMed

Conte, U; Maggi, L; Torre, M L; Giunchedi, P; La Manna, A

1993-10-01

A new dry-coated device for the release of drug after a programmable period of time is proposed. It is intended to be used mainly in the therapy of those diseases which depend on circadian rhythms. Some core formulations, characterized by different release rates and mechanisms (containing diltiazem hydrochloride or sodium diclofenac as model drugs), were coated by compression with different polymeric barrier layers (press-coated systems). The shell formulations tested contained either gellable or erodible polymers. The dissolution profiles of uncoated cores and press-coated devices were compared. The gellable and/or erodible characteristics (properties) of the barrier formulations were also examined by means of a penetrometer. The coatings prevent drug release from the core until the polymeric shell is completely eroded or swollen. This delay in release start is not influenced by the core composition and depends only on the shell formulation. Except for the time-lag, the release kinetics of the drug contained in the core are not significantly influenced by the presence of the erodible barrier, but can be widely modulated using a swellable polymeric shell.

Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations.

PubMed

Mura, P; Faucci, M T; Bramanti, G; Corti, P

2000-02-01

The influence of diethyleneglycol monoethyl ether (transcutol), alone or in combination with propylene glycol, on clonazepam permeation through an artificial membrane and excised rabbit ear skin from Carbopol hydrogels was investigated. Drug kinetic permeation parameters were determined for both series of experiments and compared. Rheological characteristics, drug solubility and membrane/vehicle partition coefficient for each gel formulation were also determined, and their role in the formulation performance was investigated. Both series of experiments showed an increase of drug permeation as a function of transcutol content in the formulation. The combination of transcutol and propylene glycol resulted in a synergistic enhancement of clonazepam flux. A different trend was found in experiments with gels containing mixtures of the two enhancers, where an increase (in the case of artificial membrane) or a decrease (in the case of rabbit ear skin) of drug permeation was found by increasing the transcutol/propylene glycol ratio in the mixture. Such a result is explained on the basis of the particular mechanism of action demonstrated for transcutol which associates the increase of drug solubility to the potent effect of a depot in the skin.

“Click” Synthesis of Dextran Macrostructures for Combinatorial-Designed Self-Assembled Nanoparticles Encapsulating Diverse Anticancer Therapeutics

PubMed Central

Abeylath, Sampath C.; Amiji, Mansoor

2011-01-01

With the non-specific toxicity of anticancer drugs to healthy tissues upon systemic administration, formulations capable of enhanced selectivity in delivery to the tumor mass and cells are highly desirable. Based on the diversity of the drug payloads, we have investigated a combinatorial-designed strategy where the nano-sized formulations are tailored based on the physicochemical properties of the drug and the delivery needs. Individually functionalized C2 to C12 lipid-, thiol-, and poly(ethylene glycol) (PEG)-modified dextran derivatives were synthesized via “click” chemistry from O-pentynyl dextran and relevant azides. These functionalized dextrans in combination with anticancer drugs form nanoparticles by self-assembling in aqueous medium having PEG surface functionalization and intermolecular disulfide bonds. Using anticancer drugs with logP values ranging from −0.5 to 3.0, the optimized nanoparticles formulations were evaluated for preliminary cellular delivery and cytotoxic effects in SKOV3 human ovarian adenocarcinoma cells. The results show that with the appropriate selection of lipid-modified dextran, one can effectively tailor the self-assembled nano-formulation for intended therapeutic payload. PMID:21978947

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.

Injectable, in situ forming poly(propylene fumarate)-based ocular drug delivery systems.

PubMed

Ueda, H; Hacker, M C; Haesslein, A; Jo, S; Ammon, D M; Borazjani, R N; Kunzler, J F; Salamone, J C; Mikos, A G

2007-12-01

This study sought to develop an injectable formulation for long-term ocular delivery of fluocinolone acetonide (FA) by dissolving the anti-inflammatory drug and the biodegradable polymer poly(propylene fumarate) (PPF) in the biocompatible, water-miscible, organic solvent N-methyl-2-pyrrolidone (NMP). Upon injection of the solution into an aqueous environment, a FA-loaded PPF matrix is precipitated in situ through the diffusion/extraction of NMP into surrounding aqueous fluids. Fabrication of the matrices and in vitro release studies were performed in phosphate buffered saline at 37 degrees C. Drug loadings up to 5% were achieved. High performance liquid chromatography was employed to determine the released amount of FA. The effects of drug loading, PPF content of the injectable formulation, and additional photo-crosslinking of the matrix surface were investigated. Overall, FA release was sustained in vitro over up to 400 days. After an initial burst release of 22 to 68% of initial FA loading, controlled drug release driven by diffusion and bulk erosion was observed. Drug release rates in a therapeutic range were demonstrated. Release kinetics were found to be dependent on drug loading, formulation PPF content, and extent of surface crosslinking. The results suggest that injectable, in situ formed PPF matrices are promising candidates for the formulation of long-term, controlled delivery devices for intraocular drug delivery. Copyright 2007 Wiley Periodicals, Inc.

A step toward development of printable dosage forms for poorly soluble drugs.

PubMed

Raijada, Dhara; Genina, Natalja; Fors, Daniela; Wisaeus, Erik; Peltonen, Jouko; Rantanen, Jukka; Sandler, Niklas

2013-10-01

The purpose of this study was to formulate printable dosage forms for a poorly soluble drug (piroxicam; PRX) and to gain understanding of critical parameters to be considered during development of such dosage forms. Liquid formulations of PRX were printed on edible paper using piezoelectric inkjet printing (PIJ) and impression printing (flexography). The printed dosage forms were characterized using scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) and the amount of drug was determined using high-performance liquid chromatography. Solutions of PRX in polyethylene glycol 400 (PEG-400):ethanol (40:60) and in PEG-400 were found to be optimal formulations for PIJ and flexography, respectively. SEM-EDX analysis revealed no visible solid particles on the printed dosage forms indicating the drug most likely remained in solution after printing. More accurate drug deposition was obtained by PIJ as compared with flexography. More than 90% drug release was achieved within 5 min regardless of printing method used. The solubility of drug in solvents/cosolvents, rheological properties of formulations, properties of substrate, feasibility and accuracy of the printing methods, and detection limit of analytical techniques for characterization of printed dosage forms are some of the concerns that need to be addressed for development of printable dosage forms of poorly soluble drugs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Design and Optimization of Floating Drug Delivery System of Acyclovir

PubMed Central

Kharia, A. A.; Hiremath, S. N.; Singhai, A. K.; Omray, L. K.; Jain, S. K.

2010-01-01

The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 32 full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t50%) and 70% (t70%) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t50% and t70% indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix. PMID:21694992

Design and optimization of floating drug delivery system of acyclovir.

PubMed

Kharia, A A; Hiremath, S N; Singhai, A K; Omray, L K; Jain, S K

2010-09-01

The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 3(2) full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t(50%)) and 70% (t(70%)) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t(50%) and t(70%) indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix.

Assessment of bioequivalence of rifampicin, isoniazid and pyrazinamide in a four drug fixed dose combination with separate formulations at the same dose levels.

PubMed

Agrawal, Shrutidevi; Kaur, Kanwal Jit; Singh, Inderjit; Bhade, Shantaram R; Kaul, Chaman Lal; Panchagnula, Ramesh

2002-02-21

Tuberculosis (TB) needs treatment with three to five different drugs simultaneously, depending on the patient category. These drugs can be given as single drug preparations or fixed dose combinations (FDCs) of two more drugs in a single formulation. World Health Organization and International Union against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. The relative bioavailability of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PYZ) was assessed on a group of 13 healthy male subjects from a four drug FDC versus separate formulations at the same dose levels. The study was designed to be an open, crossover experiment. A total of nine blood samples each of 3 ml volume were collected over a period of 24-h. The concentrations of RIF, its main metabolite desacetyl RIF (DRIF), INH and PYZ in plasma were assessed by HPLC analysis. Pharmacokinetic parameters namely AUC(0-24), AUC(0-inf), C(max), T(max), were calculated and subjected to different statistical tests (Hauschke analysis, two way ANOVA, normal and log transformed confidence interval) at 90% confidence interval. In addition, elimination rate constant (K(el)) and absorption efficiencies for each drug were also calculated. It was concluded that four drugs FDC tablet is bioequivalent for RIF, INH and PYZ to separate formulation at the same dose levels.

Value of the dorsal cutaneous guinea pig model in selecting topical antiviral formulations for the treatment of recurrent herpes simplex type 1 disease.

PubMed

Poli, G; Dall'Ara, P; Binda, S; Santus, G; Poli, A; Cocilovo, A; Ponti, W

2001-01-01

Recurrent herpes simplex labialis represents a disease still difficult to treat, despite the availability of many established antiviral drugs used in clinical research since 30 years ago. Although differences between the human disease and that obtained in experimental animal suggest caution in predicting an effective clinical response from the experimental results, some of the animal models seem to be useful in optimising the topical formulation of single antiviral drugs. In the present work the dorsal cutaneous guinea pig model was used to compare 5 different topical antiviral formulations with clinical promise (active molecule: 5% w/w micronized aciclovir, CAS 59277-89-3), using both roll-on and lipstick application systems. The aim being to evaluate which vehicle (water, oil, low melting and high melting fatty base) and application system (roll-on, lipstick) enhances the skin penetration and the antiviral activity of the drug, after an experimental intradermal infection with Herpes simplex virus type 1 (HSV-1). As reference, a commercial formulation (5% aciclovir ointment) was used. The cumulative results of this study showed that the formulation A, containing 5% aciclovir in an aqueous base in a roll-on application system, has the better antiviral efficacy in reducing the severity of cutaneous lesions and the viral titer; among the lipsticks preparations, the formulation D, containing 5% aciclovir in a low melting fatty base, demonstrates a very strong antiviral activity, though slightly less than formulation A. This experimental work confirms the validity of the dorsal cutaneous guinea pig model as a rapid and efficient method to compare the antiviral efficacy of new formulations, with clinical promise, to optimise the topical formulation of the active antiviral drugs.

Research design strategies to evaluate the impact of formulations on abuse liability.

PubMed

McColl, Shelley; Sellers, Edward M

2006-06-01

Scheduling of a chemical drug substance under the Controlled Substances Act (CSA) includes an evaluation of preclinical and clinical safety, and experimental abuse liability studies, as well as information on diversion and overdose. Formulations that mitigate abuse liability, dependence potential and public health risks (e.g., altered absorption rate and tamperability, long half-life, pro-drugs and combination products) are amenable to preclinical and clinical studies to compare their abuse potential to reference compounds. For new formulations (NF) as marketed agents, direct comparison to the immediate release (IR) formulation of the reference compound is typically needed across the full range of potential studies. While the public health advantage of formulation changes in the marketplace can be conceptualized in behavioral economic terms, generating persuasive data is challenging. Study complexity increases because of additional conditions (e.g., placebo, 2-3 doses of the IR formulation, 2-3 doses of the new formulation, and 2-3 doses of the unscheduled or negative control drug), larger sample sizes (study power driven by the comparison of the new formulation versus the IR or placebo), and associated increases in study duration. However, the use of single maximal doses of well-characterized controls can reduce the number of study arms, and using incomplete block designs can reduce study duration. Less typical experimental approaches may also be useful, such as human choice or discrimination procedures, or pre-marketing consumer studies among experienced drug tamperers. New formulations that demonstrate a substantial difference from marketed or reference products have a potential marketing advantage and should require less onerous risk management. Post-marketing epidemiological data demonstrating the lack of abuse will carry the most weight from a public health and physician perspective.

Pure drug nanoparticles in tablets: what are the dissolution limitations?

NASA Astrophysics Data System (ADS)

Heng, Desmond; Ogawa, Keiko; Cutler, David J.; Chan, Hak-Kim; Raper, Judy A.; Ye, Lin; Yun, Jimmy

2010-06-01

There has been increasing interests for drug companies to incorporate drug nanoparticles into their existing formulations. However, technical knowledge in this area is still in its infancy and more study needs to be done to stimulate growth in this fledging field. There is a need to scrutinize the performance of pure drug nanoparticles in tablets, particularly relating formulation variables to their dissolution performance. Application of the pure form, synthesized without the use of surfactants or stabilizers, is often preferred to maximize drug loading and also to minimize toxicity. Cefuroxime axetil, a poorly water-soluble cephalosporin antibiotic, was used as the model drug in the formulation development. Drug release rate, tablet disintegration time, tensile strength and energy of failure were predominantly influenced by the amount of super-disintegrant, amount of surfactant, compression force and diluent species, respectively. The compression rate had minimal impact on the responses. The main hurdle confronting the effective use of pure drug nanoparticles in tablets is the difficulty in controlling aggregation in solution, which could potentially be aggravated by the tabletting process. Through the use of elevated levels of surfactants (8 w/w% sodium dodecyl sulphate), drug release from the nanoparticle preparation was enhanced from 58.0 ± 2.7% to 72.3 ± 0.7% in 10 min. Hence, it is recommended that physical formulations for pure drug nanoparticles be focused on the particle de-aggregation step in solution, if much higher rates are to be desired. In conclusion, even though pure drug nanoparticles could be easily synthesized, limitations from aggregation may need to be overcome, before successful application in tablets can be fully realized.

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.

Evaluation of Calendula mucilage as a mucoadhesive and controlled release component in buccal tablets.

PubMed

Sabale, V; Patel, V; Paranjape, A

2014-01-01

Mucoadhesive drug delivery systems were developed to sustain drug delivery via various mucus membranes for either local or systemic delivery of poorly absorbed drugs such as peptides and proteins as well as drugs that are subjected to high first-pass metabolism. The present study was undertaken to use isolated Calendula mucilage as a mucoadhesive agent and to formulate controlled release buccoadhesive tablets with an intention to avoid hepatic first-pass metabolism as well as to enhance residence time of drug in the buccal cavity. The mucilage was isolated from the Calendula petals by aqueous extraction method and characterized for various physiochemical parameters as well as for its adhesive properties. By using direct compression technique, tablets were prepared containing dried mucilage and chlorpheniramine maleate (CPM) as a model drug. Three batches of tablets were prepared and evaluated containing three mucoadhesive components namely Methocel K4M, Carbopol 974P and isolated Calendula mucilage in 16.66%, 33.33 % and 50 % (1:2:3 ratio) resulting in 9 different formulations. FTIR studies between mucilage and CPM suggested the absence of a chemical interaction between CPM and Calendula mucilage. The results of the study showed that the isolated mucilage had good physicochemical and morphological characteristics and tablets conformed to the pharmacopoeial specifications. Also in vitro release studies showed controlled action of drug with increasing the concentration of the isolated Calendula mucilage as a mucoadhesive agent in the formulations. Permeability studies indicated that permeability behavior was not statistically different (P>0.05) by changing the mucoadhesive component. The formulated mucoadhesive tablets for buccal administration containing 75 mg Calendula mucilage showed controlled drug release. Thus, mucoadhesive natural Calendula mucilage based buccal tablets for controlled release were successfully formulated.

Evaluation of Calendula mucilage as a mucoadhesive and controlled release component in buccal tablets

PubMed Central

Sabale, V.; Patel, V.; Paranjape, A.

2014-01-01

Mucoadhesive drug delivery systems were developed to sustain drug delivery via various mucus membranes for either local or systemic delivery of poorly absorbed drugs such as peptides and proteins as well as drugs that are subjected to high first-pass metabolism. The present study was undertaken to use isolated Calendula mucilage as a mucoadhesive agent and to formulate controlled release buccoadhesive tablets with an intention to avoid hepatic first-pass metabolism as well as to enhance residence time of drug in the buccal cavity. The mucilage was isolated from the Calendula petals by aqueous extraction method and characterized for various physiochemical parameters as well as for its adhesive properties. By using direct compression technique, tablets were prepared containing dried mucilage and chlorpheniramine maleate (CPM) as a model drug. Three batches of tablets were prepared and evaluated containing three mucoadhesive components namely Methocel K4M, Carbopol 974P and isolated Calendula mucilage in 16.66%, 33.33 % and 50 % (1:2:3 ratio) resulting in 9 different formulations. FTIR studies between mucilage and CPM suggested the absence of a chemical interaction between CPM and Calendula mucilage. The results of the study showed that the isolated mucilage had good physicochemical and morphological characteristics and tablets conformed to the pharmacopoeial specifications. Also in vitro release studies showed controlled action of drug with increasing the concentration of the isolated Calendula mucilage as a mucoadhesive agent in the formulations. Permeability studies indicated that permeability behavior was not statistically different (P>0.05) by changing the mucoadhesive component. The formulated mucoadhesive tablets for buccal administration containing 75 mg Calendula mucilage showed controlled drug release. Thus, mucoadhesive natural Calendula mucilage based buccal tablets for controlled release were successfully formulated. PMID:25598798

Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs.

PubMed

Lam, Masha S H

2011-02-01

Oncology pharmacists face a constant challenge with patients who cannot swallow oral anticancer drugs, making extemporaneous oral liquid preparation a requirement. Improper extemporaneous preparation of these agents, especially with the traditional chemotherapy with a narrow therapeutic index, may increase the risk of over- or underdosing. In community pharmacies, multiple barriers exist that prevent these pharmacies from preparing extemporaneous oral anticancer drug formulations for a patient's use at home. In a home setting, patients or caregivers without proper counseling and education on how to safely handle chemotherapy are at increased risk for exposure to these drugs. Based on a review of the literature, compounding recipes are available for 46% of oral anticancer agents. A paucity of data exists on dose uniformity, bioequivalence, and stability of extemporaneous oral liquid formulations of anticancer drugs. Pharmacists must have an understanding of the basic scientific principles that are an essential foundation for the proper preparation of extemporaneous oral anticancer liquid formulations. The collaborative effort of a multidisciplinary team can also help identify different barriers in the community setting, especially in areas where community pharmacies may lack resources for the extemporaneous compounding of oral chemotherapy, and to find ways to coordinate better pharmaceutical care. There are great opportunities for oncology pharmacists, as well as community pharmacists, as a resource for educating and monitoring patients receiving oral chemotherapy to ensure dosing accuracy, safe administration, and proper disposal of hazardous drugs. Development of national guidelines to promote standards of practice in the community and/or home setting is urgently needed to help improve the safety of dispensing and handling oral chemotherapeutic agents, including extemporaneously compounded oral liquid formulations of these drugs.

Nasal Drug Absorption from Powder Formulations: Effect of Fluid Volume Changes on the Mucosal Surface.

PubMed

Tanaka, Akiko; Furubayashi, Tomoyuki; Enomura, Yuki; Hori, Tomoki; Shimomura, Rina; Maeda, Chiaki; Kimura, Shunsuke; Inoue, Daisuke; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

2017-01-01

The effect of changes in the mucosal fluid volume on the nasal drug absorption of powder formulations was evaluated using warfarin (WF), piroxicam (PXC), and norfloxacin (NFX) as model drugs. Lactose and sodium chloride (NaCl), which are water soluble and small-sized chemicals that increase osmotic pressure after dissolution, were used as excipients to change the mucosal fluid volume. The in vitro study using a Madin-Darby canine kidney (MDCK) cell monolayer indicated that lactose and NaCl, sprayed over the surface of air interface monolayers, increased the fluid volume on the monolayer surface and enhanced the transepithelial transport of the model drugs. The in vivo animal study indicated that the nasal absorption of PXC is enhanced by lactose and NaCl after nasal administration of the powder formulations. This is likely due to the enhanced dissolution of PXC on fluid-rich nasal mucosa and an increase in the effective surface area for drug permeation, which lead to better nasal absorption. However, both excipients failed to increase the nasal absorption of WF and NFX. To clarify the mechanism of the drug-dependent effect of lactose and NaCl, the nasal residence of the formulation was examined using FD70 as a non-absorbable marker. The nasal clearance of FD70 was enhanced by lactose and NaCl, leading to a decrease in the nasal drug absorption. Lactose and NaCl caused no damage to the nasal tissue. These results indicate that the addition of water-soluble excipients such as lactose to powder formulations can enhance the nasal absorption of highly permeable but poorly soluble drugs.

QbD-Enabled Development of Novel Stimuli-Responsive Gastroretentive Systems of Acyclovir for Improved Patient Compliance and Biopharmaceutical Performance.

PubMed

Singh, Bhupinder; Kaur, Anterpreet; Dhiman, Shashi; Garg, Babita; Khurana, Rajneet Kaur; Beg, Sarwar

2016-04-01

The current studies entail systematic quality by design (QbD)-based development of stimuli-responsive gastroretentive drug delivery systems (GRDDS) of acyclovir using polysaccharide blends for attaining controlled drug release profile and improved patient compliance. The patient-centric quality target product profile was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies, carried out through Ishikawa fish bone diagram and failure mode, effect, and criticality analysis, helped in identifying the plausible risks or failure modes affecting the quality attributes of the drug product. A face-centered cubic design was employed for systematic development and optimization of the concentration of sodium alginate (X 1) and gellan (X 2) as the critical material attributes (CMAs) in the stimuli-responsive formulations, which were evaluated for CQAs viz. viscosity, gel strength, onset of floatation, and drug release characteristics. Mathematical modeling was carried out for generation of design space, and optimum formulation was embarked upon, exhibiting formulation characteristics marked by excellent floatation and bioadhesion characteristics along with promising drug release control up to 24 h. Drug-excipient compatibility studies through FTIR and DSC revealed absence of any interaction(s) among the formulation excipients. In vivo pharmacokinetic studies in Wistar rats corroborated extension in the drug absorption profile from the optimized stimuli-responsive GR formulations vis-à-vis the marketed suspension (ZOVIRAX®). Establishment of in vitro/in vivo correlation (IVIVC) revealed a high degree of correlation between the in vitro and in vivo data. In a nutshell, the present investigations report the successful development of stimuli-responsive GRDDS of acyclovir, which can be applicable as a platform approach for other drugs too.

Antifungal Therapy in Birds: Old Drugs in a New Jacket.

PubMed

Antonissen, Gunther; Martel, An

2018-05-01

The use of antifungals in birds is characterized by interspecies and interindividual variability in the pharmacokinetics, affecting drug safety and efficacy. Oral antifungal drug absorption is a complex process affected by drug formulation characteristics, gastrointestinal anatomy, and physiology. New antifungal drug delivery systems can enhance drug stability, reduce off-target side effects, prolong residence time in the blood, and improve efficacy. Topical administration of antifungals through nebulization shows promising results. However, therapeutic output is highly influenced by drug formulation and type of nebulizer, indicating these factors should be taken into account when selecting this medication route. Copyright © 2018 Elsevier Inc. All rights reserved.

Influence of formulation parameters on dissolution rate enhancement of glyburide using liquisolid technique.

PubMed

Singh, Sachin Kumar; Srinivasan, K K; Gowthamarajan, K; Prakash, Dev; Gaikwad, Narayan B; Singare, Dhananjay S

2012-08-01

The aim of this study was to investigate the use of liquisolid technique in improving the dissolution of glyburide in a solid dosage form. This study was designed to evaluate the effects of different formulation variables, i.e. type of non-volatile liquid vehicles and drug concentrations, on drug dissolution rates. The liquisolid tablets were formulated with Propylene glycol, as liquid vehicle. Microcrystalline cellulose was used as a carrier material, silica as a coating material and croscaremellose as a disintegrant. In vitro drug dissolution profiles of the liquisolid formulations were studied and compared with direct compressed non-micronized and micronized tablets of glyburide using USP II, paddle apparatus at 50 rpm for 60 min using 900 ml of 0.05 M Phosphate Buffer, pH 7.5. The stability studies showed that the dissolution profiles of liquisolid tablets prepared with propylene glycol were not affected by ageing significantly, as f2 value found between aged and fresh samples was 51.92. Differential scanning calorimetry revealed that the drug has got solubilized in the liquid vehicle. This was further supported by the powder X-ray diffraction studies of pure drug and the liquisolid powder system. It can be concluded that it is possible to load poorly soluble drug into liquisolid tablets by addition of PVP to the liquid vehicle. This is valuable for the preparation of liquisolid tablets of poorly soluble drugs. The liquisolid tablets prepared with PVP showed a remarkably improved dissolution rate in comparison with DC tablet and other formulations.

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.

Bioequivalence assessment of rifampicin, isoniazid and pyrazinamide in a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol vs. separate formulations.

PubMed

Agrawal, S; Singh, I; Kaur, K J; Bhade, S R; Kaul, C L; Panchagnula, R

2002-10-01

Depending on the patient category, tuberculosis requires treatment with 3 to 5 drugs which means that patient's compliance to therapy may not be optimal. To increase patient's adherence to treatment schedules, these drugs can be given as single drug preparations or fixed dose combinations (FDCs) of 2 or more drugs in a single formulation. However, an important issue associated with a rifampicin-containing FDC is its quality. Hence, to avoid spurious formulations entering the market, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have recommended FDCs only of proven bioavailability. In this study, the relative bioavailability of rifampicin, isoniazid and pyrazinamide was assessed in a group of 14 healthy male subjects using the FDC tablet containing 4 drugs versus separate formulations at the same dose levels. The study was designed as an open, crossover trial. A total of 9 blood samples were collected over a period of 24 h. The concentration of rifampicin, its main metabolite desacetyl rifampicin, isoniazid and pyrazinamide in plasma were assessed using HPLC analysis. The pharmacokinetic parameters AUC(0-24) and Cmax were subjected to parametric and non-parametric statistical tests at 90% confidence interval. In addition, time to reach peak concentration (tmax), elimination rate constant (Kel) and terminal elimination half-life (t1/2) for each drug were also calculated. It was concluded that the FDC tablet containing 4 drugs is bioequivalent to separate rifampicin, isoniazid and pyrazinamide formulations at the same dose levels.

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.

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.

In vitro evaluation of mucoadhesive vaginal tablets of antifungal drugs prepared with thiolated polymer and development of a new dissolution technique for vaginal formulations.

PubMed

Baloglu, Esra; Ay Senyıgıt, Zeynep; Karavana, Sinem Yaprak; Vetter, Anja; Metın, Dilek Yesim; Hilmioglu Polat, Suleyha; Guneri, Tamer; Bernkop-Schnurch, Andreas

2011-01-01

The main objective of this work was to develop antifungal matrix tablet for vaginal applications using mucoadhesive thiolated polymer. Econazole nitrate (EN) and miconazole nitrate (MN) were used as antifungal drugs to prepare the vaginal tablet formulations. Thiolated poly(acrylic acid)-cysteine (PAA-Cys) conjugate was synthesized by the covalent attachment of L-cysteine to PAA with the formation of amide bonds between the primary amino group of L-cysteine and the carboxylic acid group of the polymer. Vaginal mucoadhesive matrix tablets were prepared by direct compression technique. The investigation focused on the influence of modified polymer on water uptake behavior, mucoadhesive property and release rate of drug. Thiolated polymer increased the water uptake ratio and mucoadhesive property of the formulations. A new simple dissolution technique was developed to simulate the vaginal environment for the evaluation of release behavior of vaginal tablets. In this technique, daily production amount and rate of the vaginal fluid was used without any rotational movement. The drug release was found to be slower from PAA-Cys compared to that from PAA formulations. The similarity study results confirmed that the difference in particle size of EN and MN did not affect their release profile. The release process was described by plotting the fraction released drug versus time and n fitting data to the simple exponential model: M(t)/M(∞)=kt(n). The release kinetics were determined as Super Case II for all the formulations prepared with PAA or PAA-Cys. According to these results the mucoadhesive vaginal tablet formulations prepared with PAA-Cys represent good example for delivery systems which prolong the residence time of drugs at the vaginal mucosal surface.

Combining simplicity with cost-effectiveness: Investigation of potential counterfeit of proton pump inhibitors through simulated formulations using thin-layer chromatography.

PubMed

Bhatt, Nejal M; Chavada, Vijay D; Sanyal, Mallika; Shrivastav, Pranav S

2016-11-18

A simple, accurate and precise high-performance thin-layer chromatographic method has been developed and validated for the analysis of proton pump inhibitors (PPIs) and their co-formulated drugs, available as binary combination. Planar chromatographic separation was achieved using a single mobile phase comprising of toluene: iso-propranol: acetone: ammonia 5.0:2.3:2.5:0.2 (v/v/v/v) for the analysis of 14 analytes on aluminium-backed layer of silica gel 60 FG 254 . Densitometric determination of the separated spots was done at 290nm. The method was validated according to ICH guidelines for linearity, precision and accuracy, sensitivity, specificity and robustness. The method showed good linear response for the selected drugs as indicated by the high values of correlation coefficients (≥0.9993). The limit of detection and limit of quantiation were in the range of 6.9-159.2ng/band and 20.8-478.1ng/band respectively for all the analytes. The optimized conditions afforded adequate resolution of each PPI from their co-formulated drugs and provided unambiguous identification of the co-formulated drugs from their homologous retardation factors (hR f ). The only limitation of the method was the inability to separate two PPIs, rabeprazole and lansoprazole from each other. Nevertheless, it is proposed that peak spectra recording and comparison with standard drug spot can be a viable option for assignment of TLC spots. The method performance was assessed by analyzing different laboratory simulated mixtures and some marketed formulations of the selected drugs. The developed method was successfully used to investigate potential counterfeit of PPIs through a series of simulated formulations with good accuracy and precision. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimising research to speed up availability of paediatric antiretroviral drugs and formulations

PubMed Central

Penazzato, M; Gnanashanmugam, D; Rojo, P; Lallemant, M; Lewis, L; Rocchi, F; Saint Raymond, A; Ford, N; Hazra, R; Giaquinto, C; Gibb, D; Abrams, Elaine J

2018-01-01

Globally 1.8 million children are estimated to be living with HIV, yet only 51% of those eligible actually start treatment. The completion of research and development (R&D) for paediatric antiretrovirals (ARVs) is a lengthy process and licensing of new paediatric ARVs continues to lag considerably behind adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up of paediatric treatment globally. In this manuscript we review current approaches to R&D for paediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including enrolment of multiple age-cohorts concurrently and the early introduction of dosing approaches for both single and fixed-dose combination (FDC) drug formulations (preferably scored and dispersible) that match WHO weight-bands. Efforts to speed up development of optimal drugs and formulations for children should focus on a limited number of prioritised formulations. This work should build upon existing partnerships and collaborations to ensure that paediatric investigation plans are developed early in the drug development process but can be modified in a streamlined manner as more information becomes available. In addition, simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more efficient and sustainable. Registration, implementation, and strategic use of drugs should not be seen as a sequential process, with research designed to address multiple questions simultaneously to respond to the needs of HIV-infected children where they live. It is imperative that lessons learned from HIV should be shared to support progress in developing paediatric formulations for other diseases with similar treatment challenges, including tuberculosis and viral hepatitis. PMID:29190337

The preparation by extrusion/spheronization and the properties of pellets containing drugs, microcrystalline cellulose and glyceryl monostearate.

PubMed

Chatchawalsaisin, Jittima; Podczeck, Fridrun; Newton, J Michael

2005-01-01

Pellets have been prepared by extrusion and spheronization containing microcrystalline cellulose (MCC) and four model drugs with decreasing order of solubility, paracetamol (P), diclofenac sodium (D), ibuprofen (IB) and indomethacin (IN) at a 10% level with and without the addition of a range of levels of glyceryl monostearate (GMS). The drugs differed in their response to extrusion in that all formulations containing the drug D had a 'steady state' extrusion profile whereas the other three drugs exhibited 'forced flow' indicating the possibility of water migration during the process of ram extrusion. The presence of GMS did not influence this effect. The drug D also required consistently less water to function than the other three drugs. In spite of these differences in extrusion performance, it was possible to prepare satisfactory pellets from formulations of all the drugs with 0, 30 and 60% GMS combined with 90, 60 or 30% of MCC at a range of water levels. It was also possible to prepare pellets containing the drug D with 70, 80 and 90% GMS, with corresponding quantities of 20, 10 and 0% of MCC. It was also possible to prepare the pellet formulations by dispersing the drugs in molten GMS, grinding and processing this with MCC and water. Such systems retained the processing characteristics of the composition made by the blending of the powder. The presence of GMS in all cases reduced the quantity of water required for the process to function. The steady state or the mean of the range of the forces observed during forced flow, were dependent on the composition and the quantity of water added. The surface of the extrudate appeared smooth and measurements of surface roughness established that the value of the rugosity R(a) for any of the extrudates did not exceed 6 microm. The extrudate diameter was found to increase with the quantity of GMS in the formulation. The pellets produced were all within a relatively narrow size range (three sieve fractions of a root two progression), the median value of which increased with the level of GMS. For the drug D, there was a linear increase of pellet diameter with increase in the extrudate diameter. For the three other drugs this relationship was less certain but nevertheless there was a similar trend for the pellet diameter to increase as the extrudate diameter increased, suggesting the mechanism of the process is the same irrespective of the composition. Considering the value of the shape factor e(R), all the pellets produced from the various formulations were well within acceptable levels for further processing and the only observable trend in the values was that the formulations with the lower water contents were the least round. The porosity of the pellets of the different formulations generally decreased with the increase in water used to prepare the pellets, the extent of this decrease being dependent on the drug and the level of GMS. The in vitro drug release from the pellets was controlled by the solubility of the drug, the lower the value of the solubility, the longer the mean dissolution time (MDT). This was not influenced by the presence of GMS or the method of incorporation of the drug into the formulation.

Electrically atomised formulations of timolol maleate for direct and on-demand ocular lens coatings.

PubMed

Mehta, Prina; Al-Kinani, Ali A; Haj-Ahmad, Rita; Arshad, Muhammad Sohail; Chang, Ming-Wei; Alany, Raid G; Ahmad, Zeeshan

2017-10-01

Advances in nanotechnology have enabled solutions for challenging drug delivery targets. While the eye presents numerous emerging opportunities for delivery, analysis and sensing; issues persist for conventional applications. This includes liquid phase formulation localisation on the ocular surface once administered as formulated eye-drops; with the vast majority of dosage (>90%) escaping from the administered site due to tear production and various drainage mechanisms. The work presented here demonstrates a single needle electrohydrodynamic (EHD) engineering process to nano-coat (as an on demand and controllable fiber depositing method) the surface of multiple contact lenses rendering formulations to be stationary on the lens and at the bio-interface. The coating process was operational based on ejected droplet charge and glaucoma drug timolol maleate (TM) was used to demonstrate surface coating optimisation, bio-surface permeation properties (flux, using a bovine model) and various kinetic models thereafter. Polymers PVP, PNIPAM and PVP:PNIPAM (50:50%w/w) were used to encapsulate the active. Nano-fibrous and particulate samples were characterised using SEM, FTIR, DSC and TGA to confirm structural and thermal stability of surface coated formulations. More than 52% of nano-structured coatings (for all formulations) were <200nm in diameter. In vitro studies show coatings to exhibit biphasic release profiles; an initial burst release followed by sustained release; with TM-loaded PNIPAM coating releasing most drug after 24h (89.8%). Kinetic modelling (Higuchi, Korsmeyer-Peppas) was indicative of quasi-Fickian diffusion whilst biological evaluation demonstrates adequate ocular tolerability. Results from permeation studies indicate coated lenses are ideal to reduce dosing regimen, which in turn will reduce systemic drug absorption. Florescent microscopy demonstrated probe and probe embedded coating behaviour from lens surface in vitro. The multiple lens surface coating method demonstrates sustained drug release yielding promising results; suggesting both novel device and method to enhance drug activity at the eyes surface which will reduce formulation drainage. Crown Copyright © 2017. Published by 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.

Formulation Optimization of Hot Melt Extruded Abuse Deterrent Pellet Dosage Form Utilizing Design of Experiments (DOE)

PubMed Central

Maddineni, Sindhuri; Battu, Sunil Kumar; Morott, Joe; Majumdar, Soumyajit; Repka, Michael A.

2014-01-01

The objective of the present study was to develop techniques for an abuse-deterrent (AD) platform utilizing hot melt extrusion (HME) process. Formulation optimization was accomplished by utilizing Box-Behnken design of experiments to determine the effect of the three formulation factors: PolyOx™ WSR301, Benecel™ K15M, and Carbopol 71G; each of which was studied at three levels on TR attributes of the produced melt extruded pellets. A response surface methodology was utilized to identify the optimized formulation. Lidocaine Hydrochloride was used as a model drug, and suitable formulation ingredients were employed as carrier matrices and processing aids. All of the formulations were evaluated for the TR attributes such as particle size post-milling, gelling, percentage of drug extraction in water and alcohol. All of the DOE formulations demonstrated sufficient hardness and elasticity, and could not be reduced into fine particles (<150µm), which is a desirable feature to prevent snorting. In addition, all of the formulations exhibited good gelling tendency in water with minimal extraction of drug in the aqueous medium. Moreover, Benecel™ K15M in combination with PolyOx™ WSR301 could be utilized to produce pellets with TR potential. HME has been demonstrated to be a viable technique with a potential to develop novel abuse-deterrent formulations. PMID:24433429

Comparison of high-resolution ultrasonic resonator technology and Raman spectroscopy as novel process analytical tools for drug quantification in self-emulsifying drug delivery systems.

PubMed

Stillhart, Cordula; Kuentz, Martin

2012-02-05

Self-emulsifying drug delivery systems (SEDDS) are complex mixtures in which drug quantification can become a challenging task. Thus, a general need exists for novel analytical methods and a particular interest lies in techniques with the potential for process monitoring. This article compares Raman spectroscopy with high-resolution ultrasonic resonator technology (URT) for drug quantification in SEDDS. The model drugs fenofibrate, indomethacin, and probucol were quantitatively assayed in different self-emulsifying formulations. We measured ultrasound velocity and attenuation in the bulk formulation containing drug at different concentrations. The formulations were also studied by Raman spectroscopy. We used both, an in-line immersion probe for the bulk formulation and a multi-fiber sensor for measuring through hard-gelatin capsules that were filled with SEDDS. Each method was assessed by calculating the relative standard error of prediction (RSEP) as well as the limit of quantification (LOQ) and the mean recovery. Raman spectroscopy led to excellent calibration models for the bulk formulation as well as the capsules. The RSEP depended on the SEDDS type with values of 1.5-3.8%, while LOQ was between 0.04 and 0.35% (w/w) for drug quantification in the bulk. Similarly, the analysis of the capsules led to RSEP of 1.9-6.5% and LOQ of 0.01-0.41% (w/w). On the other hand, ultrasound attenuation resulted in RSEP of 2.3-4.4% and LOQ of 0.1-0.6% (w/w). Moreover, ultrasound velocity provided an interesting analytical response in cases where the drug strongly affected the density or compressibility of the SEDDS. We conclude that ultrasonic resonator technology and Raman spectroscopy constitute suitable methods for drug quantification in SEDDS, which is promising for their use as process analytical technologies. Copyright © 2011 Elsevier B.V. All rights reserved.

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.

Readily prepared biodegradable nanoparticles to formulate poorly water soluble drugs improving their pharmacological properties: The example of trabectedin.

