Native and microwave-modified Terminalia mantaly gums as sustained-release and bioadhesive excipients in naproxen matrix tablet formulations.

PubMed

Odeniyi, Michael Ayodele; Oyedokun, Babatunde Mukhtar; Bamiro, Oluyemisi Adebowale

2017-01-01

Hydrophilic polymers provide a means of sustaining drug delivery. Native gums may be limited in function, but modification may improve their activity. The aim of the study was to evaluate native and modified forms of Terminalia mantaly gum for their sustained-release and bioadhesive properties. The native gum (NTM) was modified by microwave irradiation for 20 seconds (MTM20) and 60 seconds (MTM60) and characterized using microscopy, Fourier transform infrared spectroscopy (FTIR) and packing properties. The effects of the thermally induced molecular reorientation were determined. Tablet formulations of naproxen were produced by direct compression. The mechanical, bioadhesive and release properties of the formulations were determined. Irradiation of NTM improved the gum's flow properties, resulting in Carr's Index and Hausner's ratios lower than 16% and 1.25, respectively. Swelling studies showed that MTM20 and MTM60 had lower water absorption capacity and swelling index values, while packing properties improved upon irradiation, as depicted by lower tapped density values. FTIR spectra of samples showed that the irradiated gums were distinct from the native gums and did not interact with naproxen sodium. The gum's mechanical properties improved with MTM20 and MTM60 and sustained-release action of up 12 h was obtained. Inclusion of hydroxypropyl methylcellulose (HPMC) in the tablet formulations proved critical for bioadhesion. Microwave irradiation of native Terminalia mantaly gum improved the flow, mechanical and sustained-release properties of Naproxen tablets, and the addition of HPMC increased bioadhesion properties. The tablet properties of the native gum were significantly improved after 20 s of microwave irradiation.

A sustained release formulation of chitosan modified PLCL:poloxamer blend nanoparticles loaded with optical agent for animal imaging

NASA Astrophysics Data System (ADS)

Ranjan, Amalendu P.; Zeglam, Karim; Mukerjee, Anindita; Thamake, Sanjay; Vishwanatha, Jamboor K.

2011-07-01

The objective of this study was to develop optical imaging agent loaded biodegradable nanoparticles with indocynanine green (ICG) using chitosan modified poly(L-lactide-co-epsilon-caprolactone) (PLCL):poloxamer (Pluronic F68) blended polymer. Nanoparticles were formulated with an emulsification solvent diffusion technique using PLCL and poloxamer as blend-polymers. Polyvinyl alcohol (PVA) and chitosan were used as stabilizers. The particle size, shape and zeta potential of the formulated nanoparticles and the release kinetics of ICG from these nanoparticles were determined. Further, biodistribution of these nanoparticles was studied in mice at various time points until 24 h following intravenous administration, using a non-invasive imaging system. The average particle size of the nanoparticles was found to be 146 ± 3.7 to 260 ± 4.5 nm. The zeta potential progressively increased from - 41.6 to + 25.3 mV with increasing amounts of chitosan. Particle size and shape of the nanoparticles were studied using transmission electron microscopy (TEM) which revealed the particles to be smooth and spherical in shape. These nanoparticles were efficiently delivered to the cytoplasm of the cells, as observed in prostate and breast cancer cells using confocal laser scanning microscopy. In vitro release studies indicated sustained release of ICG from the nanoparticles over a period of seven days. Nanoparticle distribution results in mice showing improved uptake and accumulation with chitosan modified nanoparticles in various organs and slower clearance at different time points over a 24 h period as compared to unmodified nanoparticles. The successful formulation of such cationically modified nanoparticles for encapsulating optical agents may lead to a potential deep tissue imaging technique for tumor detection, diagnosis and therapy.

In vitro and ex vivo characterisation of an in situ gelling formulation for sustained lidocaine release with potential use following knee arthroplasty.

PubMed

Sharma, Manisha; Chandramouli, Kaushik; Curley, Louise; Pontre, Beau; Reilly, Keryn; Munro, Jacob; Hill, Andrew; Young, Simon; Svirskis, Darren

2018-06-01

Sustained lidocaine release via a thermoresponsive poloxamer-based in situ gelling system has the potential to alleviate pain following knee arthroplasty. A previously developed formulation showed a promising drug release profile in synthetic phosphate-buffered saline (PBS). To support the translation of this formulation, ex vivo characterisation was warranted. This study therefore aimed (1) to modify the previously developed formulation to reduce the burst release, (2) to compare the release behaviour into ex vivo human intra-articular fluid (IAF) and PBS and (3) to determine the formulation spread in an ex vivo human knee using magnetic resonance imaging (MRI). All formulations provided sustained release out to 72 h; polyvinyl pyrrolidone was the most effective additive yielding a small yet significant decrease (p < 0.05) in the burst release. Release of lidocaine from the formulation occurred significantly faster into IAF compared to PBS (1.4 times greater release in the first 24 h), correlating with faster rates of gel erosion in IAF. Injection was easily achieved through a 21-gauge (G) needle into the synovial space of a human cadaveric knee, and MRI scans revealed effective spreading of the formulation throughout the joint cavity. The pattern of spread is promising for the drug to reach the widespread nerve endings in the joint capsule; the effect of this spread on release in an in vivo setting will be the subject of future studies. The demonstrated properties indicate that the in situ gelling formulation has the potential to be used clinically to treat post-operative pain following knee arthroplasty.

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.

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2014-04-01

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

Sustained release and permeation of timolol from surface-modified solid lipid nanoparticles through bioengineered human cornea.

PubMed

Attama, A A; Reichl, S; Müller-Goymann, C C

2009-08-01

The aim of the study was to formulate and evaluate surface-modified solid lipid nanoparticles sustained delivery system of timolol hydrogen maleate, a prototype ocular drug using a human cornea construct. Surface-modified solid lipid nanoparticles containing timolol with and without phospholipid were formulated by melt emulsification with high-pressure homogenization and characterized by particle size, wide-angle X-ray diffraction, encapsulation efficiency, and in vitro drug release. Drug transport studies through cornea bioengineered from human donor cornea cells were carried out using a modified Franz diffusion cell and drug concentration analyzed by high-performance liquid chromatography. Results show that surface-modified solid lipid nanoparticles possessed very small particles (42.9 +/- 0.3 nm, 47.2 +/- 0.3 nm, 42.7 +/- 0.7 nm, and 37.7 +/- 0.3 nm, respectively for SM-SLN 1, SM-SLN 2, SM-SLN 3, and SM-SLN 4) with low polydispersity indices, increased encapsulation efficiency (> 44%), and sustained in vitro release compared with unmodified lipid nanoparticles whose particles were greater than 160 nm. Permeation of timolol hydrogen maleate from the surface-modified lipid nanoparticles across the cornea construct was sustained compared with timolol hydrogen maleate solution in distilled water. Surface-modified solid lipid nanoparticles could provide an efficient way of improving ocular bioavailability of timolol hydrogen maleate.

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.

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

PubMed

Leucuta, Sorin E

2012-11-01

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

Inlay osmotic pump tablets containing metformin and glipizide.

PubMed

Patel, R B; Patel, G N; Patel, H R; Patel, M M

2011-10-01

The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. A newly developed inlay osmotic pump tablet (IOPT) can deliver glipizide (GLZ) and metformin HCl (MET) gradually in controlled manner. The aim of present investigation was to prepare the IOPT that can deliver >75% of GLZ in 2 h, whereas MET released after 2 h and sustained up to 12 h. In the present work, HP-β-CD was used to modify the solubility of GLZ before incorporating in the osmotic system and MET was spray-dried with HPMC A15C to modify its release profile, flow property, and compressibility. Various parameters mainly G(75%) (75% GLZ release), t(LMET) (lag time of MET release from device), Q(10 h) (percent of MET released within 10 h), and RSQ(ZERO) (R(2) of release data fitted to zero-order equation) were used to compare different formulations. The effects of different formulation variables, that is, osmagents, concentration of hydrophilic polymer, diameter of drug releasing orifice, and coating composition on the drug release profile were investigated. The release rate of GLZ could be effectively modified by the addition of sodium carbonate and sodium chloride, whereas the release rate of MET was adjusted by dual-coating system and by addition of hydrophilic polymer. The developed inlay osmotic system could be effective in the multidrug therapy of diabetes by delivering both drugs in a controlled manner.

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

PubMed

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

2015-06-01

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

Artificial neural networks in evaluation and optimization of modified release solid dosage forms.

PubMed

Ibrić, Svetlana; Djuriš, Jelena; Parojčić, Jelena; Djurić, Zorica

2012-10-18

Implementation of the Quality by Design (QbD) approach in pharmaceutical development has compelled researchers in the pharmaceutical industry to employ Design of Experiments (DoE) as a statistical tool, in product development. Among all DoE techniques, response surface methodology (RSM) is the one most frequently used. Progress of computer science has had an impact on pharmaceutical development as well. Simultaneous with the implementation of statistical methods, machine learning tools took an important place in drug formulation. Twenty years ago, the first papers describing application of artificial neural networks in optimization of modified release products appeared. Since then, a lot of work has been done towards implementation of new techniques, especially Artificial Neural Networks (ANN) in modeling of production, drug release and drug stability of modified release solid dosage forms. The aim of this paper is to review artificial neural networks in evaluation and optimization of modified release solid dosage forms.

Artificial Neural Networks in Evaluation and Optimization of Modified Release Solid Dosage Forms

PubMed Central

Ibrić, Svetlana; Djuriš, Jelena; Parojčić, Jelena; Djurić, Zorica

2012-01-01

Implementation of the Quality by Design (QbD) approach in pharmaceutical development has compelled researchers in the pharmaceutical industry to employ Design of Experiments (DoE) as a statistical tool, in product development. Among all DoE techniques, response surface methodology (RSM) is the one most frequently used. Progress of computer science has had an impact on pharmaceutical development as well. Simultaneous with the implementation of statistical methods, machine learning tools took an important place in drug formulation. Twenty years ago, the first papers describing application of artificial neural networks in optimization of modified release products appeared. Since then, a lot of work has been done towards implementation of new techniques, especially Artificial Neural Networks (ANN) in modeling of production, drug release and drug stability of modified release solid dosage forms. The aim of this paper is to review artificial neural networks in evaluation and optimization of modified release solid dosage forms. PMID:24300369

Clay-based Formulations to Reduce the Environmental Impact of the Herbicide Terbuthylazine

USDA-ARS?s Scientific Manuscript database

Controlled release formulations of pesticides are receiving increasing attention as a way to reduce the environmental impact of pesticides after their application to agricultural soils. Natural and modified clay minerals have been proved to be efficient adsorbents for many pesticides and, accordingl...

The controlled release of bioactive compounds from lignin and lignin-based biopolymer matrices.

PubMed

Chowdhury, Mohammad A

2014-04-01

This article presents the perspectives on the lignin-based controlled release (CR) of bioactive materials which are based on the researches that took place over the last three decades. It encompasses three broad spectra of observations: CR formulations with mixed-matrix of lignin; CR formulations with modified lignin; and the lignin-based CR formulation modelling. The article covers a range of bioactive materials aimed for agricultural utilisations viz. herbicides, pesticides, insecticides and fertilisers for their controlled release studies, which were formulated either with lignin or lignin-based biopolymers. The inherent complexities, structural heterogeneities, and the presence of myriad range of functionalities in the lignin structure make it difficult to understand and explaining the underlying CR behaviour and process. In conjunction to this issue, the fundamental aspects of the synthetic and biocompatible polymer-based drug controlled release process are presented, and correlated with the lignin-based CR research. The articulation of this correlation and the overview presented in this article may be complemented of the future lignin-based CR research gaining better insights, reflections, and understanding. A recommended approach on the lignin depolymerisation is suggested to fragmenting the lignin, which may be tailored further using the re-polymerisation or other synthetic approaches. Thus it may allow more control with flexibilities and improved properties of the modified lignin materials, and help achieve the desired CR outcomes. Copyright © 2014 Elsevier B.V. All rights reserved.

Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide.

PubMed

Woolfson, A David; Malcolm, R Karl; Morrow, Ryan J; Toner, Clare F; McCullagh, Stephen D

2006-11-15

TMC 120 (Dapivirine) is a potent non-nucleoside reverse transcriptase inhibitor that is presently being developed as a vaginal HIV microbicide. To date, most vaginal microbicides under clinical investigation have been formulated as single-dose semi-solid gels, designed for application to the vagina before each act of intercourse. However, a clear rationale exists for providing long-term, controlled release of vaginal microbicides in order to afford continuous protection against heterosexually transmitted HIV infection and to improve user compliance. In this study we report on the incorporation of various pharmaceutical excipients into TMC 120 silicone, reservoir-type intravaginal rings (IVRs) in order to modify the controlled release characteristics of the microbicide. The results demonstrate that TMC 120 is released in zero-order fashion from the rings over a 28-day period and that release parameters could be modified by the inclusion of release-modifying excipients in the IVR. The hydrophobic liquid excipient isopropyl myristate had little effect on steady-state daily release rates, but did increase the magnitude and duration of burst release in proportion to excipient loading in the IVR. By comparison, the hydrophobic liquid poly(dimethylsiloxane) had little effect on TMC 120 release parameters. A hydrophilic excipient, lactose, had the surprising effect of decreasing TMC 120 burst release while increasing the apparent steady-state daily release in a concentration-dependent manner. Based on previous cell culture data and vaginal physiology, TMC120 is released from the various ring formulations in amounts potentially capable of maintaining a protective vaginal concentration. It is further predicted that the observed release rates may be maintained for at least a period of 1 year from a single ring device. TMC 120 release profiles and the mechanical properties of rings could be modified by the physicochemical nature of hydrophobic and hydrophilic excipients incorporated into the IVRs.

Development of Novel Warfarin-Silica Composite for Controlled Drug Release.

PubMed

Parfenyuk, Elena V; Dolinina, Ekaterina S

2017-04-01

The work is devoted to synthesis and study of warfarin composites with unmodified, methyl and phenyl modified silica in order to develop controlled release formulation of the anticoagulant. The composites were prepared by two routes, adsorption and sol-gel, and characterized with FTIR spectroscopy, dynamic light scattering and DSC methods. The drug release behavior from the composites in media with pH 1.6, 6.8 and 7.4 was analyzed in vitro. The release kinetics of the warfarin - silica composites prepared by the two routes was compared among each other and with analogous silica composites with water soluble drug molsidomine. The comparative analysis showed that in general the kinetic regularities and mechanisms of release for both drugs are similar and determined by nonuniform distribution of the drugs over the silica matrixes and stability of the matrixes in the studied media for the adsorbed composites and uniformly distributed drug and more brittle structure for the sol-gel composites. The sol-gel composite of warfarin - phenyl modified silica is perspective for further development of novel warfarin formulation with controlled release because it releases warfarin according to zero-order kinetic law with approximately equal rate in the media imitating different segments of gastrointestinal tract.

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

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.

Investigation on influence of Wurster coating process parameters for the development of delayed release minitablets of Naproxen.

PubMed

Shah, Neha; Mehta, Tejal; Aware, Rahul; Shetty, Vasant

2017-12-01

The present work aims at studying process parameters affecting coating of minitablets (3 mm in diameter) through Wurster coating process. Minitablets of Naproxen with high drug loading were manufactured using 3 mm multi-tip punches. The release profile of core pellets (published) and minitablets was compared with that of marketed formulation. The core formulation of minitablets was found to show similarity in dissolution profile with marketed formulation and hence was further carried forward for functional coating over it. Wurster processing was implemented to pursue functional coating over core formulation. Different process parameters were screened and control strategy was applied for factors significantly affecting the process. Modified Plackett Burman Design was applied for studying important factors. Based on the significant factors and minimum level of coating required for functionalization, optimized process was executed. Final coated batch was evaluated for coating thickness, surface morphology, and drug release study.

Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids

DOE PAGES

Kieler-Ferguson, Heidi M.; Chan, Darren; Sockolosky, Jonathan; ...

2017-03-03

Here, we employed a recently introduced class of sterol-modified lipids (SML) to produce m-PEG-DSPE containing liposome compositions with a range of cis-platinum content release rates. SML have a cholesterol succinate attached to the phosphatidylglycerol head group and a fatty acid at the 2 position. These compositions were compared to the well-studied liposome phospholipid compositions: mPEG-DSPE/Hydrogenated Soy PC/cholesterol or mPEG-DSPE/POPC/cholesterol to determine the effect of the cis-platinum release extent on C26 tumor proliferation in the BALB/c colon carcinoma mouse model. The release rates of cis-platinum from liposomes composed of SML are a function of the acyl chain length. SML-liposomes with shortermore » acyl chain lengths C-8 provided more rapid cisplatin release, lower in vitro IC50, and were easier to formulate compared to liposomes using traditional phospholipid compositions. Similar to other liposome cis-platinum formulations, the half-life of m-PEG-DSPE SML liposome cisplatin is substantially longer than the free drug. This resulted in a higher tumor cisplatin concentration at 48 h post-dosing compared to the free drug and higher Pt-DNA adducts in the tumor. Moreover, the maximum tolerated dose of the liposome formulations where up to four fold greater than the free drug. Using X-ray fluorescence spectroscopy on tumor sections, we compared the location of platinum, to the location of a fluorescence lipid incorporated in the liposomes. The liposome platinum co-localized with the fluorescent lipid and both were non-uniformly distributed in the tumor. Non-encapsulated Cis-platinum, albeit at a low concentration, was more uniformly distributed thorough the tumor. Three liposome formulations, including the well studied hydrogenated HSPC composition, had better antitumor activity in the murine colon 26 carcinoma model as compared to the free drug at the same dose but the SML liposome platinum formulations did not perform better than the HSPC formulation.« less

Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kieler-Ferguson, Heidi M.; Chan, Darren; Sockolosky, Jonathan

Here, we employed a recently introduced class of sterol-modified lipids (SML) to produce m-PEG-DSPE containing liposome compositions with a range of cis-platinum content release rates. SML have a cholesterol succinate attached to the phosphatidylglycerol head group and a fatty acid at the 2 position. These compositions were compared to the well-studied liposome phospholipid compositions: mPEG-DSPE/Hydrogenated Soy PC/cholesterol or mPEG-DSPE/POPC/cholesterol to determine the effect of the cis-platinum release extent on C26 tumor proliferation in the BALB/c colon carcinoma mouse model. The release rates of cis-platinum from liposomes composed of SML are a function of the acyl chain length. SML-liposomes with shortermore » acyl chain lengths C-8 provided more rapid cisplatin release, lower in vitro IC50, and were easier to formulate compared to liposomes using traditional phospholipid compositions. Similar to other liposome cis-platinum formulations, the half-life of m-PEG-DSPE SML liposome cisplatin is substantially longer than the free drug. This resulted in a higher tumor cisplatin concentration at 48 h post-dosing compared to the free drug and higher Pt-DNA adducts in the tumor. Moreover, the maximum tolerated dose of the liposome formulations where up to four fold greater than the free drug. Using X-ray fluorescence spectroscopy on tumor sections, we compared the location of platinum, to the location of a fluorescence lipid incorporated in the liposomes. The liposome platinum co-localized with the fluorescent lipid and both were non-uniformly distributed in the tumor. Non-encapsulated Cis-platinum, albeit at a low concentration, was more uniformly distributed thorough the tumor. Three liposome formulations, including the well studied hydrogenated HSPC composition, had better antitumor activity in the murine colon 26 carcinoma model as compared to the free drug at the same dose but the SML liposome platinum formulations did not perform better than the HSPC formulation.« less

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

PubMed

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

2015-11-01

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

Investigation of the Dissolution Profile of Gliclazide Modified-Release Tablets Using Different Apparatuses and Dissolution Conditions.

PubMed

Skripnik, K K S; Riekes, M K; Pezzini, B R; Cardoso, S G; Stulzer, H K

2017-07-01

In the absence of an official dissolution method for modified-release tablets of gliclazide, dissolution parameters, such as apparatuses (1, 2, and 3), rotation speeds, pH, and composition of the dissolution medium were investigated. The results show that although the drug presents a pH-mediated solubility (pH 7.0 > 6.8 > 6.4 > 6.0 > 5.5 > 4.5), the in vitro release of the studied tablets was not dependent on this parameter, despite of the apparatus tested. On the other hand, the rotation speed demonstrated a greater influence (100 rpm >50 rpm). Using similar hydrodynamic conditions, the three different apparatuses were compared in pH 6.8 and provided the following trend: apparatus 1 at 100 rpm >2 at 50 rpm ≈3 at 10 dpm. As a complete, but slow release is expected from modified-release formulations, apparatus 2, in phosphate buffer pH 6.8 and 100 rpm, were selected as the optimized dissolution method. In comparison to apparatus 1 under the same conditions, the paddle avoids the stickiness of formulation excipients at the mesh of the basket, which could prejudice the release of gliclazide. Results obtained with biorelevant medium through the developed dissolution method were similar to the buffer solution pH 6.8. The application of the optimized method as a quality control test between two different brands of gliclazide modified-release tablets showed that both dissolution profiles were considered similar by the similarity factor (f2 = 51.8). The investigation of these dissolution profiles indicated a dissolution kinetic following first-order model.

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.

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

PubMed

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

2015-01-01

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

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.

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

PubMed

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

2015-01-01

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

New Formulations of Methylphenidate for the Treatment of Attention-Deficit/Hyperactivity Disorder: Pharmacokinetics, Efficacy, and Tolerability.

PubMed

Cortese, Samuele; D'Acunto, Giulia; Konofal, Eric; Masi, Gabriele; Vitiello, Benedetto

2017-02-01

Psychostimulants are the recommended first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD). Methylphenidate is one of the most commonly used psychostimulants worldwide. Given that immediate-release and/or tablet/capsule formulations may decrease adherence to methylphenidate treatment, several drug companies have been developing novel long-acting and/or liquid/chewable formulations that may improve adherence as well as (for long-acting formulations) reduce abuse potential, decrease stigma associated with multiple administrations per day, and decrease the potential for adverse effects related to dosage peak. Here, we review the pharmacokinetics, efficacy, and tolerability of novel formulations of methylphenidate that are in development or have been approved by the US FDA or European Medicines Agency (EMA) in the last 5 years. We searched the websites of the FDA, EMA, ClinicalTrials.gov, and the pertinent drug companies. We also searched PubMed, Ovid databases (MEDLINE, PsycINFO, Embase + Embase classic), and ISI Web of Knowledge (Web of Science [Science Citation Index Expanded], Biological Abstracts, Biosis, Food Science and Technology Abstracts) to retrieve any additional pertinent information. We found data from trials for the following compounds: (1) methylphenidate extended-release oral suspension (MEROS; NWP06, Quillivant™); (2) methylphenidate extended-release chewable capsules (NWP09, QuilliChew ER™); (3) methylphenidate hydrochloride extended-release capsules (Aptensio XR™); (4) methylphenidate extended-release orally disintegrating tablets (XR-ODT; NT-0102, Cotempla™); (5) ORADUR technology (once-daily tamper-resistant formulation) methylphenidate sustained release (SR); and (6) methylphenidate modified-release (HLD-200; Bejorna™). Overall, available evidence based on trials suggests these compounds have good efficacy and tolerability. Future research should further explore the effectiveness and tolerability of these new formulations as well as their potential to improve adherence to treatment in the 'real world' via pragmatic trials.

In situ forming implants for the delivery of metronidazole to periodontal pockets: formulation and drug release studies.

PubMed

Kilicarslan, Muge; Koerber, Martin; Bodmeier, Roland

2014-05-01

This study was performed to obtain prolonged drug release with biodegradable in situ forming implants for the local delivery of metronidazole to periodontal pockets. The effect of polymer type (capped and uncapped PLGA), solvent type (water-miscible and water-immiscible) and the polymer/drug ratio on in vitro drug release studies were investigated. In situ implants with sustained metronidazole release and low initial burst consisted of capped PLGA and N-methyl-2-pyrolidone as solvent. Mucoadhesive polymers were incorporated into the in situ implants in order to modify the properties of the delivery systems towards longer residence times in vivo. Addition of the polymers changed the adhesiveness and increased the viscosity and drug release of the formulations. However, sustained drug release over 10 days was achievable. Biodegradable in situ forming implants are therefore an attractive delivery system to achieve prolonged release of metronidazole at periodontal therapy.

RES-loaded pegylated CS NPs: for efficient ocular delivery.

PubMed

Pandian, Saravanakumar; Jeevanesan, Vinoth; Ponnusamy, Chandrasekar; Natesan, Subramanian

2017-02-01

The objective of this study is to develop resveratrol (RES) loaded polyethylene glycols (PEGs) modified chitosan (CS) nanoparticles (NPs) by ionic gelation method for the treatment of glaucoma. While increasing the concentration of PEG, the particle size and polydispersity index of the formulations increased. Entrapment efficiency and RES loading (RL) of NPs decreased while increasing PEG concentration. The in vitro release of NPs showed an initial burst release of RES (45%) followed by controlled release. Osmolality of formulations revealed that the prepared NPs were iso-osmolar with the tear. Ocular tolerance of the NPs was evaluated using hen's egg test on the chorioallantoic membrane and it showed that the NPs were non-irritant. RES-loaded PEG-modified CS NPs shows an improved corneal permeation compared with RES dispersion. Fluorescein isothiocyanate loaded CS NPs accumulated on the surface of the cornea but the PEG-modified CS NPs crossed the cornea and reached retinal choroid. RES-loaded PEG-modified CS NPs reduced the intra-ocular pressure (IOP) by 4.3 ± 0.5 mmHg up to 8 h in normotensive rabbits. These results indicate that the developed NPs have efficient delivery of RES to the ocular tissues and reduce the IOP for the treatment of glaucoma.

Formulation development and release studies of indomethacin suppositories.

PubMed

Sah, M L; Saini, T R

2008-01-01

Indomethacin suppositories were prepared by using water-soluble and oil soluble suppository bases, and evaluated for in vitro release by USP I and modified continuous flow through bead bed apparatus. Effect of the Tween 80 (1% and 5%) was further studied on in vitro release of the medicament. Release rate was good in water-soluble suppositories bases in comparison to oil soluble suppositories bases. Release was found to be greater in modified continuous flow through bead bed apparatus. When surfactant was used in low concentration then release rate was much greater, as compared to high concentration. When stability studies were performed on the prepared indomethacin suppositories it was found that suppositories made by water-soluble base had no significant changes while suppositories prepared by oil soluble bases, had some signs of instability.

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.

Modulation of venlafaxine hydrochloride release from press coated matrix tablet.

PubMed

Gohel, M C; Soni, C D; Nagori, S A; Sarvaiya, K G

2008-01-01

The aim of present study was to prepare novel modified release press coated tablets of venlafaxine hydrochloride. Hydroxypropylmethylcellulose K4M and hydroxypropylmethylcellulose K100M were used as release modifier in core and coat, respectively. A 3(2) full factorial design was adopted in the optimization study. The drug to polymer ratio in core and coat were chosen as independent variables. The drug release in the first hour and drug release rate between 1 and 12 h were chosen as dependent variables. The tablets were characterized for dimension analysis, crushing strength, friability and in vitro drug release. A check point batch, containing 1:2.6 and 1:5.4 drug to polymer in core and coat respectively, was prepared. The tablets of check point batch were subjected to in vitro drug release in dissolution media with pH 5, 7.2 and distilled water. The kinetics of drug release was best explained by Korsmeyer and Peppas model (anomalous non-Fickian diffusion). The systematic formulation approach enabled us to develop modified release venlafaxine hydrochloride tablets.

The Influence of Polyethylene Glycol Solution on the Dissolution Rate of Sustained Release Morphine.

PubMed

Hodgman, Michael; Holland, Michael G; Englich, Ulrich; Wojcik, Susan M; Grant, William D; Leitner, Erich

2016-12-01

Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations. An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations. In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG. The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.

Waste Material of Propolis as a Film Forming Agent Intended to Modify the Metronidazole Release: Preparation and Characterization.

PubMed

de Toledo, Lucas de Alcântara Sica; Rosseto, Hélen Cássia; Ravani, Laura; Cortesi, Rita; Bruschi, Marcos Luciano

2016-01-01

Metronidazole is an antimicrobial agent utilized for the treatment of protozoa and anaerobic bacteria infections. Many times, it is necessary to modify the metronidazole release, and the development of modified release systems may be suggested. In this study, we are able to investigate the use of the residue normally thrown out from the preparation of propolis extracts (BP) as strategy to modify the metronidazole release. We prepared films containing polymeric adjuvant (gelatin or ethylcellulose) and metronidazole, by solvent casting method. Density, mechanical properties, water vapor permeability (WVP), moisture uptake capacity (MUC), thermogravimetry, differential scanning calorimetry, Fourier transform infrared spectroscopy (FT-IR), and in vitro metronidazole release were investigated. Thickness and density of the preparations indicated that the compounds were homogeneously dispersed throughout. Mechanical properties were influenced by film composition. Films containing gelatin showed higher resistance to stress while those containing ethylcellulose presented greater flexibility. The greater the adjuvant concentrations lower the resistance to rupture and the elasticity, but higher MUC and WVP of formulations. FT-IR tests suggested interactions between BP and the adjuvants. Films were capable to protect the metronidazole and changed its release profile. BP films are of great practical importance constituting a novel strategy to modify the metronidazole release.

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.

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

PubMed

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

2015-02-01

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

A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting.

PubMed

Zhang, Lin; Zhu, Weiwei; Yang, Chunfen; Guo, Hongxia; Yu, Aihua; Ji, Jianbo; Gao, Yan; Sun, Min; Zhai, Guangxi

2012-01-01

The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells. Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research. The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor(®) EL, 32.5% Transcutol(®) HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin.

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

PubMed Central

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

2015-01-01

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

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.

Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes.

PubMed

Jensen, J L; Appel, L E; Clair, J H; Zentner, G M

1995-05-01

The feasibility of using modified Eudragit acrylic latexes as microporous coatings for osmotic devices was investigated. Potassium chloride tablets were coated with mixtures of Eudragit RS30D and RL30D acrylic latexes that also contained a plasticizer (triethyl citrate or acetyl tributyl citrate) and a pore-forming agent (urea). A 2(5-1) fractional factorial experimental design was employed to determine the effect of five formulation variables (RS30D:RL30D polymer ratio plasticizer type, plasticizer level, urea level, and cure) on the in vitro release rate of KCl in deionized water (di water), lag time, and coat burst strength. The RS30D:RL30D polymer ratio had the greatest effect on the release rate, and both lag time and burst strength were most affected by the urea level. Statistical optimization was performed, and a coat formulation with predicted desirable in vitro performance was prepared and tested. The in vitro release rate (di water), lag time, and coat burst strength agreed well with the prediction. Dissolutions were also performed in phosphate buffered saline (PBS; pH 7.4); several formulations released markedly slower in PBS than in di water. This discrepancy was dependent on the type of plasticizer and the amount of pore former. Only those coat formulations containing acetyl tributyl citrate as the plasticizer and a 100% urea [(g urea/g polymer solids) x 100] level exhibited similar release rates in di water and PBS. The mechanism of release from these devices was primarily osmotic, whereas the release from devices coated with a formulation containing triethyl citrate and 50% urea was not dependent on the osmotic pressure difference. Devices with an osmotic release mechanism behaved similarly in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases.

PubMed

Salmonson, Heléne; Sjöberg, Gunilla; Brogren, Jacob

2018-01-01

The use of the standard procedure for managing overdoses with immediate release (IR) paracetamol is questionable when applied to overdoses with modified release (MR) formulations. This study describes the pharmacokinetics of paracetamol and the clinical outcomes following overdoses with a MR formulation. Medical records including laboratory analyses concerning overdoses of MR paracetamol from 2009 to 2015 were collected retrospectively. Inclusion criteria were ingestion of a toxic dose, known time of intake and documented measurements of serum paracetamol and liver function tests. Graphical analysis, descriptive statistics and population pharmacokinetic modelling were used to describe data. Fifty-three cases were identified. Median age was 26 years (range 13-68), median dose was 20 g (range 10-166) and 74% were females. The pharmacokinetic analysis showed a complex, dose dependent serum versus time profile with prolonged absorption and delayed serum peak concentrations with increasing dose. Ten patients had persistently high serum levels for 24 h or more, six of them had a second peak 8-19 h after ingestion. Seven of 34 patients receiving N-acetylcysteine (NAC) within 8 h had alanine aminotransferase (ALT) above reference range. Three of them developed hepatotoxicity (ALT >1000 IU/l). The pharmacokinetic and clinical analysis showed that the standard treatment protocol, including risk assessment and NAC regimen, used for IR paracetamol poisoning not appear suitable for MR formulation. Individual and tailored treatment may be valuable but further studies are warranted to determine optimal regimen of overdoses with MR formulation.

Controlled release of modified insulin glargine from novel biodegradable injectable gels.

PubMed

Anand, Om; Almoazen, Hassan; Mehrotra, Nitin; Johnson, James; Shukla, Atul

2012-03-01

The objective of this study was to investigate the duration of biological effects of modified insulin glargine released from a novel biodegradable injectable gel in type II diabetic Zucker diabetic fatty (ZDF) rats. Modified insulin glargine was purified from the marketed formulation by process of dialysis followed by freeze-drying, and the purity was confirmed by the single peak, corresponding to insulin glargine in the HPLC chromatogram. To determine and to compare the biological activity of purified insulin glargine with marketed formulation, it was suspended in isotonic saline solutions and administered subcutaneously to ZDF rats at a dose of 10 IU/kg of insulin and the blood glucose levels were measured. The blood glucose levels of ZDF rats after a subcutaneous injection of a suspension of purified insulin glargine decreased below 200 mg/dL within 2 h and remained at this level up to 6 h, then steadily raised above 400 mg/dL in 12 h. Insulin glargine particles were loaded into a novel biodegradable injectable gel formulation prepared from a blend of polylactic-co-glycolic acid (PLGA) and biocompatible plasticizers. Approximately 0.1 mL of insulin glargine-loaded gel prepared with PLGA was administered subcutaneously to the ZDF rats, and blood glucose levels were measured. The PLGA gel formulations prepared with insulin glargine particles had duration of action of 10 days following a single subcutaneous injection. The addition of zinc sulfate to the formulations prepared with purified insulin glargine particles further slowed down the drop in blood glucose concentrations.

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

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

PubMed

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

2014-11-01

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

Design and Evaluation of Hydrophilic Matrix System for pH-Independent Sustained Release of Weakly Acidic Poorly Soluble Drug.

PubMed

Huang, Jinheng; Lin, Huaqing; Peng, Bingxin; Huang, Qianfeng; Shuai, Fangzhou; Xie, Yanxian

2018-04-30

The aim of this research was to design and evaluate a hydrophilic matrix system for sustained release of glipizide, a weakly acidic poor soluble drug. A combination of inclusion complexation and microenvironmental pH modification techniques was utilized to improve the dissolution and pH-independent release of glipizide. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was used as the complexation agent while sodium citrate and magnesium oxide (MgO) were used as model pH modifiers. The hydrophilic matrix tablets were prepared by powder direct compression and evaluated by in vitro dissolution study respectively in pH 6.8 and pH 1.2 dissolution media. The formulations containing MgO exhibited increased cumulative drug release from less than 40% in the reference formulation to 90% within 24 h in acidic media (pH 1.2). The release profile in acidic media was similar to the alkaline media (pH 6.8) with a similarity factor (f 2 ) of 55.0, suggesting the weakening of the effect of pH on the dissolution efficiency of glipizide. The release profile fitted well into the Higuchi model and the dominant mechanism of drug release was Fickian diffusion while case II transport/polymer relaxation occurred. In conclusion, combining inclusion complexation agents and pH modifiers had improved the dissolution of glipizide as well as achieved the pH-independent release profile.

The effect of prime emulsion components as a function of equilibrium headspace concentration of soursop flavor compounds

PubMed Central

2014-01-01

Background Perceptions of food products start when flavor compounds are released from foods, transported and appropriate senses in the oral and nose are triggered. However, the long-term stability of flavor compounds in food product has been a major concern in the food industry due to the complex interactions between key food ingredients (e.g., polysaccharides and proteins). Hence, this study was conducted to formulate emulsion-based beverage using natural food emulsifiers and to understand the interactions between emulsion compositions and flavor compounds. Results The influences of modified starch (x 1 ), whey protein isolate (x 2 ), soursop flavor oil (x 3 ) and deionized water (x 4 ) on the equilibrium headspace concentration of soursop volatile flavor compounds were evaluated using a four-component with constrained extreme vertices mixture design. The results indicated that the equilibrium headspace concentration of soursop flavor compounds were significantly (p < 0.05) influenced by the matrix and structural compositions of the beverage emulsions. Interface formed using modified starch and whey protein isolate (WPI) proved to be capable of inhibiting the release of volatile flavor compounds from the oil to the aqueous phase. Modified starch could retard the overall flavor release through its hydrophobic interactions with volatile flavor compounds and viscosity enhancement effect. Excessive amount of modified starch was also shown to be detrimental to the stability of emulsion system. However, both modified starch and WPI showed to be a much more effective barrier in inhibiting the flavor release of flavor compounds when used as individual emulsifier than as a mixture. Conclusions Overall, the mixture design can be practical in elucidating the complex interactions between key food components and volatile flavor compounds in an emulsion system. These studies will be useful for the manufacturers for the formulation of an optimum beverage emulsion with desirable emulsion properties and desirable flavor release profile. PMID:24708894

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.

Encapsulation of Naproxen in Lipid-Based Matrix Microspheres: Characterization and Release Kinetics

PubMed Central

Bhoyar, PK; Morani, DO; Biyani, DM; Umekar, MJ; Mahure, JG; Amgaonkar, YM

2011-01-01

The objective of this study was to microencapsulate the anti-inflammatory drug (naproxen) to provide controlled release and minimizing or eliminating local side effect by avoiding the drug release in the upper gastrointestinal track. Naproxen was microencapsulated with lipid-like carnauba wax, hydrogenated castor oil using modified melt dispersion (modified congealable disperse phase encapsulation) technique. Effect of various formulation and process variables such as drug-lipid ratio, concentration of modifier, concentration of dispersant, stirring speed, stirring time, temperature of external phase, on evaluatory parameters such as size, entrapment efficiency, and in vitro release of naproxen were studied. The microspheres were characterized for particle size, scanning electron microscopy (SEM), FT-IR spectroscopy, drug entrapment efficiency, in vitro release studies, for in vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The drug entrapment efficiency of various batches of microspheres was found to be ranging from 60 to 90 %w/w. In vitro drug release studies were carried out up to 24 h in pH 7.4 phosphate buffer showing 50-65% drug release. In vitro drug release from all the batches showed better fitting with the Korsmeyer-Peppas model, indicating the possible mechanism of drug release to be by diffusion and erosion of the lipid matrix. PMID:21731354

Encapsulation of naproxen in lipid-based matrix microspheres: characterization and release kinetics.

PubMed

Bhoyar, P K; Morani, D O; Biyani, D M; Umekar, M J; Mahure, J G; Amgaonkar, Y M

2011-04-01

The objective of this study was to microencapsulate the anti-inflammatory drug (naproxen) to provide controlled release and minimizing or eliminating local side effect by avoiding the drug release in the upper gastrointestinal track. Naproxen was microencapsulated with lipid-like carnauba wax, hydrogenated castor oil using modified melt dispersion (modified congealable disperse phase encapsulation) technique. Effect of various formulation and process variables such as drug-lipid ratio, concentration of modifier, concentration of dispersant, stirring speed, stirring time, temperature of external phase, on evaluatory parameters such as size, entrapment efficiency, and in vitro release of naproxen were studied. The microspheres were characterized for particle size, scanning electron microscopy (SEM), FT-IR spectroscopy, drug entrapment efficiency, in vitro release studies, for in vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The drug entrapment efficiency of various batches of microspheres was found to be ranging from 60 to 90 %w/w. In vitro drug release studies were carried out up to 24 h in pH 7.4 phosphate buffer showing 50-65% drug release. In vitro drug release from all the batches showed better fitting with the Korsmeyer-Peppas model, indicating the possible mechanism of drug release to be by diffusion and erosion of the lipid matrix.

[The use of natural and synthetic hydrophilic polymers in the formulation of metformin hydrochloride tablets with different profile release].

PubMed

Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Metformin hydrochloride after buformin and phenformin belongs to the group of biguanid derivatives used as oral anti-diabetic drugs. The object of the study is the technological analysis and the potential effect of biodegradable macromolecular polymers on the technological and therapeutic parameters of oral anti-diabetic medicinal products with metformin hydrochloride: Siofor, Formetic, Glucophage, Metformax in doses of 500mg and 1000mg and Glucophage XR in a dose of 500 mg of modified release. Market therapeutic products containing 500 and 1000 mg of metformin hydrochloride in a normal formulation and 500 mg of metformin hydrochloride in a formulation of modified release were analyzed. Following research methods were used: technological analysis of tablets, study of disintegration time of tablets, evaluation of pharmaceutical availability of metformin hydrochloride from tested therapeutic products, mathematical and kinetic analysis of release profiles of metformin hydrochloride, statistical analysis of mean differences of release coefficients. The percentage of excipients in the XR formulation is higher and constitutes 50.5% of a tablet mass. However, in standard formulations the percentage is lower, between 5.5% and 12.76%. On the basis of the results of disintegration time studies, the analysed therapeutic products can be divided into two groups, regardless the dose. The first one are preparations with faster (not fast!) disintegration: Glucophage i Metformax. The second group are preparations with slower disintegration, more balanced in the aspect of a high dose of the biologically active substance: Formetic and Siofor. Products with a lower content of excipients (Metformax, Glucophage) disintegrate in a faster way. The disintegration rate of the products with a higher content of excipients (Formetic, Siofor) is slower. The appearance of metformin hydrochloride concentration in the gastrointestinal contents, balanced in time, caused by a slower disintegration-dissolving of a tablet, is conducive to the reduction of gastrointestinal side effects and better tolerance of the therapeutic product by a patient. The study on pharmaceutical availability indicated relevant kinetic differences between tested therapeutic products. They are particularly visible between standard formulations and the one with prolonged release (Glucophage XR500). Its release profile bears features of kinetics similar to zero-order reactions. Tested therapeutic products contain a large amount of the biologically active substance in relation to the content of excipients. A higher content of excipients in a single tablet mass distinguishes Siofor in comparison with Glucophage i Metformax. The excipients used in the formulations of tested preparations are comparable. A higher percentage of binding agents (HPMC, PVP) is observed, but there is a lack of typical disintegrants which results in a longer disintegration time up to 15 minutes. Siofor disintegrates at the same time as Formetic, but longer than Glucophage i Metformax. Considering the large content of the active substance and pharmacological properties of metformin hydrochloride, such a disintegration might have beneficial consequences, because the amount of the free active substance in the gastrointestinal tract will increase over the longer time period what will reduce the level of gastrointestinal side effects. The release profiles of metformin hydrochloride from tested therapeutic products are comparable. The Glucophage XR 500 formulation with the release kinetics of metformin hydrochloride similar to the zero-order kinetics is completely different from the others. The above is confirmed by the mathematical analysis of release profiles of metformin hydrochloride from tested preparations where equations of lines describing the release profile are characterized by similar values of correlation coefficients.

Development of modified release diltiazem HCl tablets using composite index to identify optimal formulation.

PubMed

Gohel, M C; Patel, M M; Amin, A F

2003-05-01

This article reports the preparation of tartaric acid treated ispaghula husk powder for the development of modified release tablets of diltiazem HCl by adopting direct compression technique and a 32 full factorial design. The modified ispaghula husk powder showed superior swelling and gelling as compared to untreated powder. Addition of compaction augmenting agent such as dicalcium phosphate was found to be essential for obtaining tablets with adequate crushing strength. In order to improve the crushing strength of diltiazem HCl tablets, to modulate drug release pattern, and to obtain similarity of dissolution profiles in distilled water and simulated gastric fluid (pH 1.2), modified guar gum was used along with modified ispaghula husk powder and tartaric acid. A novel composite index, which considers a positive or a negative deviation from an ideal value, was calculated considering percentage drug release in 60, 300, and 540 min as dependent variables for the selection of a most appropriate batch. Polynomial equation and contour plots are presented. The concept of similarity factor (f2) was used to prove similarity of dissolution in water and simulated gastric fluid (pH 1.2).

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.

Core/shell PLGA microspheres with controllable in vivo release profile via rational core phase design.

PubMed

Yu, Meiling; Yao, Qing; Zhang, Yan; Chen, Huilin; He, Haibing; Zhang, Yu; Yin, Tian; Tang, Xing; Xu, Hui

2018-02-27

Highly soluble drugs tend to release from preparations at high speeds, which make them need to be taken at frequent intervals. Additionally, some drugs need to be controlled to release in vivo at certain periods, so as to achieve therapeutic effects. Thus, the objective of this study is to design injectable microparticulate systems with controllable in vivo release profile. Biodegradable PLGA was used as the matrix material to fabricate microspheres using the traditional double emulsification-solvent evaporation method as well as improved techniques, with gel (5% gelatine or 25% F127) or LP powders as the inner phases. Their physicochemical properties were systemically investigated. Microspheres prepared by modified methods had an increase in drug loading (15.50, 16.72, 15.66%, respectively) and encapsulation efficiencies (73.46, 79.42, 74.40%, respectively) when compared with traditional methods (12.01 and 57.06%). The morphology of the particles was characterized by optical microscope (OM) and scanning electron microscopy (SEM), and the amorphous nature of the encapsulated drug was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. To evaluate their release behaviour, the in vitro degradation, in vitro release and in vivo pharmacodynamics were subsequently studied. Traditional microspheres prepared in this study with water as the inner phase had a relatively short release period within 16 d when compared with modified microspheres with 5% gelatine as the inner phase, which resulted in a smooth release profile and appropriate plasma LP concentrations over 21 d. Thus this type of modified microspheres can be better used in drugs requiring sustained release. The other two formulations containing 25% F127 and LP micropowders presented two-stage release profiles, resulting in fluctuant plasma LP concentrations which may be suitable for drugs requiring controlled release. All the results suggested that drug release rates from the microspheres prepared by various methods were mainly controlled by either the porosity inside the microspheres or the degradation of materials, which could, therefore, lead to different release behaviours. This results indicated great potential of the PLGA microsphere formulation as an injectable depot for controllable in vivo release profile via rational core phase design. Core/shell microspheres fabricated by modified double emulsification-solvent evaporation methods, with various inner phases, to obtain high loading drugs system, as well as appropriate release behaviours. Accordingly, control in vivo release profile via rational core phase design.

Cationic surfactants-modified natural zeolites: improvement of the excipients functionality.

PubMed

Krajisnik, Danina; Milojević, Maja; Malenović, Anđelija; Daković, Aleksandra; Ibrić, Svetlana; Savić, Snezana; Dondur, Vera; Matijasević, Srđan; Radulović, Aleksandra; Daniels, Rolf; Milić, Jela

2010-10-01

In this study an investigation of cationic surfactants-modified natural zeolites as drug formulation excipient was performed. The aim of this work was to carry out a study of the purified natural zeolitic tuff with high amount of clinoptilolite as a potential carrier for molecules of pharmaceutical interest. Two cationic surfactants (benzalkonium chloride and hexadecyltrimethylammonium bromide) were used for modification of the zeolitic surface in two levels (equal to and twice as external cation-exchange capacity of the zeolitic tuff). Prepared samples were characterized by Fourier transform infrared spectroscopy, thermogravimetric, high-performance liquid chromatography analysis, and powder flow determination. Different surfactant/zeolite composites were used for additional investigation of three model drugs: diclofenac diethylamine, diclofenac sodium, and ibuprofen by means of adsorption isotherm measurements in aqueous solutions. The modified zeolites with two levels of surfactant coverage within the short activation time were prepared. Determination of flow properties showed that modification of zeolitic surface reflected on powder flow characteristics. Investigation of the model drugs adsorption on the obtained composites revealed that a variation between adsorption levels was influenced by the surfactant type and the amount present at the surface of the composites. In vitro release profiles of the drugs from the zeolite-surfactant-drug composites revealed that sustained drug release could be attained over a period of 8 hours. The presented results for drug uptake by surfactant-zeolite composites and the afterward drug release demonstrated the potential use of investigated modified natural zeolite as excipients for advanced excipients in drug formulations.

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

PubMed

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

2015-11-30

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

Electrospun matrices for localised controlled drug delivery: release of tetracycline hydrochloride from layers of polycaprolactone and poly(ethylene-co-vinyl acetate).

PubMed

Alhusein, Nour; Blagbrough, Ian S; De Bank, Paul A

2012-12-01

We report the controlled release of tetracycline (Tet) HCl from a three-layered electrospun matrix for the first time. Five formulations of electrospun poly-ε-caprolactone (PCL) and poly(ethylene-co-vinyl acetate) (PEVA) have been designed, prepared as micro/nanofibre layers, and assayed for the controlled release of the clinically useful antibiotic Tet HCl with potential applications in wound healing and especially in complicated skin and skin-structure infections. Tet HCl was also chosen as a model drug possessing a good ultraviolet (UV) chromophore and capable of fluorescence together with limited stability. Tet HCl was successfully incorporated (essentially quantitatively at 3 %, w/w) and provided controlled release from multilayered electrospun matrices. The Tet HCl release test was carried out by a total immersion method on 2 × 2 cm(2) electrospun fibrous mats in Tris or phosphate-buffered saline heated to 37 °C. The formulation PCL/PEVA/PCL with Tet HCl in each layer gave a large initial (burst) release followed by a sustained release. Adding a third layer to the two-layered formulations led to release being sustained from 6 days to more than 15 days. There was no detectable loss of Tet chemical stability (as shown by UV and NMR) or bioactivity (as shown by a modified Kirby-Bauer disc assay). Using Tet HCl-sensitive bacteria, Staphylococcus aureus (ATCC 25923), the Tet HCl-loaded three-layered matrix formulations were still showing significantly higher antibacterial effects on days 4 and 5 than commercially available Antimicrobial Susceptibility Test Discs of Tet HCl. Electrospinning provides good encapsulation efficiency of Tet HCl within PCL/PEVA/PCL polymers in micro/nanofibre layers which display sustained antibiotic release.

A novel coating concept for ileo-colonic drug targeting: proof of concept in humans using scintigraphy.

PubMed

Varum, F J O; Hatton, G B; Freire, A C; Basit, A W

2013-08-01

The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT S neutralised to pH 8.0 and a buffer salt (10% KH₂PO₄), which was overcoated with layer of standard EUDRAGIT S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1N HCl for 2h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region. Copyright © 2013 Elsevier B.V. All rights reserved.

Geometry of modified release formulations during dissolution--influence on performance of dosage forms with diclofenac sodium.

PubMed

Dorożyński, Przemysław; Kulinowski, Piotr; Jamróz, Witold; Juszczyk, Ewelina

2014-12-30

The objectives of the work included: presentation of magnetic resonance imaging (MRI) and fractal analysis based approach to comparison of dosage forms of different composition, structure, and assessment of the influence of the compositional factors i.e., matrix type, excipients etc., on properties and performance of the dosage form during drug dissolution. The work presents the first attempt to compare MRI data obtained for tablet formulations of different composition and characterized by distinct differences in hydration and drug dissolution mechanisms. The main difficulty, in such a case stems from differences in hydration behavior and tablet's geometry i.e., swelling, cracking, capping etc. A novel approach to characterization of matrix systems i.e., quantification of changes of geometrical complexity of the matrix shape during drug dissolution has been developed. Using three chosen commercial modified release tablet formulations with diclofenac sodium we present the method of parameterization of their geometrical complexity on the base of fractal analysis. The main result of the study is the correlation between the hydrating tablet behavior and drug dissolution - the increase of geometrical complexity expressed as fractal dimension relates to the increased variability of drug dissolution results. Copyright © 2014 Elsevier B.V. All rights reserved.

Assessing bioequivalence of generic modified-release antiepileptic drugs

PubMed Central

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

2016-01-01

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

Preparation and In Vitro/Ex Vivo Evaluation of Moxifloxacin-Loaded PLGA Nanosuspensions for Ophthalmic Application.

PubMed

Mudgil, Meetali; Pawar, Pravin K

2013-01-01

The aim of the present investigation was to prepare a colloidal ophthalmic formulation to improve the residence time of moxifloxacin. Moxifloxacin-loaded poly(dl-lactide-co-glycolide) (PLGA) nanosuspensions were prepared by using the solvent evaporation technique. The nanosuspensions were characterised physically by using different techniques like particle size, zeta potential, FTIR, DSC, and XRD analysis. In vitro and ex vivo studies of nanosuspensions were carried out using a modified USP dissolution apparatus and all-glass Franz diffusion cells, respectively. The antibacterial activities of the nanosuspension and marketed formulations were performed against S. aureus and P. aeroginosa. The moxifloxacin-loaded PLGA nanosuspensions showed uniform particle size, ranging between 164-490 nm with negative zeta potential for all batches. The percentage entrapment efficiency of the drug-loaded nano-suspension was found to be between 84.09 to 92.05%. In vitro drug release studies suggest that all of the formulations showed extended drug release profiles and follow Korsemeyer-Peppas release kinetics. In vitro corneal permeability was found to be comparable with that of the marketed formulation across isolated goat cornea, indicating the suitability of the nanosuspension formulation in the ophthalmic delivery of moxifloxacin. The optimised nano-suspension was found to be more active against S. aureus and P. aeruginosa compared to the marketed eye drops.

Chemically modified carbonic anhydrases useful in carbon capture systems

DOEpatents

Novick, Scott; Alvizo, Oscar

2013-01-15

The present disclosure relates to chemically modified carbonic anhydrase polypeptides and soluble compositions, homogenous liquid formulations comprising them. The chemically modified carbonic anhydrase polypeptides have improved properties relative to the same carbonic anhydrase polypeptide that is not chemically modified including the improved properties of increased activity and/or stability in the presence of amine compounds, ammonia, or carbonate ion. The present disclosure also provides methods of preparing the chemically modified polypeptides and methods of using the chemically modified polypeptides for accelerating the absorption of carbon dioxide from a gas stream into a solution as well as for the release of the absorbed carbon dioxide for further treatment and/or sequestering.

Chemically modified carbonic anhydrases useful in carbon capture systems

DOEpatents

Novick, Scott J; Alvizo, Oscar

2013-10-29

The present disclosure relates to chemically modified carbonic anhydrase polypeptides and soluble compositions, homogenous liquid formulations comprising them. The chemically modified carbonic anhydrase polypeptides have improved properties relative to the same carbonic anhydrase polypeptide that is not chemically modified including the improved properties of increased activity and/or stability in the presence of amine compounds, ammonia, or carbonate ion. The present disclosure also provides methods of preparing the chemically modified polypeptides and methods of using the chemically modified polypeptides for accelerating the absorption of carbon dioxide from a gas stream into a solution as well as for the release of the absorbed carbon dioxide for further treatment and/or sequestering.

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

PubMed

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

2016-06-15

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

Influence of drug loading and type of ointment base on the in vitro performance of acyclovir ophthalmic ointment.

PubMed

Al-Ghabeish, Manar; Xu, Xiaoming; Krishnaiah, Yellela S R; Rahman, Ziyaur; Yang, Yang; Khan, Mansoor A

2015-11-30

The availability of in vitro performance tests such as in vitro drug release testing (IVRT) and in vitro permeation testing (IVPT) are critical to comprehensively assure consistent delivery of the active component(s) from semisolid ophthalmic drug products. The objective was to study the impact of drug loading and type of ointment base on the in vitro performance (IVRT and IVPT) of ophthalmic ointments using acyclovir as a model drug candidate. The in vitro drug release for the ointments was evaluated using a modified USP apparatus 2 with Enhancer cells. The transcorneal permeation was carried out using rabbit cornea on modified vertical Franz cells. The drug retention in cornea (DRC) was also determined at the end of transcorneal drug permeation study. The in vitro drug release, transcorneal drug permeation as well as DRC exhibited a proportional increase with increasing drug loading in the ointment. On comparing the in vitro drug release profile with transcorneal permeation profile, it appears that drug release from the ointment is controlling acyclovir transport through the cornea. Furthermore, enhanced in vitro transcorneal permeation relative to the in vitro drug release underscores the importance of the interplay between the physiology of the ocular tissue and ointment formulation. The results indicated that IVRT and IVPT could be used to discriminate the impact of changes in drug load and formulation composition of ophthalmic ointments. Copyright © 2015. Published by Elsevier B.V.