PubMed

Capasso Palmiero, Umberto; Morosi, Lavinia; Bello, Ezia; Ponzo, Marianna; Frapolli, Roberta; Matteo, Cristina; Ferrari, Mariella; Zucchetti, Massimo; Minoli, Lucia; De Maglie, Marcella; Romanelli, Pierpaolo; Morbidelli, Massimo; D'Incalci, Maurizio; Moscatelli, Davide

2018-04-28

The improvement of the pharmacological profile of lipophilic drug formulations is one of the main successes achieved using nanoparticles (NPs) in medicine. However, the complex synthesis procedure and numerous post-processing steps hamper the cost-effective use of these formulations. In this work, an approach which requires only a syringe to produce self-assembling biodegradable and biocompatible poly(caprolactone)-based NPs is developed. The effective synthesis of monodisperse NPs has been made possible by the optimization of the block-copolymer synthesized via a combination of ring opening polymerization and reversible addition-fragmentation chain transfer polymerization. These NPs can be used to formulate lipophilic drugs that are barely soluble in water, such as trabectedin, a potent anticancer therapeutic. Its biodistribution and antitumor activity have been compared with the commercially available formulation Yondelis®. The results indicate that this trabectedin NP formulation performs with the same antitumor activity as Yondelis®, but does not have the drawback of severe local vascular toxicity in the injection site. Copyright © 2018 Elsevier B.V. All rights reserved.

Self-nanoemulsifying performance of two grades of Lauroglycol (Lauroglycol-90 and Lauroglycol-FCC) in the presence of mixed nonionic surfactants.

PubMed

Shakeel, Faiyaz; Haq, Nazrul; Alanazi, Fars K; Alsarra, Ibrahim A

2014-11-01

The present study was undertaken to evaluate the impact of various combinations of nonionic surfactants on self-nanoemulsifying performance of two grades of Lauroglycol (Lauroglycol-90 and Lauroglycol-FCC) in glibenclamide (GBN) nanoemulsion. Formulations (L1-L30) were prepared by spontaneous emulsification method. Prepared formulations were subjected to thermodynamic stability and self-nanoemulsification test. Results of thermodynamic stability and self-nanoemulsification tests were confirmed by further characterization of these formulations in terms of droplet size, viscosity, refractive index and % transmittance. Formulations prepared with Labrasol, HCO-60 and Gelucire-44/14 were found to be suitable for self-emulsifying drug delivery system only whereas those prepared with Tween-80 and Cremophor-EL were found to be suitable for self-nanoemulsifying or self-microemulsifying drug delivery system of GBN with respect to Lauroglycol-90 or Lauroglycol-FCC. Formulation L24 (Lauroglycol-FCC/Tween-80/ethanol/water) was optimized as best formulation for self-nanoemulsifying drug delivery system of GBN. These results indicated that Tween-80 could be the best surfactant in terms of self-nanoemulsification.

Compounding and Extralabel Use of Drugs in Exotic Animal Medicine.

PubMed

Powers, Lauren V; Davidson, Gigi

2018-05-01

Extralabel drug use is the use of a Food and Drug Administration (FDA)-approved drug in a manner different from what is stipulated on the approved label. Compounding is the process of preparing a medication in a manner not indicated on the label to create a formulation specifically tailored to the needs of an individual patient. Extralabel drug use and compounding are vital aspects of safe and effective drug delivery to patients in exotic animal practice. There are few FDA-approved drugs for exotic animal species, and many approved drugs for other species are not available in suitable formulations for use in exotic animals. Copyright © 2018 Elsevier Inc. All rights reserved.

Systematic Development of Transethosomal Gel System of Piroxicam: Formulation Optimization, In Vitro Evaluation, and Ex Vivo Assessment.

PubMed

Garg, Varun; Singh, Harmanpreet; Bhatia, Amit; Raza, Kaisar; Singh, Sachin Kumar; Singh, Bhupinder; Beg, Sarwar

2017-01-01

Piroxicam is used in the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory diseases. Upon oral administration, it is reported to cause ulcerative colitis, gastrointestinal irritation, edema and peptic ulcer. Hence, an alternative delivery system has been designed in the form of transethosome. The present study describes the preparation, optimization, characterization, and ex vivo study of piroxicam-loaded transethosomal gel using the central composite design. On the basis of the prescreening study, the concentration of lipids and ethanol was kept in the range of 2-4% w/v and 0-40% v/v, respectively. Formulation was optimized by measuring drug retention in the skin, drug permeation, entrapment efficiency, and vesicle size. Optimized formulation was incorporated in hydrogel and compared with other analogous vesicular (liposomes, ethosomes, and transfersomes) gels for the aforementioned responses. Among the various lipids used, soya phosphatidylcholine (SPL 70) and ethanol in various percentages were found to affect drug retention in the skin, drug permeation, vesicle size, and entrapment efficiency. The optimized batch of transethosome has shown 392.730 μg cm -2 drug retention in the skin, 44.312 μg cm -2  h -1 drug permeation, 68.434% entrapment efficiency, and 655.369 nm vesicle size, respectively. It was observed that the developed transethosomes were found superior in all the responses as compared to other vesicular formulations with improved stability and highest elasticity. Similar observations were noted with its gel formulation.

Formulation, Characterization, and Antitumor Properties of Trans- and Cis-Citral in the 4T1 Breast Cancer Xenograft Mouse Model

PubMed Central

Zeng, San; Kapur, Arvinder; Patankar, Manish S.; Xiong, May P.

2015-01-01

Purpose Citral is composed of a random mixture of two geometric stereoisomers geranial (trans-citral) and neral (cis-citral) yet few studies have directly compared their in vivo antitumor properties. A micelle formulation was therefore developed. Methods Geranial and neral were synthesized. Commercially-purchased citral, geranial, and neral were formulated in PEG-b-PCL (block sizes of 5000:10000, Mw/Mn 1.26) micelles. In vitro degradation, drug release, cytotoxicity, flow cytometry, and western blot studies were conducted. The antitumor properties of drug formulations (40 mg/kg and 80 mg/kg based on MTD studies) were evaluated on the 4T1 xenograft mouse model and tumor tissues were analyzed by western blot. Results Micelles encapsulated drugs with >50% LE at 5-40% drug to polymer (w/w), displayed sustained release (t1/2 of 8-9 hours), and improved drug stability at pH 5.0. The IC50 of drug formulations against 4T1 cells ranged from 1.4-9.9 μM. Western blot revealed that autophagy was the main cause of cytotoxicity. Geranial at 80 mg/kg was most effective at inhibiting tumor growth. Conclusions Geranial is significantly more potent than neral and citral at 80 mg/kg (p<0.001) and western blot of tumor tissues confirms that autophagy and not apoptosis is the major mechanism of tumor growth inhibition in p53-null 4T1 cells. PMID:25673043

Formulation, Characterization, and Antitumor Properties of Trans- and Cis-Citral in the 4T1 Breast Cancer Xenograft Mouse Model.

PubMed

Zeng, San; Kapur, Arvinder; Patankar, Manish S; Xiong, May P

2015-08-01

Citral is composed of a random mixture of two geometric stereoisomers geranial (trans-citral) and neral (cis-citral) yet few studies have directly compared their in vivo antitumor properties. A micelle formulation was therefore developed. Geranial and neral were synthesized. Commercially-purchased citral, geranial, and neral were formulated in PEG-b-PCL (block sizes of 5000:10,000, Mw/Mn 1.26) micelles. In vitro degradation, drug release, cytotoxicity, flow cytometry, and western blot studies were conducted. The antitumor properties of drug formulations (40 and 80 mg/kg based on MTD studies) were evaluated on the 4T1 xenograft mouse model and tumor tissues were analyzed by western blot. Micelles encapsulated drugs with >50% LE at 5-40% drug to polymer (w/w), displayed sustained release (t1/2 of 8-9 h), and improved drug stability at pH 5.0. The IC50 of drug formulations against 4T1 cells ranged from 1.4 to 9.9 μM. Western blot revealed that autophagy was the main cause of cytotoxicity. Geranial at 80 mg/kg was most effective at inhibiting tumor growth. Geranial is significantly more potent than neral and citral at 80 mg/kg (p < 0.001) and western blot of tumor tissues confirms that autophagy and not apoptosis is the major mechanism of tumor growth inhibition in p53-null 4T1 cells.

Novel Pentablock Copolymers as Thermosensitive Self-Assembling Micelles for Ocular Drug Delivery

PubMed Central

Alami-Milani, Mitra; Zakeri-Milani, Parvin; Valizadeh, Hadi; Salehi, Roya; Salatin, Sara; Naderinia, Ali; Jelvehgari, Mitra

2017-01-01

Many studies have focused on how drugs are formulated in the sol state at room temperature leading to the formation of in situ gel at eye temperature to provide a controlled drug release. Stimuli-responsive block copolymer hydrogels possess several advantages including uncomplicated drug formulation and ease of application, no organic solvent, protective environment for drugs, site-specificity, prolonged and localized drug delivery, lower systemic toxicity, and capability to deliver both hydrophobic and hydrophilic drugs. Self-assembling block copolymers (such as diblock, triblock, and pentablock copolymers) with large solubility variation between hydrophilic and hydrophobic segments are capable of making temperature-dependent micellar assembles, and with further increase in the temperature, of jellifying due to micellar aggregation. In general, molecular weight, hydrophobicity, and block arrangement have a significant effect on polymer crystallinity, micelle size, and in vitro drug release profile. The limitations of creature triblock copolymers as initial burst release can be largely avoided using micelles made of pentablock copolymers. Moreover, formulations based on pentablock copolymers can sustain drug release for a longer time. The present study aims to provide a concise overview of the initial and recent progresses in the design of hydrogel-based ocular drug delivery systems. PMID:28507933

Criterion for excipients screening in the development of nanoemulsion formulation of three anti-inflammatory drugs.

PubMed

Shakeel, Faiyaz

2010-01-01

The present study was undertaken for screening of different excipients in the development of nanoemulsion formulations of three anti-inflammatory drugs namely ketoprofen, celecoxib (CXB) and meloxicam. Based on solubility profiles of each drug in oil, Triacetin (ketoprofen and CXB) and Labrafil (meloxicam) were selected as the oil phase. Based on maximum solubilization potential of oil in different surfactants, Cremophor-EL (ketoprofen and CXB) and Tween-80 (meloxicam) were selected as surfactants. Based on maximum nanoemulsion region in the pseudoternary phase diagrams, Transcutol-HP was selected as cosurfactant for all three drugs. 1:1 (ketoprofen and CXB) and 2:1 (meloxicam) mass ratio of surfactant to cosurfactant was selected for selection of different nanoemulsions on the basis of maximum nanoemulsion region in the phase diagrams. All selected nanoemulsion formulations were found thermodynamically stable. Results of these studies showed that all excipients were properly optimized for the development of nanoemulsion formulation of ketoprofen, CXB and meloxicam.

Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications

PubMed Central

Labiris, N R; Dolovich, M B

2003-01-01

Research in the area of pulmonary drug delivery has gathered momentum in the last several years, with increased interest in using the lung as a means of delivering drugs systemically. Advances in device technology have led to the development of more efficient delivery systems capable of delivering larger doses and finer particles into the lung. As more efficient pulmonary delivery devices and sophisticated formulations become available, physicians and health professionals will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung's clearance mechanisms and be retained within the lung for longer periods. It is now recognized that it is not enough just to have inhalation therapy available for prescribing; physicians and other healthcare providers need a basic understanding of aerosol science, inhaled formulations, delivery devices, and bioequivalence of products to prescribe these therapies optimally. PMID:14616419

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.

Stomach specific polymeric low density microballoons as a vector for extended delivery of rabeprazole and amoxicillin for treatment of peptic ulcer.

PubMed

Choudhary, Sandeep; Jain, Ashay; Amin, Mohd Cairul Iqbal Mohd; Mishra, Vijay; Agrawal, Govind P; Kesharwani, Prashant

2016-05-01

The study was intended to develop a new intra-gastric floating in situ microballoons system for controlled delivery of rabeprazole sodium and amoxicillin trihydrate for the treatment of peptic ulcer disease. Eudragit S-100 and hydroxypropyl methyl cellulose based low density microballoons systems were fabricated by employing varying concentrations of Eudragit S-100 and hydroxypropyl methyl cellulose, to which varying concentrations of drug was added, and formulated by stirring at various speed and time to optimize the process and formulation variable. The formulation variables like concentration and ratio of polymers significantly affected the in vitro drug release from the prepared floating device. The validation of the gastro-retentive potential of the prepared microballoons was carried out in rabbits by orally administration of microballoons formulation containing radio opaque material. The developed formulations showed improved buoyancy and lower ulcer index as compared to that seen with plain drugs. Ulcer protective efficacies were confirmed in ulcer-bearing mouse model. In conclusion, greater compatibility, higher gastro-retention and higher anti-ulcer activity of the presently fabricated formulations to improve potential of formulation for redefining ulcer treatment are presented here. These learning exposed a targeted and sustained drug delivery potential of prepared microballoons in gastric region for ulcer therapeutic intervention as corroborated by in vitro and in vivo findings and, thus, deserves further attention for improved ulcer treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Scale up, optimization and stability analysis of Curcumin C3 complex-loaded nanoparticles for cancer therapy

PubMed Central

2012-01-01

Background Nanoparticle based delivery of anticancer drugs have been widely investigated. However, a very important process for Research & Development in any pharmaceutical industry is scaling nanoparticle formulation techniques so as to produce large batches for preclinical and clinical trials. This process is not only critical but also difficult as it involves various formulation parameters to be modulated all in the same process. Methods In our present study, we formulated curcumin loaded poly (lactic acid-co-glycolic acid) nanoparticles (PLGA-CURC). This improved the bioavailability of curcumin, a potent natural anticancer drug, making it suitable for cancer therapy. Post formulation, we optimized our process by Reponse Surface Methodology (RSM) using Central Composite Design (CCD) and scaled up the formulation process in four stages with final scale-up process yielding 5 g of curcumin loaded nanoparticles within the laboratory setup. The nanoparticles formed after scale-up process were characterized for particle size, drug loading and encapsulation efficiency, surface morphology, in vitro release kinetics and pharmacokinetics. Stability analysis and gamma sterilization were also carried out. Results Results revealed that that process scale-up is being mastered for elaboration to 5 g level. The mean nanoparticle size of the scaled up batch was found to be 158.5 ± 9.8 nm and the drug loading was determined to be 10.32 ± 1.4%. The in vitro release study illustrated a slow sustained release corresponding to 75% drug over a period of 10 days. The pharmacokinetic profile of PLGA-CURC in rats following i.v. administration showed two compartmental model with the area under the curve (AUC0-∞) being 6.139 mg/L h. Gamma sterilization showed no significant change in the particle size or drug loading of the nanoparticles. Stability analysis revealed long term physiochemical stability of the PLGA-CURC formulation. Conclusions A successful effort towards formulating, optimizing and scaling up PLGA-CURC by using Solid-Oil/Water emulsion technique was demonstrated. The process used CCD-RSM for optimization and further scaled up to produce 5 g of PLGA-CURC with almost similar physicochemical characteristics as that of the primary formulated batch. PMID:22937885

Scale up, optimization and stability analysis of Curcumin C3 complex-loaded nanoparticles for cancer therapy.

PubMed

Ranjan, Amalendu P; Mukerjee, Anindita; Helson, Lawrence; Vishwanatha, Jamboor K

2012-08-31

Nanoparticle based delivery of anticancer drugs have been widely investigated. However, a very important process for Research & Development in any pharmaceutical industry is scaling nanoparticle formulation techniques so as to produce large batches for preclinical and clinical trials. This process is not only critical but also difficult as it involves various formulation parameters to be modulated all in the same process. In our present study, we formulated curcumin loaded poly (lactic acid-co-glycolic acid) nanoparticles (PLGA-CURC). This improved the bioavailability of curcumin, a potent natural anticancer drug, making it suitable for cancer therapy. Post formulation, we optimized our process by Reponse Surface Methodology (RSM) using Central Composite Design (CCD) and scaled up the formulation process in four stages with final scale-up process yielding 5 g of curcumin loaded nanoparticles within the laboratory setup. The nanoparticles formed after scale-up process were characterized for particle size, drug loading and encapsulation efficiency, surface morphology, in vitro release kinetics and pharmacokinetics. Stability analysis and gamma sterilization were also carried out. Results revealed that that process scale-up is being mastered for elaboration to 5 g level. The mean nanoparticle size of the scaled up batch was found to be 158.5±9.8 nm and the drug loading was determined to be 10.32±1.4%. The in vitro release study illustrated a slow sustained release corresponding to 75% drug over a period of 10 days. The pharmacokinetic profile of PLGA-CURC in rats following i.v. administration showed two compartmental model with the area under the curve (AUC0-∞) being 6.139 mg/L h. Gamma sterilization showed no significant change in the particle size or drug loading of the nanoparticles. Stability analysis revealed long term physiochemical stability of the PLGA-CURC formulation. A successful effort towards formulating, optimizing and scaling up PLGA-CURC by using Solid-Oil/Water emulsion technique was demonstrated. The process used CCD-RSM for optimization and further scaled up to produce 5 g of PLGA-CURC with almost similar physicochemical characteristics as that of the primary formulated batch.

Design and Evaluation of Topical Diclofenac Sodium Gel Using Hot Melt Extrusion Technology as a Continuous Manufacturing Process with Kolliphor® P407.

PubMed

Pawar, Jaywant; Narkhede, Rajkiran; Amin, Purnima; Tawde, Vaishali

2017-08-01

The aim of the present context was to develop and evaluate a Kolliphor® P407-based transdermal gel formulation of diclofenac sodium by hot melt extrusion (HME) technology; central composite design was used to optimize the formulation process. In this study, we have explored first time ever HME as an industrially feasible and continuous manufacturing technology for the manufacturing of gel formulation using Kolliphor® P407 and Kollisolv® PEG400 as a gel base. Diclofenac sodium was used as a model drug. The HME parameters such as feeding rate, screw speed, and barrel temperature were crucial for the semisolid product development, and were optimized after preliminary trials. For the processing of the gel formulation by HME, a modified screw design was used to obtain a uniform product. The obtained product was evaluated for physicochemical characterization such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), pH measurement, rheology, surface tension, and texture profile analysis. Moreover, it was analyzed for general appearance, spreadibility, surface morphology, and drug content. The optimized gel formulation showed homogeneity and transparent film when applied on a glass slide under microscope, pH was 7.02 and uniform drug content of 100.04 ± 2.74 (SD = 3). The DSC and XRD analysis of the HME gel formulation showed complete melting of crystalline API into an amorphous form. The Kolliphor® P407 and Kollisolv® PEG400 formed excellent gel formulation using HME with consistent viscoelastic properties of the product. An improved drug release was found for the HME gel, which showed a 100% drug release than that of a marketed product which showed only 88% of drug release at the end of 12 h. The Flux value of the HME gel was 106 than that of a marketed formulation, which showed only about 60 value, inferring a significant difference (P < 0.05) at the end of 1 h. This study demonstrates a novel application of the hot melt extrusion process for manufacturing of topical semisolid products.

Development and characterization of niosomal formulations of doxorubicin aimed at brain targeting.

PubMed

Bragagni, Marco; Mennini, Natascia; Ghelardini, Carla; Mura, Paola

2012-01-01

The aim of the present work was the development and characterization of a niosomal formulation functionalized with the glucose-derivative N-palmitoylglucosamine (NPG) to obtain a potential brain targeted delivery system for the anticancer agent doxorubicin. Five different methods have been examined for vesicle preparation. Light scattering and transmission electron microscopy were used for vesicle characterization, in terms of mean size, homogeneity and Zeta potential, and selection of the best composition and preparation conditions for developing NPG-functionalized niosomes. Drug entrapment efficiency was determined after separation of loaded from unloaded drug by size exclusion chromatography or dialysis. Preliminary in vivo studies were performed on rats, injected i.v. with 12 mg/kg of doxorubicin as commercial solution (Ebewe, 2 mg/mL) or NPG-niosomal formulation. Drug amounts in the blood and in the major organs of the animals, sacrificed 60 min post injection, were determined by HPLC. The selected formulation consisted in Span:cholesterol:Solulan:NPG (50:40:10:10 mol ratio) vesicles obtained by thin-layer evaporation, leading to homogeneous vesicles of less than 200 nm diameter. This formulation was used for preparation of NPG-niosomes loaded with doxorubicin (mean size 161±4 nm, encapsulation efficacy 57.8±1.8%). No significant changes (P>0.05) in vesicle dimensions, Zeta potential or entrapment efficiency were observed after six months storage at room temperature, indicative of good stability. I.v. administration to rats of the NPG-niosomal formulation allowed for reducing drug accumulation in the heart and keeping it longer in the blood circulation with respect to the commercial formulation. Moreover, a doxorubicin brain concentration of 2.9±0.4 μg/g was achieved after 60 min, while the commercial solution yielded undetectable drug brain concentrations (<0.1 μg/g). The developed NPG-niosomal formulation gave rise to stable, nano-sized vesicles, able to improve doxorubicin brain delivery. Positive results of preliminary in vivo studies require future pharmacokinetic studies to gain more insight into the mechanism of drug transport of functionalized niosomes.

In Situ Forming Polymeric Drug Delivery Systems

PubMed Central

Madan, M.; Bajaj, A.; Lewis, S.; Udupa, N.; Baig, J. A.

2009-01-01

In situ forming polymeric formulations are drug delivery systems that are in sol form before administration in the body, but once administered, undergo gelation in situ, to form a gel. The formation of gels depends on factors like temperature modulation, pH change, presence of ions and ultra violet irradiation, from which the drug gets released in a sustained and controlled manner. Various polymers that are used for the formulation of in situ gels include gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly(DL-lactic acid), poly(DL-lactide-co-glycolide) and poly-caprolactone. The choice of solvents like water, dimethylsulphoxide, N-methyl pyrrolidone, triacetin and 2-pyrrolidone for these formulations depends on the solubility of polymer used. Mainly in situ gels are administered by oral, ocular, rectal, vaginal, injectable and intraperitoneal routes. The in situ gel forming polymeric formulations offer several advantages like sustained and prolonged action in comparison to conventional drug delivery systems. The article presents a detailed review of these types of polymeric systems, their evaluation, advancements and their commercial formulations. From a manufacturing point of view, the production of such devices is less complex and thus lowers the investment and manufacturing cost. PMID:20490289

CRC/EORTC/NCI Joint Formulation Working Party: experiences in the formulation of investigational cytotoxic drugs.

PubMed Central

Beijnen, J. H.; Flora, K. P.; Halbert, G. W.; Henrar, R. E.; Slack, J. A.

1995-01-01

The pharmaceutical formulation of a new anti-tumour agent has often been perceived as the bottleneck in anti-cancer drug development. In order to increase the speed of this essential development step, the Cancer Research Campaign (CRC), the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute (NCI) agreed in 1987 to form the Joint Formulation Working Party (JFWP). The main goal of the JFWP is to facilitate the rapid progress of a new drug through pharmaceutical developmental to preclinical toxicology and subsequently to phase I clinical trial. Under the auspices of the JFWP around 50 new agents have been developed or are currently in development. In this report we present our formulation experiences since the establishment of the JFWP with a selected number of agents: aphidicolin glycinate, bryostatin 1, carmethizole, carzelesin, combretastatin A4, dabis maleate, disulphonated aluminium phthalocyanine, E.O.9, 4-hydroxyanisole, pancratistatin, rhizoxin, Springer pro-drug, SRI 62-834, temozolomide, trimelamol and V489. The approaches used and problems presented may be of general interest to scientists in related fields and those considering submitting agents for development. PMID:7599054

Mucus-penetrating nanoparticles for vaginal and gastrointestinal drug delivery

NASA Astrophysics Data System (ADS)

Ensign-Hodges, Laura

A method that could provide more uniform and longer-lasting drug delivery to mucosal surfaces holds the potential to greatly improve the effectiveness of prophylactic and therapeutic approaches for numerous diseases and conditions, including sexually transmitted infections and inflammatory bowel disease. However, the body's natural defenses, including adhesive, rapidly cleared mucus linings coating nearly all entry points to the body not covered by skin, has limited the effectiveness of drug and gene delivery by nanoscale delivery systems. Here, we investigate the use of muco-inert mucus-penetrating nanoparticles (MPP) for improving vaginal and gastrointestinal drug delivery. Conventional hydrophobic nanoparticles strongly adhere to mucus, facilitating rapid clearance from the body. Here, we demonstrate that mucoadhesive polystyrene nanoparticles (conventional nanoparticles, CP) become mucus-penetrating in human cervicovaginal mucus (CVM) after pretreatment with sufficient concentrations of Pluronic F127. Importantly, the diffusion rate of large MPP did not change in F127 pretreated CVM, implying there is no affect on the native pore structure of CVM. Additionally, there was no increase in inflammatory cytokine release in the vaginal tract of mice after daily application of 1% F127 for one week. Importantly, HSV virus remains adherent in F127-pretreated CVM. Mucosal epithelia use osmotic gradients for fluid absorption and secretion. We hypothesized that hypotonically-induced fluid uptake could be advantageous for rapidly delivering drugs through mucus to the vaginal epithelium. We evaluated hypotonic formulations for delivering water-soluble drugs and for drug delivery with MPP. Hypotonic formulations markedly increased the rate at which drugs and MPP reached the epithelial surface. Additionally, hypotonic formulations greatly enhanced drug and MPP delivery to the entire epithelial surface, including deep into the vaginal folds (rugae) that isotonic formulations failed to reach. However, hypotonic formulations caused free drugs to be drawn through the epithelium, reducing vaginal retention. In contrast, hypotonic formulations caused MPP to accumulate rapidly and uniformly on vaginal surfaces, ideally positioned for sustained drug delivery. Using a mouse model of vaginal genital herpes (HSV-2) infection, we found that hypotonic delivery of free drug led to improved immediate protection, but diminished longer-term protection. Minimally hypotonic formulations provided rapid and uniform delivery of MPP to the entire vaginal surface, thus enabling formulations with minimal risk of epithelial toxicity. We then describe an ex vivo method for characterizing particle transport on freshly excised mucosal tissues. By directly observing MPP transport on vaginal, gastrointestinal, and respiratory tissue, we were able to determine an innate difference in mucus mesh size at different anatomical locations. In addition, we were able to optimize particle size for gastrointestinal delivery in mice. As described here, there are numerous barriers to effective drug delivery in the gastrointestinal tract, including the mucus barrier. We go on to demonstrate that MPP can improve delivery in the gastrointestinal tract, both by rectal and oral administration. Finally, we describe the use of MPP for improving vaginal drug delivery. Incomplete drug coverage and short duration of action limit the effectiveness of vaginally administered drugs, including microbicides for preventing sexually transmitted infections. We show that MPP provide uniform distribution over the vaginal epithelium, whereas CP are aggregated by mouse vaginal mucus, leading to poor distribution. By penetrating into the deepest mucus layers in the rugae, more MPP were retained in the vaginal tract compared to CP. After 24 h, when delivered in a conventional vaginal gel, patches of a model drug remained on the vaginal epithelium, whereas the epithelium was coated with drug delivered by MPP. We then demonstrate that when administered 30 min prior to inoculum, anti-HSV-2 MPP protected 53% of mice compared to only 16% protected by soluble drug. Overall, MPP improved vaginal drug distribution and retention, provided more effective protection against vaginal viral challenge than soluble drug, and were non-toxic when administered daily for one week.

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

Topical Ocular Drug Delivery to the Back of the Eye by Mucus-Penetrating Particles

PubMed Central

Schopf, Lisa R.; Popov, Alexey M.; Enlow, Elizabeth M.; Bourassa, James L.; Ong, Winston Z.; Nowak, Pawel; Chen, Hongming

2015-01-01

Purpose: Enhanced drug exposure to the ocular surface typically relies on inclusion of viscosity-enabling agents, whereas delivery to the back of the eye generally focuses on invasive means, such as intraocular injections. Using our novel mucus-penetrating particle (MPP) technology, which rapidly and uniformly coats and penetrates mucosal barriers, we evaluated if such drug formulations could increase ocular drug exposure and improve topical drug delivery. Methods: Pharmacokinetic (PK) profiling of topically administered loterprednol etabonate formulated as MPP (LE-MPP) was performed in rabbits and a larger species, the mini-pig. Pharmacodynamic evaluation was done in a rabbit model of VEGF-induced retinal vascular leakage. Cellular potency and PK profile were determined for a second compound, KAL821, a novel receptor tyrosine kinase inhibitor (RTKi). Results: We demonstrated in animals that administration of LE-MPP increased exposure at the ocular surface and posterior compartments. Furthermore using a rabbit vascular leakage model, we demonstrated that biologically effective drug concentrations of LE were delivered to the back of the eye using the MPP technology. We also demonstrated that a novel RTKi formulated as MPPs provided drug levels to the back of the eye above its cellular inhibitory concentration. Conclusions: Topical dosing of MPPs of LE or KAL821 enhanced drug exposure at the front of the eye, and delivered therapeutically relevant drug concentrations to the back of the eye, in animals. Translational Relevance: These preclinical data support using MPP technology to engineer topical formulations to deliver therapeutic drug levels to the back of the eye and could provide major advancements in managing sight-threatening diseases. PMID:26101724

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates.

PubMed

Landis, Margaret S; Bhattachar, Shobha; Yazdanian, Mehran; Morrison, John

2018-01-01

This commentary reflects the collective view of pharmaceutical scientists from four different organizations with extensive experience in the field of drug discovery support. Herein, engaging discussion is presented on the current and future approaches for the selection of the most optimal and developable drug candidates. Over the past two decades, developability assessment programs have been implemented with the intention of improving physicochemical and metabolic properties. However, the complexity of both new drug targets and non-traditional drug candidates provides continuing challenges for developing formulations for optimal drug delivery. The need for more enabled technologies to deliver drug candidates has necessitated an even more active role for pharmaceutical scientists to influence many key molecular parameters during compound optimization and selection. This enhanced role begins at the early in vitro screening stages, where key learnings regarding the interplay of molecular structure and pharmaceutical property relationships can be derived. Performance of the drug candidates in formulations intended to support key in vivo studies provides important information on chemotype-formulation compatibility relationships. Structure modifications to support the selection of the solid form are also important to consider, and predictive in silico models are being rapidly developed in this area. Ultimately, the role of pharmaceutical scientists in drug discovery now extends beyond rapid solubility screening, early form assessment, and data delivery. This multidisciplinary role has evolved to include the practice of proactively taking part in the molecular design to better align solid form and formulation requirements to enhance developability potential.

A cross-sectional study of the availability and pharmacist's knowledge of nano-pharmaceutical drugs in Palestinian hospitals.

PubMed

Assali, Mohyeddin; Shakaa, Ali; Abu-Hejleh, Sabaa; Abu-Omar, Reham; Karajeh, Nareman; Ajory, Nawal; Zyoud, Saed; Sweileh, Waleed

2018-04-05

Nanomedicine is the medical application of nanomaterials that may have an infinite size with the range less than 100 nm. This science has provided solutions to many of the current limitations in the diagnosis and treatment of diseases. Therefore, the pharmacist's knowledge and awareness of nano-pharmaceutical drugs will increase their availability in the market, and will improve the patient's compliance to their drug therapy. This study aimed to determine the availability of nano-pharmaceutical drugs in Palestinian hospitals and evaluate the extent of pharmacist's knowledge about them. A cross-sectional study design questionnaire was used to determine the availability of nano-pharmaceutical drugs based on the database of the ministry of health in the Palestinian hospitals (governmental, private and non- governmental organizations). Moreover, the knowledge of these nano-pharmaceutical drugs among pharmacists working in Palestinian hospitals was assessed based on developed questionnaire from the literature of the pharmaceutical formulations and nano-formulations. The variables were analyzed using Statistical Package for Social Sciences (SPSS 22). Fifty six pharmacists from 27 hospitals in the West bank completed the survey. The results regarding the availability of nano-pharmaceutical drugs indicated only eight available in hospitals with a frequency range 0-39.3%. Moreover, pharmacist's knowledge in the pharmaceutical formulations was better than that in nano-formulations. The availability of nano-pharmaceutical drugs in Palestinian hospitals was not adequate due to the lack of various nano-pharmaceutical drugs. The knowledge among pharmacists regarding nano-pharmaceutical drugs should be improved by providing courses in nanomedicine during the undergraduate pharmacy programs.

Drug Solubility in Fatty Acids as a Formulation Design Approach for Lipid-Based Formulations: A Technical Note.

PubMed

Lee, Yung-Chi; Dalton, Chad; Regler, Brian; Harris, David

2018-06-06

Lipid-based drug delivery systems have been intensively investigated as a means of delivering poorly water-soluble drugs. Upon ingestion, the lipases in the gastrointestinal tract digest lipid ingredients, mainly triglycerides, within the formulation into monoglycerides and fatty acids. While numerous studies have addressed the solubility of drugs in triglycerides, comparatively few publications have addressed the solubility of drugs in fatty acids, which are the end product of digestion and responsible for the solubility of drug within mixed micelles. The objective of this investigation was to explore the solubility of a poorly water-soluble drug in fatty acids and raise the awareness of the importance of drug solubility in fatty acids. The model API (active pharmaceutical ingredient), a weak acid, is considered a BCS II compound with an aqueous solubility of 0.02 μg/mL and predicted partition coefficient >7. The solubility of API ranged from 120 mg/mL to over 1 g/mL in fatty acids with chain lengths across the range C18 to C6. Hydrogen bonding was found to be the main driver of the solubilization of API in fatty acids. The solubility of API was significantly reduced by water uptake in caprylic acid but not in oleic acid. This report demonstrates that solubility data generated in fatty acids can provide an indication of the solubility of the drug after lipid digestion. This report also highlights the importance of measuring the solubility of drugs in fatty acids in the course of lipid formulation development.

Formulation and evaluation of floating matrix tablet of stavudine

PubMed Central

Prajapati, Pankaj H; Nakum, Vijay V; Patel, Chhagan N

2012-01-01

Background/Aim: The purpose of the study was to prolong the gastric residence time of stavudine by designing its floating tablets and to study the influence of different polymers on its release rate. Materials and Methods: The floating mix matrix tablets of stavudine were prepared by melt granulation method. Beeswax was used as hydrophobic meltable material. Hydroxypropyl methylcellulose (HPMC), sodium bicarbonate, and ethyl cellulose were used as matrixing agent, gas generating agent, and floating enhancer, respectively. The prepared tablets were evaluated for physicochemical parameters such as hardness, weight variation, friability, floating properties (floating lag time, total floating time), drug content, stability study, and in vitro drug release. The drug- polymer interaction was studied by Differential Scanning Calorimetry (DSC) thermal analysis and Fourier transform infared (FT-IR). Results: The floating lag time of all the formulations was within the prescribed limit (<3 min). All the formulations showed good matrix integrity and retarded the release of drug for 12 h except the formulation F5.The concentration of beeswax (X1), HPMC K4M (X2), and ethyl cellulose (X3) were selected as independent variables and drug release values at 1 (Q1), at 6 (Q6) and at 12 h (Q12) as dependent variables. Formulation F7 was selected as an optimum formulation as it showed more similarity in dissolution profile with theoretical profile (similarity factor, f2 = 70.91). The dissolution of batch F7 can be described by zero-order kinetics (R2 =0.9936) with anomalous (non-Fickian) diffusion as the release mechanism (n=0.545). There was no difference observed in release profile after temperature sensitivity study at 40°C/75% relative humidity (RH) for 1 month. Conclusion: It can be concluded from this study that the combined mix matrix system containing hydrophobic and hydrophilic polymer minimized the burst release of drug from the tablet and achieved a drug release by zero-order kinetics, which is practically difficult with only hydrophilic matrix. PMID:23119237

LEVEL A IN VITRO-IN-IVO CORRELATION DEVELOPMENT AND VALIDA- TION FOR TRAMADOL HYDROCHLORIDE FORMULATIONS.

PubMed

Cai, Yangping; Li, Youshan; Li, Shu; Gao, Tian; Zhang, Lu; Yang, Zhe; Fan, Zhengfu; Bai, Chujie

2016-09-01

The objective of this article is to develop and validate the level A in vitro-in vivo correlation (IVIVC) for three different formulations of tramadol hydrochloride. The formulations included were Tramazac® (Ml, conventional tablet) and TRD CONTIN® (M2, sustained release tablet), and a new controlled release tablet prepared on the basis of osmotic technology (formulation IVB). To develop level A IVIVC, in vivo data were deconvoluted into absorption data by using Wagner-Nelson equation. The absorption data (percent drug absorbed) was plotted against percent drug dissolved keeping the former along x-axis and the later along y-axis. The highest determination coefficient (R² = 0.9278) of the level A IVIVC was observed for formulation MI, and then for M2 (R² = 0.9046) and IVB (R² = 0.8796). Additionally, plasma drug levels were approximated from in vitio dissolution data using convolution approach to calculate the prediction error (%), which was found to be < 10%.

77 FR 30025 - Importer of Controlled Substances; Notice of Registration; Formulation Technologies, LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-21

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of Registration; Formulation Technologies, LLC By Notice dated January 26, 2012, and published in the Federal..., Austin, Texas 78758, made application by renewal to the Drug Enforcement Administration (DEA) to be...

Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

PubMed

Galia, E; Nicolaides, E; Hörter, D; Löbenberg, R; Reppas, C; Dressman, J B

1998-05-01

In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.

In vitro testing of thiolated poly(aspartic acid) from ophthalmic formulation aspects.

PubMed

Budai-Szű Cs, Mária; Horvát, Gabriella; Gyarmati, Benjámin; Szilágyi, Barnabás Áron; Szilágyi, András; Csihi, Tímea; Berkó, Szilvia; Szabó-Révész, Piroska; Mori, Michela; Sandri, Giuseppina; Bonferoni, Maria Cristina; Caramella, Carla; Csányi, Erzsébet

2016-08-01

Ocular drug delivery formulations must meet anatomical, biopharmaceutical, patient-driven and regulatory requirements. Mucoadhesive polymers can serve as a better alternative to currently available ophthalmic formulations by providing improved bioavailability. If all requirements are addressed, a polymeric formulation resembling the tear film of the eye might be the best solution. The optimum formulation must not have high osmotic activity, should provide appropriate surface tension, pH and refractive index, must be non-toxic and should be transparent and mucoadhesive. We would like to highlight the importance of in vitro polymer testing from a pharmaceutical aspect. We, therefore, carried out physical-chemical investigations to verify the suitability of certain systems for ophthalmic formulations. In this work, in situ gelling, mucoadhesive thiolated poly(aspartic acid)s were tested from ophthalmic formulation aspects. The results of preformulation measurements indicate that these polymers can be used as potential carriers in ophthalmic drug delivery.