Doxycycline delivery from PLGA microspheres prepared by a modified solvent removal method.

PubMed

Patel, Roshni S; Cho, Daniel Y; Tian, Cheng; Chang, Amy; Estrellas, Kenneth M; Lavin, Danya; Furtado, Stacia; Mathiowitz, Edith

2012-01-01

We report on the development of a modified solvent removal method for the encapsulation of hydrophilic drugs within poly(lactic-co-glycolic acid) (PLGA). Using a water/oil/oil double emulsion, hydrophilic doxycycline was encapsulated within PLGA spheres with particle diameters ranging from approximately 600 nm to 19 µm. Encapsulation efficiencies of up to 74% were achieved for theoretical loadings from 1% to 10% (w/w), with biphasic release over 85 days with nearly complete release at the end of this time course. About 1% salt was added to the formulations to examine its effects on doxycycline release; salt modulated release only by increasing the magnitude of initial release without altering kinetics. Fourier transform infrared spectroscopy indicated no characteristic differences between doxycycline-loaded and control spheres. Differential scanning calorimetry and X-ray diffraction suggest that there may be a molecular dispersion of the doxycycline within the spheres and the doxycycline may be in an amorphous state, which could explain the slow, prolonged release of the drug.

Serum-Stable, Long-Circulating, pH-Sensitive PEGylated Liposomes.

PubMed

Bertrand, Nicolas; Simard, Pierre; Leroux, Jean-Christophe

2017-01-01

pH-sensitive liposomes have been designed to deliver active compounds, specifically to acidic intracellular organelles, and to augment their cytoplasmic concentrations. These systems combine the protective effects of other liposomal formulations with specific environment-controlled drug release. They are stable at physiological pH, but abruptly discharge their contents when endocytosed into acidic compartments, allowing the drug to be released before it is exposed to the harsh environment of the lysosomes.Serum-stable formulations with minimal leakage at physiological pH and rapid drug release at pH 5.0 to 5.5 can be easily prepared by inserting a hydrophobically modified N-isopropylacrylamide/methacrylic acid copolymer (poly(NIPAM-co-MAA)) in the lipid bilayer of sterically stabilized liposomes. The present chapter describes polymer synthesis, as well as the preparation and characterization of large unilamellar pH-sensitive vesicles.

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

PubMed

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

2016-11-01

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

Development of Wax-Incorporated Emulsion Gel Beads for the Encapsulation and Intragastric Floating Delivery of the Active Antioxidant from Tamarindus indica L.

PubMed

Soradech, Sitthiphong; Petchtubtim, Intira; Thongdon-A, Jeerayu; Muangman, Thanchanok

2016-03-22

In this study, tamarind (Tamarindus indica L.) seed extracts with potential antioxidant activity and toxicity to cancer cells were developed as functional foods and nutraceutical ingredients in the form of emulsion gel beads. Three extracts were obtained from ethanol and water: TSCH50, TSCH95 and TSCH. All extracts exhibited high potential for superoxide anion scavenging activity over the IC50 range < 5-11 µg/mL and had no toxic effects on normal cells, however, the water extract (TSCH) was the most effective due to its free radical scavenging activity and toxicity in mitochondrial membranes of cancer cells. Next a study was designed to develop a new formulation for encapsulation and intragastric floating delivery of tamarind seed extract (TSCH) using wax-incorporated emulsion gel beads, which were prepared using a modified ionotropic gelation technique. Tamarind seed extract at 1% (w/w) was used as the active ingredient in all formulations. The effect of the types and amounts of wax on the encapsulation efficiency and percentage of the active release of alginate gel beads was also investigated. The results demonstrated that the incorporation of both waxes into the gel beads had an effect on the percentage of encapsulation efficiency (%) and the percentage of the active ingredient release. Furthermore, the addition of water insoluble waxes (carnauba and bee wax) significantly retarded the release of the active ingredient. The addition of both waxes had a slight effect on drug release behavior. Nevertheless, the increase in incorporated waxes in all formulations could sustain the percentage of active ingredient release. In conclusion, wax-incorporated emulsion gel beads using a modified ionotropic gelation technique could be applied for the intragastric floating delivery and controlled release of functional food and nutraceutical products for their antioxidant and anticancer capacity.

Optimization of propranolol HCl release kinetics from press coated sustained release tablets.

PubMed

Ali, Adel Ahmed; Ali, Ahmed Mahmoud

2013-01-01

Press-coated sustained release tablets offer a valuable, cheap and easy manufacture alternative to the highly expensive, multi-step manufacture and filling of coated beads. In this study, propranolol HCl press-coated tablets were prepared using hydroxylpropylmethylcellulose (HPMC) as tablet coating material together with carbopol 971P and compressol as release modifiers. The prepared formulations were optimized for zero-order release using artificial neural network program (INForm, Intelligensys Ltd, North Yorkshire, UK). Typical zero-order release kinetics with extended release profile for more than 12 h was obtained. The most important variables considered by the program in optimizing formulations were type and proportion of polymer mixture in the coat layer and distribution ratio of drug between core and coat. The key elements found were; incorporation of 31-38 % of the drug in the coat, fixing the amount of polymer in coat to be not less than 50 % of coat layer. Optimum zero-order release kinetics (linear regression r2 = 0.997 and Peppas model n value > 0.80) were obtained when 2.5-10 % carbopol and 25-42.5% compressol were incorporated into the 50 % HPMC coat layer.

Development of metoprolol tartrate extended-release matrix tablet formulations for regulatory policy consideration.

PubMed

Nellore, R V; Rekhi, G S; Hussain, A S; Tillman, L G; Augsburger, L L

1998-01-02

This research study was designed to develop model extended-release (ER) matrix tablet formulations for metoprolol tartrate (100 mg) sufficiently sensitive to manufacturing variable and to serve as the scientific basis for regulatory policy development on scale-up and post approval changes for modified-release dosage forms (SUPAC-MR). Several grades and levels of hydroxypropyl methylcellulose (Methocel K4M, K15M, K100M and K100LV), fillers and binders and studied. Three granulation processes were evaluated; direct compression, fluid-bed or high-shear granulation. Lubrication was performed in a V-blender and tablets were compressed on an instrumented rotary tablet press. Direct compression formulations exhibited poor flow, picking and sticking problems during tableting. High-shear granulation resulted in the formation of hard granules that were difficult to mill but yielded good tablets. Fluid-bed granulations were made using various binders and appeared to be satisfactory in terms of flow and tableting performance. In vitro drug release testing was performed in pH 6.8 phosphate buffer using USP apparatus 2 (paddle) at 50 rpm. At a fixed polymer level, drug release from the higher viscosity grades (K100M) was slower as compared to the lower viscosity grades (K100LV). In addition, release from K100LV was found to be more sensitive to polymer level changes. Increased in polymer level from 10 to 40% and/or filler change from lactose to dicalcium phosphate resulted in about 25-30% decrease in the amount of metoprolol release after 12 h. The results of this study led to the choice of Methocel K100LV as the hydrophilic matrix polymer and fluid-bed granulation as the process of choice for further evaluation of critical and non-critical formulation and processing variables.

Development of Multiple-Unit Floating Drug Delivery System of Clarithromycin: Formulation, in vitro Dissolution by Modified Dissolution Apparatus, in vivo Radiographic Studies in Human Volunteers.

PubMed

Reddy, Arun B; Reddy, Narendar D

2017-07-01

Clarithromycin (CM), a broad spectrum macrolide antibiotic used to eradicate H. pylori in peptic ulcer. Clarithromycin (CM) is well absorbed from the gastrointestinal tract, but has a bioavailability of 50% due to rapid biodegradation. The aim of this investigation was to increase the gastric residence time, and to control the drug release of clarithromycin by formulating into multiple unit floating mini-tablets. Floating tablets were prepared by using direct compression method with HPMC K 4 M and Polyox WSR 1105 as release retarded polymers and sodium bicarbonate as gas generating agent. The prepared mini-tablets were evaluated for thickness, weight variation, friability, hardness, drug content, in vitro buoyancy, swelling studies, in vitro dissolution studies by using modified Rossett-Rice test and in vivo radiographic studies in healthy human volunteers in fasting conditions. DSC analysis revealed that no interaction between drug and excipients. All the physical parameters of the tablets were within the acceptable limits. The optimized formulation (F6) had showed controlled drug release of 99.16±3.22% in 12 h, by zero-order release kinetics, along with floating lag time of 9.5±1.28 s and total floating time of 12±0.14 h. X-ray imaging studies revealed that in vivo gastric residence time of clarithromycin floating mini-tablet in the stomach was about 3.5 h. The results demonstrated that the developed floating mini-tablets of clarithromycin caused significant enhancement in gastric retention time along with sustained effect and increased oral bioavailability. © Georg Thieme Verlag KG Stuttgart · New York.

Development of pH Sensitive Nanoparticles for Intestinal Drug Delivery Using Chemically Modified Guar Gum Co-Polymer.

PubMed

Varma, Vegesna Naga Sravan Kumar; Shivakumar, Hosakote Gurumalappa; Balamuralidhara, Veerna; Navya, Manne; Hani, Umme

2016-01-01

The aim of the research work was to chemically modify guargum (GG) as a pH sensitive co-polymer and formulating intestinal targeting ESO nanoparticles (NPs) using the synthesized co-polymer. Poly acrylamide-grafted-guar gum (PAAm-g-GG) co-polymer was synthesized by free radical polymerization. Chemical modification of PAAm-g-GG by alkaline hydrolysis results in formation of a pH-sensitive co-polymer. The effect of GG and acryl amide (AAm) on grafting was studied. Esomeprazole magnesium (ESO) loaded pH sensitive NPs were prepared by nano-emulsification polymer crosslinking method and characterized. Sixteen formulations were prepared and the concentration of process variables wasvaried to obtain nanoparticles of 200-600 nm. The NPs were found to be homogenous in size distribution. The encapsulation efficiency and drug loading ranged from 33.2% to 50.1% and 12.2% to 17.2% respectively. Particle size, encapsulation efficiency and drug loading increasedalong with co-polymer concentration. In-vitro release studies at pH 1.2 for 2 h, followed by pH 6.8 showed that environment pH significantly affected the drug release. SEM has shown that NPsare spherical with smooth surface. The pH sensitive PAAm-g-GGNPs resisted the initial release of the drug from the drug loaded NPs in acidic pH and delayed the release process to a longer period in alkaline environment.

Development of pH Sensitive Nanoparticles for Intestinal Drug Delivery Using Chemically Modified Guar Gum Co-Polymer

PubMed Central

Varma, Vegesna Naga Sravan Kumar; Shivakumar, Hosakote Gurumalappa; Balamuralidhara, Veerna; Navya, Manne; Hani, Umme

2016-01-01

The aim of the research work was to chemically modify guargum (GG) as a pH sensitive co-polymer and formulating intestinal targeting ESO nanoparticles (NPs) using the synthesized co-polymer. Poly acrylamide-grafted-guar gum (PAAm-g-GG) co-polymer was synthesized by free radical polymerization. Chemical modification of PAAm-g-GG by alkaline hydrolysis results in formation of a pH-sensitive co-polymer. The effect of GG and acryl amide (AAm) on grafting was studied. Esomeprazole magnesium (ESO) loaded pH sensitive NPs were prepared by nano-emulsification polymer crosslinking method and characterized. Sixteen formulations were prepared and the concentration of process variables wasvaried to obtain nanoparticles of 200-600 nm. The NPs were found to be homogenous in size distribution. The encapsulation efficiency and drug loading ranged from 33.2% to 50.1% and 12.2% to 17.2% respectively. Particle size, encapsulation efficiency and drug loading increasedalong with co-polymer concentration. In-vitro release studies at pH 1.2 for 2 h, followed by pH 6.8 showed that environment pH significantly affected the drug release. SEM has shown that NPsare spherical with smooth surface. The pH sensitive PAAm-g-GGNPs resisted the initial release of the drug from the drug loaded NPs in acidic pH and delayed the release process to a longer period in alkaline environment. PMID:27610149

Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles

PubMed Central

Elnaggar, Yosra SR; El-Massik, Magda A; Abdallah, Ossama Y

2011-01-01

Although sildenafil citrate (SC) is used extensively for erectile dysfunction, oral delivery of SC encounters many obstacles. Furthermore, the physicochemical characteristics of this amphoteric drug are challenging for delivery system formulation and transdermal permeation. This article concerns the assessment of the potential of nanomedicine for improving SC delivery and transdermal permeation. SC-loaded nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) were fabricated using a modified high-shear homogenization technique. Nanoparticle optimization steps included particle size analysis, entrapment efficiency (EE) determination, freeze-drying and reconstitution, differential scanning calorimetry, in vitro release, stability study and high-performance liquid chromatography analysis. Transdermal permeation of the nanocarriers compared with SC suspension across human skin was assessed using a modified Franz diffusion cell assembly. Results revealed that SLNs and NLCs could be optimized in the nanometric range (180 and 100 nm, respectively) with excellent EE (96.7% and 97.5%, respectively). Nanoparticles have significantly enhanced in vitro release and transdermal permeation of SC compared with its suspensions. Furthermore, transdermal permeation of SC exhibited higher initial release from both SLN and NLC formulations followed by controlled release, with promising implications for faster onset and longer drug duration. Nanomedicines prepared exhibited excellent physical stability for the study period. Solid nanoparticles optimized in this study successfully improved SC characteristics, paving the way for an efficient topical Viagra® product. PMID:22238508

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.

Preparation and In Vitro/Ex Vivo Evaluation of Moxifloxacin-Loaded PLGA Nanosuspensions for Ophthalmic Application

PubMed Central

Mudgil, Meetali; Pawar, Pravin K.

2013-01-01

The aim of the present investigation was to prepare a colloidal ophthalmic formulation to improve the residence time of moxifloxacin. Moxifloxacin-loaded poly(dl-lactide-co-glycolide) (PLGA) nanosuspensions were prepared by using the solvent evaporation technique. The nanosuspensions were characterised physically by using different techniques like particle size, zeta potential, FTIR, DSC, and XRD analysis. In vitro and ex vivo studies of nanosuspensions were carried out using a modified USP dissolution apparatus and all-glass Franz diffusion cells, respectively. The antibacterial activities of the nanosuspension and marketed formulations were performed against S. aureus and P. aeroginosa. The moxifloxacin-loaded PLGA nanosuspensions showed uniform particle size, ranging between 164–490 nm with negative zeta potential for all batches. The percentage entrapment efficiency of the drug-loaded nano-suspension was found to be between 84.09 to 92.05%. In vitro drug release studies suggest that all of the formulations showed extended drug release profiles and follow Korsemeyer-Peppas release kinetics. In vitro corneal permeability was found to be comparable with that of the marketed formulation across isolated goat cornea, indicating the suitability of the nanosuspension formulation in the ophthalmic delivery of moxifloxacin. The optimised nano-suspension was found to be more active against S. aureus and P. aeruginosa compared to the marketed eye drops. PMID:23833723

Modified thermoresponsive Poloxamer 407 and chitosan sol-gels as potential sustained-release vaccine delivery systems.

PubMed

Kojarunchitt, Thunjiradasiree; Baldursdottir, Stefania; Dong, Yao-Da; Boyd, Ben J; Rades, Thomas; Hook, Sarah

2015-01-01

Thermoresponsive, particle-loaded, Poloxamer 407 (P407)-Pluronic-R® (25R4) or chitosan-methyl cellulose (MC) formulations were developed as single-dose, sustained release vaccines. The sol-gels, loaded either with a particulate vaccine (cubosomes) or soluble antigen (ovalbumin) and adjuvants (Quil A and monophosphoryl lipid A), were free-flowing liquids at room temperature and formed stable gels at physiological temperatures. Rheological results showed that both systems meet the criteria of being thermoresponsive gels. The P407-25R4 sol-gels did not significantly sustain the release of antigen in vivo while the chitosan-MC sol-gels sustained the release of antigen up to at least 14 days after administration. The chitosan-MC sol-gels stimulated both cellular and humoral responses. The inclusion of cubosomes in the sol-gels did not provide a definitive beneficial effect. Further analysis of the formulations with small-angle X-ray scattering (SAXS) revealed that while cubosomes were stable in chitosan-MC gels they were not stable in P407-25R4 formulations. The reason for the mixed response to cubosome-loaded vehicles requires more investigation, however it appears that the cubosomes did not facilitate synchronous vaccine release and may in fact retard release, reducing efficacy in some cases. From these results, chitosan-MC sol-gels show potential as sustained release vaccine delivery systems, as compared to the P407-25R4 system that had a limited ability to sustain antigen release. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets.

PubMed

Goyanes, Alvaro; Buanz, Asma B M; Hatton, Grace B; Gaisford, Simon; Basit, Abdul W

2015-01-01

The aim of this study was to explore the potential of fused-deposition 3-dimensional printing (FDM 3DP) to produce modified-release drug loaded tablets. Two aminosalicylate isomers used in the treatment of inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA, mesalazine) and 4-aminosalicylic acid (4-ASA), were selected as model drugs. Commercially produced polyvinyl alcohol (PVA) filaments were loaded with the drugs in an ethanolic drug solution. A final drug-loading of 0.06% w/w and 0.25% w/w was achieved for the 5-ASA and 4-ASA strands, respectively. 10.5mm diameter tablets of both PVA/4-ASA and PVA/5-ASA were subsequently printed using an FDM 3D printer, and varying the weight and densities of the printed tablets was achieved by selecting the infill percentage in the printer software. The tablets were mechanically strong, and the FDM 3D printing was shown to be an effective process for the manufacture of the drug, 5-ASA. Significant thermal degradation of the active 4-ASA (50%) occurred during printing, however, indicating that the method may not be appropriate for drugs when printing at high temperatures exceeding those of the degradation point. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the formulated blends confirmed these findings while highlighting the potential of thermal analytical techniques to anticipate drug degradation issues in the 3D printing process. The results of the dissolution tests conducted in modified Hank's bicarbonate buffer showed that release profiles for both drugs were dependent on both the drug itself and on the infill percentage of the tablet. Our work here demonstrates the potential role of FDM 3DP as an efficient and low-cost alternative method of manufacturing individually tailored oral drug dosage, and also for production of modified-release formulations. Copyright © 2014 Elsevier B.V. All rights reserved.

Sustained Release Drug Delivery Applications of Polyurethanes.

PubMed

Lowinger, Michael B; Barrett, Stephanie E; Zhang, Feng; Williams, Robert O

2018-05-09

Since their introduction over 50 years ago, polyurethanes have been applied to nearly every industry. This review describes applications of polyurethanes to the development of modified release drug delivery. Although drug delivery research leveraging polyurethanes has been ongoing for decades, there has been renewed and substantial interest in the field in recent years. The chemistry of polyurethanes and the mechanisms of drug release from sustained release dosage forms are briefly reviewed. Studies to assess the impact of intrinsic drug properties on release from polyurethane-based formulations are considered. The impact of hydrophilic water swelling polyurethanes on drug diffusivity and release rate is discussed. The role of pore formers in modulating drug release rate is examined. Finally, the value of assessing mechanical properties of the dosage form and approaches taken in the literature are described.

Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.

PubMed

Lionberger, Robert A; Raw, Andre S; Kim, Stephanie H; Zhang, Xinyuan; Yu, Lawrence X

2012-04-01

FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times. Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations. The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test. In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.

Dual sustained release delivery system for multiple route therapy of an antiviral drug.

PubMed

Ramyadevi, D; Sandhya, P

2014-06-01

The first successful molecule against herpes infections was Acyclovir, which competes with new generations in the market, with its potential activity. The major physicochemical constraints and pharmacokinetics of Acyclovir such as low solubility, poor permeability, less half-life, high dose has initiated many researchers to develop diverse modified release dosage forms. The objective of this work was to design polymeric nanoparticles of Acyclovir and then incorporate the drug-loaded nanoparticles within an in situ gelling system to provide dual sustained release effect, whereby the duration of action and bioavailability through different routes of administration could be improved. The formulation was designed through 3(2) factorial design, first developing the nanoparticles using Polycaprolactone and Pluronic F127 by Solvent evaporation process, followed by dispersion of the suspended nanoparticles into thermosensitive in situ gelling system of Pluronic F127 with Carbopol. The characterization of the nanoparticles and its sol-gel system performed through zeta sizer, SEM, XRD, TG-DSC, FTIR and rheology helped to optimize the formulation. The drug release could be sustained to 60% and 30% at eight hours, for the nanoparticles and their in situ gel systems, respectively, with non-Fickian diffusion mechanism of drug release. The test for % cell viability with NIH3T3 cell line revealed low level of toxicity for the nanoparticles. The statistical significance obtained for the trail formulations experimentally proved its suitability for this dosage form design to achieve desired level of drug release.

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

PubMed Central

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

2014-01-01

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

Development of a rectal nicotine delivery system for the treatment of ulcerative colitis.

PubMed

Dash, A K; Gong, Z; Miller, D W; Huai-Yan, H; Laforet, J

1999-11-10

The aims of this investigation were: i. to develop a rectal nicotine delivery system with bioadhesives for the treatment of ulcerative colitis and ii. to evaluate nicotine transport and cytotoxicity of the delivery system using Caco-2 cell culture systems. Rectal nicotine suppository formulations were prepared in semi-synthetic glyceride bases (Suppocire AM and AI, Gattefosse Inc.) by fusion method. The in vitro release of nicotine was carried out in modified USP dissolution apparatus 1. Differential scanning calorimetry (DSC) and powder X-ray diffraction were used to study the polymorphic changes if any in the formulations. An LC method was used for the assay of nicotine. The effect of bioadhesives (glyceryl monooleate (GMO), and Carbopol) on the nicotine flux was evaluated using Caco-2 cell permeability studies and Caco-2 cell viability was determined using the MTT toxicity assay. In vitro release studies indicated that the low melting AI base was superior to that of the AM base. Presence of GMO in the formulation enhanced the release of nicotine whereas Carbopol showed an opposite effect. The enhanced release of nicotine in the presence of GMO was found to be partly due to the melting point lowering effect of this compound. Caco-2 cell absorption studies showed that there was a decrease in the flux of nicotine in the presence of both the bioadhesives. The flux of the fluorescein marker which is used to study the integrity of the cell monolayers was found to be slightly higher only in the presence of 10% (w/w) Carbopol. Nicotine, Carbopol, and GMO do not have any cytotoxic effect on these cell monolayers within the concentration range used in the formulations. Rectal nicotine formulations containing bioadhesives were developed and characterized. Both in vitro release and cell culture studies have indicated that one can manipulate the nicotine release from these rectal delivery systems by incorporation of various bioadhesives or the use of different bases in the formulation. Nicotine concentration below 2% (w/v) and bioadhesive concentration below 10% (w/w) do not have any cytotoxic effect on Caco-2 cells.

[Technological and pharmacotherapeutic properties of selected drugs with modified release of diclofenac sodium].

PubMed

Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Diclofenac and its sodium salt is one of the best-known and popular therapeutic agents from the group of NSAIDs used in medicine in many various pharmaceutical forms. Therapeutic products containing diclofenac sodium salt in doses of 100 mg and 75 mg with a qualitatively and quantitatively diversified share of excipients and a variable dosage form of the drug (solid capsules, tablets with modified release) were subjected to technological and pharmaceutical analysis. The effect of solid formulation components of polymer character making the core and the coating of the pharmaceutical form of therapeutic products on the disintegration time and pharmaceutical availability in pharmacopoeial receptor fluids was estimated. Market therapeutic products with diclofenac sodium in doses of 75 mg and 100 mg, technological analysis of the drug dosage form was conducted, disintegration time of solid oral dosage forms of the drug with diclofenac sodium salt was examined and research on pharmaceutical availability of diclofenac sodium salt from tested therapeutic products was conducted using the acid phase and the buffer phase according to the FP standards for delayed release enteral dosage forms. The experimental data was supplemented with the statistical analysis. There are three formulations in the form of solid capsules and one formulation in the form of a coated tablet. All therapeutic products bear features of a dosage form of modified release of diclofenac sodium salt, frequently of a delayed release formula in the duodenum or the small intestine with regard to the limitation of typical undesirable effects after taking NSAIDs. Considerable diversity between solid capsules and the tablet with modified release during disintegration or hydration and swelling has been observed. In the environment of a receptor fluid--purified water (pH = 7) the capsule Dicloberl retard disintegrates at the fastest rate in 5,49 minutes, and then in the order: DicloDuo 75 mg--8,13 minutes and Olfen 100 SR--11,27 minutes. The hydration degree of gelatin walls of capsules depends on the pH of the receptor fluid. The availability of diclofenac sodium salt in given receptor fluids confirms the fact of significant connection of clinical effectiveness of the tested pharmaceutical forms with the activity of hydrogen ions (pH) of the environment in which there are therapeutic products, and excipients used for making the pharmaceutical phase. Tested therapeutic products with diclofenac sodium salt are differentiated by the type of a dosage form. Dicloberl retard contains the minimally indispensable number of simple, commonly used excipients. The research on the disintegration time may only be related to the products Dicloberl retard, Olfen 100 SR and DicloDuo 75 mg treating it as the time of deformation and disintegration of a capsule. In all three types of receptor fluids, the capsule Dicloberl retard has the fastest disintegration rate. The "acid phase" demonstrated stability of the products with a slight dissolution of diclofenac sodium salt on the level 1,3-4,18% of the Q release coefficient. In the environment of artificial intestinal juice, Dicloberl retard is more effective releasing larger amounts of diclofenac sodium salt during 4 hours of exposition (differences from 10% to 14% of the Q release coefficient).

Effect of thiolated polymers to textural and mucoadhesive properties of vaginal gel formulations prepared with polycarbophil and chitosan.

PubMed

Cevher, Erdal; Sensoy, Demet; Taha, Mohamed A M; Araman, Ahmet

2008-01-01

The aim of this study was to design and evaluate of mucoadhesive gel formulations for the vaginal application of clomiphene citrate (CLM) for local treatment of human papilloma virus (HPV) infections. Chitosan (CHI) and polycarbophil (PC) were covalently modified using the thioglycolic acid and L-cysteine, respectively. The formation of thiol conjugates of chitosan (CHI-TG) and polycarbophil (PC-CYS) were confirmed by FT-IR analysis and PC-CYS and CHI-TG were found to have 148.42 +/- 4.16 and 41.17 +/- 2.34 micromol of thiol groups per gram of polymer, respectively. One percent CLM gels were prepared by combination of various concentrations of PC and CHI with thiolated conjugates of these polymers. Hardness, compressibility, elasticity, adhesiveness and cohesiveness of the gels were measured by Texture profile analysis and the vaginal mucoadhesion was investigated by mucoadhesion test. The increasing in the amount of the thiol conjugates was found to enhance the elasticity, cohesiveness, adhesiveness and mucoadhesion of the gel formulations but not their hardness and compressibility when compared to gels prepared using their respective parent formulations. Slower release rate of CLM from gels was achieved when the polymer concentrations were increased in the gel formulations. PC and its thiol conjugate were found to prolong the release of CLM longer than 70 h unlike gel formulations prepared using CHI and its thiol conjugate which were able to release CLM up to 12 h. Stability of CLM was preserved during the 3 month stability analysis under controlled room temperature and accelerated conditions.

Generic products of antiepileptic drugs: a perspective on bioequivalence, bioavailability, and formulation switches using Monte Carlo simulations.

PubMed

Karalis, Vangelis; Macheras, Panos; Bialer, Meir

2014-01-01

Generic products of antiepileptic drugs (AEDs) are currently a controversial topic as neurologists and patients are reluctant to switch from brand products to generics and to switch between generics. The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products. Monte Carlo simulations of the classic 2 × 2 BE studies were performed to study the effect of sample size, within-subject variability, and the true difference in pharmacokinetic values of the products under comparison on BE acceptance of generic AED products. Simulations were extended to study the comparative performance of two generic AED products against the same innovative product. The simulated results are compared with literature data on AEDs. The question with regard to bioavailability (BA) is whether two formulations are different, while for BE the question is whether two formulations are sufficiently similar in terms of extent and rate of absorption. Therefore, the criteria for BA and BE and the statistical analysis involved in their analysis are different. Two generic formulations that meet regulatory approval requirements for generics by being bioequivalent to the same innovative AED may not be bioequivalent to one another and therefore should not be regarded as equal or as therapeutically equivalent products. A switch from a standard or an immediate-release formulation to a modified-release product, which comprises extended-release or delayed-release formulations, should not be regarded as a switch between generics, but rather as a switch between different formulation types. Switches between bioequivalent generic AED products could potentially lead to larger changes in plasma levels and exposure than the brand-to-generic switch. The simulation work verified the clinical findings that not all generic AED products bioequivalent to the same innovative product are bioequivalent to one another. Two generic formulations that meet regulatory approval requirements for generics, by being bioequivalent to the innovative AED, may not be bioequivalent to one another. Additional BE criteria are needed for a formulation switch, particularly in epilepsy, where a breakthrough seizure may change a patient's status from seizure-free to refractory.

Formulation and characterization of a compacted multiparticulate system for modified release of water-soluble drugs--Part II theophylline and cimetidine.

PubMed

Cantor, Stuart L; Hoag, Stephen W; Augsburger, Larry L

2009-05-01

The purpose was to investigate the effectiveness of an ethylcellulose (EC) bead matrix and different film-coating polymers in delaying drug release from compacted multiparticulate systems. Formulations containing theophylline or cimetidine granulated with Eudragit RS 30D were developed and beads were produced by extrusion-spheronization. Drug beads were coated using 15% wt/wt Surelease or Eudragit NE 30D and were evaluated for true density, particle size, and sphericity. Lipid-based placebo beads and drug beads were blended together and compacted on an instrumented Stokes B2 rotary tablet press. Although placebo beads were significantly less spherical, their true density of 1.21 g/cm(3) and size of 855 mum were quite close to Surelease-coated drug beads. Curing improved the crushing strength and friability values for theophylline tablets containing Surelease-coated beads; 5.7 +/- 1.0 kP and 0.26 +/- 0.07%, respectively. Dissolution profiles showed that the EC matrix only provided 3 h of drug release. Although tablets containing Surelease-coated theophylline beads released drug fastest overall (t(44.2%) = 8 h), profiles showed that coating damage was still minimal. Size and density differences indicated a minimal segregation potential during tableting for blends containing Surelease-coated drug beads. Although modified release profiles >8 h were achievable in tablets for both drugs using either coating polymer, Surelease-coated theophylline beads released drug fastest overall. This is likely because of the increased solubility of theophylline and the intrinsic properties of the Surelease films. Furthermore, the lipid-based placebos served as effective cushioning agents by protecting coating integrity of drug beads under a number of different conditions while tableting.

Development of Bilayer Tablets with Modified Release of Selected Incompatible Drugs.

PubMed

Dhiman, Neha; Awasthi, Rajendra; Jindal, Shammy; Khatri, Smriti; Dua, Kamal

2016-01-01

The oral route is considered to be the most convenient and commonly-employed route for drug delivery. When two incompatible drugs need to be administered at the same time and in a single formulation, bilayer tablets are the most appropriate dosage form to administer such incompatible drugs in a single dose. The aim of the present investigation was to develop bilayered tablets of two incompatible drugs; telmisartan and simvastatin. The bilayer tablets were prepared containing telmisartan in a conventional release layer using croscarmellose sodium as a super disintegrant and simvastatin in a slow-release layer using HPMC K15M, Carbopol 934P and PVP K 30 as matrix forming polymers. The tablets were evaluated for various physical properties, drug-excipient interactions using FTIR spectroscopy and in vitro drug release using 0.1M HCl (pH 1.2) for the first hour and phosphate buffer (pH 6.8) for the remaining period of time. The release kinetics of simvastatin from the slow release layer were evaluated using the zero order, first order, Higuchi equation and Peppas equation. All the physical parameters (such as hardness, thickness, disintegration, friability and layer separation tests) were found to be satisfactory. The FTIR studies indicated the absence of interactions between the components within the individual layers, suggesting drug-excipient compatibility in all the formulations. No drug release from the slow-release layer was observed during the first hour of the dissolution study in 0.1M HCl. The release-controlling polymers had a significant effect on the release of simvastatin from the slow-release layer. Thus, the formulated bilayer tablets avoided incompatibility issues and proved the conventional release of telmisartan (85% in 45 min) and slow release of simvastatin (80% in 8 h). Stable and compatible bilayer tablets containing telmisartan and simvastatin were developed with better patient compliance as an alternative to existing conventional dosage forms.

Development and optimization of apigenin-loaded transfersomal system for skin cancer delivery: in vitro evaluation.

PubMed

Jangdey, Manmohan Singh; Gupta, Anshita; Saraf, Shailendra; Saraf, Swarnlata

2017-11-01

The aim of this work is to apply Box-Behnken design to optimize the transfersomes were formulated by modified rotary evaporation sonication technique using surfactant Tween 80. The response surface methodology was used having three-factored with three levels. The prepared formulations were characterized for vesicle shape, size, entrapment efficiency (%), stability, and in vitro permeation. The result showed that drug entrapment of 84.24% with average vesicle size of 35.41 nm and drug loading of 8.042%. Thus, optimized formulation was found good stability and is a promising approach to improve the permeability of apigenin in sustained release for prolonged period of time.

Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs.

PubMed

Nart, Viviane; Beringhs, André O'Reilly; França, Maria Terezinha; de Espíndola, Brenda; Pezzini, Bianca Ramos; Stulzer, Hellen Karine

2017-01-01

Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (<0.1%). The melt-granulated captopril in matrix systems containing 50% EC (45P, 100P or 100FP) and the melt-granulated metformin hydrochloride in reservoir systems coated with Kollicoat® SR 30D and Opadry® II (80:20 with 10% weight gain or 70:30 with 20% weight gain) exhibited release profiles adequate to sustained release formulations, for over 450min. Therefore, carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Drug release and swelling kinetics of directly compressed glipizide sustained-release matrices: establishment of level A IVIVC.

PubMed

Sankalia, Jolly M; Sankalia, Mayur G; Mashru, Rajashree C

2008-07-02

The purpose of this study was to examine a level A in vitro-in vivo correlation (IVIVC) for glipizide hydrophilic sustained-release matrices, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. The effect of polymeric blends of ethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500, and lactose on in vitro release profiles was studied and fitted to various release kinetics models. Water uptake kinetics with scanning electron microscopy (SEM) was carried out to support the drug release mechanism. An IVIVC was established by comparing the pharmacokinetic parameters of optimized (M-24) and marketed (Glytop-2.5 SR) formulations after single oral dose studies on white albino rabbits. The matrix M-19 (xanthan:MCC PH301 at 70:40) and M-24 (xanthan:HPMC K4M:Starch 1500 at 70:25:15) showed the glipizide release within the predetermined constraints at all time points with Korsmeyer-Peppas' and zero-order release mechanism, respectively. Kopcha model revealed that the xanthan gum is the major excipient responsible for the diffusional release profile and was further supported by SEM and swelling studies. A significant level A IVIVC with acceptable limits of prediction errors (below 15%) enables the prediction of in vivo performance from their in vitro release profile. It was concluded that proper selection of rate-controlling polymers with release rate modifier excipients will determine overall release profile, duration and mechanism from directly compressed matrices.

Effect of bioadhesion on initial in vitro buoyancy of effervescent floating matrix tablets of ciprofloxacin HCL

PubMed Central

Negi, Jeetendra Singh; Trivedi, Abhinav; Khanduri, Praveen; Negi, Vandana; Kasliwal, Nikhil

2011-01-01

The purpose of this study was to investigate effect of bioadhesion on the initial in vitro buoyancy behaviour of effervescent matrix tablets of ciprofloxacin HCl (CIPRO). Tablets were prepared by direct compression using HPMC K4M and Carbopol 971P as hydrophilic-controlled release polymers, sodium bicarbonate (NaHCO3) as gas-generating agent, polyplasdone XL, Explotab and Ac-Di-Sol as swelling agents. Tablets were evaluated for normal and modified initial in vitro floating behavior, floating duration, swelling behavior and in vitro drug release studies. A modified buoyancy lag time for tablets was determined in order to include the effect of bioadhesion on initial buoyancy. The initial buoyancy was found depended on bioadhesion ability of tablets. The lowest modified buoyancy lag time of 20 seconds was obtained for Formulation F7 having both NaHCO3 and polyplasdone XL. The floating duration was also found dependent on concentration of NaHCO3 and swelling agents. The drug release of F7 was also sustained up to 12-hr duration with anomalous drug transport mechanism. PMID:22171304

Gelatin modified lipid nanoparticles for anti- viral drug delivery.

PubMed

K S, Joshy; S, Snigdha; Kalarikkal, Nandakumar; Pothen, Laly A; Thomas, Sabu

2017-10-01

The major challenges to clinical application of zidovudine are its moderate aqueous solubility and relative short half-life and serious side effects due to frequent administrations. We investigated the preparation of zidovudine-loaded nanoparticles based on lipids which were further modified with the polymer gelatin. Formulation and stability of the modified nanoparticles were analysed from the physico-chemical characterizations. The interactions of nanoparticles with blood components were tested by haemolysis and aggregation studies. The drug content and entrapment efficiencies were assessed by UV analysis. The effect of nanoparticles on protein adsorption was assessed by native polyacrylamide gel electrophoresis (PAGE). In vitro release studies showed a sustained release profile of zidovudine. In vitro cytotoxicity and cellular uptake of the zidovudine-loaded nanoparticles were performed in MCF-7 and neuro 2a brain cells. The enhanced cellular internalization of drug loaded modified nanoparticles in both the cell lines were revealed by fluorescence microscopy. Hence the present study focuses on the feasibility of zidovudine-loaded polymer modified lipid nanoparticles as carriers for safe and efficient HIV/AIDS therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Ion-exchange and iontophoresis-controlled delivery of apomorphine.

PubMed

Malinovskaja, Kristina; Laaksonen, Timo; Kontturi, Kyösti; Hirvonen, Jouni

2013-04-01

The objective of this study was to test a drug delivery system that combines iontophoresis and cation-exchange fibers as drug matrices for the controlled transdermal delivery of antiparkinsonian drug apomorphine. Positively charged apomorphine was bound to the ion-exchange groups of the cation-exchange fibers until it was released by mobile counter-ions in the external solution. The release of the drug was controlled by modifying either the fiber type or the ionic composition of the external solution. Due to high affinity of apomorphine toward the ion-exchanger, a clear reduction in the in vitro transdermal fluxes from the fibers was observed compared to the respective fluxes from apomorphine solutions. Changes in the ionic composition of the donor formulations affected both the release and iontophoretic flux of the drug. Upon the application of higher co-ion concentrations or co-ions of higher valence in the donor formulation, the release from the fibers was enhanced, but the iontophoretic steady-state flux was decreased. Overall, the present study has demonstrated a promising approach using ion-exchange fibers for controlling the release and iontophoretic transdermal delivery of apomorphine. Copyright © 2012 Elsevier B.V. All rights reserved.

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

PubMed

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

2015-09-01

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

Design of a novel bilayered gastric mucoadhesive system for localized and unidirectional release of lamotrigine

PubMed Central

Mohana Raghava Srivalli, K.; Lakshmi, P.K.; Balasubramaniam, J.

2012-01-01

Lamotrigine is a BCS class II drug with pH dependent solubility. The bilayered gastric mucoadhesive tablets of lamotrigine were designed such that the drug and controlled release polymers were incorporated in the upper layer and the lower layer had the mucoadhesive polymers. The major ingredients selected for the upper layer were the drug and control release polymer (either HPMC K15M or polyox) while the lower MA layer predominantly comprised of Carbopol 974P. A 23 full factorial design was constructed for this study and the tablets were optimized for parameters like tablet size, shape, ex vivo mucoadhesive properties and unidirectional drug release. Oval tablets with an average size of 14 mm diameter were set optimum. Maximum mucoadhesive bond strength of 79.3 ± 0.91 * 103 dyn/cm2 was achieved with carbopol when used in combination with a synergistic resin polymer. All the tested formulations presented a mucoadhesion time of greater than 12 h. The incorporation of methacrylic polymers in the lower layer ensured unidirectional drug release from the bilayered tablets. The unidirectional drug release was confirmed after comparing the dissolution results of paddle method with those of a modified basket method. Model independent similarity and dissimilarity factor methods were used for the comparison of dissolution results. Controlled drug release profiles with zero order kinetics were obtained with polyox and HPMC K15M which reported t90% at 6th and 12th hours, respectively. The “n” value with polyox was 0.992 and that with HPMC K15M was 0.946 indicating an approximate case II transport. These two formulations showed the potential for oral administration of lamotrigine as bilayered gastric mucoadhesive tablets by yielding highest similarity factor values, 96.06 and 92.47, respectively, between the paddle and modified basket method dissolution release profiles apart from reporting the best tablet physical properties and maximum mucoadhesive strength. PMID:24109205

Sol-gel Derived Warfarin - Silica Composites for Controlled Drug Release.

PubMed

Dolinina, Ekaterina S; Parfenyuk, Elena V

2017-01-01

Warfarin, commonly used anticoagulant in clinic, has serious shortcomings due to its unsatisfactory pharmacodynamics. One of the efficient ways for the improvement of pharmacological and consumer properties of drugs is the development of optimal drug delivery systems. The aim of this work is to synthesize novel warfarin - silica composites and to study in vitro the drug release kinetics to obtain the composites with controlled release. The composites of warfarin with unmodified (UMS) and mercaptopropyl modified silica (MPMS) were synthesized by sol-gel method. The composite formation was confirmed by FTIR spectra. The concentrations of warfarin released to media with pH 1.6, 6.8 and 7.4 were measured using UV spectroscopy. The drug release profiles from the solid composites were described by a series of kinetic models which includes zero order kinetics, first order kinetics, the modified Korsmeyer-Peppas model and Hixson-Crowell model. The synthesized sol-gel composites have different kinetic behavior in the studied media. In contrast to the warfarin composite with unmodified silica, the drug release from the composite with mercaptopropyl modified silica follows zero order kinetics for 24 h irrespective to the release medium pH due to mixed mechanism (duffusion + degradation and/or disintegration of silica matrix). The obtained results showed that warfarin - silica sol-gel composites have a potential application for the development of novel oral formulation of the drug with controlled delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

In vitro release of diclofenac diethylamine from caprylocaproyl macrogolglycerides based microemulsions.

PubMed

Djordjevic, Ljiljana; Primorac, Marija; Stupar, Mirjana

2005-05-30

The purpose of the present study was to determine the influence of both formulation parameters and vehicle structure on in vitro release rate of amphiphilic drug diclofenac diethylamine (DDA) from microemulsion vehicles containing PEG-8 caprylic/capric glycerides (surfactant), polyglyceryl-6 dioleate (cosurfactant), isopropyl myristate and water. From the constructed pseudo-ternary phase diagram at surfactant-cosurfactant mass ratio (K(m) 1:1), the optimum oil-to-surfactant-cosurfactant mass ratio values (O/SC 0.67-1.64) for formulation of microemulsions with similar concentrations of hydrophilic, lipophilic and amphiphilic phases (balanced microemulsions) were found. The results of characterization experiments indicated bicontinuous or nonspherical water-continuous internal structure of the selected microemulsion vehicles. Low water/isopropyl myristate apparent partition coefficient for DDA as well as elevated electrical conductivity and apparent viscosity values for the investigated microemulsion formulations containing 1.16% (w/w) of DDA, suggested that the drug molecules was predominantly partitioned in the water phase and most likely selfaggregate and interact with interfacial film. Release of DDA from the selected water-continuous (W/O), oil-continuous (O/W) and balanced microemulsions was investigated using rotating paddle dissolution apparatus modified by addition of enhancer cell. A linear diffusion of DDA through regenerated cellulose membrane was observed for the W/O and O/W formulations with the low content of dispersed phase. Non-linearity of the drug release profile in the case of bicontinuous formulations was related to the more complex distribution of DDA including interactions between the drug and vehicle. The membrane flux value increases from 25.02 microgcm(-2)h(-1) (W/O microemulsion) to 117.94 microgcm(-2)h(-1) (O/W microemulsion) as the water phase concentration increases. Moreover, the obtained flux values for balanced microemulsions (29.38-63.70 microgcm(-2)h(-1)) suggested that bicontinuous microstructure hampers the release of the amphiphilic drug.

Formulation and characterization of ORMOSIL particles loaded with budesonide for local colonic delivery.

PubMed

Petrovska-Jovanovska, Vesna; Geskovski, Nikola; Crcarevska, Maja Simonoska; Memed, Oya; Petruševski, Gjorgji; Chachorovska, Marina; Petrusevska, Marija; Poceva-Panovska, Ana; Mladenovska, Kristina; Ugarkovic, Sonja; Glavas-Dodov, Marija

2015-04-30

In this study, hybrid silica xerogel particles were developed as carriers of budesonide (BDS) for efficient local treatment of inflammatory bowel diseases (IBD). Organically modified silica particles (ORMOSILs) were prepared by co-condensation of 3-aminopropyltriethoxysilane (APTES) and tetraethyl orthosilicate (TEOS) by an ambient temperature acid catalysed sol-gel process followed by spray-drying. Formulation for preparation of BDS-loaded particles was optimized and their physicochemical parameters and drug release profiles were evaluated in vitro. Optimal formulation had a small particle size (mean diameter of 1.45±0.02μm) with unimodal narrow size distribution and high encapsulation efficiency (98.0 ± 1.85%). Due to the positive surface charge originated from amino group of APTES, ORMOSILs showed excessive mucoadhesiveness in comparison to native TEOS particles. The drug release decreased with increasing pH from 2.0 to 7.4. In order to avoid undesirable erroneous performance in the upper GI tract, particles were additionally coated with Eudragit(®) FS 30D, as a barrier to the drug release at pH range from 2.0 to 7.0. After Eudragit(®) FS 30D coating, the release of BDS in acidic media was sustained, while no significant differences in drug release were observed at pH 7.4. In conclusion, pH-responsive ORMOSILs showed great potential for efficient BDS delivery to the colon region. Copyright © 2015 Elsevier B.V. All rights reserved.

Diazepam-loaded solid lipid nanoparticles: design and characterization.

PubMed

Abdelbary, Ghada; Fahmy, Rania H

2009-01-01

The aim of the present study was to investigate the feasibility of the inclusion of a water-insoluble drug (diazepam, DZ) into solid lipid nanoparticles (SLNs), which offer combined advantages of rapid onset and prolonged release of the drug. This work also describes a new approach to prepare suppositories containing DZ-loaded SLN dispersions, as potential drug carrier for the rectal route. Modified high-shear homogenization and ultrasound techniques were employed to prepare SLNs. The effect of incorporation of different concentrations of Compritol ATO 888 or Imwitor 900K and Poloxamer 188 or Tween 80 was investigated. Results showed that varying the type or concentration of lipid matrix or surfactant had a noticeable influence on the entrapment efficiencies, particle size, and release profiles of prepared SLNs. Differential scanning calorimetry and X-ray diffraction measurements showed that the majority of SLNs possessed less ordered arrangements of crystals than the corresponding bulk lipids, which was favorable for increasing the drug loading capacity. Transmission electron microscopy and laser diffractometry studies revealed that the prepared nanoparticles were round and homogeneous and 60% of the formulations were less than 500 nm. Additionally, SLN formulations showed significant (P < 0.05) prolonged release than DZ solution. The subsequent step encompassed the preparation and evaluation of SLN-based suppositories utilizing SLN formulations that illustrated optimal release profiles. The in vitro release of DZ from the suppositories prepared using DZ-loaded SLN dispersions (equivalent to 2 mg DZ) was significantly (P < 0.05) extended compared to suppositories containing 2 mg DZ free drug.

Role of In Vitro Release Methods in Liposomal Formulation Development: Challenges and Regulatory Perspective.

PubMed

Solomon, Deepak; Gupta, Nilesh; Mulla, Nihal S; Shukla, Snehal; Guerrero, Yadir A; Gupta, Vivek

2017-11-01

In the past few years, measurement of drug release from pharmaceutical dosage forms has been a focus of extensive research because the release profile obtained in vitro can give an indication of the drug's performance in vivo. Currently, there are no compendial in vitro release methods designed for liposomes owing to a range of experimental challenges, which has created a major hurdle for both development and regulatory acceptance of liposome-based drug products. In this paper, we review the current techniques that are most often used to assess in vitro drug release from liposomal products; these include the membrane diffusion techniques (dialysis, reverse dialysis, fractional dialysis, and microdialysis), the sample-and-separate approach, the in situ method, the continuous flow, and the modified United States Pharmacopeia methods (USP I and USP IV). We discuss the principles behind each of the methods and the criteria that assist in choosing the most appropriate method for studying drug release from a liposomal formulation. Also, we have included information concerning the current regulatory requirements for liposomal drug products in the United States and in Europe. In light of increasing costs of preclinical and clinical trials, applying a reliable in vitro release method could serve as a proxy to expensive in vivo bioavailability studies. Graphical Abstract Appropriate in-vitro drug release test from liposomal products is important to predict the in-vivo performance.

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

Temozolomide-based dry powder formulations for lung tumor-related inhalation treatment.

PubMed

Wauthoz, Nathalie; Deleuze, Philippe; Saumet, Amandine; Duret, Christophe; Kiss, Robert; Amighi, Karim

2011-04-01

Temozolomide dry powder formulations for inhalation, performed with no excipient or with a lipid or lactose coating, have been evaluated. The particle size of raw temozolomide in suspension was reduced by a high-pressure homogenizing technique, and the solvent was evaporated by spray-drying to obtain a dry powder. The physicochemical properties of this powder were evaluated and included its crystalline state, thermal properties, morphology, particle size and moisture and drug content, and these properties were determined by X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, laser light scattering, thermogravimetric analysis and high-performance liquid chromatography, respectively. The aerodynamic properties and release profiles were also evaluated using a multistage liquid impinger and a modified USP type 2 dissolution apparatus adapted for inhaler products, respectively. The dry powder inhalation formulations had a high temozolomide content that ranged from 70% to 100% in the crystalline state and low moisture content. Aerodynamic evaluations showed high fine-particle fractions of up to 51% related to the metered dose. The dissolution profile revealed a similarly fast temozolomide release from the formulations. Dry temozolomide powder formulations, based on the use of acceptable excipients for inhalation and showing good dispersion properties, represent an attractive alternative for use in local lung cancer therapy.

Docetaxel-loaded PLGA and PLGA-PEG nanoparticles for intravenous application: pharmacokinetics and biodistribution profile

PubMed Central

Rafiei, Pedram; Haddadi, Azita

2017-01-01

Docetaxel is a highly potent anticancer agent being used in a wide spectrum of cancer types. There are important matters of concern regarding the drug’s pharmacokinetics related to the conventional formulation. Poly(lactide-co-glycolide) (PLGA) is a biocompatible/biodegradable polymer with variable physicochemical characteristics, and its application in human has been approved by the United States Food and Drug Administration. PLGA gives polymeric nanoparticles with unique drug delivery characteristics. The application of PLGA nanoparticles (NPs) as intravenous (IV) sustained-release delivery vehicles for docetaxel can favorably modify pharmacokinetics, biofate, and pharmacotherapy of the drug in cancer patients. Surface modification of PLGA NPs with poly(ethylene glycol) (PEG) can further enhance NPs’ long-circulating properties. Herein, an optimized fabrication approach has been used for the preparation of PLGA and PLGA–PEG NPs loaded with docetaxel for IV application. Both types of NP formulations demonstrated in vitro characteristics that were considered suitable for IV administration (with long-circulating sustained-release purposes). NP formulations were IV administered to an animal model, and docetaxel’s pharmacokinetic and biodistribution profiles were determined and compared between study groups. PLGA and PEGylated PLGA NPs were able to modify the pharmacokinetics and biodistribution of docetaxel. Accordingly, the mode of changes made to pharmacokinetics and biodistribution of docetaxel is attributed to the size and surface properties of NPs. NPs contributed to increased blood residence time of docetaxel fulfilling their role as long-circulating sustained-release drug delivery systems. Surface modification of NPs contributed to more pronounced docetaxel blood concentration, which confirms the role of PEG in conferring long-circulation properties to NPs. PMID:28184163

Influence of formulation technique on acrylate methacrylate copolymer modified paracetamol matrix tablets.

PubMed

Cash-Torunarigha, Omonyemen Edoise; Eichie, Florence Egbomonjiade; Arhewoh, Matthew Ikhuoria

2015-03-01

This work was designed to evaluate the influence of various methods such as dry granulation (DG), wet granulation (using the polymer in an ethanolic solution (WGO) or aqueous dispersion (WGA) and solid dispersion (SD) techniques, on properties of paracetamol matrix tablets prepared using varying concentrations of acrylate methacrylate copolymer. Tablet properties were investigated using official and unofficial standards. Drug dissolution profile assessed at pH 1.2 was studied spectrophotometrically at λ(max) of 245 nm. With the use of various kinetic models, the release mechanism of the drug was analyzed. The parameters, maximum amount of drug release (m(∞)) at time t(∞) were obtained, m(∞) was ≥ 91.36 %, while t(∞) was ≥ 4.5 h. The release rate constant (k) for DG tablets was 15.61 h(sup>-1(/sup>, while, WGO, WGA and SD tablets were 12.90, 11.03 and 10.75 h(-1) respectively. The matrix tablets, which exhibited marked retardation in drug release displayed a Higuchi square root of time model (R(2) > 0.98). The mechanism through which the drug was released was governed by Fickian diffusion release (n values < 0.5). The performance of the drug was affected by the formulation technique in the order of SD > WGO > WGA > DG.

Biopharmaceutical Evaluation and CMC Aspects of Oral Modified Release Formulations.

PubMed

Chang, Rong-Kun; Mathias, Neil; Hussain, Munir A

2017-09-01

This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form. The quality-by-design (QbD) aspects of MR dosage form design and development are discussed with the emphasis on the regulatory view of the data required to support dosage form development.

Formulation optimization of gentamicin loaded Eudragit RS100 microspheres using factorial design study.

PubMed

Singh, Deependra; Saraf, Swarnlata; Dixit, Vinod Kumar; Saraf, Shailendra

2008-04-01

Gentamicin-Eudragit RS100 microspheres were prepared by modified double emulsion method. A 3(2) full factorial experiment was designed to study the effects of the composition of outer aqueous phase in terms of amount of glycerol (viscosity effect) and sodium chloride (osmotic pressure gradient effect) on the entrapment efficiency and % yield and microsphere size. The results of analysis of variance test for responses measured indicated that the test is significant (p>0.05). The contribution of sodium chloride concentration was found to be higher on entrapment efficiency and % yield, whereas glycerol produced significant effect on the mean diameter of microspheres. Microspheres demonstrated spherical particles in the size range of 33.24-60.43 microm. In vitro release profile of optimized formulation demonstrated sustained release for 24 h following Higuchi kinetics. Finally, drug bioactivity was found to remain intact after microencapsulation. Response surface graphs are presented to examine the effects of independent variables on the responses studied. Thus, by formulation design important parameters affecting formulation characteristics of gentamicin loaded Eudragit RS100 microspheres can be identified for controlled delivery with desirable characters in terms of maximum entrapment and yield.

Repellent effects of Melaleuca alternifolia (tea tree) oil against cattle tick larvae (Rhipicephalus australis) when formulated as emulsions and in β-cyclodextrin inclusion complexes.