Novel swellable polymer of orchidaceae family for gastroretentive drug delivery of famotidine

PubMed Central

Razavi, Mahboubeh; Nyamathulla, Shaik; Karimian, Hamed; Noordin, Mohamed Ibrahim

2014-01-01

This study aimed to develop hydrophilic, gastroretentive matrix tablets of famotidine with good floating and swelling properties. A novel gastroretentive drug delivery formulation was designed using salep, also known as salepi, a flour obtained from grinding dried palmate tubers of Orchis morio var mascula (Orchidaceae family). The main polysaccharide content of salep is glucomannan, highly soluble in cold and hot water, which forms a viscous solution. Salep was characterized for physicochemical properties, thermal stability, chemical interaction, and surface morphology using X-ray diffraction analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Ten different formulations (S1–S10) were prepared using famotidine to salep ratios from 1:0.5 to 1:5. Results demonstrated that all formulations were able to sustain the drug release for more than 24 hours. The S5 formulation, with a famotidine to salep ratio of 1:2.5, had the shortest floating lag time of 35 seconds and 100% drug release within 24 hours. The dissolution data were fitted into popular mathematical models to assess the mechanism of drug release. S5 showed Zero order release (R=0.9746) with Higuchi diffusion (R=0.9428). We conclude that salep, a novel polymer, can be used in controlled release formulations to sustain release for 24 hours, due to inherent swelling and gelling properties. PMID:25246773

UV-curable gels as topical nail medicines:In vivo residence, anti-fungal efficacy and influence of gel components on their properties.

PubMed

Kerai, L V; Hilton, S; Maugueret, M; Kazi, B B; Faull, J; Bhakta, S; Murdan, S

2016-11-30

UV-curable gels, used as nail cosmetics for their in vivo durability, were reported to be promising as topical nail medicines. Our first aim was thus to investigate whether such durability applies to drug-loaded formulations. This was found to be true. However, ethanol inclusion in the pharmaceutical formulation (to enable drug loading) reduced the in vivo residence. The second aim was therefore to determine any other effects of ethanol, and if ethanol could be avoided by the choice of monomers. Thus, three methacrylate monomers, ethyl methacrylate, isobornyl methacrylate and 2-hydroxyethyl methacrylate (HEMA) were selected, and their influence on the formulation properties were determined. Ethanol and the methacrylate monomer influenced some (but not all) of the formulation properties. The most significant was that HEMA could dissolve drug and enable the preparation of ethanol-free, drug-loaded formulations, which would benefit in vivo residence. The absence of ethanol reduced drug loading, release and ungual flux, but had no negative impact on the in vitro anti-fungal efficacy. Thus, judicious selection of gel components enabled the exclusion of ethanol. The long in vivo residence, little residual monomers, sufficient ungual permeation and in vitro anti-fungal activity of the gels indicates their potential as anti-onychomycotic topical medicines. Copyright © 2016 Elsevier B.V. All rights reserved.

Pharmacokinetics of rectal drug administration, Part I. General considerations and clinical applications of centrally acting drugs.

PubMed

van Hoogdalem, E; de Boer, A G; Breimer, D D

1991-07-01

Generally, oral administration is the route of choice in the daily practice of pharmacotherapy. However, in some circumstances this is impractical or even impossible (during nausea and vomiting or convulsions, in uncooperative patients and before surgery). In these cases, the rectal route may represent a practical alternative and rectal administration is now well accepted for delivering, for example, anticonvulsants, non-narcotic and narcotic analgesics, theophylline, antiemetics and antibacterial agents, and for inducing anaesthesia in children. It may also represent an interesting alternative to intravenous or other injection routes of drug administration. The rate and extent of rectal drug absorption are often lower than with oral absorption, possibly an inherent factor owing to the relatively small surface area available for drug uptake. In addition, the composition of the rectal formulation (solid vs liquid, nature of the suppository base) appears to be an important factor in the absorption process by determining the pattern of drug release. This relation between formulation and drug uptake has been clearly demonstrated for drugs like diazepam, paracetamol (acetaminophen), indomethacin, methadone and diflunisal. Coadministration of absorption-promoting agents (surfactants, sodium salicylate, enamines) represents another approach towards manipulating rectal drug absorption, although this concept requires further research concerning both efficacy and safety. For a number of drugs the extent of rectal absorption has been reported to exceed oral values, which may reflect partial avoidance of hepatic first-pass metabolism after rectal delivery. This phenomenon has been reported for morphine, metoclopramide, ergotamine, lidocaine (lignocaine) and propranolol. Rectal drug delivery in a site- and rate-controlled manner using osmotic pumps or hydrogel formulations may provide opportunities for manipulating systemic drug concentrations and drug effects. The extent of first-pass metabolism may be influenced (lidocaine), depending on the site of drug administration in the rectum. The rate of delivery may determine systemic drug action and side effects (nifedipine), and it may affect the local action of concurrently administered absorption promoters on drug uptake (cefoxitin). Local irritation is increasingly being acknowledged as a possible complication of rectal drug therapy. Long term medication with rectal ergotamine and acetylsalicylic acid, for example, may result in rectal ulceration, and irritation after a single administration of several drugs and formulations has been described. The assessment of tolerability and safety is imperative in the design of rectal formulations. Recent studies corroborate the clinical relevance of rectal drug therapy, and the value of the rectal route as an alternative to parenteral administration has been assessed for several drugs, e.g. diazepam, midazolam, morphine and diclofenac.(ABSTRACT TRUNCATED AT 400 WORDS)

Formulation and in vitro evaluation of xanthan gum-based bilayered mucoadhesive buccal patches of zolmitriptan.

PubMed

Shiledar, Rewathi R; Tagalpallewar, Amol A; Kokare, Chandrakant R

2014-01-30

A novel bilayered mucoadhesive buccal patch of zolmitriptan was prepared using xanthan gum (XG) as mucoadhesive polymer. Hydroxypropyl methylcellulose E-15 was used as film-former and polyvinyl alcohol (PVA) was incorporated, to increase the tensile strength of the patches. To study the effect of independent variables viz. concentrations of XG and PVA, on various dependent variables like in vitro drug release, ex vivo mucoadhesive strength and swelling index, 3(2) factorial design was employed. In vitro drug release studies of optimized formulation showed initially, rapid drug release; 43.15% within 15 min, followed by sustained release profile over 5h. Incorporation of 4% dimethyl sulfoxide enhanced drug permeability by 3.29 folds, transported 29.10% of drug after 5h and showed no buccal mucosal damage after histopathological studies. In conclusion, XG can be used as a potential drug release modifier and mucoadhesive polymer for successful formulation of zolmitriptan buccal patches. Copyright © 2013 Elsevier Ltd. All rights reserved.

Medicated chewing gum--a potential drug delivery system.

PubMed

Chaudhary, Shivang A; Shahiwala, Aliasgar F

2010-07-01

Over the years, patient convenience and patient compliance-orientated research in the field of drug delivery has resulted in bringing out potential innovative drug delivery options. Out of which, medicated chewing gum (MCG) offers a highly convenient patient-compliant way of dosing medications, not only for special population groups with swallowing difficulties such as children and the elderly, but also for the general population, including the young generation. In this review, various formulation ingredients, different manufacturing processes, and assessment of in vivo and in vitro drug release from MCG are thoroughly discussed along with the therapeutic potential and limitations of MCG. Readers will gain knowledge about the rationale and prominent formulation and performance evaluation strategies behind chewing gum as a drug delivery system. The availability of directly compressible co-processed gum material enables rapid, safe and low-cost development of MCG as a drug delivery option. By MCG formulation, revitalization of old products and reformulation of new patented products is possible, to differentiate them from upcoming generics competition in the market.

Otic drug delivery systems: formulation principles and recent developments.

PubMed

Liu, Xu; Li, Mingshuang; Smyth, Hugh; Zhang, Feng

2018-04-25

Disorders of the ear severely impact the quality of life of millions of people, but the treatment of these disorders is an ongoing, but often overlooked challenge particularly in terms of formulation design and product development. The prevalence of ear disorders has spurred significant efforts to develop new therapeutic agents, but perhaps less innovation has been applied to new drug delivery systems to improve the efficacy of ear disease treatments. This review provides a brief overview of physiology, major diseases, and current therapies used via the otic route of administration. The primary focuses are on the various administration routes and their formulation principles. The article also presents recent advances in otic drug deliveries as well as potential limitations. Otic drug delivery technology will likely evolve in the next decade and more efficient or specific treatments for ear disease will arise from the development of less invasive drug delivery methods, safe and highly controlled drug delivery systems, and biotechnology targeting therapies.

Benzyl Benzoate-Loaded Microemulsion for Topical Applications: Enhanced Dermatokinetic Profile and Better Delivery Promises.

PubMed

Sharma, Gajanand; Dhankar, Geeta; Thakur, Kanika; Raza, Kaisar; Katare, O P

2016-10-01

Benzyl benzoate (BB) is one of the oldest drugs used for the treatment of scabies and is recommended as the "first-line intervention" for the cost-effective treatment of the disease. Though a promising candidate, its application is reported to be associated with irritation of the skin and eye, resulting in poor patient compliance. Hence, the present study aims to develop BB-loaded topical microemulsion for the safer and effective delivery of BB. Pseudo-ternary phase diagrams with BB as the oily phase itself, along with Tween 80 as surfactant, and mixture of phospholipid and ethanol as the co-surfactant along with aqueous solution as the external phase were constructed and various compositions were formulated. The optimized formulation was characterized for particle-size, zeta-potential, drug-content, globule-morphology pH, and refractive-index, whereas evaluated for skin permeation, retention, compliance, and dermatokinetics. The nanosized formulation offered threefold higher drug permeation vis-a-vis plain drug solution across LACA mice abdominal skin. The drug retention of the selected formulation was nearly twice of that from the marketed product, assuring depot formulation and sustained release. The skin histopathology revealed the non-irritant nature of the formulation, as no changes in the normal skin histology were observed. The dermatokinetic studies confirmed better permeation and enhanced skin bioavailability of BB to epidermis as well as dermis vis-à-vis the conventional product. The results indicate that the developed lipid-based microemulsion hydrogel can alleviate the concerns associated with BB and can provide a better and safer delivery option in substantial amounts to various skin layers.

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.

Intraocular distribution of topically applied hydrophilic and lipophilic substances in rat eyes.

PubMed

Abdul Nasir, Nurul Alimah; Agarwal, Puneet; Agarwal, Renu; Iezhitsa, Igor; Alyautdin, Renad; Nukolova, Natalia N; Chekhonin, Vladimir P; Mohd Ismail, Nafeeza

2016-10-01

Topical administration is the preferred route of drug delivery for ophthalmic ailments. However, poor permeation through ocular surface and significant systemic absorption, makes the topical drug delivery challenging. Furthermore, distribution of topically delivered drugs varies with their physicochemical properties and the type of formulation used. Hence, this study was done to understand the pattern of ocular drug distribution of topically applied hydrophilic and lipophilic substances in two different formulations. 5-Carboxyfluorescein and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate were used as representative candidates for hydrophilic and lipophilic substances, respectively. They were formulated in solution and liposomes. Single drop of either formulation containing hydrophilic or lipophilic substance was instilled topically, unilaterally to rat eyes. Subsequently, rats were sacrificed at 10, 30 and 120 min post-instillation. Eyes were cryosectioned and examined under confocal microscope to determine the fluorescence intensity in ocular tissues. Corneal permeation of hydrophilic and lipophilic substances in both formulations peaked at 30 min post-instillation. Liposomal-lipophilic dye and non-liposomal-hydrophilic dye showed better corneal distribution. Fluorescence was absent in contralateral eyes of non-liposomal-hydrophilic dye-treated animals but was present in contralateral eyes of liposomal-hydrophilic dye-treated animals. Fluorescence in contralateral eyes of liposomal-lipophilic dye-treated animals was significantly higher compared to non-liposomal-lipophilic dye-treated animals. Topically applied liposomal formulation of lipophilic substance provides higher corneal concentration of drug with lesser systemic absorption compared to its solution. For hydrophilic substance, topical use of solution provides greater corneal concentration compared to liposomes which is more likely to be absorbed systemically.

Design of lipid-based formulations for oral administration of poorly water-soluble drug fenofibrate: effects of digestion.

PubMed

Mohsin, Kazi

2012-06-01

Lipid-based drug carriers are likely to have influence on bioavailability through enhanced solubilization of the drug in the gastrointestinal tract. The study was designed to investigate the lipid formulation digestibility in the simulated gastro intestinal media. Fenofibrate was formulated in representative Type II, IIIA, IIIB and IV self-emulsifying/microemulsifying lipid delivery systems (SEDDS and SMEDDS designed for oral administration) using various medium-chain glyceride components, non-ionic surfactants and cosolvents as excipients. Soybean oil was used only as an example of long-chain triglycerides to compare the effects of formulation with their counterparts. The formulations were subjected to in vitro digestion specifically to predict the fate of the drug in the gastro intestinal tract after exposure of the formulation to pancreatic enzymes and bile. In vitro digestion experiments were carried out using a pH-stat maintained at pH 7.5 for 30 min using intestinal fluids simulating the fed and fasted states. The digestion rate was faster and almost completed in Type II and IIIA systems. Most of the surfactants used in the studies are digestible. However, the high concentration of surfactant and/or cosolvent used in Type IIIB or IV systems lowered the rate of digestion. The digestion of medium-chain triglycerides was faster than long-chain triglycerides, but kept comparatively less drug in the post digestion products. Medium-chain mixed glycerides are good solvents for fenofibrate as rapidly digested but to improve fenofibrate concentration in post digestion products the use of long-chain mixed glycerides are suggested for further investigations.

Adsorption onto Mesoporous Silica Using Supercritical Fluid Technology Improves Dissolution Rate of Carbamazepine-a Poorly Soluble Compound.

PubMed

Gandhi, Aditya V; Thipsay, Priyanka; Kirthivasan, Bharat; Squillante, Emilio

2017-11-01

The purpose of this research was to design and characterize an immediate-release formulation of carbamazepine (CBZ), a poorly soluble anti-epileptic drug, using a porous silica carrier. Carbon dioxide in its supercritical state (2000 psi, 30-35°C) was used as an anti-solvent to precipitate CBZ onto two particle size variants of silica. Adsorption isotherms were used as a pre-formulation strategy to select optimum ratios of silica and CBZ. The obtained drug-silica formulations were characterized by dissolution studies, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). This formulation strategy resulted in a 2.4-fold improvement in dissolution rate when compared to pure drug after 30 min of dissolution testing. PXRD and DSC confirmed the amorphous nature of CBZ in the formulations as well as the differences in polymorphic forms of commercial and supercritical fluid-processed CBZ. Additionally, solid-state NMR spectroscopy showed that the spin-lattice relaxation time for bulk drug (without silica) was ∼7.5 times greater than that for silica-confined CBZ, implying that when CBZ was adsorbed onto mesoporous silica, it is structurally disordered and had higher structural mobility, a characteristic of amorphous solids. The mesoporous silica matrix prevented CBZ crystal growth by imposing spatial constraint on CBZ nuclei and hence resulted in faster dissolution compared to bulk solid drug. Adsorption onto mesoporous silica using supercritical fluid technology may be used as a novel formulation strategy for amorphization of poorly soluble compounds, in turn improving their dissolution rate.

Formulation and evaluation of floating tablet of H2-receptor antagonist.

PubMed

Kesarla, Rajesh S; Vora, Pratik Ashwinbhai; Sridhar, B K; Patel, Gunvant; Omri, Abdelwahab

2015-01-01

Conventional sustained dosage form of ranitidine hydrochloride (HCl) does not prevent frequent administration due to its degradation in colonic media and limited absorption in the upper part of GIT. Ranitidine HCl floating tablet was formulated with sublimation method to overcome the stated problem. Compatibility study for screening potential excipients was carried out using Fourier transform infrared spectroscopy (FT-IR) and differential scanning chromatography (DSC). Selected excipients were further evaluated for optimizing the formulation. Preliminary screening of binder, polymer and sublimating material was based on hardness and drug release, drug release with release kinetics and floating lag time with total floatation time, respectively. Selected excipients were subjected to 3(2) factorial design with polymer and sublimating material as independent factors. Matrix tablets were obtained by using 16/32" flat-faced beveled edges punches followed by sublimation. FT-IR and DSC indicated no significant incompatibility with selected excipients. Klucel-LF, POLYOX WSR N 60 K and l-menthol were selected as binder, polymer and sublimating material, respectively, for factorial design batches after preliminary screening. From the factorial design batches, optimum concentration to release the drug within 12 h was found to be 420 mg of POLYOX and 40 mg of l-menthol. Stability studies indicated the formulation as stable. Ranitidine HCl matrix floating tablets were formulated to release 90% of drug in stomach within 12 h. Hence, release of the drug could be sustained within narrow absorption site. Moreover, the dosage form was found to be floating within a fraction of second independent of the pH of media ensuring a robust formulation.

Buccal drug delivery.

PubMed

Smart, John D

2005-05-01

Buccal formulations have been developed to allow prolonged localised therapy and enhanced systemic delivery. The buccal mucosa, however, while avoiding first-pass effects, is a formidable barrier to drug absorption, especially for biopharmaceutical products (proteins and oligonucleotides) arising from the recent advances in genomics and proteomics. The buccal route is typically used for extended drug delivery, so formulations that can be attached to the buccal mucosa are favoured. The bioadhesive polymers used in buccal drug delivery to retain a formulation are typically hydrophilic macro-molecules containing numerous hydrogen bonding groups. Newer second-generation bioadhesives have been developed and these include modified or new polymers that allow enhanced adhesion and/or drug delivery, in addition to site-specific ligands such as lectins. Over the last 20 years a wide range of formulations has been developed for buccal drug delivery (tablet, patch, liquids and semisolids) but comparatively few have found their way onto the market. Currently, this route is restricted to the delivery of a limited number of small lipophilic molecules that readily cross the buccal mucosa. However, this route could become a significant means for the delivery of a range of active agents in the coming years, if the barriers to buccal drug delivery are overcome. In particular, patient acceptability and the successful systemic delivery of large molecules (proteins, oligonucleotides and polysaccharides) via this route remains both a significant opportunity and challenge, and new/improved technologies may be required to address these.

Parenteral formulation of an antileishmanial drug candidate--tackling poor solubility, chemical instability, and polymorphism.

PubMed

Kupetz, Eva; Preu, Lutz; Kunick, Conrad; Bunjes, Heike

2013-11-01

The paullon chalcone derivative KuRei300 is active against Leishmania donovani, the protozoans causing visceral leishmaniasis. The aim of this study was the development of a parenteral formulation of the virtually water insoluble compound in order to enable future studies in mice. Mixed lecithin/bile salt micelles, liposomes, supercooled smectic cholesterol myristate nanoparticles, cubic phase nanoparticles and a triglyceride emulsion were screened for their solubilizing properties. Due to the limited available amount of KuRei300 a passive loading approach with pre-formulated carriers that were incubated with drug substance deposited onto the walls of glass vials was used. The loading capacities of the nanocarriers, the influence of the solid state properties of the drug and its deposits on the loading results and chemical stability aspects of KuRei300 were investigated. Employed methods included HPLC, UV spectroscopy, (1)H NMR, XRPD, and DSC. All nanocarriers substantially improved the solubility of KuRei300; the mixed micelles exhibited the highest drug load. Related to the lipid matrix, however, the smectic nanoparticles solubilized the significantly highest amount of drug. Loading from physically altered drug deposits improved the obtainable concentration to the threefold compared with untreated drug powder. Formulations with KuRei300 must be stored excluded from light under a nitrogen atmosphere as the substance is susceptible to photoisomerization and decomposition. Copyright © 2013 Elsevier B.V. All rights reserved.

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

Efficient co-delivery of immiscible hydrophilic/hydrophobic chemotherapeutics by lipid emulsions for improved treatment of cancer

PubMed Central

Zhang, Bo; Song, Yunmei; Wang, Tianqi; Yang, Shaomei; Zhang, Jing; Liu, Yongjun; Zhang, Na; Garg, Sanjay

2017-01-01

Combinational nanomedicine is becoming a topic of much interest in cancer therapy, although its translation into the clinic remains extremely challenging. One of the main obstacles lies in the difficulty to efficiently co-deliver immiscible hydrophilic/hydrophobic drugs into tumor sites. The aim of this study was to develop co-loaded lipid emulsions (LEs) to co-deliver immiscible hydrophilic/hydrophobic drugs to improve cancer therapy and to explore the co-delivery abilities between co-loaded LEs and mixture formulation. Multiple oxaliplatin/irinotecan drug–phospholipid complexes (DPCs) were formulated. Co-loaded LEs were prepared using DPC technique to efficiently encapsulate both drugs. Co-loaded LEs exhibited uniform particle size distribution, desired stability and synchronous release profiles in both drugs. Co-loaded LEs demonstrated superior anti-tumor activity compared with the simple solution mixture and the mixture of single-loaded LEs. Furthermore, co-loaded nanocarriers could co-deliver both drugs into the same cells more efficiently and exhibited the optimized synergistic effect. These results indicate that co-loaded LEs could be a desired formulation for enhanced cancer therapy with potential application prospects. The comparison between co-loaded LEs and mixture formulation is significant for pharmaceutical designs aimed at co-delivery of multiple drugs. PMID:28435264

Contribution of hot-melt extrusion technology to advance drug delivery in the 21st century.

PubMed

Tiwari, Roshan V; Patil, Hemlata; Repka, Michael A

2016-01-01

Hot-melt extrusion (HME) technology is applied successfully in the plastic, rubber and food industry. HME has also emerged as an important technology for drug delivery applications in pharmaceutical research and manufacturing because of its process automation and low-cost scale-up properties, which reduce labor costs and capital investment. There are a number of commercial FDA-approved HME-derived products, signifying the commercial feasibility of this novel technique in drug delivery applications. HME is a highly efficient, solvent-free continuous processing technique for the development of solid dispersions; thus, research efforts to develop sustained, modified and targeted drug delivery systems to improve the solubility and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) are of interest. This review focuses on both the innovations and applications of HME in the production of pharmaceutical formulations, and on the significant findings of the general principles regarding formulation and process development via HME as described in published articles. Challenges faced by pharmaceutical companies to produce efficient drug formulations may be partly overcome by HME's advantages - high drug-loading capacity, good content uniformity, cost-effectiveness, and ease of processing scale-up. Nevertheless, HME's high processing temperatures may be an obstacle if adequate knowledge about the product's formulation is lacking.

Optimization of controlled release nanoparticle formulation of verapamil hydrochloride using artificial neural networks with genetic algorithm and response surface methodology.

PubMed

Li, Yongqiang; Abbaspour, Mohammadreza R; Grootendorst, Paul V; Rauth, Andrew M; Wu, Xiao Yu

2015-08-01

This study was performed to optimize the formulation of polymer-lipid hybrid nanoparticles (PLN) for the delivery of an ionic water-soluble drug, verapamil hydrochloride (VRP) and to investigate the roles of formulation factors. Modeling and optimization were conducted based on a spherical central composite design. Three formulation factors, i.e., weight ratio of drug to lipid (X1), and concentrations of Tween 80 (X2) and Pluronic F68 (X3), were chosen as independent variables. Drug loading efficiency (Y1) and mean particle size (Y2) of PLN were selected as dependent variables. The predictive performance of artificial neural networks (ANN) and the response surface methodology (RSM) were compared. As ANN was found to exhibit better recognition and generalization capability over RSM, multi-objective optimization of PLN was then conducted based upon the validated ANN models and continuous genetic algorithms (GA). The optimal PLN possess a high drug loading efficiency (92.4%, w/w) and a small mean particle size (∼100nm). The predicted response variables matched well with the observed results. The three formulation factors exhibited different effects on the properties of PLN. ANN in coordination with continuous GA represent an effective and efficient approach to optimize the PLN formulation of VRP with desired properties. Copyright © 2015 Elsevier B.V. All rights reserved.

Isolation, characterization and investigation of Plantago ovata husk polysaccharide as superdisintegrant.

PubMed

Pawar, Harshal; Varkhade, Chhaya

2014-08-01

Psyllium husk (Plantago ovata, Family: Plantaginaceae) contains a high proportion of hemicellulose, composed of a xylan backbone linked with arabinose, rhamnose, and galacturonic acid units (arabinoxylans). Polysaccharide was isolated from Psyllium husk using solvent precipitation method. The isolated polysaccharide was evaluated for various physicochemical parameters. The rheological behavior of polysaccharide (1% w/v in water) was studied using Brookfield viscometer. Polysaccharide derived from the husk of P. ovata was investigated as superdisintegrant in the fast dissolving tablets. Valsartan, an antihypertensive drug, was selected as a model drug. The tablets of Valsartan were prepared separately using different concentrations (1, 2.5, 5, 7.5% w/w) of isolated Plantago ovata (P. ovata) husk polysaccharide (Natural) and crospovidone as a synthetic superdisintegrant by direct compression method. The prepared tablets were evaluated for various pre-compression and post-compression parameters. The drug excipient interactions were characterized by FTIR studies. The formulation F4 containing7.5% polysaccharide showed rapid wetting time and disintegration time as compared to formulation prepared using synthetic superdisintegrant at the same concentration level. Hence batch F4 was considered as optimized formulation. The stability studies were performed on formulation F4. The disintegration time and in vitro drug release of the optimized formulation was compared with the marketed formulation (Conventional tablets). Copyright © 2014 Elsevier B.V. All rights reserved.

Thiolated chitosans: design and in vivo evaluation of a mucoadhesive buccal peptide drug delivery system.

PubMed

Langoth, Nina; Kahlbacher, Hermann; Schöffmann, Gudrun; Schmerold, Ivo; Schuh, Maximilian; Franz, Sonja; Kurka, Peter; Bernkop-Schnürch, Andreas

2006-03-01

Intravenous application of pituitary adenylate cyclase-activating polypeptide (PACAP) has been identified as a promising strategy for the treatment of type 2 diabetes. To generate a more applicable formulation, it was the aim of this study to develop a sustained buccal delivery system for this promising therapeutic peptide. 2-Iminothiolane was covalently bound to chitosan to improve the mucoadhesive and permeation-enhancing properties of chitosan used as drug carrier matrix. The resulting chitosan-4-thiobutylamidine conjugate was homogenized with the enzyme inhibitor and permeation mediator glutathione (gamma-Glu-Cys-Gly), Brij 35, and PACAP (formulation A). The mixture was lyophilized and compressed into flat-faced discs (18 mm in diameter). One formulation was additionally coated on one side with palm wax (formulation B). Tablets consisting of unmodified chitosan and PACAP (formulation C) or of unmodified chitosan, Brij 35, and PACAP (formulation D) served as controls. Bioavailability studies were performed in pigs by buccal administration of these test formulations. Blood samples were analyzed via an ELISA method. Formulations A and B led to an absolute bioavailability of 1%, whereas PACAP did not reach the systemic circulation when administered via formulations C and D. Moreover, in the case of formulations A and B, a continuously raised plasma level of the peptide drug being in the therapeutic range could be maintained over the whole period of application (6 h). Formulations A and B were removed by moderate force from the buccal mucosa after 6 h, whereas formulations C and D detached from the mucosa 4 h after application. The study reveals this novel mucoadhesive delivery system to be a promising approach for buccal delivery of PACAP.

Investigating the Impact of Drug Crystallinity in Amorphous Tacrolimus Capsules on Pharmacokinetics and Bioequivalence Using Discriminatory In Vitro Dissolution Testing and Physiologically Based Pharmacokinetic Modeling and Simulation.

PubMed

Purohit, Hitesh S; Trasi, Niraj S; Sun, Dajun D; Chow, Edwin C Y; Wen, Hong; Zhang, Xinyuan; Gao, Yi; Taylor, Lynne S

2018-05-01

Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or on storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both United States Pharmacopeia and noncompendial dissolution tests with different dissolution media and volumes. A physiologically based pharmacokinetic (PBPK) absorption model was developed to predict the impact of crystallinity extent on the oral absorption of the products and to evaluate the discriminatory ability of the different dissolution methods. Virtual bioequivalence simulations between partially crystallized tacrolimus capsules versus fresh Prograf or generic tacrolimus capsules were performed using the PBPK model and in vitro dissolution data of the various fresh and partially crystallized capsules under United States Pharmacopeia and noncompendial dissolution conditions. The results suggest that compendial dissolution tests may not be sufficiently discriminatory with respect to the presence of crystallinity in an amorphous formulation. Nonsink dissolution tests using lower dissolution volumes generate more discriminatory profiles that predict different pharmacokinetics of tacrolimus capsules containing different extents of drug crystallinity. In conclusion, the PBPK modeling approach can be used to assess the impact of partial drug crystallinity in the formulated product and to guide the development of appropriate dissolution methods. Copyright © 2018 American Pharmacists Association®. All rights reserved.

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

PubMed Central

Rashid, Rehmana; Kim, Dong Wuk; Yousaf, Abid Mehmood; Mustapha, Omer; Din, Fakhar ud; Park, Jong Hyuck; Yong, Chul Soon; Oh, Yu-Kyoung; Youn, Yu Seok; Kim, Jong Oh; Choi, Han-Gon

2015-01-01

Background The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability. Methods For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pseudoternary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder. Results The drug existed in the crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 µm, respectively. All of these formulations significantly improved the aqueous solubility and dissolution in the order of solid SNEDDS ≥ SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability. Conclusion Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility. PMID:26491288

Naproxen Microparticulate Systems Prepared Using In Situ Crystallisation and Freeze-Drying Techniques.

PubMed

Solaiman, Amanda; Tatari, Adam Keenan; Elkordy, Amal Ali

2017-07-01

Poor drug solubility and dissolution rate remain to be one of the major problems facing pharmaceutical scientists, with approximately 40% of drugs in the industry categorised as practically insoluble or poorly water soluble. This in turn can lead to serious delivery challenges and poor bioavailability. The aim of this research was to investigate the effects of the surfactants, poloxamer 407 (P407) and caprol® PGE 860 (CAP), at various concentrations (0.1, 0.5, 1 and 3% w/v) on the enhancement of the dissolution properties of poorly water-soluble drug, naproxen, using in situ micronisation by solvent change method and freeze-drying. The extent at which freeze-drying influences the dissolution rate of naproxen microcrystals is investigated in this study by comparison with desiccant-drying. All formulations were evaluated and characterised using particle size analysis and morphology, in vitro dissolution studies, differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy. An increase in poloxamer 407 concentration in freeze-dried formulations led to enhancement of drug dissolution compared to desiccator-dried formulations, naproxen/caprol® PGE 860 formulations and untreated drug. DSC and FT-IR results show no significant chemical interactions between drug and poloxamer 407, with only very small changes to drug crystallinity. On the other hand, caprol® PGE 860 showed some interactions with drug components, alterations to the crystal lattice of naproxen, and poor dissolution profiles using both drying methods, making it a poor choice of excipient.

Computer-Assisted Drug Formulation Design: Novel Approach in Drug Delivery.

PubMed

Metwally, Abdelkader A; Hathout, Rania M

2015-08-03

We hypothesize that, by using several chemo/bio informatics tools and statistical computational methods, we can study and then predict the behavior of several drugs in model nanoparticulate lipid and polymeric systems. Accordingly, two different matrices comprising tripalmitin, a core component of solid lipid nanoparticles (SLN), and PLGA were first modeled using molecular dynamics simulation, and then the interaction of drugs with these systems was studied by means of computing the free energy of binding using the molecular docking technique. These binding energies were hence correlated with the loadings of these drugs in the nanoparticles obtained experimentally from the available literature. The obtained relations were verified experimentally in our laboratory using curcumin as a model drug. Artificial neural networks were then used to establish the effect of the drugs' molecular descriptors on the binding energies and hence on the drug loading. The results showed that the used soft computing methods can provide an accurate method for in silico prediction of drug loading in tripalmitin-based and PLGA nanoparticulate systems. These results have the prospective of being applied to other nano drug-carrier systems, and this integrated statistical and chemo/bio informatics approach offers a new toolbox to the formulation science by proposing what we present as computer-assisted drug formulation design (CADFD).

Continuous production of fenofibrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic study based on a quality by design approach.

PubMed

Patil, Hemlata; Feng, Xin; Ye, Xingyou; Majumdar, Soumyajit; Repka, Michael A

2015-01-01

This contribution describes a continuous process for the production of solid lipid nanoparticles (SLN) as drug-carrier systems via hot-melt extrusion (HME). Presently, HME technology has not been used for the manufacturing of SLN. Generally, SLN are prepared as a batch process, which is time consuming and may result in variability of end-product quality attributes. In this study, using Quality by Design (QbD) principles, we were able to achieve continuous production of SLN by combining two processes: HME technology for melt-emulsification and high-pressure homogenization (HPH) for size reduction. Fenofibrate (FBT), a poorly water-soluble model drug, was incorporated into SLN using HME-HPH methods. The developed novel platform demonstrated better process control and size reduction compared to the conventional process of hot homogenization (batch process). Varying the process parameters enabled the production of SLN below 200 nm. The dissolution profile of the FBT SLN prepared by the novel HME-HPH method was faster than that of the crude FBT and a micronized marketed FBT formulation. At the end of a 5-h in vitro dissolution study, a SLN formulation released 92-93% of drug, whereas drug release was approximately 65 and 45% for the marketed micronized formulation and crude drug, respectively. Also, pharmacokinetic study results demonstrated a statistical increase in Cmax, Tmax, and AUC0-24 h in the rate of drug absorption from SLN formulations as compared to the crude drug and marketed micronized formulation. In summary, the present study demonstrated the potential use of hot-melt extrusion technology for continuous and large-scale production of SLN.

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH.

PubMed

Rashid, Jahidur; Alobaida, Ahmad; Al-Hilal, Taslim A; Hammouda, Samia; McMurtry, Ivan F; Nozik-Grayck, Eva; Stenmark, Kurt R; Ahsan, Fakhrul

2018-06-28

Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH. Copyright © 2018 Elsevier B.V. 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.

QbD-Oriented Development and Characterization of Effervescent Floating-Bioadhesive Tablets of Cefuroxime Axetil.

PubMed

Bansal, Sanjay; Beg, Sarwar; Garg, Babita; Asthana, Abhay; Asthana, Gyati S; Singh, Bhupinder

2016-10-01

The objective of the present studies was systematic development of floating-bioadhesive gastroretentive tablets of cefuroxime axetil employing rational blend of hydrophilic polymers for attaining controlled release drug delivery. As per the QbD-based approach, the patient-centric target product profile and quality attributes of tablet were earmarked, and preliminary studies were conducted for screening the suitability of type of polymers, polymer ratio, granulation technique, and granulation time for formulation of tablets. A face-centered cubic design (FCCD) was employed for optimization of the critical material attributes, i.e., concentration of release controlling polymers, PEO 303 and HPMC K100 LV CR, and evaluating in vitro buoyancy, drug release, and ex vivo mucoadhesion strength. The optimized formulation was embarked upon through numerical optimization, which yield excellent floatation characteristic with drug release control (i.e., T 60% > 6 h) and bioadhesion strength. Drug-excipient compatibility studies through FTIR and P-XRD revealed the absence of any interaction between the drug and polymers. In vivo evaluation of the gastroretentive characteristics through X-ray imaging and in vivo pharmacokinetic studies in rabbits revealed significant extension in the rate of drug absorption (i.e., T max, K a, and MRT) from the optimized tablet formulation as compared to the marketed formulation. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC) substantiated high degree of prognostic ability of in vitro dissolution conditions in predicting the in vivo performance. In a nutshell, the studies demonstrate successful development of the once-a-day gastroretentive formulations of cefuroxime axetil with controlled drug release profile and improved compliance.

Development and evaluation of orally disintegrating tablets comprising taste-masked mirtazapine granules.

PubMed

Yıldız, Simay; Aytekin, Eren; Yavuz, Burçin; Bozdağ Pehlivan, Sibel; Vural, İmran; Ünlü, Nurşen

2018-06-01

Orally disintegrating tablets (ODTs) provide an important treatment option for pediatric, geriatric and psychiatric patients. In our previous study, we have performed the initial studies for the formulation development and characterization of new ODT formulations containing a bitter taste drug, mirtazapine, coated with 6% (w/w) Eudragit ® E-100 (first group of formulations, FGF) without taste evaluation. In present study, coating ratio of the drug was increased to 8% (w/w) (second group of formulations, SGF) to examine the effect of increased coating ratio of drug on in vitro characterization of the formulations including in vitro taste masking study. Coacervation technique using Eudragit ® E-100 was employed to obtain taste-masked mirtazapine granules. FGF and SGF were compared to original product (Remeron SolTab, an antidepressant drug which produced by pellet technology) in terms of in vitro permeability, in vitro taste masking efficiency which was performed by dissolution studies in salivary medium and dissolution stability. Also, the other tablet characteristics (such as diameter, thickness) of SGF were examined. The disintegration time of the SGF were found as A1 < A2 < A3 < A5 < A4 (8% Eudragit ® E-100), but all of the formulations dissolved under 30 seconds and friability values were less than 1%. In vitro taste masking efficiency studies demonstrated that C2 formulation (in FGF) had the most similar dissolution profile to Remeron SolTab. According to these findings, B2 or C2 (with citric acid or sodium bicarbonate, respectively, with 6% Eudragit ® E-100) formulations could be promising alternatives to Remeron SolTab.

Long-Circulating Curcumin-Loaded Liposome Formulations with High Incorporation Efficiency, Stability and Anticancer Activity towards Pancreatic Adenocarcinoma Cell Lines In Vitro.

PubMed

Mahmud, Mohamed; Piwoni, Adriana; Filipczak, Nina; Janicka, Martyna; Gubernator, Jerzy

2016-01-01

The incorporation of hydrophobic drugs into liposomes improve their bioavailability and leads to increased stability and anticancer activity, along with decreased drug toxicity. Curcumin (Cur) is a natural polyphenol compound with a potent anticancer activity in pancreatic adenocarcinoma (PA). In the present study, different types of Cur-loaded liposomal formulations were prepared and characterized in terms of size, shape, zeta potential, optimal drug-to-lipid ratio and stability at 4°C, 37°C; and in human plasma in vitro. The best formulation in terms of these parameters was PEGylated, cholesterol-free formulation based upon hydrogenated soya PC (HSPC:DSPE-PEG2000:Cur, termed H5), which had a 0.05/10 molar ratio of drug-to-lipid, was found to be stable and had a 96% Cur incorporation efficiency. All Cur-loaded liposomal formulations had potent anticancer activity on the PA cancer cell lines AsPC-1 and BxPC-3, and were less toxic to a normal cell line (NHDF). Furthermore, apoptosis-induction induced by Cur in PA cells was associated with morphological changes including cell shrinkage, cytoplasmic blebbing, irregularity in shape and the externalization of cell membrane phosphatidylserine, which was preceded by an increase in intracellular reactive oxygen species (ROS) generation and caspase 3/7 activation. Because the liposomal formulations tested here, especially the H5 variant which exhibited slow release of the Cur in the human plasma test, the formulation may be stable enough to facilitate the accumulation of pharmacologically active amounts of Cur in target cancer tissue by EPR. Therefore, our formulations could serve as a promising therapeutic approach for pancreatic cancer and other cancers.

Mucoadhesive Microparticles in a Rapidly Dissolving Tablet for Sustained Drug Delivery to the Eye

PubMed Central

Choy, Young Bin; Patel, Samirkumar R.; Park, Jung-Hwan; McCarey, Bernard E.; Edelhauser, Henry F.