PubMed

Yim, Wei Tsun; Bhandari, Bhesh; Jackson, Louise; James, Peter

2016-07-30

Rhipicephalus australis (formerly Boophilus microplus) is a one host tick responsible for major economic loss in tropical and subtropical cattle production enterprises. Control is largely dependent on the application of acaricides but resistance has developed to most currently registered chemical groups. Repellent compounds that prevent initial attachment of tick larvae offer a potential alternative to control with chemical toxicants. The repellent effects of Melaleuca alternifolia oil (TTO) emulsions and two β-cyclodextrin complex formulations, a slow release form (SR) and a modified faster release form (FR), were examined in a series of laboratory studies. Emulsions containing 4% and 5% TTO applied to cattle hair in laboratory studies completely repelled ascending tick larvae for 24h whereas 2% and 3% formulations provided 80% protection. At 48h, 5% TTO provided 78% repellency but lower concentrations repelled less than 60% of larvae. In a study conducted over 15 days, 3% TTO emulsion applied to cattle hair provided close to 100% repellency for 2 days, but then protection fell to 23% by day 15. The FR formulation gave significantly greater repellency than the emulsion and the SR formulation from day 3 until the end of the study (P<0.05), providing almost complete repellency at day 3 (99.5%), then decreasing over the period of the study to 49% repellency at day 15. Proof of concept is established for the use of appropriately designed controlled-release formulations to extend the period of repellency provided by TTO against R. australis larvae. Copyright © 2016 Elsevier B.V. All rights reserved.

On demand manufacturing of patient-specific liquid capsules via co-ordinated 3D printing and liquid dispensing.

PubMed

Okwuosa, Tochukwu C; Soares, Cindy; Gollwitzer, Verena; Habashy, Rober; Timmins, Peter; Alhnan, Mohamed A

2018-06-15

A method for the production of liquid capsules with the potential of modifying drug dose and release is presented. For the first time, the co-ordinated use of fused deposition modelling (FDM), 3D printing and liquid dispensing to fabricate individualised dosage form on demand in a fully automated fashion has been demonstrated. Polymethacrylate shells (Eudragit EPO and RL) for immediate and extended release were fabricated using FDM 3D printing and simultaneously filled using a computer-controlled liquid dispenser loaded with model drug solution (theophylline) or suspension (dipyridamole). The impact of printing modes: simultaneous shell printing and filling (single-phase) or sequential 3D printing of shell bottom, filling and shell cap (multi-phase), nozzle size, syringe volume, and shell structure has been reported. The use of shell thickness of 1.6 mm, and concentric architecture allowed successful containment of liquid core whilst maintaining the release properties of the 3D printed liquid capsule. The linear relationship between the theoretical and the actual volumes from the dispenser reflected its potential for accurate dosing (R 2  = 0.9985). Modifying the shell thickness of Eudragit RL capsule allowed a controlled extended drug release without the need for formulation change. Owing to its low cost and versatility, this approach can be adapted to wide spectrum of liquid formulations such as small and large molecule solutions and obviate the need for compatibility with the high temperature of FDM 3D printing process. In a clinical setting, health care staff will be able to instantly manufacture in small volumes liquid capsules with individualised dose contents and release pattern in response to specific patient's needs. Copyright © 2018 Elsevier B.V. All rights reserved.

Diclofenac sodium delivery to the eye: in vitro evaluation of novel solid lipid nanoparticle formulation using human cornea construct.

PubMed

Attama, Anthony A; Reichl, Stephan; Müller-Goymann, Christel C

2008-05-01

Solid lipid nanoparticles (SLNs) were prepared with a combination of homolipid from goat (goat fat) and phospholipid, and evaluated for diclofenac sodium (DNa) delivery to the eye using bio-engineered human cornea, produced from immortalized human corneal endothelial cells (HENC), stromal fibroblasts and epithelial cells CEPI 17 CL 4. Encapsulation efficiency was high and sustained release of DNa and high permeation through the bio-engineered cornea were achieved. Results obtained in this work showed that permeation of DNa through the cornea construct was improved by formulation as SLN modified with phospholipid.

Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations.

PubMed

Sferrazza, Gianluca; Siviero, Paolo D; Nicotera, Giuseppe; Turella, Paola; Serafino, Annalucia; Blandizzi, Corrado; Pierimarchi, Pasquale

2017-09-01

Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice. Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence. Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs.

[Role of food interaction pharmacokinetic studies in drug development. Food interaction studies of theophylline and nifedipine retard and buspirone tablets].

PubMed

Drabant, S; Klebovich, I; Gachályi, B; Renczes, G; Farsang, C

1998-09-01

Due to several mechanism, meals may modify the pharmacokinetics of drug products, thereby eliciting to clinically significant food interaction. Food interactions with the drug substance and with the drug formulation should be distinguished. Food interaction of different drug products containing the same active ingredient can be various depending on the pharmaceutical formulation technology. Particularly, in the case of modified release products, the food/formulation interaction can play an important role in the development of food interaction. Well known example, that bioavailability of theophylline can be influenced in different way (either increased, decreased or unchanged) by concomitant intake of food in the case of different sustained release products. The role and methods of food interaction studies in the different kinds of drug development (new chemical entity, modified release products, generics) are reviewed. Prediction of food effect response on the basis of the physicochemical and pharmacokinetic characteristics of the drug molecule or formulations is discussed. The results of three food interaction studies carried out the products of EGIS Pharmaceuticals Ltd. are also reviewed. The pharmacokinetic parameters of theophyllin 400 mg retard tablet were practically the same in both fasting condition and administration after consumption of a high fat containing standard breakfast. The ingestion of a high fat containing breakfast, increased the AUC of nifedipine from 259.0 +/- 101.2 ng h/ml to 326.7 +/- 122.5 ng h/ml and Cmax from 34.5 +/- 15.9 ng/ml to 74.3 +/- 23.9 ng/ml in case of nifedipine 20 mg retard tablet, in agreement with the data of literature. The statistical evaluation indicated significant differences between the pharmacokinetic parameters in the case of two administrations (before and after meal). The effect of a high fat containing breakfast for a generic version of buspiron 10 mg tablet and the bioequivalence after food consumption were studied in a single-dose, three-way (test and reference products administered after consumption of standard breakfast, as well as test product in fasting condition), cross-over, food effect bioequivalence study. According to the results, the test product--which, in a former study proved to be bioequivalent with the reference product in fasting state--is bioequivalent with the reference product under feeding conditions and the food intake influenced the pharmacokinetics of the test tablets.

Modified tricalcium silicate cement formulations with added zirconium oxide.

PubMed

Li, Xin; Yoshihara, Kumiko; De Munck, Jan; Cokic, Stevan; Pongprueksa, Pong; Putzeys, Eveline; Pedano, Mariano; Chen, Zhi; Van Landuyt, Kirsten; Van Meerbeek, Bart

2017-04-01

This study aims to investigate the effect of modifying tricalcium silicate (TCS) cements on three key properties by adding ZrO 2 . TCS powders were prepared by adding ZrO 2 at six different concentrations. The powders were mixed with 1 M CaCl 2 solution at a 3:1 weight ratio. Biodentine (contains 5 wt.% ZrO 2 ) served as control. To evaluate the potential effect on mechanical properties, the mini-fracture toughness (mini-FT) was measured. Regarding bioactivity, Ca release was assessed using ICP-AES. The component distribution within the cement matrix was evaluated by Feg-SEM/EPMA. Cytotoxicity was assessed using an XTT assay. Adding ZrO 2 to TCS did not alter the mini-FT (p = 0.52), which remained in range of that of Biodentine (p = 0.31). Ca release from TSC cements was slightly lower than that from Biodentine at 1 day (p > 0.05). After 1 week, Ca release from TCS 30 and TCS 50 increased to a level that was significantly higher than that from Biodentine (p < 0.05). After 1 month, Ca release all decreased (p < 0.05), yet TCS 0 and TCS 50 released comparable amounts of Ca as at 1 day (p > 0.05). EPMA revealed a more even distribution of ZrO 2 within the TCS cements. Particles with an un-reacted core were surrounded by a hydration zone. The 24-, 48-, and 72-h extracts of TCS 50 were the least cytotoxic. ZrO 2 can be added to TCS without affecting the mini-FT; Ca release was reduced initially, to reach a prolonged release thereafter; adding ZrO 2 made TCS cements more biocompatible. TCS 50 is a promising cement formulation to serve as a biocompatible hydraulic calcium silicate cement.

Risk management and statistical multivariate analysis approach for design and optimization of satranidazole nanoparticles.

PubMed

Dhat, Shalaka; Pund, Swati; Kokare, Chandrakant; Sharma, Pankaj; Shrivastava, Birendra

2017-01-01

Rapidly evolving technical and regulatory landscapes of the pharmaceutical product development necessitates risk management with application of multivariate analysis using Process Analytical Technology (PAT) and Quality by Design (QbD). Poorly soluble, high dose drug, Satranidazole was optimally nanoprecipitated (SAT-NP) employing principles of Formulation by Design (FbD). The potential risk factors influencing the critical quality attributes (CQA) of SAT-NP were identified using Ishikawa diagram. Plackett-Burman screening design was adopted to screen the eight critical formulation and process parameters influencing the mean particle size, zeta potential and dissolution efficiency at 30min in pH7.4 dissolution medium. Pareto charts (individual and cumulative) revealed three most critical factors influencing CQA of SAT-NP viz. aqueous stabilizer (Polyvinyl alcohol), release modifier (Eudragit® S 100) and volume of aqueous phase. The levels of these three critical formulation attributes were optimized by FbD within established design space to minimize mean particle size, poly dispersity index, and maximize encapsulation efficiency of SAT-NP. Lenth's and Bayesian analysis along with mathematical modeling of results allowed identification and quantification of critical formulation attributes significantly active on the selected CQAs. The optimized SAT-NP exhibited mean particle size; 216nm, polydispersity index; 0.250, zeta potential; -3.75mV and encapsulation efficiency; 78.3%. The product was lyophilized using mannitol to form readily redispersible powder. X-ray diffraction analysis confirmed the conversion of crystalline SAT to amorphous form. In vitro release of SAT-NP in gradually pH changing media showed <20% release in pH1.2 and pH6.8 in 5h, while, complete release (>95%) in pH7.4 in next 3h, indicative of burst release after a lag time. This investigation demonstrated effective application of risk management and QbD tools in developing site-specific release SAT-NP by nanoprecipitation. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of dry heating and ionic gum on the physicochemical and release properties of starch from Dioscorea.

PubMed

Vashisht, Deepika; Pandey, Anima; Hermenean, Anca; Yáñez-Gascón, Maria Josefa; Pérez-Sánchez, Horacio; Kumar, K Jayaram

2017-02-01

To meet the ever increasing industrial demand for excipients with desirable properties, modified starch is regarded as an alternative to it. With this in mind, the present study focuses on the modification of starches of Dioscorea from Jharkhand (India) using dry heat treatment with and without ionic gum. Modified starches were prepared using sodium alginate (1% w/w). Native and modified starches were subjected to heat treatment at 130°C for 2h and 4h. The effect of heating and ionic gum on the properties of Dioscorea starch was investigated. The amylose content, water holding capacity, micromeritic properties, swelling power, solubility and morphology of starches were evaluated. Dry heat treatment of starches without gum showed an increment in water-holding capacity after two-hours heating, but no such increment was found after four-hours heating. Oil binding capacity of starches modified with gum varied from 62% to 78%. Strongest effect of heat treatment occurred on the morphology of starches and thereby modified starches showed distorted surface morphology. Amylose content (21.09-21.89%) found to be decreased with the addition of gum which lead to decrease in paste clarity. Starches heated with gum at high-temperature resulted in restrict swelling and slight increase in solubility. Micromeritic properties of the modified starches showed the good flow properties. Further, the modified starches were investigated for in-vitro release studies and that the thermally modified derivatives can be a good prospect in slow release formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative assessment of in vitro release kinetics of calcitonin polypeptide from biodegradable microspheres.

PubMed

Prabhu, Sunil; Sullivan, Jennifer L; Betageri, Guru V

2002-01-01

The objective of our study was to compare the in vitro release kinetics of a sustained-release injectable microsphere formulation of the polypeptide drug, calcitonin (CT), to optimize the characteristics of drug release from poly-(lactide-co-glycolide) (PLGA) copolymer biodegradable microspheres. A modified solvent evaporation and double emulsion technique was used to prepare the microspheres. Release kinetic studies were carried out in silanized tubes and dialysis bags, whereby microspheres were suspended and incubated in phosphate buffered saline, sampled at fixed intervals, and analyzed for drug content using a modified Lowry protein assay procedure. An initial burst was observed whereby about 50% of the total dose of the drug was released from the microspheres within 24 hr and 75% within 3 days. This was followed by a period of slow release over a period of 3 weeks in which another 10-15% of drug was released. Drug release from the dialysis bags was more gradual, and 50% CT was released only after 4 days and 75% after 12 days of release. Scanning electron micrographs revealed spherical particles with channel-like structures and a porous surface after being suspended in an aqueous solution for 5 days. Differential scanning calorimetric studies revealed that CT was present as a mix of amorphous and crystalline forms within the microspheres. Overall, these studies demonstrated that sustained release of CT from PLGA microspheres over a 3-week period is feasible and that release of drug from dialysis bags was more predictable than from tubes.

A solid-state NMR method to determine domain sizes in multi-component polymer formulations

NASA Astrophysics Data System (ADS)

Schlagnitweit, Judith; Tang, Mingxue; Baias, Maria; Richardson, Sara; Schantz, Staffan; Emsley, Lyndon

2015-12-01

Polymer domain sizes are related to many of the physical properties of polymers. Here we present a solid-state NMR experiment that is capable of measuring domain sizes in multi-component mixtures. The method combines selective excitation of carbon magnetization to isolate a specific component with proton spin diffusion to report on domain size. We demonstrate the method in the context of controlled release formulations, which represents one of today's challenges in pharmaceutical science. We show that we can measure domain sizes of interest in the different components of industrial pharmaceutical formulations at natural isotopic abundance containing various (modified) cellulose derivatives, such as microcrystalline cellulose matrixes that are film-coated with a mixture of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC).

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

PubMed

Abinusawa, Adeyinka; Tenjarla, Srini

2015-05-01

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

Liposomal Aerosols of Nitric Oxide (NO) Donor as a Long-Acting Substitute for the Ultra-Short-Acting Inhaled NO in the Treatment of PAH.

PubMed

Nahar, Kamrun; Rashid, Jahidur; Absar, Shahriar; Al-Saikhan, Fahad I; Ahsan, Fakhrul

2016-07-01

This study seeks to develop a liposomal formulation of diethylenetriamine NONOate (DN), a long acting nitric oxide (NO) donor, with a goal to replace inhaled NO (iNO) in the treatment of pulmonary arterial hypertension (PAH). Liposomal formulations were prepared by a lipid film hydration method and modified with a cell penetrating peptide, CAR. The particles were characterized for size, polydispersity index (PDI), zeta potential, entrapment efficiency, storage and nebulization stability, and in-vitro release profiles. The cellular uptake and transport were assessed in rat alveolar macrophages (NR8383) and transforming growth factor β (TGF-β) activated rat pulmonary arterial smooth muscle cells (PASMCs). The fraction of the formulation that enters the systemic circulation, after intratracheal administration, was determined in an Isolated Perfused Rat Lung (IPRL) model. The safety of the formulations were assessed using an MTT assay and by measuring injury markers in the bronchoalveolar lavage (BAL) fluid; the pharmacological efficacy was evaluated by monitoring the changes in the mean pulmonary arterial (mPAP) and systemic pressure (mSAP) in a monocrotaline (MCT) induced-PAH rat model Liposome size, zeta potential, and entrapment efficiency were 171 ± 4 nm, -37 ± 3 mV, and 46 ± 5%, respectively. The liposomes released 70 ± 5% of the drug in 8 h and were stable when stored at 4°C. CAR-conjugated-liposomes were taken up more efficiently by PASMCs than liposomes-without-CAR; the uptake of the formulations by rat alveolar macrophages was minimal. DN-liposomes did not increase lung weight, protein quantity, and levels of injury markers in the BAL fluid. Intratracheal CAR-liposomes reduced the entry of liposomes from the lung to blood; the formulations produced a 40% reduction in mPAP for 180 minutes. This study establishes the proof-of-concept that peptide modified liposomal formulations of long-acting NO donor can be an alternative to short-acting iNO.

A Phase 2 Study of Chronocort, a Modified-Release Formulation of Hydrocortisone, in the Treatment of Adults With Classic Congenital Adrenal Hyperplasia

PubMed Central

Sinaii, Ninet; Kumar, Parag; Whitaker, Martin J.; Daley, Lori-Ann; Digweed, Dena; Eckland, David J. A.; Van Ryzin, Carol; Nieman, Lynnette K.; Arlt, Wiebke; Merke, Deborah P.

2015-01-01

Context: Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. Objectives: The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration. Design, Setting, and Patients: Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology. Main Outcome Measures: The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP). Results: In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs 25.9 ± 7.1 mg/d), with lower 24-hour (P = .004), morning (0700–1500 h; P = .002), and afternoon (1500–2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700–1500 h; P = .02) 17-OHP AUC. Conclusions: Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH. PMID:25494662

A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia.

PubMed

Mallappa, Ashwini; Sinaii, Ninet; Kumar, Parag; Whitaker, Martin J; Daley, Lori-Ann; Digweed, Dena; Eckland, David J A; Van Ryzin, Carol; Nieman, Lynnette K; Arlt, Wiebke; Ross, Richard J; Merke, Deborah P

2015-03-01

Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration. Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology. The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP). In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs 25.9 ± 7.1 mg/d), with lower 24-hour (P = .004), morning (0700-1500 h; P = .002), and afternoon (1500-2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700-1500 h; P = .02) 17-OHP AUC. Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH.

Release behavior and bioefficacy of imazethapyr formulations based on biopolymeric hydrogels.

PubMed

Kumar, Vikas; Singh, Anupama; Das, T K; Sarkar, Dhruba Jyoti; Singh, Shashi Bala; Dhaka, Rashmi; Kumar, Anil

2017-06-03

Controlled release formulations of imazethapyr herbicide have been developed employing guar gum-g-cl-polyacrylate/bentonite clay hydrogel composite (GG-HG) and guar gum-g-cl-PNIPAm nano hydrogel (GG-NHG) as carriers, to assess the suitability of biopolymeric hydrogels as controlled herbicide release devices. The kinetics of imazethapyr release from the developed formulations was studied in water and it revealed that the developed formulations of imazethapyr behaved as slow release formulations as compared to commercial formulation. The calculated diffusion exponent (n) values showed that Fickian diffusion was the predominant mechanism of imazethapyr release from the developed formulations. Time for release of half of the loaded imazethapyr (t 1/2 ) ranged between 0.06 and 4.8 days in case of GG-NHG and 4.4 and 12.6 days for the GG-HG formulations. Weed control index (WCI) of GG-HG and GG-NHG formulations was similar to that of the commercial formulation and the herbicidal effect was observed for relatively longer period. Guar gum-based biopolymeric hydrogels in both macro and nano particle size range can serve as potential carriers in developing slow release herbicide formulations.

Preparation and in vitro-in vivo evaluation of none gastric resident dipyridamole (DIP) sustained-release pellets with enhanced bioavailability.

PubMed

Xu, Lishuang; Luo, Yanfei; Feng, Jia; Xu, Ming; Tao, Xiaoguang; He, Haibing; Tang, Xing

2012-01-17

The objective of this study was to develop none gastric resident sustained-release pellets loaded with dipyridamole with a high bioavailability. Two different kinds of core pellets, one containing citric acid as a pH-modifier (CAP) and, the other without pH-modifier (NCAP) were prepared by extrusion-spheronization and then coated with mixtures of enteric soluble and insoluble polymers (referred to as CAP(1) and NCAP(1)) or insoluble polymer alone (referred to as CAP(2) and NCAP(2)). The relative bioavailability of the sustained-release pellets was studied in fasted beagle dogs after oral administration using a commercially available immediate release tablet (IRT) as a reference. The in vitro release, in vivo absorption and in vitro-in vivo correlation were also evaluated. Results revealed that the plasma drug concentrations after administration of CAP(2), NCAP(1) and NCAP(2) were undetectable, indicating that the drug release was almost zero from the preparations throughout the gastro-intestinal tract. The C(max), T(max) and AUC((0→24)) of CAP(1) were 0.78 ± 0.23 (μg/ml), 3.80 ± 0.30 (h), and 6.74 ± 0.47 (μg/mlh), respectively. While the corresponding values were 2.23 ± 0.32 (μg/ml), 3.00 ± 0.44 (h) and 9.42 ± 0.69 (μg/mlh) for IRT. The relative bioavailability of CAP(1) was 71.55% compared with IRT. By combined incorporation of a pH-modifier into the core of pellets to modify the inner micro-environment and employing mixtures of enteric soluble and insoluble polymers as a retarding layer, drugs with high solubility in stomach and limited solubility in small intestine, such as DIP, could be successfully formulated as sustained release preparations with no pH-dependence in drug release and enhanced bioavailability. Copyright © 2011 Elsevier B.V. All rights reserved.

Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt.

PubMed

Arora, Priyanka; Mukherjee, Biswajit

2002-09-01

In this study, matrix-type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied. Copyright 2002 Wiley-Liss, Inc.

Modified extrusion-spheronization as a technique of microencapsulation for stabilization of choline bitartrate using hydrogenated soya bean oil.

PubMed

Gangurde, Avinash Bhaskar; Sav, Ajay Kumar; Javeer, Sharadchandra Dagadu; Moravkar, Kailas K; Pawar, Jaywant N; Amin, Purnima D

2015-01-01

Choline bitartrate (CBT) is a vital nutrient for fetal brain development and memory function. It is hygroscopic in nature which is associated with stability related problem during storage such as development of fishy odor and discoloration. Microencapsulation method was adopted to resolve the stability problem and for this hydrogenated soya bean oil (HSO) was used as encapsulating agent. Industrially feasible modified extrusion-spheronization technique was selected for microencapsulation. HSO was used as encapsulating agent, hydroxypropyl methyl cellulose E5/E15 as binder and microcrystalline cellulose as spheronization aid. Formulated pellets were evaluated for parameters such as flow property, morphological characteristics, hardness-friability index (HFI), drug content, encapsulation efficiency, and in vitro drug release. The optimized formulations were also characterized for particle size (by laser diffractometry), differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy, and scanning electron microscopy. The results from the study showed that coating of 90% and 60% CBT was successful with respect to all desired evaluation parameters. Optimized formulation was kept for 6 months stability study as per ICH guidelines, and there was no change in color, moisture content, drug content, and no fishy odor was observed. Microencapsulated pellets of CBT using HSO as encapsulating agent were developed using modified extrusion spheronization technique. Optimized formulations, CBT 90% (F5), and CBT 60% (F10), were found to be stable for 4M and 6M, respectively, at accelerated conditions.

Effect of particle size of parenteral suspensions on in vitro muscle damage.

PubMed

Brazeau, Gayle; Sauberan, Shauna L; Gatlin, Larry; Wisniecki, Peter; Shah, Jaymin

2011-01-01

Suspension particle size plays a key role in the release and stability of drugs for oral and parenteral formulations. However, the role of particle size in suspension formulations on tissue damage (myotoxicity) following intramuscular (IM) injection has not been systematically investigated. Myotoxicity was assessed by the release of cumulative creatine kinase (CCK) from the isolated extensor digitorium longus (EDL) and soleus (SOL) rat muscles for selected suspensions of phenytoin, bupivicane and diazepam. Particle size effects on myotoxicity, independent of any specific drug, were also investigated using characterized non-dissolving polystyrene beads. Myotoxicity was quantitated by the cumulative release of creatine kinase (CCK) from these isolated muscles over 90 or 120 min. The relationship between particle size and myotoxicity was dependent upon the drug in these suspensions. Diazepam and phenytoin suspensions were found to be less myotoxic than bupivicaine. Using unmodified and carboxy modified polystyrene beads, an optimal particle size for reduced myotoxicity following IM injection ranges from approx. 500 nm to 1 µM. The relationship between myotoxicity of IM suspensions and particle size is dependent upon the particular drug and suspension particle size.

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

PubMed Central

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

2011-01-01

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

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.

Ondansetron Suppositories: Extemporaneous Preparation, Drug Release, Stability and Flux through Rabbit Rectal Membrane.

PubMed

Tenjarla, S N; Ward, E S; Fox, J L

1998-01-01

The objective of this study was to determine the feasibility and develop a formulation for an extemporaneously prepared ondansetron suppository form Zofran 8-mg tablets. The stability of the formulation over 28 days of refrigerated storage and the initial and poststorage drug-release profiles were evaluated. The ondansetron flux in an in vitro model (a rabbit rectal membrane) from each formulation was determined. Suppositories containing 8 or 16 mg ondansetron were made using commercially available hydrophobic and hydrophilic suppository bases. A sensitive, stability-indication high-performance liquid chromatography assay was used for the analysis of ondansetron. The partition coefficient (octanol/water) of ondansetron and the displacement factor of tablets with each of the two bases were determined . The suppositories, formed in disposable molds, were kept in plastic wwrap and stored at 5 deg C in the refrigerator. The effect of storage on ondansetron release from the suppository base and the stability of ondansetron in the two suppository bases were evaluated over a period of 28 days. The dissolution study provided data on the release profile of the drug over 28 days, as well as the stabilty of the drug during the storage period. Ondansetron flux through rabbit rectal membrane from the various formulations was determined in vitro using modified Franz diffusion cells. Greater than 90% of the intiial amount (8 or 16 mg) of ondansetron was retained in the suppositories after 28-day storage at 5 deg C for both hydrophilic and hydrophobic formulations. There was no statistically siginificant difference in the drug-release profiles during this period. Ondansetron flux through the rabbit rectal membrane from 8- and 16-mg hydrophobic suppositories was 393 +/- 58 and 76.2 +/- 13.8 micrograms per centimeters squared -hour, respectively (n=6). The corresponding flux from 8- and 16-mg hydrophilic suppositories was 37.8 +/- 16 and 81.7 +/- 22.9 micrograms per centimeter squared - hour, respectively. The variablility in the flux required further study but the levels achieved indicated that extemporaneous preparation of ondansetron suppositories is reasonable using commercially available components.

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

PubMed

Hiremath, Praveen S; Saha, Ranendra N

2008-10-01

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

Development and evaluation of a novel biodegradable sustained release microsphere formulation of paclitaxel intended to treat breast cancer

PubMed Central

Shiny, Jacob; Ramchander, Thadkapally; Goverdhan, Puchchakayala; Habibuddin, Mohammad; Aukunuru, Jithan Venkata

2013-01-01

Objective: The objective of this study was to develop a novel 1 month depot paclitaxel (PTX) microspheres that give a sustained and complete drug release. Materials and Methods: PTX loaded microspheres were prepared by o/w emulsion solvent evaporation technique using the blends of poly(lactic-co-glycolic acid) (PLGA) 75/25, polycaprolactone 14,000 and polycaprolactone 80,000. Fourier transform infrared spectroscopy was used to investigate drug excipient compatibility. Compatible blends were used to prepare F1-F6 microspheres, the process was characterised and the optimum formulation was selected based on the release. Optimised formulation was characterised for solid state of the drug using the differential scanning calorimetry (DSC) studies, surface morphology using the scanning electron microscopy (SEM), in vivo drug release, in vitro in vivo correlation (IVIVC) and anticancer activity. Anticancer activity of release medium was determined using the cell viability assay in Michigan Cancer Foundation (MCF-7) cell line. Results: Blend of PLGA with polycaprolactone (Mwt 14,000) at a ratio of 1:1 (F5) resulted in complete release of the drug in a time frame of 30 days. F5 was considered as the optimised formulation. Incomplete release of the drug resulted from other formulations. The surface of the optimised formulation was smooth and the drug changed its solid state upon fabrication. The formulation also resulted in 1-month drug release in vivo. The released drug from F5 demonstrated anticancer activity for 1-month. Cell viability was reduced drastically with the release medium from F5 formulation. A 100% IVIVC was obtained with F5 formulation suggesting the authenticity of in vitro release, in vivo release and the use of the formulation in breast cancer. Conclusions: From our study, it was concluded that with careful selection of different polymers and their combinations, PTX 1 month depot formulation with 100% drug release and that can be used in breast cancer was developed. PMID:24167783

Design of composite microparticle systems based on pectin and waste material of propolis for modified l-alanyl-l-glutamine release and with immunostimulant activity.

PubMed

Villa Nova, Mônica; Ratti, Bianca A; Herculano, Leandro S; Bittencourt, Paulo R S; Novello, Cláudio R; Bazotte, Roberto Barbosa; Lautenschlager, Sueli de Oliveira Silva; Bruschi, Marcos Luciano

2017-12-12

Catabolic conditions like acquired immunodeficiency syndrome, cancer, and burn can cause immunosuppression. Amino acids such as alanine and glutamine are essential for the activity of the immune system. Propolis is immunostimulant and the waste of propolis extraction has been reused with technological and therapeutic purposes. Therefore, this study describes the association of propolis byproduct extract (BPE) with pectin to prepare spray-dried microparticles containing the dipeptide l-alanyl-l-glutamine as stimulant systems of neutrophils. The use of a factorial design allowed selecting the best formulation, which was characterized by morphology, size, and entrapment efficiency analyses. In addition, the systems were characterized by thermal and X-ray diffraction analysis, Fourier-transform infrared spectroscopy, in vitro drug release, and in vitro cytotoxicity and stimulation test of neutrophils. Small well-structured microparticles with good entrapment efficiency values were achieved. Thermal stability of formulation was observed, and it was proved that pectin, BPE and l-alanyl-l-glutamine were dispersed throughout the matrix. The drug was released from the microparticles during 24 h governed by swelling and diffusion. The drug-loaded formulations showed a significant stimulating effect on neutrophils. These structures could increase the activity of immune cells, and other in vitro and in vivo studies should be performed in the future.

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.

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

PubMed

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

2017-11-01

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

Basics of Compounding: 3D Printing--Pharmacy Applications: Geometric Shape Effects on 3D Printing.

PubMed

Allen, Loyd V

2017-01-01

As patient therapy becomes more specialized and individualized, one applicable method of drug delivery is through 3D printing. With 3D printing, pharmacists can provide either immediate or modified drug release of either an individual drug or multiple drugs in a singledosage unit. The release rates can be varied, not only by excipients in the formulation, but also to some extent by the shapes of the finished-drug preparation. Some studies demonstrating these concepts are included in this article, along with their method of compounding using 3D printing. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

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

PubMed

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

2011-03-01

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

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.

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

PubMed

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

2018-01-15

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

Modified extrusion-spheronization as a technique of microencapsulation for stabilization of choline bitartrate using hydrogenated soya bean oil

PubMed Central

Gangurde, Avinash Bhaskar; Sav, Ajay Kumar; Javeer, Sharadchandra Dagadu; Moravkar, Kailas K; Pawar, Jaywant N; Amin, Purnima D

2015-01-01

Introduction: Choline bitartrate (CBT) is a vital nutrient for fetal brain development and memory function. It is hygroscopic in nature which is associated with stability related problem during storage such as development of fishy odor and discoloration. Aim: Microencapsulation method was adopted to resolve the stability problem and for this hydrogenated soya bean oil (HSO) was used as encapsulating agent. Materials and Methods: Industrially feasible modified extrusion-spheronization technique was selected for microencapsulation. HSO was used as encapsulating agent, hydroxypropyl methyl cellulose E5/E15 as binder and microcrystalline cellulose as spheronization aid. Formulated pellets were evaluated for parameters such as flow property, morphological characteristics, hardness-friability index (HFI), drug content, encapsulation efficiency, and in vitro drug release. The optimized formulations were also characterized for particle size (by laser diffractometry), differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy, and scanning electron microscopy. Results and Discussions: The results from the study showed that coating of 90% and 60% CBT was successful with respect to all desired evaluation parameters. Optimized formulation was kept for 6 months stability study as per ICH guidelines, and there was no change in color, moisture content, drug content, and no fishy odor was observed. Conclusion: Microencapsulated pellets of CBT using HSO as encapsulating agent were developed using modified extrusion spheronization technique. Optimized formulations, CBT 90% (F5), and CBT 60% (F10), were found to be stable for 4M and 6M, respectively, at accelerated conditions. PMID:26682198

Modified release terbutaline (SKP1052) for hypoglycaemia prevention: a proof-of-concept study in people with type 1 diabetes mellitus.

PubMed

Nosek, L; Cardot, J-M; Owens, D R; Ibarra, P; Bagate, K; Vergnault, G; Kaiser, K; Fischer, A; Heise, T

2012-12-01

In this randomized, single blind, cross-over study 2.5 mg and 5 mg of the modified-release terbutaline formulation (SKP-1052) were compared with conventional immediate-release terbutaline (IRT, 5 mg) and placebo on overnight blood glucose (BG) and hypoglycaemia in 30 subjects with type 1 diabetes mellitus. Subjects received subcutaneous injections of insulin glargine (individualized doses) before dinner. SKP-1052, IRT or placebo was administered around 21:00 hours. BG and terbutaline concentrations were monitored overnight for 10 h post-dosing. Endpoints comprised of the nadir BG (BGn 0-10 h, primary endpoint), mean overnight BG (BGmean), morning BG (BGmorning) and hypoglycaemia rates as well as pharmacokinetic (PK) endpoints. SKP-1052 delayed release of terbutaline by 2 h [PK-tmax (mean ± SD) 5.0 ± 2.1 h (2.5 mg) and 4.7 ± 1.7 h (5 mg) vs. 2.6 ± 1.3 h with IRT, p < 0.01, respectively]. Compared with placebo, no significant differences were observed for BGn 0-10 h across treatments, but both 5 mg formulations showed less hypoglycaemic events [10 (IRT), 16 (SKP-1052) vs. 33], higher BGmean (120, 114 and 95 mg/dl) and BGmorning (126, 126 and 101 mg/dl, all comparisons p < 0.05 vs. placebo). Numerically higher BG-levels between 3 and 8 h post-dosing were observed with 2.5 mg SKP-1052 vs. placebo. Compared with IRT SKP-1052 delays release of terbutaline. 2.5 mg SKP-1052 led to numerically higher BG 3 to 8 h post-dose without fasting hyperglycaemia while 5 mg SKP-1052 resulted in fasting hyperglycaemia vs. placebo. Future studies will investigate optimized doses of SKP-1052 for nocturnal hypoglycaemia prevention. © 2012 Blackwell Publishing Ltd.

The Role of Polydimethylsiloxane in the Molecular Structure of Silica Xerogels Intended for Drug Carriers

PubMed Central

Czarnobaj, Katarzyna

2015-01-01

The aim of this study was to prepare and examine polymer/oxide xerogels with metronidazole (MT) as delivery systems for the local application of a drug to a bone. The nanoporous SiO2-CaO and PDMS-modified SiO2-CaO xerogel materials with different amounts of the polymer, polydimethylsiloxane (PDMS), were prepared by the sol-gel method. Characterization assays comprised the analysis of the composite materials by using Fourier transform infrared spectroscopy (FTIR), determining the specific surface area of solids (BET), using X-ray powder diffraction (XRD) and scanning electron microscope (SEM) techniques, and further monitoring in the ultraviolet and visible light regions (UV-Vis) of the in vitro release of the drug (metronidazole) over time. According to these results, the bioactive character and chemical stability of PDMS-modified silica xerogels have been proven. The release of MT from xerogels was strongly correlated with the composition of the matrix. In comparison with the pure oxide matrix, PDMS-modified matrices accelerated the release of the drug through its bigger pores, and additionally, on account of weaker interactions with the drug. The obtained results for the xerogel composites suggest that the metronidazole-loaded xerogels could be promising candidates for formulations in local delivery systems particularly to bone. PMID:26839836

Preparation and in vitro evaluation of pyridostigmine bromide microparticles.

PubMed

Hegazy, Nahed; Demirel, Müzeyyen; Yazan, Yasemin

2002-08-21

Pyridostigmine bromide (PB) is an anticholinesterase agent whose aqueous solubility is high and which has a short elimination half-life. Its dosage rate in the treatment of myastenia gravis is frequent due to the short half-life and it exhibits side effects. Microparticles designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose and also to enhance stability, reduce side effects and modify drug release were prepared in this study using an acrylic polymer (Eudragit) as the vehicle by the spray-drying technique. The drug was either dissolved or dispersed in the polymeric solution and following the preparation of microparticles using different ratios of ingredients, characterization studies including the determination of shape, particle size distribution, amount loaded, release and stability of PB were performed. The results obtained were compared to those of pure PB. Drug release from microparticles could be modified and was found to depend on the shapes of the microparticles. In vitro evaluation results indicate that the frequent dosage and side effects of pure PB may be reduced with the formulation of microparticles.

Dermal quercetin lipid nanocapsules: Influence of the formulation on antioxidant activity and cellular protection against hydrogen peroxide.

PubMed

Hatahet, T; Morille, M; Shamseddin, A; Aubert-Pouëssel, A; Devoisselle, J M; Bégu, S

2017-02-25

Quercetin is a plant flavonoid with strong antioxidant and antiinflammatory properties interesting for skin protection. However, its poor water solubility limits its penetration and so its efficiency on skin. For this purpose, quercetin lipid nanocapsules were formulated implementing phase inversion technique wherein several modifications were introduced to enhance quercetin loading. Quercetin lipid nanocapsules were formulated with two particle size range, (50nm and 20nm) allowing a drug loading of 18.6 and 32mM respectively. The successful encapsulation of quercetin within lipid nanocapsules increased its apparent water solubility by more than 5000 fold (from 0.5μg/ml to about 5mg/ml). The physicochemical properties of these formulations such as surface charge, stability and morphology were characterized. Lipid nanocapsules had spherical shape and were stable for 28days at 25°C. Quercetin release from lipid nanocapsules was studied and revealed a prolonged release kinetics during 24h. Using DPPH assay, we demonstrated that the formulation process of lipid nanocapsules did not modify the antioxidant activity of quercetin in vitro (92.3%). With the goal of a future dermal application, quercetin lipid nanocapsules were applied to THP-1 monocytes and proved the cellular safety of the formulation up to 2μg/ml of quercetin. Finally, formulated quercetin was as efficient as the crude form in the protection of THP-1 cells from oxidative stress by exogenous hydrogen peroxide. With its lipophilic nature and occlusive effect on skin, lipid nanocapsules present a promising strategy to deliver quercetin to skin tissue and can be of value for other poorly water soluble drug candidates. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design.

PubMed

Hao, Jifu; Fang, Xinsheng; Zhou, Yanfang; Wang, Jianzhu; Guo, Fengguang; Li, Fei; Peng, Xinsheng

2011-01-01

The purpose of the present study was to optimize a solid lipid nanoparticle (SLN) of chloramphenicol by investigating the relationship between design factors and experimental data using response surface methodology. A Box-Behnken design was constructed using solid lipid (X(1)), surfactant (X(2)), and drug/lipid ratio (X(3)) level as independent factors. SLN was successfully prepared by a modified method of melt-emulsion ultrasonication and low temperature-solidification technique using glyceryl monostearate as the solid lipid, and poloxamer 188 as the surfactant. The dependent variables were entrapment efficiency (EE), drug loading (DL), and turbidity. Properties of SLN such as the morphology, particle size, zeta potential, EE, DL, and drug release behavior were investigated, respectively. As a result, the nanoparticle designed showed nearly spherical particles with a mean particle size of 248 nm. The polydispersity index of particle size was 0.277 ± 0.058 and zeta potential was -8.74 mV. The EE (%) and DL (%) could reach up to 83.29% ± 1.23% and 10.11% ± 2.02%, respectively. In vitro release studies showed a burst release at the initial stage followed by a prolonged release of chloramphenicol from SLN up to 48 hours. The release kinetics of the optimized formulation best fitted the Peppas-Korsmeyer model. These results indicated that the chloramphenicol-loaded SLN could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release.

Sustained release of antibiotics from injectable and thermally responsive polypeptide depots.

PubMed

Adams, Samuel B; Shamji, Mohammed F; Nettles, Dana L; Hwang, Priscilla; Setton, Lori A

2009-07-01

Biodegradable polymeric scaffolds are of interest for delivering antibiotics to local sites of infection in orthopaedic applications, such as bone and diarthrodial joints. The objective of this study was to develop a biodegradable scaffold with ease of drug loading in aqueous solution, while providing for drug depot delivery via syringe injection. Elastin-like polypeptides (ELPs) were used for this application, biopolymers of repeating pentapeptide sequences that were thermally triggered to undergo in situ depot formation at body temperature. ELPs were modified to enable loading with the antibiotics, cefazolin, and vancomycin, followed by induction of the phase transition in vitro. Cefazolin and vancomycin concentrations were monitored, as well as bioactivity of the released antibiotics, to test an ability of the ELP depot to provide for prolonged release of bioactive drugs. Further tests of formulation viscosity were conducted to test suitability as an injectable drug carrier. Results demonstrate sustained release of therapeutic concentrations of bioactive antibiotics by the ELP, with first-order time constants for drug release of approximately 25 h for cefazolin and approximately 500 h for vancomycin. These findings illustrate that an injectable, in situ forming ELP depot can provide for sustained release of antibiotics with an effect that varies across antibiotic formulation. ELPs have important advantages for drug delivery, as they are known to be biocompatible, biodegradable, and elicit no known immune response. These benefits suggest distinct advantages over currently used carriers for antibiotic drug delivery in orthopedic applications. (c) 2008 Wiley Periodicals, Inc.

Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design

PubMed Central

Hao, Jifu; Fang, Xinsheng; Zhou, Yanfang; Wang, Jianzhu; Guo, Fengguang; Li, Fei; Peng, Xinsheng

2011-01-01

The purpose of the present study was to optimize a solid lipid nanoparticle (SLN) of chloramphenicol by investigating the relationship between design factors and experimental data using response surface methodology. A Box-Behnken design was constructed using solid lipid (X1), surfactant (X2), and drug/lipid ratio (X3) level as independent factors. SLN was successfully prepared by a modified method of melt-emulsion ultrasonication and low temperature-solidification technique using glyceryl monostearate as the solid lipid, and poloxamer 188 as the surfactant. The dependent variables were entrapment efficiency (EE), drug loading (DL), and turbidity. Properties of SLN such as the morphology, particle size, zeta potential, EE, DL, and drug release behavior were investigated, respectively. As a result, the nanoparticle designed showed nearly spherical particles with a mean particle size of 248 nm. The polydispersity index of particle size was 0.277 ± 0.058 and zeta potential was −8.74 mV. The EE (%) and DL (%) could reach up to 83.29% ± 1.23% and 10.11% ± 2.02%, respectively. In vitro release studies showed a burst release at the initial stage followed by a prolonged release of chloramphenicol from SLN up to 48 hours. The release kinetics of the optimized formulation best fitted the Peppas–Korsmeyer model. These results indicated that the chloramphenicol-loaded SLN could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release. PMID:21556343

Paclitaxel loaded folic acid targeted nanoparticles of mixed lipid-shell and polymer-core: in vitro and in vivo evaluation.

PubMed

Zhao, Peiqi; Wang, Hanjie; Yu, Man; Liao, Zhenyu; Wang, Xianhuo; Zhang, Fei; Ji, Wei; Wu, Bing; Han, Jinghua; Zhang, Haichang; Wang, Huaqing; Chang, Jin; Niu, Ruifang

2012-06-01

A functional drug carrier comprised of folic acid modified lipid-shell and polymer-core nanoparticles (FLPNPs) including poly(D,L-lactide-co-glycolide) (PLGA) core, PEGylated octadecyl-quaternized lysine modified chitosan (PEG-OQLCS) as lipid-shell, folic acid as targeting ligand and cholesterol was prepared and evaluated for targeted delivery of paclitaxel (PTX). Confocal microscopy analysis confirmed the coating of the lipid-shell on the polymer-core. Physicochemical characterizations of FLPNPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. The internalization efficiency and targeting ability of FLPNPs were demonstrated by flow cytometry and confocal microscopy. PTX loaded FLPNPs showed a significantly higher cytotoxicity than the commercial PTX formulation (Taxol®). The intravenous administration of PTX encapsulated FLPNPs led to tumor regression and improvement of animal survival in a murine model, compared with that observed with Taxol® and biodistribution study showed that PTX concentration in tumor for PTX encapsulated FLPNPs was higher than other PTX formulations. Our data indicate that PTX loaded FLPNPs are a promising nano-sized drug formulation for cancer therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

Low molecular weight polylactic acid as a matrix for the delayed release of pesticides.

PubMed

Zhao, Jing; Wilkins, Richard M

2005-05-18

Low molecular weight polylactic acid (LMW PLA) was used as a matrix to formulate biodegradable matrix granules and films with bromacil using a melt process. The compatibility of the PLA with bromacil was evaluated. The release characteristics of the formulations were investigated in vitro. The degradation and erosion of the formulations were monitored by pH and gravimetric analysis during the course of release. Various granules and films had similar biphasic release patterns, a delayed release followed by an explosive release. The release rates were independent of bromacil content in the matrix, but varied with the geometry of matrices. The mechanisms of diffusion and erosion were involved in the release. The delayed release of the formulations was dominantly governed by the degradation and erosion of PLA. LMW PLA underwent bulk erosion. LMW PLA-based matrix formulations could thus be useful for the application of pesticides to sensitive targets such as seed treatment.

Preparation and characterization of poly(ε-caprolactone) nanospheres containing the local anesthetic lidocaine.

PubMed

Ramos Campos, Estefânia Vangelie; Silva de Melo, Nathalie Ferreira; Guilherme, Viviane Aparecida; de Paula, Eneida; Rosa, André Henrique; de Araújo, Daniele Ribeiro; Fraceto, Leonardo Fernandes

2013-01-01

The objective of this work was to develop a modified release system for the local anesthetic lidocaine (LDC), using poly(ε-caprolactone) (PCL) nanospheres (NSs), to improve the pharmacological properties of the drug when administered by the infiltration route. In vitro experiments were used to characterize the system and investigate the release mechanism. The NSs presented a polydispersion index of 0.072, an average diameter of 449.6 nm, a zeta potential of -20.1 mV, and an association efficiency of 93.3%. The release profiles showed that the release of associated LDC was slower than that of the free drug. Atomic force microscopy analyses showed that the spherical structure of the particles was preserved as a function of time, as well as after the release experiments. Cytotoxicity and pharmacological tests confirmed that association with the NSs reduced the toxicity of LDC, and prolonged its anesthetic action. This new formulation could potentially be used in applications requiring gradual anesthetic release, especially dental procedures. Copyright © 2012 Wiley Periodicals, Inc.

[Modern polymers in matrix tablets technology].

PubMed

Zimmer, Łukasz; Kasperek, Regina; Poleszak, Ewa

2014-01-01

Matrix tablets are the most popular method of oral drug administration, and polymeric materials have been used broadly in matrix formulations to modify and modulate drug release rate. The main goal of the system is to extend drug release profiles to maintain a constant in vivo plasma drug concentration and a consistent pharmacological effect. Polymeric matrix tablets offer a great potential as oral controlled drug delivery systems. Cellulose derivatives, like hydroxypropyl methylcellulose (HPMC) are often used as matrix formers. However, also other types of polymers can be used for this purpose including: Kollidon SR, acrylic acid polymers such as Eudragits and Carbopols. Nevertheless, polymers of natural origin like: carragens, chitosan and alginates widely used in the food and cosmetics industry are now coming to the fore of pharmaceutical research and are used in matrix tablets technology. Modern polymers allow to obtain matrix tablets by 3D printing, which enables to develop new formulation types. In this paper, the polymers used in matrix tablets technology and examples of their applications were described.

Enhanced intracellular delivery and controlled drug release of magnetic PLGA nanoparticles modified with transferrin.

PubMed

Cui, Yan-Na; Xu, Qing-Xing; Davoodi, Pooya; Wang, De-Ping; Wang, Chi-Hwa

2017-06-01

Owing to the presence of multidrug resistance in tumor cells, conventional chemotherapy remains clinically intractable. To enhance the therapeutic efficacy of chemotherapeutic agents, targeting strategies based on magnetic polymeric nanoparticles modified with targeting ligands have gained significant attention in cancer therapy. In this study, we synthesized transferrin (Tf)-modified poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NPs) loaded with paclitaxel (PTX) and superparamagnetic nanoparticle (MNP) using a solid-in-oil-in-water solvent evaporation method, followed by Tf adsorption on the surface of NPs. The Tf-modified magnetic PLGA NPs were characterized in terms of particle morphology and size, magnetic properties, encapsulation efficiency and drug release. Furthermore, the cytotoxicity and cellular uptake of the drug-loaded magnetic PLGA NPs were evaluated in both MCF-7 breast cancer and U-87 glioma cells in vitro. We found that Tf-modified PTX-MNP-PLGA NPs showed the highest cytotoxicity effect and cellular uptake efficiency under Tf receptor mediation in both MCF-7 and U-87 cells compared to unmodified PLGA NPs and free PTX. The cellular uptake efficiency of Tf-modified magnetic PLGA NPs appeared to be facilitated by the applied magnetic field, but the difference did not reach statistical significance. This study illustrates that this proposed formulation can be used as one new alternative treatment for patients bearing inaccessible tumors.

Enhanced intracellular delivery and controlled drug release of magnetic PLGA nanoparticles modified with transferrin

PubMed Central

Cui, Yan-na; Xu, Qing-xing; Davoodi, Pooya; Wang, De-ping; Wang, Chi-Hwa

2017-01-01

Owing to the presence of multidrug resistance in tumor cells, conventional chemotherapy remains clinically intractable. To enhance the therapeutic efficacy of chemotherapeutic agents, targeting strategies based on magnetic polymeric nanoparticles modified with targeting ligands have gained significant attention in cancer therapy. In this study, we synthesized transferrin (Tf)-modified poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NPs) loaded with paclitaxel (PTX) and superparamagnetic nanoparticle (MNP) using a solid-in-oil-in-water solvent evaporation method, followed by Tf adsorption on the surface of NPs. The Tf-modified magnetic PLGA NPs were characterized in terms of particle morphology and size, magnetic properties, encapsulation efficiency and drug release. Furthermore, the cytotoxicity and cellular uptake of the drug-loaded magnetic PLGA NPs were evaluated in both MCF-7 breast cancer and U-87 glioma cells in vitro. We found that Tf-modified PTX-MNP-PLGA NPs showed the highest cytotoxicity effect and cellular uptake efficiency under Tf receptor mediation in both MCF-7 and U-87 cells compared to unmodified PLGA NPs and free PTX. The cellular uptake efficiency of Tf-modified magnetic PLGA NPs appeared to be facilitated by the applied magnetic field, but the difference did not reach statistical significance. This study illustrates that this proposed formulation can be used as one new alternative treatment for patients bearing inaccessible tumors. PMID:28552909

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

PubMed

Hiremath, Praveen S; Saha, Ranendra N

2008-01-01

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

Clinical Acceptability Of Trimetazidine Modified-Release 80 mg Once Daily Versus Trimetazidine Modified-Release 35 mg Twice Daily In Stable Angina Pectoris.

PubMed

Pozdnyakov, Yuri M

2018-06-01

Trimetazidine (TMZ) is an anti-ischemic metabolic agent that has been shown to be efficacious in angina treatment, both in monotherapy and in combination. A new formulation of TMZ modified-release (MR) 80 mg was developed, which is to be taken once daily (od), instead of twice daily (bid) for the currently available TMZ MR 35 mg, with the aim of simplifying the medication regimen. The present study was an international, multicenter, randomized, double-blind, parallel-group phase III study with a 12-week treatment period. The safety of TMZ MR 80 mg once daily was assessed compared to TMZ MR 35 mg twice daily, in patients previously treated successfully by the latter. Emergent adverse events (EAEs), biological parameters, vital signs, 12-lead resting ECG (electrocardiogram) and Canadian Cardiovascular Society (CCS) classification were recorded. One-hundred and sixty-five patients previously diagnosed with stable angina pectoris on treatment were randomized to receive either TMZ MR 80 mg od or TMZ MR 35 mg bid. In the TMZ MR 80 mg group, fewer patients had ≥ 1 EAE (17.1 vs. 22.9% in the TMZ MR 35 mg group). Serious EAEs were reported by three patients in each group. No EAE required dose modification, withdrawal, or temporary interruption of study treatments. Vital signs, 12-lead ECG, and laboratory parameters did not change. No worsening in CCS classes was observed with either treatment. TMZ MR 80 mg od and TMZ MR 35 mg bid have similar safety profiles. This new once-daily formulation could improve patient compliance with therapy, thereby enhancing clinical benefit. ISRCTN registry, ISRCTN 84362208. Institut de Recherches Internationales Servier and Servier, Moscow, Russian Federation. Plain language summary available for this article.

Non-steroidal anti-inflammatory drugs and gastroprotection with proton pump inhibitors: a focus on ketoprofen/omeprazole.

PubMed

Gigante, Antonio; Tagarro, Ignacio

2012-04-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed agents for rheumatic disorders such as osteoarthritis (OA), rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Despite the known association between NSAID use and gastropathy, however, only around one-third of patients at risk of NSAID-induced gastrointestinal toxicity receive adequate gastroprotection, and as many as 44% of these patients are non-adherent. We review the co-prescription of proton pump inhibitors (PPIs) for the prevention of NSAID-induced gastropathy, with a particular focus on the first fixed-dose NSAID/PPI formulation: ketoprofen/omeprazole modified-release capsules. The ketoprofen/omeprazole fixed-dose combination is available in doses of 100 mg/20 mg, 150 mg/20 mg or 200 mg/20 mg as a single capsule for once-daily administration. Ketoprofen monotherapy has been shown to be generally equivalent to other NSAIDs when used in the treatment of OA. In RA, ketoprofen has demonstrated equivalent efficacy to diclofenac, indometacin, piroxicam, aceclofenac, phenylbutazone, naproxen and flurbiprofen. Studies comparing ketoprofen with ibuprofen and sulindac in patients with RA have, in general, favoured ketoprofen. Studies in AS have generally reported similar efficacy between ketoprofen and phenylbutazone and pirprofen. Prophylaxis with omeprazole is effective for the prevention of gastroduodenal ulcers, maintenance of remission and alleviation of dyspeptic symptoms in NSAID recipients. Omeprazole is well tolerated, and adverse events are generally gastrointestinal in nature. The fixed-dose combination of ketoprofen and omeprazole has demonstrated bioequivalence to the respective monotherapies. The incidence of digestive symptoms and the need for dose reduction was reported to be lower with the combination than with its components. Ketoprofen/omeprazole modified-release capsules are the first fixed-dose NSAID/PPI formulation to be approved. This formulation ensures compliance with the gastroprotective prophylaxis, as whenever the NSAID is taken, the PPI is co-administered. Additionally, the once-daily formulation has the potential to improve adherence to anti-inflammatory therapy. © 2012 Adis Data Information BV. All rights reserved.

Proposal for defining the relevance of drug accumulation derived from single dose study data for modified release dosage forms

PubMed Central

Scheerans, Christian; Heinig, Roland; Mueck, Wolfgang

2015-01-01

Recently, the European Medicines Agency (EMA) published the new draft guideline on the pharmacokinetic and clinical evaluation of modified release (MR) formulations. The draft guideline contains the new requirement of performing multiple dose (MD) bioequivalence studies, in the case when the MR formulation is expected to show ‘relevant’ drug accumulation at steady state (SS). This new requirement reveals three fundamental issues, which are discussed in the current work: first, measurement for the extent of drug accumulation (MEDA) predicted from single dose (SD) study data; second, its relationship with the percentage residual area under the plasma concentration–time curve (AUC) outside the dosing interval (τ) after SD administration, %AUC(τ-∞)SD; and third, the rationale for a threshold of %AUC(τ-∞)SD that predicts ‘relevant’ drug accumulation at SS. This work revealed that the accumulation ratio RA,AUC, derived from the ratio of the time-averaged plasma concentrations during τ at SS and after SD administration, respectively, is the ‘preferred’ MEDA for MR formulations. A causal relationship was derived between %AUC(τ-∞)SD and RA,AUC, which is valid for any drug (product) that shows (dose- and time-) linear pharmacokinetics regardless of the shape of the plasma concentration–time curve. Considering AUC thresholds from other guidelines together with the causal relationship between %AUC(τ-∞)SD and RA,AUC indicates that values of %AUC(τ-∞)SD ≤ 20%, resulting in RA,AUC ≤ 1.25, can be considered as leading to non-relevant drug accumulation. Hence, the authors suggest that 20% for %AUC(τ-∞)SD is a reasonable threshold and selection criterion between SD or MD study designs for bioequivalence studies of new MR formulations. © 2014 The Authors Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd. PMID:25327367

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.

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

PubMed

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

2012-04-01

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

Minocycline encapsulated chitosan nanoparticles for central antinociceptive activity.

PubMed

Nagpal, Kalpana; Singh, S K; Mishra, D N

2015-01-01

The purpose of the study is to explore the central anti-nociceptive activity of brain targeted nanoparticles (NP) of minocycline hydrochloride (MH). The NP were formulated using the modified ionotropic gelation method (MHNP) and were coated with Tween 80 (T80) to target them to brain (cMHNP). The formulated nanoparticles have already been characterized for particle size, zeta potential, drug entrapment efficiency and in vitro drug release. The nanoparticles were then evaluated for pharmacodynamic activity using thermal methods. The pure drug and the formulation, MHNP were not able to show a statistically significant central analgesic activity. cMHNP on the other hand evidenced a significant central analgesic activity. Animal models evidenced that brain targeted nanoparticles may be utilized for effective delivery of central anti-nociceptive effect of MH. Further clinical studies are required to explore the activity for mankind. Copyright © 2014 Elsevier B.V. All rights reserved.

Proposing the Use of Partial AUC as an Adjunctive Measure in Establishing Bioequivalence Between Deltoid and Gluteal Administration of Long-Acting Injectable Antipsychotics.

PubMed

Lee, Lik Hang N; Choi, Charles; Gershkovich, Pavel; Barr, Alasdair M; Honer, William G; Procyshyn, Ric M

2016-12-01

The maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC) are commonly used to establish bioequivalence between two formulations of the same oral medication. Similarly, these pharmacokinetic parameters have also been used to establish bioequivalence between two sites of administration for the same injectable formulation. However, these conventional methods of establishing bioequivalence are of limited use when comparing modified-release formulations of a drug, particularly those with rates of absorption that are amenable to change with the site of injection. Inherent differences in the rate of absorption can result in clinically significant differences in early exposure and drug response. Here, we propose the use of the partial AUC (pAUC) as a measure of early exposure to aid in the assessment of bioequivalence between the gluteal and the deltoid site of administration for long-acting injectable antipsychotics.

L-Cysteine conjugated poly L-lactide nanoparticles containing 5-fluorouracil: formulation, characterization, release and uptake by tissues in vivo.

PubMed

Mishra, Brijeshkunvar J; Kaul, Ankur; Trivedi, Piyush

2015-02-01

Targeted delivery of drugs is still a therapeutic challenge and numerous methods have been reported for the same. In this study, emphasis was placed on developing nanoparticles loaded with 5-fluorouracil (FU) and modifying the surface of the nanoparticles by conjugation with amino acid, to improve the distribution of 5-FU in the lungs. An emulsion solvent evaporation technique was used to formulate nanoparticles of FU using Poly L-lactide and Pluronic F-68. The nanoparticles were conjugated with L-Cysteine using EDC as the activator of COOH group and were evaluated for product yield, particle size, surface morphology, amount of conjugation by Ellman's method and in vitro drug release study. The results indicated 60-65% yield with an average particle size of 242.7 ± 37.11 nm for the cysteine conjugated nanoparticle (CNP) formulation and more than 70% conjugation of cysteine. The cumulative percentage of drug released over a period of 24 h was found to be 58%. An increase in distribution of the delivery system in lungs (11.4% ID after 1 h) in mice was found indicating the role of L-Cysteine in the transport mechanism to the lungs. In vivo kinetic studies in rats revealed higher circulation time of CNP as compared to pure FU solution. The study helps in designing a colloidal delivery system for increased distribution of drugs to the lungs and may be helpful in delivery of drugs in conditions like non-small cell lung carcinomas.

PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery.

PubMed

Chan, Juliana M; Zhang, Liangfang; Yuet, Kai P; Liao, Grace; Rhee, June-Wha; Langer, Robert; Farokhzad, Omid C

2009-03-01

Current approaches to encapsulate and deliver therapeutic compounds have focused on developing liposomal and biodegradable polymeric nanoparticles (NPs), resulting in clinically approved therapeutics such as Doxil/Caelyx and Genexol-PM, respectively. Our group recently reported the development of biodegradable core-shell NP systems that combined the beneficial properties of liposomal and polymeric NPs for controlled drug delivery. Herein we report the parameters that alter the biological and physicochemical characteristics, stability, drug release properties and cytotoxicity of these core-shell NPs. We further define scalable processes for the formulation of these NPs in a reproducible manner. These core-shell NPs consist of (i) a poly(D,L-lactide-co-glycolide) hydrophobic core, (ii) a soybean lecithin monolayer, and (iii) a poly(ethylene glycol) shell, and were synthesized by a modified nanoprecipitation method combined with self-assembly. Preparation of the NPs showed that various formulation parameters such as the lipid/polymer mass ratio and lipid/lipid-PEG molar ratio controlled NP physical stability and size. We encapsulated a model chemotherapy drug, docetaxel, in the NPs and showed that the amount of lipid coverage affected its drug release kinetics. Next, we demonstrated a potentially scalable process for the formulation, purification, and storage of NPs. Finally, we tested the cytotoxicity using MTT assays on two model human cell lines, HeLa and HepG2, and demonstrated the biocompatibility of these particles in vitro. Our data suggest that the PLGA-lecithin-PEG core-shell NPs may be a useful new controlled release drug delivery system.

Investigation of drug loading and in vitro release mechanisms of insulin-lauryl sulfate complex loaded PLGA nanoparticles.

PubMed

Shi, K; Cui, F; Yamamoto, H; Kawashima, Y

2008-12-01

Insulin, a water soluble peptide hormone, was hydrophobically ion-paired with sodium lauryl sulfate (SDS) at the stoichiometric molar ratio of 6:1. The obtained insulin-SDS complex precipitation was subsequently formulated in biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles by a modified spontaneous emulsion solvent diffusion method. Compared with a conventional method for free insulin encapsulation, direct dissolution of SDS-paired insulin in the non-aqueous organic phase led to an increase in drug recovery from 42.5% to 89.6%. The more hydrophobic complex contributes to the improved affinity of insulin to the polymer matrix, resulting in a higher drug content in the nanoparticles. The drug loading was investigated by determining initial burst release at the first 30 min. The results showed that 64.8% of recovered drug were preferentially surface bound on complex loaded nanoparticles. The in vitro drug release was characterized by an initial burst and subsequent delayed release in dissolution media of deionized water and phosphate buffer saline (PBS). Compared with that in PBS, nanoparticles in deionized water medium presented very low initial burst release (15% vs. 65%) and incomplete cumulative release (25% vs. 90%) of the drug. In addition, dialysis experiments were performed to clarify the form of the released insulin in the dissolution media. The results suggested that the ion-pair complex was sensitive to ionic strength, insulin was released from the particular matrix as complex form and subsequently suffered dissociation from SDS in buffer saline. Moreover, the in vivo bioactivity of the SDS-paired insulin and nanoparticulate formulations were evaluated in mice by estimation of their blood sugar levels. The results showed that the bioactivity of insulin was unaltered after the ion-pairing process.

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.

Controlled-release tablet formulation of isoniazid.

PubMed

Jain, N K; Kulkarni, K; Talwar, N

1992-04-01

Guar (GG) and Karaya gums (KG) alone and in combination with hydroxy-propylmethylcellulose (HPMC) were evaluated as release retarding materials to formulate a controlled-release tablet dosage form of isoniazid (1). In vitro release of 1 from tablets followed non-Fickian release profile with rapid initial release. Urinary excretion studies in normal subjects showed steady-state levels of 1 for 13 h. In vitro and in vivo data correlated (r = 0.9794). The studies suggested the potentiality of GG and KG as release retarding materials in formulating controlled-release tablet dosage forms of 1.

Can lipid nanoparticles improve intestinal absorption?

PubMed

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

2016-12-30

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

3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release.

PubMed

Kyobula, Mary; Adedeji, Aremu; Alexander, Morgan R; Saleh, Ehab; Wildman, Ricky; Ashcroft, Ian; Gellert, Paul R; Roberts, Clive J

2017-09-10

A hot melt 3D inkjet printing method with the potential to manufacture formulations in complex and adaptable geometries for the controlled loading and release of medicines is presented. This first use of a precisely controlled solvent free inkjet printing to produce drug loaded solid dosage forms is demonstrated using a naturally derived FDA approved material (beeswax) as the drug carrier and fenofibrate as the drug. Tablets with bespoke geometries (honeycomb architecture) were fabricated. The honeycomb architecture was modified by control of the honeycomb cell size, and hence surface area to enable control of drug release profiles without the need to alter the formulation. Analysis of the formed tablets showed the drug to be evenly distributed within the beeswax at the bulk scale with evidence of some localization at the micron scale. An analytical model utilizing a Fickian description of diffusion was developed to allow the prediction of drug release. A comparison of experimental and predicted drug release data revealed that in addition to surface area, other factors such as the cell diameter in the case of the honeycomb geometry and material wettability must be considered in practical dosage form design. This information when combined with the range of achievable geometries could allow the bespoke production of optimized personalised medicines for a variety of delivery vehicles in addition to tablets, such as medical devices for example. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Controlled Release of Imidacloprid from Poly Styrene-Diacetone - Nanoformulation

NASA Astrophysics Data System (ADS)

Qian, Kun; Guo, Yanzhen; He, Lin

2012-01-01

Imidacloprid is a neonicotinoids insecticide, which is important for the cash crops such as tomato, rape and so on. The conventional formulation does not only increase the loss of pesticide but also leads to environmental pollution. Controlled-release formulations of pesticide are highly desirable not only for attaining the most effective utilization of the pesticide, but also for reducing environmental pollution. Pesticide imidacloprid was incorporated in poly (styrene-diacetone crylamide)-based formulation to obtain controlled release properties, and the imidacloprid nanocontrolled release formulation was characterized by infrared (IR) and field emission scanning electron microscope (FESEM). Factors related to loading efficiency, swelling and release behaviors of the formulation were investigated. It showed that the loading efficiency could reach about 40% (w/w). The values for the diffusion exponent "n" were in the range of 0.31-0.58, which indicated that the release of imidacloprid was diffusion-controlled. The time taken for 50% of the active ingredient to be released into water, T50, was also calculated for the comparison of formulations in different conditions. The results showed that the formulation with higher temperature and more diacetone crylamide had lower value of T50, which means a quicker release of the active ingredient. This study highlighted some pieces of evidence that improved pesticide incorporation and slower release were linked to potential interactions between the pesticide and the polymer.

Preparation and characterization of dutasteride-loaded nanostructured lipid carriers coated with stearic acid-chitosan oligomer for topical delivery.

PubMed

Noor, Norhayati Mohamed; Sheikh, Khalid; Somavarapu, Satyanarayana; Taylor, Kevin M G

2017-08-01

Dutasteride, used for treating benign prostate hyperplasia (BPH), promotes hair growth. To enhance delivery to the hair follicles and reduce systemic effects, in this study dutasteride has been formulated for topical application, in a nanostructured lipid carrier (NLC) coated with chitosan oligomer-stearic acid (CSO-SA). CSO-SA has been successfully synthesized, as confirmed using 1 H NMR and FTIR. Formulation of dutasteride-loaded nanostructured lipid carriers (DST-NLCs) was optimized using a 2 3 full factorial design. This formulation was coated with different concentrations of stearic acid-chitosan solution. Coating DST-NLCs with 5% SA-CSO increased mean size from 187.6±7.0nm to 220.1±11.9nm, and modified surface charge, with zeta potentials being -18.3±0.9mV and +25.8±1.1mV for uncoated and coated DST-NLCs respectively. Transmission electron microscopy showed all formulations comprised approximately spherical particles. DST-NLCs, coated and uncoated with CSO-SA, exhibited particle size stability over 60days, when stored at 4-8°C. However, NLCs coated with CSO (without conjugation) showed aggregation when stored at 4-8°C after 30days. The measured particle size for all formulations stored at 25°C suggested aggregation, which was greatest for DST-NLCs coated with 10% CSO-SA and 5% CSO. All nanoparticle formulations exhibited rapid release in an in vitro release study, with uncoated NLCs exhibiting the fastest release rate. Using a Franz diffusion cell, no dutasteride permeated through pig ear skin after 48h, such that it was not detected in the receptor chamber for all samples. The amount of dutasteride in the skin was significantly different (p<0.05) for DST-NLCs (6.09±1.09μg/cm 2 ) without coating and those coated with 5% CSO-SA (2.82±0.40μg/cm 2 ), 10% CSO-SA (2.70±0.35μg/cm 2 ) and CSO (2.11±0.64μg/cm 2) . There was a significant difference (p<0.05) in the cytotoxicity (IC 50 ) between dutasteride alone and in the nanoparticles. DST-NLCs coated and uncoated with CSO-SA increased the maximum non-toxic concentration by 20-fold compared to dutasteride alone. These studies indicate that a stearic acid-chitosan conjugate was successfully prepared, and modified the surface charge of DST-NLCs from negative to positive. These stable, less cytotoxic, positively-charged dutasteride-loaded nanostructured lipid carriers, with stearic acid-chitosan oligomer conjugate, are appropriate for topical delivery and have potential for promotion of hair growth. Copyright © 2017. Published by Elsevier B.V.

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.

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.

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

Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing.

PubMed

Goyanes, Alvaro; Fina, Fabrizio; Martorana, Annalisa; Sedough, Daniel; Gaisford, Simon; Basit, Abdul W

2017-07-15

The aim of this study was to manufacture 3D printed tablets (printlets) from enteric polymers by single filament fused deposition modeling (FDM) 3D printing (3DP). Hot melt extrusion was used to generate paracetamol-loaded filaments from three different grades of the pharmaceutical excipient hypromellose acetate succinate (HPMCAS), grades LG, MG and HG. One-step 3DP was used to process these filaments into enteric printlets incorporating up to 50% drug loading with two different infill percentages (20 and 100%). X-ray Micro Computed Tomography (Micro-CT) analysis revealed that printlets with 20% infill had cavities in the core compared to 100% infill, and that the density of the 50% drug loading printlets was higher than the equivalent formulations loaded with 5% drug. In biorelevant bicarbonate dissolution media, drug release from the printlets was dependent on the polymer composition, drug loading and the internal structure of the formulations. All HPMCAS-based printlets showed delayed drug release properties, and in the intestinal conditions, drug release was faster from the printlets prepared with polymers with a lower pH-threshold: HPMCAS LG > HPMCAS MG > HPMCAS HG. These results confirm that FDM 3D printing makes it possible not only to manufacture delayed release printlets without the need for an outer enteric coating, but it is also feasible to adapt the release profile in response to the personal characteristics of the patient, realizing the full potential of additive manufacturing in the development of personalised dose medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

Mini-tablets versus pellets as promising multiparticulate modified release delivery systems for highly soluble drugs.

PubMed

Gaber, Dina M; Nafee, Noha; Abdallah, Osama Y

2015-07-05

Whether mini-tablets (tablets, diameters ≤6mm) belong to single- or multiple-unit dosage forms is still questionable. Accordingly, Pharmacopoeial evaluation procedures for mini-tablets are lacking. In this study, the aforementioned points were discussed. Moreover, their potential for oral controlled delivery was assessed. The antidepressant venlafaxine hydrochloride (Vx), a highly soluble drug undergoing first pass effect, low bioavailability and short half-life was selected as a challenging payload. In an attempt to weigh up mini-tablets versus pellets as multiparticulate carriers, Vx-loaded mini-tablets were compared to formulated pellets of the same composition and the innovator Effexor(®)XR pellets. Formulations were prepared using various polymer hydrogels in the core and ethyl cellulose film coating with increasing thickness. Mini-tablets (diameter 2mm) showed extended Vx release (<60%, 8h). Indeed, release profiles comparable to Effexor(®)XR pellets were obtained. Remarkably higher coating thickness was required for pellets to provide equivalent retardation. Ethyl cellulose in the core ensured faster release due to polymer migration to the surface and pore formation in the coat. mini-tablets showed higher stability to pellets upon storage. Industrially speaking, mini-tablets proved to be superior to pellets in terms of manufacturing, product quality and economical aspects. Results point out the urgent need for standardized evaluation procedures for mini-tablets. Copyright © 2015. Published by Elsevier B.V.

Enhanced bone formation in the vicinity of porous β-TCP scaffolds exhibiting slow release of collagen-derived tripeptides.

PubMed

Kamikura, Keita; Minatoya, Tsutomu; Terada-Nakaishi, Michiko; Yamamoto, Shoko; Sakai, Yasuo; Furusawa, Toshitake; Matsushima, Yuta; Unuma, Hidero

2017-09-01

It has been experimentally proven that orally ingested collagen-derived tripeptides (Ctp) are quickly absorbed in the body and effectively promote the regeneration of connective tissues including bone and skin. Ctp are capable to activate osteoblasts and fibroblasts, which eventually promotes tissue regeneration. Based on these findings, a hypothesis was formulated in this study that direct delivery of Ctp to bone defect would also facilitate tissue regeneration as well as oral administration. To test the hypothesis, we prepared a bone augmentation material with the ability to slowly release Ctp, and investigated its in vivo bone regeneration efficacy. The implant material was porous β-tricalcium phosphate (β-TCP) scaffold which was coated with a co-precipitated layer of bone-like hydroxyapatite and Ctp. The β-TCP was impregnated with approximately 0.8%(w/w) Ctp. Then, the Ctp-modified β-TCP was implanted into bone defects of Wistar rats to evaluate in vivo efficacy of Ctp directly delivered from the material to the bone defects. The control was pristine porous β-TCP. In vitro tests showed that Ctp were steadily released from the co-precipitated layer for approximately two weeks. The Ctp-modified scaffolds significantly promoted new bone formation in vivo in their vicinity as compared with pristine β-TCP scaffolds; 6 weeks after the implantation, Ctp-modified scaffolds promoted twice as much bone formation as the control implants. Consequently, we achieved the slow and steady release of Ctp, and found that direct delivery of Ctp from implant materials was effective for bone regeneration as well as oral administration. A β-TCP scaffold capable of slowly releasing bone-enhancing substances significantly promoted bone formation.

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.

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.

Characterization of modified allergen extracts by in vitro beta-hexosaminidase release from rat basophils.

PubMed

Gehlhar, Kirsten; Peters, Marcus; Brockmann, Kirsten; van Schijndel, Hans; Bufe, Albrecht

2005-04-01

To date, there is no well-established test available that can be used to measure functional properties of modified allergens (allergoids). Due to the cross-linking process, the IgE-binding capacity of the allergens, normally necessary for their characterization, is lost. The aim of this study was to test whether the rat basophilic leukaemia (RBL) cell assay (beta-hexosaminidase release by rat basophils upon allergen stimulation) can be adopted to characterize allergoids and to evaluate the assay for testing allergoids and native allergens as well. Mice were immunized with native and modified Phleumpratense extracts in the presence of alum. Their sera were used to sensitize RBL-2H3 cells and measure basophil stimulation induced by different allergen extracts in the presence or absence of various additives. Sera containing specific IgE against both extract formulations were obtained. Native as well as modified extracts induced dose-dependent beta-hexosaminidase release from RBL cells. Both extracts were used to evaluate the characteristics of the assay, which showed high precision. Storage conditions were chosen to enhance extract degradation, which could be read directly from the altered stimulatory capacity of the extracts. Additives turned out to have diverse effects on the assay, whereas phenol had no measurable effect, alum had an inhibitory effect and glycerol elevated basophil activation. For the first time, a reliable, precise in vitro assay is available that is able to directly measure the properties of modified allergen extracts after their production process. The test is well evaluated and its advantages and limitations are discussed in this report. Copyright (c) 2005 S. Karger AG, Basel

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.

Effect of food on early drug exposure from extended-release stimulants: results from the Concerta, Adderall XR Food Evaluation (CAFE) Study.

PubMed

Auiler, J F; Liu, K; Lynch, J M; Gelotte, C K

2002-01-01

Stimulant therapy is the mainstay of treatment for children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). Once-daily, extended-release oral formulations offer long acting control of symptoms by modifying drug delivery and absorption. In particular, consistency in early drug exposure is important for symptom control during school or work hours. Because these once-daily formulations are usually taken in the morning, the timing of the doses with breakfast is important. This study compared the effect of a high-fat breakfast on early drug exposure from a morning dose of two extended-release stimulant formulations: the osmotic-controlled OROS tablet of methylphenidate HCI (CONCERTA) and the capsule containing extended-release beads of mixed amphetamine salts (ADDERALL XR). The study had a single-dose, open-label, randomised, four-treatment, crossover design in which healthy subjects received either 36 mg CONCERTA or 20 mg ADDERALL XR in the morning after an overnight fast or a high-fat breakfast. Serial blood samples were collected over 28h to determine plasma concentrations of methylphenidate and amphetamine. The food effect on early drug exposure and the pharmacokinetic profiles up to 8 h after dosing of the two extended-release stimulants were directly compared using partial area (AUC(p4h), AUC(p6h) and AUC(p8h)) fed/fasted ratios. Amphetamine concentrations were markedly lower when the subjects had eaten breakfast, resulting in lower early drug exposures (p < 0.0001). By contrast, methylphenidate concentrations over the same 8 h were unaffected by breakfast, providing consistent levels of early drug exposure. Therefore, as a child's or adult's eating pattern varies, methylphenidate exposure over the first 8 h would be expected to have less day-to-day variation compared with amphetamine exposure. The osmotic-controlled OROS tablet provides a reliable and consistent delivery of methylphenidate HCI, independent of food, for patients with ADHD.

European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy.

PubMed

Ekman, Bertil; Fitts, David; Marelli, Claudio; Murray, Robert D; Quinkler, Marcus; Zelissen, Pierre M J

2014-05-09

Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93-140/million), secondary AI (estimated prevalence, 150-280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387). Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy. Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands. EU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.

Formulation and characterization of a compacted multiparticulate system for modified release of water-soluble drugs--part 1--acetaminophen.

PubMed

Cantor, Stuart L; Hoag, Stephen W; Augsburger, Larry L

2009-03-01

The aim of this study was to characterize and evaluate a modified release, multiparticulate tablet formulation consisting of placebo beads and drug-loaded beads. Acetaminophen (APAP) bead formulations containing ethylcellulose (EC) from 40-60% and placebo beads containing 30% calcium silicate and prepared using 0-20% alcohol were developed using extrusion-spheronization and studied using a central composite experimental design. Particle size and true density of beads were measured. Segregation testing was performed using the novel ASTM D6940-04 method on a 50:50 blend of uncoated APAP beads (60%EC) : calcium silicate placebo beads (10% alcohol). Tablets were prepared using an instrumented Stokes-B2 rotary tablet press and evaluated for crushing strength and dissolution rate. Compared with drug beads (60%EC), placebo beads (10% alcohol) were smaller but had higher true densities: 864.8 mum and 1.27 g/cm(3), and 787.1 mum and 1.73 g/cm(3), respectively. Segregation testing revealed that there was approximately a 20% difference in drug content (as measured by the coefficient of variation) between initial and final blend samples. Although calcium silicate-based placebo beads were shown to be ineffective cushioning agents in blends with Surelease(R)-coated APAP beads, they were found to be very compactibile when used alone and gave tablet crushing strength values between 14 and 17 kP. The EC in the APAP bead matrix minimally suppressed the drug release from uncoated beads (t(100%) = 2 h). However, while tablets containing placebo beads reformulated with glycerol monostearate (GMS) showed a slower release rate (t(60%)= 5 h) compared with calcium silicate-based placebos, some coating damage ( approximately 30%) still occurred on compression as release was faster than coated APAP beads alone. While tablets containing coated drug beads can be produced with practical crushing strengths (>8 kP) and low compression pressures (10-35 MPa), dissolution studies revealed that calcium silicate-based placebos are ineffective as cushioning agents. Blend segregation was likely observed due to the particle size and the density differences between APAP beads and calcium silicate-based placebo beads; placebo bead percolation can perhaps be minimized by increasing their size during the extrusion-spheronization process. The GMS- based placebos offer greater promise as cushioning agents for compacted, coated drug beads; however, this requires an optimized compression pressure range and drug bead : placebo bead ratio (i.e., 50:50).

Novel system for reducing leaching of the herbicide metribuzin using clay-gel-based formulations.

PubMed

Maqueda, Celia; Villaverde, Jaime; Sopeña, Fátima; Undabeytia, Tomás; Morillo, Esmeralda

2008-12-24

Metribuzin is an herbicide widely used for weed control that has been identified as a groundwater pollutant. It contaminates the environment even when it is used according to the manufacturer's instructions. To reduce herbicide leaching and increase weed control, new controlled release formulations were developed by entrapping metribuzin within a sepiolite-gel-based matrix using two clay/herbicide proportions (0.5/0.2 and 1/0.2) (loaded at 28.6 and 16.7% a.i.) as a gel (G28, G16) or as a powder after freeze-drying (LF28, LF16). The release of metribuzin from the control released formulations into water was retarded, when compared with commercial formulation (CF) except in the case of G28. The mobility of metribuzin from control released formulations into soil columns of sandy soil was greatly diminished in comparison with CF. Most of the metribuzin applied as control released formulations (G16, LF28 and LF16) was found at a depth of 0-8 cm depth. In contrast, residues from CF and G28 along the column were almost negligible. Bioassays from these control released formulations showed high efficacy at 0-12 cm depth. The use of these novel formulations could minimize the risk of groundwater contamination while maintaining weed control for a longer period.

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

PubMed

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

2016-10-01

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

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.

Synthesis and characterization of emamectin-benzoate slow-release microspheres with different surfactants.

PubMed

Wang, Yan; Wang, Anqi; Wang, Chunxin; Cui, Bo; Sun, Changjiao; Zhao, Xiang; Zeng, Zhanghua; Shen, Yue; Gao, Fei; Liu, Guoqiang; Cui, Haixin

2017-10-06

Pesticide slow-release formulations provide a way to increase the efficiency of active components by reducing the amount of pesticide that needs to be applied. Slow-release formulations also increase the stability and prolong the control effect of photosensitive pesticides. Surfactants are an indispensable part of pesticide formulations, and the choice of surfactant can strongly affect formulation performance. In this study, emamectin-benzoate (EMB) slow-release microspheres were prepared by the microemulsion polymerization method. We explored the effect of different surfactants on the particle size and dispersity of EMB in slow-release microspheres. The results indicated that the samples had uniform spherical shapes with an average diameter of 320.5 ±5.24 nm and good dispersity in the optimal formulation with the polymeric stabilizer polyvinyl alcohol (PVA) and composite non-ionic surfactant polyoxyethylene castor oil (EL-40). The optimal EMB pesticide slow-release microspheres had excellent anti-photolysis performance, stability, controlled release properties, and good leaf distribution. These results demonstrated that EMB slow-release microspheres are an attractive candidate for improving pesticide efficacy and prolonging the control effect of EMB in the environment.

Cyclodextrin based nanosponges for pharmaceutical use: a review.

PubMed

Tejashri, Gursalkar; Amrita, Bajaj; Darshana, Jain

2013-09-01

Nanosponges are a novel class of hyper-crosslinked polymer based colloidal structures consisting of solid nanoparticles with colloidal sizes and nanosized cavities. These nano-sized colloidal carriers have been recently developed and proposed for drug delivery, since their use can solubilize poorly water-soluble drugs and provide prolonged release as well as improve a drug's bioavailability by modifying the pharmacokinetic parameters of actives. Development of nanosponges as drug delivery systems, with special reference to cyclodextrin based nanosponges, is presented in this article. In the current review, attempts have been made to illustrate the features of cyclodextrin based nanosponges and their applications in pharmaceutical formulations. Special emphasis has been placed on discussing the methods of preparation, characterization techniques and applications of these novel drug delivery carriers for therapeutic purposes. Nanosponges can be referred to as solid porous particles having a capacity to load drugs and other actives into their nanocavity; they can be formulated as oral, parenteral, topical or inhalation dosage forms. Nanosponges offer high drug loading compared to other nanocarriers and are thus suitable for solving issues related to stability, solubility and delayed release of actives. Controlled release of the loaded actives and solubility enhancement of poorly water-soluble drugs are major advantages of nanosponge drug delivery systems.

Dissolution of Commercially Available Mesalamine Formulations at Various pH Levels.

PubMed

Tenjarla, Srini

2015-06-01

Mesalamine (5-aminosalicylic acid; 5-ASA) is recommended first-line therapy for mild-to-moderate ulcerative colitis. Many mesalamine formulations employ a pH-dependent release mechanism designed to maximize drug release in the colon. This study compared the in vitro release of 5-ASA from six commercially available mesalamine formulations at pH levels similar to those typically encountered in the human gastrointestinal tract. The release of 5-ASA from six mesalamine formulations [Mesalazin-Kohlpharma (Kohlpharma, Germany), Mesalazin-Eurim (Eurimpharm, Germany), Mesalazina-Faes (Faes Farma, Spain), Mesalazine EC (Actavis B.V., Netherlands), Mesalazine EC 500 PCH (Pharmachemie B.V., Netherlands); multimatrix mesalamine (Shire US Inc., USA)] was monitored separately at three different pH levels [1.0 (2 h), 6.4 (1 h), and 7.2 (8 h)] using United States Pharmacopeia dissolution apparatus II. The dissolution percentage was calculated as a mean of 12 units for each formulation. At pH 1.0 and 6.4, <1 % of 5-ASA release was observed for each of the mesalamine formulations tested. At pH 7.2, complete release of 5-ASA occurred within 1 h for Mesalazine EC and Mesalazine EC 500 PCH, and within 2 h for Mesalazin-Kohlpharma, Mesalazin-Eurim, and Mesalazina-Faes; complete release of 5-ASA from multimatrix mesalamine occurred within 7 h. Little variability in rate of 5-ASA dissolution was observed between tablets of each formulation. At pH 7.2, 5-ASA release profiles were variable among the commercially available mesalamine formulations that were tested.

Development of controlled release formulations of azadirachtin-A employing poly(ethylene glycol) based amphiphilic copolymers.

PubMed

Kumar, Jitendra; Shakil, Najam A; Singh, Manish K; Singh, Mukesh K; Pandey, Alka; Pandey, Ravi P

2010-05-01

Controlled release (CR) formulations of azadirachtin-A, a bioactive constituent derived from the seed of Azadirachta indica A. Juss (Meliaceae), have been prepared using commercially available polyvinyl chloride, polyethylene glycol (PEG) and laboratory synthesized poly ethylene glycol-based amphiphilic copolymers. Copolymers of polyethylene glycol and various dimethyl esters, which self assemble into nano micellar aggregates in aqueous media, have been synthesized. The kinetics of azadirachtin-A, release in water from the different formulations was studied. Release from the commercial polyethylene glycol (PEG) formulation was faster than the other CR formulations. The rate of release of encapsulated azadirachtin-A from nano micellar aggregates is reduced by increasing the molecular weight of PEG. The diffusion exponent (n value) of azadirachtin-A, in water ranged from 0.47 to 1.18 in the tested formulations. The release was diffusion controlled with a half release time (t(1/2)) of 3.05 to 42.80 days in water from different matrices. The results suggest that depending upon the polymer matrix used, the application rate of azadirachtin-A can be optimized to achieve insect control at the desired level and period.

Current Strategies in the Modification of PLGA-based Gene Delivery System.

PubMed

Ramezani, Mohammad; Ebrahimian, Mahboubeh; Hashemi, Maryam

2017-01-01

Successful gene therapy has been limited by safe and efficient delivery of nucleic acid to the target cells. Poly (d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) are able to deliver drugs and genes efficiently. This formulation has several advantages in comparison with other formulations including improvement in solubility, stability, controlling of degradation and release of the entrapped agents. For application of PLGA as a gene carrier, there exist many challenges. PLGA NPs could protect the encapsulated DNA from in vivo degradation but the DNA release is slow and the negative charge acts as a barrier to DNA incorporation and delivery. Also, during the preparation process, DNA could be exposed to high shear stress and organic solvents which could result in its inactivation. Moreover, PLGA NPs could be modified with different agents to reduce cytotoxicity, to enhance delivery efficiency and to target specific tissues/cells. This review summarizes different methods used for the preparation of PLGA NPs as gene carriers and recent strategies for the modification of PLGA particles applied in gene therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

PubMed

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

2017-01-01

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

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

PubMed Central

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

2017-01-01

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

Development of Intra-knee Joint Sustained-Release Gel Formulation and Evaluation of Its Pharmacological Efficiency in Rats.

PubMed

Noda, Takehiro; Okuda, Tomoyuki; Ban, Kousuke; Mizuno, Ryota; Tagami, Tatsuaki; Ozeki, Tetsuya; Okamoto, Hirokazu

2017-06-01

In the development of a drug for intra-articular administration, a sustained-release formulation is desirable since it is difficult to sustain the effects of conventional injections due to fast drug leakage from the joint cavity. In this study, we prepared sustained release gel formulations for intra-articular administration containing indocyanine green (ICG) as a model drug to follow its fate after intra-articular administration in rats with in-vivo imaging system (IVIS). ICG administered as an aqueous solution leaked from the joint cavity in a short time and was excreted out of the body within a day. On the other hand, ICG in the sustained-release formulations was retained and released in the joint cavity for a week. Next, we prepared a sustained-release formulation with hyaluronic acid (HA) as the gel base containing a pain-relief drug (Drug A). We had administered it and other formulations into the rat knee where we injected bradykinin to evaluate their walking distance after 1 and 3 d. The effect of an aqueous solution of Drug A disappeared on day 3. The HA gel formulation without Drug A was more effective than the aqueous solution. The HA gel formulation with Drug A was the most effective; the walking distance was about 85% of the baseline on day 3. This study showed that the gel formulations were effective to sustain the release of a drug in the knee joint, and that the combination of a pain-relief drug with HA gel was effective to improve the mobility of the acute pain model rats.

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.

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.

The tetrapeptide N-acetyl-Pro-Pro-Tyr-Leu in skin care formulations-Physicochemical and release studies.

PubMed

Olejnik, Anna; Schroeder, Grzegorz; Nowak, Izabela

2015-08-15

Recently there has been a growth of interest in the novel skin care formulations containing active ingredients such as low molecular weight peptides. In this paper we present new skincare formulations such as hydrogels, oil-in-water emulsions and water-in-oil emulsion containing a tetrapeptide (N-acetyl-Pro-Pro-Tyr-Leu). These formulations were characterized in terms of physicochemical parameters (pH, viscosity), stability and particle size distribution. Additionally, the diffusion parameters of the peptide in the obtained formulations were calculated based on the Einstein-Smoluchowski equation. Furthermore, in order to determine the penetration of the tetrapeptide through membranes its release kinetics were investigated. On the basis of release curves, the release rate constants were determined. The results proved that the properties of the formulations strongly determined the release rate of the tetrapeptide. The higher viscosity of the semisolid, the slower was the permeation through the membrane. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Thiol Modification of Psyllium Husk Mucilage and Evaluation of Its Mucoadhesive Applications

PubMed Central

Bhatia, Meenakshi

2013-01-01

Thiol functionalization of psyllium was carried out to enhance its mucoadhesive potential. Thiolation of psyllium was achieved by esterification with thioglycolic acid. Thiolation was observed to change the surface morphology of psyllium from fibrous to granular and result in a slight increase in the crystallinity and swelling. Thiolated psyllium was found to contain 3.282 m moles of thiol groups/g of the polymer. Mucoadhesive applications of thiolated psylium were explored by formulating gels using metronidazole as the model drug. On comparative evaluation thiolated psyllium gels showed 3-fold higher mucoadhesive strength than the psyllium gels as determined by modified physical balance using chicken buccal pouch. The results of in vitro release study revealed that thiolated psyllium gels provided a prolonged release of metronidazole. Further, the psyllium and thiolated psyllium gels were found to release the drug following first-order kinetics by combination of polymer relaxation and diffusion through the matrix. PMID:24348147

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

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

PubMed

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

2011-11-01

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

pH-Sensitive O6-Benzylguanosine Polymer Modified Magnetic Nanoparticles for Treatment of Glioblastomas.

PubMed

Stephen, Zachary R; Gebhart, Rachel N; Jeon, Mike; Blair, Allison A; Ellenbogen, Richard G; Silber, John R; Zhang, Miqin

2017-01-18

Nanoparticle-mediated delivery of chemotherapeutics has demonstrated potential in improving anticancer efficacy by increasing serum half-life and providing tissue specificity and controlled drug release to improve biodistribution of hydrophobic chemotherapeutics. However, suboptimal drug loading, particularly for solid core nanoparticles (NPs), remains a challenge that limits their clinical application. In this study we formulated a NP coated with a pH-sensitive polymer of O 6 -methylguanine-DNA methyltransferase (MGMT) inhibitor analog, dialdehyde modified O 6 -benzylguanosine (DABGS) to achieve high drug loading, and polyethylene glycol (PEG) to ameliorate water solubility and maintain NP stability. The base nanovector consists of an iron oxide core (9 nm) coated with hydrazide functionalized PEG (IOPH). DABGS and PEG-dihydrazide were polymerized on the iron oxide nanoparticle surface (IOPH-pBGS) through acid-labile hydrazone bonds utilizing a rapid, freeze-thaw catalysis approach. DABGS polymerization was confirmed by FTIR and quantitated by UV-vis spectroscopy. IOPH-pBGS demonstrated excellent drug loading of 33.4 ± 5.1% by weight while maintaining small size (36.5 ± 1.8 nm). Drug release was monitored at biologically relevant pHs and demonstrated pH dependent release with maximum release at pH 5.5 (intracellular conditions), and minimal release at physiological pH (7.4). IOPH-pBGS significantly suppressed activity of MGMT and potentiated Temozolomide (TMZ) toxicity in vitro, demonstrating potential as a new treatment option for glioblastomas (GBMs).

Solid lipid nanoparticles as carrier for sunscreens: in vitro release and in vivo skin penetration.

PubMed

Wissing, S A; Müller, R H

2002-06-17

The aim of this study was the comparison of two different formulations (solid lipid nanoparticles (SLN) and conventional o/w emulsion) as carrier systems for the molecular sunscreen oxybenzone. The influence of the carrier on the rate of release was studied in vitro with a membrane-free model. The release rate could be decreased by up to 50% with the SLN formulation. Further in vitro measurements with static Franz diffusion cells were performed. In vivo, penetration of oxybenzone into stratum corneum on the forearm was investigated by the tape stripping method. It was shown that the rate of release is strongly dependent upon the formulation and could be decreased by 30-60% in SLN formulations. In all test models, oxybenzone was released and penetrated into human skin more quickly and to a greater extent from the emulsions. The rate of release also depends upon the total concentration of oxybenzone in the formulation. In vitro-in vivo correlations could be made qualitatively.

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.

In-vitro release and permeation studies of ketoconazole from optimized dermatological vehicles using powder, nanoparticles and solid dispersion forms of drug

NASA Astrophysics Data System (ADS)

Mohammed, Irfan A.

To optimize the clinical efficacy of Ketoconazole from an externally applied product, this project was undertaken to evaluate the drug release/permeation profile from various dermatological vehicles using regular powder, nanoparticles and solid dispersion forms with reduced level of drug. Nanoparticles of drug were prepared by wet media milling method using Polyvinylpyrrolidone (PVP-10K) as a stabilizer. The nanoparticles were in the size range of 250-300nm. Solid dispersion was prepared by solvent evaporation method using drug to PVP-10K at a weight ratio of (1:2). Formulations containing 1% w/w drug were developed using HPMC gel, Carbomer gel and a cationic cream as the vehicles. Penetration enhancers including propylene glycol (PG), dimethylsulfoxide (DMSO) and polyethylene glycol 400 (PEG-400) at various levels were evaluated. A commercial 2% w/w ketoconazole product was included as a control for comparison. Studies were carried out with Franz Diffusion Cells using cellulose membrane and human cadaver skin for two and six hour studies. Among the formulations evaluated, the general rank order of the drug release through the cellulose membrane was observed to be: HPMC gel base > Anionic gel base > Cationic gel base > Commercial product. The addition of penetration enhancers showed variable effects in all samples evaluated. However, the HPMC gel-based vehicle showed significant effect in enhancing the drug release in the presence of DMSO. The formulation containing 1% w/w ketoconazole and 20% w/w DMSO gave a maximum drug release of 20.21% when compared to only 1.60% from the commercial product. This represents a twelve fold increase in the release of ketoconazole from the formulation. Furthermore, when the optimum gel-based formulation containing 1% w/w ketoconazole was studied over an extended period of 6 hours, it gave 36.01% drug release from the sample formulation compared to only 2.00% from the commercial product. Finally, this formulation was selected to study for its drug release/permeation profile using the human cadaver skin as the diffusion barrier. Here, as expected, the drug release from both the formulations tested was significantly reduced due to the resistance posed by the skin. After 6 hours, the drug release form the commercial product was 0.17% when compared to 2.80% from the optimum formulation. Once again, this indicated that the experimental formulation exhibits superior drug release dynamics. The selected formulations were further evaluated for their in-vitro anti-fungal activities using yeast microorganisms. The results correlated to the in-vitro drug release profile, where HPMC based formulations exhibited a greater area of zone of inhibition for the growth of microorganisms when compared to diminutive area of zone of inhibition for the commercial product. The release data from all the samples were treated to calculate various physical parameters including: diffusion co-efficient, partition co-efficient, steady state flux and lag period etc. Interestingly, the values for the steady state flux and diffusion coefficient were found to be the highest from the optimum formulation and the values for the lag time and partition coefficient were observed to be the lowest. This supports the evidence that the drug from this formulation is readily diffusible to the skin at a steady rate after its application at the site. In-vitro drug diffusion studies and in-vitro anti-fungal studies proved useful in screening various dermatological formulations of ketoconazole compared to the commercial product containing 2% w/w drug. The HPMC based optimum formulation with reduced level of drug represents 15 folds increase through human cadaver skin and also exhibited augmented anti-fungal activity. This supports that by using an appropriate vehicle and proper incorporation of drug, one can optimize the drug release from topical formulation for maximum therapeutic effect.

Sucrose ester stabilized solid lipid nanoparticles and nanostructured lipid carriers. II. Evaluation of the imidazole antifungal drug-loaded nanoparticle dispersions and their gel formulations.

PubMed

Das, Surajit; Ng, Wai Kiong; Tan, Reginald B H

2014-03-14

This study focused on: (i) feasibility of the previously developed sucrose ester stabilized SLNs and NLCs to encapsulate different imidazole antifungal drugs and (ii) preparation and evaluation of topical gel formulations of those SLNs and NLCs. Three imidazole antifungal drugs; clotrimazole, ketoconazole and climbazole were selected for this study. The results suggested that size, size distribution and drug encapsulation efficiency depend on the drug molecule and type of nanoparticles (SLN/NLC). The drug release experiment always showed faster drug release from NLCs than SLNs when the same drug molecule was loaded in both nanoparticles. However, drug release rate from both SLNs and NLCs followed the order of climbazole > ketoconazole > clotrimazole. NLCs demonstrated better physicochemical stability than SLNs in the case of all drugs. The drug release rate from ketoconazole- and clotrimazole-loaded SLNs became faster after three months than a fresh formulation. There was no significant change in drug release rate from climbazole-loaded SLNs and all drug-loaded NLCs. Gel formulations of SLNs and NLCs were prepared using polycarbophil polymer. Continuous flow measurements demonstrated non-Newtonian flow with shear-thinning behavior and thixotropy. Oscillation measurements depicted viscoelasticity of the gel formulations. Similar to nanoparticle dispersion, drug release rate from SLN- and NLC-gel was in the order of climbazole > ketoconazole > clotrimazole. However, significantly slower drug release was noticed from all gel formulations than their nanoparticle counterparts. Unlike nanoparticle dispersions, no significant difference in drug release from gel formulations containing SLNs and NLCs was observed for each drug. This study concludes that gel formulation of imidazole drug-loaded SLNs and NLCs can be used for sustained/prolonged topical delivery of the drugs.

In Vitro Drug Release After Crushing: Evaluation of Xtampza® ER and Other ER Opioid Formulations.

PubMed

Mayock, Stephen P; Saim, Said; Fleming, Alison B

2017-12-01

Extended-release (ER) opioids are associated with high rates of abuse. Recreational opioid users often manipulate ER formulations to achieve a high plasma concentration in a short amount of time, resulting in a more rapid and intense high. Patients may also manipulate ER tablets to facilitate swallowing, without recognizing that manipulation could increase release rate. The goal of this study was to assess the ability of oxycodone DETERx (Xtampza ® ER, Collegium Pharmaceutical, Inc., Canton, MA, USA) and other commercially available ER opioid formulations with and without physicochemical abuse-deterrent characteristics to be manipulated by crushing in an in vitro setting. In vitro dissolution techniques were used to compare the opioid release from a variety of ER opioid formulations. Dissolution was assessed for intact and crushed dosage forms. Opioid release was quantified using high-performance liquid chromatography. Intact formulations exhibited drug release rates characteristic of 12- or 24-h dosage forms. After crushing using commonly available household tools, only Xtampza ER maintained ER of opioid. Xtampza ER maintained its ER characteristics after crushing, unlike many other commercially available opioid formulations, including some formulated with abuse-deterrent properties. As such, Xtampza ER may be less appealing to abusers and offer a margin of safety for patients who manipulate dosage forms to facilitate swallowing.

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.

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.

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.

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.

Thermosensitive and mucoadhesive in situ gel based on poloxamer as new carrier for rectal administration of nimesulide.

PubMed

Yuan, Yuan; Cui, Ying; Zhang, Li; Zhu, Hui-Ping; Guo, Yi-Sha; Zhong, Bo; Hu, Xia; Zhang, Ling; Wang, Xiao-Hui; Chen, Li

2012-07-01

Poloxamer 407 has excellent thermo-sensitive gelling properties. Nevertheless, these gels possess inadequate poor bioadhesiveness and high permeability to water, which limited its' application as a thermoresponsive matrix. The main aim of the present investigation was to develop thermosensitive and mucoadhesive rectal in situ gel of nimesulide (NM) by using mucoadhesive polymers such as sodium alginate (Alg-Na) and HPMC. These gels were prepared by addition of mucoadhesive polymers (0.5%) to the formulations of thermosensitive gelling solution containing poloxamer 407 (18%) and nimesulide (2.0%). Polyethylene glycol (PEG) was used to modify gelation temperature and drug release properties. The gelation temperature and drug release rate of the prepared in situ gels were evaluated. Gelation temperature was significantly increased with incorporation of nimesulide (2.0%) in the poloxamer solution, while the addition of the mucoadhesive polymers played a reverse role on gelation temperature. The addition of PEG polymers increased the gelation temperature and the drug release rate. Among the formulations examined, the poloxamer 407/nimesulide/sodium alginate/PEG 4000 (18/2.0/0.5/1.2%) exhibited the appropriate gelation temperature, acceptable drug release rate and rectal retention at the administration site. Furthermore, the micrographic results showed that in situ gel, given at the dose of 20mg/kg, was safe for no mucosa irritation. In addition, it resulted in significantly higher initial serum concentrations, C(max) and AUC of NM compared to the solid suppository. Copyright © 2012 Elsevier B.V. All rights reserved.

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

PubMed

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

2016-09-25

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

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.

Development, optimization and characterization of glycyrrhetinic acid-chitosan nanoparticles of atorvastatin for liver targeting.

PubMed

Rohilla, Raman; Garg, Tarun; Bariwal, Jitender; Goyal, Amit K; Rath, Goutam

2016-09-01

Glycyrrhetinic acid-modified chitosan (mGA-suc-CTS) is used as liver-targeted carrier for drug delivery. In this study, nanoparticles were prepared by ionic gelation process, and glycyrrhetinic acid act as the targeting ligand. The structure of the product was confirmed by IR and NMR techniques. The main aim of this study was to deliver atorvastatin directly to the liver by using same conjugate and reduce the associated side-effects, i.e. hepatotoxicity at high dose. Characterization of the developed formulation was performed by differential scanning calorimetry, particle size measurements and cellular uptake studies. Release profile, pharmacokinetics studies and organ distribution studies showed that developed formulation shows a relative higher liver uptake. The optimized formulation showed increased plasma concentration than the CTS nanoparticles as well as plain drug and the accumulation in the liver was nearly 2.59 times more than that of obtained with the CTS nanoparticles. Pharmaceutical and pharmacological indicators suggested that the proposed strategy can be successfully utilized for liver targeting of therapeutics.

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.

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.

Strategies to overcome pH-dependent solubility of weakly basic drugs by using different types of alginates.

PubMed

Gutsche, S; Krause, M; Kranz, H

2008-12-01

Weakly basic drugs demonstrate higher solubility at lower pH, thus often leading to faster drug release at lower pH. The objective of this study was to achieve pH-independent release of weakly basic drugs from extended release formulations based on the naturally occurring polymer sodium alginate. Three approaches to overcome the pH-dependent solubility of the weakly basic model drug verapamil hydrochloride were investigated. First, matrix tablets were prepared by direct compression of drug substance with different types of sodium alginate only. Second, pH-modifiers were added to the drug/alginate matrix systems. Third, press-coated tablets consisting of an inner pH-modifier tablet core and an outer drug/sodium alginate coat were prepared. pH-Independent drug release was achieved from matrix tablets consisting of selected alginates and drug substance only. Alginates are better soluble at higher pH. Therefore, they are able to compensate the poor solubility of weakly basic drugs at higher pH as the matrix of the tablets dissolves faster. This approach was successful when using alginates that demonstrated fast hydration and erosion at higher pH. The approach failed for alginates with less-pronounced erosion at higher pH. The addition of fumaric acid to drug/alginate-based matrix systems decreased the microenvironmental pH within the tablets thus increasing the solubility of the weakly basic drug at higher pH. Therefore, pH-independent drug release was achieved irrespective of the type of alginate used. Drug release from press-coated tablets did not provide any further advantages as compound release remained pH-dependent.

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.

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.

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.

Bilayer tablets of Paliperidone for Extended release osmotic drug delivery

NASA Astrophysics Data System (ADS)

Chowdary, K. Sunil; Napoleon, A. A.

2017-11-01

The purpose of this study is to develop and optimize the formulation of paliperidone bilayer tablet core and coating which should meet in vitro performance of trilayered Innovator sample Invega. Optimization of core formulations prepared by different ratio of polyox grades and optimization of coating of (i) sub-coating build-up with hydroxy ethyl cellulose (HEC) and (ii).enteric coating build-up with cellulose acetate (CA). Some important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated. The optimization of formulation and process was conducted by comparing different in vitro release behaviours of Paliperidone. In vitro dissolution studies of Innovator sample (Invega) with formulations of different release rate which ever close release pattern during the whole 24 h test is finalized.

Intravaginal immunization using the recombinant HIV-1 clade-C trimeric envelope glycoprotein CN54gp140 formulated within lyophilized solid dosage forms

PubMed Central

Donnelly, Louise; Curran, Rhonda M.; Tregoning, John S.; McKay, Paul F.; Cole, Tom; Morrow, Ryan J.; Kett, Vicky L.; Andrews, Gavin P.; Woolfson, A. David; Malcolm, R. Karl; Shattock, Robin J.

2011-01-01

Vaccine-mediated prevention of primary HIV-1 infection at the heterosexual mucosal portal of entry may be facilitated by highly optimised formulations or drug delivery devices for intravaginal (i.vag) immunization. Previously we described hydroxyethylcellulose (HEC)-based rheologically structured gel vehicles (RSVs) for vaginal immunization of an HIV-1 vaccine candidate, a soluble recombinant trimeric HIV-1 clade-C envelope glycoprotein designated CN54gp140. Here we investigated the efficacy of lyophilized solid dosage formulations (LSDFs) for prolonging antigen stability and as i.vag delivery modalities. LSDFs were designed and developed that upon i.vag administration they would reconstitute with the imbibing of vaginal fluid to mucoadhesive, site-retentive semi-solids. Mice were immunized with lyophilized equivalents of (i) RSVs, (ii) modified versions of the RSVs more suited to lyophilization (sodium carboxymethyl cellulose (NaCMC)-based gels) and (iii) Carbopol® gel, all containing CN54gp140. NaCMC-based LSDFs provided significantly enhanced antigen stability compared to aqueous-based RSVs. Rheological analysis indicated the NaCMC-based LSDFs would offer enhanced vaginal retention in woman compared to more conventional vaginal gel formulations. All LSDFs were well tolerated in the mouse model. Following i.vag administration, all LSDFs boosted systemic CN54gp140-specific antibody responses in sub-cutaneously primed mice. Induction of CN54gp140-specific antibody responses in the female genital tract was evident. Of all the LSDFs the fastest releasing which was lyophilized Carbopol® gel elicited immune responses comparable to buffer instillation of antigen suggesting that rather than slower sustained release, initial high burst release from the LSDFs may suffice. The boosting of specific immune responses upon i.vag administration indicates that LSDFs are viable mucosal vaccine delivery modalities promoting antigen stability and facilitating intimate exposure of CN54gp140 to the mucosal-associated lymphoid tissue of the female genital tract. PMID:21514349

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.

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.

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

PubMed

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

2016-11-01

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

Wax-incorporated emulsion gel beads of calcium pectinate for intragastric floating drug delivery.

PubMed

Sriamornsak, Pornsak; Asavapichayont, Panida; Nunthanid, Jurairat; Luangtana-Anan, Manee; Limmatvapirat, Sontaya; Piriyaprasarth, Suchada

2008-01-01

The purpose of this study was to prepare wax-incorporated pectin-based emulsion gel beads using a modified emulsion-gelation method. The waxes in pectin-olive oil mixtures containing a model drug, metronidazole, were hot-melted, homogenized and then extruded into calcium chloride solution. The beads formed were separated, washed with distilled water and dried for 12 h. The influence of various types and amounts of wax on floating and drug release behavior of emulsion gel beads of calcium pectinate was investigated. The drug-loaded gel beads were found to float on simulated gastric fluid if the sufficient amount of oil was used. Incorporation of wax into the emulsion gel beads affected the drug release. Water-soluble wax (i.e. polyethylene glycol) increased the drug release while other water-insoluble waxes (i.e. glyceryl monostearate, stearyl alcohol, carnauba wax, spermaceti wax and white wax) significantly retarded the drug release. Different waxes had a slight effect on the drug release. However, the increased amount of incorporated wax in the formulations significantly sustained the drug release while the beads remained floating. The results suggest that wax-incorporated emulsion gel beads could be used as a carrier for intragastric floating drug 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.

Concanavalin A conjugated biodegradable nanoparticles for oral insulin delivery

NASA Astrophysics Data System (ADS)

Hurkat, Pooja; Jain, Aviral; Jain, Ashish; Shilpi, Satish; Gulbake, Arvind; Jain, Sanjay K.

2012-11-01

Major research issues in oral protein delivery include the stabilization of protein in delivery devices which could increase its oral bioavailability. The study deals with development of oral insulin delivery system utilizing biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and modifying its surface with Concanavalin A to increase lymphatic uptake. Surface-modified PLGA nanoparticles were characterized for conjugation efficiency of ligand, shape and surface morphology, particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro drug release. Stability of insulin in the developed formulation was confirmed by SDS-PAGE, and integrity of entrapped insulin was assessed using circular dichroism spectrum. Ex vivo study was performed on Wistar rats, which exhibited the higher intestinal uptake of Con A conjugated nanoparticles. In vivo study performed on streptozotocin-induced diabetic rats which indicate that a surface-modified nanoparticle reduces blood glucose level effectively within 4 h of its oral administration. In conclusion, the present work resulted in successful production of Con A NPs bearing insulin with sustained release profile, and better absorption and stability. The Con A NPs showed high insulin uptake, due to its relative high affinity for non-reducing carbohydrate residues i.e., fucose present on M cells and have the potential for oral insulin delivery in effective management of Type 1 diabetes condition.

Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA.

PubMed

Jensen, Ditte Krohn; Jensen, Linda Boye; Koocheki, Saeid; Bengtson, Lasse; Cun, Dongmei; Nielsen, Hanne Mørck; Foged, Camilla

2012-01-10

Matrix systems based on biocompatible and biodegradable polymers like the United States Food and Drug Administration (FDA)-approved polymer poly(DL-lactide-co-glycolide acid) (PLGA) are promising for the delivery of small interfering RNA (siRNA) due to favorable safety profiles, sustained release properties and improved colloidal stability, as compared to polyplexes. The purpose of this study was to design a dry powder formulation based on cationic lipid-modified PLGA nanoparticles intended for treatment of severe lung diseases by pulmonary delivery of siRNA. The cationic lipid dioleoyltrimethylammoniumpropane (DOTAP) was incorporated into the PLGA matrix to potentiate the gene silencing efficiency. The gene knock-down level in vitro was positively correlated to the weight ratio of DOTAP in the particles, and 73% silencing was achieved in the presence of 10% (v/v) serum at 25% (w/w) DOTAP. Optimal properties were found for nanoparticles modified with 15% (w/w) DOTAP, which reduced the gene expression with 54%. This formulation was spray-dried with mannitol into nanocomposite microparticles of an aerodynamic size appropriate for lung deposition. The spray-drying process did not affect the physicochemical properties of the readily re-dispersible nanoparticles, and most importantly, the in vitro gene silencing activity was preserved during spray-drying. The siRNA content in the powder was similar to the theoretical loading and the siRNA was intact, suggesting that the siRNA is preserved during the spray-drying process. Finally, X-ray powder diffraction analysis demonstrated that mannitol remained in a crystalline state upon spray-drying with PLGA nanoparticles suggesting that the sugar excipient might exert its stabilizing effect by sterical inhibition of the interactions between adjacent nanoparticles. This study demonstrates that spray-drying is an excellent technique for engineering dry powder formulations of siRNA nanoparticles, which might enable the local delivery of biologically active siRNA directly to the lung tissue. Copyright © 2011 Elsevier B.V. All rights reserved.

A systematic review on evidence of the effectiveness and safety of a wax-matrix niacin formulation.

PubMed

Dunatchik, Andrew P; Ito, Matthew K; Dujovne, Carlos A

2012-01-01

Niacin is a uniquely efficacious therapy in the treatment of dyslipidemia because of its broad spectrum of beneficial effects on every aspect of the lipid profile and because it has been shown to reduce both total mortality and coronary death. However, niacin therapy is hindered by its side-effect profile, which appears to be dependent on its formulation with immediate-release niacin, associated with a greater incidence of flushing, and sustained-release niacin, associated with greater liver function test (LFT) abnormalities and hepatotoxicity. One such sustained-release niacin nutritional supplement formulation, Endur-acin (Endurance Products Company, Tigard, OR), claims to have clinical evidence to support its use in the treatment of dyslipidemias, which prompted us to systematically review the literature. We identified four published papers in which the authors reported the results of two separate clinical trials and one pharmacokinetic study that fulfilled the inclusion criteria and were included in this review. Endur-acin significantly reduced total cholesterol, low-density lipoprotein cholesterol, and total cholesterol/high-density lipoprotein cholesterol ratio with mean reductions up to 19%, 26%, and 20%, respectively, at a dose of 2000 mg/day. Less-impressive benefits were also seen with high-density lipoprotein cholesterol (+10%) and serum triglycerides (-23%). Mean LFT elevations of up to 1.6-fold were seen at the 2000 mg per day dose, however, not exceeding three times the upper limit of normal, with abnormal results occurring at similar frequency in placebo and one patient experiencing marked gastrointestinal symptoms and a hepatitis-like syndrome with reversible elevated LFT. Short-term randomized controlled trials suggest Endur-acin is effective in modifying serum lipids, although study limitations prevent a comprehensive evaluation of safety. Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Local Toxicity from Local Anesthetic Polymeric Microparticles

PubMed Central

McAlvin, J. Brian; Reznor, Gally; Shankarappa, Sahadev A.; Stefanescu, Cristina F.; Kohane, Daniel S.

2013-01-01

Background Local tissue injury from sustained release formulations for local anesthetics can be severe. There is considerable variability in reporting of that injury. We investigated the influence of the intrinsic myotoxicity of the encapsulated local anesthetic (lidocaine, low; bupivacaine, high) on tissue reaction in rats. Methods Cytotoxicity from a range of lidocaine and bupivacaine concentrations was measured in C2C12 myotubes over 6 days. Rats were given sciatic nerve blocks with 4 microparticulate formulations of lidocaine and bupivacaine: 10% (w/w) lidocaine poly-lactic-co-glycolic acid (PLGA), 10% (w/w) bupivacaine PLGA, 50% (w/w) lidocaine PLGA, and 50% (w/w) bupivacaine PLGA. Effectiveness of nerve blockade was assessed by a modified hotplate test and weight-bearing measurements. Myotoxicity was scored in histologic sections of injection sites. Bupivacaine and lidocaine release kinetics from the particles were measured. Results Median sensory blockade duration for 50% (w/w) lidocaine was 255 (90–540) min versus 840 (277–1215) min for 50% (w/w) bupivacaine (P=0.056). All microparticulate formulations resulted in myotoxicity. The choice of local anesthetic did not influence the severity of myotoxicity. Median myotoxicity scores for 50% (w/w) lidocaine compared to 50% (w/w) bupivacaine at 4 days was 3.4 (2.1–4.2) vs. 3.3 (2.9–3.5)(P=0.44) and at 14 days 1.9 (1.8–2.4) versus 1.7 (1.3–1.9)(P=0.23) respictively. Conclusions Lidocaine and bupivacaine PLGA microspheres resulted in similar degrees of myotoxicity, irrespective of drug loading. Intrinsic myotoxicity did not predict tissue injury from sustained release of these anesthetics. Caution is warranted in the use of such devices near muscle and nerve. PMID:23460564

9th International Symposium on the Biosafety of Genetically Modified Organisms. Session II: Identifying and defining hazards and potential consequences I: Concepts for problem formulation and non-target risk assessment.

PubMed

Bigler, Franz

2006-01-01

The scientific organizers of the symposium put much emphasis on the identification and definition of hazard and the potential consequences thereof and three full sessions with a total of 13 presentations encompassing a wide range of related themes were planned for this topic. Unfortunately, one talk had to be cancelled because of illness of the speaker (BM Khadi, India). Some presentations covered conceptual approaches for environmental risk assessment (ERA) of GM plants (problem formulation in the risk assessment framework, familiarity approach, tiered and methodological frameworks, non-target risk assessment) and the use of models in assessing invasiveness and weediness of GM plants. Other presentations highlighted the lessons learned for future ERA from case studies and commercialized GM crops, and from monitoring of unintended releases to the environment. When the moderators of the three sessions came together after the presentations to align their summaries, there was an obvious need to restructure the 12 presentations in a way that allowed for a consistent summarizing discussion. The following new organization of the 12 talks was chosen: (1) Concepts for problem formulation and non-target risk assessment, (2) Modeling as a tool for predicting invasiveness of GM plants, (3) Case-studies of ERA of large-scale release, (4) Lessons learned for ERA from a commercialized GM plant, (5) Monitoring of unintended release of Bt maize in Mexico. The new thematic structure facilitates a more in-depth discussion of the presentations related to a specific topic, and the conclusions to be drawn are thus more consistent. Each moderator agreed to take responsibility for summarizing one or more themes and to prepare the respective report.

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.

Surface functionalization of PLGA nanoparticles by non-covalent insertion of a homo-bifunctional spacer for active targeting in cancer therapy.

PubMed

Thamake, S I; Raut, S L; Ranjan, A P; Gryczynski, Z; Vishwanatha, J K

2011-01-21

This work reports the surface functionalization of polymeric PLGA nanoparticles by non-covalent insertion of a homo-bifunctional chemical crosslinker, bis(sulfosuccinimidyl) suberate (BS3) for targeted cancer therapy. We dissolved BS3 in aqueous solution of PVA during formulation of nanoparticles by a modified solid/oil/water emulsion solvent evaporation method. The non-covalent insertion of BS3 was confirmed by Fourier transform infrared (FTIR) spectroscopy. Curcumin and annexin A2 were used as a model drug and a cell specific target, respectively. Nanoparticles were characterized for particle size, zeta potential and surface morphology. The qualitative assessment of antibody attachment was performed by transmission electron microscopy (TEM) as well as confocal microscopy. The optimized formulation showed antibody attachment of 86%. However, antibody attachment was abolished upon blocking the functional groups of BS3. The availability of functional antibodies was evaluated by the presence of a light chain fraction after gel electrophoresis. We further evaluated the in vitro release kinetics of curcumin from antibody coated and uncoated nanoparticles. The release of curcumin is enhanced upon antibody attachment and followed an anomalous release pattern. We also observed that the cellular uptake of nanoparticles was significantly higher in annexin A2 positive cells than in negative cells. Therefore, these results demonstrate the potential use of this method for functionalization as well as to deliver chemotherapeutic agents for treating cancer.

Surface functionalization of PLGA nanoparticles by non-covalent insertion of a homo-bifunctional spacer for active targeting in cancer therapy

NASA Astrophysics Data System (ADS)

Thamake, S. I.; Raut, S. L.; Ranjan, A. P.; Gryczynski, Z.; Vishwanatha, J. K.

2011-01-01

This work reports the surface functionalization of polymeric PLGA nanoparticles by non-covalent insertion of a homo-bifunctional chemical crosslinker, bis(sulfosuccinimidyl) suberate (BS3) for targeted cancer therapy. We dissolved BS3 in aqueous solution of PVA during formulation of nanoparticles by a modified solid/oil/water emulsion solvent evaporation method. The non-covalent insertion of BS3 was confirmed by Fourier transform infrared (FTIR) spectroscopy. Curcumin and annexin A2 were used as a model drug and a cell specific target, respectively. Nanoparticles were characterized for particle size, zeta potential and surface morphology. The qualitative assessment of antibody attachment was performed by transmission electron microscopy (TEM) as well as confocal microscopy. The optimized formulation showed antibody attachment of 86%. However, antibody attachment was abolished upon blocking the functional groups of BS3. The availability of functional antibodies was evaluated by the presence of a light chain fraction after gel electrophoresis. We further evaluated the in vitro release kinetics of curcumin from antibody coated and uncoated nanoparticles. The release of curcumin is enhanced upon antibody attachment and followed an anomalous release pattern. We also observed that the cellular uptake of nanoparticles was significantly higher in annexin A2 positive cells than in negative cells. Therefore, these results demonstrate the potential use of this method for functionalization as well as to deliver chemotherapeutic agents for treating cancer.

Development and Evaluation of Mouth Dissolving Films of Amlodipine Besylate for Enhanced Therapeutic Efficacy

PubMed Central

Maheswari, K. M.; Devineni, Pavan Kumar; Deekonda, Sravanthi; Shaik, Salma; Uppala, Naga Pravallika; Nalluri, Buchi N.

2014-01-01

The present investigation was undertaken with an objective of formulating mouth dissolving films (MDFs) of Amlodipine Besylate (AMLO) to enhance convenience and compliance of the elderly and pediatric patients for better therapeutic efficacy. Film formers like hydroxy propyl methyl cellulose (HPMC) and methyl cellulose (MC) along with film modifiers like poly vinyl pyrrolidone K30 (PVP K30), and sodium lauryl sulphate (SLS) as solubilizing agents were evaluated. The prepared MDFs were evaluated for in vitro dissolution characteristics, in vitro disintegration time, and their physicomechanical properties. All the prepared MDFs showed good mechanical properties like tensile strength, folding endurance, and % elongation. MDFs were evaluated by means of FTIR, SEM, and X-RD studies. MDFs with 7.5% (w/w) of HPMC E3 gave better dissolution properties when compared to HPMC E5, HPMC E15, and MC. MDFs with PVP K30 and SLS gave superior dissolution properties when compared to MDFs without PVP K30 and SLS. The dissolution properties of MDFs with PVP K30 were superior when compared to MDFs with SLS. In the case of F3 containing 7.5% of HPMC E3 and 0.04% of PVP K30, complete and faster release was observed within 60 sec when compared to other formulations. Release kinetics data reveals diffusion is the release mechanism. PMID:26556197

Development and Evaluation of Mouth Dissolving Films of Amlodipine Besylate for Enhanced Therapeutic Efficacy.

PubMed

Maheswari, K M; Devineni, Pavan Kumar; Deekonda, Sravanthi; Shaik, Salma; Uppala, Naga Pravallika; Nalluri, Buchi N

2014-01-01

The present investigation was undertaken with an objective of formulating mouth dissolving films (MDFs) of Amlodipine Besylate (AMLO) to enhance convenience and compliance of the elderly and pediatric patients for better therapeutic efficacy. Film formers like hydroxy propyl methyl cellulose (HPMC) and methyl cellulose (MC) along with film modifiers like poly vinyl pyrrolidone K30 (PVP K30), and sodium lauryl sulphate (SLS) as solubilizing agents were evaluated. The prepared MDFs were evaluated for in vitro dissolution characteristics, in vitro disintegration time, and their physicomechanical properties. All the prepared MDFs showed good mechanical properties like tensile strength, folding endurance, and % elongation. MDFs were evaluated by means of FTIR, SEM, and X-RD studies. MDFs with 7.5% (w/w) of HPMC E3 gave better dissolution properties when compared to HPMC E5, HPMC E15, and MC. MDFs with PVP K30 and SLS gave superior dissolution properties when compared to MDFs without PVP K30 and SLS. The dissolution properties of MDFs with PVP K30 were superior when compared to MDFs with SLS. In the case of F3 containing 7.5% of HPMC E3 and 0.04% of PVP K30, complete and faster release was observed within 60 sec when compared to other formulations. Release kinetics data reveals diffusion is the release mechanism.

Development and evaluation of resveratrol, Vitamin E, and epigallocatechin gallate loaded lipid nanoparticles for skin care applications.

PubMed

Chen, Jin; Wei, Ning; Lopez-Garcia, Maria; Ambrose, Dianna; Lee, Jason; Annelin, Colin; Peterson, Teresa

2017-08-01

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been studied as potential carriers for both dermal and transdermal drug delivery. SLN contain lipid droplets that are fully crystallized and have a highly-ordered crystalline structure. NLC are modified SLN in which the lipid phase contains both solid and liquid lipids at room temperature. SLN and NLC are thought to combine the advantages of polymeric particles, liposomes and emulsions. Therefore they provide high encapsulation percentages, better protection for incorporated actives and allow for control of desired release profile. In this work, Resveratrol, Vitamin E (VE), and Epigallocatechin Gallate (EGCG) all potent antioxidants known to provide protection to the skin, were formulated into lipid nanoparticles. Several different formulations were successfully developed and demonstrated high uniformity and stability. Both resveratrol and VE lipid nanoparticles provided effective protection of actives against UV induced degradation. However, lipid nanoparticles did not show protection from UV degradation for EGCG in this work. An active release study exhibited a sustained release of resveratrol over 70% after 24h. Skin penetration studies showed that lipid nanoparticles directionally improved the penetration of resveratrol through the stratum corneum. Our findings suggest that lipid nanoparticles are promising viable carriers for the delivery of resveratrol and VE to provide longlasting antioxidant benefits to the skin. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed

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

2016-08-01

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

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

PubMed

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

2017-08-01

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

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

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

PubMed

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

2016-09-01

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

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.

The ameliorated longevity and pharmacokinetics of valsartan released from a gel system of ultradeformable vesicles.

PubMed

Ahad, Abdul; Aqil, Mohd; Kohli, Kanchan; Sultana, Yasmin; Mujeeb, Mohd

2016-09-01

The present study traces the development and characterization of the gel formulation of valsartan-loaded ultradeformable vesicles for management of hypertension. The prepared gel formulation of ultradeformable vesicles was evaluated for in vitro skin permeation, release kinetics, skin irritation, pharmacokinetics, and stability. The in vitro skin permeation study showed that the gel formulation of ultradeformable vesicles presented a flux value of 368.74 μg/cm(2)/h, in comparison to that of the traditional liposomal gel formulation, with an enhancement ratio of 26.91, through rat skin. The data for release kinetics showed that the release profile followed zero-order kinetics, and that the drug release mechanism was non-Fickian. The results of the skin irritation study demonstrated that the prepared formulation was safe, less irritant, and well-tolerated for transdermal delivery. The results of the pharmacokinetic study demonstrated that the AUC value of valsartan after transdermal administration was apparently increased. The formulation stored under a refrigerated condition showed greater stability, and results were found to be within the specification under storage conditions. It is evident from this study that the gel formulation of ultradeformable vesicles of valsartan is a promising delivery system for lipophilic drugs, and has reasonably good stability characteristics.

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

PubMed

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

2004-06-11

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

Elucidation of release characteristics of highly soluble drug trimetazidine hydrochloride from chitosan-carrageenan matrix tablets.

PubMed

Li, Liang; Wang, Linlin; Shao, Yang; Tian, Ye; Li, Conghao; Li, Ying; Mao, Shirui

2013-08-01

The aim of this study was to better understand the underlying drug release characteristics from matrix tablets based on the combination of chitosan (CS) and different types of carrageenans [kappa (κ)-CG, iota (ι)-CG, and lambda (λ)-CG]. Highly soluble trimetazidine hydrochloride (TH) was used as a model drug. First, characteristics of drug release from different formulations were investigated, and then in situ complexation capacity of CG with TH and CS was studied by differential scanning calorimetry and Fourier transform infrared spectroscopy. Erosion and swelling of matrix were also characterized to better understand the drug-release mechanisms. Effects of pH and ionic strength on drug release were also studied. It was found that not only ι-CG and λ-CG could reduce the burst release of TH by the effect of TH-CG interaction, CS-ι-CG- and CS-λ-CG-based polyelectrolyte film could further modify the controlled-release behavior, but not CS-κ-CG. High pH and high ionic strength resulted in faster drug release from CS-κ-CG- and CS-ι-CG-based matrix, but drug release from CS-λ-CG-based matrix was less sensitive to pH and ionic strength. In conclusion, CS-λ-CG-based matrix tablets are quite promising as controlled-release drug carrier based on multiple mechanisms. Copyright © 2013 Wiley Periodicals, Inc.

Tunable diblock copolypeptide hydrogel depots for local delivery of hydrophobic molecules in healthy and injured central nervous system

PubMed Central

Zhang, Shanshan; Anderson, Mark A.; Ao, Yan; Khakh, Baljit S.; Fan, Jessica; Deming, Timothy J.; Sofroniew, Michael V.

2014-01-01

Many hydrophobic small molecules are available to regulate gene expression and other cellular functions. Locally restricted application of such molecules in the central nervous system (CNS) would be desirable in many experimental and therapeutic settings, but is limited by a lack of innocuous vehicles able to load and easily deliver hydrophobic cargo. Here, we tested the potential for diblock copolypeptide hydrogels (DCH) to serve as such vehicles. In vitro tests on loading and release were conducted with cholesterol and the anti-cancer agent, temozolomide (TMZ). Loading of hydrophobic cargo modified DCH physical properties such as stiffness and viscosity, but these could readily be tuned to desired ranges by modifying DCH concentration, amino acid composition or chain lengths. Different DCH formulations exhibited different loading capacities and different rates of release. For example, comparison of different DCH with increasing alanine contents showed corresponding increases in both cargo loading capacity and time for cargo release. In vivo tests were conducted with tamoxifen, a small synthetic hydrophobic molecule widely used to regulate transgene expression. Tamoxifen released from DCH depots injected into healthy or injured CNS efficiently activated reporter gene expression in a locally restricted manner in transgenic mice. These findings demonstrate the facile and predictable tunability of DCH to achieve a wide range of loading capacities and release profiles of hydrophobic cargos while retaining CNS compatible physical properties. In addition, the findings show that DCH depots injected into the CNS can efficiently deliver small hydrophobic molecules that regulate gene expression in local cells. PMID:24314556

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

PubMed

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

2016-08-01

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

A novel intracellular pH-responsive formulation for FTY720 based on PEGylated graphene oxide nano-sheets.

PubMed

Masoudipour, Elham; Kashanian, Soheila; Maleki, Nasim; Karamyan, Ali; Omidfar, Kobra

2018-01-01

This study was performed to investigate a novel pH-responsive nanocarrier based on modified nano graphene oxide (nGO) to promote the acid-triggered intracellular release of a poorly soluble drug, FTY720. To synthesize a drug conjugated to modified nGO, first the polyethylene glycol (PEG) was conjugated to nGO, then the produced PEG-nGO was functionalized with the anticancer drug, FTY720, through amide bonding. It was characterized by the scanning electron microscopy (SEM), the atomic force microscopy (AFM), the Fourier transform infrared (FTIR) spectroscopy and the UV-vis spectroscopy. In vitro drug release of the FTY720-conjugated PEG-nGO was evaluated at pH 7.4 and 4.6 PBS at 37 °C. Furthermore, the antineoplastic action of unloaded and drug-loaded carrier against the human breast adenocarcinoma cell line MCF7 was explored using MTT and BrdU assays. Characterization methods indicated successful drug deposition on the surface of nGO. In vitro, drug release results revealed a significantly faster release of FTY720 from PEG-nGO at acidic pH, compared with physiological pH. The proliferation assays proved that the unloaded nGO had no significant cytotoxicity against MCF7 cells, while free FTY720- and FTY720-loaded PEG-nGO had an approximately equal cytotoxic effect on the MCF7 cells. It was found that the extended release characteristic of FTY720 was well fitted to Korsmeyer-Peppas model and the release profile of FTY720 from PEG-nGO is diffusion controlled. PEGylated GO can act as a pH-responsive drug carrier to improve the efficacy of anticancer drug delivery.

Formulation and evaluation of non-effervescent floating tablets of losartan potassium.

PubMed

Getyala, Anil; Gangadharappa, H V; Prasad, M Sarat Chandra; Reddy, M Praveen Kumar; Kumar, T M Pramod

2013-10-01

The aim of the work is to modify the solubility and bioavailability of Losartan potassium, by employing noneffervescent floating drug delivery (tablet dosage forms). Non-effervescent systems are a type of floating drug delivery systems, that have been used to boost the gastric residence and the floatation time in the gastro intestinal tract. The study included formulation of floating tablets using polymers like Chitosan and Karaya gum as matrix forming agents. Accurel(®) MP 1000 was used as floating agent. The tablets were prepared by direct compression technique. FTIR, DSC studies conformed that there was no incompatibility between the polymer and the drug. Tablet preformulation parameters were within the Pharmacopoeial limit. Tablet showed zero lag time, contisnuance of buoyancy for >12 h. The tablet showed good in vitro release. Drug release was through swelling and abided by the gellation mechanism. In vivo X-ray studies depicted that tablets continued to float in the GIT for 12 h. Accelerated stability showed that, tablets were stable for over 6 month. Thus the prepared non-effervescent floating tablet of Losartan potassium can be used for the treatment of hypertension for more than 12 h with single dose administration.

Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets.

PubMed

Arafat, Basel; Wojsz, Magdalena; Isreb, Abdullah; Forbes, Robert T; Isreb, Mohammad; Ahmed, Waqar; Arafat, Tawfiq; Alhnan, Mohamed A

2018-06-15

Fused deposition modelling (FDM) 3D printing has shown the most immediate potential for on-demand dose personalisation to suit particular patient's needs. However, FDM 3D printing often involves employing a relatively large molecular weight thermoplastic polymer and results in extended release pattern. It is therefore essential to fast-track drug release from the 3D printed objects. This work employed an innovative design approach of tablets with unique built-in gaps (Gaplets) with the aim of accelerating drug release. The novel tablet design is composed of 9 repeating units (blocks) connected with 3 bridges to allow the generation of 8 gaps. The impact of size of the block, the number of bridges and the spacing between different blocks was investigated. Increasing the inter-block space reduced mechanical resistance of the unit, however, tablets continued to meet pharmacopeial standards for friability. Upon introduction into gastric medium, the 1 mm spaces gaplet broke into mini-structures within 4 min and met the USP criteria of immediate release products (86.7% drug release at 30 min). Real-time ultraviolet (UV) imaging indicated that the cellulosic matrix expanded due to swelling of hydroxypropyl cellulose (HPC) upon introduction to the dissolution medium. This was followed by a steady erosion of the polymeric matrix at a rate of 8 μm/min. The design approach was more efficient than a comparison conventional formulation approach of adding disintegrants to accelerate tablet disintegration and drug release. This work provides a novel example where computer-aided design was instrumental at modifying the performance of solid dosage forms. Such an example may serve as the foundation for a new generation of dosage forms with complicated geometric structures to achieve functionality that is usually achieved by a sophisticated formulation approach. Copyright © 2018 Elsevier B.V. All rights reserved.

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

PubMed

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

2008-10-01

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

[Application of an artificial neural network in the design of sustained-release dosage forms].

PubMed

Wei, X H; Wu, J J; Liang, W Q

2001-09-01

To use the artificial neural network (ANN) in Matlab 5.1 tool-boxes to predict the formulations of sustained-release tablets. The solubilities of nine drugs and various ratios of HPMC: Dextrin for 63 tablet formulations were used as the ANN model input, and in vitro accumulation released at 6 sampling times were used as output. The ANN model was constructed by selecting the optimal number of iterations (25) and model structure in which there are one hidden layer and five hidden layer nodes. The optimized ANN model was used for prediction of formulation based on desired target in vitro dissolution-time profiles. ANN predicted profiles based on ANN predicted formulations were closely similar to the target profiles. The ANN could be used for predicting the dissolution profiles of sustained release dosage form and for the design of optimal formulation.

Preparation and In Vitro/In Vivo Evaluation of Vinpocetine Elementary Osmotic Pump System

PubMed Central

Ning, Meiying; Zhou, Yue; Chen, Guojun; Mei, Xingguo

2011-01-01

Preparation and in vitro and in vivo evaluation of vinpocetine (VIN) elementary osmotic pump (EOP) formulations were investigated. A method for the preparation of VIN elementary osmotic pump tablet was obtained by adding organic acid additives to increase VIN solubility. VIN was used as the active pharmaceutical ingredient, lactose and mannitol as osmotic agent. Citric acid was used as increasing API solubility and without resulting in the API degradation. It is found that the VIN release rate was increasing with the citric acid amount at a constant range. Cellulose acetate 398-3 was employed as semipermeable membrane containing polyethylene glycol 6000 and diethyl-o-phthalate as pore-forming agent and plasticizer for controlling membrane permeability. In addition, a clear difference between the pharmacokinetic patterns of VIN immediate release and VIN elementary osmotic pump formulations was revealed. The area under the plasma concentration-time curve after oral administration of elementary osmotic pump formulations was equivalent to VIN immediate release formulation. Furthermore, significant differences found for mean residence time, elimination half-life, and elimination rate constant values corroborated prolonged release of VIN from elementary osmotic pump formulations. These results suggest that the VIN osmotic pump controlled release tablets have marked controlled release characters and the VIN osmotic pump controlled release tablets and the normal tablets were bioequivalent. PMID:21577257

Development of orally disintegrating tablets comprising controlled-release multiparticulate beads

PubMed Central

2012-01-01

Melperone is an atypical antipsychotic agent that has shown a wide spectrum of neuroleptic properties, particularly effective in the treatment of senile dementia and Parkinson’s-associated psychosis, and is marketed in Europe as an immediate-release (IR) tablet and syrup. An orally disintegrating tablet (ODT) dosage form would be advantageous for patients who experience difficulty in swallowing large tablets or capsules or those who experience dysphagia. Controlled-release (CR) capsule and ODT formulations containing melperone HCl were developed with target in vitro release profiles suitable for a once-daily dosing regimen. Both dosage forms allow for the convenient production of dose-proportional multiple strengths. Two ODT formulations exhibiting fast and medium release profiles and one medium release profile capsule formulation (each 50 mg) were tested in vivo using IR syrup as the reference. The two medium release formulations were shown to be bioequivalent to each other and are suitable for once-daily dosing. Based on the analytical and organoleptic test results, as well as the blend uniformity and in-process compression data at various compression forces using coated beads produced at one-tenth (1/10) commercial scale, both formulations in the form of CR capsules and CR ODTs have shown suitability for progression into further clinical development. PMID:22356215

A mathematical approach for the simultaneous in vitro spectrophotometric analysis of rifampicin and isoniazid from modified-release anti-TB drug delivery systems.

PubMed

du Toit, Lisa; Pillay, Viness; Choonara, Yahya

2010-01-01

Dissolution testing with subsequent analysis is considered as an imperative tool for quality evaluation of the combination rifampicin-isoniazid (RIF-INH) combination. Partial least squares (PLS) regression has been successfully undertaken to select suitable predictor variables and to identify outliers for the generation of equations for RIF and INH determination in fixed-dose combinations (FDCs). The aim of this investigation was to ascertain the applicability of the described technique in testing a novel oral FDC anti-TB drug delivery system and currently available two-drug FDCs, in comparison to the United States Pharmacopeial method for analysis of RIF and INH Capsules with chromatographic determination of INH and colorimetric RIF determination. Regression equations generated employing the statistical coefficients satisfactorily predicted RIF release at each sampling point (R(2)>or=0.9350). There was an acceptable degree of correlation between the drug release data, as predicted by regressional analysis of UV spectrophotometric data, and chromatographic and colorimetric determination of INH (R(2)=0.9793 and R(2)=0.9739) and RIF (R(2)= 0.9976 and R(2)=0.9996) for the two-drug FDC and the novel oral anti-TB drug delivery system, respectively. Regressional analysis of UV spectrophotometric data for simultaneous RIF and INH prediction thus provides a simplified methodology for use in diverse research settings for the assurance of RIF bioavailability from FDC formulations, specifically modified-release forms.

Monitoring of internal pH gradients within multi-layer tablets by optical methods and EPR imaging.

PubMed

Eisenächer, Friederike; Schädlich, Andreas; Mäder, Karsten

2011-09-30

The high variability of gastrointestinal pH is a general challenge regarding constant release from oral drug delivery systems, especially for ionisable drugs. These drugs often show a pH-dependent solubility and therewith associated intra- and inter-individual variability of emerging drug plasma levels. Several strategies have been investigated with the intention to influence the microenvironmental pH (pH(M)) within solid formulations and therefore achieve pH-independent release profiles. Because of the heterogeneity of solid systems, a precise prediction of the occurring pH(M) is rather difficult. It is therefore important to monitor the pH(M) within the formulations to achieve requested release as well as to minimise pH-dependent degradation processes of the active compound. The purpose of the current study was the analysis of pH(M) gradients within 2- and 3-layer tablets during hydration using 3 different techniques for comparison intensions, in particular a pH indicator dye, fluorescence imaging and EPR imaging. The influence of the presence or absence of pH modifying substances and of an additional lipophilic inter layer on the pH(M) was investigated as well as the variation of matrix forming excipient and buffer pH. The influence of the pH(M) on drug release was analysed as well. In addition, benchtop MRI was accomplished to gain a deeper insight on the hydration and erosion behaviour of 2- and 3-layer tablets. Copyright © 2010 Elsevier B.V. All rights reserved.

A novel accelerated in vitro release method to evaluate the release of thymopentin from PLGA microspheres.

PubMed

Xie, Xiangyang; Li, Zhiping; Zhang, Ling; Chi, Qiang; Yang, Yanfang; Zhang, Hui; Yang, Yang; Mei, Xingguo

2015-01-01

A novel accelerated method of good correlations with "real-time" release to evaluate in vitro thymopentin release from poly (D, L-lactide-co-glycolide) (PLGA) microsphere was developed. Thymopentin-loaded microspheres were made from three types of PLGA, and peptide release was studied in various conditions. Incomplete release of peptide (<60%) from microspheres was found in accelerated testing with two typical release media. This problem was circumvented by adding organic solvents to the release media and varying the temperature in the media heating process. Release media containing three kinds of organic solvents at 50 °C were tested, respectively, and hydro-alcoholic solution was selected for further study. After the surfactant concentration (0.06%, W/V) and ethanol concentration (20%, V/V) were fixed, a gradient heating program, consisting of three stages and each stage with a different temperature, was introduced to enhance the correlations between the short- and long-term release. After adjusting the heating time of each stage, a good correlation (R(2) = 9896, formulation 8 K; R(2) = 0.9898, formulation 13 K; R(2) = 0.9886, formulation 28 K) between accelerated and "real-time" release was obtained. By optimizing the conditions as ethanol concentration and temperature gradients, this accelerated method may be appropriate for similar peptide formulations that not well correlate with "real-time" release.

Modified release matrix prepared by compaction of spheres containing waxy material.

PubMed

Bado, L; Ghaly, E S

1995-09-01

In this study, chlorpheniramine maleate spheres were prepared by the extruder/marumerizer. A new waxy material, Gelucire 50/02 at three levels (10%, 30% and 50%) was added and Avicel PH-101 was used as spheronizing material. The drug was incorporated into the waxy material by two methods. The first was the direct method, in which the drug (10%), wax and Avicel PH-101 were mixed together. The second was the fusion method, in which the drug was dispersed in the melted wax and the solidified mass was milled and mixed with Avicel PH-101. The data obtained indicated that simple addition of waxy material into chlorpheniramine maleate-Avicel PH-101 spheres interrupted matrix formation and increased drug release. Also in this study, a multiparticulate delivery system was prepared successfully by compaction of spheres into tablets. Tablets compacted from spheres prepared by fusion method gave less drug release than those compacted from spheres of the same composition but prepared with direct method. As the level of wax was increased in tablet formulation, drug release was decreased.

Release of Liposomal Contents by Cell-Secreted Matrix Metalloproteinase-9

PubMed Central

Banerjee, Jayati; Hanson, Andrea J.; Gadam, Bhushan; Elegbede, Adekunle I.; Tobwala, Shakila; Ganguly, Bratati; Wagh, Anil; Muhonen, Wallace W.; Law, Benedict; Shabb, John B.; Srivastava, D. K.; Mallik, Sanku

2011-01-01

Liposomes have been widely used as a drug delivery vehicle and currently, more than 10 liposomal formulations are approved by the Food and Drug Administration for clinical use. However, upon targeting, the release of the liposome-encapsulated contents is usually slow. We have recently demonstrated that contents from appropriately-formulated liposomes can be rapidly released by the cancer-associated enzyme matrix metalloproteinase-9 (MMP-9). Herein, we report our detailed studies to optimize the liposomal formulations. By properly selecting the lipopeptide, the major lipid component and their relative amounts, we demonstrate that the contents are rapidly released in the presence of cancer-associated levels of recombinant human MMP-9. We observed that the degree of lipid mismatch between the lipopepides and the major lipid component profoundly affects the release profiles from the liposomes. By utilizing the optimized liposomal formulations, we also demonstrate that cancer cells (HT-29) which secrete low levels of MMP-9 failed to release significant amount of the liposomal contents. Metastatic cancer cells (MCF7) secreting high levels of the enzyme rapidly release the encapsulated contents from the liposomes. PMID:19601658

Effects of polyvinylpyrrolidone both as a binder and pore-former on the release of sparingly water-soluble topiramate from ethylcellulose coated pellets.

PubMed

Yang, Meiyan; Xie, Si; Li, Qiu; Wang, Yuli; Chang, Xinyi; Shan, Li; Sun, Lei; Huang, Xiaoli; Gao, Chunsheng

2014-04-25

Delivering sparingly water-soluble drugs from ethylcellulose (EC) coated pellets with a controlled-release pattern remains challenging. In the present study, hydrophilic polyvinylpyrrolidone (PVP) was used both as a binder and a pore-former in EC coated pellets to deliver sparingly water-soluble topiramate, and the key factors that influenced drug release were identified. When the binder PVP content in drug layers below 20% w/w was decreased, the physical state of topiramate changed from amorphous to crystalline, making much difference to drug solubility and dissolution rates while modifying the drug release profile from first-order to zero-order. In addition, without PVP in drug layering solution, drug layered particles were less sticky during layering process, thus leading to a shorter process and higher loading efficiency. Furthermore, PVP level as a pore-former in EC coating layers mainly governed drug release from the coated pellets with the sensitivity ranging from 23% to 29%. PVP leaching rate and water permeability from EC/PVP film increased with the PVP level, which was perfectly correlated with drug release rate. Additionally, drug release from this formulation was independent of pH of release media or of the paddle mixing speed, but inversely proportional to the osmolality of release media above the physiological range. Copyright © 2014. Published by Elsevier B.V.

Spray drying of silica microparticles for sustained release application with a new sol-gel precursor.

PubMed

Wang, Bifeng; Friess, Wolfgang

2017-10-30

A new precursor, tetrakis(2-methoxyethyl) orthosilicate (TMEOS) was used to fabricate microparticles for sustained release application, specifically for biopharmaceuticals, by spray drying. The advantages of TMEOS over the currently applied precursors are its water solubility and hydrolysis at moderate pH without the need of organic solvents or catalyzers. Thus a detrimental effect on biomolecular drug is avoided. By generating spray-dried silica particles encapsulating the high molecular weight model compound FITC-dextran 150 via the nano spray dryer Büchi-90, we demonstrated how formulation parameters affect and enable control of drug release properties. The implemented strategies to regulate release included incorporating different quantities of dextrans with varying molecular weight as well as adjusting the pH of the precursor solution to modify the internal microstructures. The addition of dextran significantly altered the released amount, while the release became faster with increasing dextran molecular weight. A sustained release over 35days could be achieved with addition of 60 kD dextran. The rate of FITC-Dextran 150 release from the dextran 60 containing particles decreased with higher precursor solution pH. In conclusion, the new precursor TMEOS presents a promising alternative sol-gel technology based carrier material for sustained release application of high molecular weight biopharmaceutical drugs. Copyright © 2017 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

Prolonged release matrix tablet of pyridostigmine bromide: formulation and optimization using statistical methods.

PubMed

Bolourchian, Noushin; Rangchian, Maryam; Foroutan, Seyed Mohsen

2012-07-01

The aim of this study was to design and optimize a prolonged release matrix formulation of pyridostigmine bromide, an effective drug in myasthenia gravis and poisoning with nerve gas, using hydrophilic - hydrophobic polymers via D-optimal experimental design. HPMC and carnauba wax as retarding agents as well as tricalcium phosphate were used in matrix formulation and considered as independent variables. Tablets were prepared by wet granulation technique and the percentage of drug released at 1 (Y(1)), 4 (Y(2)) and 8 (Y(3)) hours were considered as dependent variables (responses) in this investigation. These experimental responses were best fitted for the cubic, cubic and linear models, respectively. The optimal formulation obtained in this study, consisted of 12.8 % HPMC, 24.4 % carnauba wax and 26.7 % tricalcium phosphate, had a suitable prolonged release behavior followed by Higuchi model in which observed and predicted values were very close. The study revealed that D-optimal design could facilitate the optimization of prolonged release matrix tablet containing pyridostigmine bromide. Accelerated stability studies confirmed that the optimized formulation remains unchanged after exposing in stability conditions for six months.

Effect of vehicles on topical application of aloe vera and arnica montana components.

PubMed

Bergamante, Valentina; Ceschel, Gian Carlo; Marazzita, Sergio; Ronchi, Celestino; Fini, Adamo

2007-10-01

In this study two types of gels and microemulsions are investigated for their ability to dissolve, release, and induce the permeation of helenalin, a flavonoid responsible for the anti-inflammatory activity of arnica montana extract, and aloin, an anthrone-C-glucosyls with antibacterial activity present in aloe vera extract. The release of these agents from each vehicle was followed by HPLC, and transcutaneous permeation was examined using a modified Franz cell and a porcine skin membrane. The study showed that a microemulsion can be a good vehicle to increase the permeation of helenalin, while the gel formulation, containing Sepigel 305, proved able to reduce the release and permeation of aloin, with a consequent activity limited to the surface of application, without any permeation. This is in accordance with the necessity to avoid this process, since human skin fibroblasts can metabolize absorbed aloin into a structurally related compound that increases the sensitivity of skin to ultraviolet light.

Effect of formulation and process variables on lipid based sustained release tablets via continuous twin screw granulation: A comparative study.

PubMed

Kallakunta, Venkata Raman; Tiwari, Roshan; Sarabu, Sandeep; Bandari, Suresh; Repka, Michael A

2018-05-14

The current study's aim is to prepare lipid based sustained release tablets via a twin-screw granulation technique and compare those dosage forms with conventional techniques, namely wet granulation and direct compression. The granules were successfully manufactured in a single-step, continuous twin-screw granulation process with a low proportion of binder (Klucel™ EF, HPC SSL) using Compritol® 888 ATO, Precirol® ATO 5 and Geleol™ as sustained release agents. The granules prepared showed good flow characteristics and compaction properties. DSC and XRD studies were conducted to characterize the granules prepared via a twin-screw granulation method and the results demonstrated the crystalline nature of lipids within the granules. FTIR data indicated that there were no interactions with the formulation components investigated. The formulations developed by all three methods were compressed into tablets with a mechanical strength of 14-16 KP. The tablets formulated were characterized for physicochemical properties, in vitro drug release studies, water uptake and erosion studies. These results showed that the drug was not completely released after 24 h for tablets developed by the wet granulation process using all three lipids. The tablets prepared by the direct compression method demonstrated a burst release within 8 to 10 h from Precirol ATO 5® and Geleol™ formulations compared to Compritol® 888 ATO. However, tablets prepared using twin-screw granulation exhibited sustained release of the drug over 24 h and the water uptake and erosion results were in accordance with dissolution data. Stability data for 45 days at accelerated conditions (40 °C/75% RH) showed similar release profiles with ƒ2 values above 50 for all of the twin screw granulation formulations, indicating the suitability of the process for formulating sustained release tablets. These findings of a single-step, continuous twin-screw granulation process are novel and demonstrate new opportunities for development of sustained release tablets. Copyright © 2017. Published by Elsevier B.V.

Formulation and evaluation of gastroretentive microballoons containing baclofen for a floating oral controlled drug delivery system.

PubMed

Dube, T S; Ranpise, N S; Ranade, A N

2014-01-01

The objective of the present study was to fabricate and evaluate a multiparticulate oral gastroretentive dosage form of baclofen characterized by a central large cavity (hollow core) promoting unmitigated floatation with practical applications to alleviate the signs and symptoms of spasticity and muscular rigidity. Solvent diffusion and evaporation procedure were applied to prepare floating microspheres with a central large cavity using various combinations of ethylcellulose (release retardant) and HPMC K4M (release modifier) dissolved in a mixture of dichloromethane and methanol (2:1). The obtained microspheres (700-1000 µm) exhibit excellent floating ability (86 ± 2.00%) and release characteristics with entrapment efficiency of 95.2 ± 0.32%. Microspheres fabricated with ethylcellulose to HPMC K4M in the ratio 8.5:1.5 released 98.67% of the entrapped drug in 12 h. Muscle relaxation caused by baclofen microspheres impairs the rotarod performance for more than 12 h. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate- labeled microspheres was no less than 10 h. The buoyant baclofen microspheres provide a promising gastroretentive drug delivery system to deliver baclofen in spastic patients with a sustained release rate.

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.

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

PubMed

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

2017-01-01

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

Impact of atomization technique on the stability and transport efficiency of nebulized liposomes harboring different surface characteristics.

PubMed

Lehofer, Bernhard; Bloder, Florian; Jain, Pritesh P; Marsh, Leigh M; Leitinger, Gerd; Olschewski, Horst; Leber, Regina; Olschewski, Andrea; Prassl, Ruth

2014-11-01

The objective of this study was to evaluate the impact of nebulization on liposomes with specific surface characteristics by applying three commercially available inhaler systems (air-jet, ultrasonic and vibrating-mesh). Conventional liposome formulations composed of phosphatidylcholine and cholesterol were compared to sterically stabilized PEGylated liposomes and cationic polymer coated liposomes.Liposomes of similar size (between 140 and 165 nm in diameter with polydispersity indices <0.1) were prepared by dry lipid film rehydration followed by size extrusion. Their stability upon nebulization was determined in terms of size, polydispersity index and leakage using a fluorescence quenching system. The transport efficiencies of the nebulizer devices and the influences of both salt and liposomes on the droplet size distribution of the aerosol were investigated. While the droplet size of the aerosol decreased with increasing salt concentration the liposomes had no influence on the droplet size distribution. The output of the nebulizers in terms of liposomal transport efficiencies differed significantly among the nebulizer principles (20–100%, p < 0.05), with the vibrating-mesh nebulizers being the most effective. The integrity of the conventional liposomes was almost unaffected by the atomization process, while polymer coated and especially positively charged liposomes showed enhanced leakage. The release rates for the hydrophilic model drug system were highest for the vibrating-mesh nebulizers regardless of the surface characteristics of the liposomes (increasing from 10% to 20% and 50% for the conventional, PEGylated and positively charged formulations, respectively). In view of surface modified liposomes our data suggest that drug delivery via nebulization necessitates the finding of a compromise between nebulizer efficiency, formulation stability and drug release profile to accomplish the development of tailored formulations suitable for advanced inhalation therapy.

Controlled release of liraglutide using thermogelling polymers in treatment of diabetes

PubMed Central

Chen, Yipei; Li, Yuzhuo; Shen, Wenjia; Li, Kun; Yu, Lin; Chen, Qinghua; Ding, Jiandong

2016-01-01

In treatment of diabetes, it is much desired in clinics and challenging in pharmaceutics and material science to set up a long-acting drug delivery system. This study was aimed at constructing a new delivery system using thermogelling PEG/polyester copolymers. Liraglutide, a fatty acid-modified antidiabetic polypeptide, was selected as the model drug. The thermogelling polymers were presented by poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) (PCGA-PEG-PCGA) and poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA). Both the copolymers were soluble in water, and their concentrated solutions underwent temperature-induced sol-gel transitions. The drug-loaded polymer solutions were injectable at room temperature and gelled in situ at body temperature. Particularly, the liraglutide-loaded PCGA-PEG-PCGA thermogel formulation exhibited a sustained drug release manner over one week in both in vitro and in vivo tests. This feature was attributed to the combined effects of an appropriate drug/polymer interaction and a high chain mobility of the carrier polymer, which facilitated the sustained diffusion of drug out of the thermogel. Finally, a single subcutaneous injection of this formulation showed a remarkably improved glucose tolerance of mice for one week. Hence, the present study not only developed a promising long-acting antidiabetic formulation, but also put forward a combined strategy for controlled delivery of polypeptide. PMID:27531588

Design and immunological evaluation of anti-CD205-tailored PLGA-based nanoparticulate cancer vaccine.

PubMed

Jahan, Sheikh Tasnim; Sadat, Sams Ma; Haddadi, Azita

2018-01-01

The aim of this research was to develop a targeted antigen-adjuvant assembled delivery system that will enable dendritic cells (DCs) to efficiently mature to recognize antigens released from tumor cells. It is important to target the DCs with greater efficiency to prime T cell immune responses. In brief, model antigen, ovalbumin (OV), and monophosphoryl lipid A adjuvant were encapsulated within the nanoparticle (NP) by double emulsification solvent evaporation method. Targeted NPs were obtained through ligand incorporation via physical adsorption or chemical conjugation process. Intracellular uptake of the NPs and the maturation of DCs were evaluated with flow cytometry. Remarkably, the developed delivery system had suitable physicochemical properties, such as particle size, surface charge, OV encapsulation efficiency, biphasic OV release pattern, and safety profile. The ligand modified formulations had higher targeting efficiency than the non-tailored NPs. This was also evident when the targeted formulations expressed comparatively higher fold increase in surface activation markers such as CD40, CD86, and major histocompatibility complex class II molecules. The maturation of DCs was further confirmed through secretion of extracellular cytokines compared to control cells in the DC microenvironment. Physicochemical characterization of NPs was performed based on the polymer end groups, their viscosities, and ligand-NP bonding type. In conclusion, the DC stimulatory response was integrated to develop a relationship between the NP structure and desired immune response. Therefore, the present study narrates a comparative evaluation of some selected parameters to choose a suitable formulation useful for in vivo cancer immunotherapy.

Controlled release of glaucocalyxin - a self-nanoemulsifying system from osmotic pump tablets with enhanced bioavailability.

PubMed

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

2017-03-01

The purpose of this study was to develop a new formulation to enhance the bioavailability simultaneously with controlled release of glaucocalyxin A (GLA). In this study, controlled release of GLA was achieved by the osmotic release strategy taking advantage of the bioavailability enhancing capacity of self-nanoemulsifying drug delivery systems (SNEDDS). The formulation of GLA-SNEDDS was selected by the solubility and pseudoternary-phase diagrams studies. The prepared GLA-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis and zeta potential. The optimized GLA-SNEDDS were used to prepare GLA-SNEDDS osmotic pump tablet via direct powder compression method. The effect of formulation variables on the release characteristic was investigated. GLA-SNEDDS osmotic pump tablets were administered to beagle dogs and their pharmacokinetics were compared to GLA and GLA-SNEDDS as a control. In vitro drug release studies indicated that the GLA-SNEDDS osmotic pump tablet showed sustained release profiles with 90% released within 12 h. Pharmacokinetic study showed steady blood GLA with prolonged T max and mean residence time (MRT), and enhanced bioavailability for GLA-SNEDDS osmotic pump tablet. It was concluded that simultaneous controlling on GLA release and enhanced bioavailability had been achieved by a combination of osmotic pump tablet and SNEDDS.

Formulation of mucoadhesive gastric retentive drug delivery using thiolated xyloglucan.

PubMed

Bhalekar, Mangesh R; Bargaje, Rajesh V; Upadhaya, Prashant G; Madgulkar, Ashwini R; Kshirsagar, Sanjay J

2016-01-20

Tamarind seed xyloglucan is a polymer reported to possess mucoadhesive property. In the present work, role of cysteine derivative of tamarind seed polysaccharide (thiomer) to enhance the mucoadhesion and its influence on drug permeation has been studied. The xyloglucan was first chemically modified to carboxymethyl derivative which was further converted to thiomer by conjugation with cysteine in presence of a coupling agent, EDAC. The matrix tablets of simvastatin prepared using thiomer demonstrated drug release retardation, increased mucoadhesion force and increased ex vivo permeation, the same were proportional to the increase in the amount of thiomer. The in vivo residence of thiomer placebo was more than 7h in rabbit. Pharmacokinetic evaluation in rabbits indicated higher AUC for the formulation with highest content of thiomer and level 'A' correlation could be established from the generated dissolution and bioavailability data. Copyright © 2015 Elsevier Ltd. All rights reserved.

Development of biodegradable PLGA nanoparticles surface engineered with hyaluronic acid for targeted delivery of paclitaxel to triple negative breast cancer cells.

PubMed

Cerqueira, Brenda Brenner S; Lasham, Annette; Shelling, Andrew N; Al-Kassas, Raida

2017-07-01

This study aimed at development of poly (lactic-co-glycolic acid) (PLGA) nanoparticles embedded with paclitaxel and coated with hyaluronic acid (HA-PTX-PLGA) to actively target the drug to a triple negative breast cancer cells. Nanoparticles were successfully fabricated using a modified oil-in-water emulsion method. The effect of various formulations parameters on the physicochemical properties of the nanoparticles was investigated. SEM imaging confirmed the spherical shape and nano-scale size of the nanoparticles. A sustained drug release profile was obtained and enhanced PTX cytotoxicity was observed when MDA-MB-231 cells were incubated with the HA-PTX-PLGA formulation compared to cells incubated with the non-HA coated nanoparticles. Moreover, HA-PLGA nanoparticles exhibited improved cellular uptake, based on a possible receptor mediated endocytosis due to interaction of HA with CD44 receptors when compared to non-coated PLGA nanoparticles. The non-haemolytic potential of the nanoparticles indicated the suitability of the developed formulation for intravenous administration. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Optimizing novel implant formulations for the prolonged release of biopharmaceuticals using in vitro and in vivo imaging techniques.

PubMed

Beyer, Susanne; Xie, Li; Schmidt, Mike; de Bruin, Natasja; Ashtikar, Mukul; Rüschenbaum, Sabrina; Lange, Christian M; Vogel, Vitali; Mäntele, Werner; Parnham, Michael J; Wacker, Matthias G

2016-08-10

As a rapidly growing class of therapeutics, biopharmaceuticals have conquered the global market. Despite the great potential from a therapeutic perspective, such formulations often require frequent injections due to their short half-life. Aiming to establish a parenteral dosage form with prolonged release properties, a biodegradable implant was developed, based on a combination of nanoencapsulation of protein-heparin complexes, creation of a slow release matrix by freeze-drying, and compression using hyaluronan and methylcellulose. In order to investigate this novel delivery system, formulations containing IFN-β-1a and trypsinogen as model proteins were developed. No degradation of the proteins was observed at any stage of the formulation processing. The potential of the delivery system was evaluated in vivo and in vitro after fluorescence-labeling of the biopharmaceuticals. An optimized agarose gel was utilized as in vitro release medium to simulate the subcutaneous environment in a biorelevant manner. In addition, the formulations were administered to female SJL mice and release was innovatively tracked by fluorescence imaging, setting up an in vitro-in vivo correlation. A prolonged time of residence of approximately 12days was observed for the selected formulation design. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2013-01-01

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

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

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.

Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations.

PubMed

Gesquiere, Ina; Darwich, Adam S; Van der Schueren, Bart; de Hoon, Jan; Lannoo, Matthias; Matthys, Christophe; Rostami, Amin; Foulon, Veerle; Augustijns, Patrick

2015-11-01

The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB. A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6-8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB. After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC(0-24 h)) was shown, although a tendency towards an increased oral exposure could be observed as the AUC(0-24 h) was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity. The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation. © 2015 The British Pharmacological Society.

Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations

PubMed Central

Gesquiere, Ina; Darwich, Adam S; Van der Schueren, Bart; de Hoon, Jan; Lannoo, Matthias; Matthys, Christophe; Rostami, Amin; Foulon, Veerle; Augustijns, Patrick

2015-01-01

Aims The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB. Methods A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6–8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB. Results After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC0–24 h) was shown, although a tendency towards an increased oral exposure could be observed as the AUC0–24 h was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity. Conclusions The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation. PMID:25917170

Preparation of mesoporous silica microparticles by sol-gel/emulsion route for protein release.

PubMed

Vlasenkova, Mariya I; Dolinina, Ekaterina S; Parfenyuk, Elena V

2018-04-06

Encapsulation of therapeutic proteins into particles from appropriate material can improve both stability and delivery of the drugs, and the obtained particles can serve as a platform for development of their new oral formulations. The main goal of this work was development of sol-gel/emulsion method for preparation of silica microcapsules capable of controlled release of encapsulated protein without loss of its native structure. For this purpose, the reported in literature direct sol-gel/W/O/W emulsion method of protein encapsulation was used with some modifications, because the original method did not allow to prepare silica microcapsules capable for protein release. The particles were synthesized using sodium silicate and tetraethoxysilane as silica precursors and different compositions of oil phase. In vitro kinetics of bovine serum albumin (BSA) release in buffer (pH 7.4) was studied by Fourier transform infrared (FTIR) and fluorescence spectrometry, respectively. Structural state of encapsulated BSA and after release was evaluated. It was found that the synthesis conditions influenced substantially the porous structure of the unloaded silica particles, release properties of the BSA-loaded silica particles and structural state of the encapsulated and released protein. The modified synthesis conditions made it possible to obtain the silica particles capable of controlled release of the protein during a week without loss of the protein native structure.

[Studies on preparation of sustained-release Shuxiong formulation, a traditional Chinese medicine compound recipe, using time-controlled release techniques].