2011-01-01

Purpose. To test the hypothesis that mucoadhesive microparticles formulated in a rapidly dissolving tablet can achieve sustained drug delivery to the eye. Methods. Mucoadhesive microparticles, smaller than 5 μm were fabricated with poly(lactic-co-glycolic acid) and poly(ethylene glycol) as a core material and mucoadhesion promoter, respectively, and encapsulated pilocarpine as a model drug. These microparticles were embedded in a poly(vinyl alcohol) matrix to form a dry tablet designed to reduce rapid clearance of the microparticles on initial application to the eye. Results. This in vitro drug release study exhibited that for all formulations, approximately 90% of pilocarpine was released during the first 10 minutes, and the remaining 10% was released slowly for 3 hours. In vivo mucoadhesion test on the rabbit eye indicated that mucoadhesive microparticles adhered significantly better to the preocular surface than other formulations. To assess the pharmacodynamics, the most prolonged pilocarpine-induced pupil constriction was observed in rabbit eyes in vivo using a tablet with mucoadhesive microparticles; it lasted up to 330 minutes. Conclusions. The authors conclude that mucoadhesive microparticles formulated into a dry dosage form is a promising system for sustained drug delivery to the eye. PMID:21245405

Development and Application of a High-Performance Liquid Chromatography Stability-Indicating Assay for Beyond-Use Date Determination of Compounded Topical Gels Containing Multiple Active Drugs.

PubMed

Gorman, Gregory; Sokom, Simara; Coward, Lori; Arnold, John J

2017-01-01

Topical gels compounded by pharmacists are important clinical tools for the management of pain. Nevertheless, there is often a dearth of information about the chemical stability of drugs included in these topical formulations, complicating the assignment of beyond-use dating. The purpose of this study was to develop a high-performance liquid chromatography photodiode array-based stability-indicating assay that could simultaneously resolve six drugs (amitriptyline, baclofen, clonidine, gabapentin, ketoprofen, lidocaine) commonly included in topical gels for pain management and their potential degradation products. Furthermore, this method was applied to the determination of beyond-use dating of combinations of these drugs prepared in commonly utilized bases (Lipobase, Lipoderm, Pluronic organogel). Gabapentin was determined to be the least stable component in all formulations tested. Measured stability ranged between 7 to 49 days depending on the base and other active drugs present in the formulation. In the absence of gabapentin, baclofen was the next least stable component, lasting for 120 days, regardless of the type of formulating base used. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

PEG-PE/clay composite carriers for doxorubicin: Effect of composite structure on release, cell interaction and cytotoxicity.

PubMed

Kohay, Hagay; Sarisozen, Can; Sawant, Rupa; Jhaveri, Aditi; Torchilin, Vladimir P; Mishael, Yael G

2017-06-01

A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was developed. DOX was incorporated in micelles (M-DOX) of polyethylene glycol-phosphatidylethanolamine (PEG-PE) which in turn were adsorbed by the clay, montmorillonite (MMT). The nano-structures of the PEG-PE/MMT composites of LOW and HIGH polymer loadings were characterized by XRD, TGA, FTIR, size (DLS) and zeta measurements. These measurements suggest that for the LOW composite a single layer of polymer intercalates in the clay platelets and the polymer only partially covers the external surface, while for the HIGH composite two layers of polymer intercalate and a bilayer may form on the external surface. These nanostructures have a direct effect on formulation stability and on the rate of DOX release. The release rate was reversely correlated with the degree of DOX interaction with the clay and followed the sequence: M-DOX>HIGH formulation>LOW formulation>DOX/MMT. Despite the slower release from the HIGH formulation, its cytotoxicity effect on sensitive cells was as high as the "free" DOX. Surprisingly, the LOW formulation, with the slowest release, demonstrated the highest cytotoxicity in the case of Adriamycin (ADR) resistant cells. Confocal microscopy images and association tests provided an insight into the contribution of formulation-cell interactions vs. the contribution of DOX release rate. Internalization of the formulations was suggested as a mechanism that increases DOX efficiency, particularly in the ADR resistant cell line. The employment of organic-inorganic hybrid materials as drug delivery systems, has not reached its full potential, however, its functionality as an efficient tunable release system was demonstrated. DOX PEG-PE/clay formulations were design as an efficient drug delivery system. The main aim was to develop PEG-PE/clay formulations of different structures based on various PEG-PE/clay ratios in order to achieve tunable release rates, to control the external surface characteristics and formulation stability. The formulations showed significantly higher toxicity in comparison to "free" DOX, explained by formulation internalization. For each cell line tested, sensitive and ADR resistant, a different formulation structure was found most efficient. The potential of PEG-PE/clay-DOX formulations to improve DOX administration efficacy was demonstrated and should be further explored and implemented for other cancer drugs and cells. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Formulation of multifunctional oil-in-water nanosized emulsions for active and passive targeting of drugs to otherwise inaccessible internal organs of the human body.

PubMed

Tamilvanan, Shunmugaperumal

2009-10-20

Oil-in-water (o/w) type nanosized emulsions (NE) have been widely investigated as vehicles/carrier for the formulation and delivery of drugs with a broad range of applications. A comprehensive summary is presented on how to formulate the multifunctional o/w NE for active and passive targeting of drugs to otherwise inaccessible internal organs of the human body. The NE is classified into three generations based on its development over the last couple of decades to make ultimately a better colloidal carrier for a target site within the internal and external organs/parts of the body, thus allowing site-specific drug delivery and/or enhanced drug absorption. The third generation NE has tremendous application for drug absorption enhancement and for 'ferrying' compounds across cell membranes in comparison to its first and second generation counterparts. Furthermore, the third generation NE provides an interesting opportunity for use as drug delivery vehicles for numerous therapeutics that can range in size from small molecules to macromolecules.

Peptides, proteins and peptide/protein-polymer conjugates as drug delivery system.

PubMed

Mukherjee, Biswajit; Karmakar, Swapna D; Hossain, Chowdhury M; Bhattacharya, Sanchari

2014-01-01

In the last few decades, novel drug delivery strategies have been a big priority to the formulation scientists. Peptides and proteins have drawn a special attention for their wide scope in the area. Serum albumin, transferrin, recom- binant proteins, virus capsids etc. are used as carrier for drug and biomolecules. Conjugates of polymers with proteins have also shown strong potency in the field of drug delivery. Polyethylene glycol is one of the most successful polymers that has been used extensively to develop protein conjugated formulations. Besides, polyvinyl pyrrolidone, polylactic-co- glycolic acid, N-(2-hydroxypropyl) methacrylamide copolymer, polyglutamic acid have also been investigated. In this re- view, we will highlight on the most recent overview of various advantages, limitations and marketed products of proteins, peptides and protein/peptide-polymer conjugates as drug carriers, such products in clinical trials and their various uses in the field of modern drug delivery. Understanding the key features of these materials and the vigorous research in this field will develop new drug formulations that will combat various types of life-threatening diseases.

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.

Formulation and pharmacokinetics of diclofenac lipid nanoemulsions for parenteral application.

PubMed

Ramreddy, Srividya; Kandadi, Prabhakar; Veerabrahma, Kishan

2012-01-01

The objective of the present study was to formulate and determine the pharmacokinetics of stable o/w parenteral lipid nanoemulsions (LNEs) of diclofenac acid used to treat arthritic conditions. The LNEs of diclofenac acid with a mean size ranging from 200 to 240 nm and a zeta potential of -29.4 ± 1.04 mV (negatively charged LNEs) and 62.1 ± 3.5 (positively charged LNEs) emulsions were prepared by hot homogenization and ultrasonication process. The influence of formulation variables, such as the change in proportion of cholesterol, was studied, and optimized formulations were developed. The optimized formulations were relatively stable during centrifugal stress, dilution stress, and storage. The drug content and entrapment efficiency were determined using high-performance liquid chromatography. The in vitro drug release was carried out in phosphate-buffered saline pH 7.4 and cumulative amount of drug released was estimated using a UV-visible spectro-photometer. During in vivo pharmacokinetic studies in male Wistar rats, diclofenac serum concentration from LNEs was higher than that of Voveran injection and was detectable up to 12 h. Diclofenac in LNEs showed improved pharmacokinetic profile with increase in area under the curve, elimination half-life and mean residence time in comparison to Voveran. Our aim was to prepare and determine the pharmacokinetics of injectable lipid nanoemulsions of diclofenac acid for treating arthritic conditions by reducing the frequency of dosing and pain at site of injection. The nanoemulsions of diclofenac acid were prepared by homogenization and ultrasonication process. The sizes and charges of oil globules were determined. The effect of cholesterol on stability of emulsion was studied, and an optimized preparation was developed. The optimized formulations were stable during centrifugation, dilution, and storage. The total amount of drug in emulsion and percentage amount of drug present in emulsion globules were determined using high-performance liquid chromatography. The drug release from preparation was carried out in phosphate-buffered saline pH 7.4. The cumulative amount of drug released was estimated using a spectrophotometer. The time course of the released drug in rat serum was determined. Diclofenac concentrations from lipid nanoemulsions were higher than that of Voveran injection (solution form) in serum.

Ex vivo localization and permeation of cisplatin from novel topical formulations through excised pig, goat, and mice skin and in vitro characterization for effective management of skin-cited malignancies.

PubMed

Gupta, Vandana; Trivedi, Piyush

2015-01-01

It would be advantageous to administer cisplatin topically for treatment of cutaneous malignancies. Present work focuses on ex vivo and in vitro characterization of proultraflexible topical formulations. Permeation of cisplatin through the excised pig, goat, and mice skin was quantitatively determined. Data indicate that protransfersome carbopol gel (pcg) formulation clearly delayed drug permeation through skin. Permeation of cisplatin from protransfersome system (ps) formulation was enhanced by approximately 1.5 fold compared with pcg for pig and goat skin. Localization of drug from pcg was higher and showed less permeation. Cisplatin-loaded pcg formulation is better to treat cutaneous malignancies.

Pectin-based oral drug delivery to the colon.

PubMed

Sande, Sverre Arne

2005-05-01

This review presents an overview of studies concerning oral formulations intended for site-specific drug delivery to the colon with pectin as the main excipient. The biological aspects covered include gastrointestinal transit and the enzymatic degradation of pectin. Scintigraphic methods demonstrating the functionality of pectin formulations are discussed. The main focus is on the various formulations reported, including matrix tablets, multiparticulate formulations as pellets and hydrogel beads, and pectin-based coatings. Also included is an evaluation of common excipients employed to improve colon specificity by crosslinking or increasing the hydrophobicity. Finally, properties of the pectin molecules that are important for successful formulations are examined. The conclusion is that the studies found in the literature provide an excellent platform for the development of pectin-based colon delivery systems.

Improved Skin Penetration Using In Situ Nanoparticulate Diclofenac Diethylamine in Hydrogel Systems: In Vitro and In Vivo Studies.

PubMed

Sengupta, Soma; Banerjee, Sarita; Sinha, Biswadip; Mukherjee, Biswajit

2016-04-01

Delivering diclofenac diethylamine transdermally by means of a hydrogel is an approach to reduce or avoid systemic toxicity of the drug while providing local action for a prolonged period. In the present investigation, a process was developed to produce nanosize particles (about 10 nm) of diclofenac diethylamine in situ during the development of hydrogel, using simple mixing technique. Hydrogel was developed with polyvinyl alcohol (PVA) (5.8% w/w) and carbopol 71G (1.5% w/w). The formulations were evaluated on the basis of field emission scanning electron microscopy, texture analysis, and the assessment of various physiochemical properties. Viscosity (163-165 cps for hydrogel containing microsize drug particles and 171-173 cps for hydrogel containing nanosize drug particles, respectively) and swelling index (varied between 0.62 and 0.68) data favor the hydrogels for satisfactory topical applications. The measured hardness of the different hydrogels was uniform indicating a uniform spreadability. Data of in vitro skin (cadaver) permeation for 10 h showed that the enhancement ratios of the flux of the formulation containing nanosize drug (without the permeation enhancer) were 9.72 and 1.30 compared to the formulation containing microsized drug and the marketed formulations, respectively. In vivo plasma level of the drug increased predominantly for the hydrogel containing nanosize drug-clusters. The study depicts a simple technique for preparing hydrogel containing nanosize diclofenac diethylamine particles in situ, which can be commercially viable. The study also shows the advantage of the experimental transdermal hydrogel with nanosize drug particles over the hydrogel with microsize drug particles.

Complexity of intravenous iron nanoparticle formulations: implications for bioequivalence evaluation.

PubMed

Pai, Amy Barton

2017-11-01

Intravenous iron formulations are a class of complex drugs that are commonly used to treat a wide variety of disease states associated with iron deficiency and anemia. Venofer® (iron-sucrose) is one of the most frequently used formulations, with more than 90% of dialysis patients in the United States receiving this formulation. Emerging data from global markets outside the United States, where many iron-sucrose similars or copies are available, have shown that these formulations may have safety and efficacy profiles that differ from the reference listed drug. This may be attributable to uncharacterized differences in physicochemical characteristics and/or differences in labile iron release. As bioequivalence evaluation guidance evolves, clinicians should be educated on these potential clinical issues before a switch to the generic formulation is made in the clinical setting. © 2017 New York Academy of Sciences.

Inhaled Micro/Nanoparticulate Anticancer Drug Formulations: An Emerging Targeted Drug Delivery Strategy for Lung Cancers.

PubMed

Islam, Nazrul; Richard, Derek

2018-05-24

Local delivery of drug to the target organ via inhalation offers enormous benefits in the management of many diseases. Lung cancer is the most common of all cancers and it is the leading cause of death worldwide. Currently available treatment systems (intravenous or oral drug delivery) are not efficient in accumulating the delivered drug into the target tumor cells and are usually associated with various systemic and dose-related adverse effects. The pulmonary drug delivery technology would enable preferential accumulation of drug within the cancer cell and thus be superior to intravenous and oral delivery in reducing cancer cell proliferation and minimising the systemic adverse effects. Site-specific drug delivery via inhalation for the treatment of lung cancer is both feasible and efficient. The inhaled drug delivery system is non-invasive, produces high bioavailability at low dose and avoids first pass metabolism of the delivered drug. Various anticancer drugs including chemotherapeutics, proteins and genes have been investigated for inhalation in lung cancers with significant outcomes. Pulmonary delivery of drugs from dry powder inhaler (DPI) formulation is stable and has high patient compliance. Herein, we report the potential of pulmonary drug delivery from dry powder inhaler (DPI) formulations inhibiting lung cancer cell proliferation at very low dose with reduced unwanted adverse effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Application of a handheld NIR spectrometer in prediction of drug content in inkjet printed orodispersible formulations containing prednisolone and levothyroxine.

PubMed

Vakili, Hossein; Wickström, Henrika; Desai, Diti; Preis, Maren; Sandler, Niklas

2017-05-30

Quality control tools to assess the quality of printable orodispersible formulations are yet to be defined. Four different orodispersible dosage forms containing two poorly soluble drugs, levothyroxine and prednisolone, were produced on two different edible substrates by piezoelectric inkjet printing. Square shaped units of 4cm 2 were printed in different resolutions to achieve an escalating drug dose by highly accurate and uniform displacement of droplets in picoliter range from the printhead onto the substrates. In addition, the stability of drug inks in a course of 24h as well as the mechanical properties and disintegration behavior of the printed units were examined. A compact handheld near-infrared (NIR) spectral device in the range of 1550-1950nm was used for quantitative estimation of the drug amount in printed formulations. The spectral data was treated with mean centering, Savitzky-Golay filtering and a third derivative approach. Principal component analysis (PCA) and orthogonal partial least squares (OPLS) regression were applied to build predictive models for quality control of the printed dosage forms. The accurate tuning of the dose in each formulation was confirmed by UV spectrophotometry for prednisolone (0.43-1.95mg with R 2 =0.999) and high performance liquid chromatography for levothyroxine (0.15-0.86mg with R 2 =0.997). It was verified that the models were capable of clustering and predicting the drug dose in the formulations with both Q 2 and R 2 Y values between 0.94-0.99. Copyright © 2017 Elsevier B.V. All rights reserved.

Investigation of in situ gelling alginate formulations as a sustained release vehicle for co-precipitates of dextromethrophan and Eudragit S 100.

PubMed

El Maghraby, Gamal Mohamed; Elzayat, Ehab Mostafa; Alanazi, Fars Kaed

2014-03-01

Alginate vehicles are capable of forming a gel matrix in situ when they come into contact with gastric medium in the presence of calcium ions. However, the gel structure is pH dependent and can break after gastric emptying, leading to dose dumping. The aim of this work was to develop modified in situ gelling alginate formulations capable of sustaining dextromethorphan release throughout the gastrointestinal tract. Alginate solution (2 %, m/m) was used as a vehicle for the tested formulations. Solid matrix of the drug and Eudragit S 100 was prepared by dissolving the drug and polymer in acetone. The organic solvent was then evaporated and the deposited solid matrix was micronized, sieved and dispersed in alginate solution to obtain candidate formulations. The release behavior of dextromethorphan was monitored and evaluated in a medium simulating the gastric and intestinal pH. Drug-polymer compatibility and possible solid-state interactions suggested physical interaction through hydrogen bonding between the drug and the polymer. A significant decrease in the rate and extent of dextromethorphan release was observed with increasing Eudragit S 100 concentration in the prepared particles. Most formulations showed sustained release profiles similar to that of a commercial sustained-release liquid based on ion exchange resin. The release pattern indicated strict control of drug release both under gastric and intestinal conditions, suggesting the potential advantage of using a solid dispersion of drug-Eudragit S 100 to overcome the problem of dose dumping after the rupture of the pH dependent alginate gels.

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

Current HPLC Methods for Assay of Nano Drug Delivery Systems.

PubMed

Tekkeli, Serife Evrim Kepekci; Kiziltas, Mustafa Volkan

2017-01-01

In nano drug formulations the mechanism of release is a critical process to recognize controlled and targeted drug delivery systems. In order to gain high bioavailability and specificity from the drug to reach its therapeutic goal, the active substance must be loaded into the nanoparticles efficiently. Therefore, the amount in biological fluids or tissues and the remaining amount in nano carriers are very important parameters to understand the potential of the nano drug delivery systems. For this aim, suitable and validated quantitation methods are required to determine released drug concentrations from nano pharmaceutical formulations. HPLC (High Performance Liquid Chromatography) is one of the most common techniques used for determination of released drug content out of nano drug formulations, in different physical conditions, over different periods of time. Since there are many types of HPLC methods depending on detector and column types, it is a challenge for the researchers to choose a suitable method that is simple, fast and validated HPLC techniques for their nano drug delivery systems. This review's goal is to compare HPLC methods that are currently used in different nano drug delivery systems in order to provide detailed and useful information for researchers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Co-formulation of P-glycoprotein Substrate and Inhibitor in Nanocarriers: An Emerging Strategy for Cancer Chemotherapy.

PubMed

Saneja, Ankit; Dubey, Ravindra Dhar; Alam, Noor; Khare, Vaibhav; Gupta, Prem N

2014-01-01

Scientific community is striving to understand the role of P-glycoprotein (P-gp) in drug discovery programs due to its impact on pharmacokinetic and multi-drug resistance (MDR) of anticancer drugs. A number of efforts to resolve the crystal structure and understanding the mechanism of P-gp mediated efflux have been made. Several generations of Pgp inhibitors have been developed to tackle this multi-specific efflux protein. Unfortunately, these inhibitors lack selectivity, exhibit poor solubility and severe pharmacokinetic interactions restricting their clinical use. The nanocarrier drug delivery systems (NDDS) are receiving increasing attention for P-gp modulating activity of pharmaceutical excipients which are used in their fabrication. In addition, NDDS can enhance the solubility and exhibited ability to bypass P-gp mediated efflux. The co-formulation of P-gp inhibitors and substrate anticancer drugs in single drug delivery system offers the advantage of bypassing P-gp mediated drug efflux as well as inhibiting the P-gp. Moreover, severe pharmacokinetic interactions between P-gp inhibitor and substrate anticancer drugs could be avoided by using this strategy. In this article we describe the co-formulation strategies using nanocarriers for modulation of pharmacokinetics as well as multi-drug resistance of anticancer drugs along with the challenges in this area.

[Optimization and characterization of curcumin-piperine dual drug loaded self-microemulsifying drug delivery system by simplex lattice design].

PubMed

Li, Qiu-Ping; Dai, Jun-Dong; Zhai, Wen-Wen; Jiang, Qiao-Li

2014-10-01

The objective of the study was to prepare and evaluate the quality of curcumin-piperinedual drug loaded self-microemulsifying drug delivery system(Cur-PIP-SMEDDS). Simplex lattice design was constructed using optimal oil phase, surfactant and co-surfactant concentration as independent variables, and the curcumin and piperine were used as model drugs to optimize Cur-PIP-SMEDDS formulation. In the present study, the drug loadings of curcumin and piperine, mean particle size of Cur-PIP-SMEDDS were made as indicators, and the experiment design, model building and response surface analysis were established using Design Expert 8. 06 software to optimize and verify the composition of SMEDDS formulation. The quality of Cur-PIP-SMEDDS was evaluated by observing the appearance status, transmission electron microscope micrographs and determining particle diameter, electric potential, drug entrapment efficiency and drug loading of it. As a result, the optimal formulation of SMEDDS was CapryoL 90-Cremophor RH40-TranscutoL HP (10:60:30). The appearance of Cur-PIP-SMEDDS remained clarified and transparent, and the microemulsion droplets appeared spherical without aggregation with uniform particle size distribution. The mean size of microemulsion droplet formed from Cur-PIP-SMEDDS was 15.33 nm, the drug loading of SMEDDS for Cur and PIP were 40.90 mg · g(-1) and 0.97 mg · g(-1), respectively, the drug entrapment efficiency were 94.98% and 90.96%, respectively. The results show that Cur-PIP-SMEDDS can increase the solubility and stability of curcumin significantly, in the expectation of enhancing the bioavailability of it. Taken together, these findings can provide the reference to a preferable choice of the Cur formulation and contribute to therapeutic application in clinical research.

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

Development and characterization of nano-fiber patch for the treatment of glaucoma.

PubMed

Gagandeep; Garg, Tarun; Malik, Basant; Rath, Goutam; Goyal, Amit K

2014-03-12

In the present work polymeric nano-fiber patches was developed for the effective treatment of glaucoma using timolol maleate and dorzolamide hydrochloride as model drugs. The nano-fibers were prepared by electrospinning technique and were characterized on the basis of fiber diameter, morphology, entrapment efficiency, mucoadhesive strength, and drug release behavior, etc. Final formulations were inserted in the cul-de-sac of glaucoma induced rabbits and the efficacy of the formulation was evaluated. The results clearly indicated the potential of the developed formulation for occur drug delivery. There was a significant fall in the intraocular pressure compared to commercial eye drops. Copyright © 2013 Elsevier B.V. All rights reserved.

Anti-inflammatory and Antihistaminic Study of a Unani Eye Drop Formulation.

PubMed

Abdul, Latif; Abdul, Razique; Sukul, R R; Nazish, Siddiqui

2010-01-01

The Unani eye drop is an ophthalmic formulation prepared for its beneficial effects in the inflammatory and allergic conditions of the eyes. In the present study, the Unani eye drop formulation was prepared and investigated for its anti-inflammatory and antihistaminic activity, using in vivo and in vitro experimental models respectively. The Unani eye drop formulation exhibited significant anti-inflammatory activity in turpentine liniment-induced ocular inflammation in rabbits. The preparation also showed antihistaminic activity in isolated guinea-pig ileum. The anti-inflammatory and antihistaminic activity of eye drop may be due to presence of active ingredients in the formulation. Although there are many drugs in Unani repository which are mentioned in classical books or used in Unani clinical practice effectively in treatment of eye diseases by various Unani physicians. Inspite of the availability of vast literature, there is a dearth of commercial Unani ocular preparations. So, keeping this in mind, the eye drop formulation was prepared and its anti-inflammatory and antihistaminic activity was carried out in animal models. Thus, in view of the importance of alternative anti-inflammatory and antiallergic drugs, it becomes imperative to bring these indigenous drugs to the front foot and evaluate their activities.

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 1: method parameterization and comparison of in vitro digestion profiles across a range of representative formulations.

PubMed

Williams, Hywel D; Sassene, Philip; Kleberg, Karen; Bakala-N'Goma, Jean-Claude; Calderone, Marilyn; Jannin, Vincent; Igonin, Annabel; Partheil, Anette; Marchaud, Delphine; Jule, Eduardo; Vertommen, Jan; Maio, Mario; Blundell, Ross; Benameur, Hassan; Carrière, Frédéric; Müllertz, Anette; Porter, Christopher J H; Pouton, Colin W

2012-09-01

The Lipid Formulation Classification System Consortium is an industry-academia collaboration, established to develop standardized in vitro methods for the assessment of lipid-based formulations (LBFs). In this first publication, baseline conditions for the conduct of digestion tests are suggested and a series of eight model LBFs are described to probe test performance across different formulation types. Digestion experiments were performed in vitro using a pH-stat apparatus and danazol employed as a model poorly water-soluble drug. LBF digestion (rate and extent) and drug solubilization patterns on digestion were examined. To evaluate cross-site reproducibility, experiments were conducted at two sites and highly consistent results were obtained. In a further refinement, bench-top centrifugation was explored as a higher throughput approach to separation of the products of digestion (and compared with ultracentrifugation), and conditions under which this method was acceptable were defined. Drug solubilization was highly dependent on LBF composition, but poorly correlated with simple performance indicators such as dispersion efficiency, confirming the utility of the digestion model as a means of formulation differentiation. Copyright © 2012 Wiley Periodicals, Inc.

Physicochemical stability of captopril and enalapril extemporaneous formulations for pediatric patients.

PubMed

Casas, Marta; Álvarez, José; Lucero, María Jesús

2015-05-01

The prevalence of hypertension among children has been increasing. Community and Hospital Pharmacists are often challenged to provide an oral liquid extemporaneous formulation for pediatric patients, because there are no appropriate dosage drugs to the specific needs of the child. The objective of this study is to choose and develop suitable pediatric extemporaneous formulations for captopril and enalapril maleate and to determine their physicochemical stability. A survey was carried out to evaluate the extent of dispensation of these drugs in Hospitals in Spain. Stability studies of formulations have been studied according to ICH normative at 5, 25 and 40 °C. Three samples from each temperature were withdrawn and assessed for stability on days 0, 15, 30, 50 and 90 using a high-performance liquid chromatography (HPLC) mass spectrometer assay. Rheological studies were carried out to ensure the maintenance of the physical characteristics of these non-Newtonian fluids. Captopril and enalapril maleate formulations used the pure drug and were stable during 50 days at 5 °C. We have developed easy antihypertensive oral liquid extemporaneous formulations for pediatric patients with physical and chemical stability higher than those provided by the majority of Hospitals.

Development of poloxamer gel formulations via hot-melt extrusion technology.

PubMed

Mendonsa, Nicole S; Murthy, S Narasimha; Hashemnejad, Seyed Meysam; Kundu, Santanu; Zhang, Feng; Repka, Michael A

2018-02-15

Poloxamer gels are conventionally prepared by the "hot" or the "cold" process. But these techniques have some disadvantages such as high energy consumption, requires expensive equipment and often have scale up issues. Therefore, the objective of this work was to develop poloxamer gels by hot-melt extrusion technology. The model drug selected was ketoprofen. The formulations developed were 30% and 40% poloxamer gels. Of these formulations, the 30% poloxamer gels were selected as ideal gels. DSC and XRD studies showed an amorphous nature of the drug after extrusion. It was observed from the permeation studies that with increasing poloxamer concentration, a decrease in drug permeation was obtained. Other studies conducted for the formulations included in-vitro release studies, texture analysis, rheological studies and pH measurements. In conclusion, the hot-melt extrusion technology could be successfully employed to develop poloxamer gels by overcoming the drawbacks associated with the conventional techniques. Published by Elsevier B.V.

Application of mixture experimental design in the formulation and optimization of matrix tablets containing carbomer and hydroxy-propylmethylcellulose.

PubMed

Petrovic, Aleksandra; Cvetkovic, Nebojsa; Ibric, Svetlana; Trajkovic, Svetlana; Djuric, Zorica; Popadic, Dragica; Popovic, Radmila

2009-12-01

Using mixture experimental design, the effect of carbomer (Carbopol((R)) 971P NF) and hydroxypropylmethylcellulose (Methocel((R)) K100M or Methocel((R)) K4M) combination on the release profile and on the mechanism of drug liberation from matrix tablet was investigated. The numerical optimization procedure was also applied to establish and obtain formulation with desired drug release. The amount of TP released, release rate and mechanism varied with carbomer ratio in total matrix and HPMC viscosity. Increasing carbomer fractions led to a decrease in drug release. Anomalous diffusion was found in all matrices containing carbomer, while Case - II transport was predominant for tablet based on HPMC only. The predicted and obtained profiles for optimized formulations showed similarity. Those results indicate that Simplex Lattice Mixture experimental design and numerical optimization procedure can be applied during development to obtain sustained release matrix formulation with desired release profile.

Formulation of thermoresponsive and buccal adhesive in situ gel for treatment of oral thrush containing poorly water soluble drug bifonazole.

PubMed

Patel, Dimendra; Patel, Dipti; Prajapati, Jatin; Patel, Umang; Patel, Vijay

2012-03-01

The aim of the present work is to formulate and evaluate in situ oral topical gels of poorly water soluble drug Bifonazole based on temperature induced systems for the treatment of oral candidiasis. Bifonazole is poorly water soluble and low permeable drug means it's belongs to BCS Class IV. Due to its poor water solubility, it necessary to enhance solubility in water by make complex with Beta- Cyclodextrin (Drug to βCyclo Dextrine ratio is 1:1). After in situ gel preparation done by using Poloxamer (10% and 15%w/w) along with carbopol 934 (0.2 to 1.0% w/w) and Bifonazole - β CD complex (1%w/w). The formulations were evaluated for physiochemical parameter, gelation Temperature, viscosity, gel strength, content uniformity mucoadhesive force, Diffusion Study.

Formulation of thermoresponsive and buccal adhesive in situ gel for treatment of oral thrush containing poorly water soluble drug bifonazole

PubMed Central

Patel, Dimendra; Patel, Dipti; Prajapati, Jatin; Patel, Umang; Patel, Vijay

2012-01-01

The aim of the present work is to formulate and evaluate in situ oral topical gels of poorly water soluble drug Bifonazole based on temperature induced systems for the treatment of oral candidiasis. Bifonazole is poorly water soluble and low permeable drug means it's belongs to BCS Class IV. Due to its poor water solubility, it necessary to enhance solubility in water by make complex with Beta- Cyclodextrin (Drug to βCyclo Dextrine ratio is 1:1). After in situ gel preparation done by using Poloxamer (10% and 15%w/w) along with carbopol 934 (0.2 to 1.0% w/w) and Bifonazole – β CD complex (1%w/w). The formulations were evaluated for physiochemical parameter, gelation Temperature, viscosity, gel strength, content uniformity mucoadhesive force, Diffusion Study. PMID:23066185

Drug delivery strategies for poorly water-soluble drugs.

PubMed

Fahr, Alfred; Liu, Xiangli

2007-07-01

The drug candidates coming from combinatorial chemistry research and/or the drugs selected from biologically based high-throughput screening are quite often very lipophilic, as these drug candidates exert their pharmacological action at or in biological membranes or membrane-associated proteins. This challenges drug delivery institutions in industry or academia to develop carrier systems for the optimal oral and parenteral administration of these drugs. To mention only a few of the challenges for this class of drugs: their oral bioavailability is poor and highly variable, and carrier development for parenteral administration is faced with problems, including the massive use of surface-active excipients for solubilisation. Formulation specialists are confronted with an even higher level of difficulties when these drugs have to be delivered site specifically. This article addresses the emerging formulation designs for delivering of poorly water-soluble drugs.

Formulation Development of Spherical Crystal Agglomerates of Itraconazole for Preparation of Directly Compressible Tablets with Enhanced Bioavailability.

PubMed

Fadke, Janki; Desai, Jagruti; Thakkar, Hetal

2015-12-01

The objective of the present work was to formulate tablet dosage form of itraconazole with enhanced bioavailability. Spherical crystal agglomerates (SCA) of itraconazole prepared by quasi emulsification solvent diffusion method using Soluplus and polyethylene glycol 4000 (PEG 4000) showed increased solubility (540 μg/ml) in 0.1 N hydrochloric acid as compared to pure drug (12 μg/ml). A Fourier transform infrared (FTIR) study indicated compatibility of drug with the excipients. The developed SCA were spherical with smooth surface having an average size of 412 μm. The significantly improved micromeritic properties compared to the plain drug suggested its suitability for direct compression. The antifungal activity of itraconazole was retained in the SCA form as evidenced from the results of the disc diffusion method. The optimized SCA formulation could be easily compressed into tablet with desirable characteristics of hardness (5 kg/cm(2)) and disintegration time (6.3 min). The in vitro dissolution studies showed significant difference in the dissolution profiles of pure drug (21%) and SCA formulation (85%) which was even greater than that of marketed preparation (75%). In vivo pharmacokinetic showed significant enhancement in C max and AUC0-t with relative bioavailability of 225%. The SCA formulation seems to be promising for enhancement of oral bioavailability of itraconazole.

Laboratory-based testing to evaluate abuse-deterrent formulations and satisfy the Food and Drug Administration's recommendation for Category 1 Testing.

PubMed

Altomare, Christopher; Kinzler, Eric R; Buchhalter, August R; Cone, Edward J; Costantino, Anthony

The US Food and Drug Administration (FDA) considers the development of abuse-deterrent formulations of solid oral dosage forms a public health priority and has outlined a series of premarket studies that should be performed prior to submitting an application to the Agency. Category 1 studies are performed to characterize whether the abuse-deterrent properties of a new formulation can be easily defeated. Study protocols are designed to evaluate common abuse patterns of prescription medications as well as more advanced methods that have been reported on drug abuse websites and forums. Because FDA believes Category 1 testing should fully characterize the abuse-deterrent characteristics of an investigational formulation, Category 1 testing is time consuming and requires specialized laboratory resources as well as advanced knowledge of prescription medication abuse. Recent Advisory Committee meetings at FDA have shown that Category 1 tests play a critical role in FDA's evaluation of an investigational formulation. In this article, we will provide a general overview of the methods of manipulation and routes of administration commonly utilized by prescription drug abusers, how those methods and routes are evaluated in a laboratory setting, and discuss data intake, analysis, and reporting to satisfy FDA's Category 1 testing requirements.

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 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

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.

Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

PubMed

Penazzato, Martina; Gnanashanmugam, Devasena; Rojo, Pablo; Lallemant, Marc; Lewis, Linda L; Rocchi, Francesca; Saint Raymond, Agnes; Ford, Nathan; Hazra, Rohan; Giaquinto, Carlo; Belew, Yodit; Gibb, Diana M; Abrams, Elaine J

2017-06-01

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Development and characterization of fast-dissolving tablet formulations of glyburide based on solid self-microemulsifying systems.

PubMed

Cirri, Marzia; Roghi, Alessandra; Valleri, Maurizio; Mura, Paola

2016-07-01

The aim of this work was to develop effective fast-dissolving tablet formulations of glyburide, endowed with improved dissolution and technological properties, investigating the actual effectiveness of the Solid-Self MicroEmulsifying Drug Delivery System (S-SMEDDS) approach. An initial screening aimed to determine the solubility of the drug in different oils, Surfactants and CoSurfactants allowed the selection of the most suitable components for liquid SMEDDS, whose relative amounts were defined by the construction of pseudo-ternary phase diagrams. The selected liquid SMEDDS formulations (Capyol 90 as oil, Tween 20 as Surfactant and Glycofurol or Transcutol as CoSurfactant) were converted into Solid-SMEDDS, by adsorbing them onto Neusilin (1:1 and 1:0.8w/w S-SMEDDS:carrier), and fully characterized in terms of solid state (DSC and X-ray powder diffraction), morphological (ESEM) and dissolution properties, particle size and reconstitution ability. Finally, the 1:1 S-SMEDDS containing Glycofurol as CoSurfactant, showing the best performance, was selected to prepare two final tablet formulations. The ratio test (t10 min ratio and DE60 ratio) and pair-wise procedures (difference (f1) and similarity (f2) factors) highlighted the similarity of the new developed tablets and the marked difference between their drug dissolution profiles and those of formulations based on the micronized drug. The S-SMEDDS approach allowed to develop fast-dissolving tablets of glyburide, endowed with good technological properties and able to achieve the complete drug dissolution in a time ranging from 10 to 15min, depending on the formulation composition. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity.

PubMed

Tang, L; Khan, S U; Muhammad, N A

2001-11-01

The purpose of this work is to develop a bio-relevant dissolution method for formulation screening in order to select an enhanced bioavailable formulation for a poorly water-soluble drug. The methods used included a modified rotating disk apparatus for measuring intrinsic dissolution rate of the new chemical entity (NCE) and the USP dissolution method II for evaluating dissolution profiles of the drug in three different dosage forms. The in vitro dissolution results were compared with the in vivo bioavailability for selecting a bio-relevant medium. The results showed that the solubility of the NCE was proportional to the concentration of sodium lauryl sulfate (SLS) in the media. The apparent intrinsic dissolution rate of the NCE was linear to the rotational speed of the disk, which indicated that the dissolution of the drug is a diffusion-controlled mechanism. The apparent intrinsic dissolution rate was also linear to the surfactant concentration in the media, which was interpreted using the Noyes and Whitney Empirical Theory. Three formulations were studied in three different SLS media using the bulk drug as a reference. The dissolution results were compared with the corresponding bioavailability results in dogs. In the 1% SLS--sink conditions--the drug release from all the formulations was complete and the dissolution results were discriminative for the difference in particle size of the drug in the formulations. However, the data showed poor IVIV correlation. In the 0.5% SLS medium--non-sink conditions--the dissolution results showed the same rank order among the tested formulations as the bioavailability. The best IVIV correlation was obtained from the dissolution in 0.25% SLS medium, an over-saturated condition. The conclusions are: a surfactant medium increases the apparent intrinsic dissolution rate of the NCE linearly due to an increase in solubility. A low concentration of surfactant in the medium (0.25%) is more bio-relevant than higher concentrations of surfactant in the media for the poorly water-soluble drug. Creating sink conditions (based on bulk drug solubilities) by using a high concentration of a surfactant in the dissolution medium may not be a proper approach in developing a bio-relevant dissolution method for a poorly water-soluble drug.

Liquid Salt as Green Solvent: A Novel Eco-Friendly Technique to Enhance Solubility and Stability of Poorly Soluble Drugs

NASA Astrophysics Data System (ADS)

Patel, Anant A.