PubMed

Song, Hong-Tao; Zhang, Qian; Jiang, Peng; Guo, Tao; Chen, Da-Wei; He, Zhong-Gui

2006-09-01

To prepare a sustained-release formulation of traditional Chinese medicine compound recipe by adopting time-controlled release techniques. Shuxiong tablets were chosen as model drug. The prescription and technique of core tablets were formulated with selecting disintegrating time and swelling volume of core tablets in water as index. The time-controlled release tablets were prepared by adopting press-coated techniques, using PEG6000, HCO and EVA as coating materials. The influences of compositions, preparation process and dissolution conditions in vitro on the lag time (T(lag)) of drug release were investigated. The composition of core tablets was as follow: 30% of drug, 50% MCC and 20% CMS-Na. The T(lag) of time-controlled release tablets was altered remarkably by PEG6000 content of the outer layer, the amount of outer layer and hardness of tablet. The viscosity of dissolution media and basket rotation had less influence on the T(lag) but more on rate of drug release. The core tablets pressed with the optimized composition had preferable swelling and disintegrating properties. The shuxiong sustained-release formulations which contained core tablet and two kinds of time-controlled release tablets with 3 h and 6 h of T(lag) could release drug successively at 0 h, 3 h and 6 h in vitro. The technique made it possible that various components with extremely different physicochemical properties in these preparations could release synchronously.

Extensive preclinical investigation of polymersomal formulation of doxorubicin versus Doxil-mimic formulation.

PubMed

Alibolandi, Mona; Abnous, Khalil; Mohammadi, Marzieh; Hadizadeh, Farzin; Sadeghi, Fatemeh; Taghavi, Sahar; Jaafari, Mahmoud Reza; Ramezani, Mohammad

2017-10-28

Due to the severe cardiotoxicity of doxorubicin, its usage is limited. This shortcoming could be overcome by modifying pharmacokinetics of the drugs via preparation of various nanoplatforms. Doxil, a well-known FDA-approved nanoplatform of doxorubicin as antineoplastic agent, is frequently used in clinics in order to reduce cardiotoxicity of doxorubicin. Since Doxil shows some shortcomings in clinics including hand and food syndrome and very slow release pattern thus, there is a demand for the development and preparation of new doxorubicin nanoformulation with fewer side effects. The new formulation of the doxorubicin, synthesized previously by our group was extensively examined in the current study. This new formulation is doxorubicin encapsulated in PEG-PLGA polymersomes (PolyDOX). The main aim of the study was to compare the distribution and treatment efficacy of a new doxorubicin-polymersomal formulation (PolyDOX) with regular liposomal formulation (Doxil-mimic) in murine colon adenocarcinoma model. Additionally, the pathological, hematological changes, pharmacodynamics, biodistribution, tolerated dose and survival rate in vivo were evaluated and compared. Murine colon cancer model was induced by subcutaneous inoculation of BALB/c mice with C26 cells. Afterwards, either Doxil-mimic or PolyDOX was administered intravenously. The obtained results from biodistribution study showed a remarkable difference in the distribution of drugs in murine organs. In this regard, Doxil-mimic exhibited prolonged (48h) presence within liver tissues while PolyDOX preferentially accumulate in tumor and the presence in liver 48h post-treatment was significantly lower than that of Doxil-mimic. Obtained results demonstrated comparable final length of life for mice receiving either Doxil-mimic or PolyDOX formulations whereas tolerated dose of mice receiving Doxil-mimic was remarkably higher than those receiving PolyDOX. Therapeutic efficacy of formulation in term of tumor growth rate after one injection of formulations (5mg/kg, 10mg/kg or 15mg/kg) demonstrated better efficacy at lower dose for PolyDOX. Analysis of Kaplan Meier curve was in favor of both formulations in their treatment-dose. Pathological and hematological surveys of mice treated with both formulations did not show considerable difference except for a small atrophy in liver observed after successive administration of Doxil-mimic. It could be concluded that PolyDOX can potentially limit off-site effects of Doxil due to its biodegradability and sustained release properties while it exhibited favorable safety profile comparable to Doxil. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Liposomal Aloe vera trans-emulgel drug delivery of naproxen and nimesulide: A study

PubMed Central

Venkataharsha, Panuganti; Maheshwara, Ellutla; Raju, Y Prasanna; Reddy, Vayalpati Ashok; Rayadu, Bandugalla Sanjeev; Karisetty, Basappa

2015-01-01

Introduction: The present aim of this study was to formulate naproxen and nimesulide liposomal formulation for incorporation in Aloe vera transemulgel and to carry out in vitro and in vivo evaluation of the formulation. Material and Methods: A. vera gel was prepared and used as a gel base for formulation. Carbopol 934 is used as a gelling agent and Methyl paraben was used as a preservative for the formulation of the gel. Liposomes was formulated by using hydration method. The formulated naproxen and nimesulide liposomal formulation using A. vera trans-emul gel were evaluated for in vitro studies such as drug release, permeation study, and drug content and entrapment efficiency. Paw edema method in Wistar rats induced by carrageenan is used to study in vivo anti-inflammatory action. Result: From the in vitro studies such permeability drug release naproxen 65% (69.6), Nimesulide 65% (61.1), and commercial Nimsulide gel (60.82) at 240 min. In vivo data shows that formulated liposomal transemulgel formulation are superior in their efficacy compared to commercial and A. vera gel. The results are compared with the commercial formulations. Conclusion: From our results, it is concluded that the A. vera trans emul gel using nimesulide and naproxen liposomal formulation is stable and prepared gel base is effective for formulation with high drug release and drug content compared with commercial formulation with significant anti-inflammatory effect. PMID:25599030

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.

Cell-penetrating peptide-doxorubicin conjugate loaded NGR-modified nanobubbles for ultrasound triggered drug delivery.

PubMed

Lin, Wen; Xie, Xiangyang; Deng, Jianping; Liu, Hui; Chen, Ying; Fu, Xudong; Liu, Hong; Yang, Yang

2016-01-01

A new drug-targeting system for CD13(+) tumors has been developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, the CPP-doxorubicin conjugate (CPP-DOX) was entrapped in the asparagine-glycine-arginine (NGR) peptide modified NB (CPP-DOX/NGR-NB) and the penetration of CPP-DOX was temporally masked; local ultrasound stimulation could trigger the CPP-DOX release from NB and activate its penetration. The CPP-DOX/NGR-NBs had particle sizes of about 200 nm and drug entrapment efficiency larger than 90%. In vitro release results showed that over 85% of the encapsulated DOX or CPP-DOX would release from NBs in the presence of ultrasound, while less than 1.5% of that (30 min) without ultrasound. Cell experiments showed the higher cellular CPP-DOX uptake of CPP-DOX/NGR-NB among the various NB formulations in Human fibrosarcoma cells (HT-1080, CD13(+)). The CPP-DOX/NGR-NB with ultrasound treatment exhibited an increased cytotoxic activity than the one without ultrasound. In nude mice xenograft of HT-1080 cells, CPP-DOX/NGR-NB with ultrasound showed a higher tumor inhibition effect (3.1% of T/C%, day 24), longer median survival time (50 days) and excellent body safety compared with the normal DOX injection group. These results indicate that the constructed vesicle would be a promising drug delivery system for specific cancer treatment.

Conceptuation, formulation and evaluation of sustained release floating tablets of captopril compression coated with gastric dispersible hydrochlorothiazide using 23 factorial design

PubMed Central

Sirisha, Pathuri Lakshmi; Babu, Govada Kishore; Babu, Puttagunta Srinivasa

2014-01-01

Ambulatory blood pressure monitoring is regarded as the gold standard for hypertensive therapy in non-dipping hypertension patients. A novel compression coated formulation of captopril and hydrochlorothiazide (HCTZ) was developed in order to improve the efficacy of antihypertensive therapy considering the half-life of both drugs. The synergistic action using combination therapy can be effectively achieved by sustained release captopril (t1/2= 2.5 h) and fast releasing HCTZ (average t1/2= 9.5 h). The sustained release floating tablets of captopril were prepared by using 23 factorial design by employing three polymers i.e., ethyl cellulose (EC), carbopol and xanthan gum at two levels. The formulations (CF1-CF8) were optimized using analysis of variance for two response variables, buoyancy and T50%. Among the three polymers employed, the coefficients and P values for the response variable buoyancy and T50% using EC were found to be 3.824, 0.028 and 0.0196, 0.046 respectively. From the coefficients and P values for the two response variables, formulation CF2 was optimized, which contains EC polymer alone at a high level. The CF2 formulation was further compression coated with optimized gastric dispersible HCTZ layer (HF9). The compression coated tablet was further evaluated using drug release kinetics. The Q value of HCTZ layer is achieved within 20 min following first order release whereas the Q value of captopril was obtained at 6.5 h following Higuchi model, from which it is proved that rapid release HCTZ and slow release of captopril is achieved. The mechanism of drug release was analyzed using Peppas equation, which showed an n >0.90 confirming case II transportation mechanism for drug release. PMID:25006552

Accelerating the dissolution of enteric coatings in the upper small intestine: evolution of a novel pH 5.6 bicarbonate buffer system to assess drug release.

PubMed

Varum, Felipe J O; Merchant, Hamid A; Goyanes, Alvaro; Assi, Pardis; Zboranová, Veronika; Basit, Abdul W

2014-07-01

Despite rapid dissolution in compendial phosphate buffers, gastro resistant (enteric coated) products can take up to 2 h to disintegrate in the human small intestine, which clearly highlights the inadequacy of the in vitro test method to predict in vivo behaviour of these formulations. The aim of this study was to establish the utility of a novel pH 5.6 bicarbonate buffer, stabilized by an Auto pH™ System, as a better surrogate of the conditions of the proximal small intestine to investigate the dissolution behaviour of standard and accelerated release enteric double coating formulations. Prednisolone tablets were coated with 3 or 5 mg/cm(2) of partially neutralized EUDRAGIT(®) L 30 D-55, HP-55 or HPMC adjusted to pH 6 or 8. An outer layer of EUDRAGIT(®) L 30 D-55 was applied at 5mg/cm(2). For comparison purposes, a standard single layer of EUDRAGIT(®) L 30 D-55 was applied to the tablets. Dissolution was carried out using USP II apparatus in 0.1 M HCl for 2 h, followed by pH 5.6 bicarbonate buffer. EUDRAGIT(®) L 30 D-55 single-coated tablets showed a slow drug release with a lag time of 75 min in buffer, whereas release from the EUDRAGIT(®) L 30 D-55 double-coated tablets was accelerated. These in vitro lag times closely match the in vivo disintegration times for these coated tablets reported previously. Drug release was further accelerated from modified double coatings, particularly in the case of coatings with a thinner inner layer of HP-55 or HPMC (pH 8 and KH2PO4). This study confirms that the pH 5.6 bicarbonate buffer system offers significant advantages during the development of dosage forms designed to release the drug in the upper small intestine. Copyright © 2014. Published by Elsevier B.V.

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.

A mathematical model for interpreting in vitro rhGH release from laminar implants.

PubMed

Santoveña, A; García, J T; Oliva, A; Llabrés, M; Fariña, J B

2006-02-17

Recombinant human growth hormone (rhGH), used mainly for the treatment of growth hormone deficiency in children, requires daily subcutaneous injections. The use of controlled release formulations with appropriate rhGH release kinetics reduces the frequency of medication, improving patient compliance and quality of life. Biodegradable implants are a valid alternative, offering the feasibility of a regular release rate after administering a single dose, though it exists the slight disadvantage of a very minor surgical operation. Three laminar implant formulations (F(1), F(2) and F(3)) were produced by different manufacture procedures using solvent-casting techniques with the same copoly(D,L-lactic) glycolic acid (PLGA) polymer (Mw=48 kDa). A correlation in vitro between polymer matrix degradation and drug release rate from these formulations was found and a mathematical model was developed to interpret this. This model was applied to each formulation. The obtained results where explained in terms of manufacture parameters with the aim of elucidate whether drug release only occurs by diffusion or erosion, or by a combination of both mechanisms. Controlling the manufacture method and the resultant changes in polymer structure facilitates a suitable rhGH release profile for different rhGH deficiency treatments.

[Study on sustained release preparations of Epimedium component].

PubMed

Yan, Hong-mei; Ding, Dong-mei; Zhang, Zhen-hai; Sun, E; Song, Jie; Jia, Xiao-bin

2015-04-01

The formulation for sustained release tablet of Epinedium component was selected and the evaluation equation of in vitro release was established. The liquidity of component was improved with the help of colloidal silica aided by spray drying, which would be the main drug in the sustained release tablets. Dissolution was selected as an evaluation index to investigate skeletal material type, fillers, impact porogen, lubricants and other materials on the quality of sustained release tablet. The sustained release tablets were prepared by dry compression. Formulation of sustained release preparations was main drug 35%, HPMC K(4M) 20% and HPMC K(15M) 10% as skeleton material, MCC 31% as filler, PEG6000 2% as porogen and magnesium stearate 2% as lubricant. The sustained release tablets released up to 80% in 8 h. The zero order equation, primary equation and Higuchi equation could simulate the release characteristics of sustained release tablets in vitro, the correlation coefficients r were larger than 0.96. The primary equation was most similar in vitro release characteristics and its correlation coefficient r was 0.9950. The preparation method is simple and the results of formulation selection are reliable. It can be used to guide the production of Epimedium component sustained release preparations.

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.

The effect of excipients on the release kinetics of diclofenac sodium and papaverine hydrochloride from composed tablets.

PubMed

Kasperek, Regina; Trebacz, Hanna; Zimmer, Łukasz; Poleszak, Ewa

2014-01-01

For increased analgesic effect, new composed tablets containing diclofenac sodium (DIC) with an addition of papaverine hydrochloride (PAP) were prepared to investigate the mechanism of release of the active substances from tablets with different excipients in eight different formulations. To detect the possible interactions between active substances and excipients differential scanning calorimetry (DSC) was used. A shift of the melting point and enthalpy values of the physical mixtures of tablets components suggested a kind of interaction between components in certain formulations, however, the tabletting process was not disturbed in any of them. Kinetics of drug release from formulations was estimated by zero order, first order and Higuchi and Korsmeyer-Peppas models using results of dissolution of DIC and PAP from tablets. The study revealed that the mechanism of release of active substances was dependent on the excipients contained in tablets and the best fitted kinetics models were obtained for formulations with potentially prolonged release of DIC and PAP.

A novel hydrogel plug of Sterculia urens for pulsatile delivery: in vitro and in vivo evaluation.

PubMed

Amrutkar, Jitendra R; Gattani, Surendra G

2012-01-01

The objective of this study was to investigate a novel hydrogel plug using isolated root mucilage of Sterculia urens to obtain a desired lag time for an oral chronotherapeutic colon-specific pulsatile drug delivery of indomethacin. Pulsatile drug delivery was developed using chemically treated hard gelatin capsule bodies filled with eudragit multiparticulates of indomethacin, and sealed with different hydrogel plugs (root mucilage of S. urens, xanthan gum, guar gum, HPMC K4M and combination of maltodextrin with guar gum). Indomethacin multiparticulates were prepared using extrusion spheronization, spray drying and solvent evaporation techniques with Eudragit® L-100 and S-100 (1:2) by varying drug-to-polymer ratio. After oral administration, the water-soluble cap of capsule dissolved in the intestinal fluid and the hydrogel plug swells. After a controlled time, the swollen plug subsequently ejected from the dosage form, releases the contents of the capsule. The formulation factors affecting the drug release were concentration and types of hydrogel plug used. In vivo gamma scintigraphy study in healthy rabbits proved the capability of the system to release drug in lower parts of the gastrointestinal tract after a programmed lag time. This study demonstrates that the indomethacin multiparticulates could be successfully colon-targeted by the design of time and pH-dependent modified chronopharmaceutical formulation. In conclusion, the investigated novel hydrogel plug could be a valuable tool for achieving desired lag time.

Depot formulation of vasoactive intestinal peptide by protamine-based biodegradable nanoparticles.

PubMed

Wernig, Karin; Griesbacher, Martin; Andreae, Fritz; Hajos, Franz; Wagner, Julian; Mosgoeller, Wilhelm; Zimmer, Andreas

2008-09-10

Drug delivery of protein and peptide-based drugs, which represent a growing and important therapeutic class, is hampered by these drugs' very short half-lives. High susceptibility towards enzymatic degradation necessitates frequent drug administration followed by poor adherence to therapy. Among these drugs is vasoactive intestinal peptide (VIP), a potent systemic and pulmonary vasodilator, which is a promising drug for the treatment of idiopathic pulmonary arterial hypertension (IPAH). Encapsulation of VIP into the nanoparticle matrix of biodegradable protamine-oligonucleotide nanoparticles (proticles) protects the peptide against rapid enzymatic degradation. Additionally, the nanoparticle matrix will be able to sustain drug release. Proticles consist of 18mer non-sense oligonucleotides and protamine, a polycationic arginine-rich peptide. VIP encapsulation occurs during self-assembly of the components. Within the present study, we evaluate nanoparticle size (hydrodynamic diameter) and zeta potential of VIP-loaded proticles as well as encapsulation efficiency and VIP release. Further, the pharmacological VIP response of "encapsulated VIP" is investigated using an ex vivo lung arterial model system. We found satisfying encapsulation efficiency (up to 80%), VIP release (77-87%), and an appropriate nanoparticle size (177-251 nm). Investigations on rat pulmonary arteries showed a modified VIP response of proticle-associated VIP. We noted differences in the profile of artery relaxation where VIP proticles lead to a 20-30% lower relaxation maximum than aqueous VIP solutions followed by prolonged vasodilatation. Our data indicate that proticles could be a feasible drug delivery system for a pulmonary VIP depot formulation.

Assessment of PLGA-PEG-PLGA Copolymer Hydrogel for Sustained Drug Delivery in the Ear

PubMed Central

Feng, Liang; Ward, Jonette A.; Li, S. Kevin; Tolia, Gaurav; Hao, Jinsong; Choo, Daniel I.

2014-01-01

Temperature sensitive copolymer systems were previously studied using modified diffusion cells in vitro for intratympanic injection, and the PLGA-PEG-PLGA copolymer systems were found to provide sustained drug delivery for several days. The objectives of the present study were to assess the safety of PLGA-PEG-PLGA copolymers in intratympanic injection in guinea pigs in vivo and to determine the effects of additives glycerol and poloxamer in PLGA-PEG-PLGA upon drug release in the diffusion cells in vitro for sustained inner ear drug delivery. In the experiments, the safety of PLGA-PEG-PLGA copolymers to inner ear was evaluated using auditory brainstem response (ABR). The effects of the additives upon drug release from PLGA-PEG-PLGA hydrogel were investigated in the modified Franz diffusion cells in vitro with cidofovir as the model drug. The phase transition temperatures of the PLGA-PEG-PLGA copolymers in the presence of the additives were also determined. In the ABR safety study, the PLGA-PEG-PLGA copolymer alone did not affect hearing when delivered at 0.05-mL dose but caused hearing loss after 0.1-mL injection. In the drug release study, the incorporation of the bioadhesive additive, poloxamer, in the PLGA-PEG-PLGA formulations was found to decrease the rate of drug release whereas the increase in the concentration of the humectant additive, glycerol, provided the opposite effect. In summary, the PLGA-PEG-PLGA copolymer did not show toxicity to the inner ear at the 0.05-mL dose and could provide sustained release that could be controlled by using the additives for inner ear applications. PMID:24438444

Modified-release hydrocortisone to provide circadian cortisol profiles.

PubMed

Debono, Miguel; Ghobadi, Cyrus; Rostami-Hodjegan, Amin; Huatan, Hiep; Campbell, Michael J; Newell-Price, John; Darzy, Ken; Merke, Deborah P; Arlt, Wiebke; Ross, Richard J

2009-05-01

Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm. Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles. The study was performed at a Clinical Research Facility. Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen. The key variables in the physiological cortisol profile included: peak 15.5 microg/dl (95% reference range 11.7-20.6), acrophase 0832 h (95% confidence interval 0759-0905), nadir less than 2 microg/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (sem) maximum observed concentration of 16.6 (1.4) microg/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol.

In vivo biocompatibility, sustained-release and stability of triptorelin formulations based on a liquid, degradable polymer.

PubMed

Asmus, Lutz R; Tille, Jean-Christophe; Kaufmann, Béatrice; Melander, Louise; Weiss, Torsten; Vessman, Kerstin; Koechling, Wolfgang; Schwach, Grégoire; Gurny, Robert; Möller, Michael

2013-02-10

Hexylsubstituted poly(lactic acid) (hexPLA) is a viscous polymer, which degrades in the presence of water similar to the structure related poly(lactic acid). With hydrophilic active compounds, like Triptorelin acetate, the lipophilic polymer was formulated in form of parenterally injectable suspensions. This first in vivo study toward the biocompatibility of hexPLA implants in rats over 3 months in comparison to in situ forming poly(lactic-co-glycolic acid) (PLGA) formulations is presented here. The hexPLA implants showed only a mild acute inflammation at the injection site after application, which continuously regressed. In contrast to the PLGA formulations, hexPLA did not provoke an encapsulation of the implant with extracellular matrix. Prior to the formulation application, the stability of Triptorelin inside the hexPLA matrix was assessed under different storage conditions and in the presence of buffer to simulate a peptide degrading environment. At 5°C Triptorelin showed a stability of 98% inside the polymer for at least 6 months. The stability was still 78% at an elevated temperature of 40°C. HexPLA protected the incorporated peptide from the surrounding aqueous environment, which resulted in 20% less degradation inside the polymer compared to the solution. This protection effect supports the use of Triptorelin-hexPLA formulations for parenteral sustained-release formulations. In a second in vivo evaluation in Wistar Hannover rats, formulations containing 5% and 10% Triptorelin in the polymeric matrix released the active compound continuously for 6 months. The formulations showed a higher release during the initial 7 days, which is necessary for the clinical use to down-regulate all GnRH-receptors. Afterwards, a zero order drug release was observed over the first 3 months. After 3 months, the plasma levels decreased slowly but remained at effective concentrations for the total of 6 months. Furthermore, a qualitative in vitro-in vivo correlation was observed, possibly facilitating future optimization of the Triptorelin-hexPLA sustained-release formulations. Copyright © 2012 Elsevier B.V. All rights reserved.

Eco-friendly PEG-based controlled release nano-formulations of Mancozeb: Synthesis and bioefficacy evaluation against phytopathogenic fungi Alternaria solani and Sclerotium rolfsii.

PubMed

Majumder, Sujan; Shakil, Najam A; Kumar, Jitendra; Banerjee, Tirthankar; Sinha, Parimal; Singh, Braj B; Garg, Parul

2016-12-01

Controlled release (CR) nano-formulations of Mancozeb (manganese-zinc double salt of N,N-bisdithiocarbamic acid), a protective fungicide, have been prepared using laboratory-synthesized poly(ethylene glycols) (PEGs)-based functionalized amphiphilic copolymers without using any surfactants or external additives. The release kinetics of the developed Mancozeb CR formulations were studied and compared with that of commercially available 42% suspension concentrate and 75% wettable powder. Maximum amount of Mancozeb was released on 42nd day for PEG-600 and octyl chain, PEG-1000 and octyl chain, and PEG-600 and hexadecyl chain, on 35th day for PEG-1000 and hexadecyl chain, on 28th day for PEG-1500 and octyl chain, PEG-2000 and octyl chain, PEG-1500 and hexadecyl chain, and PEG-2000 and hexadecyl chain in comparison to both commercial formulations (15th day). The diffusion exponent (n value) of Mancozeb in water ranged from 0.42 to 0.62 in tested formulations. The half-release (t 1/2 ) values ranged from 17.35 to 35.14 days, and the period of optimum availability of Mancozeb ranged from 18.54 to 35.42 days. Further, the in vitro bioefficacy evaluation of developed formulations was done against plant pathogenic fungi Alternaria solani and Sclerotium rolfsii by poison food technique. Effective dose for 50% inhibition in mgL -1 (ED 50 ) values of developed formulations varied from 1.31 to 2.79 mg L -1 for A. solani, and 1.60 to 3.14 mg L -1 for S. rolfsii. The present methodology is simple, economical, and eco-friendly for the development of environment-friendly CR formulations of Mancozeb. These formulations can be used to optimize the release of Mancozeb to achieve disease control for the desired period depending upon the matrix of the polymer used. Importantly, the maximum amount of active ingredient remains available for a reasonable period after application. In addition, the developed CR formulations were found to be suitable for fungicidal applications, allowing use of Mancozeb in lower doses.

Formulation and development of pH-independent/dependent sustained release matrix tablets of ondansetron HCl by a continuous twin-screw melt granulation process.

PubMed

Patil, Hemlata; Tiwari, Roshan V; Upadhye, Sampada B; Vladyka, Ronald S; Repka, Michael A

2015-12-30

The objective of the present study was to develop pH-independent/dependent sustained release (SR) tablets of ondansetron HCl dihydrate (OND), a selective 5-HT3 receptor antagonist that is used for prevention of nausea and vomiting caused by chemotherapy, radiotherapy and postoperative treatment. The challenge with the OND API is its pH-dependent solubility and relatively short elimination half-life. Therefore, investigations were made to solve these problems in the current study. Formulations were prepared using stearic acid as a binding agent via a melt granulation process in a twin-screw extruder. The micro-environmental pH of the tablet was manipulated by the addition of fumaric acid to enhance the solubility and release of OND from the tablet. The in vitro release study demonstrated sustained release for 24h with 90% of drug release in formulations using stearic acid in combination with ethyl cellulose, whereas 100% drug release in 8h for stearic acid-hydroxypropylcellulose matrices. The formulation release kinetics was correlated to the Higuchi diffusion model and a non-Fickian drug release mechanism. The results of the present study demonstrated for the first time the pH dependent release from hydrophilic-lipid matrices as well as pH independent release from hydrophobic-lipid matrices for OND SR tablets manufactured by means of a continuous melt granulation technique utilizing a twin-screw extruder. Copyright © 2015 Elsevier B.V. All rights reserved.

An Accelerated Release Method of Risperidone Loaded PLGA Microspheres with Good IVIVC.

PubMed

Hu, Xiaoqin; Zhang, Jianwei; Tang, Xuemei; Li, Mingyuan; Ma, Siyu; Liu, Cheng; Gao, Yue; Zhang, Yue; Liu, Yan; Yu, Fanglin; Yang, Yang; Guo, Jia; Li, Zhiping; Mei, Xingguo

2018-01-01

A long release period lasting several days or several weeks is always needed and thereby it is tedious and time consuming to screen formulations of such microspheres with so long release period and evaluate their release profiles in vitro with conventional long-term or "real-time" release method. So, an accelerated release testing of such system is necessary for formulation design as well as quality control purpose. The purpose of this study is to obtain an accelerated release method of risperidone loaded poly(lactic-co-glycolic acid) (PLGA) microspheres with good in vitro/in vivo correlation (IVIVC). Two formulations of risperidone loaded PLGA microspheres used for evaluating IVIVC were prepared by O/W method. The accelerated release condition was optimized by investigating the effect of pH, osmotic pressure, temperature and ethanol concentration on the release of risperidone from microspheres and the in vitro accelerated release profiles of risperidone from PLGA microspheres were obtained under this optimized accelerated release condition. The plasma concentration of risperidone were also detected after subcutaneous injection of risperidone loaded microspheres to rats. The in vivo cumulative absorption profiles were then calculated using Wagner-Nelson model, Loo- Riegelman model and numerical convolution model, respectively. The correlation between in vitro accelerated release and in vivo cumulative absorption were finally evaluated with Least Square Method. It was shown that temperature and ethanol concentration significantly affected the release of risperidone from the microspheres while pH and osmotic pressure of release media slightly affected the release behavior of risperidone. The in vitro release of risperidone from microspheres were finally undergone in PBS (pH7.0, 300mosm) with 20% (V/V) ethanol at 45°C. The sustained and complete release of risperidone was observed in both formulations under the accelerated release condition although these two release profiles were dissimilar. The correlation coefficients (R2) of IVIVC were all above 0.95 and the slopes were all between 0.9564 and 1.1868 in spite of fitted model and microsphere formulation. An in vitro accelerated release method of risperidone microspheres with good IVIVC was established in this paper and this accelerated release method was supposed to have great potential in both in vivo performance prediction and quality control for risperidone loaded PLGA microspheres. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Formulation and In Vitro, In Vivo Evaluation of Effervescent Floating Sustained-Release Imatinib Mesylate Tablet

PubMed Central

Kadivar, Ali; Kamalidehghan, Behnam; Javar, Hamid Akbari; Davoudi, Ehsan Taghizadeh; Zaharuddin, Nurul Dhania; Sabeti, Bahareh; Chung, Lip Yong; Noordin, Mohamed Ibrahim

2015-01-01

Introduction Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT). Conventional imatinib mesylate (Gleevec) tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets. Methodology Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M), with Sodium alginate (SA) and Carbomer 934P (CP) as release-retarding polymers, sodium bicarbonate (NaHCO3) as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec) in 0.1 N HCl (pH 1.2) at 37 ± 0.5°C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted. Results and Discussion Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO3 produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower Cmax and higher Tmax compared to the conventional tablet (Gleevec). Thus, formulated SR tablets preserved persistent concentration of plasma up to 24 hours. Conclusion In conclusion, in order to suggest a better drug delivery system with constant favorable release, resulting in optimized absorption and less side effects, formulated CP-HPMC-SA based imatinib mesylate floating sustained-release tablets can be a promising candidate for cancer chemotherapy. PMID:26035710

Innovative Approach for Interstitial Cystitis: Vaginal Pessaries Loaded Diazepam—A Preliminary Study

PubMed Central

Capra, P.; Perugini, P.; Bleve, M.; Pavanetto, P.; Musitelli, G.; Rovereto, B.; Porru, D.

2013-01-01

Bladder pain is a characteristic disorder of interstitial cystitis. Diazepam is well known for its antispasmodic activity in the treatment of muscular hypertonus. The aim of this work was to develop and characterize vaginal pessaries as an intravaginal delivery system of diazepam for the treatment of interstitial cystitis. In particular, the performance of two types of formulations, with and without beta-glucan, was compared. In particular, the preparation of pessaries, according to the modified Pharmacopeia protocol, the setup of the analytical method to determine diazepam, pH evaluation, dissolution profile, and photostability assay were reported. Results showed that the modified protocol permitted obtaining optimal vaginal pessaries, without air bubbles, with good consistency and handling and with good pH profiles. In order to determine the diazepam amount, calibration curves with good correlation coefficients were obtained, by the spectrophotometric method, using placebo pessaries as matrix with the addition of diazepam standard solution. This method was demonstrated sensible and accurate to determine the amount of drug in batches. Dissolution profiles showed a complete diazepam release just after 15 minutes, even if beta-glucan pessaries released drug more gradually. Finally, a possible drug photodegradation after exacerbated UV-visible exposition was evaluated. PMID:26555976

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 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

Hyaluronic acid modified pH-sensitive liposomes for targeted intracellular delivery of doxorubicin.

PubMed

Paliwal, Shivani Rai; Paliwal, Rishi; Agrawal, Govind Prasad; Vyas, Suresh Prasad

2016-12-01

Surface-modified pH-sensitive liposomal system may be useful for intracellular delivery of chemotherapeutics. Achieving site-specific targeting with over-expressed hyaluronic acid (HA) receptors along with using pH sensitive liposome carrier for intracellular drug delivery was the aim of this study. Stealth HA-targeted pH-sensitive liposomes (SL-pH-HA) were developed and evaluated to achieve effective intracellular delivery of doxorubicin (DOX) vis-a-vis enhanced antitumor activity. The in vitro release studies demonstrated that the release of DOX from SL-pH-HA was pH-dependent, i.e. faster at mildly acidic pH ∼5, compared to physiological pH ∼7.4. SLpH-HA was evaluated for their cytotoxicity potential on CD44 receptor expressing MCF-7 cells. The half maximal inhibitory concentration (IC50) of SL-pH-HA and SL-HA were about 1.9 and 2.5 μM, respectively, after 48 h of incubation. The quantitative uptake study revealed higher localization of targeted liposomes in the receptor positive cells, which was further confirmed by fluorescent microscopy. The antitumor efficacy of the DOX-loaded HA-targeted pH-sensitive liposomes was also verified in a tumor xenograft mouse model. DOX was efficiently delivered to the tumor site by active targeting via HA and CD44 receptor interaction. The major side-effect of conventional DOX formulation, i.e. cardiotoxicity was also estimated by measuring serum enzyme levels of LDH and CPK and found to be minimized with developed formulation. Overall, HA targeted pH-sensitive liposomes were significantly more potent than the non-targeted liposomes in cells expressing high levels of CD44. Results strongly implies the promise of such liposomal system as an intracellular drug delivery carrier developed for potential anticancer treatment.

Nanostructured lipid systems modified with waste material of propolis for wound healing: Design, in vitro and in vivo evaluation.

PubMed

Rosseto, Hélen Cássia; Toledo, Lucas de Alcântara Sica de; Francisco, Lizziane Maria Belloto de; Esposito, Elisabetta; Lim, Yunsook; Valacchi, Giuseppe; Cortesi, Rita; Bruschi, Marcos Luciano

2017-10-01

Propolis, a natural compound that can accelerate the wound healing process, is mainly used as ethanolic extract. The extractive solution may also be obtained from the propolis by-product (BP), transforming this waste material into a pharmaceutical active ingredient. Even if propolis does not show toxicity, when used as an extract over harmed skin or mucosa, the present ethanol content may be harmful to the tissue recovering, besides hindering the drug release. This study describes the development of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) as topical propolis delivery systems and the investigation of their in vitro and in vivo activities. The extracts were evaluated to guarantee their quality, and the lipid dispersions were characterized with respect to morphology (cryo-TEM), size and diffractometry (X-ray) properties. The occlusive capacity of formulations was also evaluated by an in vitro technique, which determines the occlusion factor. The drug entrapment efficiency (EE), as well as the in vitro drug release profile from the nanoparticulate systems was investigated as well. The size analysis performed through 90days was favorable to a topical administration and the polydispersity index, though not ideal in all cases due to the high content of resins and gums from the extracts, were relatively stable for the SLN. The propolis extract contributes to the occlusive potential of the formulations. The human immortalized keratinocytes presented good cell viability when tested with both extracts (propolis and BP) freely or entrapped in the systems. SLN modified with propolis material provided an acceleration of the in vivo wound healing process. Copyright © 2017 Elsevier B.V. All rights reserved.

Polymer brush hexadecyltrimethylammonium bromide (CTAB) modified poly (propylene-g-styrene sulphonic acid) fiber (ZB-1): CTAB/ZB-1 as a promising strategy for improving the dissolution and physical stability of poorly water-soluble drugs.

PubMed

Cao, Jinxu; Yang, Baixue; Wang, Yumei; Wei, Chen; Wang, Hongyu; Li, Sanming

2017-11-01

The feasibility of polymer brush as drug delivery vehicle was demonstrated with the goal of improving the dissolution and physical stability of poorly water-soluble drugs. Polymer brush CTAB/ZB-1 was synthesized by electrostatic interaction using a physical modification method with anionic poly (propylene-g-styrene sulphonic acid) fiber (ZB-1) as the substrate and cationic hexadecyltrimethylammonium bromide (CTAB) as the modifier. The polymer brush structure of CTAB/ZB-1 was validated by atomic force microscopy (AFM) and the channels of brush provided the drug loading sites. Flurbiprofen (FP), a BCS class II representative drug, was selected as the model poorly water-soluble drug to be loaded into this polymer brush. Then the drug loading and release were systematically investigated. Besides, the transformation from crystalline FP to amorphous state was observed by differential scanning calorimeter (DSC). In vitro dissolution in pure water and pH1.2 HCl media with/without 0.1% sodium dodecyl sulfate (SDS) was tested. Moreover, the optimal formulations (namely carrier/drug ratios) were determined. The results demonstrated prominent improvement of dissolution when FP was released from CTAB/ZB-1. After a long time storage, FP remained amorphous in CTAB/ZB-1 according to DSC determinations and performed an approximately equivalent dissolution compared with fresh samples, suggesting the advantage of CTAB/ZB-1 as carrier in enhancing the physical stability of drugs. The study introduced the versatile easily formulated polymer brush CTAB/ZB-1 and demonstrated the potential of polymer brush as an alternative approach for improving the dissolution and physical stability of poorly water-soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Characterization of drug release from liposomal formulations in ocular fluid.

PubMed

Jafari, M R; Jones, A B; Hikal, A H; Williamson, J S; Wyandt, C M

1998-01-01

The successful application of liposomes in topical ophthalmic drug delivery requires knowledge of vesicle stabilization in the presence of tear fluid. The release of procaine hydrochloride (PCH) from large unilamellar liposomes in the presence of simulated tear fluid was studied in vitro as a function of bilayer lipid content and tear protein composition. Reverse-phase evaporation vesicles were prepared from egg phosphatidylcholine, stearylamine or dicetyl phosphate, and cholesterol. The relationship between lipid composition and encapsulation efficiency, vesicle size, drug leakage upon storage at 4 degrees C, and the release of PCH-loaded liposomes was studied. The encapsulation efficiency was found to be dependent upon the lipid composition used in the liposome preparation. In particular, phosphatidylcholine vesicles containing cholesterol and/or charged lipids had a lower entrapment efficiency than liposomes prepared with phosphatidylcholine alone. However, the drug release rate was reduced significantly by inclusion of cholesterol and/or charged lipids in the liposomes. The release kinetics of the entrapped agent seemed to be a biphasic process and the drug-release in both simulated tear fluid (STF) and pH 7.4 phosphate buffered saline (PBS) solutions followed pseudo first-order kinetics in the early stage of the release profile. The drug-release appeared to be diffusion and/or partition controlled. Drug release from liposomes into STF, pH 7.4 PBS, and five different modified tear formulations was also evaluated. While serum-induced leakage is attributed to high-density lipoprotein-mediated destabilization, it was determined that lactoferrin might be the protein component in tear fluid that has the primary influence on the liposome-entrapped drug release rate. Five local anesthetics, benoxinate, proparacaine, procaine, tetracaine, and benzocaine were entrapped in liposomal vesicles by a reverse-phase evaporation (REV) technique. The release of these structurally similar topical anesthetics entrapped in positively charged liposomes (egg phosphatidylcholine, stearylamine, and cholesterol in a 7:2:1 molar ratio) was evaluated in a simulated tear fluid and pH 7.4 phosphate buffered saline solution. The liposomes appeared to be useful carriers for these drugs to retard their in vitro release in tear fluid and perhaps sustain or control their release in the eye for better therapeutic efficacy. An analysis of the release data demonstrated that for this series of drugs, drug partition coefficient has the largest effect on release rate, with molecular weight exhibiting a smaller effect. Release rate was found to decrease with increased lipophilicity or increased molecular weight.

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.

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

Single Layer Extended Release Two-in-One Guaifenesin Matrix Tablet: Formulation Method, Optimization, Release Kinetics Evaluation and Its Comparison with Mucinex® Using Box-Behnken Design.

PubMed

Morovati, Amirhosein; Ghaffari, Alireza; Erfani Jabarian, Lale; Mehramizi, Ali

2017-01-01

Guaifenesin, a highly water-soluble active (50 mg/mL), classified as a BCS class I drug. Owing to its poor flowability and compressibility, formulating tablets especially high-dose one, may be a challenge. Direct compression may not be feasible. Bilayer tablet technology applied to Mucinex®, endures challenges to deliver a robust formulation. To overcome challenges involved in bilayer-tablet manufacturing and powder compressibility, an optimized single layer tablet prepared by a binary mixture (Two-in-one), mimicking the dual drug release character of Mucinex ® was purposed. A 3-factor, 3-level Box-Behnken design was applied to optimize seven considered dependent variables (Release "%" in 1, 2, 4, 6, 8, 10 and 12 h) regarding different levels of independent one (X 1 : Cetyl alcohol, X 2 : Starch 1500 ® , X 3 : HPMC K100M amounts). Two granule portions were prepared using melt and wet granulations, blended together prior to compression. An optimum formulation was obtained (X 1 : 37.10, X 2 : 2, X 3 : 42.49 mg). Desirability function was 0.616. F2 and f1 between release profiles of Mucinex® and the optimum formulation were 74 and 3, respectively. An n-value of about 0.5 for both optimum and Mucinex® formulations showed diffusion (Fickian) control mechanism. However, HPMC K100M rise in 70 mg accompanied cetyl alcohol rise in 60 mg led to first order kinetic (n = 0.6962). The K values of 1.56 represented an identical burst drug releases. Cetyl alcohol and starch 1500 ® modulated guaifenesin release from HPMC K100M matrices, while due to their binding properties, improved its poor flowability and compressibility, too.

Single Layer Extended Release Two-in-One Guaifenesin Matrix Tablet: Formulation Method, Optimization, Release Kinetics Evaluation and Its Comparison with Mucinex® Using Box-Behnken Design

PubMed Central

Morovati, Amirhosein; Ghaffari, Alireza; Erfani jabarian, Lale; Mehramizi, Ali

2017-01-01

Guaifenesin, a highly water-soluble active (50 mg/mL), classified as a BCS class I drug. Owing to its poor flowability and compressibility, formulating tablets especially high-dose one, may be a challenge. Direct compression may not be feasible. Bilayer tablet technology applied to Mucinex®, endures challenges to deliver a robust formulation. To overcome challenges involved in bilayer-tablet manufacturing and powder compressibility, an optimized single layer tablet prepared by a binary mixture (Two-in-one), mimicking the dual drug release character of Mucinex® was purposed. A 3-factor, 3-level Box-Behnken design was applied to optimize seven considered dependent variables (Release “%” in 1, 2, 4, 6, 8, 10 and 12 h) regarding different levels of independent one (X1: Cetyl alcohol, X2: Starch 1500®, X3: HPMC K100M amounts). Two granule portions were prepared using melt and wet granulations, blended together prior to compression. An optimum formulation was obtained (X1: 37.10, X2: 2, X3: 42.49 mg). Desirability function was 0.616. F2 and f1 between release profiles of Mucinex® and the optimum formulation were 74 and 3, respectively. An n-value of about 0.5 for both optimum and Mucinex® formulations showed diffusion (Fickian) control mechanism. However, HPMC K100M rise in 70 mg accompanied cetyl alcohol rise in 60 mg led to first order kinetic (n = 0.6962). The K values of 1.56 represented an identical burst drug releases. Cetyl alcohol and starch 1500® modulated guaifenesin release from HPMC K100M matrices, while due to their binding properties, improved its poor flowability and compressibility, too. PMID:29552045

Factors Affecting the Design of Slow Release Formulations of Herbicides Based on Clay-Surfactant Systems. A Methodological Approach

PubMed Central

Galán-Jiménez, María del Carmen; Mishael, Yael-Golda; Nir, Shlomo; Morillo, Esmeralda; Undabeytia, Tomás

2013-01-01

A search for clay-surfactant based formulations with high percentage of the active ingredient, which can yield slow release of active molecules is described. The active ingredients were the herbicides metribuzin (MZ), mesotrione (MS) and flurtamone (FL), whose solubilities were examined in the presence of four commercial surfactants; (i) neutral: two berols (B048, B266) and an alkylpolyglucoside (AG6202); (ii) cationic: an ethoxylated amine (ET/15). Significant percent of active ingredient (a.i.) in the clay/surfactant/herbicide formulations could be achieved only when most of the surfactant was added as micelles. MZ and FL were well solubilized by berols, whereas MS by ET/15. Sorption of surfactants on the clay mineral sepiolite occurred mostly by sorption of micelles, and the loadings exceeded the CEC. Higher loadings were determined for B266 and ET/15. The sorption of surfactants was modeled by using the Langmuir-Scatchard equation which permitted the determination of binding coefficients that could be used for further predictions of the sorbed amounts of surfactants under a wide range of clay/surfactant ratios. A possibility was tested of designing clay-surfactant based formulations of certain herbicides by assuming the same ratio between herbicides and surfactants in the formulations as for herbicides incorporated in micelles in solution. Calculations indicated that satisfactory FL formulations could not be synthesized. The experimental fractions of herbicides in the formulations were in agreement with the predicted ones for MS and MZ. The validity of this approach was confirmed in in vitro release tests that showed a slowing down of the release of a.i. from the designed formulations relative to the technical products. Soil dissipation studies with MS formulations also showed improved bioactivity of the clay-surfactant formulation relative to the commercial one. This methodological approach can be extended to other clay-surfactant systems for encapsulation and slow release of target molecules of interest. PMID:23527087

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.

Review article: new drug formulations, chemical entities and therapeutic approaches for the management of ulcerative colitis.

PubMed

Ng, S C; Kamm, M A

2008-10-01

Treatment options for ulcerative colitis (UC) are expanding with the development of novel drug formulations and dosing regimens and new chemical entities. Although the goals of medical therapy for UC remain unchanged, that is to induce and to maintain remission, focus has also centred on improving patient compliance, modifying the natural course of disease and healing the mucosa. To examine novel formulations, new chemical entities and novel therapeutic approaches to the management of UC. Searches for all studies related to UC treatment in Medline and abstracts from major national and international meetings published in the last 10 years. 5-Aminosalicylic acids (5-ASA) remain the standard first-line treatment for patients with mild to moderately active UC. New formulations with altered delivery, and new dosing regimens have demonstrated possible improvements in efficacy compared with historically available preparations and dosing patterns. Once-daily dosing, micropellet formulations,and high-dose tablets offer enhanced efficacy and improved compliance. 5-ASA is now recognized as a ligand for peroxisome proliferator activated receptor-gamma (PPAR-gamma) and it has a role as a chemo-preventive agent in long-standing UC. New colonic release corticosteroid formulations help to limit systemic toxicity; turmeric, tacrolimus and infliximab have shown promising results. New anti-inflammatory targeted therapies include an anti-CD3 antibody, selective integrin blockers, anti-IL-2 antibody and PPAR-gamma agonists. The evolution of novel oral 5-ASA formulations and dosage regimens,and recent development of new molecules have expanded the therapeutic armamentarium of UC.

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

PubMed

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

2006-03-01

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

Cell-penetrating peptide-siRNA conjugate loaded YSA-modified nanobubbles for ultrasound triggered siRNA delivery.

PubMed

Xie, Xiangyang; Yang, Yanfang; Lin, Wen; Liu, Hui; Liu, Hong; Yang, Yang; Chen, Ying; Fu, Xudong; Deng, Jianping

2015-12-01

Due to the absence of effective in vivo delivery systems, the employment of small interference RNA (siRNA) in the clinic has been hindered. In this paper, a new siRNA targeting system for EphA2-positive tumors was developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, a CPP-siRNA conjugate (CPP-siRNA) was entrapped in an ephrin mimetic peptide (YSA peptide)-modified NB (CPP-siRNA/YSA-NB) and the penetration of the CPP-siRNA was temporally masked; local ultrasound stimulation triggered the release of CPP-siRNA from the NBs and activated its penetration. Subsequent research demonstrated that the CPP-siRNA/YSA-NBs had particle sizes of approximately 200 nm and a siRNA entrapment efficiency of more than 85%. The in vitro release results showed that over 90% of the encapsulated CPP-siRNA released from the NBs in the presence of ultrasound, while less than 1.5% of that (30 min) released without ultrasound. Cell experiments showed a the higher CPP-siRNA cellular uptake of CPP-siRNA/YSA-NB among the various formulations in human breast adenocarcinoma cells (MCF-7, EphA2 positive cells). Additionally, after systemic administration in mice, CPP-siRNA/YSA-NB accumulated in the tumor, augmented c-Myc silencing and delayed tumor progression. In conclusion, the application of CPP-siRNA/YSA-NB with ultrasound may provide a strategy for the selective and efficient delivery of siRNA. Copyright © 2015 Elsevier B.V. All rights reserved.

Formulation and optimization of coated PLGA – Zidovudine nanoparticles using factorial design and in vitro in vivo evaluations to determine brain targeting efficiency

PubMed Central

Peter Christoper, G.V.; Vijaya Raghavan, C.; Siddharth, K.; Siva Selva Kumar, M.; Hari Prasad, R.

2013-01-01

In the current study zidovudine loaded PLGA nanoparticles were prepared, coated and further investigated for its effectiveness in brain targeting. IR and DSC studies were performed to determine the interaction between excipients used and to find out the nature of drug in the formulation. Formulations were prepared by adopting 23 factorial designs to evaluate the effects of process and formulation variables. The prepared formulations were subjected for in vitro and in vivo evaluations. In vitro evaluations showed particle size below 100 nm, entrapment efficiency of formulations ranges of 28–57%, process yield of 60–76% was achieved and drug release for the formulations were in the range of 50–85%. The drug release from the formulations was found to follow Higuchi release pattern, n–value obtained after Korsemeyer plot was in the range of 0.56–0.78. In vivo evaluations were performed in mice after intraperitoneal administration of zidovudine drug solution, uncoated and coated formulation. Formulation when coated with Tween 80 achieved a higher concentration in the brain than that of the drug in solution and of the uncoated formulation. Stability studies indicated that there was no degradation of the drug in the formulation after 90 days of preparation when stored in refrigerated condition. PMID:24648825

Evaluation of acetylated moth bean starch as a carrier for controlled drug delivery

PubMed Central

Singh, Akhilesh V.; Nath, Lila K.

2012-01-01

The present investigation concerns with the development of controlled release tablets of lamivudine using acetylated moth bean starch. The acetylated starch was synthesized with acetic anhydride in pyridine medium. The acetylated moth bean starch was tested for acute toxicity and drug–excipient compatibility study. The formulations were evaluated for physical characteristics like hardness, friability, % drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi kinetic model and the release mechanism study proved that the formulation showed a combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (Tmax, Cmax, AUC, Vd, T1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir®, which proved controlled release potential of acetylated moth bean starch. PMID:22210486

Modified-release ointment with nitroglycerin β-cyclodextrin inclusion complex for treatment of anal fissures.

PubMed

Centkowska, Katarzyna; Sznitowska, Malgorzata

2013-10-01

The aim was to evaluate ointments for local treatment of anal fissures. Nitroglycerin (NTG) was complexed with β-cyclodextrin (β-CD) to provide prolonged NTG release, with the intention of decreasing systemic drug absorption and thus reducing side effects. Gels, creams and anhydrous water-emulsifying (AWE) ointment with NTG-CD were compared with preparations containing uncomplexed NTG (diluted with crospovidone, NTG-cP). The in-vitro NTG release and ex-vivo skin absorption were studied. The prolonged-release ointment with the NTG-CD complex was formulated using AWE base or w/o cream (20% water); release of NTG from a hydrogel was very fast with both the complexed and uncomplexed forms. From the AWE ointment base, 16.4% or 4.5% of the total NTG dose was released after 6 h when NTG-cP or NTG-CD was incorporated, respectively. With the complexed form, NTG absorption to the skin after a 5-h application was 18.1 or 11.1 μg/g from AWE ointment or cream, respectively; absorption of the uncomplexed NTG was higher: 52.3 or 21.9 μg/g from AWE ointment and cream, respectively. Complexation with β-CD results in prolonged release of NTG from AWE ointment and w/o cream, which was confirmed by the ex-vivo skin absorption results. © 2013 Royal Pharmaceutical Society.

Hydrophobic ion pairing of a minocycline/Ca(2+)/AOT complex for preparation of drug-loaded PLGA nanoparticles with improved sustained release.

PubMed

Holmkvist, Alexander Dontsios; Friberg, Annika; Nilsson, Ulf J; Schouenborg, Jens

2016-02-29

Polymeric nanoparticles is an established and efficient means to achieve controlled release of drugs. Incorporation of minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, into biodegradable nanoparticles may therefore provide an efficient means to combat foreign body reactions to implanted electrodes in the brain. However, minocycline is commonly associated with poor encapsulation efficiencies and/or fast release rates due to its high solubility in water. Moreover, minocycline is unstable under conditions of low and high pH, heat and exposure to light, which exacerbate the challenges of encapsulation. In this work drug loaded PLGA nanoparticles were prepared by a modified emulsification-solvent-diffusion technique and characterized for size, drug encapsulation and in vitro drug release. A novel hydrophobic ion pair complex of minocycline, Ca(2+) ions and the anionic surfactant AOT was developed to protect minocycline from degradation and prolong its release. The optimized formulation resulted in particle sizes around 220 nm with an entrapment efficiency of 43% and showed drug release over 30 days in artificial cerebrospinal fluid. The present results constitute a substantial increase in release time compared to what has hitherto been achieved for minocycline and indicate that such particles might provide useful for sustained drug delivery in the CNS. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Formulation of polylactide-co-glycolic acid nanospheres for encapsulation and sustained release of poly(ethylene imine)-poly(ethylene glycol) copolymers complexed to oligonucleotides

PubMed Central

Sirsi, Shashank R; Schray, Rebecca C; Wheatley, Margaret A; Lutz, Gordon J

2009-01-01

Antisense oligonucleotides (AOs) have been shown to induce dystrophin expression in muscles cells of patients with Duchenne Muscular Dystrophy (DMD) and in the mdx mouse, the murine model of DMD. However, ineffective delivery of AOs limits their therapeutic potential. Copolymers of cationic poly(ethylene imine) (PEI) and non-ionic poly(ethylene glycol) (PEG) form stable nanoparticles when complexed with AOs, but the positive surface charge on the resultant PEG-PEI-AO nanoparticles limits their biodistribution. We adapted a modified double emulsion procedure for encapsulating PEG-PEI-AO polyplexes into degradable polylactide-co-glycolic acid (PLGA) nanospheres. Formulation parameters were varied including PLGA molecular weight, ester end-capping, and sonication energy/volume. Our results showed successful encapsulation of PEG-PEI-AO within PLGA nanospheres with average diameters ranging from 215 to 240 nm. Encapsulation efficiency ranged from 60 to 100%, and zeta potential measurements confirmed shielding of the PEG-PEI-AO cationic charge. Kinetic measurements of 17 kDa PLGA showed a rapid burst release of about 20% of the PEG-PEI-AO, followed by sustained release of up to 65% over three weeks. To evaluate functionality, PEG-PEI-AO polyplexes were loaded into PLGA nanospheres using an AO that is known to induce dystrophin expression in dystrophic mdx mice. Intramuscular injections of this compound into mdx mice resulted in over 300 dystrophin-positive muscle fibers distributed throughout the muscle cross-sections, approximately 3.4 times greater than for injections of AO alone. We conclude that PLGA nanospheres are effective compounds for the sustained release of PEG-PEI-AO polyplexes in skeletal muscle and concomitant expression of dystrophin, and may have translational potential in treating DMD. PMID:19351396

The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance.

PubMed

Ullah, Majeed; Hussain, Izhar; Sun, Changquan Calvin

2016-01-01

The use of soluble cocrystal for delivering drugs with low solubility, although a potentially effective approach, often suffers the problem of rapid disproportionation during dissolution, which negates the solubility advantages offered by the cocrystal. This necessitates their robust stabilization in order for successful use in a tablet dosage form. The cocrystal between carbamezepine and succinic acid (CBZ-SUC) exhibits a higher aqueous solubility than its dihydrate, which is the stable form of CBZ in water. Using this model system, we demonstrate an efficient and material-sparing tablet formulation screening approach enabled by intrinsic dissolution rate measurements. Three tablet formulations capable of stabilizing the cocrystal both under accelerated condition of 40 °C and 75% RH and during dissolution were developed using three different polymers, Soluplus® (F1), Kollidon VA/64 (F2) and Hydroxypropyl methyl cellulose acetate succinate (F3). When compared to a marketed product, Epitol® 200 mg tablets (F0), drug release after 60 min from formulations F1 (∼82%), F2 (∼95%) and F3 (∼95%) was all higher than that from Epitol® (79%) in a modified simulated intestinal fluid. Studies in albino rabbits show correspondingly better bioavailability of F1-F3 than Epitol.

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.

Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation.

PubMed

El Massik, M A; Abdallah, O Y; Galal, S; Daabis, N A

2003-05-01

Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30 degrees C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.

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

PubMed

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

2016-01-01

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

Model-based decision making in early clinical development: minimizing the impact of a blood pressure adverse event.

PubMed

Stroh, Mark; Addy, Carol; Wu, Yunhui; Stoch, S Aubrey; Pourkavoos, Nazaneen; Groff, Michelle; Xu, Yang; Wagner, John; Gottesdiener, Keith; Shadle, Craig; Wang, Hong; Manser, Kimberly; Winchell, Gregory A; Stone, Julie A

2009-03-01

We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumped-parameter pharmacokinetic-pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlled-release (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program.