As a result of tremendous efforts in past few decades, various techniques have been developed in order to resolve solubility issues associated with class II and IV drugs, However, majority of these techniques offer benefits associated with certain drawbacks; majorly including low drug loading, physical instability on storage and excessive use of environmentally challenging organic solvents. Hence, current effort was to develop an eco-friendly technique using liquid salt as green solvent, which can offer improvement in dissolution while maintaining long term stability. The liquid salt formulations (LSF) of poorly soluble model drugs ibuprofen, gemfibrozil and indomethacin were developed using 1-Ethyl-3-methylimidazolium ethyl sulfate (EMIM ES) as a non-toxic and environmentally friendly alternate to organic solvents. Liquid medications containing clear solutions of drug, EMIM ES and polysorbate 20, were adsorbed onto porous carrier Neusilin US2 to form free flowing powder. The LSF demonstrated greater rate and extent of dissolution compared to crystalline drugs. The dissolution data revealed that more than 80% drug release from LSF within 20 mins compared to less than 18% release from pure drugs. As high as 70% w/w liquid loading was achieved while maintaining good flowability and compressibility. In addition, the LSF samples exposed to high temperature and high humidity i.e. 40°C/80% RH for 8 weeks, demonstrated excellent physical stability without any signs of precipitation or crystallization. As most desirable form of administration is tablet, the developed liquid salt formulations were transformed into tablets using design of experiment approach by Design Expert Software. The tablet formulation composition and critical parameter were optimized using Box-Behnken Design. This innovative liquid salt formulation technique offered improvement in dissolution rate and extent as well as contributed to excellent physical stability on storage. Moreover, this formulation approach served as eco-friendly compelling alternate to conventional techniques involving organic solvents.

Formulation design space for stable, pH sensitive crystalline nifedipine nanoparticles.

PubMed

Jog, Rajan; Unachukwu, Kenechi; Burgess, Diane J

2016-11-30

Enteric coated formulations protect drugs from degrading in the harsh environment of the stomach (acidic pH and enzymes), and promotes drug delivery to and absorption into the duodenum and/or later parts of the intestine. Four DoE models were applied to optimize formulation parameters for the preparation of pH sensitive nifedipine nanoparticles. Stability studies were performed on the optimized formulations to monitor any possible variation in particle size distribution, homogeneity index, surface charge and drug release (pH 1.2 and pH 6.8). Stability studies were performed for 3 months at 4°C, 25°C and 40°C. A combination of Eudragit ® L 100-55 and polyvinyl alcohol was determined to be the most effective in stabilizing the nanoparticle suspension. The average particle size distribution, polydispersity index and surface charge of the optimized pH sensitive nifedipine nanoparticles were determined to be 131.86±8.21nm, 0.135±0.008 and -7.631±0.146mV, respectively. Following three months storage, it was observed that the formulations stored at 4°C were stable in terms of particle size distribution, polydispersity index, surface charge, drug loading and drug release, whereas those stored at 25°C and 40°C were relatively unstable. A predictive model to prepare stable pH sensitive nifedipine nanoparticles, was successfully developed using multiple linear regression analysis. Copyright © 2016 Elsevier B.V. All rights reserved.

Formulation and in vitro characterization of xanthan gum-based sustained release matrix tables of isosorbide-5- mononitrate.

PubMed

Kar, Rajat; Mohapatra, Snehamayee; Bhanja, Satyabrata; Das, Debjyoti; Barik, Bhaktibhusan

2010-01-01

In the present investigation an attempt has been made to increase therapeutic efficacy, to reduce frequency of administration and to improve patient compliance by developing a sustained release matrix tablets of isosorbide-5-mononitrate. Sustained release matrix tablets of isosorbide-5-mononitrate were developed by using different drug: polymer ratios, such in F1 (1:0.75), F2 (1:1), F3 (1:1.5), F4 (1:1.75) and F6 (1:2). Xanthan gum was used as matrix former and microcrystalline cellulose as diluent. All the lubricated formulations were compressed, using 8mm flat faced punches. Compressed tablets were evaluated for uniformity of weight, content of active ingredient, friability, hardness, thickness, in vitro dissolution study using basket method and swelling index. Each formulation showed compliance with pharmacopoeial standards. Among all formulations, F5 showed a greater sustained release pattern of drug over a 12 h period with 92.12% of drug being released. The kinetic studies showed that drug release follows the Higuchi model (r(2) =0.9851). Korsemeyer and Peppas equation gave an n-value of 0.4566, which was close to 0.5, indicating that drug release follows the Fickian diffusion. Thus, xanthan gum can be used as an effective matrix former to extend the release of isosorbide-5-mononitrate. No significant difference was observed in the dissolution profile of optimized formulation, using basket and paddle apparatus.

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.

Transdermal Patches for the Treatment of Neurologic Conditions in Elderly Patients: A Review

PubMed Central

Somogyi, Monique

2011-01-01

Objective: The mode of drug delivery can be an important consideration in optimizing drug therapy, as it can affect treatment compliance and outcomes. It is particularly important to develop optimal drug formulations for chronic diseases or conditions in the elderly for which treatment compliance is known to be low. In this review, the features and benefits of transdermal formulations for treating neurologic conditions in elderly patients are described. Data Sources: English-language articles were identified by searching MEDLINE in November 2010 (there were no search parameters on date of publication) using the search terms transdermal patch, transdermal system, neurology, rivastigmine, rotigotine, selegiline, lidocaine, capsaicin, compliance, and neuropathic pain. Data Selection: Articles describing the development, use, efficacy, and safety of licensed transdermal patch treatments for neurologic conditions that affect the elderly were included. Data Extraction: The features of transdermal systems and comparisons between transdermal and oral formulations for the treatment of specific neurologic conditions in elderly patients were reviewed. Data Synthesis: There are 5 transdermal patch systems currently available for neurologic conditions in adults: rivastigmine, rotigotine, selegiline, lidocaine, and capsaicin. These are all modern formulations in matrix patches, developed to provide appropriate drug dosage in an acceptable and well-tolerated form. Conclusions: Transdermal patches can offer benefits to patients over oral formulations in terms of ease of use, simple treatment regimens, avoidance of the first-pass effect, and avoidance of high maximum plasma concentrations with rapid changes in drug levels, without the invasive procedures associated with intravenous treatment. PMID:22454804

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

NanoClusters Enhance Drug Delivery in Mechanical Ventilation

NASA Astrophysics Data System (ADS)

Pornputtapitak, Warangkana

The overall goal of this thesis was to develop a dry powder delivery system for patients on mechanical ventilation. The studies were divided into two parts: the formulation development and the device design. The pulmonary system is an attractive route for drug delivery since the lungs have a large accessible surface area for treatment or drug absorption. For ventilated patients, inhaled drugs have to successfully navigate ventilator tubing and an endotracheal tube. Agglomerates of drug nanoparticles (also known as 'NanoClusters') are fine dry powder aerosols that were hypothesized to enable drug delivery through ventilator circuits. This Thesis systematically investigated formulations of NanoClusters and their aerosol performance in a conventional inhaler and a device designed for use during mechanical ventilation. These engineered powders of budesonide (NC-Bud) were delivered via a MonodoseRTM inhaler or a novel device through commercial endotracheal tubes, and analyzed by cascade impaction. NC-Bud had a higher efficiency of aerosol delivery compared to micronized stock budesonide. The delivery efficiency was independent of ventilator parameters such as inspiration patterns, inspiration volumes, and inspiration flow rates. A novel device designed to fit directly to the ventilator and endotracheal tubing connections and the MonodoseRTM inhaler showed the same efficiency of drug delivery. The new device combined with NanoCluster formulation technology, therefore, allowed convenient and efficient drug delivery through endotracheal tubes. Furthermore, itraconazole (ITZ), a triazole antifungal agent, was formulated as a NanoCluster powder via milling (top-down process) or precipitation (bottom-up process) without using any excipients. ITZ NanoClusters prepared by wet milling showed better aerosol performance compared to micronized stock ITZ and ITZ NanoClusters prepared by precipitation. ITZ NanoClusters prepared by precipitation methods also showed an amorphous state while milled ITZ NanoClusters maintained the crystalline character. Overall, NanoClusters prepared by various processes represent a potential engineered drug particle approach for inhalation therapy since they provide effective aerosol properties and stability due to the crystalline state of the drug powders. Future work will continue to explore formulation and delivery performance in vitro and in vivo..

In vitro and in vivo topical delivery studies of tretinoin-loaded ultradeformable vesicles.

PubMed

Ascenso, Andreia; Salgado, Ana; Euletério, Carla; Praça, Fabíola Garcia; Bentley, Maria Vitória Lopes Badra; Marques, Helena C; Oliveira, Helena; Santos, Conceição; Simões, Sandra

2014-09-01

Ultradeformable vesicles are highly promising tools to enhance the percutaneous transport of different drugs such as tretinoin across the skin barrier and also to increase the formulation stability at absorption site and reduce the drug induced irritation. Topical delivery of tretinoin-loaded ultradeformable vesicles (tretinoin-UDV) was evaluated concerning different studies, such as: the release and permeation profiles (tape stripping); skin penetration (fluorescence analysis); induced electrical changes in skin barrier properties; cytotoxicity (Trypan Blue assay) and skin irritation in in vivo conditions (Draize test). The novel formulation performance was also compared to a commercial tretinoin formulation regarding in vivo studies. It was obtained a sustained and controlled drug release, as expected for UDV formulation. In addition, a dermal delivery was observed regarding the permeation study since it was not detected any drug amount in the receptor phase after 24h. Nile Red-UDV stained intensively mostly in the stratum corneum, corroborating the tape stripping results. Tretinoin-UDV decreased skin resistance, suggesting its ability to induce skin barrier disruption. Finally, the formulation vehicle (empty UDV) and tretinoin-UDV were not toxic under in vitro and in vivo conditions, at least, at 5×10(-3)mg/mL and 0.5mg/mL of tretinoin, respectively. Tretinoin-UDV is a promising delivery system for tretinoin dermal delivery without promoting skin irritation (unlike other commercial formulations), which is quite advantageous for therapeutic purpose. Copyright © 2014 Elsevier B.V. All rights reserved.

Active intestinal drug absorption and the solubility-permeability interplay.

PubMed

Porat, Daniel; Dahan, Arik

2018-02-15

The solubility-permeability interplay deals with the question: what is the concomitant effect on the drug's apparent permeability when increasing the apparent solubility with a solubility-enabling formulation? The solubility and the permeability are closely related, exhibit certain interplay between them, and ongoing research throughout the past decade shows that treating the one irrespectively of the other may be insufficient. The aim of this article is to provide an overview of the current knowledge on the solubility-permeability interplay when using solubility-enabling formulations for oral lipophilic drugs, highlighting active permeability aspects. A solubility-enabling formulation may affect the permeability in opposite directions; the passive permeability may decrease as a result of the apparent solubility increase, according to the solubility-permeability tradeoff, but at the same time, certain components of the formulation may inhibit/saturate efflux transporters (when relevant), resulting in significant apparent permeability increase. In these cases, excipients with both solubilizing and e.g. P-gp inhibitory properties may lead to concomitant increase of both the solubility and the permeability. Intelligent development of such formulation will account for the simultaneous effects of the excipients' nature/concentrations on the two arms composing the overall permeability: the passive and the active arms. Overall, thorough mechanistic understanding of the various factors involved in the solubility-permeability interplay may allow developing better solubility-enabling formulations, thereby exploiting the advantages analyzed in this article, offering oral delivery solution even for BCS class IV drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility-Permeability Interplay.

PubMed

Beig, Avital; Miller, Jonathan M; Lindley, David; Carr, Robert A; Zocharski, Philip; Agbaria, Riad; Dahan, Arik

2015-09-01

The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility-permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-β-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility-permeability interplay. All formulations significantly increased etoposide's apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility-permeability tradeoff associated with other formulation techniques. Accounting for the solubility-permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Montmorillonite-lipid hybrid carriers for ionizable and neutral poorly water-soluble drugs: Formulation, characterization and in vitro lipolysis studies.

PubMed

Dening, Tahnee J; Rao, Shasha; Thomas, Nicky; Prestidge, Clive A

2017-06-30

Lipid-based formulations (LBFs) are a popular strategy for enhancing the gastrointestinal solubilization and absorption of poorly water-soluble drugs. In light of this, montmorillonite-lipid hybrid (MLH) particles, composed of medium-chain triglycerides, lecithin and montmorillonite clay platelets, have been developed as a novel solid-state LBF. Owing to the unique charge properties of montmorillonite, whereby the clay platelet surfaces carry a permanent negative charge and the platelet edges carry a pH-dependent charge, three model poorly water-soluble drugs with different charge properties; blonanserin (weak base, pKa 7.7), ibuprofen (weak acid, pKa 4.5) and fenofibrate (neutral), were formulated as MLH particles and their performance during biorelevant in vitro lipolysis at pH 7.5 was investigated. For blonanserin, drug solubilization during in vitro lipolysis was significantly reduced 3.4-fold and 3.2-fold for MLH particles in comparison to a control lipid solution and silica-lipid hybrid (SLH) particles, respectively. It was hypothesized that strong electrostatic interactions between the anionic montmorillonite platelet surfaces and cationic blonanserin molecules were responsible for the inferior performance of MLH particles. In contrast, no significant influence on drug solubilization was observed for ibuprofen- and fenofibrate-loaded MLH particles. The results of the current study indicate that whilst MLH particles are a promising novel formulation strategy for poorly water-soluble drugs, drug ionization tendency and the potential for drug-clay interactions must be taken into consideration to ensure an appropriate performance. Copyright © 2017 Elsevier B.V. All rights reserved.

Tools for Early Prediction of Drug Loading in Lipid-Based Formulations

PubMed Central

2015-01-01

Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R2 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R2 0.85; Polysorbate 80, R2 0.90; Cremophor EL, R2 0.93). A melting point below 150 °C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R2 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R2 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug. PMID:26568134

Tools for Early Prediction of Drug Loading in Lipid-Based Formulations.

PubMed

Alskär, Linda C; Porter, Christopher J H; Bergström, Christel A S

2016-01-04

Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R(2) 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R(2) 0.85; Polysorbate 80, R(2) 0.90; Cremophor EL, R(2) 0.93). A melting point below 150 °C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R(2) 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R(2) 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug.

Formulation, in vitro evaluation and study of variables on tri-layered gastro-retentive delivery system of diltiazem HCl.

PubMed

Raut Desai, Shilpa; Rohera, Bhagwan D

2014-03-01

Tri-layered floating tablets using only one grade of polyethylene oxide (PEO) would enable easy manufacturing, reproducibility and controlled release for highly soluble drugs. To evaluate the potential of PEO as a sole polymer for the controlled release and to study the effect of formulation variables on release and gastric retention of highly soluble Diltiazem hydrochloride (DTZ). Tablets were compressed with middle layer consisting of drug and polymer while outer layers consisted of polymer with sodium bicarbonate. Design of formulation to obtain 12 h, zero-order release and rapid floatation was done by varying the grades, quantity of PEO and sodium bicarbonate. Dissolution data were fitted in drug release models and swelling/erosion studies were undertaken to verify the drug release mechanism. Effect of formulation variables and tablet surface morphology using scanning electron microscopy were studied. The optimized formula passed the criteria of USP dissolution test I and exhibited floating lag-time of 3-4 min. Drug release was faster from low molecular weight (MW) PEO as compared to high MW. With an increase in the amount of sodium bicarbonate, faster buoyancy was achieved due to the increased CO2 gas formation. Drug release followed zero-order and gave a good fit to the Korsmeyer-Peppas model, which suggested that drug release was due to diffusion through polymer swelling. Zero-order, controlled release profile with the desired buoyancy can be achieved by using optimum formula quantities of sodium bicarbonate and polymer. The tri-layered system shows promising delivery of DTZ, and possibly other water-soluble drugs.

Evaluation of Influence of Various Polymers on Dissolution and Phase Behavior of Carbamazepine-Succinic Acid Cocrystal in Matrix Tablets.

PubMed

Ullah, Majeed; Ullah, Hanif; Murtaza, Ghulam; Mahmood, Qaisar; Hussain, Izhar

2015-01-01

The aim of current study was to explore the influence of three commonly used polymers, that is, cellulosics and noncellulosics, for example, Methocel K4M, Kollidon VA/64, and Soluplus, on the phase disproportionation and drug release profile of carbamazepine-succinic acid (CBZ-SUC) cocrystal at varying drug to polymer ratios (1 : 1 to 1 : 0.25) in matrix tablets. The polymorphic phase disproportionation during in-depth dissolution studies of CBZ-SUC cocrystals and its crystalline properties were scrutinized by X-ray powder diffractrometry and Raman spectroscopy. The percent drug release from HPMC formulations (CSH) showed inverse relation with the concentration of polymer; that is, drug release increased with decrease in polymer concentration. On contrary, direct relation was observed between percent drug release and polymer concentrations of Kollidon VA 64/Soluplus (CSK, CSS). At similar polymer concentration, drug release from pure carbamazepine was slightly lower with HPMC formulations than that of cocrystal; however, opposite trend in release rate was observed with Kollidon VA/64 and Soluplus. The significant increase in dissolution rate of cocrystal occurred with Kollidon VA/64 and Soluplus at higher polymer concentration. Moreover, no phase change took place in Methocel and Kollidon formulations. No tablet residue was left for Soluplus formulation so the impact of polymer on cocrystal integrity cannot be predicted.

Evaluation of Influence of Various Polymers on Dissolution and Phase Behavior of Carbamazepine-Succinic Acid Cocrystal in Matrix Tablets

PubMed Central

Ullah, Majeed; Ullah, Hanif; Mahmood, Qaisar; Hussain, Izhar

2015-01-01

The aim of current study was to explore the influence of three commonly used polymers, that is, cellulosics and noncellulosics, for example, Methocel K4M, Kollidon VA/64, and Soluplus, on the phase disproportionation and drug release profile of carbamazepine-succinic acid (CBZ-SUC) cocrystal at varying drug to polymer ratios (1 : 1 to 1 : 0.25) in matrix tablets. The polymorphic phase disproportionation during in-depth dissolution studies of CBZ-SUC cocrystals and its crystalline properties were scrutinized by X-ray powder diffractrometry and Raman spectroscopy. The percent drug release from HPMC formulations (CSH) showed inverse relation with the concentration of polymer; that is, drug release increased with decrease in polymer concentration. On contrary, direct relation was observed between percent drug release and polymer concentrations of Kollidon VA 64/Soluplus (CSK, CSS). At similar polymer concentration, drug release from pure carbamazepine was slightly lower with HPMC formulations than that of cocrystal; however, opposite trend in release rate was observed with Kollidon VA/64 and Soluplus. The significant increase in dissolution rate of cocrystal occurred with Kollidon VA/64 and Soluplus at higher polymer concentration. Moreover, no phase change took place in Methocel and Kollidon formulations. No tablet residue was left for Soluplus formulation so the impact of polymer on cocrystal integrity cannot be predicted. PMID:26380301

Theophylline cocrystals prepared by spray drying: physicochemical properties and aerosolization performance.

PubMed

Alhalaweh, Amjad; Kaialy, Waseem; Buckton, Graham; Gill, Hardyal; Nokhodchi, Ali; Velaga, Sitaram P

2013-03-01

The purpose of this work was to characterize theophylline (THF) cocrystals prepared by spray drying in terms of the physicochemical properties and inhalation performance when aerosolized from a dry powder inhaler. Cocrystals of theophylline with urea (THF-URE), saccharin (THF-SAC) and nicotinamide (THF-NIC) were prepared by spray drying. Milled THF and THF-SAC cocrystals were also used for comparison. The physical purity, particle size, particle morphology and surface energy of the materials were determined. The in vitro aerosol performance of the spray-dried cocrystals, drug-alone and a drug-carrier aerosol, was assessed. The spray-dried particles had different size distributions, morphologies and surface energies. The milled samples had higher surface energy than those prepared by spray drying. Good agreement was observed between multi-stage liquid impinger and next-generation impactor in terms of assessing spray-dried THF particles. The fine particle fractions of both formulations were similar for THF, but drug-alone formulations outperformed drug-carrier formulations for the THF cocrystals. The aerosolization performance of different THF cocrystals was within the following rank order as obtained from both drug-alone and drug-carrier formulations: THF-NIC>THF-URE>THF-SAC. It was proposed that micromeritic properties dominate over particle surface energy in terms of determining the aerosol performance of THF cocrystals. Spray drying could be a potential technique for preparing cocrystals with modified physical properties.

Application of transglycosylated stevia and hesperidin as drug carriers to enhance biopharmaceutical properties of poorly-soluble artemisinin.

PubMed

Letchmanan, Kumaran; Shen, Shou-Cang; Ng, Wai Kiong; Tan, Reginald B H

2018-01-01

Biopharmaceutical properties of poorly water-soluble antimalarial drug, Artemisinin (ART), were improved by formulating amorphous solid dispersions with transglycosylated food additives (Hsp-G and Stevia-G) via co-spray drying. Both the formulated ART/Hsp-G and ART/Stevia-G showed superior dissolution properties with a burst release of more than 95% of drug within 5 min, whereas untreated ART dissolved only 4% in 5min. The supersaturation solubility of the formulated ART was enhanced by 2-fold as compared with untreated counterpart. The storage stability tests indicated that these formulations chemically stable at room temperature and under low humidity (<18% RH) conditions. However, high humidity (75% RH) induced re-crystallization and caused changes in the physical appearance of the solid dispersions. In addition, both the food additives and ART formulated samples showed low cytotoxicity to Caco-2 cell line suggesting their good biocompatibility. Thus, the formation of solid dispersions of ART with transglycosylated food additives is a potentially safe and effective approach to enhance the bioavailability of poorly water-soluble ART. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparative studies of binding potential of Prunus armeniaca and Prunus domestica gums in tablets formulations.

PubMed

Rahim, Haroon; Khan, Mir Azam; Sadiq, Abdul; Khan, Shahzeb; Chishti, Kamran Ahmad; Rahman, Inayat U

2015-05-01

The current study was undertaken to compare the binding potential of Prunus armeniaca L. and Prunus domestica L. gums in tablets' formulations. Tablet batches (F-1 to F-9) were prepared Diclofenac sodium as model drug using 5%, 7.5% and 10% of each Prunus armeniaca L., Prunus domestica L. gums as binder. PVP K30 was used as a standard binder. Magnesium stearate was used as lubricant. Flow properties of granules (like bulk density, tapped density, Carr's index, Hausner's ratio, angle of repose) as well as the physical parameters of compressed tablets including hardness, friability, thickness and disintegration time were determined. Flow parameters of granules of all the batches were found good. Physical parameters (drug content, weight variation, thickness, hardness, friability, disintegration time) of formulated tablets were found within limit when tested. The dissolution studies showed that tablets formulations containing each Prunus domestica showed better binding capacity compared to Prunus armeniaca gum. The binding potential increased as the concentration of gums increased. The FTIR spectroscopic investigation showed that the formulations containing plant gum are compatible with the drug and other excipients used.

Improving ex vivo skin permeation of non-steroidal anti-inflammatory drugs: enhancing extemporaneous transformation of liposomes into planar lipid bilayers.

PubMed

Vázquez-González, Martha L; Bernad, Rafael; Calpena, Ana C; Domènech, Oscar; Montero, M T; Hernández-Borrell, Jordi

2014-01-30

Transdermal delivery of active principles is a versatile method widely used in medicine. The main drawback for the transdermal route, however, is the low efficiency achieved in the absorption of many drugs, mostly due to the complexity of the skin barrier. To improve drug delivery through the skin, we prepared and characterized liposomes loaded with ibuprofen and designed pharmaceutical formulations based on the extemporaneous addition of penetration enhancer (PE) surfactants. Afterwards, permeation and release studies were carried out. According to the permeation studies, the ibuprofen liposomal formulation supplemented with PEs exhibited similar therapeutic effects, but at lower doses (20%) comparing with a commercial formulation used as a reference. Atomic force microscopy (AFM) was used to investigate the effect caused by PEs on the adsorption mechanism of liposomal formulations onto the skin. Non-fused liposomes, bilayers and multilayered lipid structures were observed. The transformation of vesicles into planar structures is proposed as a possible rationale for explaining the lower doses required when a liposome formulation is supplemented with surfactant PEs. Copyright © 2013 Elsevier B.V. All rights reserved.

The effects of particle properties on nanoparticle drug retention and release in dynamic minoxidil foams.

PubMed

Zhao, Yanjun; Brown, Marc B; Jones, Stuart A

2010-01-04

Nanocarriers may act as useful tools to deliver therapeutic agents to the skin. However, balancing the drug-particle interactions; to ensure adequate drug loading, with the drug-vehicle interactions; to allow efficient drug release, presents a significant challenge using traditional semi-solid vehicles. The aim of this study was to determine how the physicochemical properties of nanoparticles influenced minoxidil release pre and post dose application when formulated as a simple aqueous suspension compared to dynamic hydrofluoroalkane (HFA) foams. Minoxidil loaded lipid nanoparticles (LN, 1.4 mg/ml, 50 nm) and polymeric nanoparticles with a lipid core (PN, 0.6 mg/ml, 260 nm) were produced and suspended in water to produce the aqueous suspensions. These aqueous suspensions were emulsified with HFA using pluronic surfactant to generate the foams. Approximately 60% of the minoxidil loaded into the PN and 80% of the minoxidil loaded into the LN was released into the external aqueous phase 24h after production. Drug permeation was superior from the PN, i.e. it was the particle that retained the most drugs, irrespective of the formulation method. Premature drug release, i.e. during storage, resulted in the performance of the topical formulation being dictated by the thermodynamic activity of the solubilised drug not the particle properties.

Acridine Orange Conjugated Polymersomes for Simultaneous Nuclear Delivery of Gemcitabine and Doxorubicin to Pancreatic Cancer Cells.

PubMed

Anajafi, Tayebeh; Scott, Michael D; You, Seungyong; Yang, Xiaoyu; Choi, Yongki; Qian, Steven Y; Mallik, Sanku

2016-03-16

Considering the systemic toxicity of chemotherapeutic agents, there is an urgent need to develop new targeted drug delivery systems. Herein, we have developed a new nuclear targeted, redox sensitive, drug delivery vehicle to simultaneously deliver the anticancer drugs gemcitabine and doxorubicin to the nuclei of pancreatic cancer cells. We prepared polymeric bilayer vesicles (polymersomes), and actively encapsulated the drug combination by the pH gradient method. A redox-sensitive polymer (PEG-S-S-PLA) was incorporated to sensitize the formulation to reducing agent concentration. Acridine orange (AO) was conjugated to the surface of the polymersomes imparting nuclear localizing property. The polymersomes' toxicity and efficacy were compared with those of a free drug combination using monolayer and three-dimensional spheroid cultures of pancreatic cancer cells. We observed that the redox sensitive, nuclear-targeted polymersomes released more than 60% of their encapsulated contents in response to 50 mM glutathione. The nanoparticles are nontoxic; however, the drug encapsulated vesicles have significant toxicity. The prepared formulation can increase the drug's therapeutic index by delivering the drugs directly to the cells' nuclei, one of the key organelles in the cells. This study is likely to initiate research in targeted nuclear delivery using other drug formulations in other types of cancers.

Microsponges based novel drug delivery system for augmented arthritis therapy.

PubMed

Osmani, Riyaz Ali M; Aloorkar, Nagesh H; Ingale, Dipti J; Kulkarni, Parthasarathi K; Hani, Umme; Bhosale, Rohit R; Jayachandra Dev, Dandasi

2015-10-01

The motive behind present work was to formulate and evaluate gel containing microsponges of diclofenac diethylamine to provide prolonged release for proficient arthritis therapy. Quasi-emulsion solvent diffusion method was implied using Eudragit RS-100 and microsponges with varied drug-polymer ratios were prepared. For the sake of optimization, diverse factors affecting microparticles physical properties were too investigated. Microsponges were characterized by SEM, DSC, FT-IR, XRPD and particle size analysis, and evaluated for morphology, drug loading, in vitro drug release and ex vivo diffusion as well. There were no chemical interactions between drug and polymers used as revealed by compatibility studies outcomes. The drug polymer ratio reflected notable effect on drug content, encapsulation efficiency and particle size. SEM results revealed spherical microsponges with porous surface, and had 7.21 μm mean particle size. The microsponges were then incorporated in gel; which exhibited viscous modulus along with pseudoplastic behavior. In vitro drug release results depicted that microsponges with 1:2 drug-polymer ratio were more efficient to give extended drug release of 75.88% at the end of 8 h; while conventional formulation get exhausted incredibly earlier by releasing 81.11% drug at the end of 4 h only. Thus the formulated microsponge-based gel of diclofenac diethylamine would be a promising alternative to conventional therapy for safer and efficient treatment of arthritis and musculoskeletal disorders.

Formulation, in vitro evaluation and kinetic analysis of chitosan-gelatin bilayer muco-adhesive buccal patches of insulin nanoparticles.

PubMed

Mahdizadeh Barzoki, Zahra; Emam-Djomeh, Zahra; Mortazavian, Elaheh; Akbar Moosavi-Movahedi, Ali; Rafiee Tehrani, M

2016-11-01

The present study was performed to optimise the formulation of a muco-adhesive buccal patch for insulin nanoparticles (NPs) delivery. Insulin NPs were synthesised by an ionic gelation technique using N-di methyl ethyl chitosan cysteine (DMEC-Cys) as permeation enhancer biopolymer, tripolyphosphate (TPP) and insulin. Buccal patches were developed by solvent-casting technique using chitosan and gelatine as muco-adhesive polymers. Optimised patches were embedded with 3 mg of insulin-loaded NPs with a homogeneous distribution of NPs in the muco-adhesive matrix, which displayed adequate physico-mechanical properties. The drug release characteristics, release mechanism and kinetics were investigated. Data fitting to Peppas equation with a correlation coefficient indicated that the mechanism of drug release followed an anomalous transport that means drug release was afforded through drug diffusion along with polymer erosion. In vitro drug release, release kinetics, physical and mechanical studies for all patch formulations reflected the ideal characteristics of this buccal patch for the delivery of insulin NPs.

Preparation and characterization of spironolactone-loaded nano-emulsions for extemporaneous applications.

PubMed

Hallouard, François; Dollo, Gilles; Brandhonneur, Nolwenn; Grasset, Fabien; Corre, Pascal Le

2015-01-15

In neonates as well as in adults having swallowing difficulty, oral medication is given through a nasogastric tube making liquid formulations preferable. In this study, we present the high potential of nanometric emulsions formulated by spontaneous surfactant diffusion, as extemporaneous formulations of hydrophobic drug. Spironolactone used as hydrophobic drug model, was incorporated in oil before formulation at a concentration of 13.5mg/g oil. Then, all formulations were evaluated from pharmacotechnical and clinical standpoints, for their use in hospital or community pharmacy. The strength of this new liquid formulation lies on the simplicity, efficiency and reproducibility of their low energy process as on clinical aspects: high dose uniformity, facility to be administered through in nasogastric tube without any retention and a stability of 2 months at least compatible for an extemporaneous use. Moreover, this emulsion presented spironolactone content of 3.75 mg/ml among the most concentrated formulations published. Copyright © 2014 Elsevier B.V. All rights reserved.

Metronidazole loaded pectin microspheres for colon targeting.

PubMed

Vaidya, Ankur; Jain, Aviral; Khare, Piush; Agrawal, Ram K; Jain, Sanjay K

2009-11-01

A multiparticulate system having pH-sensitive property and specific enzyme biodegradability for colon-targeted delivery of metronidazole was developed. Pectin microspheres were prepared using emulsion-dehydration technique. These microspheres were coated with Eudragit(R) S-100 using oil-in-oil solvent evaporation method. The SEM was used to characterize the surface of these microspheres and a distinct coating over microspheres could be seen. The in vitro drug release studies exhibited no drug release at gastric pH, however continuous release of drug was observed from the formulation at colonic pH. Further, the release of drug from formulation was found to be higher in the presence of rat caecal contents, indicating the effect of colonic enzymes on the pectin microspheres. The in vivo studies were also performed by assessing the drug concentration in various parts of the GIT at different time intervals which exhibited the potentiality of formulation for colon targeting. Hence, it can be concluded that Eudragit coated pectin microspheres can be used for the colon specific delivery of drug. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association

Quantitative spatial distribution of sirolimus and polymers in drug-eluting stents using confocal Raman microscopy.

PubMed

Balss, K M; Llanos, G; Papandreou, G; Maryanoff, C A

2008-04-01

Raman spectroscopy was used to differentiate each component found in the CYPHER Sirolimus-eluting Coronary Stent. The unique spectral features identified for each component were then used to develop three separate calibration curves to describe the solid phase distribution found on drug-polymer coated stents. The calibration curves were obtained by analyzing confocal Raman spectral depth profiles from a set of 16 unique formulations of drug-polymer coatings sprayed onto stents and planar substrates. The sirolimus model was linear from 0 to 100 wt % of drug. The individual polymer calibration curves for poly(ethylene-co-vinyl acetate) [PEVA] and poly(n-butyl methacrylate) [PBMA] were also linear from 0 to 100 wt %. The calibration curves were tested on three independent drug-polymer coated stents. The sirolimus calibration predicted the drug content within 1 wt % of the laboratory assay value. The polymer calibrations predicted the content within 7 wt % of the formulation solution content. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra from five formulations confirmed a linear response to changes in sirolimus and polymer content. Copyright 2007 Wiley Periodicals, Inc.

Effects of absorption enhancers in chloroquine suppository formulations: I. In vitro release characteristics.

PubMed

Onyeji, C O; Adebayo, A S; Babalola, C P

1999-12-01

The need to develop chloroquine suppository formulations that yield optimal bioavailability of the drug has been emphasized. This study demonstrates the effects of incorporation of known absorption-enhancing agents (nonionic surfactants and sodium salicylate) on the in vitro release characteristics of chloroquine from polyethylene glycol (1000:4000, 75:25%, w/w) suppositories. The release rates were determined using a modification of the continuous flow bead-bed dissolution apparatus for suppositories. Results showed that the extent of drug release from suppositories containing any of three surfactants (Tween 20, Tween 80 and Brij 35) was 100%, whereas 88% release was obtained with control formulation (without enhancer) (P<0.05). However, Tween 20 was more effective than Brij 35 and Tween 80 in improving the drug release rate. There was a concentration-dependent effect with Tween 20, and 4% (w/w) of this surfactant was associated with the highest increase in the rate of drug release from the suppositories. Sodium salicylate at a concentration of 25% (w/w) also significantly enhanced the drug release rate, but a higher concentration of the adjuvant markedly reduced both the rate and extent of drug release. Combined incorporation of Tween 20 and sodium salicylate did not significantly modify (P0.05) the rate of drug release when compared to the effect of the more effective single agent. Due to their effects in improving the drug release profiles coupled with their intrinsic absorption-promoting properties, it is suggested that incorporation of 4% (w/w) Tween 20 and/or 25% (w/w) sodium salicylate in the composite polyethylene glycol chloroquine suppository formulations, may result in enhancement of rectal absorption of the drug. This necessitates an in vivo validation.

Silica encapsulated lipid-based drug delivery systems for reducing the fed/fasted variations of ziprasidone in vitro.

PubMed

Dening, Tahnee J; Rao, Shasha; Thomas, Nicky; Prestidge, Clive A

2016-04-01

Ziprasidone is a poorly water-soluble antipsychotic drug that demonstrates low fasted state oral bioavailability and a clinically significant two-fold increase in absorption when dosed postprandially. Owing to significant compliance challenges faced by schizophrenic patients, a novel oral formulation of ziprasidone that demonstrates improved fasted state absorption and a reduced food effect is of major interest, and is therefore the aim of this research. Three lipid-based drug delivery systems (LBDDS) were developed and investigated: (a) a self-nanoemulsifying drug delivery system (SNEDDS), (b) a solid SNEDDS formulation, and (c) silica-lipid hybrid (SLH) microparticles. SNEDDS was developed using Capmul MCM® and Tween 80®, and solid SNEDDS was fabricated by spray-drying SNEDDS with Aerosil 380® silica nanoparticles as the solid carrier. SLH microparticles were prepared in a similar manner to solid SNEDDS using a precursor lipid emulsion composed of Capmul MCM® and soybean lecithin. The performance of the developed formulations was evaluated under simulated digesting conditions using an in vitro lipolysis model, and pure (unformulated) ziprasidone was used as a control. While pure ziprasidone exhibited the lowest rate and extent of drug solubilization under fasting conditions and a significant 2.4-fold increase in drug solubilization under fed conditions, all three LBDDS significantly enhanced the extent of drug solubilization under fasting conditions between 18- and 43-folds in comparison to pure drug. No significant difference in drug solubilization for the fed and fasted states was observed for the three LBDDS systems. To highlight the potential of LBDDS, mechanism(s) of action and various performance characteristics are discussed. Importantly, LBDDS are identified as an appropriate formulation strategy to explore further for the improved oral delivery of ziprasidone. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimization of formulation variables of benzocaine liposomes using experimental design.

PubMed

Mura, Paola; Capasso, Gaetano; Maestrelli, Francesca; Furlanetto, Sandra

2008-01-01

This study aimed to optimize, by means of an experimental design multivariate strategy, a liposomal formulation for topical delivery of the local anaesthetic agent benzocaine. The formulation variables for the vesicle lipid phase uses potassium glycyrrhizinate (KG) as an alternative to cholesterol and the addition of a cationic (stearylamine) or anionic (dicethylphosphate) surfactant (qualitative factors); the percents of ethanol and the total volume of the hydration phase (quantitative factors) were the variables for the hydrophilic phase. The combined influence of these factors on the considered responses (encapsulation efficiency (EE%) and percent drug permeated at 180 min (P%)) was evaluated by means of a D-optimal design strategy. Graphic analysis of the effects indicated that maximization of the selected responses requested opposite levels of the considered factors: For example, KG and stearylamine were better for increasing EE%, and cholesterol and dicethylphosphate for increasing P%. In the second step, the Doehlert design, applied for the response-surface study of the quantitative factors, pointed out a negative interaction between percent ethanol and volume of the hydration phase and allowed prediction of the best formulation for maximizing drug permeation rate. Experimental P% data of the optimized formulation were inside the confidence interval (P < 0.05) calculated around the predicted value of the response. This proved the suitability of the proposed approach for optimizing the composition of liposomal formulations and predicting the effects of formulation variables on the considered experimental response. Moreover, the optimized formulation enabled a significant improvement (P < 0.05) of the drug anaesthetic effect with respect to the starting reference liposomal formulation, thus demonstrating its actually better therapeutic effectiveness.

Pluronic lecithin organogel as a topical drug delivery system.

PubMed

Pandey, Mohit; Belgamwar, Veena; Gattani, Surendra; Surana, Sanjay; Tekade, Avinash

2010-01-01

The objective of this study was to formulate and evaluate the pluronic lecithin organogel containing flurbiprofen for topical application. Different formulations of pluronic lecithin organogels were prepared by using pluronic F127, lecithin, flurbiprofen, isopropyl palmitate, water, sorbic acid, and potassium sorbate. To study the in vitro potential of these formulations, permeation studies were performed with Keshary-Chien diffusion cells. The results of the in vitro permeation studies found that release of flurbiprofen from dialysis membrane-70 was more than excised dorsal rat skin. Gelation temperature study was carried out to determine the temperature where sol-gel transformation takes place. The viscosities of different formulations were determined by using Brookfield Viscometer at 25°C, the viscosity of formulations increases as the lecithin concentration increases. Also the formulations were tested for appearance and feel psychorheologically, pH, and drug content. Interactions between the components of the gel have been investigated by differential scanning calorimetry and X-ray powder diffractometry. The optimized formulation subjected to differential scanning calorimetry shows no drug-polymer interaction. To investigate the in vivo performance of the formulations, a carrageenan-induced rat paw edema model and skin irritation study was used. The stability studies and freeze-thaw thermal cyclic test were carried out, showing no phase separation of gel, and representing gel stability. Statistical analysis of the data of animal study (anti-inflammatory activity) was done by using one way analysis of variance (ANOVA) followed by Dunnett's test. The formulation shows a statistically significant anti-inflammatory activity and is non-irritant to skin.

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.

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

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.

The role of surfactants in the formulation of elastic liposomal gels containing a synthetic opioid analgesic.

PubMed

Singh, Sima; Vardhan, Harsh; Kotla, Niranjan G; Maddiboyina, Balaji; Sharma, Dinesh; Webster, Thomas J

2016-01-01

Transdermal drug delivery systems have made significant contributions to the medical community, but have yet to completely substitute oral or parenteral delivery. Recently, various strategies have been used to augment the transdermal delivery of therapeutics. Primarily, they include iontophoresis, electrophoresis, sonophoresis, chemical permeation enhancers, microneedles, and vesicular systems. Among these strategies, elastic liposomes appear promising. Elastic vesicle scaffolds have been developed and evaluated as novel topical and transdermal delivery systems, with an infrastructure consisting of hydrophobic and hydrophilic moieties together, and as a result, such scaffolds can accommodate drug molecules with a wide range of solubility. High deformability of these vesicles provides for better penetration of intact vesicles. This system is much more efficient at delivering low- and high-molecular-weight drugs to the skin in terms of quantity and depth. In this work, elastic liposomes of Tramadol HCl were prepared using a solvent evaporation method with different surfactants and were characterized using microscopy, and particle size, shape, drug content, ex vivo release, and zeta potential were also calculated. The prepared elastic liposomes were found to be in the range of 152.4 nm with a zeta potential of -22.4 mV; the entrapment efficiencies of the selected formulation was found to be 79.71%±0.27%. All formulations in the form of a gel were evaluated for physicochemical properties and were found to be homogeneous with no grittiness, and the pH of all formulations was found to be neutral. The optimized selected elastic liposomal formulation followed the Higuchi equation and Fickian diffusion and released the drug for a period of 24 hours. The overall results provide much promise for the continued investigation of deformable vesicles as transdermal drug carriers.

Development of sustained and dual drug release co-extrusion formulations for individual dosing.

PubMed

Laukamp, Eva Julia; Vynckier, An-Katrien; Voorspoels, Jody; Thommes, Markus; Breitkreutz, Joerg

2015-01-01

In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethyleneglycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 ± 0.2 °C, 45%r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 ± 2.0 N and 26.4 ± 2.8 N and E-modulus of 118.1 ± 8.4 and 33.9 ± 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

The role of surfactants in the formulation of elastic liposomal gels containing a synthetic opioid analgesic

PubMed Central

Singh, Sima; Vardhan, Harsh; Kotla, Niranjan G; Maddiboyina, Balaji; Sharma, Dinesh; Webster, Thomas J

2016-01-01

Transdermal drug delivery systems have made significant contributions to the medical community, but have yet to completely substitute oral or parenteral delivery. Recently, various strategies have been used to augment the transdermal delivery of therapeutics. Primarily, they include iontophoresis, electrophoresis, sonophoresis, chemical permeation enhancers, microneedles, and vesicular systems. Among these strategies, elastic liposomes appear promising. Elastic vesicle scaffolds have been developed and evaluated as novel topical and transdermal delivery systems, with an infrastructure consisting of hydrophobic and hydrophilic moieties together, and as a result, such scaffolds can accommodate drug molecules with a wide range of solubility. High deformability of these vesicles provides for better penetration of intact vesicles. This system is much more efficient at delivering low- and high-molecular-weight drugs to the skin in terms of quantity and depth. In this work, elastic liposomes of Tramadol HCl were prepared using a solvent evaporation method with different surfactants and were characterized using microscopy, and particle size, shape, drug content, ex vivo release, and zeta potential were also calculated. The prepared elastic liposomes were found to be in the range of 152.4 nm with a zeta potential of −22.4 mV; the entrapment efficiencies of the selected formulation was found to be 79.71%±0.27%. All formulations in the form of a gel were evaluated for physicochemical properties and were found to be homogeneous with no grittiness, and the pH of all formulations was found to be neutral. The optimized selected elastic liposomal formulation followed the Higuchi equation and Fickian diffusion and released the drug for a period of 24 hours. The overall results provide much promise for the continued investigation of deformable vesicles as transdermal drug carriers. PMID:27114707

Dropwise additive manufacturing of pharmaceutical products for amorphous and self emulsifying drug delivery systems.

PubMed

Içten, Elçin; Purohit, Hitesh S; Wallace, Chelsey; Giridhar, Arun; Taylor, Lynne S; Nagy, Zoltan K; Reklaitis, Gintaras V

2017-05-30

The improvements in healthcare systems and the advent of the precision medicine initiative have created the need to develop more innovative manufacturing methods for the delivery and production of individualized dosing and personalized treatments. In accordance with the changes observed in healthcare systems towards more innovative therapies, this paper presents dropwise additive manufacturing of pharmaceutical products (DAMPP) for small scale, distributed manufacturing of individualized dosing as an alternative to conventional manufacturing methods A dropwise additive manufacturing process for amorphous and self-emulsifying drug delivery systems is reported, which utilizes drop-on-demand printing technology for automated and controlled deposition of melt-based formulations onto inert tablets. The advantages of drop on demand technology include reproducible production of droplets with adjustable sizing and high placement accuracy, which enable production of individualized dosing even for low dose and high potency drugs. Flexible use of different formulations, such as lipid-based formulations, allows enhancement of the solubility of poorly water soluble and highly lipophilic drugs with DAMPP. Here, DAMPP is used to produce solid oral dosage forms from melts of an active pharmaceutical ingredient and a surfactant. The dosage forms are analyzed to show the amorphous nature, self-emulsifying drug delivery system characteristics and dissolution behavior of these formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Development and application of a biorelevant dissolution method using USP apparatus 4 in early phase formulation development.

PubMed

Fang, Jiang B; Robertson, Vivian K; Rawat, Archana; Flick, Tawnya; Tang, Zhe J; Cauchon, Nina S; McElvain, James S

2010-10-04

Dissolution testing is frequently used to determine the rate and extent at which a drug is released from a dosage form, and it plays many important roles throughout drug product development. However, the traditional dissolution approach often emphasizes its application in quality control testing and usually strives to obtain 100% drug release. As a result, dissolution methods are not necessarily biorelevant and meaningful application of traditional dissolution methods in the early phases of drug product development can be very limited. This article will describe the development of a biorelevant in vitro dissolution method using USP apparatus 4, biorelevant media, and real-time online UV analysis. Several case studies in the areas of formulation selection, lot-to-lot variability, and food effect will be presented to demonstrate the application of this method in early phase formulation development. This biorelevant dissolution method using USP apparatus 4 provides a valuable tool to predict certain aspects of the in vivo drug release. It can be used to facilitate the formulation development/selection for pharmacokinetic (PK) and clinical studies. It may also potentially be used to minimize the number of PK studies, and to aid in the design of more efficient PK and clinical studies.

Statistical evaluation for stability studies under stress storage conditions.

PubMed

Gil-Alegre, M E; Bernabeu, J A; Camacho, M A; Torres-Suarez, A I

2001-11-01

During the pharmaceutical development of a new drug, it is necessary to select as soon as possible the formulation with the best stability characteristics. The current International Commission for Harmonisation (ICH) regulations regarding stability testing requirements for a Registration Application provide the stress testing conditions with the aim of assessing the effect of severe conditions on the drug product. In practice, the well-known Arrhenius theory is still used to make a rapid stability prediction, to estimate a drug product shelf life during early stages of its pharmaceutical development. In this work, both the planning of a stress stability study to obtain a correct stability prediction from a temperature extrapolation and the suitable data treatment to discern the reliability of the stability results are discussed. The study was focused on the early formulation step of a very stable drug, Mitonafide (antineoplastic agent), formulated in a parenteral solution and in tablets. It was observed, for the solid system, that the extrapolated results using Arrhenius theory might be statistically good, but far from the real situation if the stability study is not designed in a correct way. The statistical data treatment and the stress-stability test proposed in this work are suitable to make a reliable stability prediction of different formulations with the same drug, within its pharmaceutical development.

Development of Orodispersible Tablets of Candesartan Cilexetil-β-cyclodextrin Complex

PubMed Central

Sravya, Maddukuri; Deveswaran, Rajamanickam; Bharath, Srinivasan; Basavaraj, Basappa Veerbadraiah; Madhavan, Varadharajan

2013-01-01

The aim of this study was to investigate the use of inclusion complexation technique employing β-cyclodextrin in improving the dissolution profile of candesartan cilexetil, a BCS class-II drug, and to formulate the inclusion complex into orodispersible tablets. The inclusion complexes were formed by physical mixing, kneading, coevaporation, and lyophilisation methods. Inclusion complexes were characterized by FTIR, DSC, XRD, NMR, and mass spectral studies. Inclusion complexes prepared using kneading, and lyophilisation techniques in the molar ratio 1 : 5 with β-cyclodextrin were used for formulating orodispersible tablets by direct compression with different superdisintegrants like croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose in varying concentrations. The directly compressible powder was evaluated for precompression parameters, and the prepared orodispersible tablets were evaluated for postcompression parameters. Drug-excipient compatibility studies showed no interaction, and characterization proved the formation of inclusion complex. In vitro disintegration time was found to be within 3 minutes, and all the formulations showed complete drug release of 100% within 20 minutes. The optimized formulation was found to be stable after 6 months and showed no significant change in drug content. This work proved β-cyclodextrins to be effective solubilizing agent in improving the solubility of poorly water soluble drugs. PMID:26555987

Optimization of primaquine diphosphate tablet formulation for controlled drug release using the mixture experimental design.

PubMed

Duque, Marcelo Dutra; Kreidel, Rogério Nepomuceno; Taqueda, Maria Elena Santos; Baby, André Rolim; Kaneko, Telma Mary; Velasco, Maria Valéria Robles; Consiglieri, Vladi Olga

2013-01-01

A tablet formulation based on hydrophilic matrix with a controlled drug release was developed, and the effect of polymer concentrations on the release of primaquine diphosphate was evaluated. To achieve this purpose, a 20-run, four-factor with multiple constraints on the proportions of the components was employed to obtain tablet compositions. Drug release was determined by an in vitro dissolution study in phosphate buffer solution at pH 6.8. The polynomial fitted functions described the behavior of the mixture on simplex coordinate systems to study the effects of each factor (polymer) on tablet characteristics. Based on the response surface methodology, a tablet composition was optimized with the purpose of obtaining a primaquine diphosphate release closer to a zero order kinetic. This formulation released 85.22% of the drug for 8 h and its kinetic was studied regarding to Korsmeyer-Peppas model, (Adj-R(2) = 0.99295) which has confirmed that both diffusion and erosion were related to the mechanism of the drug release. The data from the optimized formulation were very close to the predictions from statistical analysis, demonstrating that mixture experimental design could be used to optimize primaquine diphosphate dissolution from hidroxypropylmethyl cellulose and polyethylene glycol matrix tablets.

Laser-induced disruption of systemically administered liposomes for targeted drug delivery

NASA Astrophysics Data System (ADS)

Mackanos, Mark A.; Larabi, Malika; Shinde, Rajesh; Simanovskii, Dmitrii M.; Guccione, Samira; Contag, Christopher H.

2009-07-01

Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 °C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration.

PubMed

Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

2015-01-01

The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

PubMed Central

Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

2015-01-01

The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions. PMID:26073995

Nanoformulated water-soluble paclitaxel to enhance drug efficacy and reduce hemolysis side effect.

PubMed

Gu, Weiting; Chen, Jie; Patra, Prabir; Yang, Xiaoyan; Gu, Quanrong; Wei, Lingxuan; Acker, Jason P; Kong, Beihua

2017-07-01

Surgery, chemotherapy, and radiotherapy are the three top cancer treatment modalities. Paclitaxel (PTX) is one of the most widely used chemotherapy drugs. However, its clinical applications have been significantly limited due to: (i) serious hemolysis effect of currently available commercial paclitaxel formulations and (ii) its water insolubility. An easy way to deliver paclitaxel by a new nanocarrier system using pluronic copolymers of P123/F68 and Sorbitan monopalmitate (Span 40) was reported in our previous research article. The characterization of the formulation and analysis of drug release and cellular uptake were also presented. In this article, we reported discoveries of our follow-up in vivo antitumor and in vitro hemolytic study discoveries. The experimental results showed that the nanoformulated PTX achieved much better tumor suppression performance while reducing hemolysis side effects. This newly formulated drug can significantly improve patient outcomes in cancer chemotherapy.

Medicated chewing gum, a novel drug delivery system

PubMed Central

Aslani, Abolfazl; Rostami, Farnaz

2015-01-01

New formulations and technologies have been developed through oral drug delivery systems’ researches. Such researches display significance of oral route amongst patients. We’ve reviewed all the features associated with medicated chewing gum as a modern drug delivery by introducing the history, advantages and disadvantages, methods of manufacturing, composition differences, evaluation tests and examples of varieties of medicated chewing gums. Acceptance of medicated chewing gum has been augmented through years. The advantages and therapeutic benefits of chewing gum support its development as we can see new formulations with new drugs contained have been produced from past and are going to find a place in market by formulation of new medicated chewing gums. Potential applications of medicated chewing gums are highly widespread as they will be recognized in future. Nowadays standards for qualifying chewing gums are the same as tablets. Patient-centered studies include medicated chewing gums as a delivery system too which creates compliance for patients. PMID:26109999

Doxorubicin loaded magneto-niosomes for targeted drug delivery.

PubMed

Tavano, Lorena; Vivacqua, Marco; Carito, Valentina; Muzzalupo, Rita; Caroleo, Maria Cristina; Nicoletta, Fiore

2013-02-01

In chemotherapy the magnetic drug targeting to a specific organ or tissue is proposed on the assumption that magnetic fields are harmless to biological systems. In this light we have vehiculated doxorubicin as model drug by novel magneto-niosomes in order to evaluate the physico-chemical properties of the obtained formulations and the in vitro release profile. Tween 60 and Pluronic L64 have been used as surfactants and the formulation cytotoxicity has been performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide and trypan blue dye esclusion tests. Results show that niosome dimensions and doxorubicin entrapment efficiencies are influenced by bilayer composition. In addition, formulations are able to control the deliver and release of the drug active form in a retarded manner. No additional toxicity, due to the encapsulation of ferrofluid into niosomes core, has been detected. Copyright © 2012 Elsevier B.V. All rights reserved.

Formulation and optimization of fast dissolving intraoral drug delivery system for clobazam using response surface methodology

PubMed Central

Bala, Rajni; Khanna, Sushil; Pawar, Pravin K.

2013-01-01

Clobazam is a newer 1,5-benzodiazepine used for the treatment of epilepsy. It is better tolerated and less sedating than other benzodiazepines. Absorption of the drug can be impacted by oral fast dissolving dosage form; this may have implications for epilepsy in pediatrics and those having difficulty in swallowing tablets/capsules resulting in improved patient compliance. The purpose of the present investigation was to formulate and optimize clobazam oro-dissolving tablets by direct compression method using response surface methodology (RSM). Oro-dispersible tablets of clobazam were prepared by direct compression method using crospovidone (2-6%) as a superdisintegrant, microcrystalline cellulose (MCC) (20-40%) was used as diluents along with directly compressible mannitol to enhance mouth feel. A 32 full factorial design was applied to investigate the combined effect of two formulation variables: amount of crospovidone and MCC over the independent variables disintegration time, wetting time and percent drug release. Disintegration time showed by all formulations was found to be in the range of 24.3-193 s based on evaluation parameters the formulation containing 6% of crospovidone and 30% of MCC showed promising performance against all other formulations. The results demonstrated that the RSM could efficiently be applied for the formulation of clobazam oro-dispersible tablets; therefore, constitute an advance in the management of epileptic attacks. PMID:24083203

Acceptance survey of a fast dissolving tablet pharmaceutical formulation in allergic patients. Satisfaction and expectancies.

PubMed

Roger Reig, Albert; Plazas Fernández, M Josep; Galván Cervera, Jordi; Heras Navarro, Joan; Artés Ferragud, Maite; Gabarrón Hortal, Elia

2006-01-01

One of the factors affecting compliance is the pharmaceutical formulation used. Many patients find it difficult to swallow tablets or capsules. The fast dissolving tablet (FDT) formulation could help to enhance patient compliance, because of its ease of administration and because no liquid is required to help intake. A survey was conducted in patients diagnosed with allergic rhinitis or dermatitis (positive skin tests and/or specific IgE) and urticaria to asses the degree of acceptance of and preference for an FDT formulation. Of the 7,686 patients who participated in the survey, 90 % considered the initial flavor and 83 % considered the aftertaste to be very or quite satisfactory, 95 % were very satisfied with the disintegration time, 79 % were very satisfied with the form, 82 % with the size, 72 % with the packaging and 78 % with the instructions for use. Ninety-three percent considered that being able to take the drug at any time or place was very important or fairly important. Ninety-four percent considered the ease of use to be much better or better. If given the choice, 93 % would choose an FDT formulation. Eighty-eight percent of the patients would like to change their current antihistaminic drug for a new allergy drug in an FDT formulation. Most of the patients were highly satisfied with the characteristics of the FDT formulation and would choose it for the treatment of their allergies.

Gamma scintigraphic evaluation of floating gastroretentive tablets of metformin HCl using a combination of three natural polymers in rabbits

PubMed Central

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

2015-01-01

The present research was aimed at formulating a metformin HCl sustained-release formulation from a combination of polymers, using the wet granulation technique. A total of 16 formulations (F1–F16) were produced using different combinations of the gel-forming polymers: tamarind kernel powder, salep (palmate tubers of Orchis morio), and xanthan. Post-compression studies showed that there were no interactions between the active drug and the polymers. Results of in vitro drug-release studies indicated that the F10 formulation which contained 5 mg of tamarind kernel powder, 33.33 mg of xanthan, and 61.67 mg of salep could sustain a 95% release in 12 hours. The results also showed that F2 had a 55% similarity factor with the commercial formulation (C-ER), and the release kinetics were explained with zero order and Higuchi models. The in vivo study was performed in New Zealand White rabbits by gamma scintigraphy; the F10 formulation was radiolabeled using samarium (III) oxide (153Sm2O3) to trace transit of the tablets in the gastrointestinal tract. The in vivo data supported the retention of F10 formulation in the gastric region for 12 hours. In conclusion, the use of a combination of polymers in this study helped to develop an optimal gastroretentive drug-delivery system with improved bioavailability, swelling, and floating characteristics. PMID:26273196

Distinctive features of "chronotherapeutic" and "pulsatile" drug delivery systems negating the practice of their interchangeable terminology.

PubMed

Ali, Javed; Baboota, Sanjula; Ahuja, Alka; Saigal, Nitin

2010-07-01

The term pulsatile drug delivery has often been used as a synonym to chronotherapeutic drug delivery. This needs to be given a thought as both the drug delivery systems are entirely addressing different needs of the patients as well as the intentions of the formulators being different. Chronotherapeutic systems are based completely on circadian needs and response of the body and the need of the drug to be in its maximum concentrations at a particular time of the day, the fact being supported by endless list of ailments which elicit the related symptoms at a particular time of the day. Considering the formulation approach, one does not find major differences among site-specific chronotherapeutic systems and the basic and more conventional intestinal or colon targeted systems due to the mechanism and the site of landing of drug of both being almost similar even though the intention of the formulator being different. An ideal pulsatile system is the one delivering drug in different pulses with multiple troughs in release profile. The article explores the major differences in between the two systems and highlights the need of using appropriate terminology for these individual and distinct systems catering different needs.

Colon-targeted oral drug delivery systems: design trends and approaches.

PubMed

Amidon, Seth; Brown, Jack E; Dave, Vivek S

2015-08-01

Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

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

Creation of a Long-Acting Nanoformulated 2′,3′-Dideoxy-3′-Thiacytidine

PubMed Central

Guo, Dongwei; Zhou, Tian; Araínga, Mariluz; Palandri, Diana; Gautam, Nagsen; Bronich, Tatiana; Alnouti, Yazen; McMillan, JoEllyn; Edagwa, Benson

2017-01-01

Background: Antiretroviral drug discovery and formulation design will facilitate viral clearance in infectious reservoirs. Although progress has been realized for selected hydrophobic integrase and nonnucleoside reverse transcriptase inhibitors, limited success has been seen to date with hydrophilic nucleosides. To overcome these limitations, hydrophobic long-acting drug nanoparticles were created for the commonly used nucleoside reverse transcriptase inhibitor, lamivudine (2′,3′-dideoxy-3′-thiacytidine, 3TC). Methods: A 2-step synthesis created a slow-release long-acting hydrophobic 3TC. Conjugation of 3TC to a fatty acid created a myristoylated prodrug which was encased into a folate-decorated poloxamer 407. Both in vitro antiretroviral efficacy in human monocyte-derived macrophages and pharmacokinetic profiles in mice were evaluated for the decorated nanoformulated drug. Results: A stable drug formulation was produced by poloxamer encasement that improved monocyte–macrophage uptake, antiretroviral activities, and drug pharmacokinetic profiles over native drug formulations. Conclusions: Sustained release of long-acting antiretroviral therapy is a new therapeutic frontier for HIV/AIDS. 3TC depot formation in monocyte-derived macrophages can be facilitated through stable subcellular internalization and slow drug release. PMID:27559685

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.

Cyclodextrins as excipients in tablet formulations.

PubMed

Conceição, Jaime; Adeoye, Oluwatomide; Cabral-Marques, Helena Maria; Lobo, José Manuel Sousa

2018-04-22

This paper aims to provide a critical review of cyclodextrins as excipients in tablet formulations, highlighting: (i) the principal pharmaceutical applications of cyclodextrins; (ii) the most relevant technological aspects in pharmaceutical formulation development; and (iii) the actual regulatory status of cyclodextrins. Moreover, several illustrative examples are presented. Cyclodextrins can be used as complexing excipients in tablet formulations for low-dose drugs. By contrast, for medium-dose drugs and/or when the complexation efficiency is low, the methods to enhance the complexation efficiency play a key part in reducing the cyclodextrin quantity. In addition, these compounds are used as fillers, disintegrants, binders and multifunctional direct compression excipients of the tablets. Copyright © 2018 Elsevier Ltd. All rights reserved.

Formulation of wax oxybenzone microparticles using a factorial approach.

PubMed

Gomaa, Y A; Darwish, I A; Boraei, N A; El-Khordagui, L K

2010-01-01

Oxybenzone wax microparticles (MPs) were prepared by the hydrophobic congealable disperse phase method. The formulation of oxybenzone-loaded MPs was optimized using a 2⁴ experimental design. Factorial analysis indicated that the main MP characteristics were influenced by initial drug loading, emulsification speed, emulsifier concentration and hydrophilic-lipophilic balance. MPs were spherical with 50.5–88.1 μm size range, 17.8–38.9 drug content in mg/100 mg MPs and 33.1–87.2% oxybenzone release in 1 h. A wide range of sunscreen delivery systems suitable for different formulation purposes were generated which may contribute to the advanced formulation of sunscreen products with improved performance.

Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: A Government of India NMITLI arthritis project

PubMed Central

Chopra, Arvind; Saluja, Manjit; Tillu, Girish; Venugopalan, Anuradha; Narsimulu, Gumdal; Sarmukaddam, Sanjeev; Patwardhan, Bhushan

2012-01-01

Background: Results of an exploratory trial suggested activity trends of Zingiber officinale-Tinopsora cordifolia (platform combination)-based formulations in the treatment of Osteoarthritis (OA) Knees. These formulations were “platform combination+Withania somnifera+Tribulus terrestris” (formulation B) and “platform combination+Emblica officinale” (formulation C). This paper reports safety of these formulations when used in higher doses (1.5–2 times) along with Sallaki Guggul and Bhallataka Parpati (a Semecarpus anacardium preparation). Materials and Methods: Ninety-two patients with symptomatic OA knees were enrolled in a 6 weeks investigator blind, randomized parallel efficacy 4-arm multicenter drug trial. The 4 arms were (I) formulation B, 2 t.i.d.; (II) formulation B, 2 q.i.d.; (III) platform combination+Sallaki Guggul; (IV) Bhallataka Parpati+formulation C. A detailed enquiry was carried out for adverse events (AE) and drug toxicity as per a priori check list and volunteered information. Laboratory evaluation included detailed hematology and metabolic parameters. Patients were examined at baseline, first and fourth weeks, and on completion. Standard statistical program (SPSS version 12.5) was used for analysis. Results: None of the patients reported serious AE or withdrew due to any drug-related toxicity. Mild gut–related (mostly epigastric burning) AE was reported. A mild increase in liver enzymes [serum glutamic pyruvate transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT)] without any other hepatic abnormality was reported in 2 patients (group IV). Other laboratory parameters remained normal. The mean improvement in active pain visual analog scale (1.4, CI 0.5–2.22), WOMAC (functional activity questionnaire) pain score (1.37, CI 0.22–2.5), and urinary C-TAX (cartilage collagen breakdown product) assay was maximum (NS) in group IV. Lower dose group I showed numerically superior improvement compared with higher dose group II. Conclusion: The results suggested that despite higher doses, standardized Ayurvedic formulations demonstrated a good safety profile. An improved efficacy and likely chondroprotective effect was shown by group IV intervention. A confirmatory drug trial with adequate power and sample size was planned based on the learning from this trial. PMID:22529679

Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: A Government of India NMITLI arthritis project.

PubMed

Chopra, Arvind; Saluja, Manjit; Tillu, Girish; Venugopalan, Anuradha; Narsimulu, Gumdal; Sarmukaddam, Sanjeev; Patwardhan, Bhushan

2012-01-01

Results of an exploratory trial suggested activity trends of Zingiber officinale-Tinopsora cordifolia (platform combination)-based formulations in the treatment of Osteoarthritis (OA) Knees. These formulations were "platform combination+Withania somnifera+Tribulus terrestris" (formulation B) and "platform combination+Emblica officinale" (formulation C). This paper reports safety of these formulations when used in higher doses (1.5-2 times) along with Sallaki Guggul and Bhallataka Parpati (a Semecarpus anacardium preparation). Ninety-two patients with symptomatic OA knees were enrolled in a 6 weeks investigator blind, randomized parallel efficacy 4-arm multicenter drug trial. The 4 arms were (I) formulation B, 2 t.i.d.; (II) formulation B, 2 q.i.d.; (III) platform combination+Sallaki Guggul; (IV) Bhallataka Parpati+formulation C. A detailed enquiry was carried out for adverse events (AE) and drug toxicity as per a priori check list and volunteered information. Laboratory evaluation included detailed hematology and metabolic parameters. Patients were examined at baseline, first and fourth weeks, and on completion. Standard statistical program (SPSS version 12.5) was used for analysis. None of the patients reported serious AE or withdrew due to any drug-related toxicity. Mild gut-related (mostly epigastric burning) AE was reported. A mild increase in liver enzymes [serum glutamic pyruvate transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT)] without any other hepatic abnormality was reported in 2 patients (group IV). Other laboratory parameters remained normal. The mean improvement in active pain visual analog scale (1.4, CI 0.5-2.22), WOMAC (functional activity questionnaire) pain score (1.37, CI 0.22-2.5), and urinary C-TAX (cartilage collagen breakdown product) assay was maximum (NS) in group IV. Lower dose group I showed numerically superior improvement compared with higher dose group II. The results suggested that despite higher doses, standardized Ayurvedic formulations demonstrated a good safety profile. An improved efficacy and likely chondroprotective effect was shown by group IV intervention. A confirmatory drug trial with adequate power and sample size was planned based on the learning from this trial.

Recent Progress in Nanomedicine: Therapeutic, Diagnostic and Theranostic Applications

PubMed Central

Rizzo, Larissa Y.; Theek, Benjamin; Storm, Gert; Kiessling, Fabian; Lammers, Twan

2013-01-01

In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathological sites, as well as for visualizing and quantifying important (patho-) physiological processes. In addition, ever more efforts have been undertaken to combine diagnostic and therapeutic properties within a single nanomedicine formulation. These so-called nanotheranostics are able to provide valuable information on drug delivery, drug release and drug efficacy, and they are considered to be highly useful for personalizing nanomedicine-based (chemo-) therapeutic interventions. PMID:23578464

Feline Transdermal Formulation Considerations.

PubMed

Forsythe, Lauren Eichstadt

2017-01-01

Transdermal delivery of drugs is comparatively new in feline patients. However, transdermal formulations can be a desirable option for treating feline patients that are not willing participants to medication administration. However, achieving drug penetration across the skin is not always easy, and there are a wide variety of variables that can further affect penetration. This, coupled with a lack of studies, make transdermal administration an unknown with regards to efficacy and safety for many drugs. This article focuses on drugs that are administered transdermally with the intent of producing systemic effects. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

The study of marketed and experimental formulation approaches enabling site-specific delivery of mesalamine in patients with inflammatory bowel disease.

PubMed

Kadiyala, Irina; Jacobs, Dylan

2014-04-01

This patent review focuses exclusively on the oral delivery of mesalamine (5-ASA) and excludes oral mesalamine pro-drug and rectal delivery formulations. The formulation strategies of marketed formulations (Apriso(®), Asacol(®), Lialda(®) and Pentasa(®)) and non-marketed formulations are reviewed and explained by decoding formulation specifics that enable the site specific delivery for the treatment of inflammatory bowel disease.

[New and "old" antiretroviral drugs in Pediatrics: new doses, formulations and associations].

PubMed

Villarroel B, Julia

2010-10-01

Of the 25 antiretroviral drugs available in the market, only 16 are allowed for prescription in the pediatric patients. The antiretroviral, pertaining to the first three families, used for two decades, remain valid and are important components of antiretroviral therapy in naive children. We describe doses, presentations and current associations for these drugs in children, and also discuss new co-formulations that will reduce the number of doses, improve tolerance and therefore achieve better adherence of pediatric patients.

Thermodynamics of Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs-Impact of a Second Drug on the Solution Phase Behavior and Implications for Combination Products.

PubMed

Trasi, Niraj S; Taylor, Lynne S

2015-08-01

There is increasing interest in formulating combination products that contain two or more drugs. Furthermore, it is also common for different drug products to be taken simultaneously. This raises the possibility of interactions between different drugs that may impact formulation performance. For poorly water-soluble compounds, the supersaturation behavior may be a critical factor in determining the extent of oral absorption. The goal of the current study was to evaluate the maximum achievable supersaturation for several poorly water-soluble compounds alone, and in combination. Model compounds included ritonavir, lopinavir, paclitaxel, felodipine, and diclofenac. The "amorphous solubility" for the pure drugs was determined using different techniques and the change in this solubility was then measured in the presence of differing amounts of a second drug. The results showed that "amorphous solubility" of each component in aqueous solution is substantially decreased by the second component, as long as the two drugs are miscible in the amorphous state. A simple thermodynamic model could be used to predict the changes in solubility as a function of composition. This information is of great value when developing co-amorphous or other supersaturating formulations and should contribute to a broader understanding of drug-drug physicochemical interactions in in vitro assays as well as in the gastrointestinal tract. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Reduction-Responsive Polymeric Micelles and Vesicles for Triggered Intracellular Drug Release

PubMed Central

Sun, Huanli; Cheng, Ru; Deng, Chao

2014-01-01

Abstract Significance: The therapeutic effects of current micellar and vesicular drug formulations are restricted by slow and inefficient drug release at the pathological site. The development of smart polymeric nanocarriers that release drugs upon arriving at the target site has received a tremendous amount of attention for cancer therapy. Recent Advances: Taking advantage of a high reducing potential in the tumor tissues and in particular inside the tumor cells, various reduction-sensitive polymeric micelles and vesicles have been designed and explored for triggered anticancer drug release. These reduction-responsive nanosystems have demonstrated several unique features, such as good stability under physiological conditions, fast response to intracellular reducing environment, triggering drug release right in the cytosol and cell nucleus, and significantly improved antitumor activity, compared to traditional reduction-insensitive counterparts. Critical Issues: Although reduction-sensitive micelles and polymersomes have accomplished rapid intracellular drug release and enhanced in vitro antitumor effect, their fate inside the cells including the mechanism, site, and rate of reduction reaction remains unclear. Moreover, the systemic fate and performance of reduction-sensitive polymeric drug formulations have to be investigated. Future Directions: Biophysical studies should be carried out to gain insight into the degradation and drug release behaviors of reduction-responsive nanocarriers inside the tumor cells. Furthermore, novel ligand-decorated reduction-sensitive nanoparticulate drug formulations should be designed and explored for targeted cancer therapy in vivo. Antioxid. Redox Signal. 21, 755–767. PMID:24279980

Drug solubility in lipid nanocarriers: Influence of lipid matrix and available interfacial area.

PubMed

Göke, Katrin; Bunjes, Heike

2017-08-30

Amongst other strategies for the formulation of poorly water-soluble drugs, solubilization of these drugs in lipid-based formulations is a promising option. Most screening methods for the identification of a suitable lipid-based formulation fail to elucidate the role interfacial effects play for drug solubility in disperse systems. In a novel screening approach called passive drug loading, different preformed lipid nanocarrier dispersions are incubated with drug powder. Afterwards, undissolved drug is filtered off and the amount of solubilized drug is determined. The aim of this study was to identify parameters for drug solubility in pure lipids as well as for drug loading to the lipid-water interface of lipid nanoparticles. Using passive loading, the solubility of eight poorly water-soluble drugs in seven lipid nanocarriers varying in particle size or lipid matrix was investigated. Drug solubility in the nanocarriers did not follow any apparent trend and different drugs dissolved best in different carriers. Drugs with a melting point below approximately 150°C displayed distinctly better solubility than higher melting drugs. Additionally, relating the specific lipid nanocarrier surface area to the drug solubility allowed drawing conclusions on the drug localization. Fenofibrate, dibucaine and, less distinctly also clotrimazole, which all melt below 150°C, were predominantly located in the lipid droplet core of the nanoparticles. In contrast, the five remaining drugs (betamethasone valerate, flufenamic acid, itraconazole, ketoconazole, mefenamic acid) were also located at the lipid-water interface to different, but substantial degrees. The ability to account for drug loading to the lipid-water interface is thus a major advantage of passive loading. Copyright © 2017 Elsevier B.V. All rights reserved.

Designing and developing suppository formulations for anti-HIV drug delivery.

PubMed

Ham, Anthony S; Buckheit, Robert W

2017-08-01

Despite a long history of use for rectal and vaginal drug delivery, the current worldwide market for suppositories is limited primarily due to a lack of user acceptability. Therefore, virtually no rational pharmaceutical development of antiviral suppositories has been performed. However, suppositories offer several advantages over other antiviral dosage forms. Current suppository designs have integrated active pharmaceutical ingredients into existing formulation designs without optimization. As such, emerging suppository development has been focused on improving upon the existing classical design to enhance drug delivery and is poised to open suppository drug delivery to a broader range of drugs, including antiretroviral products. Thus, with continuing research into rational suppository design and development, there is significant potential for antiretroviral suppository drug delivery.

Nanocarriers for cancer-targeted drug delivery.

PubMed

Kumari, Preeti; Ghosh, Balaram; Biswas, Swati

2016-01-01

Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the pharmacokinetics of the loaded poorly soluble hydrophobic drugs by solubilizing them in the hydrophobic compartments, nanoparticles allowed cancer specific drug delivery by inherent passive targeting phenomena and adopted active targeting strategies. For this reason, nanoparticles-drug formulations are capable of enhancing the safety, pharmacokinetic profiles and bioavailability of the administered drugs leading to improved therapeutic efficacy compared to conventional therapy. The focus of this review is to provide an overview of various nanoparticle formulations in both research and clinical applications with a focus on various chemotherapeutic drug delivery systems for the treatment of cancer. The use of various nanoparticles, including liposomes, polymeric nanoparticles, dendrimers, magnetic and other inorganic nanoparticles for targeted drug delivery in cancer is detailed.

Swelling/Floating Capability and Drug Release Characterizations of Gastroretentive Drug Delivery System Based on a Combination of Hydroxyethyl Cellulose and Sodium Carboxymethyl Cellulose

PubMed Central

Chen, Ying-Chen; Ho, Hsiu-O; Liu, Der-Zen; Siow, Wen-Shian; Sheu, Ming-Thau

2015-01-01

The aim of this study was to characterize the swelling and floating behaviors of gastroretentive drug delivery system (GRDDS) composed of hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (NaCMC) and to optimize HEC/NaCMC GRDDS to incorporate three model drugs with different solubilities (metformin, ciprofloxacin, and esomeprazole). Various ratios of NaCMC to HEC were formulated, and their swelling and floating behaviors were characterized. Influences of media containing various NaCl concentrations on the swelling and floating behaviors and drug solubility were also characterized. Finally, release profiles of the three model drugs from GRDDS formulation (F1-4) and formulation (F1-1) were examined. Results demonstrated when the GRDDS tablets were tested in simulated gastric solution, the degree of swelling at 6 h was decreased for each formulation that contained NaCMC in comparison to those in de-ionized water (DIW). Of note, floating duration was enhanced when in simulated gastric solution compared to DIW. Further, the hydration of tablets was found to be retarded as the NaCl concentration in the medium increased resulting in smaller gel layers and swelling sizes. Dissolution profiles of the three model drugs in media containing various concentrations of NaCl showed that the addition of NaCl to the media affected the solubility of the drugs, and also their gelling behaviors, resulting in different mechanisms for controlling a drug’s release. The release mechanism of the freely water-soluble drug, metformin, was mainly diffusion-controlled, while those of the water-soluble drug, ciprofloxacin, and the slightly water-soluble drug, esomeprazole, were mainly anomalous diffusion. Overall results showed that the developed GRDDS composed of HEC 250HHX and NaCMC of 450 cps possessed proper swelling extents and desired floating periods with sustained-release characteristics. PMID:25617891

Assessment of extended-release opioid analgesics for the treatment of chronic pain.

PubMed

Gudin, Jeffrey A

2013-03-01

Approximately 3.8 million patients annually receive extended-release (ER) or long-acting opioid prescriptions in the outpatient setting, around half of which are written by primary care physicians. Compared with short-acting, immediate-release (IR) formulations, ER and oral long-acting opioid analgesics are associated with clinical advantages, such as extended periods of time during which drug plasma levels are within the therapeutic range, decreased peak-to-trough fluctuations, and prolonged analgesia over the dosing period. Additionally, ER opioids offer a more convenient, less frequent dosing regimen to chronic pain patients who are often taking several concomitant medications. The increased utilization of ER opioids has been accompanied by a rise in the misuse and abuse of these formulations. Certain pharmacokinetic parameters (e.g., longer time to maximum drug plasma concentration, lower maximum drug plasma concentration) may decrease the abuse potential of intact ER opioids by limiting the positive subjective and reinforcing effects relative to IR formulations. Putative abuse-deterrent formulations have also recently been introduced to impede physical manipulation of these formulations, or reduce the harm resulting from such behavior. Such formulations may represent an incremental advance to reduce non-oral forms of abuse. This article reviews the pharmacokinetic profiles and abuse-deterrent features of newer ER opioid analgesics for the treatment of moderate to severe chronic pain.