Inkjet printing of antiviral PCL nanoparticles and anticancer cyclodextrin inclusion complexes on bioadhesive film for cervical administration.

PubMed

Varan, Cem; Wickström, Henrika; Sandler, Niklas; Aktaş, Yeşim; Bilensoy, Erem

2017-10-15

Personalized medicine is an important treatment approach for diseases like cancer with high intrasubject variability. In this framework, printing is one of the most promising methods since it permits dose and geometry adjustment of the final product. With this study, a combination product consisting of anticancer (paclitaxel) and antiviral (cidofovir) drugs was manufactured by inkjet printing onto adhesive film for local treatment of cervical cancers as a result of HPV infection. Furthermore, solubility problem of paclitaxel was overcome by maintaining this poorly soluble drug in a cyclodextrin inclusion complex and release of cidofovir was controlled by encapsulation in polycaprolactone nanoparticles. In vitro characterization studies of printed film formulations were performed and cell culture studies showed that drug loaded film formulation was effective on human cervical adenocarcinoma cells. Our study suggests that inkjet printing technology can be utilized in the development of antiviral/anticancer combination dosage forms for mucosal application. The drug amount in the delivery system can be accurately controlled and modified. Moreover, prolonged drug release time can be obtained. Printing of anticancer and antiviral drugs on film seem to be a potential approach for HPV-related cervical cancer treatment and a good candidate for further studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Block copolymer micelles for controlled delivery of glycolytic enzyme inhibitors.

PubMed

Akter, Shanjida; Clem, Brian F; Lee, Hyun Jin; Chesney, Jason; Bae, Younsoo

2012-03-01

To develop block copolymer micelles as an aqueous dosage form for a potent glycolytic enzyme inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). The micelles were prepared from poly(ethylene glycol)-poly(aspartate hydrazide) [PEG-p(HYD)] block copolymers to which 3PO was conjugated through an acid-labile hydrazone bond. The optimal micelle formulation was determined following the screening of block copolymer library modified with various aromatic and aliphatic pendant groups. Both physical drug entrapment and chemical drug conjugation methods were tested to maximize 3PO loading in the micelles during the screening. Particulate characterization showed that the PEG-p(HYD) block copolymers conjugated with 3PO (2.08∼2.21 wt.%) appeared the optimal polymer micelles. Block copolymer compositions greatly affected the micelle size, which was 38 nm and 259 nm when 5 kDa and 12 kDa PEG chains were used, respectively. 3PO release from the micelles was accelerated at pH 5.0, potentiating effective drug release in acidic tumor environments. The micelles retained biological activity of 3PO, inhibiting various cancer cells (Jurkat, He-La and LLC) in concentration ranges similar to free 3PO. A novel micelle formulation for controlled delivery of 3PO was successfully prepared.

Nanostructured lipid carriers as novel ophthalmic delivery system for mangiferin: improving in vivo ocular bioavailability.

PubMed

Liu, Rui; Liu, Zhidong; Zhang, Chengui; Zhang, Boli

2012-10-01

The aim of this study was to develop a novel nanostructured lipid carriers (NLCs) system to improve ocular bioavailability of mangiferin (MGN) for the potential treatment of cataract. The physicochemical properties of MGN-loaded NLC (MGN-NLC) formulation were characterized by particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, morphological property, and crystalline state. in vitro characteristics were investigated by drug release from NLC system, physical stability, and corneal permeation through excised rabbit cornea. Moreover, in vivo ocular tolerability was assessed by a modified Draize test and histological microscopy. Preocular retention capability was evaluated by slit-lamp observation. Pharmacokinetic study in the aqueous humor was performed by microdialysis technique. Transmission electron microscopy depicted spherical and uniform morphology. Differential scanning calorimetry and X-ray diffractometry displayed imperfect crystalline lattice. The optimized MGN-NLC formulation exhibited a sustained drug release with 3 months stability and 4.31-fold increase of in vitro corneal permeation. Furthermore, in vivo studies exhibited a high tolerance in the ocular tissues and prolonged drug retention capacity on the corneal surface. Finally, pharmacokinetic study suggested a 5.69-fold increase of ocular bioavailability compared with MGN solution (MGN-SOL). Therefore, NLC system is a promising approach for ocular delivery of MGN. Copyright © 2012 Wiley Periodicals, Inc.

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

The release profiles of intact and enzymatically digested hyaluronic acid from semisolid formulations using multi-layer membrane system.

PubMed

Alkrad, Jamal Alyoussef; Mrestani, Yahya; Neubert, Reinhard H H

2003-07-01

A multi-layer membrane system was used to measure in vitro release of hydrophilic macromolecules such as hyaluronic acid (HA) from semisolid formulations. One enzymatically digested HA-derivative with molecular mass of 22 kDa (HA-D) and 1200 kDa intact HA (HA) were incorporated into three semisolid formulations: water-containing hydrophilic ointment (WHO), amphiphilic cream (AC) and water-containing wool wax alcohol ointment (WWO). Because of the high hydrophilic properties of HA-D and HA, the artificial model membranes consisted of collodion as the matrix and glycerol as the hydrophilic acceptor phase. The area under the concentration-time curve and the mean dissolution time were used as a quantitative parameter to characterise the rate and extent of release in vitro. This study showed that the HA-D and HA release as hydrophilic substances from WHO was higher than both from AC and WWO. It was observed that 83% of HA-D1 was released from WHO after 2 h; in contrast, only 10% was released from 2% HA from the same vehicle during the same time. In conclusion, the in vitro availability of enzymatically digested HA-D was higher for WHO than for the other formulations, AC and WWO. Similarly, the availability of HA-D was higher than that of HA from the same formulations.

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.

Physical aging in pharmaceutical polymers and the effect on solid oral dosage form stability.

PubMed

Kucera, Shawn A; Felton, Linda A; McGinity, James W

2013-12-05

The application of a polymeric film to a solid oral dosage form can be an effective technique to modify drug release. Most polymers used for such purposes are amorphous in nature and are subject to physical aging. This physical aging phenomenon has been shown to cause changes not only in the mechanical and drug release properties of polymeric films, but also the permeability of these films due to a densification and decrease in free volume of the polymer as the material relaxes to an equilibrated thermodynamic state. Temperature, humidity, and additional excipients in the coating formulations have been shown to influence the aging process. This review article discusses the process of physical aging in films prepared from aqueous dispersions, describes various analytical techniques that can be used to investigate the aging process, and highlights strategies to prevent such aging. Copyright © 2013 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2017-01-01

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

Formulation development of allopurinol suppositories and injectables.

PubMed

Lee, D K; Wang, D P

1999-11-01

Allopurinol was formulated into injectable and suppository dosage forms. The injectable formulation was prepared by dissolving allopurinol in a cosolvent system consisting of dimethyl sulfoxide (DMSO) and propylene glycol (v/v = 50/50). The stability of allopurinol in the cosolvent system was studied under accelerated storage conditions, and results indicate first-order degradation kinetics with an activation energy of 24.3 kcal/mol. The development of suppository dosage forms was performed by formulating allopurinol with polyethylene glycol (PEG) mixtures of different molecular weights. In vitro release profiles of suppositories formulated with different polyethylene bases were obtained in the pH 7.4 buffer solution using the USP 23 paddle method at 100 rpm. Results indicate that the release rate of the suppository formulations containing PEG 1500/PEG 4000 at the ratio (w/w) of 2.5/10 to 10/2.5 appeared to be similar. However, the addition of sodium lauryl sulfate in the suppository decreased the release rate of allopurinol significantly. A future study to establish in vitro/in vivo correlation (iv/ivc) is suggested.

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

Nonclinical evaluation of the potential for mast cell activation by an erythropoietin analog

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weaver, James L., E-mail: James.Weaver@fda.hhs.gov; Boyne, Michael, E-mail: mboyne@biotechlogic.com; Pang, Eric, E-mail: Eric.Pang@fda.hhs.gov

The erythropoietin analog peginesatide was withdrawn from marketing due to unexpected severe anaphylactic reactions associated with administration of the multi-use formulation. The adverse events occurred rapidly following the first ever administration of the drug with most affected patients becoming symptomatic in less than 30 min. This is most consistent with an anaphylactoid reaction due to direct activation of mast cells. Laboratory evaluation was undertaken using rat peritoneal mast cells as the model system. Initial studies showed that high concentrations of the formulated drug as well as formulated vehicle alone could cause mast cell degranulation as measured by histamine release. Themore » purified active drug was not able to cause histamine release whereas the vehicle filtrate and lab created drug vehicle were equally potent at causing histamine release. Individual formulations of vehicle leaving one component out showed that histamine release was due to phenol. Dose response studies with phenol showed a very sharp dose response curve that was similar in three buffer systems. Cellular analysis by flow cytometry showed that the histamine release was not due to cell death, and that changes in light scatter parameters consistent with degranulation were rapidly observed. Limited testing with primary human mast cells showed a similar dose response of histamine release with exposure to phenol. To provide in vivo confirmation, rats were injected with vehicle formulated with various concentrations of phenol via a jugular vein cannula. Significant release of histamine was detected in blood samples taken 2 min after dosing at the highest concentrations tested. - Highlights: • Peginesatide caused severe anaphylactoid reactions in 0.2% of patients. • Both formulated drug and vehicle cause degranulation of rat mast cells. • Phenol was identified as the vehicle component causing degranulation. • Human mast cells show similar dose response to phenol as rat mast cells. • Histamine release could be caused in vivo in rats by rapid phenol injection.« less

Development of a discriminative biphasic in vitro dissolution test and correlation with in vivo pharmacokinetic studies for differently formulated racecadotril granules.

PubMed

Deng, Jia; Staufenbiel, Sven; Hao, Shilei; Wang, Bochu; Dashevskiy, Andriy; Bodmeier, Roland

2017-06-10

The purpose of this study was to discriminate the release behavior from three differently formulated racecadotril (BCS II) granules and to establish an in vitro-in vivo correlation. Three granule formulations of the lipophilic drug were prepared with equivalent composition but prepared with different manufacturing processes (dry granulation, wet granulation with or without binder). In vitro release of the three granules was investigated using a biphasic dissolution system (phosphate buffer pH6.8 and octanol) and compared to the conventional single phase USP II dissolution test performed under sink and non-sink conditions. In vivo studies with each granule formulation were performed in rats. Interestingly, the granule formulations exhibited pronouncedly different behavior in the different dissolution systems depending on different wetting and dissolution conditions. Single phase USP II dissolution tests lacked discrimination. In contrast, remarkable discrimination between the granule formulations was observed in the octanol phase of biphasic dissolution system with a rank order of release from granules prepared by wet granulation with binder>wet granulation without binder>dry granulation. This release order correlated well with the wettability of these granules. An excellent correlation was also established between in vitro release in the octanol phase of the biphasic test and in vivo data (R 2 =0.999). Compared to conventional dissolution methods, the biphasic method provides great potential to discriminate between only minor formulation and process changes within the same dosage form for poorly soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Analysis of in vitro release through reconstructed human epidermis and synthetic membranes of multi-vitamins from cosmetic formulations.

PubMed

Gabbanini, Simone; Matera, Riccardo; Beltramini, Claudia; Minghetti, Andrea; Valgimigli, Luca

2010-08-01

A convenient method for in vitro investigation of the release of lipid- and water-soluble vitamins from cosmetic formulations was developed. The permeation of (d)-alpha-tocopherol (vitamin E), retinyl acetate (pro-vitamin A), ascorbic acid (vitamin C) and pyridoxine (vitamin B6) through SkinEthic reconstructed human epidermis (RHE), and synthetic polyethersulfone and polycarbonate membranes was studied in vitro using a Franz-type diffusion apparatus, coupled either to a spectrophotometer for continuous reading (dynamic setting) or to HPLC-DAD analysis of the receptor medium (static setting). O/W and W/O emulsions were compared with simple aqueous solutions for their kinetic of vitamins release, to evaluate the influence of the cosmetic formulation on the bioavailability of active ingredients. Results indicate that synthetic membranes offer a limited barrier to the diffusion of vitamins, but may provide information on the release ability of the formulation. Penetration was more effective when water was the external phase of the formulation, i.e. W/O emulsions were less effective in the release of vitamins than O/W emulsion or aqueous solutions. RHE (17 days old) offered a significantly higher barrier to penetration of vitamins, as expected for native human epidermis. The relative ranking in coefficient of permeability (Ps (cm/h)) was: ascorbic acid>pyridoxine>retinyl acetate>alpha-tocopherol approximately 0, the absolute values depending on the formulation. The method herein described showed to be a practical and convenient tool for the quality-control and efficacy evaluation of cosmetic formulations. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Matrix tablets for sustained release of repaglinide: Preparation, pharmacokinetics and hypoglycemic activity in beagle dogs.

PubMed

He, Wei; Wu, Mengmeng; Huang, Shiqing; Yin, Lifang

2015-01-15

Repaglinide (RG) is an efficient antihyperglycemic drug; however, due to its short half-life, patients are required to take the marketed products several times a day, which compromises the therapeutic effects. The present study was conducted to develop a hydrophilic sustained release matrix tablet for RG with the aims of prolonging its action time, reducing the required administration times and side effects and improving patient adherence. The matrix tablets were fabricated by a direct compression method, the optimized formulation for which was obtained by screening the factors that affected the drug release. Moreover, studies of the pharmacokinetics and hypoglycemic activity as measured by glucose assay kits were performed in dogs. Sustained drug releases profiles over 10h and a reduced influence of medium pHs on release were achieved with the optimized formulation; moreover, the in vivo performance of extended release formulation was also examined, and better absorption, a one-fold decrease in Cmax, a two-fold increase of Tmax and a prolonged hypoglycemic effect compared to the marketed product were observed. In conclusion, sustained RG release and prolonged action were observed with present matrix tablets, which therefore provide a promising formulation for T2D patients who require long-term treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Release kinetics of papaverine hydrochloride from tablets with different excipients.

PubMed

Kasperek, Regina; Polski, Andrzej; Zimmer, Łukasz; Poleszak, Ewa

2014-01-01

The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, (3-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release.

Release Kinetics of Papaverine Hydrochloride from Tablets with Different Excipients

PubMed Central

Kasperek, Regina; Polski, Andrzej; Zimmer, Łukasz; Poleszak, Ewa

2014-01-01

Abstract The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, (3-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release. PMID:25853076

Design and in vitro/in vivo evaluation of sustained-release floating tablets of itopride hydrochloride.

PubMed

Ahmed, Sayed M; Ahmed Ali, Adel; Ali, Ahmed Ma; Hassan, Omiya A

2016-01-01

The aim of the present study was to improve the bioavailability of itopride (ITO) and sustain its action by formulating as a floating dosage form. Sustained-release floating tablets of ITO hydrochloride (HCl) were prepared by direct compression using different hydrocolloid polymers such as hydroxypropyl methylcellulose and ethylcellulose and/or methacrylic acid polymers Eudragit RSPM and Carbopol 934P. The floating property was achieved using an effervescent mixture of sodium bicarbonate and anhydrous citric acid (1:1 mol/mol). Hardness, friability, content uniformity, and dissolution rate of the prepared floating tablets were evaluated. The formulation F 10 composed of 28.5% Eudragit RSPM, 3% NaHCO 3 , and 7% citric acid provided sustained drug release. In vitro results showed sustained release of F 10 where the drug release percentage was 96.51%±1.75% after 24 hours ( P =0.031). The pharmacokinetic results indicated that the area under the curve (AUC 0-∞ ) of the prepared sustained-release floating tablets at infinity achieved 93.69 µg·h/mL compared to 49.89 µg·h/mL for the reference formulation (Ganaton ® ) and the relative bioavailability of the sustained-release formulation F 10 increased to 187.80% ( P =0.022). The prepared floating tablets of ITO HCl (F 10 ) could be a promising drug delivery system with sustained-release action and enhanced drug bioavailability.

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

PubMed Central

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

2016-01-01

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

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.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu; Chen, Jing; Schlueter, Connie F.

Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were produced by spray-drying, which generated generally spherical microparticles that were suitable for intramuscular injection. Multiple parameters were varied to produce formulations with a wide range of in vitro release kinetics. Testing of selected formulations in chlorine-exposedmore » mice demonstrated efficacy against key aspects of acute lung injury. The results show the feasibility of developing microencapsulated formulations that could be used to treat chlorine-induced acute lung injury by intramuscular injection, which represents a preferred route of administration in a mass casualty situation. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Countermeasures for treatment of chlorine-induced acute lung injury are needed. • Formulations containing rolipram, triptolide, or budesonide were produced. • Formulations with a wide range of release properties were developed. • Countermeasure formulations inhibited chlorine-induced lung injury in mice.« less

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.

Preparation and in vitro evaluation of heparin-loaded polymeric nanoparticles.

PubMed

Jiao, Y Y; Ubrich, N; Marchand-Arvier, M; Vigneron, C; Hoffman, M; Maincent, P

2001-01-01

Nanoparticles of a highly soluble macromolecular drug, heparin, were formulated with two biodegradable polymers (poly-E-caprolactone [PCL] and poly (D, L-lactic-co-glycolic-acid) 50/50 [PLAGA]) and two nonbiodegradable positively charged polymers (Eudragit RS and RL) by the double emulsion and solvent evaporation method, using a high-pressure homogenization device. The encapsulation efficiency and heparin release profiles were studied as a function of the type of polymers employed (alone or in combination) and the concentration of heparin. Optimal encapsulation efficiency was observed when 5000 IU of heparin were incorporated in the first emulsion. High drug entrapment efficiency was observed in both Eudragit RS and RL nanoparticles (60% and 98%, respectively), compared with PLAGA and PCL nanoparticles (<14%). The use of the two types of Eudragit in combination with PCL and PLAGA increased the encapsulation efficiency compared with these two biodegradable polymers used alone; however, the in vitro drug release was not modified and remained low. On the other hand, the addition of esterase to the dissolution medium resulted in a significant increase in heparin release. The in vitro biological activity of released heparin, evaluated by measuring the anti-Xa activity by a colorimetric assay, was conserved after the encapsulation process.

Polymeric and Solid Lipid Nanoparticles for Sustained Release of Carbendazim and Tebuconazole in Agricultural Applications

NASA Astrophysics Data System (ADS)

Campos, Estefânia Vangelie Ramos; Oliveira, Jhones Luiz De; da Silva, Camila Morais Gonçalves; Pascoli, Mônica; Pasquoto, Tatiane; Lima, Renata; Abhilash, P. C.; Fernandes Fraceto, Leonardo

2015-09-01

Carbendazim (MBC) (methyl-2-benzimidazole carbamate) and tebuconazole (TBZ) ((RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol) are widely used in agriculture for the prevention and control of fungal diseases. Solid lipid nanoparticles and polymeric nanocapsules are carrier systems that offer advantages including changes in the release profiles of bioactive compounds and their transfer to the site of action, reduced losses due to leaching or degradation, and decreased toxicity in the environment and humans. The objective of this study was to prepare these two types of nanoparticle as carrier systems for a combination of TBZ and MBC, and then investigate the release profiles of the fungicides as well as the stabilities and cytotoxicities of the formulations. Both nanoparticle systems presented high association efficiency (>99%), indicating good interaction between the fungicides and the nanoparticles. The release profiles of MBC and TBZ were modified when the compounds were loaded in the nanoparticles, and cytotoxicity assays showed that encapsulation of the fungicides decreased their toxicity. These fungicide systems offer new options for the treatment and prevention of fungal diseases in plants.

3D printing of drug-loaded gyroid lattices using selective laser sintering.

PubMed

Fina, Fabrizio; Goyanes, Alvaro; Madla, Christine M; Awad, Atheer; Trenfield, Sarah J; Kuek, Jia Min; Patel, Pavanesh; Gaisford, Simon; Basit, Abdul W

2018-05-19

Three-dimensional printing (3DP) is gaining momentum in the field of pharmaceuticals, offering innovative opportunities for medicine manufacture. Selective laser sintering (SLS) is a novel, high resolution and single-step printing technology that we have recently introduced to the pharmaceutical sciences. The aim of this work was to use SLS 3DP to fabricate printlets (3D printed tablets) with cylindrical, gyroid lattice and bi-layer structures having customisable release characteristics. Paracetamol-loaded constructs from four different pharmaceutical grade polymers including polyethylene oxide, Eudragit (L100-55 and RL) and ethyl cellulose, were created using SLS 3DP. The novel gyroid lattice structure was able to modulate the drug release from all four polymers. This work is the first to demonstrate the feasibility of using SLS to achieve customised drug release properties of several polymers, in a swift, cost-effective manner, avoiding the need to alter the formulation composition. By creating these constructs, it is therefore possible to modify drug release, which in practice, could enable the tailoring of drug performance to the patient simply by changing the 3D design. Copyright © 2018 Elsevier B.V. All rights reserved.

Clinical pharmacokinetic study for the effect of glimepiride matrix tablets developed by quality by design concept.

PubMed

Ahmed, Tarek A; Suhail, Mohammad A A; Hosny, Khaled M; Abd-Allah, Fathy I

2018-01-01

Implementation of a new pharmaceutical technique to improve aqueous solubility and thus dissolution, enhancement of drug permeation, and finally formulation of a controlled release tablet loaded with glimepiride (GLMP). Improve GLMP bioavailability and pharmacokinetics in type II diabetic patients. Different polymers were used to enhance aqueous GLMP solubility of which a saturated polymeric drug solution was prepared and physically adsorbed onto silica. An experimental design was employed to optimize the formulation parameters affecting the preparation of GLMP matrix tablets. A compatibility study was conducted to study components interactions. Scanning electron microscope (SEM) was performed before and after the tablets were placed in the dissolution medium. An in vivo study in human volunteers was performed with the optimized GLMP tablets, which were compared to pure and marketed drug products. Enhancement of GLMP aqueous solubility, using the polymeric drug solution technique, by more than 6-7 times when compared with the binary system. All the studied formulation factors significantly affected the studied variables. No significant interaction was detected among components. SEM illustrated the surface and inner tablet structure, and confirmed the drug release which was attributed to diffusion mechanism. The volunteer group administered the optimized GLMP tablet exhibited higher drug plasma concentration (147.4 ng/mL), longer time to reach maximum plasma concentration (4 h) and longer t 1/2 (7.236 h) compared to other groups. Matrix tablet loaded with a physically modified drug form could represent a key solution for drugs with inconsistent dissolution and absorption profiles.

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

PubMed

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

2018-06-01

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

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

Floating matrix tablets based on low density foam powder: effects of formulation and processing parameters on drug release.

PubMed

Streubel, A; Siepmann, J; Bodmeier, R

2003-01-01

The aim of this study was to develop and physicochemically characterize single unit, floating controlled drug delivery systems consisting of (i). polypropylene foam powder, (ii). matrix-forming polymer(s), (iii). drug, and (iv). filler (optional). The highly porous foam powder provided low density and, thus, excellent in vitro floating behavior of the tablets. All foam powder-containing tablets remained floating for at least 8 h in 0.1 N HCl at 37 degrees C. Different types of matrix-forming polymers were studied: hydroxypropyl methylcellulose (HPMC), polyacrylates, sodium alginate, corn starch, carrageenan, gum guar and gum arabic. The tablets eroded upon contact with the release medium, and the relative importance of drug diffusion, polymer swelling and tablet erosion for the resulting release patterns varied significantly with the type of matrix former. The release rate could effectively be modified by varying the "matrix-forming polymer/foam powder" ratio, the initial drug loading, the tablet geometry (radius and height), the type of matrix-forming polymer, the use of polymer blends and the addition of water-soluble or water-insoluble fillers (such as lactose or microcrystalline cellulose). The floating behavior of the low density drug delivery systems could successfully be combined with accurate control of the drug release patterns.

Oil and drug control the release rate from lyotropic liquid crystals.

PubMed

Martiel, Isabelle; Baumann, Nicole; Vallooran, Jijo J; Bergfreund, Jotam; Sagalowicz, Laurent; Mezzenga, Raffaele

2015-04-28

The control of the diffusion coefficient by the dimensionality d of the structure appears as a most promising lever to efficiently tune the release rate from lyotropic liquid crystalline (LLC) phases and dispersed particles towards sustained, controlled and targeted release. By using phosphatidylcholine (PC)- and monolinoleine (MLO)-based mesophases with various apolar structural modifiers and water-soluble drugs, we present a comprehensive study of the dimensional structural control of hydrophilic drug release, including 3-d bicontinuous cubic, 2-d lamellar, 1-d hexagonal and 0-d micellar cubic phases in excess water. We investigate how the surfactant, the oil properties and the drug hydrophilicity mitigate or even cancel the effect of structure variation on the drug release rate. Unexpectedly, the observed behavior cannot be fully explained by the thermodynamic partition of the drug into the lipid matrix, which points out to previously overlooked kinetic effects. We therefore interpret our results by discussing the mechanism of structural control of the diffusion rate in terms of drug permeation through the lipid membrane, which includes exchange kinetics. A wide range of implications follow regarding formulation and future developments, both for dispersed LLC delivery systems and topical applications in bulk phase. Copyright © 2015 Elsevier B.V. All rights reserved.

Challenges and opportunities in establishing scientific and regulatory standards for determining therapeutic equivalence of modified-release products: Workshop summary report.

PubMed

Chen, Mei-Ling; Shah, Vinod P; Ganes, Derek; Midha, Kamal K; Caro, James; Nambiar, Prabu; Rocci, Mario L; Thombre, Avinash G; Abrahamsson, Bertil; Conner, Dale; Davit, Barbara; Fackler, Paul; Farrell, Colm; Gupta, Suneel; Katz, Russell; Mehta, Mehul; Preskorn, Sheldon H; Sanderink, Gerard; Stavchansky, Salomon; Temple, Robert; Wang, Yaning; Winkle, Helen; Yu, Lawrence

2010-09-01

Modified-release (MR) products are complex dosage forms designed to release drug in a controlled manner to achieve the desired efficacy and safety profiles. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This paper is a summary report of the American Association of Pharmaceutical Scientists, International Pharmaceutical Federation, and Product Quality Research Institute workshop titled "Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products", held October 1-2, 2009, in Baltimore, Maryland. The workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current regulatory expectations and industry practices for evaluating the pharmaceutical equivalence and bioequivalence of oral MR products. In the case of conventional monophasic MR formulations, the current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and inter-changeability of drug products. Additional measures may occasionally be needed to determine the bioequivalence of multiphasic MR products. The metric of partial AUC proposed by the US Food and Drug Administration received broad support as an additional measure for evaluating bioequivalence of multiphasic MR products designed to have a rapid onset of drug action followed by sustained response. The cutoff for partial AUCs may be based on the pharmacokinetic/pharmacodynamic or pharmacokinetic/ response characteristics of the products under examination. If the new metric is highly variable, the bioequivalence limits may be set based on the known within-subject variability for the reference product. The current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and interchangeability of conventional monophasic MR products. Additional measures may occasionally be needed to establish the bioequivalence of multiphasic MR products, and development of such measures is an important objective. The metric of partial AUC was proposed for products designed to have a rapid drug action followed by sustained response. Copyright © 2010 Excerpta Medica Inc. All rights reserved.

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.

Redox-sensitive self-assembled nanoparticles based on alpha-tocopherol succinate-modified heparin for intracellular delivery of paclitaxel.

PubMed

Yang, Xiaoye; Cai, Xiaoqing; Yu, Aihua; Xi, Yanwei; Zhai, Guangxi

2017-06-15

To remedy the problems riddled in cancer chemotherapy, such as poor solubility, low selectivity, and insufficient intra-cellular release of drugs, novel heparin-based redox-sensitive polymeric nanoparticles were developed. The amphiphilic polymer, heparin-alpha-tocopherol succinate (Hep-cys-TOS) was synthesized by grafting hydrophobic TOS to heparin using cystamine as the redox-sensitive linker, which could self-assemble into nanoparticles in phosphate buffer saline (PBS) with low critical aggregation concentration (CAC) values ranging from 0.026 to 0.093mg/mL. Paclitaxel (PTX)-loaded Hep-cys-TOS nanoparticles were prepared via a dialysis method, exhibiting a high drug-loading efficiency of 18.99%. Physicochemical properties of the optimized formulation were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM) and differential scanning calorimetry (DSC). Subsequently, the redox-sensitivity of Hep-cys-TOS nanoparticles was confirmed by the changes in size distribution, morphology and appearance after dithiothreitol (DTT) treatment. Besides, the in vitro release of PTX from Hep-cys-TOS nanoparticles also exhibited a redox-triggered profile. Also, the uptake behavior and pathways of coumarin 6-loaded Hep-cys-TOS nanoparticles were investigated, suggesting the nanoparticles could be taken into MCF-7 cells in energy-dependent, caveolae-mediated and cholesterol-dependent endocytosis manners. Later, MTT assays of different PTX-free and PTX-loaded formulations revealed the desirable safety of PTX-free nanoparticles and the enhanced anti-cancer activity of PTX-loaded Hep-cys-TOS nanoparticles (IC 50 =0.79μg/mL). Apoptosis study indicated the redox-sensitive formulation could induce more apoptosis of MCF-7 cells than insensitive one (55.2% vs. 41.7%), showing the importance of intracellular burst release of PTX. Subsequently, the hemolytic toxicity confirmed the safety of the nanoparticles for intravenous administration. The results indicated the developed redox-sensitive nanoparticles were promising as intracellular drug delivery vehicles for cancer treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics

PubMed Central

Bose, Anirbandeep; Wong, Tin Wui; Singh, Navjot

2012-01-01

The objective of this present investigation was to develop and formulate sustained release (SR) matrix tablets of Itopride HCl, by using different polymer combinations and fillers, to optimize by Central Composite Design response surface methodology for different drug release variables and to evaluate drug release pattern of the optimized product. Sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: hydroxy propyl methyl cellulose (HPMC) and polyvinyl pyrolidine (pvp) and lactose as fillers. Study of pre-compression and post-compression parameters facilitated the screening of a formulation with best characteristics that underwent here optimization study by response surface methodology (Central Composite Design). The optimized tablet was further subjected to scanning electron microscopy to reveal its release pattern. The in vitro study revealed that combining of HPMC K100M (24.65 MG) with pvp(20 mg)and use of LACTOSE as filler sustained the action more than 12 h. The developed sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet. PMID:23960836

Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics.

PubMed

Bose, Anirbandeep; Wong, Tin Wui; Singh, Navjot

2013-04-01

The objective of this present investigation was to develop and formulate sustained release (SR) matrix tablets of Itopride HCl, by using different polymer combinations and fillers, to optimize by Central Composite Design response surface methodology for different drug release variables and to evaluate drug release pattern of the optimized product. Sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: hydroxy propyl methyl cellulose (HPMC) and polyvinyl pyrolidine (pvp) and lactose as fillers. Study of pre-compression and post-compression parameters facilitated the screening of a formulation with best characteristics that underwent here optimization study by response surface methodology (Central Composite Design). The optimized tablet was further subjected to scanning electron microscopy to reveal its release pattern. The in vitro study revealed that combining of HPMC K100M (24.65 MG) with pvp(20 mg)and use of LACTOSE as filler sustained the action more than 12 h. The developed sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.

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.

The impact of manufacturing variables on in vitro release of clobetasol 17-propionate from pilot scale cream formulations.

PubMed

Fauzee, Ayeshah Fateemah Beebee; Khamanga, Sandile Maswazi; Walker, Roderick Bryan

2014-12-01

The purpose of the study was to evaluate the effect of different homogenization speeds and times, anchor speeds and cooling times on the viscosity and cumulative % clobetasol 17-propionate released per unit area at 72 h from pilot scale cream formulations. A 2(4) full factorial central composite design for four independent variables were investigated. Thirty pilot scale batches of cream formulations were manufactured using a Wintech® cream/ointment plant. The viscosity and in vitro release of CP were monitored and compared to an innovator product that is commercially available on the South African market, namely, Dermovate® cream. Contour and three-dimensional response surface plots were produced and the viscosity and cumulative % CP released per unit area at 72 h were found to be primarily dependent on the homogenization and anchor speeds. An increase in the homogenization and anchor speeds appeared to exhibit a synergistic effect on the resultant viscosity of the cream whereas an antagonistic effect was observed for the in vitro release of CP from the experimental cream formulations. The in vitro release profiles were best fitted to a Higuchi model and diffusion proved to be the dominant mechanism of drug release that was confirmed by use of the Korsmeyer-Peppas model. The research was further validated and confirmed by the high prognostic ability of response surface methodology (RSM) with a resultant mean percentage error of (±SD) 0.17 ± 0.093 suggesting that RSM may be an efficient tool for the development and optimization of topical formulations.

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.

Application of an amine functionalized biopolymer in the colonic delivery of glycyrrhizin: a design and in vivo efficacy study.

PubMed

Kumar De, Amit; Datta, Sriparna; Mukherjee, Arup

2013-01-01

In our current study, a newer amine functionalized guar gum derivative was studied for its efficacy in colonic drug delivery. Glycyrrhizic acid mono-ammonium salt was used as the model drug. Drug-loaded microparticles were formulated by ionic crosslinking using sodium tripolyphosphate. The Scanning Electron Microscopic study revealed spherical particles of sizes from 4.9 ± 3.8 μm to 6.9 ± 3.9 μm. The FT-IR studies presented a possible interaction between the drug and the polymer. The drug was encapsulated in amorphous form as observed from the powder X-Ray Diffraction studies. A cumulative drug release study was carried out in simulated gastric, intestinal, and colonic fluids. The cumulative drug release studies presented a burst release followed by a sustained release of the drug in simulated colonic fluid containing rat cecal contents. The drug-polymer ratio was optimised using a 3(2) factorial design by taking the amounts of glycyrrhizic acid (X1) and guar gum alkyl amine (X2) as the independant variables. The percent cumulative drug release at 240 mins (Q240), 720 mins (Q720), and at 1,440 mins (Q1440) were considered as the dependant variables. The efficacy of the optimized formulation was studied in a 2,4,6-trinitrobenzene sulfonic acid-induced rat colitis model. The tissue's nitric oxide, malondialdehyde, and myeloperoxidase activities were found to be much lower in the microparticle-treated group compared to free drug-treated group. The histology of the colonic tissue from the treated group of animals revealed almost no infiltration of inflammatory cells in the tissue for the microparticle-treated group of animals. The synthesized amine derivative of guar gum was found to be better in vitro with a better in vivo efficacy in the colonic delivery of glycyrrhizic acid monoammonium salt and can be considered as a newer modified biopolymer for colonic drug delivery.

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.

[Leptin: aspects on energetic balance, physical exercise and athletic amenorhea].

PubMed

Ribeiro, Sandra Maria Lima; dos Santos, Zirlene Adriana; da Silva, Renata Juliana; Louzada, Eliana; Donato, José; Tirapegui, Julio

2007-02-01

The aim of this manuscript was to review the knowledge about leptin, detailing its relationship with energetic intake and physical activity. Leptin is an adipocyte hormone, recognized mainly for its putative role in control of energy expenditure, food intake, body weight and reproductive function. Leptin has still important peripheral actions, including its role on the ovarian tissue. The intracellular signaling mechanisms are recognized in hypothalamus, but in peripheral tissue are not fully understood. The exercise, when practiced by women, if not appropriately planned according to food intake, can modify the leptin release. When energy imbalances induced by exercise and/or deficient food ingestion occurs, low leptin levels are observed, leading to a reduction in GnRH (gonadotropin-release hormone), in LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in pituitary, and consequently a minor release of ovarian estrogens. This process is named hypothalamic amenorrhea, and has repercussions in the woman's health. In this perspective, it is important to emphasize the need to evaluate the energy expenditure from exercise and to formulate adequate alimentary plans to these individuals.

Killing bacteria within biofilms by sustained release of tetracycline from triple-layered electrospun micro/nanofibre matrices of polycaprolactone and poly(ethylene-co-vinyl acetate).

PubMed

Alhusein, Nour; De Bank, Paul A; Blagbrough, Ian S; Bolhuis, Albert

2013-12-01

We report the controlled release of the antibiotic tetracycline (tet) HCl from a triple-layered electrospun matrix consisting of a central layer of poly(ethylene-co-vinyl acetate (PEVA) sandwiched between outer layers of poly-ε-caprolactone (PCL). These micro/nanofibre layers with tet successfully encapsulated (essentially quantitatively at 3 and 5 % w/w) in each layer, efficiently inhibited the growth of a panel of bacteria, including clinical isolates, as shown by a modified Kirby-Bauer disc assay. Furthermore, they demonstrated high biological activity in increasingly complex models of biofilm formation (models that are moving closer to the situation in a wound) by stopping biofilm formation, by killing preformed biofilms and killing mature, dense biofilm colonies of Staphylococcus aureus MRSA252. Tet is clinically useful with potential applications in wound healing and especially in complicated skin and skin-structure infections; electrospinning provides good encapsulation efficiency of tet within PCL/PEVA/PCL polymers in micro/nanofibre layers which display sustained antibiotic release in formulations that are anti-biofilm.

Characteristics of platelet gels combined with silk

PubMed Central

Pallotta, Isabella; Kluge, Jonathan A.; Moreau, Jodie; Calabrese, Rossella

2014-01-01

Platelet gel, a fibrin network containing activated platelets, is widely used in regenerative medicine due the capacity of platelet-derived growth factors to accelerate and direct healing processes. However, limitations to this approach include poor mechanical properties, relatively rapid degradation, and the lack of control of release of growth factors at the site of injection. These issues compromise the ability of platelet gels for sustained function in regenerative medicine. In the present study, a combination of platelet gels with silk fibroin gel was studied to address the above limitations. Mixing sonicated silk gels with platelet gels extended the release of growth factors without inhibiting gel forming ability. The released growth factors were biologically active and their delivery was modified further by manipulation of the charge of the silk protein. Moreover, the silk gel augmented both the rheological properties and compressive stiffness of the platelet gel, tuned by the silk concentration and/or silk/platelet gel ratio. Silk-platelet gel injections in nude rats supported enhanced cell infiltration and blood vessel formation representing a step towards new platelet gel formulations with enhanced therapeutic impact. PMID:24480538

Dexamethasone acetate encapsulation into Trojan particles.

PubMed

Gómez-Gaete, Carolina; Fattal, Elias; Silva, Lídia; Besnard, Madeleine; Tsapis, Nicolas

2008-05-22

We have combined the therapeutic potential of nanoparticles systems with the ease of manipulation of microparticles by developing a hybrid vector named Trojan particles. We aim to use this new delivery vehicle for intravitreal administration of dexamethasone. Initialy, dexamethasone acetate (DXA) encapsulation into biodegradable poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles was optimized. Then, Trojan particles were formulated by spray drying 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC), hyaluronic acid (HA) and different concentrations of nanoparticle suspensions. The effect of nanoparticles concentration on Trojan particle physical characteristics was investigated as well as the effect of the spray drying process on nanoparticles size. Finally, DXA in vitro release from nanoparticles and Trojan particles was evaluated under sink condition. SEM and confocal microscopy show that most of Trojan particles are spherical, hollow and possess an irregular surface due to the presence of nanoparticles. Neither Trojan particle tap density nor size distribution are significantly modified as a function of nanoparticles concentration. The mean nanoparticles size increase significantly after spray drying. Finally, the in vitro release of DXA shows that the excipient matrix provides protection to encapsulated nanoparticles by slowing drug release.

Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: drug release and fronts movement kinetics.

PubMed

Marinich, J A; Ferrero, C; Jiménez-Castellanos, M R

2012-04-01

A previous paper deals with the physicochemical and technological characterization of novel graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS). The results obtained suggested the potential application of these copolymers as excipients for compressed non-disintegrating matrix tablets. Therefore, the purpose of the present study was to investigate the mechanism governing drug release from matrix systems prepared with the new copolymers and anhydrous theophylline or diltiazem HCl as model drugs with different solubility. The influence of the carbohydrate nature, drying procedure and initial pore network on drug release kinetics was also evaluated. Drug release experiments were performed from free tablets. Radial drug release and fronts movement kinetics were also analysed, and several mathematical models were employed to ascertain the drug release mechanisms. The drug release markedly depends on the drug solubility and the carbohydrate nature but is practically not affected by the drying process and the initial matrix porosity. A faster drug release is observed for matrices containing diltiazem HCl compared with those containing anhydrous theophylline, in accordance with the higher drug solubility and the higher friability of diltiazem matrices. In fact, although diffusion is the prevailing drug release mechanism for all matrices, the erosion mechanism seems to have some contribution in several formulations containing diltiazem. A reduction in the surface exposed to the dissolution medium (radial release studies) leads to a decrease in the drug release rate, but the release mechanism is not essentially modified. The nearly constant erosion front movement confirms the behaviour of these systems as inert matrices where the drugs are released mainly by diffusion through the porous structure. Copyright © 2011 Elsevier B.V. All rights reserved.

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

PubMed

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

2016-01-01

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

Chronotherapeutically Modulated Pulsatile System of Valsartan Nanocrystals-an In Vitro and In Vivo Evaluation.

PubMed

Biswas, Nikhil; Kuotsu, Ketousetuo

2017-02-01

The objective was to improve the dissolution of valsartan by developing valsartan nanocrystals and design a pulsed release system for the chronotherapy of hypertension. Valsartan nanocrystals were prepared by sonication-anti-solvent precipitation method and lyophilized to obtain dry powder. Nanocrystals were directly compressed to minitablets and coated to achieve pulsatile valsartan release. Pharmacokinetic profiles of optimized and commercial formulations were compared in rabbit model. The mean particle size and PDI of the optimized nanocrystal batch V4 was reported as 211 nm and 0.117, respectively. DSC and PXRD analysis confirmed the crystalline nature of valsartan in nanocrystals. The dissolution extent of valsartan was markedly enhanced with both nanocrystals and minitablets as compared to pure valsartan irrespective of pH of the medium. Core minitablet V4F containing 5% w/w polyplasdone XL showed quickest release of valsartan, over 90% within 15 min. Coated formulation CV4F showed two spikes in release profile after successive lag times of 235 and 390 min. The pharmacokinetic study revealed that the bioavailability of optimized formulation (72.90%) was significantly higher than the commercial Diovan tablet (30.18%). The accelerated stability studies showed no significant changes in physicochemical properties, release behavior, and bioavialability of CV4F formulation. The formulation was successfully designed to achieve enhanced bioavailability and dual pulsatile release. Bedtime dosing will more efficiently control the circadian spikes of hypertension in the morning.

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

PubMed Central

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

2016-01-01

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

A novel ropivacaine-loaded in situ forming implant prolongs the effect of local analgesia in rats

PubMed Central

Lu, Lei; Zhang, Wei; Wu, Xin; Wang, Xiaoyu; Zhang, Min; Zhu, Quangang; Ding, Xueying; Xu, Zhiyun

2012-01-01

Introduction Prolonged postoperative analgesia cannot be achieved by a single injection of local anesthetic solution. The objective of this study was to optimize the formulation of a ropivacaine hydrochloride (Ropi-HCl) loaded in situ forming implant (ISI) by addition of different co-solvents, and evaluate the in vitro release of Ropi-HCl, and the analgesic effect and toxicity of the optimized formulation in rats. Material and methods Triacetin (TA), benzyl benzoate (BB) and polyethylene glycol 400 (PEG 400) were used as additives and added to the solvent of N-methyl-2-pyrrolidone (NMP). Drug release to the surface and inner structural properties of the formed implant were evaluated by scanning electron microscopy (SEM). The analgesic effect was determined by injection near the rat sciatic nerve. Results The solvent system added with TA or BB significantly decreased the burst release, whereas PEG 400 increased the Ropi-HCl burst release from the formulation. Over 70% of the incorporated Ropi-HCl was released from all formulations in 14 days in the in vitro assay. The SEM showed that the surface of NMP-BB formulation was less porous and more homogeneous, compared with the other formulations. Compared with Ropi-HCl injection, the optimized formulation (NMP-BB) significantly prolonged the analgesic effect in 48 h (p < 0.05), with a mild degree of motor block from 3 h to 12 h. Histological evaluation of the injection site revealed only mild inflammatory infiltration without obvious pathological nerve alterations. Conclusions The biodegradable Ropi-HCl-loaded ISI system with NMP-BB may prove to be an attractive and safe alternative for the delivery of parenteral local anesthetics to prolong pain relief. PMID:24049519

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

PubMed

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

2002-11-01

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

Development of a reservoir type prolonged release system with felodipine via simplex methodology

PubMed Central

IOVANOV, RAREŞ IULIU; TOMUŢĂ, IOAN; LEUCUŢA, SORIN EMILIAN

2016-01-01

Background and aims Felodipine is a dihydropyridine calcium antagonist that presents good characteristics to be formulated as prolonged release preparations. The aim of the study was the formulation and in vitro characterization of a reservoir type prolonged release system with felodipine, over a 12 hours period using the Simplex method. Methods The first step of the Simplex method was to study the influence of the granules coating method on the felodipine release. Furthermore the influence of the coating polymer type, the percent of the coating polymer and the percent of pore forming agent in the coating on the felodipine release were studied. Afterwards these two steps of the experimental design the percent of Surelease applied on the felodipine loaded granules and the percent of pore former in the polymeric coating formulation variables were studied. The in vitro dissolution of model drug was performed in phosphate buffer solution (pH 6.5) with 1% sodium lauryl sulfate. The released drug quantification was done using an HPLC method. The release kinetics of felodipine from the final granules was assessed using different mathematical models. Results A 12 hours release was achieved using granules with the size between 315–500 μm coated with 45% Surelease with different pore former ratios in the coating via the top-spray method. Conclusion We have prepared prolonged release coated granules with felodipine using a fluid bed system based on the Simplex method. The API from the studied final formulations was released over a 12 hours period and the release kinetics of the model drug substance from the optimized preparations fitted best the Higuchi and Peppas kinetic models. PMID:27004036

Use of Microsphere Technology for Targeted Delivery of Rifampin to Mycobacterium tuberculosis-Infected Macrophages

PubMed Central

Barrow, Esther L. W.; Winchester, Gary A.; Staas, Jay K.; Quenelle, Debra C.; Barrow, William W.

1998-01-01

Microsphere technology was used to develop formulations of rifampin for targeted delivery to host macrophages. These formulations were prepared by using biocompatible polymeric excipients of lactide and glycolide copolymers. Release characteristics were examined in vitro and also in two monocytic cell lines, the murine J774 and the human Mono Mac 6 cell lines. Bioassay assessment of cell culture supernatants from monocyte cell lines showed release of bioactive rifampin during a 7-day experimental period. Treatment of Mycobacterium tuberculosis H37Rv-infected monocyte cell lines with rifampin-loaded microspheres resulted in a significant decrease in numbers of CFU at 7 days following initial infection, even though only 8% of the microsphere-loaded rifampin was released. The levels of rifampin released from microsphere formulations within monocytes were more effective at reducing M. tuberculosis intracellular growth than equivalent doses of rifampin given as a free drug. These results demonstrate that rifampin-loaded microspheres can be formulated for effective sustained and targeted delivery to host macrophages. PMID:9756777

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

PubMed

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

2016-04-01

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

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.

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.

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

PubMed

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

2016-11-01

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

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.

Preparation of bilayer-core osmotic pump tablet by coating the indented core tablet.

PubMed

Liu, Longxiao; Xu, Xiangning

2008-03-20

In this paper, a bilayer-core osmotic pump tablet (OPT) which does not require laser drilling to form the drug delivery orifice is described. The bilayer-core consisted of two layers: (a) push layer and (b) drug layer, and was made with a modified upper tablet punch, which produced an indentation at the center of the drug layer surface. The indented tablets were coated by using a conventional pan-coating process. Although the bottom of the indentation could be coated, the side face of the indentation was scarcely sprayed by the coating solution and this part of the tablet remained at least partly uncoated leaving an aperture from which drug release could occur. Nifedipine was selected as the model drug. Sodium chloride was used as osmotic agent, polyvinylpyrrolidone as suspending agent and croscarmellose sodium as expanding agent. The indented core tablet was coated by ethyl cellulose as semipermeable membrane containing polyethylene glycol 400 for controlling the membrane permeability. The formulation of core tablet was optimized by orthogonal design and the release profiles of various formulations were evaluated by similarity factor (f(2)). It was found that the optimal OPT was able to deliver nifedipine at an approximate zero-order up to 24 h, independent on both release media and agitation rates. The preparation of bilayer-core OPT was simplified by coating the indented core tablet, by which sophisticated technology of the drug layer identification and laser drilling could be eliminated. It might be promising in the field of preparation of bilayer-core OPT.

Development and optimization of methotrexate-loaded lipid-polymer hybrid nanoparticles for controlled drug delivery applications.

PubMed

Tahir, Nayab; Madni, Asadullah; Balasubramanian, Vimalkumar; Rehman, Mubashar; Correia, Alexandra; Kashif, Prince Muhammad; Mäkilä, Ermei; Salonen, Jarno; Santos, Hélder A

2017-11-25

Lipid-polymer hybrid nanoparticles (LPHNPs) are emerging platforms for drug delivery applications. In the present study, methotrexate loaded LPHNPs consisted of PLGA and Lipoid S100 were fabricated by employing a single-step modified nanoprecipitation method combined with self-assembly. A three factor, three level Box Behnken design using Design-Expert ® software was employed to access the influence of three independent variables on the particle size, drug entrapment and percent drug release. The optimized formulation was selected through numeric optimization approach. The results were supported with the ANOVA analysis, regression equations and response surface plots. Transmission electron microscope images indicated the nanosized and spherical shape of the LPHNPs with fair size distribution. The nanoparticles ranged from 176 to 308nm, which increased with increased polymer concentration. The increase in polymer and lipid concentration also increased the drug entrapment efficiency. The in vitro drug release was in range 70.34-91.95% and the release mechanism follow the Higuchi model (R 2 =0.9888) and Fickian diffusion (n<0.5). The in vitro cytotoxicity assay and confocal microscopy of the optimized formulation demonstrate the good safety and better internalization of the LPHNPs. The cell antiproliferation showed the spatial and controlled action of the nanoformulation as compared to the plain drug solution. The results suggest that LPHNPs can be a promising delivery system envisioned to safe, stable and potentially controlled delivery of methotrexate to the cancer cells to achieve better therapeutic outcomes. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

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

PubMed Central

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

2015-01-01

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

Design and in vitro/in vivo evaluation of sustained-release floating tablets of itopride hydrochloride

PubMed Central

Ahmed, Sayed M; Ahmed Ali, Adel; Ali, Ahmed MA; Hassan, Omiya A

2016-01-01

Purpose The aim of the present study was to improve the bioavailability of itopride (ITO) and sustain its action by formulating as a floating dosage form. Materials and methods Sustained-release floating tablets of ITO hydrochloride (HCl) were prepared by direct compression using different hydrocolloid polymers such as hydroxypropyl methylcellulose and ethylcellulose and/or methacrylic acid polymers Eudragit RSPM and Carbopol 934P. The floating property was achieved using an effervescent mixture of sodium bicarbonate and anhydrous citric acid (1:1 mol/mol). Hardness, friability, content uniformity, and dissolution rate of the prepared floating tablets were evaluated. The formulation F10 composed of 28.5% Eudragit RSPM, 3% NaHCO3, and 7% citric acid provided sustained drug release. Results In vitro results showed sustained release of F10 where the drug release percentage was 96.51%±1.75% after 24 hours (P=0.031). The pharmacokinetic results indicated that the area under the curve (AUC0–∞) of the prepared sustained-release floating tablets at infinity achieved 93.69 µg·h/mL compared to 49.89 µg·h/mL for the reference formulation (Ganaton®) and the relative bioavailability of the sustained-release formulation F10 increased to 187.80% (P=0.022). Conclusion The prepared floating tablets of ITO HCl (F10) could be a promising drug delivery system with sustained-release action and enhanced drug bioavailability. PMID:28008229

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

PubMed

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

2011-08-01

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

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.

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.

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

A modified spontaneous emulsification solvent diffusion method for the preparation of curcumin-loaded PLGA nanoparticles with enhanced in vitro anti-tumor activity

NASA Astrophysics Data System (ADS)

Chen, Cen; Yang, Wei; Wang, Dan-Tong; Chen, Chao-Long; Zhuang, Qing-Ye; Kong, Xiang-Dong

2014-12-01

To improve the anti-tumor activity of hydrophobic drug curcumin, we prepared curcumin-loaded PLGA nanoparticles (PLGA-Cur NPs) through a modified spontaneous emulsification solvent diffusion (modified-SESD) method. The influence of main preparation parameters was investigated, such as the volume ratio of binary organic solvents and the concentration of surfactant. Results indicated that the synthesized regular spherical PLGA NPs with the average diameter of 189.7 nm exhibited relatively higher yield (58.9%), drug loading (11.0% (w/w)) and encapsulation efficiency (33.5%), and also a controllable drug release profile. In order to evaluate the in vitro cytotoxicity of the prepared NPs, MTT assay was conducted, and results showed that the NPs could effectively inhibit HL60 and HepG2 cells with lower IC50 values compared with free curcumin. Furthermore, confocal microscopy together with flow cytometry analysis proved the enhanced apoptosis-inducing ability of PLGA-Cur NPs. Polymeric NP formulations are potential to be used for hydrophobic drug delivery systems in cancer therapy.

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.

Long-Acting Phospholipid Gel of Exenatide for Long-Term Therapy of Type II Diabetes.

PubMed

Hu, Mei; Zhang, Yu; Xiang, Nanxi; Zhong, Ying; Gong, Tao; Zhang, Zhi-Rong; Fu, Yao

2016-06-01

This study aimed to develop a sustained-release formulation of exenatide (EXT) for the long-term therapeutic efficacy in the treatment of type II diabetes. In this study, we present an injectable phospholipid gel by mixing biocompatible phospholipid S100, medium chain triglyceride (MCT) with 85% (w/w) ethanol. A systemic pre-formulation study has been carried out to improve the stability of EXT during formulation fabrication. With the optimized formulation, the pharmacokinetic profiles in rats were studied and two diabetic animal models were employed to evaluate the therapeutic effect of EXT phospholipid gel via a single subcutaneous injection versus repeated injections of normal saline and EXT solution. With optimized formulation, sustained release of exenatide in vivo for over three consecutive weeks was observed after one single subcutaneous injection. Moreover, the pharmacodynamic study in two diabetic models justified that the gel formulation displayed a comparable hypoglycemic effect and controlled blood glucose level compared with exenatide solution treated group. EXT-loaded phospholipid gel represents a promising controlled release system for long-term therapy of type II diabetes.

Dendrimers for Drug Delivery.

PubMed

Chauhan, Abhay Singh

2018-04-18

Dendrimers have come a long way in the last 25 years since their inception. Originally created as a wonder molecule of chemistry, dendrimer is now in the fourth class of polymers. Dr. Donald Tomalia first published his seminal work on Poly(amidoamine) (PAMAM) dendrimers in 1985. Application of dendrimers as a drug delivery system started in late 1990s. Dendrimers for drug delivery are employed using two approaches: (i) formulation and (ii) nanoconstruct. In the formulation approach, drugs are physically entrapped in a dendrimer using non-covalent interactions, whereas drugs are covalently coupled on dendrimers in the nanoconstruct approach. We have demonstrated the utility of PAMAM dendrimers for enhancing solubility, stability and oral bioavailability of various drugs. Drug entrapment and drug release from dendrimers can be controlled by modifying dendrimer surfaces and generations. PAMAM dendrimers are also shown to increase transdermal permeation and specific drug targeting. Dendrimer platforms can be engineered to attach targeting ligands and imaging molecules to create a nanodevice. Dendrimer nanotechnology, due to its multifunctional ability, has the potential to create next generation nanodevices.

Efficacy of tebuconazole embedded in biodegradable poly-3-hydroxybutyrate to inhibit the development of Fusarium moniliforme in soil microecosystems.