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.

Lyophilization closures for protein based drugs.

PubMed

DeGrazio, F; Flynn, K

1992-01-01

Rubber stopper formulations which are currently used as lyophilization stoppers vary widely in their capacities to absorb and release moisture. Release of moisture from the stopper over the shelf life of the product may result in drug degradation for extremely low cake weight products. The degree to which rubber formulations absorb water is dependent upon the components of these formulations. Independently, polymers and fillers absorb water during autoclave cycles to varying levels depending upon such factors as the solubility, structure, possibility of chemical reactions and impurity levels of these materials. Once combined into a stopper formulation, the raw materials can react to form species which further promote absorption. Data is presented comparing the absorption characteristics of low versus high absorbent rubber formulations. The release of moisture from these formulas when stoppered on vials containing dry product is also discussed.

Liposheres as a Novel Carrier for Lipid Based Drug Delivery: Current and Future Directions.

PubMed

Swain, Suryakanta; Beg, Sarwar; Babu, Sitty M

2016-01-01

Researchers are facing challenges to develop robust formulation and to enhance the bioavailability of poorly water-soluble drugs towards clinical applications. The development of new drug molecule alone is not adequate to assure ample pharmacotherapy of various diseases. Considerable results obtained from in vitro studies are not supported by in vivo data due to inadequate plasma drug concentrations. This may occur due to limited drug solubility and absorption. To resolve these problems, development of new drug delivery systems will be a promising approach. One of the promising pharmaceutical strategies is the use of lipospheres drug delivery system to deliver the poorly water-soluble drugs. Therefore, the present review described the methodology for manufacturing of lipospheres and factors influencing the formulation to deliver the drugs to the targeted site. Apart from that, this review also enlisted briefly the various applications of liposphers in medical and biomedical fields and critically discussed the recent patent system.

Colloidal microgels in drug delivery applications

PubMed Central

Vinogradov, Serguei V.

2005-01-01

Colloidal microgels have recently received attention as environmentally responsive systems and now are increasingly used in applications as carriers for therapeutic drugs and diagnostic agents. Synthetic microgels consist of a crosslinked polymer network that provides a depot for loaded drugs, protection against environmental hazards and template for post-synthetic modification or vectorization of the drug carriers. The aim of this manuscript is to review recent attempts to develop new microgel formulations for oral drug delivery, to design metal-containing microgels for diagnostic and therapeutic applications, and to advance approaches including the systemic administration of microgels. Novel nanogel drug delivery systems developed in the authors’ laboratory are discussed in details including aspects of their synthesis, vectorization and recent applications for encapsulation of low molecular weight drugs or formulation of biological macromolecules. The findings reviewed here are encouraging for further development of the nanogels as intelligent drug carriers with such features as targeted delivery and triggered drug release. PMID:17168773

Nanogel Carrier Design for Targeted Drug Delivery

PubMed Central

Eckmann, D. M.; Composto, R. J.; Tsourkas, A.; Muzykantov, V. R.

2014-01-01

Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanogel drug carrier design. In particular, we highlight published studies of nanogel design, descriptions of nanogel functional characteristics and their behavior in biological models. These studies form a compendium of information that supports the scientific and clinical rationale for development of this carrier for targeted therapeutic interventions. PMID:25485112

Formulation and evaluation of bucco-adhesive tablets of sumatriptan succinate

PubMed Central

Prasanna, R Indira; Anitha, P; Chetty, C Madhusudhana

2011-01-01

Background: A novel aspiration in treatment of migraine, to provide greater therapeutic effect, overcome the side effects by complex therapeutic regimen and to improve patient compliance upon administering bucco-adhesive tablet formulations of sumatriptan succinate which have not been tested literally. Materials and Methods: This study was designed to develop a bucco-adhesive tablet containing sumatriptan succinate using blends of different bio-adhesive polymeric combinations such as hydroxy propyl methyl cellulose K4M, sodium carboxy methyl cellulose, and Carbopol 934P with a backing layer of ethyl cellulose by a direct compression technique. Tablets were subjected to physico-chemical parameters, swelling index, surface pH, ex vivo bioadhesive force, in vitro drug release, ex vivo drug permeation, and stability in saliva. Results: Good results were obtained in all the evaluated parameters. The drug release of all formulation follows zero-order kinetics by a diffusion mechanism type. Stability studies in human saliva, ex vivo buccal permeation studies by using sheep and porcine buccal mucosa were carried out for the optimized formulation (S4 CP:HPMC 3:1). Conclusion: The developed buccal drug delivery system containing sumatriptan succinate might be the alternative routes available to bypass the first pass metabolism and might be a milestone in the therapy of migraine and among all formulations S4 shows good controlled release results correlated with ex vivo permeation studies. PMID:23071941

Formulation, optimization, and evaluation of self-emulsifying drug delivery systems of nevirapine

PubMed Central

Chintalapudi, Ramprasad; Murthy, T. E. G. K.; Lakshmi, K. Rajya; Manohar, G. Ganesh

2015-01-01

Background: The aim of the present study was to formulate and optimize the self-emulsifying drug delivery systems (SEDDS) of nevirapine (NVP) by use of 22 factorial designs to enhance the oral absorption of NVP by improving its solubility, dissolution rate, and diffusion profile. SEDDS are the isotropic mixtures of oil, surfactant, co-surfactant and drug that form oil in water microemulsion when introduced into the aqueous phase under gentle agitation. Materials and Methods: Solubility of NVP in different oils, surfactants, and co-surfactants was determined for the screening of excipients. Pseudo-ternary phase diagrams were constructed by the aqueous titration method, and formulations were developed based on the optimum excipient combinations with the help of data obtained through the maximum micro emulsion region containing combinations of oil, surfactant, and co-surfactant. The formulations of SEDDS were optimized by 22 factorial designs. Results: The optimum formulation of SEDDS contains 32.5% oleic acid, 44.16% tween 20, and 11.9% polyethylene glycol 600 as oil, surfactant, and co-surfactant respectively. The SEDDS was evaluated for the following drug content, self-emulsification time, rheological properties, zeta potential, in vitro diffusion studies, thermodynamic stability studies, and in vitro dissolution studies. An increase in dissolution was achieved by SEDDS compared to pure form of NVP. Conclusion: Overall, this study suggests that the dissolution and oral bioavailability of NVP could be improved by SEDDS technology. PMID:26682191

Current Challenges and Future of Lipid nanoparticles formulations for topical drug application to oral mucosa, skin, and eye.

PubMed

Guilherme, Viviane A; Ribeiro, Ligia N M; Tofoli, Giovana Radomille; Franz-Montan, Michelle; de Paula, Eneida; de Jesus, Marcelo Bispo

2017-11-21

Topical drug administration offers an attractive route with minimal invasiveness. It also avoids limitations of intravenous administration such as the first pass metabolism and presystemic elimination within the gastrointestinal tract. Furthermore, topical drug administration is safe, have few side effects, is easy to apply, and offers a fast onset of action. However, the development of effective topical formulations still represents a challenge for the desired effect to be reached, locally or systemically. Solid lipid nanoparticles and nanostructured lipid carriers are particular candidates to overcome the problem of topical drug administration. The nanometric particle size of lipid nanoparticles favors the physical adhesion to the skin or mucosal, what can also be attained with the formation of hybrid (nanoparticles/polymer) systems. In this review, we discuss the major challenges for lipid nanoparticles formulations for topical application to oral mucosa, skin, and eye, highlighting the strategies to improve the performance of lipid nanoparticles for topical applications. Next, we critically analyzed the in vitro and in vivo approaches used to evaluate lipid nanoparticles performance and toxicity. We addressed some major drawbacks related to lipid nanoparticle topical formulations and concluded the key points that have to be overcome to help them to reach the market in topical formulations to oral mucosa, skin and eye. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability

PubMed Central

Yeom, Dong Woo; Chae, Bo Ram; Kim, Jin Han; Chae, Jun Soo; Shin, Dong Jun; Kim, Chang Hyun; Kim, Sung Rae; Choi, Ji Ho; Song, Seh Hyon; Oh, Dongho; Sohn, Se Il; Choi, Young Wook

2017-01-01

In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul® MCM (13.2 mg), Tween® 80 (59.2 mg), Transcutol® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite® PS-10 (119.1 mg) and Vivapur® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility. PMID:29212229

Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability.

PubMed

Yeom, Dong Woo; Chae, Bo Ram; Kim, Jin Han; Chae, Jun Soo; Shin, Dong Jun; Kim, Chang Hyun; Kim, Sung Rae; Choi, Ji Ho; Song, Seh Hyon; Oh, Dongho; Sohn, Se Il; Choi, Young Wook

2017-11-07

In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul ® MCM (13.2 mg), Tween ® 80 (59.2 mg), Transcutol ® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite ® PS-10 (119.1 mg) and Vivapur ® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan ® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.

Formulation Optimization and Ex Vivo and In Vivo Evaluation of Celecoxib Microemulsion-Based Gel for Transdermal Delivery.

PubMed

Cao, Mengyuan; Ren, Lili; Chen, Guoguang

2017-08-01

Celecoxib (CXB) is a poorly aqueous solubility sulfonamide non-steroidal anti-inflammatory drug (NSAID). Hence, the formulation of CXB was selected for solubilization and bioavailability. To find out suitable formulation for microemulsion, the solubility of CXB in triacetin (oil phase), Tween 80 (surfactant), and Transcutol-P (co-surfactant) was screened respectively and optimized by using orthogonal experimental design. The Km value and concentration of oil, S mix , and water were confirmed by pseudo-ternary phase diagram studies and central composite design. One percent carbopol 934 was added to form CXB microemulsion-based gel. The final formulation was evaluated for its appearance, pH, viscosity, stability, drug content determination, globule size, and zeta potential. Its ex vivo drug permeation and the in vivo pharmacokinetic was investigated. Further research was performed to ensure the safety and validity by skin irritation study and in vivo anti-inflammatory activity study. Ex vivo permeation study in mice was designed to compare permeation and transdermal ability between microemulsion formulation and conventional gel. The results revealed that optimized microemulsion-based gel gained higher permeation based on smaller globule size and high drug loading of microemulsion. Transdermal ability was also greatly improved. Bioavailability was compared to market Celebrex® by the in vivo pharmacokinetic study in rabbits. The results indicated that CXB microemulsion-based gel had better bioavailability than Celebrex®.

Investigating the dissolution profiles of amoxicillin, metronidazole, and zidovudine formulations used in Trinidad and Tobago, West Indies.

PubMed

Stuart, Arlene Villarroel; Zuo, Jieyu; Löbenberg, Raimar

2014-10-01

Trinidad and Tobago is a twin-island Republic in the Caribbean and like many developing countries, it has included generic drugs on the national drug formulary to decrease the financial burden of pharmaceutical medications. However, to ensure that medications received by patients are beneficial, generic drugs need to be interchangeable with the innovator which has demonstrated safety, efficacy, and quality. The objective of the study was to compare the dissolution profiles and weight variations for different formulations of amoxicillin, metronidazole, and zidovudine that are on the national drug formulary and marketed in Trinidad and Tobago. All the products investigated are categorized as class 1 drugs according to the Biopharmaceutics Classification System (BCS) and the dissolution profiles were assessed according to the World Health Organization (WHO) criteria for interchangeability between products. The similarity factor, f 2, was used to determine sameness between the products. No generic formulation was found to be similar to Amoxil® 500-mg capsules. The two generic products for metronidazole 200-mg tablets demonstrated more than 85% drug release within 15 min in all three of the buffers; however, their 400-mg counterparts did not fulfill this requirement. The zidovudine 300-mg tablet complied with the requirements in buffer pH 4.5 and simulated gastric fluid (SGF) but not for simulated intestinal fluid (SIF). Some Class 1 pharmaceutical formulations may possess the same active ingredient and amount of drug but may show significant differences to in vitro equivalence requirements. Nevertheless, the dissolution process is suitable to detect these variations.

Design of eudragit RL nanoparticles by nanoemulsion method as carriers for ophthalmic drug delivery of ketotifen fumarate

PubMed Central

Soltani, Saieede; Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Jelvehgari, Mitra

2016-01-01

Objective(s): Ketotifen fumarate (KF) is a selective and noncompetitive histamine antagonist (H1-receptor) that is used topically in the treatment of allergic conditions of rhinitis and conjunctivitis. The aim of this study was to formulate and improve an ophthalmic delivery system of KF. Ocular nanoparticles were prepared with the objective of reducing the frequency of administration and obtaining controlled release to improve the anti-inflammatory drug delivery. Materials and Methods: In the present study, ocular KF loaded Eudragit RL 100 nanoparticles were prepared using O/W solvent diffusion method. The nanoparticles were evaluated for particle size, entrapment efficiency, surface morphology, X-ray diffraction (XRD), Fourier transform spectroscopy (FTIR), and differential scanning calorimetry (DSC). In vitro release and permeation studies were also carried out on nanoparticles. Results: An average size range of 182 to 314.30 nm in diameter was obtained and encapsulation efficiency up to 95.0% was observed for all the formulations. Drug release for all formulations after 24 hr was between 65.51% and 88.82% indicating effective controlled release property of KF. The mechanism of drug release for best formulation was found to be fickian diffusion mechanism. KF nanoparticles containing high polymer concentration (1:15) presented a faster drug release and a higher drug penetration; on the contrary, nanoparticles containing low polymer concentration (1:7.5) were able to give a more sustained release of the drug and thus a slower KF permeation through the cornea. Conclusion: The study revealed that KF NPs were capable of releasing the drug for a prolonged period of time and increasing the ocular bioavailability. PMID:27403262

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.

Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems.

PubMed

Danaei, M; Dehghankhold, M; Ataei, S; Hasanzadeh Davarani, F; Javanmard, R; Dokhani, A; Khorasani, S; Mozafari, M R

2018-05-18

Lipid-based drug delivery systems, or lipidic carriers, are being extensively employed to enhance the bioavailability of poorly-soluble drugs. They have the ability to incorporate both lipophilic and hydrophilic molecules and protecting them against degradation in vitro and in vivo. There is a number of physical attributes of lipid-based nanocarriers that determine their safety, stability, efficacy, as well as their in vitro and in vivo behaviour. These include average particle size/diameter and the polydispersity index (PDI), which is an indication of their quality with respect to the size distribution. The suitability of nanocarrier formulations for a particular route of drug administration depends on their average diameter, PDI and size stability, among other parameters. Controlling and validating these parameters are of key importance for the effective clinical applications of nanocarrier formulations. This review highlights the significance of size and PDI in the successful design, formulation and development of nanosystems for pharmaceutical, nutraceutical and other applications. Liposomes, nanoliposomes, vesicular phospholipid gels, solid lipid nanoparticles, transfersomes and tocosomes are presented as frequently-used lipidic drug carriers. The advantages and limitations of a range of available analytical techniques used to characterize lipidic nanocarrier formulations are also covered.

Evaluation of a water-soluble bioadhesive patch for photodynamic therapy of vulval lesions.

PubMed

McCarron, Paul A; Donnelly, Ryan F; Zawislak, Agnieszka; Woolfson, A David; Price, John H; McClelland, Raymond

2005-04-11

An innovative bioadhesive patch intended primarily as a vulval drug delivery system and, specifically, as a means to deliver photosensitisers, or their prodrugs, for photodynamic purposes is described. The patch was formulated with a copolymer of methyl vinyl ether and maleic anhydride (PMVE/MA) as a bioadhesive matrix and poly(vinyl chloride) as a drug-impervious backing layer. Adhesive strength to neonate porcine skin, as a model substrate, was evaluated using peel and tensile testing measurements. Acceptabilities of non-drug loaded patches were appraised using human volunteers and visual-analogue scoring devices. An optimal formulation, with water uptake and peel strengths appropriate for vulval drug delivery, was cast from a 20% (w/w) PMVE/MA solution and adhered with a strength of approximately 1.7 Ncm(-2). Patient evaluation demonstrated comfort and firm attachment for up to 4h in mobile patients. Aminolevulinic acid, a commonly used photosensitiser, was formulated into the candidate formulation and applied to vulval intraepithelial neoplastic lesions. Fluorescence under ultraviolet illumination revealed protoporphyrin synthesis. The patch achieves the extended application times obligatory in topical photodynamic therapy of vulval lesions, thereby contributing to potential methods for the eradication of neoplastic lesions in the lower female reproductive tract.

Preclinical evaluation of anti-HIV microbicide products: New models and biomarkers.

PubMed

Doncel, Gustavo F; Clark, Meredith R

2010-12-01

A safe and effective microbicide product designed to prevent sexual transmission of HIV-1 rests on a solid foundation provided by the proper selection and preclinical characterization of both its active pharmaceutical ingredient (API) and formulation. The evaluation of API and formulation physicochemical properties, drug release, specific antiviral activity, cell and tissue toxicity, organ toxicity, pharmacokinetics, and pharmacodynamics and efficacy provides information to understand the product, make go/no go decisions in the critical path of product development and complete a regulatory dossier to file an investigational new drug (IND) with the US Food and Drug Administration. Incorporation of new models, assays and biomarkers has expanded our ability to understand the mechanisms of action underlying microbicide toxicity and efficacy, enabling a more rational selection of drug and formulation candidates. This review presents an overview of the models and endpoints used to comprehensively evaluate an anti-HIV microbicide in preclinical development. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA. Copyright © 2010 Elsevier B.V. All rights reserved.

Strategies for bringing drug delivery tools into discovery.

PubMed

Kwong, Elizabeth; Higgins, John; Templeton, Allen C

2011-06-30

The past decade has yielded a significant body of literature discussing approaches for development and discovery collaboration in the pharmaceutical industry. As a result, collaborations between discovery groups and development scientists have increased considerably. The productivity of pharma companies to deliver new drugs to the market, however, has not increased and development costs continue to rise. Inability to predict clinical and toxicological response underlies the high attrition rate of leads at every step of drug development. A partial solution to this high attrition rate could be provided by better preclinical pharmacokinetics measurements that inform PD response based on key pathways that drive disease progression and therapeutic response. A critical link between these key pharmacology, pharmacokinetics and toxicology studies is the formulation. The challenges in pre-clinical formulation development include limited availability of compounds, rapid turn-around requirements and the frequent un-optimized physical properties of the lead compounds. Despite these challenges, this paper illustrates some successes resulting from close collaboration between formulation scientists and discovery teams. This close collaboration has resulted in development of formulations that meet biopharmaceutical needs from early stage preclinical in vivo model development through toxicity testing and development risk assessment of pre-clinical drug candidates. Published by Elsevier B.V.

Bio-based topical system for enhanced salicylic acid delivery: preparation and performance of gels.

PubMed

Langasco, Rita; Spada, Gianpiera; Tanriverdi, Sakine Tuncay; Rassu, Giovanna; Giunchedi, Paolo; Özer, Özgen; Gavini, Elisabetta

2016-08-01

New salicylic acid (SA)-loaded gels were developed using excipients made from renewable materials, and our goal was to improve drug permeation in the topical treatment of acne vulgaris. We studied the preparation parameters to obtain suitable gel formulations. Only naturally occurring polymers were used as gelling agents. Two hydrogels and three lipogels were selected and characterized in terms of drug loading, pH, viability cells, rheology, mechanical properties and in vitro permeation; these hydrogels and lipogels were compared with the traditional ointment. We also evaluated skin parameters before and after gel application. The formulations that we studied are non-Newtonian fluids; they have high drug loading and suitable mechanical properties. Lipogels exhibit a slower and more linear in vitro permeation profile compared with hydrogels. The different vehicles that we used affected drug permeation and improve patient compliance. Cytotoxicity studies suggest that all of the formulations are non-toxic. Lipogels demonstrate appropriate technological features and improved performance compared with the traditional ointment with regard to their composition. Lipogels may represent a new bio-based topical system for SA delivery. The use of 'green' excipients leads to 'skin-friendly' formulations that are able to satisfy environmental safety. © 2016 Royal Pharmaceutical Society.

Application of hydroxyapatite nanoparticles in development of an enhanced formulation for delivering sustained release of triamcinolone acetonide

PubMed Central

Koocheki, Saeid; Madaeni, Sayed Siavash; Niroomandi, Parisa

2011-01-01

We report an analysis of in vitro and in vivo drug release from an in situ formulation consisting of triamcinolone acetonide (TR) and poly(d,l-lactide-co-glycolide) (PLGA) and the additives glycofurol (GL) and hydroxyapatite nanoparticles (HA). We found that these additives enhanced drug release rate. We used the Taguchi method to predict optimum formulation variables to minimize the initial burst. This method decreased the burst rate from 8% to 1.3%. PLGA-HA acted as a strong buffer, thereby preventing tissue inflammation at the injection site caused by the acidic degradation products of PLGA. Characterization of the optimized formulation by a variety of techniques, including scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transform near infrared spectroscopy, revealed that the crystalline structure of TR was converted to an amorphous form. Therefore, this hydrophobic agent can serve as an additive to modify drug release rates. Data generated by in vitro and in vivo experiments were in good agreement. PMID:21589650

Hot-melt extrusion--basic principles and pharmaceutical applications.

PubMed

Lang, Bo; McGinity, James W; Williams, Robert O

2014-09-01

Originally adapted from the plastics industry, the use of hot-melt extrusion has gained favor in drug delivery applications both in academia and the pharmaceutical industry. Several commercial products made by hot-melt extrusion have been approved by the FDA, demonstrating its commercial feasibility for pharmaceutical processing. A significant number of research articles have reported on advances made regarding the pharmaceutical applications of the hot-melt extrusion processing; however, only limited articles have been focused on general principles regarding formulation and process development. This review provides an in-depth analysis and discussion of the formulation and processing aspects of hot-melt extrusion. The impact of physicochemical properties of drug substances and excipients on formulation development using a hot-melt extrusion process is discussed from a material science point of view. Hot-melt extrusion process development, scale-up, and the interplay of formulation and process attributes are also discussed. Finally, recent applications of hot-melt extrusion to a variety of dosage forms and drug substances have also been addressed.

Development of PEG-PLGA based Intravenous Low Molecular Weight Heparin (LMWH) Nanoparticles Intended to Treat Venous Thrombosis.

PubMed

Jogala, Satheesh; Rachamalla, Shyam Sunder; Aukunuru, Jithan

2016-01-01

Anticoagulant therapy is effective in the treatment of DVT. In this regard, LMWH demonstrated significant promise. It is widely used clinically. The goal of this study was to prepare and evaluate intravenous sustained release stealth nanoparticles encapsulating LMWH using PLGA (polylactidecoglycolide) and different grades of PEG (poly ethylene glycols). The nanoparticles were prepared using w/o/w solvent evaporation technique. Prepared nanoparticles were evaluated for particle size, encapsulation efficiency, in-vitro drug release, anti-thrombotic activity in venous thrombosis rat model, estimation of aPTT, tissue bio-distribution studies and stability. Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) studies confirmed the formation of smooth spherical particles. FTIR study reveals successful coating of PEG on the nanoparticles. DSC and XRD results demonstrated that drug changed its physical form in the formulation. The encapsulation efficiency was 63-74%. In vitro drug release was 57-75% for 48 hrs. Macrophage uptake of LMWH with pegylated nanoparticles was less compared to conventional PLGA nanoparticles. In vivo drug release was sustained for 48hrs; Optimized formulation exhibited good enhancement in pharmacokinetic parameters when compared to free drug solution. In vivo sustained release was also demonstrated with antithrombotic activity as well aPTT activity. Optimized formulation demonstrated significant stability, excellent antithrombotic activity in venous thrombosis rat model, improved aPTT levels when compared to free drug solution. An effective stealth LMWH nanoparticle formulation to treat venous thrombosis was successfully developed using w/o/w solvent evaporation technique.

Controlled release of beta-estradiol from PLAGA microparticles: the effect of organic phase solvent on encapsulation and release.

PubMed

Birnbaum, D T; Kosmala, J D; Henthorn, D B; Brannon-Peppas, L

2000-04-03

To determine the effect of the organic solvent used during microparticle preparation on the in vitro release of beta-estradiol, a number of formulations were evaluated in terms of size, shape and drug delivery performance. Biodegradable microparticles of poly(lactide-co-glycolide) were prepared containing beta-estradiol that utilized dichloromethane, ethyl acetate or a mixture of dichloromethane and methanol as the organic phase solvent during the particle preparation. The drug delivery behavior from the microparticles was studied and comparisons were made of their physical properties for different formulations. The varying solubilities of beta-estradiol and poly(lactide-co-glycolide) in the solvents studied resulted in biodegradable microparticles with very different physical characteristics. Microparticles prepared from solid suspensions of beta-estradiol using dichloromethane as the organic phase solvent were similar in appearance to microparticles prepared without drug. Microparticles prepared from dichloromethane/methanol solutions appeared transparent to translucent depending on the initial amount of drug used in the formulation. Microparticles prepared using ethyl acetate appeared to have the most homogeneous encapsulation of beta-estradiol, appearing as solid white spheres regardless of initial drug content. Studies showed that microparticles prepared from either ethyl acetate or a mixture of dichloromethane and methanol gave a more constant release profile of beta-estradiol than particles prepared using dichloromethane alone. For all formulations, an initial burst of release increased with increasing drug loading, regardless of the organic solvent used.

Dorzolamide-loaded PLGA/vitamin E TPGS nanoparticles for glaucoma therapy: Pharmacoscintigraphy study and evaluation of extended ocular hypotensive effect in rabbits.

PubMed

Warsi, Musarrat H; Anwar, Mohammed; Garg, Vaidehi; Jain, Gaurav K; Talegaonkar, Sushama; Ahmad, Farhan J; Khar, Roop K

2014-10-01

Poor drug penetration and rapid clearance after topical instillation of a drug formulation into the eyes are the major causes for the lower ocular bioavailability from conventional eye drops. Along with this, poor encapsulation efficiency of hydrophilic drug in polymeric nanoparticles remains a major formulation challenge. Taking this perspective into consideration, dorzolamide (DZ)-loaded PLGA nanoparticles were developed employing two different emulsifiers (PVA and vitamin E TPGS) and the effects of various formulation and process variables on particle size and encapsulation efficiency were assessed. Nanoparticles emulsified with vitamin E TPGS (DZ-T-NPs) were found to possess enhanced drug encapsulation (59.8±6.1%) as compared to those developed with PVA as emulsifier (DZ-P-NPs). Transcorneal permeation study revealed a significant enhancement in permeation (1.8-2.5 fold) as compared to solution. In addition, ex vivo biodistribution study showed a higher concentration of drug in the aqueous humour (1.5-2.3 fold). Histological and IR-camera studies proved the non-irritant potential of the formulations. Pharmacoscintigraphic studies revealed the reduced corneal clearance, as well as naso-lachrymal drainage in comparison to drug solution. Furthermore, efficacy study revealed that DZ-P-NPs and DZ-T-NPs significantly reduced the intraocular pressure by 22.81% and 29.12%, respectively, after a single topical instillation into the eye. Copyright © 2014 Elsevier B.V. All rights reserved.

Sustained ocular delivery of brimonidine tartrate using ion activated in situ gelling system.

PubMed

Geethalakshmi, A; Karki, Roopa; Jha, Sajal Kumar; Venkatesh, D P; Nikunj, B

2012-03-01

The poor bioavailability and therapeutic response exhibited by conventional eye drops due to rapid precorneal elimination of the drug may be overcome by the use of an in situ gelling systems that are instilled as drops into the eye and undergo a sol-to-gel transition in the cul-de-sac which improves patient compliance as the dosage regimen is one drop of the dosage form twice a day. The loss of drug overcomes due to the immediate gel formation between the eye membrane and the drug being entrapped simultaneously in sol-gel transition in the cul de sac. The present work describes the formulation and evaluation of an ophthalmic delivery system of an antiglaucomal agent, brimonidine tartrate based on the concept of ion-activated in situ gelation. Gelrite was used as the gelling agent, which gels in the presence of mono or divalent cations present in the lacrimal fluid. The formulations were evaluated for clarity, pH measurement, gelling capacity, drug content estimation, rheological study, in-vitro diffusion study, antibacterial activity, isotonicity testing, eye irritation testing. In the developed formulations Gelrite Brimonidine-3 (GB3) exhibited sustained release of drug from formulation over a period of 8 hrs thus increasing residence time of the drug, non-irritating with no ocular damage or abnormal clinical signs to the cornea, iris or conjunctiva, stable and sterile. These results demonstrate that the developed system is an alternative to conventional ophthalmic drops, with better patient compliance, and is industrially oriented and economical.

Development of novel encapsulated formulations using albumin-chitosan as a polymer matrix for ocular drug delivery

NASA Astrophysics Data System (ADS)

Addo, Richard Tettey

Designing formulations for ophthalmic drug delivery is one of the most challenging endeavors facing the pharmaceutical scientist due to the unique anatomy, physiology, and biochemistry of the eye. Current treatment protocols for administration of drugs in eye diseases are primarily solution formulations, gels or ointments. However, these modes of delivery have several drawbacks such as short duration of exposure, need for repeated administrations and non-specific toxicity. We hypothesize that development of ocular drugs in microparticles will overcome the deficiencies of the current modalities of treatment. We based the hypothesis on the preliminary studies conducted with encapsulated tetracaine, an anesthetic used for surgical purposes and atropine, a medication used for several ophthalmic indications including mydriatic and cycloplegic effects. However, atropine is well absorbed into the systemic circulation and has been reported to exert severe systemic side effects after ocular administration (Hoefnagel D. 1961, Morton H. G. 1939 and Lang J. C. 1995) and may lead to serious side effects including death in extreme cases with pediatric use. Based on these observations, the focus of this dissertation is to formulate microparticulate drug carrier for treatment of various conditions of the eye. Purpose: To prepare, characterize, study the in vitro and in vivo interaction of albumin-chitosan microparticles (BSA-CSN MS), a novel particulate drug carrier for ocular drug delivery. Method: Microparticle formulations were prepared by method of spray drying. The percentage drug loading and efficiency were assessed using USP (I) dissolution apparatus. Using Malvern Zeta-Sizer, we determined size and surface charge of the fabrication. Surface morphology of the microparticles was examined using Scanning Electron Microscopy. Microparticles were characterized in terms of thermal properties using Differential Scanning Calorimetry. Human corneal epithelial cells (HCET-1) were exposed up to 120 minutes to different BSA-CSN MS concentrations. Using fluorometry, the influence of temperature and effect of metabolic inhibition were studied. The in vitro uptake and internalization studies were evaluated using confocal microscopy in HCET-1. In vivo studies were evaluated in rabbit's eye using blink response and pupil to cornea ratio for tetracaine and atropine studies respectively. Results: Our results showed particles size in the range of 3-5 microns with encapsulation efficiency of about 96 percent. Differential Scanning Calorimetry showed no drug-polymer interactions. BSA-CSN MS were internalized by the HCET-1 and was affected both by temperature and metabolic inhibitor, sodium azide. There were no signs of ocular surface toxicity or inflammation. The encapsulated drugs exhibited superior properties in vivo compared to the solution formulations currently in clinical use. Conclusion: We successfully developed microparticulate drug carriers for ocular delivery. BSA-CSN MS were internalized by the HCET-1 by temperature dependent active transport mechanism that did not compromise cell viability.

Nonclinical dose formulation analysis method validation and sample analysis.

PubMed

Whitmire, Monica Lee; Bryan, Peter; Henry, Teresa R; Holbrook, John; Lehmann, Paul; Mollitor, Thomas; Ohorodnik, Susan; Reed, David; Wietgrefe, Holly D

2010-12-01

Nonclinical dose formulation analysis methods are used to confirm test article concentration and homogeneity in formulations and determine formulation stability in support of regulated nonclinical studies. There is currently no regulatory guidance for nonclinical dose formulation analysis method validation or sample analysis. Regulatory guidance for the validation of analytical procedures has been developed for drug product/formulation testing; however, verification of the formulation concentrations falls under the framework of GLP regulations (not GMP). The only current related regulatory guidance is the bioanalytical guidance for method validation. The fundamental parameters for bioanalysis and formulation analysis validations that overlap include: recovery, accuracy, precision, specificity, selectivity, carryover, sensitivity, and stability. Divergence in bioanalytical and drug product validations typically center around the acceptance criteria used. As the dose formulation samples are not true "unknowns", the concept of quality control samples that cover the entire range of the standard curve serving as the indication for the confidence in the data generated from the "unknown" study samples may not always be necessary. Also, the standard bioanalytical acceptance criteria may not be directly applicable, especially when the determined concentration does not match the target concentration. This paper attempts to reconcile the different practices being performed in the community and to provide recommendations of best practices and proposed acceptance criteria for nonclinical dose formulation method validation and sample analysis.

Microsponges based novel drug delivery system for augmented arthritis therapy

PubMed Central

Osmani, Riyaz Ali M.; Aloorkar, Nagesh H.; Ingale, Dipti J.; Kulkarni, Parthasarathi K.; Hani, Umme; Bhosale, Rohit R.; Jayachandra Dev, Dandasi

2015-01-01

The motive behind present work was to formulate and evaluate gel containing microsponges of diclofenac diethylamine to provide prolonged release for proficient arthritis therapy. Quasi-emulsion solvent diffusion method was implied using Eudragit RS-100 and microsponges with varied drug–polymer ratios were prepared. For the sake of optimization, diverse factors affecting microparticles physical properties were too investigated. Microsponges were characterized by SEM, DSC, FT-IR, XRPD and particle size analysis, and evaluated for morphology, drug loading, in vitro drug release and ex vivo diffusion as well. There were no chemical interactions between drug and polymers used as revealed by compatibility studies outcomes. The drug polymer ratio reflected notable effect on drug content, encapsulation efficiency and particle size. SEM results revealed spherical microsponges with porous surface, and had 7.21 μm mean particle size. The microsponges were then incorporated in gel; which exhibited viscous modulus along with pseudoplastic behavior. In vitro drug release results depicted that microsponges with 1:2 drug–polymer ratio were more efficient to give extended drug release of 75.88% at the end of 8 h; while conventional formulation get exhausted incredibly earlier by releasing 81.11% drug at the end of 4 h only. Thus the formulated microsponge-based gel of diclofenac diethylamine would be a promising alternative to conventional therapy for safer and efficient treatment of arthritis and musculoskeletal disorders. PMID:26594124

Design and characterization of submicron formulation for a poorly soluble drug: the effect of Vitamin E TPGS and other solubilizers on skin permeability enhancement.

PubMed

Ghosh, Indrajit; Michniak-Kohn, Bozena

2012-09-15

In transdermal drug delivery systems (TDDS), it is a challenge to achieve stable and prolonged high permeation rates across the skin since the concentrations of the drug dissolved in the matrix have to be high in order to maintain zero order release kinetics. Several attempts have been reported to improve the permeability of poorly soluble drug compounds using supersaturated systems, however, due to thermodynamic challenges, there was a high tendency for the drug to nucleate immediately after formulating or even during storage. The present study focuses on the efficiency of drug crystals at the submicron/nano range in presence of different solubilizers to improve the permeation rate. Effect of several solubilizers, e.g. Pluronic F-127, Vitamin E TPGS, propylene glycol were studied on the submicron suspension systems of ibuprofen as a model drug. Various stabilizers such as hydroxylpropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were examined to evaluate their crystal inhibitory effects on particle growth of the drug compound at submicron range. The overall permeation enhancement process through the skin seems to be influenced by the presence of solubilizers and also the presence of submicron drug crystal. The most promising stable formulation was developed with Vitamin E TPGS+HPMC submicron suspension, which produced higher permeation rate compared to other vehicles. Copyright © 2012 Elsevier B.V. All rights reserved.

Assessment of Aprotinin Loaded Microemulsion Formulations for Parenteral Drug Delivery: Preparation, Characterization, in vitro Release and Cytotoxicity Studies.

PubMed

Okur, Neslihan Üstündağ; Özdemir, Derya İlem; Kahyaoğlu, Şennur Görgülü; Şenyiğit, Zeynep Ay; Aşıkoğlu, Makbule; Genç, Lütfi; Karasulu, H Yeşim

2015-01-01

The object of the current study was to prepare novel microemulsion formulations of aprotinin for parenteral delivery and to compare in vitro characteristics and release behaviour of different Technetium-99m ((99m)Tc)-Aprotinin loaded microemulsion formulations. In addition, cytotoxicity of microemulsion formulation was evaluated with cell culture studies on human immortalized pancreatic duct epithelial-like cells. For this aim, firstly, pseudo-ternary phase diagrams were plotted to detect the formulation region and optimal microemulsions were characterized for their thermodynamic stability, conductivity, particle size, zeta potential, viscosity, pH and in vitro release properties. For in vitro release studies aprotinin was labelled with (99m)Tc and labelling efficiency, radiochemical purity and stability of the radiolabeled complex were determined by several chromatography techniques. Radiolabeling efficiency of (99m)Tc-Aprotinin was found over than 90% without any significant changes up to 6 hours after labelling at room temperature. After that, in vitro release studies of (99m)Tc-Aprotinin loaded microemulsions were performed with two different methods; dissolution from diffusion cells and dialysis bags. Both methods showed that release rate of (99m)Tc- Aprotinin from microemulsion could be controlled by microemulsion formulations. Drug release from the optimized microemulsion formulations was found lower compared to drug solution at the end of six hours. According to stability studies, the optimized formulation was found to be stable over a period of 12 months. Also, human immortalized pancreatic duct epithelial-like cells were used to evaluate the cytotoxicity of optimum formulation. Developed microemulsion did not reveal cytotoxicity. In conclusion the present study indicated that the M1-APT microemulsion is appropriate for intravenous application of aprotinin.

Sustained release of intravitreal flurbiprofen from a novel drug-in-liposome-in-hydrogel formulation.

PubMed

Pachis, K; Blazaki, S; Tzatzarakis, M; Klepetsanis, P; Naoumidi, E; Tsilimbaris, M; Antimisiaris, S G

2017-11-15

A novel Flurbiprofen (FLB)-in-liposome-in-hydrogel formulation was developed, as a method to sustain the release and increase the ocular bioavailability of FLB following intravitreal injection. For this, FLB loading into liposomes was optimized and liposomes were entrapped in thermosensitive hydrogels consisted of Pluronic F-127 (P). FLB solution, liposomes, and FLB dissolved in hydrogel were also used as control formulations. Actively loaded liposomes were found to be optimal for high FLB loading and small size, while in vitro studies revealed that P concentration of 18% (w/v) was best to retain the integrity of the hydrogel-dispersed liposome, compared to a 20% concentration. The in vitro release of FLB was significantly sustained when FLB-liposomes were dispersed in the hydrogel compared to hydrogel dissolved FLB, as well as the other control formulations. In vivo studies were carried out in pigmented rabbits which were injected through a 27G needle with 1mg/mL FLB in the different formulation-types. Ophthalmic examinations after intravitreal injection of all FLB formulations, revealed no evidence of inflammation, hemorrhage, uveitis or endophthalmitis. Pharmacokinetic analysis results confirm that the hybrid drug delivery system increases the bioavailability (by 1.9 times compared to solution), and extends the presence of the drug in the vitreous cavity, while liposome and hydrogel formulations demonstrate intermediate performance. Furthermore the hybrid system increases MRT of FLB in aqueous humor and retina/choroid tissues, compared to all the control formulations. Currently the potential therapeutic advances of FLB sustained release formulations for IVT administration are being evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Formulation of poorly water-soluble Gemfibrozil applying power ultrasound.

PubMed

Ambrus, R; Naghipour Amirzadi, N; Aigner, Z; Szabó-Révész, P

2012-03-01

The dissolution properties of a drug and its release from the dosage form have a basic impact on its bioavailability. Solubility problems are a major challenge for the pharmaceutical industry as concerns the development of new pharmaceutical products. Formulation problems may possibly be overcome by modification of particle size and morphology. The application of power ultrasound is a novel possibility in drug formulation. This article reports on solvent diffusion and melt emulsification, as new methods supplemented with drying in the field of sonocrystallization of poorly water-soluble Gemfibrozil. During thermoanalytical characterization, a modified structure was detected. The specific surface area of the drug was increased following particle size reduction and the poor wettability properties could also be improved. The dissolution rate was therefore significantly increased. Copyright © 2011 Elsevier B.V. All rights reserved.

Vitamin C-driven epirubicin loading into liposomes.

PubMed

Lipka, Dominik; Gubernator, Jerzy; Filipczak, Nina; Barnert, Sabine; Süss, Regine; Legut, Mateusz; Kozubek, Arkadiusz

2013-01-01

The encapsulation of anticancer drugs in a liposome structure protects the drug during circulation and increases drug accumulation in the cancer tissue and antitumor activity while decreasing drug toxicity. This paper presents a new method of active drug loading based on a vitamin C pH/ion gradient. Formulations were characterized in terms of the following parameters: optimal external pH, time and drug-to-lipid ratio for the purpose of remote loading, and in vitro stability. In the case of the selected drug, epirubicin (EPI), its coencapsulation increases its anticancer activity through a possibly synergistic effect previously reported by other groups for a free nonencapsulated drug/vitamin C cocktail. The method also has another advantage over other remote-loading methods: it allows faster drug release through liposome destabilization at the tumor site, thanks to the very good solubility of the EPI vitamin C salt, as seen on cryogenic transmission electron microscopy images. This influences the drug-release process and increases the anticancer activity of the liposome formulation. The liposomes are characterized as stable, with very good pharmacokinetics (half-life 18.6 hours). The antitumor activity toward MCF-7 and 4T-1 breast cancer cells was higher in the case of EPI loaded via our gradient than via an ammonium sulfate gradient. Finally, the EPI liposomal formulation and the free drug were tested using the murine 4T-1 breast cancer model. The antitumor activity of the encapsulated drug was confirmed (tumor-growth inhibition over 40% from day 16 until the end of the experiment), and the free drug was shown to have no anticancer activity at the tested dose.

Kinetic Analysis of Drug Release from Compounded Slow-release Capsules of Liothyronine Sodium (T3).

PubMed

Bakhteyar, Hamid; Cassone, Clayton; Kohan, Hamed Gilzad; Sani, Shabnam N

2017-01-01

The purpose of this study was to formulate extemporaneously compounded Liothyronine Sodium (T3) slow-release capsules and to evaluate their in vitro drug release performance. Twenty-one formulations containing T3 (7.5 µg) with various compositions of two different grades of Methocel E4M and K100M premium (30% to 90%), and/or SimpleCap/Lactose (10% to 70%) were examined. Quality assessment of the capsules was conducted by standard quality control criteria of the United States Pharmacopeia (i.e., weight variation, content uniformity) to ensure their compliance. The dissolution release profile of the formulations was evaluated using United States Pharmacopeia Apparatus type II (paddle method) at a speed of 50 rpm and temperature of 37°C in phosphate buffered saline media ( pH = 7.2 to 7.4). Aliquots from the media were taken periodically up to 24 hours and analyzed using a validated enzyme-linked immunosorbent assay method. The cumulative percentage of drug release for each formulation was fitted to eleven major release kinetic equations to determine the best-fit model of drug release, as well as the mechanism of release. Assay sensitivity was as low as 1 ng/mL and the optimal calibration range was found to be between 0 ng/mL and 7.5 ng/mL, which corresponded well with the average physiological plasma concentrations of T3. Liothyronine sodium with either SimpleCap (100%) or Methocel E4M (100%) exhibited slowrelease kinetic patterns of Peppas and Zero Order, respectively. The formulation with SimpleCap (100%) had a higher percentage of drug release (as compared to 100% Methocel E4M) within the first four hours; this formulation released 80% of the drug within 12 hours when the release was plateaued thereafter. The formulation with 30% Methocel E4M and 70% SimpleCap released 100% of the drug within the initial 12 hours and exhibited a Zero Order slow-release kinetic pattern. In general, the release kinetic rate of the formulations containing Methocel K100M appeared to be slower than Methocel E4M. This alteration may be due to a higher molecular weight and apparent viscosity of Methocel K100M. While most of the formulations were fitted to a slow-release kinetic pattern, several others including Methocel E4M 100%, 30% Methocel E4M+ 70% Simple Cap, 40% Methocel K100M+ 60% SimpleCap, 50% Methocel K100M+ 50% SimpleCap, 30% Methocel E4M+ 70% Lactose, 90% Methocel E4M+ 10% Lactose, 40% Methocel K100M+ 60% Lactose, and 50% Methocel K100M+ 50% Lactose followed an ideal slow-release kinetic pattern of Zero Order or Higuchi. The results of this study successfully demonstrated the optiomal composition of slow-release compounded capsules of T3. Future studies are warranted to evaluate the in vivo performance of the optimal formulations and to establish an in vitro-in vivo correlation. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Novel Approaches in Formulation and Drug Delivery using Contact Lenses

PubMed Central

Singh, Kishan; Nair, Anroop B; Kumar, Ashok; Kumria, Rachna

2011-01-01

The success of ocular delivery relies on the potential to enhance the drug bioavailability by controlled and extended release of drug on the eye surface. Several new approaches have been attempted to augment the competence and diminish the intrinsic side effects of existing ocular drug delivery systems. In this contest, progress has been made to develop drug-eluting contact lens using different techniques, which have the potential to control and sustain the delivery of drug. Further, the availability of novel polymers have facilitated and promoted the utility of contact lenses in ocular drug delivery. Several research groups have already explored the feasibility and potential of contact lens using conventional drugs for the treatment of periocular and intraocular diseases. Contact lenses formulated using modern technology exhibits high loading, controlled drug release, apposite thickness, water content, superior mechanical and optical properties as compared to commercial lenses. In general, this review discus various factors and approaches designed and explored for the successful delivery of ophthalmic drugs using contact lenses as drug delivery device PMID:24826007

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

Spreading of a Lidocaine Formulation on Microneedle-Treated Skin.

PubMed

Nayak, Atul; Das, Diganta B; Chao, Tzu C; Starov, Victor M

2015-12-01

The spreadability of a liquid drug formulation on skin is an indication of it either remaining stationary or distributing (spreading) as a droplet. Factors determining droplet spreadability of the formulation are spreading area, diameter of the droplet base, viscosity of the liquid, contact angle, volume of droplet on skin and any others. The creation of microcavities from the application of microneedle (MN) has the potential to control droplet spreading, and hence, target specific areas of skin for drug delivery. However, there is little work that demonstrates spreading of liquid drug formulation on MN-treated skin. Below, spreading of a lidocaine hydrogel formulation and lidocaine solution (reference liquid) on porcine skin is investigated over MN-treated skin. Controlled spreadability was achieved with the lidocaine hydrogel on MN-treated skin as compared with lidocaine solution. It was observed that the droplet spreading parameters such as spreading radius, droplet height and dynamic contact angle were slightly lower for the lidocaine hydrogel than the lidocaine solution on skin. Also, the lidocaine hydrogel on MN-treated skin resulted in slower dynamic reduction of droplet height, contact angle and reduced time taken in attaining static advancing droplets because of the MN microcavities. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

PubMed

Kou, Dawen; Dwaraknath, Sudharsan; Fischer, Yannick; Nguyen, Daniel; Kim, Myeonghui; Yiu, Hiuwing; Patel, Preeti; Ng, Tania; Mao, Chen; Durk, Matthew; Chinn, Leslie; Winter, Helen; Wigman, Larry; Yehl, Peter

2017-10-02

In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

[Optimization of Formulation and Process of Paclitaxel PEGylated Liposomes by Box-Behnken Response Surface Methodology].

PubMed

Shi, Ya-jun; Zhang, Xiao-feil; Guo, Qiu-ting

2015-12-01

To develop a procedure for preparing paclitaxel encapsulated PEGylated liposomes. The membrane hydration followed extraction method was used to prepare PEGylated liposomes. The process and formulation variables were optimized by "Box-Behnken Design (BBD)" of response surface methodology (RSM) with the amount of Soya phosphotidylcholine (SPC) and PEG2000-DSPE as well as the rate of SPC to drug as independent variables and entrapment efficiency as dependent variables for optimization of formulation variables while temperature, pressure and cycle times as independent variables and particle size and polydispersion index as dependent variables for process variables. The optimized liposomal formulation was characterized for particle size, Zeta potential, morphology and in vitro drug release. For entrapment efficiency, particle size, polydispersion index, Zeta potential, and in vitro drug release of PEGylated liposomes was found to be 80.3%, (97.15 ± 14.9) nm, 0.117 ± 0.019, (-30.3 ± 3.7) mV, and 37.4% in 24 h, respectively. The liposomes were found to be small, unilamellar and spherical with smooth surface as seen in transmission electron microscopy. The Box-Behnken response surface methodology facilitates the formulation and optimization of paclitaxel PEGylated liposomes.

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 of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.

PubMed

Liu, Sha; Watts, Alan B; Du, Ju; Bui, Amanda; Hengsawas, Soraya; Peters, Jay I; Williams, Robert O

2015-10-01

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0-24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

Preparation of nanobubbles for ultrasound imaging and intracelluar drug delivery.

PubMed

Wang, Ye; Li, Xiang; Zhou, Yan; Huang, Pengyu; Xu, Yuhong

2010-01-15

Echogenic bubble formulations have wide applications in both disease diagnosis and therapy. In the current study, nanobubbles were prepared and the contrast agent function was evaluated in order to study the nanosized bubble's property for ultrasonic imaging. Coumarin-6 as a model drug was loaded into nanobubbles to investigate the drug delivery potential to cells. The results showed that the nanobubbles composed of 1% of Tween 80, and 3 mg/ml of lipid worked well as an ultrasonic contrast agent by presenting a contrast effect in the liver region in vivo. The drug-loaded nanobubbles could enhance drug delivery to cells significantly, and the process was analyzed by sigmoidally fitting the pharmacokinetic curve. It can be concluded that the nanobubble formulation is a promising approach for both ultrasound imaging and drug delivery enhancing.

Enhancement of in-vitro drug dissolution of ketoconazole for its optimal in-vivo absorption using Nanoparticles and Solid Dispersion forms of the drug

NASA Astrophysics Data System (ADS)

Syed, Mohammed Irfan

Ketoconazole is one of the most widely prescribed oral antifungal drugs for the systemic treatment of various fungal infections. However, due its hydrophobic nature and poor solubility profiles in the gastro-intestinal fluids, variations in its bioavailability have been documented. Therefore, to enhance its dissolution in the biological fluids, this study was initiated to develop and evaluate Nanoparticles and Solid Dispersion forms of the drug. Nanoparticles of ketoconazole were developed by Wet Bead Milling technique using PVP-10k as the stabilizing material at a weight ratio of (2:1). Solid dispersion powder was prepared by Hot Melt method using PEG-8000 at a weight ratio of (1:2). A commercial product containing 200mg of ketoconazole tablet and pure drug powder were used as the control for comparison purposes. The dissolution studies were carried out in SGF, SIF, USP; and SIF with 0.2% sodium lauryl sulfate using the USP-II method for a 2 hours period. Physical characterizations were carried out using SEM, DSC, XRD and FTIR studies. Wet Bead Milling method yielded nanoparticles in the particles size range of (100-300nm.). First all samples were evaluated for their in-vitro dissolution in SGF at pH=1.2. After 15 minutes, the amounts of drug dissolved were observed to be 27% from both the pure powder and commercial tablet (control), 29% from solid dispersion and 100% from the Nanoparticles dosage form. This supports the fact that Nanoparticles had a strong influence on the dissolution rate of the drug and exhibited much faster dissolution of ketoconazole. When the same formulations were studied in the SIF, USP medium, the control formulation gave 3%, solid dispersion 8% and Nanoparticles 8% drug dissolution after 2 hours period. This could be because the weakly basic ketoconazole drug remained un-dissociated in the alkaline medium. Since this medium was unable to clearly distinguish the dissolution profiles from different formulation of the drug, the SIF solution was modified to include 0.02%, 0.05% and 0.1% sodium lauryl sulfate. Here, after 2 hours, the amount of drug dissolved was calculated to be 10% from controls, 21% from solid dispersion and 36% from nanoparticles in SIF with 0.02% SLS. Drug release was 20% from controls, 41% from solid dispersion and 52% from nanoparticle formulation in SIF with 0.05% SLS. Whereas amount of drug released in SIF with 0.1% SLS showed 21% from the control, 62% from solid dispersion and 85% from Nanoparticles respectively. This data supports that the ketoconazole Nanoparticles and its solid-dispersion exhibit many fold increase in dissolution of the drug, which could lead to a less variable and enhanced in-vivo drug absorption profiles. In addition, the data from the Physical Characterization (DSC, XRD and FTIR) supports that there were no interaction within the ingredients occurred in Nanoparticles and solid-dispersion formulations of the drug sample. Wet Bead Milling and Hot Melt methods proved useful in developing the Nanoparticles and solid dispersion form of ketoconazole. Results from particle size analysis were in correlation with data obtained from Scanning electron Microscopy and size of the nanoparticles was below 100nm. The dissolution studies with the modified simulated intestinal fluid (SIF) exhibited several fold increase in the dissolution of the drug compared to the pure drug powder and the commercial products used as the control. Also, the results from the physical characterization studies clearly support the stability of ketoconazole in both of these formulations.

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.

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 potential of polymeric film-forming systems as sustained delivery platforms for topical drugs.

PubMed

Frederiksen, Kit; Guy, Richard H; Petersson, Karsten

2016-01-01

Dosing regimens requiring multiple daily applications frequently result in poor patient compliance, especially in the treatment of chronic skin diseases. Consequently, development of sustained delivery systems for topical drugs permitting less frequent dosing is of continuing interest for dermatological therapy. This potential of polymeric film-forming systems (FFS), created in situ on the skin, as sustained delivery platforms for topical drug delivery is reviewed. Key formulation parameters that determine delivery efficiency are considered focussing on those that permit a drug reservoir to be established in the upper layers of the skin and/or on the skin surface from which release can be sustained over a prolonged period. The advantageous and superior cosmetic attributes of FFS (compared to conventional semi-solid formulations) that offer significantly improved patient compliance are also addressed. The promise of polymeric FFS as convenient and aesthetic platforms for sustained topical drug delivery is clear. Manipulation of the formulation allows the delivery profile to be customized and optimized to take advantage of both a rapid, initial input of drug into the skin (likely due to a transient period of supersaturation) and a slower, controlled release over an extended time from the residual film created thereafter.

Time-controlled release pseudoephedrine tablets: bioavailability and in vitro/in vivo correlations.

PubMed

Halsas, M; Penttinen, T; Veski, P; Jürjenson, H; Marvola, M

2001-09-01

In chronopharmacotherapy, circadian changes in disease symptoms are taken into account. Press-coated, time-controlled release tablets containing pseudoephedrine hydrochloride as a model drug have been formulated and the suitability of this highly soluble drug in relation to the new drug delivery system was evaluated. Hydroxypropylmethylcellulose was used in the coat of the tablet to adjust drug release. If such a formulation was administered in the evening it would have maximal effect in the early morning, and would be useful for the treatment of nocturnal symptoms. Two cross-over, single-dose bioavailability studies were carried out on eight healthy volunteers. A dissolution test method was developed to establish level A and level C in vitro/in vivo correlation for four formulations. With a low viscosity grade of polymer, peak concentrations were achieved after five hours. The drug was absorbed much more slowly from tablets containing a high viscosity grade polymer, with a plasma peak at ten hours. For further development of the drug delivery system described, a dissolution test method at pH 7.2 at a rotation speed of 150 min-1 is recommended on the basis of level A in vitro/in vivo correlation.

Low molecular mass chitosan as carrier for a hydrodynamically balanced system for sustained delivery of ciprofloxacin hydrochloride.

PubMed

Verma, Anurag; Bansal, Ashok K; Ghosh, Amitava; Pandit, Jayanta K

2012-06-01

Chitosan has become a focus of major interest in recent years due to its excellent biocompatibility, biodegradability and non-toxicity. Although this material has already been extensively investigated in the design of different types of drug delivery systems, it is still little explored for stomach specific drug delivery systems. The objective of the present investigation was to explore the potential of low molecular mass chitosan (LMCH) as carrier for a hydrodynamically balanced system (HBS) for sustained delivery of water soluble drug ciprofloxacin hydrochloride (CP). Various formulations were prepared by physical blending of drug and polymer(s) in varying ratios followed by encapsulation into hard gelatin capsules. All the formulations remained buoyant in 0.1 mol L⁻¹ HCl (pH 1.2) throughout the experiment. Effect of addition of xanthan gum (XG) or ethyl cellulose (EC) on drug release was also investigated. Zero order drug release was obtained from the formulations containing LMCH alone or in combination with XG, and in one instance also with EC. Our results suggest that LMCH alone or in combination with XG is an excellent material for stomach specific sustained delivery of CP from hydrodynamically balanced single unit capsules.

Identification and control of unspecified impurity in trimetazidine dihydrochloride tablet formulation

NASA Astrophysics Data System (ADS)

Jefri; Puspitasari, A. D.; Talpaneni, J. S. R.; Tjandrawinata, R. R.

2018-04-01

Trimetazidine dihydrochloride is an anti-ischemic metabolic agent which is used as drug for angina pectoris treatment. The drug substance monograph is available in European Pharmacopoeia and British Pharmacopoeia, while the drug product monograph is not available in any of the pharmacopoeias. During development of trimetazidine dihydrochloride tablet formulation, we found increase of an unspecified impurity during preliminary stability study. The unspecified impurity was identified by high performance liquid chromatography coupled with mass spectrometry (LC-MS) and the molecular weight obtained was matching with the molecular weight of N-formyl trimetazidine (m/z 295). Further experiments were performed to confirm the suspected result by injecting the impurity standard and spiking formic acid into the drug substance. The retention time of N-formyl trimetazidine was similar to the unspecified impurity in drug product. Even spiking of formic acid into drug substance showed that the suspected impurity increased with increasing concentration of formic acid. The proposed mechanism of impurity formation is via amidation of piperazine moiety of trimetazidine by formic acid which present as residual solvent in tablet binder used in the formulation. Subsequently, the impurity in our product was controlled by choosing the primary packaging which could minimize the formation of impurity.

Discomfort from an Alkaline Formulation Delivered Subcutaneously in Humans

PubMed Central

Ward, W. Kenneth; Castle, Jessica R.; Branigan, Deborah L.; Massoud, Ryan G.; Youssef, Joseph El

2013-01-01

Background and Objective There is a paucity of data regarding tolerability of alkaline drugs administered subcutaneously. The aim of this study was to assess the tolerability of alkaline preparations of human albumin delivered subcutaneously to healthy humans. Methods We compared the tolerability of neutral versus alkaline (pH 10) formulations of human albumin in ten volunteers. With an intent to minimize the time required to reach physiological pH after injection, the alkaline formulation was buffered with a low concentration of glycine (20 mmol/L). Each formulation was given at two rates: over 5 seconds and over 60 seconds. A six-point scale was used to assess discomfort. Results For slow injections, there was a significant difference between pH 7.4 and pH 10 injections (0.4 ± 0.2 vs 1.1 ± 0.2, mean ± SEM; p = 0.025), though the degree of discomfort at pH 10 injections was only ‘mild or slight’. For fast injections, the difference between neutral and alkaline formulations was of borderline significance. Inflammation and oedema, as judged by a physician, were very minimal for all injections, irrespective of pH. Conclusion For subcutaneous drug administration (especially when delivered slowly), there was more discomfort associated with alkaline versus neutral formulations of albumin, though the discomfort was mild. This study suggests that there is little discomfort and inflammation resulting from subcutaneous administration of protein drugs formulated with weak buffers at alkaline pH. PMID:22568666

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.

Discomfort from an alkaline formulation delivered subcutaneously in humans: albumin at pH 7 versus pH 10.

PubMed

Ward, W Kenneth; Castle, Jessica R; Branigan, Deborah L; Massoud, Ryan G; El Youssef, Joseph

2012-07-01

There is a paucity of data regarding tolerability of alkaline drugs administered subcutaneously. The aim of this study was to assess the tolerability of alkaline preparations of human albumin delivered subcutaneously to healthy humans. We compared the tolerability of neutral versus alkaline (pH 10) formulations of human albumin in ten volunteers. With an intent to minimize the time required to reach physiological pH after injection, the alkaline formulation was buffered with a low concentration of glycine (20 mmol/L). Each formulation was given at two rates: over 5 seconds and over 60 seconds. A six-point scale was used to assess discomfort. For slow injections, there was a significant difference between pH 7.4 and pH 10 injections (0.4 ± 0.2 vs 1.1 ± 0.2, mean ± SEM; p = 0.025), though the degree of discomfort at pH 10 injections was only 'mild or slight'. For fast injections, the difference between neutral and alkaline formulations was of borderline significance. Inflammation and oedema, as judged by a physician, were very minimal for all injections, irrespective of pH. For subcutaneous drug administration (especially when delivered slowly), there was more discomfort associated with alkaline versus neutral formulations of albumin, though the discomfort was mild. This study suggests that there is little discomfort and inflammation resulting from subcutaneous administration of protein drugs formulated with weak buffers at alkaline pH.

Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions.

PubMed

Trasi, Niraj S; Purohit, Hitesh S; Taylor, Lynne S

2017-10-01

Tacrolimus, an immunosuppressant, is a poorly water soluble compound whereby the commercially available capsule formulations contain the drug in amorphous form. The goal of this study was to evaluate the robustness of the innovator product and five generic formulations to crystallization following storage at stress conditions. Products were purchased from a pharmacy and stored at 40°C/75% relative humidity (RH), open dish conditions. Crystallinity was determined using X-ray diffraction. The quantity of the ingredients in the formulations were determined using different approaches and the various factors that might cause instability in the formulations were studied. After 4 weeks of open dish storage at 40°C/75% RH, one of the generic formulations showed evidence of tacrolimus crystallization. Further investigations revealed batch-to-batch variations in crystallization tendency with the extent of crystallinity varying between 50 and 100% for different batches. Crystallization was also observed at lower storage temperatures (30°C) when the RH was maintained at 75%. It was found that crystallization could be induced in a model formulation by wet granulating an ethanolic solution of the drug with lactose and drying at 60-70°C followed by exposure to stress conditions. It seems probable that the generic that was susceptible to crystallization contains amorphous drug physically mixed with polymeric excipients, rather than as an amorphous solid dispersion. This study highlights the importance of considering the manufacturing process on the stability of the resultant amorphous product.

Formulation and in vitro evaluation of sustained release matrix tablets using cross-linked natural gum.

PubMed

Jamil, Qurratul Ain; Masood, Muhammad Irfan; Jamil, Muhammad Nauman; Masood, Imran; Iqbal, Shahid Muhammad

2017-03-01

Polysaccharide gums because of their biocompatibility, biodegradability and non-immunogenic properties are considered as the best choice for preparing sustained release tablets as compared to their synthetic counterpart. The cross linking of natural gums in matrix tablets increase the sustained release property of matrix tablets. Isoniazid is a first line therapy of tuberculosis, belongs to BCS I with half-life of 3-4 hours. These characteristics make isoniazid a good candidate for sustained release dosage form. Karaya gum crossed linked with trisodium tri metaphosphate was used as release rate retardant for preparing isoniazid cross-linked matrix tablet. Total 8 sustained release formulations were prepared. Both granules and tablets were evaluated under in vitro condition against different parameters. Dissolution studies were performed with all eight formulations for 12 hours using USP apparatus I. Four formulations designated as F1, F2, F3, F4 have drug and karaya gum while other four formulations F5, F6, F7, F8 have drug and crossed linked polymer in ratios of 1:1, 1:2, 1:3 and 1:4 respectively. Dissolution data was analyzed by using different kinetic models. Best fit model for most efficient formulation was zero order while release mechanism was super case I. Formulation 8 showed sufficiently slow release kinetics and about 83% of drug was released in 10 hours, indicating that cross-linked karaya gum proved efficient in preparing sustained release tablets.

Insoluble drug delivery strategies: review of recent advances and business prospects

PubMed Central

Kalepu, Sandeep; Nekkanti, Vijaykumar

2015-01-01

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects. PMID:26579474

Association between cardiovascular events and sodium-containing effervescent, dispersible, and soluble drugs: nested case-control study

PubMed Central

George, Jacob; Majeed, Waseem; Mackenzie, Isla S; Wei, Li

2013-01-01

Objective To determine whether patients taking formulations of drugs that contain sodium have a higher incidence of cardiovascular events compared with patients on non-sodium formulations of the same drugs. Design Nested case-control study. Setting UK Primary Care Patients registered on the Clinical Practice Research Datalink (CPRD). Participants All patients aged 18 or over who were prescribed at least two prescriptions of sodium-containing formulations or matched standard formulations of the same drug between January 1987 and December 2010. Main outcome measures Composite primary outcome of incident non-fatal myocardial infarction, incident non-fatal stroke, or vascular death. We performed 1:1 incidence density sampling matched controls using the UK Clinical Practice Research Datalink (CPRD). For the secondary analyses, cases were patients with the individual components of the primary study composite endpoint of hypertension, incident heart failure, and all cause mortality. Results 1 292 337 patients were included in the study cohort. Mean follow-up time was 7.23 years. A total of 61 072 patients with an incident cardiovascular event were matched with controls. For the primary endpoint of incident non-fatal myocardial infarction, incident non-fatal stroke, or vascular death the adjusted odds ratio for exposure to sodium-containing drugs was 1.16 (95% confidence interval 1.12 to 1.21). The adjusted odds ratios for the secondary endpoints were 1.22 (1.16 to 1.29) for incident non-fatal stroke, 1.28 (1.23 to 1.33) for all cause mortality, 7.18 (6.74 to 7.65) for hypertension, 0.98 (0.93 to 1.04) for heart failure, 0.94 (0.88 to 1.00) for incident non-fatal myocardial infarction, and 0.70 (0.31 to 1.59) for vascular death. The median time from date of first prescription (that is, date of entry into cohort) to first event was 3.92 years. Conclusions Exposure to sodium-containing formulations of effervescent, dispersible, and soluble medicines was associated with significantly increased odds of adverse cardiovascular events compared with standard formulations of those same drugs. Sodium-containing formulations should be prescribed with caution only if the perceived benefits outweigh these risks. PMID:24284017

Formulation and evaluation of delayed-onset extended-release tablets of metoprolol tartrate using hydrophilic-swellable polymers.

PubMed

Dadarwal, Subhash Chand; Madan, Sarika; Agrawal, Shyam Sunder

2012-03-01

In view of the circadian rhythm of cardiovascular diseases, a delayed-onset extended-release (DOER) formulation of metoprolol tartrate (MT) was prepared. This was achieved through dissolution-guided optimization of the proportion of Methocel K4M and Methocel K15M. Core erosion ratio was greater than 50 %, thereby showing steady release of the drug after the lag time until complete dissolution. Optimized formulation produced a lag phase of 6 h followed by complete release of 98.7 ± 2.1 % in 24 h. Water uptake study revealed that Methocel K15M has lower water uptake (30 ± 1 %) than Methocel K4M (40 ± 2 %) after 24 h. Axial swelling of polymers was higher than swelling in the radial direction. Drug-polymer interaction study precludes any interaction between drug and polymer. Such a drug delivery system may provide a viable alternative for effective management of hypertension and other related disorders. This work also proposes an approach to attain DOER for a hydrophilic drug by using a hydrophilic swellable polymer in press coat.

From conventional towards new - natural surfactants in drug delivery systems design: current status and perspectives.

PubMed

Savić, Snezana; Tamburić, Slobodanka; Savić, Miroslav M

2010-03-01

Surfactants play an important role in the development of both conventional and advanced (colloidal) drug delivery systems. There are several commercial surfactants, but a proportionally small group of them is approved as pharmaceutical excipients, recognized in various pharmacopoeias and therefore widely accepted by the pharmaceutical industry. The review covers some of the main categories of natural, sugar-based surfactants (alkyl polyglucosides and sugar esters) as prospective pharmaceutical excipients. It provides analysis of the physicochemical characteristics of sugar-based surfactants and their possible roles in the design of conventional or advanced drug delivery systems for different routes of administration. Summary and analysis of recent data on functionality, applied concentrations and formulation improvements produced by alkyl polyglucosides and sugar esters in different conventional and advanced delivery systems could be of interest to researchers dealing with drug formulation. Recent FDA certification of an alkyl polyglucoside surfactant for topical formulation presents a significant step in the process of recognition of this relatively new group of surfactants. This could trigger further research into the potential benefits of naturally derived materials in both conventional and new drug delivery systems.

Prodrug Strategy for PSMA-targeted Delivery of TGX-221 to Prostate Cancer Cells

PubMed Central

Zhao, Yunqi; Duan, Shaofeng; Zeng, Xing; Liu, Chunjing; Davies, Neal M.; Li, Benyi; Forrest, M. Laird

2013-01-01

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles were significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than the naked drug, and the drug clearance rate was 17.5-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment. PMID:22494444

Healthcare Costs Associated with Switching from Brand to Generic Levothyroxine

PubMed Central

Katz, Michael; Scherger, Joseph; Conard, Scott; Montejano, Leslie; Chang, Stella

2010-01-01

Background Controversy exists over the true therapeutic equivalence of branded and generic levothyroxine—the drug of choice for treating hypothyroidism—so professional societies recommend against switching between different formulations of the drug and suggest that patients who do switch be monitored. Payers typically encourage switching to generic drugs because of lower drug acquisition costs. Objective To evaluate the impact of switching levothyroxine formulations on actual healthcare costs. Methods Patients with hypothyroidism and at least 6 months of branded levothyroxine therapy were identified from a large healthcare claims database. Patients who subsequently switched to another levothyroxine formulation and could be followed for 6 months postswitch were matched to demographically similar patients who were continuous users of branded levothyroxine. Pre- and postswitch healthcare costs for each group were compared. Results The savings in prescription drug costs after switching from branded to generic levothyroxine are offset by increases in costs for other healthcare services, such that switching is actually associated with an increase, not a decrease, in total healthcare costs. Conclusion In the absence of cost-savings, there is no clear rationale for switching patients from brand to generic levothyroxine. PMID:25126314

Preclinical pilot study monitoring topical drug penetration and dermal bioavailability of a peptidase inhibitor from different galenic formulations into pig dermis, using cutaneous microdialysis.

PubMed

Quist, S R; Heimburg, A; Bank, U; Mahnkopf, D; Koch, G; Gollnick, H; Täger, M; Ansorge, S

2017-08-01

Cutaneous microdialysis (CM) is an ex vivo technique that allows study of tissue chemistry, including bioavailability of actual tissue concentration of unbound drug in the interstitial fluid of the body. To test the penetration and dermal bioavailability of galenic formulations of the small-molecule IP10.C8, a dual-protease inhibitor of the dipeptidyl peptidase and aminopeptidase families. Using CM, we tested the penetration and dermal bioavailability of IP10.C8 into the dermis and subcutis of pigs, and determined the tissue concentration of IP10.C8 enzymatically, using an enzyme activity assay (substrate Gly-Pro-pNA) and high performance liquid chromatography. Dermal bioavailability was enhanced by using microemulsion or the addition of the penetration enhancer oleic acid to a hydroxyethylcellulose (HEC) gel formulation. Dermal bioavailability was also enhanced when galenic formulations were prepared with higher pH (7.5 vs. 6.5) or higher drug concentration (5% vs. 1%) in HEC gel. It seems possible, using CM for topical skin penetration testing in anaesthetized domestic pigs, to test the bioavailability of newly designed drugs. However, the experimental time is limited due to the anaesthesia, and is dependent on drug recovery. Validation of this technique for routine use is challenging, and more experiments are needed to validate this preclinical set-up. © 2017 British Association of Dermatologists.

An Extrusion Spheronization Approach to Enable a High Drug Load Formulation of a Poorly Soluble Drug with a Low Melting Surfactant.

PubMed

Tatavarti, Aditya; Kesisoglou, Filippos

2015-11-01

Vitamin E tocopherol polyethylene glycol succinate (TPGS) is a non-ionic surface active agent, known to enhance the bioavailability of lipophilic compounds via wettability, solubility, and in some cases permeability enhancement. MK-0536 is an anti-retroviral drug with poor wettability and solubility and a high dose. Based on pharmacokinetic studies in dogs and humans, use of vitamin E TPGS in oral solid formulations of MK-0536 provides desired PK characteristics. The use of vitamin E TPGS, however, in solid dosage forms is limited because of the processing challenges resulting from its waxy nature and low melting temperature (∼37°C). The current study, for the first time, demonstrates the use of an alternative low pressure extrusion and spheronization approach to enable high loadings of the poorly soluble, poorly compactable drug and relatively high levels of vitamin E TPGS. This approach not only aided in mitigating processing challenges arising from most high energy process steps such as milling, compression, and coating, but also enabled a higher drug load formulation that provided superior bioperformance relative to a conventional high shear wet granulated formulation. An encapsulated dosage form consisting of pellets prepared by extrusion spheronization with 75% (w/w) MK-0536 and 10% (w/w) vitamin E TPGS was developed. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

In vivo assessment of parenteral formulations of oligo(3-hydroxybutyric Acid) conjugates with the model compound Ibuprofen.

PubMed

Stasiak, Pawel; Sznitowska, Malgorzata; Ehrhardt, Carsten; Luczyk-Juzwa, Maria; Grieb, Pawel

2010-12-01

Polymer-drug conjugates have gained significant attention as pro-drugs releasing an active substance as a result of enzymatic hydrolysis in physiological environment. In this study, a conjugate of 3-hydroxybutyric acid oligomers with a carboxylic acid group-bearing model drug (ibuprofen) was evaluated in vivo as a potential pro-drug for parenteral administration. Two different formulations, an oily solution and an o/w emulsion were prepared and administered intramuscularly (IM) to rabbits in a dose corresponding to 40 mg of ibuprofen/kilogramme. The concentration of ibuprofen in blood plasma was analysed by HPLC, following solid-phase extraction and using indometacin as internal standard (detection limit, 0.05 microg/ml). No significant differences in the pharmacokinetic parameters (C (max), T (max), AUC) were observed between the two tested formulations of the 3-hydroxybutyric acid conjugate. In comparison to the non-conjugated drug in oily solution, the relative bioavailability of ibuprofen conjugates from oily solution, and o/w emulsion was reduced to 17% and 10%, respectively. The 3-hydroxybutyric acid formulations released the active substance over a significantly extended period of time with ibuprofen still being detectable 24 h post-injection, whereas the free compound was almost completely eliminated as early as 6 h after administration. The conjugates remained in a muscle tissue for a prolonged time and can hence be considered as sustained release systems for carboxylic acid derivatives.

Development and characterisation of electrospun timolol maleate-loaded polymeric contact lens coatings containing various permeation enhancers.

PubMed

Mehta, Prina; Al-Kinani, Ali A; Arshad, Muhammad Sohail; Chang, Ming-Wei; Alany, Raid G; Ahmad, Zeeshan

2017-10-30

Despite exponential growth in research relating to sustained and controlled ocular drug delivery, anatomical and chemical barriers of the eye still pose formulation challenges. Nanotechnology integration into the pharmaceutical industry has aided efforts in potential ocular drug device development. Here, the integration and in vitro effect of four different permeation enhancers (PEs) on the release of anti-glaucoma drug timolol maleate (TM) from polymeric nanofiber formulations is explored. Electrohydrodynamic (EHD) engineering, more specifically electrospinning, was used to engineer nanofibers (NFs) which coated the exterior of contact lenses. Parameters used for engineering included flow rates ranging from 8 to 15μL/min and a novel EHD deposition system was used; capable of hosting four lenses, masked template and a ground electrode to direct charged atomised structures. SEM analysis of the electrospun structures confirmed the presence of smooth nano-fibers; whilst thermal analysis confirmed the stability of all formulations. In vitro release studies demonstrated a triphasic release; initial burst release with two subsequent sustained release phases with most of the drug being released after 24h (86.7%) Biological evaluation studies confirmed the tolerability of all formulations tested with release kinetics modelling results showing drug release was via quasi-Fickian or Fickian diffusion. There were evident differences (p<0.05) in TM release dependant on permeation enhancer. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Novel formulations of taxanes: a review. Old wine in a new bottle?

PubMed

Hennenfent, K L; Govindan, R

2006-05-01

Over the past two decades, the taxanes have played a significant role in the treatment of various malignancies. However, the poor solubility of these compounds necessitates the inclusion of surfactant vehicles in their commercial formulations. Cremophor EL and polysorbate 80 have long comprised the standard solvent system for paclitaxel and docetaxel, respectively. A number of pharmacologic and biologic effects related to both of these drug formulations have been described, including clinically relevant acute hypersensitivity reactions and peripheral neuropathy. In addition, these solvents affect the disposition of intravenously administered solubilized drugs and leach plasticizers from polyvinylchloride infusion sets. A number of strategies to develop formulations of surfactant-free taxanes have been developed. They include albumin nanoparticles, polyglutamates, taxane analogs and prodrugs, emulsions, and lipsomes. An overview of these novel formulations of taxanes, their mechanisms of action, pharmacokinetics, dose and administration, adverse effects, and clinical efficacy will be discussed.

Development of an ANN optimized mucoadhesive buccal tablet containing flurbiprofen and lidocaine for dental pain.

PubMed

Hussain, Amjad; Syed, Muhammad Ali; Abbas, Nasir; Hanif, Sana; Arshad, Muhammad Sohail; Bukhari, Nadeem Irfan; Hussain, Khalid; Akhlaq, Muhammad; Ahmad, Zeeshan

2016-06-01

A novel mucoadhesive buccal tablet containing flurbiprofen (FLB) and lidocaine HCl (LID) was prepared to relieve dental pain. Tablet formulations (F1-F9) were prepared using variable quantities of mucoadhesive agents, hydroxypropyl methyl cellulose (HPMC) and sodium alginate (SA). The formulations were evaluated for their physicochemical properties, mucoadhesive strength and mucoadhesion time, swellability index and in vitro release of active agents. Release of both drugs depended on the relative ratio of HPMC:SA. However, mucoadhesive strength and mucoadhesion time were better in formulations, containing higher proportions of HPMC compared to SA. An artificial neural network (ANN) approach was applied to optimise formulations based on known effective parameters (i.e., mucoadhesive strength, mucoadhesion time and drug release), which proved valuable. This study indicates that an effective buccal tablet formulation of flurbiprofen and lidocaine can be prepared via an optimized ANN approach.