PubMed

Volova, Tatiana G; Prudnikova, Svetlana V; Zhila, Natalia O; Vinogradova, Olga N; Shumilova, Anna A; Nikolaeva, Elena D; Kiselev, Evgeniy G; Shishatskaya, Ekaterina I

2017-05-01

An important line of research is the development of a new generation of formulations with targeted and controlled release of the pesticide, using matrices made from biodegradable materials. In this study, slow-release formulations of the fungicide tebuconazole (TEB) have been prepared by embedding it into the matrix of poly-3-hydroxybutyrate (P3HB) in the form of films, microgranules and pellets. The average rates of P3HB degradation were determined by the geometry of the formulation, reaching, for 63 days, 0.095-0.116, 0.081-0.083 and 0.030-0.055 mg day -1 for films, microgranules and pellets respectively. The fungicidal activity of P3HB/TEB against the plant pathogen Fusarium moniliforme was compared with that of the commercial formulation Raxil Ultra. A pronounced fungicidal effect of the experimental P3HB/TEB formulations was observed in 2-4 weeks after application, and it was retained for 8 weeks, without affecting significantly the development of soil aboriginal microflora. TEB release can be regulated by the process employed to fabricate the formulation and the fungicide loading, and the TEB accumulates in the soil gradually, as the polymer is degraded. The experimental forms of TEB embedded in the slowly degraded P3HB can be used as a basis for developing slow-release fungicide formulations. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

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.

Formulation of unidirectional release buccal patches of carbamazepine and study of permeation through porcine buccal mucosa

PubMed Central

Govindasamy, Parthasarathy; Kesavan, Bhaskar Reddy; Narasimha, Jayaveera Korlakunta

2013-01-01

Objective To achieve transbuccal release of carbamazepine by loading in unidirectional release mucoadhesive buccal patches. Methods Buccal patches of carbamazepine with unidirectional drug release were prepared using hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and ethyl cellulose by solvent casting method. Water impermeable backing layer (Pidilite® Biaxially-oriented polypropylene film) of patches provided unidirectional drug release. They were evaluated for thickness, mass uniformity, surface pH and folding endurance. Six formulations FA2, FA8, FA10, FB1, FB14 and FB16 (folding endurance above 250) were evaluated further for swelling studies, ex vivo mucoadhesive strength, ex vivo mucoadhesion time, in vitro drug release, ex vivo permeation, accelerated stability studies and FTIR and XRD spectral studies. Results The ex vivo mucoadhesion time of patches ranged between 109 min (FA10) to 126 min (FB14). The ex vivo mucoadhesive force was in the range of 0.278 to 0.479 kg/m/s. The in vitro drug release studies revealed that formulation FA8 released 84% and FB16 released 99.01% of drug in 140 min. Conclusions The prepared unidirectional buccal patches of carbamazepine provided a maximum drug release within specified mucoadhesion period and it indicates a potential alternative drug delivery system for systemic delivery of carbamazepine. PMID:24093793

A modelling framework for the transport, transformation and biouptake of manufactured nanoparticles in the aquatic environment

NASA Astrophysics Data System (ADS)

Lofts, Stephen; Keller, Virginie; Dumont, Egon; Williams, Richard; Praetorius, Antonia; von der Kammer, Frank

2016-04-01

The development of innovative new chemical products is a key aspect of the modern economy, yet society demands that such development is environmentally sustainable. Developing knowledge of how new classes of chemicals behave following release to the environment is key to understanding the hazards that will potentially result. Nanoparticles are a key example of a class of chemicals that have undergone a significant expansion in production and use in recent years and so there is a need to develop tools to predict their potential hazard following their deliberate or incidental release to the environment. Generalising the understanding of the environmental behaviour of manufactured nanoparticles in general is challenging, as they are chemically and physically diverse (e.g. metals, metal oxides, carbon nanotubes, cellulose, quantum dots). Furthermore, nanoparticles may be manufactured with capping agents to modify their desired behaviour in industrial applications; such agents may also influence their environmental behaviour. Also, nanoparticles may become significantly modified from their as-manufactured forms both prior to and after the point of environmental release. Tools for predicting nanoparticle behaviour and hazard need to be able to consider a wide range of release scenarios and aspects of nanoparticle behaviour in the environment (e.g. dissolution, transformation of capping agents, agglomeration and aggregation behaviour), where such behaviours are not shared by all types of nanoparticle. This implies the need for flexible, futureproofed tools capable of being updated to take new understanding of behavioural processes into account as such knowledge emerges. This presentation will introduce the NanoFASE model system, a multimedia modelling framework for the transport, transformation and biouptake of manufactured nanoparticles. The complete system will comprise atmospheric, terrestrial and aquatic compartments to allow holistic simulation of nanoparticles; this presentation will focus on the aquatic compartment but will demonstrate the linkages with the other compartments. The system is intended for application at scales up to a large European river catchment at a resolution suitable for assessing spatially-resolved fate and biouptake. The model will be built around a transport framework which will deal with the bulk movement of water, sediments and nanoparticles through the system. Transformation processes such as dissolution, capping agent transformation, sorption of environmental molecules to particle surfaces, heteroaggregation with sediments, will be dealt with within 'reactors' with each grid cell. The reactor concept is intended to provide a separation between transport and transformation process, to allow alternative formulations of transformation processes for different classes of nanoparticles, and to allow new and updated formulations to be readily incorporated. Using this structure we aim to develop a flexible system capable of simulating the environmental transformation and fate of diverse nanoparticle classes under varying release scenarios. We will show conceptual model structures for release scenarios most relevant to the aquatic environment.

A Novel Approach for Dry Powder Coating of Pellets with Ethylcellulose. Part II: Evaluation of Caffeine Release.

PubMed

Albertini, Beatrice; Melegari, Cecilia; Bertoni, Serena; Dolci, Luisa Stella; Passerini, Nadia

2018-04-01

The objective of this study was to assess the efficacy and the capability of a novel ethylcellulose-based dry-coating system to obtain prolonged and stable release profiles of caffeine-loaded pellets. Lauric and oleic acids at a suitable proportion were used to plasticize ethylcellulose. The effect of coating level, percentage of drug loading, inert core particle size, and composition of the coating formulation including the anti-sticking agent on the drug release profile were fully investigated. A coating level of 15% w/w was the maximum layered amount which could modify the drug release. The best controlled drug release was obtained by atomizing talc (2.5% w/w) together with the solid plasticizer during the dry powder-coating process. SEM pictures revealed a substantial drug re-crystallization on the pellet surface, and the release studies evidenced that caffeine diffused through the plasticized polymer acting as pore former. Therefore, the phenomenon of caffeine migration across the coating layer had a strong influence on the permeability of the coating membrane. Comparing dry powder-coated pellets to aqueous film-coated ones, drug migration happened during storage, though more sustained release profiles were obtained. The developed dry powder-coating process enabled the production of stable caffeine sustained release pellets. Surprisingly, the release properties of the dry-coated pellets were mainly influenced by the way of addition of talc into the dry powder-coating blend and by the drug nature and affinity to the coating components. It would be interesting to study the efficacy of novel coating system using a different API.

Bioadhesive hydrogels for cosmetic applications.

PubMed

Parente, M E; Ochoa Andrade, A; Ares, G; Russo, F; Jiménez-Kairuz, Á

2015-10-01

The use of bioadhesive hydrogels for skin care presents important advantages such as long residence times on the application site and reduced product administration frequency. The aim of the present work was to develop bioadhesive hydrogels for skin application, using caffeine as a model active ingredient. Eight hydrogels were formulated using binary combinations of a primary polymer (carbomer homopolymer type C (Carbopol(®) 980) or kappa carrageenan potassium salt (Gelcarin(®) GP-812 NF)) and a secondary polymer (carbomer copolymer type B (Pemulen(™) TR-1), xanthan gum or guar gum). Hydrogels were characterized by means of physico-chemical (dynamic rheological measurements, spreadability and adhesion measurements) and sensory methods (projective mapping in combination with a check-all-that-apply (CATA) question). Caffeine hydrogels were formulated using two of the most promising formulations regarding adhesion properties and sensory characteristics. In vitro active ingredient release studies were carried out. Hydrogel formulations showed a prevalently elastic rheological behaviour. Complex viscosity of carbomer homopolymer type C hydrogels was higher than that of the kappa carrageenan hydrogels. Besides, complex viscosity values were dependent on the secondary polymer present in the formulation. Significant differences among hydrogels were found in detachment force, work of adhesion and spreading diameter results. Association of projective mapping with CATA allowed to determine similarities and dissimilarities among samples. Cluster analysis associated the samples in two groups. Two hydrogels were selected to study the release of caffeine. Both hydrogels presented similar release profiles which were well described by the Higuchi model. Caffeine release was exclusively controlled by a diffusive process. Physico-chemical and sensory techniques enabled the identification of bioadhesive hydrogel formulations with positive characteristics for cosmetic applications. Formulations which combined carbomer homopolymer type C with xanthan gum or with carbomer copolymer type B were the most promising for bioadhesive skin products. Caffeine release profiles of selected formulations were not statistically different. Both hydrogels gradually released the active ingredient, reaching approximately 80% within the first 5 h, and their profiles were well described by the Higuchi model. In this context, it could be concluded that the selected hydrogels are suitable bioadhesive hydrogel formulations for cosmetic application on the skin. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Formulation and evaluation of controlled release matrix mucoadhesive tablets of domperidone using Salvia plebeian gum

PubMed Central

Arora, Gurpreet; Malik, Karan; Singh, Inderbir; Arora, Sandeep; Rana, Vikas

2011-01-01

The aim of study was to prepare controlled release matrix mucoadhesive tablets of domperidone using Salvia plebeian gum as natural polymer. Tablets were formulated by direct compression technology employing the natural polymer in different concentrations (5, 10, 15 and 20% w/w). The prepared batches were evaluated for drug assay, diameter, thickness, hardness and tensile strength, swelling index, mucoadhesive strength (using texture analyzer) and subjected to in vitro drug release studies. Real-time stability studies were also conducted on prepared batches. In vitro drug release data were fitted in various release kinetic models for studying the mechanism of drug release. Tensile strength was found to increase from 0.808 ± 0.098 to 1.527 ± 0.10 mN/cm2 and mucoadhesive strength increased from 13.673 ± 1.542 to 40.378 ± 2.345 N, with an increase in the polymer concentration from 5 to 20% (A1 to A4). Swelling index was reported to increase with both increase in the concentration of gum and the time duration. The in vitro drug release decreased from 97.76 to 83.4% (A1 to A4) with the increase in polymer concentration. The drug release from the matrix tablets was found to follow zero-order and Higuchi models, indicating the matrix-forming potential of natural polymer. The value of n was found to be between 0.5221 and 0.8992, indicating the involvement of more than one drug release mechanism from the formulation and possibly the combination of both diffusion and erosion. These research findings clearly indicate the potential of S. plebeian gum to be used as binder, release retardant and mucoadhesive natural material in tablet formulations. PMID:22171313

Optimization of novel pentablock copolymer based composite formulation for sustained delivery of peptide/protein in the treatment of ocular diseases

PubMed Central

Patel, Sulabh P.; Vaishya, Ravi; Patel, Ashaben; Agrahari, Vibhuti; Pal, Dhananjay; Mitra, Ashim K.

2016-01-01

This manuscript is focused on the development of pentablock (PB) copolymer based sustained release formulation for the treatment of posterior segment ocular diseases. We have successfully synthesized biodegradable and biocompatible PB copolymers for the preparation of nanoparticles (NPs) and thermosensitive gel. Achieving high drug loading with hydrophilic biotherapeutics (peptides /proteins) is a challenging task. Moreover, small intravitreal injection volume (≤100 μL) requires high loading to develop a long term (6 months) sustained release formulation. We have successfully investigated various formulation parameters to achieve maximum peptide/protein (octreotide, insulin, lysozyme, IgG-Fab, IgG, and catalase) loading in PB NPs. Improvement in drug loading can facilitate delivery of larger doses of therapeutic proteins via limited injection volume. A composite formulation comprised of NPs in gel system exhibited sustained release (without burst effect) of peptides and proteins, may serve as a platform technology for the treatment of posterior segment ocular diseases. PMID:26964498

The effect of additives on release and in vitro skin retention of flavonoids from emulsion and gel semisolid formulations.

PubMed

Dyja, R; Jankowski, A

2017-08-01

To assess the effect of two different additives (propylene glycol (PG) and polyethylene glycol 400 (PEG 400)) on release and in vitro skin retention of quercetin and chrysin from semisolid bases (amphiphilic creams and acidic carbomer gels). For obtaining semisolid formulations, flavonoids were pre-dissolved in the liquid (PG or PEG 400) or directly suspended in the semisolid base. Three chrysin formulations ('cream 0', 'PG-cream' and 'PEG 400-cream') and five quercetin formulations ('cream 0', 'PG cream', 'PEG 400 cream', 'gel 0' and 'PG gel') were prepared. The release studies were carried out in Franz diffusion cells by means of a cellulose membrane. The porcine ear skin was used in in vitro skin retention studies. The dissolution was a prerequisite to increase the release rates of tested flavonoids from obtained semisolid formulations. The cumulative amount of chrysin released after 6 h from 'PEG 400 cream' containing partly dissolved form of that flavonoid was higher than that from 'cream 0' or 'PG cream' containing its suspended form. The formulations containing quercetin dissolved in PG ('PG cream', 'PG gel') or PEG 400 ('PEG 400 cream') exhibited higher release rates of that flavonoid than corresponding semisolid suspensions ('cream 0' or 'gel 0'). The effects of both liquid additives (PG and PEG 400) on the cumulative amount of quercetin released after 6 h were comparable. However, there was no correlation between the release rate and the skin retention. The amounts of the flavonoids found in the skin were strongly affected by the type of the used solvent. While PG increased the skin retention of both flavonoids, PEG 400 had no effect on chrysin skin retention and delayed quercetin skin absorption. The proper choice of the solvent added to the semisolid base is crucial for enhanced skin delivery of the tested flavonoids. PG is more efficient absorption promoter than PEG 400 of both chrysin and quercetin. © 2017 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

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

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.

Novel sustained-release dosage forms of proteins using polyglycerol esters of fatty acids.

PubMed

Yamagata, Y; Iga, K; Ogawa, Y

2000-02-03

In order to develop a novel delivery system for proteins based on polyglycerol esters of fatty acids (PGEFs), we studied a model system using interferon-alpha (IFN-alpha) as the test protein. A cylindrical matrix was prepared by a heat extrusion technique using a lyophilized powder of the protein and 11 different types of synthetic PGEFs, which varied in degree of glycerol polymerization (di- and tetra-), chain length of fatty acids (myristate, palmitate and stearate) and degree of fatty acid esterification (mono-, di- and tri-). In an in-vitro release study using an enzyme-linked immunosorbent assay (ELISA) as a detection method, the matrices prepared from a monoglyceride (used for comparison) and from diglycerol esters exhibited a biphasic release pattern with a large initial burst followed by slow release. In contrast, the matrices prepared from tetraglycerol esters showed a steady rate of release without a large initial burst. In an in vivo release study, initial bursts of IFN-alpha release were, also, dramatically reduced when the matrices were prepared from the tetraglycerol esters of palmitate and stearate, and the mean residence time (MRT) of IFN-alpha was prolonged, whereas the matrices prepared from monoglyceride and from diglycerol esters showed large initial bursts of IFN-alpha release. Since the release rates from the matrices prepared from the tetraglycerol esters of palmitate and stearate were governed by Jander's equation modified for a cylindrical matrix, the release from those matrices was concluded to be a diffusion-controlled process. The bioavailability of IFN-alpha after implantation of the matrix formulation prepared using all types of PGEFs, except for tetraglycerol triesters, was almost equivalent to that after injection of IFN-alpha solution; consequently, IFN-alpha in these matrices appears to remain stable during the release period.

Plasma stable, pH-sensitive non-ionic surfactant vesicles simultaneously enhance antiproliferative effect and selectivity of Sirolimus.

PubMed

Ghanbarzadeh, Saeed; Khorrami, Arash; Pourmoazzen, Zhaleh; Arami, Sanam

2015-05-01

The purpose of the present investigation was to prepare a plasma stable, pH-sensitive niosomal formulation to enhance Sirolimus efficacy and selectivity. pH-sensitive niosomal formulations bearing PEG-Poly (monomethyl itaconate)-CholC6 (PEG-PMMI-CholC6) copolymers and cholesteryl hemisuccinate (CHEMS) were prepared by a modified ethanol injection method and characterized with regard to pH-responsiveness and stability in human serum. The ability of pH-sensitive niosomes to enhance the Sirolimus cytotoxicity was evaluated in vitro using human erythromyeloblastoid leukemia cell line (K562) and compared with cytotoxicity effect on human umbilical vein endothelial cells (HUVEC). This study showed that both formulations can be rendered pH-sensitive property and were found to rapidly release their contents under mildly acidic conditions. However, the CHEMS-based niosomes lost their pH-sensitivity after incubation in plasma, whereas, PEG-PMMI-CholC6 niosomes preserved their ability to respond to pH change. Sirolimus encapsulated in pH-sensitive niosomes exhibited a higher cytotoxicity than the control conventional formulation on K562 cell line. On the other hand, both pH-sensitive niosomes showed lower antiproliferative effect on HUVEC cells. Plasma stable, pH-sensitive PEG-PMMI-CholC6-based niosomes can improve the in vitro efficiency and also reduce the side effects of Sirolimus.

Influence of some formulation variables on the optimization of pH-dependent, colon-targeted, sustained-release mesalamine microspheres.

PubMed

El-Bary, Ahmed Abd; Aboelwafa, Ahmed A; Al Sharabi, Ibrahim M

2012-03-01

The aim of this work was to understand the influence of different formulation variables on the optimization of pH-dependent, colon-targeted, sustained-release mesalamine microspheres prepared by O/O emulsion solvent evaporation method, employing pH-dependent Eudragit S and hydrophobic pH-independent ethylcellulose polymers. Formulation variables studied included concentration of Eudragit S in the internal phase and the ratios between; internal to external phase, drug to Eudragit S and Eudragit S to ethylcellulose to mesalamine. Prepared microspheres were evaluated by carrying out in vitro release studies and determination of particle size, production yield, and encapsulation efficiency. In addition, morphology of microspheres was examined using optical and scanning electron microscopy. Emulsion solvent evaporation method was found to be sensitive to the studied formulation variables. Particle size and encapsulation efficiency increased by increasing Eudragit S concentration in the internal phase, ratio of internal to external phase, and ratio of Eudragit S to the drug. Employing Eudragit S alone in preparation of the microspheres is only successful in forming acid-resistant microspheres with pulsatile release pattern at high pH. Eudragit S and ethylcellulose blend microspheres were able to control release under acidic condition and to extend drug release at high pH. The stability studies carried out at 40°C/75% RH for 6 months proved the stability of the optimized formulation. From the results of this investigation, microencapsulation of mesalamine in microspheres using blend of Eudragit S and ethylcellulose could constitute a promising approach for site-specific and controlled delivery of drug in colon.

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.

Tailoring sub-micron PLGA particle release profiles via centrifugal fractioning

PubMed Central

Dutta, Dipankar; Salifu, Mariama; Sirianni, Rachael W.; Stabenfeldt, Sarah E.

2016-01-01

Poly(D,L-lactic-co-glycolic) acid (PLGA)-based submicron particles are uniquely posed to overcome limitations of conventional drug delivery systems. However, tailoring cargo/payload release profiles from PLGA micro/nanoparticles typically requires optimization of the multi-parameter formulation, where small changes may cause drastic shifts in the resulting release profiles. In this study, we aimed to establish whether refining the average diameter of submicron particle populations after formulation alters protein release profiles. PLGA particles were first produced via double emulsion-solvent evaporation method to encapsulate bovine serum albumin. Particles were then subjected to centrifugal fractioning protocols varying in both spin time and force to determine encapsulation efficiency and release profile of differently sized populations that originated from a single batch. We found the average particle diameter was related to marked alterations in encapsulation efficiencies (range: 36.4–49.4%), burst release (range: 15.8–49.1%), and time for total cargo release (range: 38–78 days). Our data corroborate previous reports relating PLGA particle size with such release characteristics, however, this is the first study, to our knowledge, to directly compare particle population size while holding all formulation parameters constant. In summary, centrifugal fractioning to selectively control the population distribution of sub-micron PLGA particles represents a feasible tool to tailor release characteristics. PMID:26517011

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

PubMed

Jannin, V; Pochard, E; Chambin, O

2006-02-17

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

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

PubMed

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

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

Nanoscale Formulations and Diagnostics With Their Recent Trends: A Major Focus of Future Nanotechnology.

PubMed

Mukherjee, Biswajit; Dutta, Lopamudra; Mondal, Laboni; Dey, Niladri Shekhar; Chakraborty, Samrat; Maji, Ruma; Shaw, Tapan Kumar

2015-01-01

Nanomedicine is an emerging and rapidly growing field, possibly exploring for high expectation to healthcare. Nanoformulations have been designed to overcome challenges due to the development and fabrication of nanostructures. Unique size-dependent properties of nanoformulations make them superior and indispensable in many areas of human activity. Nano drug delivery systems are formulated and engineered to carry and deliver a number of substances in a targeted and controlled way. The vision of nanocarriers can be designed that will serve a dual purpose, allowing both treatment and diagnosis to be contained in an 'all-in-one' package. Nanoscale drugdelivery systems efficiently regulate the release, pharmacokinetics, pharmacodynamics, solubility, immunocompatibility, cellular uptake and biodistribution of chemical entities (drug). Their cellular uptake takes place by various mechanisms such as micropinocytosis, phagocytosis and receptor mediated endocytosis. These phenomena cause longer retention in blood circulation resulting in the release of the encapsulated materials in a sustained manner thus minimize the plasma fluctuations and toxic side effects. In this manner, the therapeutic index of conventional pharmaceuticals is efficiently increased. They can be used to deliver both micro and macro biomolecules such as peptides, proteins, plasmid DNA and synthetic oligodeoxynucleotides. In this present review, several recent developing and modifying nano-products for the detection, analysis, and treatment of diseases with their US and world patents along with various diagnostic kits have been discussed.

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

PubMed Central

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

2014-01-01

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

Design of sustained release pellets of ferrous fumarate using cow ghee as hot-melt coating agent.

PubMed

Sakarkar, Dinesh M; Dorle, Avinash K; Mahajan, Nilesh Manoharrao; Sudke, Suresh Gendappa

2013-07-01

The objective of the present study was to design ferrous fumarate (FF) sustained release (SR) pellets using of cow ghee (CG) as an important hot-melt coating (HMC) agent. The pellets were coated by HMC technique using CG and ethyl cellulose composition by conventional coating pan without the use of spray system. FF formulated as pellets and characterized with regard to the drug content and physico-chemical properties. Stability studies were carried out on the optimized formulation for a period of 6 months at 40 ± 2°C and 75 ± 5% relative humidity. Pellets with good surface morphology and smooth texture confirmed by stereo micrographs. HMC is easy, efficient, rapid and simple method since virtually no agglomeration seen during coating. In-vitro release from pellets at a given level of coating and for present pellet size was dependent upon the physico-chemical property of the drug and mostly aqueous solubility of the drug. The selection of optimized FF formulation was confirmed by comparing percent cumulative drug release with theoretical release profile. Formulation F2 had difference factor (f 1) and similarity factor (f 2) values was found to be 5 and 66 respectively. F2 showed SR of drug for 8 h with cumulative per cent release of 98.03 ± 4.49%. Release kinetics indicates approximately zero order release pattern. HMC pellets were stable during the course of stability study. By means of HMC using CG and ethyl cellulose, SR pellets containing FF were successfully prepared.

Formulation and evaluation of chitosan/polyethylene oxide nanofibers loaded with metronidazole for local infections.

PubMed

Zupančič, Špela; Potrč, Tanja; Baumgartner, Saša; Kocbek, Petra; Kristl, Julijana

2016-12-01

Nanofibers combined with an antimicrobial represent a powerful strategy for treatment of various infections. Local infections usually have a low fluid volume available for drug release, whereas pharmacopoeian dissolution tests include a much larger receptor volume. Therefore, the development of novel drug-release methods that more closely resemble the in-vivo conditions is necessary. We first developed novel biocompatible and biodegradable chitosan/polyethylene oxide nanofibers using environmentally friendly electrospinning of aqueous polymer solutions, with the inclusion of the antimicrobial metronidazole. Here, the focus is on the characterization of these nanofibers, which have high potential for bioadhesion and retention at the site of application. These can be used where prolonged retention of the delivery system at an infected target site is needed. Drug release was studied using three in-vitro methods: a dissolution apparatus (Apparatus 1 of the European Pharmacopoeia), vials, and a Franz diffusion cell. In contrast to other studies, here the Franz diffusion cell method was modified to introduce a small volume of medium with the nanofibers in the donor compartment, where the nanofibers swelled, eroded, and released the metronidazole, which then diffused into the receptor compartment. This set-up with nanofibers in a limited amount of medium released the drug more slowly compared to the other two in-vitro methods that included larger volumes of medium. These findings show that drug release from nanofibers strongly depends on the release method used. Therefore, in-vitro test methods should closely resemble the in-vivo conditions for more accurate prediction of drug release at a therapeutic site. Copyright © 2016 Elsevier B.V. All rights reserved.

Two release rates from monolithic carboxymethyl starch tablets: formulation, characterization, and in vitro/in vivo evaluation.

PubMed

Le, Tien Canh; Mateescu, Mircea Alexandru

2017-08-01

Most of non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen at more than 1200 mg/day may generate gastrointestinal and cardiovascular side effects. Bilayer or multiparticulate devices have been developed for controlled release in order to prevent undesired side effects. A new "two release rate (2RR) monolithic tablets" approach is now proposed for controlled release of poorly soluble drugs, particularly NSAIDs. Ibuprofen was used as model drug. This concept is based on a calcium carboxymethyl-starch (CaCMS) complex as a novel, low-cost excipient for monolithic dosage forms easy to manufacture by direct compaction. The in vitro dissolution from CaCMS formulations (tablets containing 400 or 600 mg active principle) showed two distinct release rates: (i) an initial fast release (for 30 min in simulated gastric fluid) of about 200 mg ibuprofen, an amount similar to the dosage of conventional immediate-release form (Motrin® 200 mg), and (ii) a slow release of remaining about 200 or 400 mg for a period of 12 h. A preliminary in vivo study (beagle dogs) showed pharmacokinetic parameters of one single controlled-release dosage of ibuprofen (400 mg) formulated with CaCMS, near equivalence with multiple doses (three tablets of 200 mg ibuprofen) of conventional Motrin®. A marked reduction (with 33%) of administered dose (400 instead 600 mg) was achieved by the new formulation with equivalent therapeutic effects. This dose reduction may be beneficial and is expected to minimize side damage risks. Although the present study was limited to NSAIDs, the 2RR concept can be applied for other drugs, particularly for subjects unable to follow frequent administrations.

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

Trigger chemistries for better industrial formulations.

PubMed

Wang, Hsuan-Chin; Zhang, Yanfeng; Possanza, Catherine M; Zimmerman, Steven C; Cheng, Jianjun; Moore, Jeffrey S; Harris, Keith; Katz, Joshua S

2015-04-01

In recent years, innovations and consumer demands have led to increasingly complex liquid formulations. These growing complexities have provided industrial players and their customers access to new markets through product differentiation, improved performance, and compatibility/stability with other products. One strategy for enabling more complex formulations is the use of active encapsulation. When encapsulation is employed, strategies are required to effect the release of the active at the desired location and time of action. One particular route that has received significant academic research effort is the employment of triggers to induce active release upon a specific stimulus, though little has translated for industrial use to date. To address emerging industrial formulation needs, in this review, we discuss areas of trigger release chemistries and their applications specifically as relevant to industrial use. We focus the discussion on the use of heat, light, shear, and pH triggers as applied in several model polymeric systems for inducing active release. The goal is that through this review trends will emerge for how technologies can be better developed to maximize their value through industrial adaptation.

Review of extended-release formulations of Tramadol for the management of chronic non-cancer pain: focus on marketed formulations

PubMed Central

Kizilbash, Arshi; Ngô-Minh, Cường

2014-01-01

Patients with chronic non-malignant pain report impairments of physical, social, and psychological well-being. The goal of pain management should include reducing pain and improving quality of life. Patients with chronic pain require medications that are able to provide adequate pain relief, have minimum dosing intervals to maintain efficacy, and avoid breakthrough pain. Tramadol has proven efficacy and a favourable safety profile. The positive efficacy and safety profile has been demonstrated historically in numerous published clinical studies as well as from post-marketing experience. It is a World Health Organization “Step 2” opioid analgesic that has been shown to be effective, well-tolerated, and valuable, where treatment with strong opioids is not required. A number of extended release formulations of Tramadol are available in Canada and the United States. An optimal extended release Tramadol formulation would be expected to provide consistent pain control with once daily dosing, few sleep interruptions, flexible dosing schedules, and no limitation on taking with meals. Appropriate treatment options should be based on the above proposed attributes. A comparative review of available extended release Tramadol formulations shows that these medications are not equivalent in their pharmacokinetic profile and this may have implications for selecting the optimal therapy for patients with pain syndromes where Tramadol is an appropriate analgesic agent. Differences in pharmacokinetics amongst the formulations may also translate into varied clinical responses in patients. Selection of the appropriate formulation by the health care provider should therefore be based on the patient’s chronic pain condition, needs, and lifestyle. PMID:24711710

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

PubMed

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

2013-11-01

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

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

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization, in vitro and in vivo pharmacokinetic studies.

PubMed

Thakar, Krishna; Joshi, Garima; Sawant, Krutika K

2013-06-01

The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS). Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3(2) factorial design was done using Polyox WSR 303 (X1) and HPMC K4M (X2) as independent variables and cumulative percentage drug released at 6 h (Q6h) as dependent variable. Optimized formulation showed floating lag time of 4-5 s, floated for more than 12 h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6 h. In vivo pharmacokinetic studies in rabbits showed Cmax of 189.96 ± 13.04 ng/mL and Tmax of 4 ± 0.35 h for GFDDS. The difference for AUC(0-T) and AUC(0-∞) between the test and reference formulation was statistically significant (p > 0.05). AUC(0-T) and AUC(0-∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively. GFDDS provided prolonged gastric residence and showed significant increase in bioavailability of baclofen.

Impact of formulation and process variables on solid-state stability of theophylline in controlled release formulations.

PubMed

Korang-Yeboah, Maxwell; Rahman, Ziyaur; Shah, Dhaval; Mohammad, Adil; Wu, Suyang; Siddiqui, Akhtar; Khan, Mansoor A

2016-02-29

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 °C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration-dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution. Published by Elsevier B.V.

Physicochemical characterization of camptothecin membrane binding properties and polymeric microsphere formulations

NASA Astrophysics Data System (ADS)

Selvi, Bilge

In an effort to design novel formulation strategies to optimize the antitumor activity of camptothecin (CPT), the physicochemical and membrane binding properties of the drug, were investigated by various techniques in acidic and physiological pH. The intrinsic solubility of the CPT-lactone free base was determined to be 3.44 muM and 5.11 muM at 22°C and 37°C, respectively. The equilibrium solubility of the drug was found to increase with increasing temperature and decreasing pH. The enhanced solubility of the drug at very low pH is attributed to the protonation of the nitrogen atom in the ring B and the increased solvency of the highly acidic media. The logarithmic value of the intrinsic partition coefficient P of the free base CPT-lactone form was estimated to be 1.65, characteristic of a molecule suitable for oral absorption. The association constants Kf of the drug for bilayers composed of the zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and the negatively-charged 1,2-dioleoyl-sn-glycero-3-phospho- rac-(1-glycerol) (DOPG) were studied at acidic pH by fluorescence anisotropy and determined to be 35.4 +/- 4.5 M-1 and 93.1 +/- 11.0 M-1 for DOPC and DOPG, respectively, indicating a tendency of CPT to preferentially bind to negatively charged membranes. The energy of activation for the hydrolysis of CPT at physiological pH was found to be 114.3 +/- 33.4 kj/mole. The calculated t½ of the reaction at pH 7.2 at temperatures 25°C and 10°C was found to be 0.07 days and 5.12 days, respectively, whereas the time required for 1% of CPT-lactone to hydrolyze to CPT-carboxylate (t99%) was determined to be 1.8 hours, thus offering enough time to safely handle CPT-lactone at low temperatures. The preformulation results indicated that at highly acidic media CPT is positively charged and exists at its stable lactone form of increased solubility and has a capacity to bind to negatively charged membranes. Taking advantage of the increased stability of CPT in acidic media CPT-loaded microspheres were prepared in a 10 N HCl-methylene chloride mixture using the H-series of poly(D,L-lactide-co-glycolide) (H-PLGA). The system was then compared with a standard microsphere formation method and the results were evaluated with respect to particle morphology and drug release profile. Rough surface of the particles were obtained from the preparation method where a 10 N HCl solution was used. The release pattern of CPT was biphasic comprising a first burst effect followed by zero order release for all the formulations. However, the release of the drug was slightly faster from the microspheres formed with the modified method compared to the standard. Until now clinical application of CPT has been highly restricted by the insolubility and instability of the drug in its active lactone form, resulting in less antitumor potency and poor bioavailability. The pH-dependent release of the CPT-loaded microspheres was also compared and faster initial release (burst phase) was found at neutral pH, whereas at low pH the release was zero order for all the formulations. The results indicate that the stabilization and sustained release of CPT from H-PLGA microspheres might reduce local toxicity while simultaneously prolonging efficiency, suggesting new perspectives in CPT chemotherapy.

Substitution of modified starch with hydrogen peroxide-modified rice bran in salad dressing formulation: physicochemical, texture, rheological and sensory properties.

PubMed

Maani, Bahareh; Alimi, Mazdak; Shokoohi, Shirin; Fazeli, Fatemeh

2017-06-01

Rice bran samples were treated under different conditions including hydrogen peroxide content (1, 4, and 7 wt%) and media pH (10.5, 11.5, and 12.5). Water holding capacity and color measurement results showed acceptable improvements compared with the untreated native bran confirmed by Fourier transform infrared analysis. Optimization of modification conditions upon characterization results suggested the introduction of 7% hydrogen peroxide at pH = 12.5. Accordingly, 1, 2 and 3 wt% of the rice bran treated under the optimized conditions, was used in salad dressing formulation; as for .3 wt% of modified starch in the formulation of blank sample, 1 wt% of treated rice bran dietary fiber was substituted. Biopolymer swelling and formation of a stable viscous gel network promoted by the chemical treatment of lignocellulosic rice bran restrict the mobility of oil droplets dispersed in the continuous phase which would consequently retard the emulsion instability phenomena. This effect was also confirmed by flow behavior and viscoelastic characterization results. Salad dressing samples containing 1 and 2 wt% treated rice bran showed acceptable physicochemical, rheological and organoleptic properties besides superior nutritional characteristics compared with the commercial modified starch traditionally used in salad dressing formulations. Despite recommended consumption of dietary fibers, addition of unprocessed lignocellulosic materials to food products usually raise negative effects in sensory, color, and texture quality. This study investigates the modification of rice bran, the byproduct of brown rice milling, to substitute modified starch traditionally used in salad dressing formulations to achieve optimum properties desirable for the final product. Optimization of modification conditions upon characterization of the formulated samples in this study would suggest new improved formulation for the commercial product. © 2016 Wiley Periodicals, Inc.

Characterization of new functionalized calcium carbonate-polycaprolactone composite material for application in geometry-constrained drug release formulation development.

PubMed

Wagner-Hattler, Leonie; Schoelkopf, Joachim; Huwyler, Jörg; Puchkov, Maxim

2017-10-01

A new mineral-polymer composite (FCC-PCL) performance was assessed to produce complex geometries to aid in development of controlled release tablet formulations. The mechanical characteristics of a developed material such as compactibility, compressibility and elastoplastic deformation were measured. The results and comparative analysis versus other common excipients suggest efficient formation of a complex, stable and impermeable geometries for constrained drug release modifications under compression. The performance of the proposed composite material has been tested by compacting it into a geometrically altered tablet (Tablet-In-Cup, TIC) and the drug release was compared to commercially available product. The TIC device exhibited a uniform surface, showed high physical stability, and showed absence of friability. FCC-PCL composite had good binding properties and good compactibility. It was possible to reveal an enhanced plasticity characteristic of a new material which was not present in the individual components. The presented FCC-PCL composite mixture has the potential to become a successful tool to formulate controlled-release dosage solid forms.

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.

Isotretinoin Oil-Based Capsule Formulation Optimization

PubMed Central

Tsai, Pi-Ju; Huang, Chi-Te; Lee, Chen-Chou; Li, Chi-Lin; Huang, Yaw-Bin; Tsai, Yi-Hung; Wu, Pao-Chu

2013-01-01

The purpose of this study was to develop and optimize an isotretinoin oil-based capsule with specific dissolution pattern. A three-factor-constrained mixture design was used to prepare the systemic model formulations. The independent factors were the components of oil-based capsule including beeswax (X 1), hydrogenated coconut oil (X 2), and soybean oil (X 3). The drug release percentages at 10, 30, 60, and 90 min were selected as responses. The effect of formulation factors including that on responses was inspected by using response surface methodology (RSM). Multiple-response optimization was performed to search for the appropriate formulation with specific release pattern. It was found that the interaction effect of these formulation factors (X 1 X 2, X 1 X 3, and X 2 X 3) showed more potential influence than that of the main factors (X 1, X 2, and X 3). An optimal predicted formulation with Y 10 min, Y 30 min, Y 60 min, and Y 90 min release values of 12.3%, 36.7%, 73.6%, and 92.7% at X 1, X 2, and X 3 of 5.75, 15.37, and 78.88, respectively, was developed. The new formulation was prepared and performed by the dissolution test. The similarity factor f 2 was 54.8, indicating that the dissolution pattern of the new optimized formulation showed equivalence to the predicted profile. PMID:24068886

Pulmonary sustained release of insulin from microparticles composed of polyelectrolyte layer-by-layer assembly.

PubMed

Amancha, Kiran Prakash; Balkundi, Shantanu; Lvov, Yuri; Hussain, Alamdar

2014-05-15

The present study tests the hypothesis that layer-by-layer (LbL) nanoassembly of thin polyelectrolyte films on insulin particles provides sustained release of the drug after pulmonary delivery. LbL insulin microparticles were formulated using cationic and anionic polyelectrolytes. The microparticles were characterized for particle size, particle morphology, zeta potential and in vitro release. The pharmacokinetics and pharmacodynamics of drug were assessed by measuring serum insulin and glucose levels after intrapulmonary administration in rats. Bronchoalveolar lavage (BAL) and evans blue (EB) extravasation studies were performed to investigate the cellular or biochemical changes in the lungs caused by formulation administration. The mass median aerodynamic diameter (MMAD) of the insulin microparticles was 2.7 μm. Confocal image of the formulation particles confirmed the polyelectrolyte deposition around the insulin particles. Zeta potential measurements showed that there was charge reversal after each layering. Pulmonary administered LbL insulin formulation resulted in sustained serum insulin levels and concomitant decrease in serum glucose levels. The BAL and EB extravasation studies showed that the LbL insulin formulation did not elicit significant increase in marker enzymes activities compared to control group. These results demonstrate that the sustained release of insulin could be achieved using LbL nanoassembly around the insulin particles. Copyright © 2014 Elsevier B.V. All rights reserved.

Technology of stable, prolonged-release eye-drops containing Cyclosporine A, distributed between lipid matrix and surface of the solid lipid microspheres (SLM).

PubMed

Wolska, Eliza; Sznitowska, Małgorzata

2013-01-30

The aim of this study was to prepare solid lipid microspheres (SLM) with incorporated Cyclosporine A (Cs), suitable for ocular application. For this purpose, SLM were formulated by using different lipids and three different nonionic surfactants. The SLM were produced using a hot emulsification method. The SLM dispersions contained 10, 20 or 30% of lipid (w/w) and up to 2% (w/w) of Cs. The size of the microspheres with Cs ranged from 1 to 15 μm. Physically stable SLM with Cs were prepared using Compritol, as a lipid matrix, and Tween 80, as a surfactant. In contrast, dispersion with Precirol alone, formed semi-solid gels during storage, while in formulations with Precirol and Miglyol, crystals of Cs were observed. In vitro release profile of Compritol formulations showed that 40% of Cs is released within 1h, while the release of the following 40% takes more time, depending on lipid content in the formulations. The large part of Cs, added to SLM formulations (from 45 to 80%), was found on the surface of microparticles, but no drug crystallization occurred during a long-term storage. Copyright © 2012 Elsevier B.V. All rights reserved.

Localized In Situ Nanoemulgel Drug Delivery System of Quercetin for Periodontitis: Development and Computational Simulations.

PubMed

Aithal, Gururaj C; Nayak, Usha Yogendra; Mehta, Chetan; Narayan, Reema; Gopalkrishna, Pratibha; Pandiyan, Sudharsan; Garg, Sanjay

2018-06-06

This study was aimed at formulating a bioabsorbable, controlled-release, nanoemulgel of Quercetin, a potent antimicrobial and anti-inflammatory agent for the treatment of periodontitis that could improve its solubility and bioavailability. Screening of components was carried out based on the solubility studies. Nanoemulsion containing cinnamon oil as the oil phase, tween 80 and Carbitol ® as the surfactant-cosurfactant mixture (S mix ) and water as the aqueous phase containing 125 µg/200 µL of Quercetin was prepared by using spontaneous emulsification method. Nanoemulgel was prepared using 23% w / v poloxamer 407 as gel base. Comprehensive evaluation of the formulated nanoemulgel was carried out, and the optimized formulation was studied for drug release using Franz vertical diffusion cells. The formulated nanoemulgelexhibited a remarkable release of 92.4% of Quercetin at the end of 6 h, as compared to that of pure Quercetin-loaded gel (<3% release). The viscosity of the prepared nanoemulgel was found to be 30,647 ± 0.32 cPs at 37 °C. Also, molecular dynamics (MD) simulation was utilized to understand the gelation process and role of each component in the formulation. The present study revealed that the developed nanoemulgel of Quercetin could be a potential delivery system for clinical testing in periodontitis.

Development and evaluation of co-formulated docetaxel and curcumin biodegradable nanoparticles for parenteral administration.

PubMed

Pawar, Harish; Wankhade, Shrikant Rameshrao; Yadav, Dharmendra K; Suresh, Sarasija

2016-09-01

Technology for development of biodegradable nanoparticles encapsulating combinations for enhanced efficacy. To develop docetaxel (DTX) and curcumin (CRM) co-encapsulated biodegradable nanoparticles for parenteral administration with potential for prolonged release and decreased toxicity. Modified emulsion solvent-evaporation technique was employed in the preparation of the nanoparticles optimized by the face centered-central composite design (FC-CCD). The uptake potential was studied in MCF-7 cells, while the toxicity was evaluated by in vitro hemolysis test. In vivo pharmacokinetic was evaluated in male Wistar rats. Co-encapsulated nanoparticles were developed of 219 nm size, 0.154 PDI, -13.74 mV zeta potential and 67.02% entrapment efficiency. Efficient uptake was observed by the nanoparticles in MCF-7 cells with decreased toxicity in comparison with the commercial DTX intravenous injection, Taxotere®. The nanoparticles exhibited biphasic release with initial burst release followed by sustained release for 5 days. The nanoparticles displayed a 4.3-fold increase in AUC (391.10 ± 32.94 versus 89.77 ± 10.58 μg/ml min) in comparison to Taxotere® with a 6.2-fold increase in MRT (24.78 ± 2.36 versus 3.58 ± 0.21 h). The nanoparticles exhibited increased uptake, prolonged in vitro and in vivo release, with decreased toxicity thus exhibiting potential for enhanced efficacy.

Design and In-vitro Evaluation of Sustained Release Floating Tablets of Metformin HCl Based on Effervescence and Swelling

PubMed Central

Senjoti, Faria Gias; Mahmood, Syed; Jaffri, Juliana Md; Mandal, Uttam Kumar

2016-01-01

An oral sustained-release floating tablet formulation of metformin HCl was designed and developed. Effervescence and swelling properties were attributed on the developed tablets by sodium bicarbonate and HPMC-PEO polymer combination, respectively. Tablet composition was optimized by response surface methodology (RSM). Seventeen (17) trial formulations were analyzed according to Box-Behnken design of experiment where polymer content of HPMC and PEO at 1: 4 ratio (A), amount of sodium bi-carbonate (B), and amount of SSG (C) were adopted as independent variables. Floating lag time in sec (Y1), cumulative percent drug released at 1 h (Y2) and 12 h (Y3) were chosen as response variables. Tablets from the optimized formulation were also stored at accelerated stability condition (40°C and 75% RH) for 3 months to assess their stability profile. RSM could efficiently optimize the tablet composition with excellent prediction ability. In-vitro drug release until 12 h, floating lag time, and duration of floating were dependent on the amount of three selected independent variables. Optimized tablets remained floating for more than 24 h with a floating lag time of less than 4 min. Based on best fitting method, optimized formulation was found to follow Korsmeyer-Peppas release kinetic. Accelerated stability study revealed that optimized formulation was stable for three months without any major changes in assay, dissolution profile, floating lag time and other physical properties. PMID:27610147

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

PubMed

Brouillet, F; Bataille, B; Cartilier, L

2008-05-22

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

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

PubMed

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

2018-01-01

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

Controlling protein release using biodegradable microparticles

NASA Astrophysics Data System (ADS)

Kline, Benjamin Patrick

Research in the field of protein therapeutics has exploded over the past decade and continues to grow in both academia and in industry. Protein drugs have advantages of being highly specific and highly active making them coveted targets for high profile disease states like cancer and multiple sclerosis. Unfortunately, their many advantages are complemented by their obstacles. Because proteins are highly active and highly specific, the window between efficacy and toxicity is very narrow and drug development can be long and arduous. In addition, protein activity is dependent on its specific folding conformation that is easily disrupted by a variety of development processes. This research aimed to identify microparticle formulations to control protein release and also to determine which formulation parameters affected burst release, encapsulation, and steady-state release the most. It was found that polymer type and composition were two of the most important factors. Long-term controlled release of bovine serum albumin (BSA) was achieved as well as a wide variety of release profiles. A method was identified for micronizing protein at low cost to retain activity and coacervation was evaluated as a method for preparing protein loaded microspheres. This research provides a basis from which researchers can create better controlled release formulations for future protein therapeutics.

Development of a simple analytical methodology for determination of glucosamine release from modified release matrix tablets.

PubMed

Wu, Yunqi; Hussain, Munir; Fassihi, Reza

2005-06-15

A simple spectrophotometric method for determination of glucosamine release from sustained release (SR) hydrophilic matrix tablet based on reaction with ninhydrin is developed, optimized and validated. The purple color (Ruhemann purple) resulted from the reaction was stabilized and measured at 570 nm. The method optimization was essential as many procedural parameters influenced the accuracy of determination including the ninhydrin concentration, reaction time, pH, reaction temperature, purple color stability period, and glucosamine/ninhydrin ratio. Glucosamine tablets (600 mg) with different hydrophilic polymers were formulated and manufactured on a rotary press. Dissolution studies were conducted (USP 26) using deionized water at 37+/-0.2 degrees C with paddle rotation of 50 rpm, and samples were removed manually at appropriate time intervals. Under given optimized reaction conditions that appeared to be critical, glucosamine was quantitatively analyzed and the calibration curve in the range of 0.202-2.020 mg (r=0.9999) was constructed. The recovery rate of the developed method was 97.8-101.7% (n=6). Reproducible dissolution profiles were achieved from the dissolution studies performed on different glucosamine tablets. The developed method is easy to use, accurate and highly cost-effective for routine studies relative to HPLC and other techniques.

Insomnia: Zolpidem Extended-Release for the Treatment of Sleep Induction and Sleep Maintenance Symptoms

PubMed Central

Doghramji, Paul P.

2007-01-01

Insomnia impairs daytime functioning or causes clinically significant daytime distress. The consequences of insomnia, if left untreated, may contribute to the risks of developing additional serious conditions, such as psychiatric illness, cardiovascular disease, or metabolic issues. Furthermore, some comorbidities associated with insomnia may be bidirectional in their causality because psychiatric and other medical problems can increase the risk for insomnia. Regardless of the serious consequences of inadequately treated insomnia, clinicians often do not inquire into their patients' sleep habits, and patients, in turn, are not forthcoming with details of their sleep difficulties. The continuing education of physicians and patients with regard to insomnia and currently available therapies for the treatment of insomnia is, therefore, essential. Insomnia may present as either a difficulty falling asleep, difficulty maintaining sleep, or waking too early without being able to return to sleep. Furthermore, these symptoms often change over time in an unpredictable manner. Therefore, when considering a sleep medication, one with efficacy for the treatment of multiple insomnia symptoms is recommended. A modified-release formulation of zolpidem, zolpidem extended-release, has been approved for the treatment of insomnia characterized by both difficulty in falling asleep and maintaining sleep. Here, we review studies supporting the use of zolpidem extended-release in the treatment of sleep-onset and sleep maintenance difficulties. PMID:17435620

Comparative study on the in vitro performance of blister molded and conventional lornoxicam immediate release liquitablets: accelerated stability study and anti-inflammatory and ulcerogenic effects.

PubMed

El-Setouhy, Doaa Ahmed; Gamiel, Alaa Abdel-Rahman; Badawi, Alia Abd El-Latif; Osman, Afaf Sayed; Labib, Dina Ahmed

2017-03-01

Lornoxicam is a potent non-steroidal anti-inflammatory drug (NSAID). It shows limited solubility in the gastric pH, delayed bioavailability and pharmacodynamic effects with aggravated gastric side effects (due to longer residence in the stomach wall). To enhance dissolution of lornoxicam in the gastric fluid and expectedly absorption and pharmacological action, with less ulcerogenic effects. Formulation of immediate release (IR) lornoxicam liquitablets containing both liquid and solid release modulators (wetting agent, solubilizers and microenvironmental pH modifiers). Beside the traditional direct compression technique employed for the preparation of liquitablets a new technique, blister molding, was also used. The effect of the two different manufacturing methods on the fast release characteristics (rapid disintegration and dissolution) was studied. Stability and pharmacological activity of the optimum formula were also explored. Similarity factor pointed out the superiority of molding technique in enhancing dissolution of lornoxicam owing to significant crystallinity reduction (XRD). Optimum formula showed negligible change in drug content and dissolution profiles over 12 weeks, significantly improved anti-inflammatory activity and significantly reduced gastric ulcerative effect over pure lornoxicam and commercial formula. Blister molded lornoxicam liquitablet of improved dissolution and pharmacological activity and less gastric erosion was successfully prepared.

Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters.

PubMed

Kanani, Kunal; Gatoulis, Sergio C; Voelker, Michael

2015-08-03

Aspirin has been used therapeutically for over 100 years. As the originator and an important marketer of aspirin-containing products, Bayer's clinical trial database contains numerous reports of the pharmacokinetics of various aspirin formulations. These include evaluations of plain tablets, effervescent tablets, granules, chewable tablets, and fast-release tablets. This publication seeks to expand upon the available pharmacokinetic information concerning aspirin formulations. In the pre-systemic circulation, acetylsalicylic acid (ASA) is rapidly converted into its main active metabolite, salicylic acid (SA). Therefore, both substances are measured in plasma and reported in the results. The 500 mg strength of each formulation was chosen for analysis as this is the most commonly used for analgesia. A total of 22 studies were included in the analysis. All formulations of 500 mg aspirin result in comparable plasma exposure to ASA and SA as evidenced by AUC. Tablets and dry granules provide a consistently lower Cmax compared to effervescent, granules in suspension and fast release tablets. Effervescent tablets, fast release tablets, and granules in suspension provide a consistently lower median Tmax compared to dry granules and tablets for both ASA and SA. This report reinforces the importance of formulation differences and their impact on pharmacokinetic parameters.

Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters

PubMed Central

Kanani, Kunal; Gatoulis, Sergio C.; Voelker, Michael

2015-01-01

Aspirin has been used therapeutically for over 100 years. As the originator and an important marketer of aspirin-containing products, Bayer’s clinical trial database contains numerous reports of the pharmacokinetics of various aspirin formulations. These include evaluations of plain tablets, effervescent tablets, granules, chewable tablets, and fast-release tablets. This publication seeks to expand upon the available pharmacokinetic information concerning aspirin formulations. In the pre-systemic circulation, acetylsalicylic acid (ASA) is rapidly converted into its main active metabolite, salicylic acid (SA). Therefore, both substances are measured in plasma and reported in the results. The 500 mg strength of each formulation was chosen for analysis as this is the most commonly used for analgesia. A total of 22 studies were included in the analysis. All formulations of 500 mg aspirin result in comparable plasma exposure to ASA and SA as evidenced by AUC. Tablets and dry granules provide a consistently lower Cmax compared to effervescent, granules in suspension and fast release tablets. Effervescent tablets, fast release tablets, and granules in suspension provide a consistently lower median Tmax compared to dry granules and tablets for both ASA and SA. This report reinforces the importance of formulation differences and their impact on pharmacokinetic parameters. PMID:26247959

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

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.

Direct comparison of two different mesalamine formulations for the induction of remission in patients with ulcerative colitis: A double-blind, randomized study

PubMed Central

Ito, Hiroaki; Iida, Mitsuo; Matsumoto, Takayuki; Suzuki, Yasuo; Sasaki, Hidetaka; Yoshida, Toyomitsu; Takano, Yuichi; Hibi, Toshifumi

2010-01-01

Background: Mesalamine is the first-line drug for the treatment of ulcerative colitis (UC). We directly compared the efficacy and safety of two mesalamine formulations for the induction of remission in patients with UC. Methods: In a multicenter, double-blind, randomized study, 229 patients with mild-to-moderate active UC were assigned to 4 groups: 66 and 65 received a pH-dependent release formulation of 2.4 g/day (pH-2.4 g) or 3.6 g/day (pH-3.6 g), respectively; 65 received a time-dependent release formulation of 2.25 g/day (Time-2.25 g), and 33 received placebo (Placebo). The drugs were administered three times daily for eight weeks. The primary endpoint was a decrease in the UC disease activity index (UC-DAI). Results: In the full analysis set (n = 225) the decrease in UC-DAI in each group was 1.5 in pH-2.4 g, 2.9 in pH-3.6 g, 1.3 in Time-2.25 g and 0.3 in Placebo, respectively. These results demonstrate the superiority of pH-3.6 g over Time-2.25 g (P = 0.003) and the noninferiority of pH-2.4 g to Time-2.25 g. Among the patients with proctitis-type UC, a significant decrease in UC-DAI was observed in pH-2.4 g and pH-3.6 g as compared to Placebo, but not in Time-2.25 g. No differences were observed in the safety profiles. Conclusions: Higher dose of the pH-dependent release formulation was more effective for induction of remission in patients with mild-to-moderate active UC. Additionally, the pH-dependent release formulation was preferable to the time-dependent release formulation for patients with proctitis-type UC (UMIN Clinical Trials Registry, no. C000000288). (Inflamm Bowel Dis 2010) PMID:20049950

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.

Formulation and In-vitro Evaluation of Tretinoin Microemulsion as a Potential Carrier for Dermal Drug Delivery

PubMed Central

Mortazavi, Seyed Alireza; Pishrochi, Sanaz; Jafari azar, Zahra

2013-01-01

In this study, tretinoin microemulsion has been formulated based on phase diagram studies by changing the amounts and proportions of inactive ingredients, such as surfactants, co-surfactants and oils. The effects of these variables have been determined on microemulsion formation, particle size of the dispersed phase and release profile of tretinoin from microemulsion through dialysis membrane. In released studies, static Franz diffusion cells mounted with dialysis membrane were used. Sampling was conducted every 3 h at room temperature over a period of 24 h. The amount of released drug was measured with UV-spectrophotometer and the percentage of drug released was calculated. Based on the results obtained, the oil phase concentration had a proportional effect on particle size which can consequently influence on drug release. The particle size and the amount of released drug were affected by the applied surfactants. The components of the optimized microemulsion formulation were 15% olive oil, 12% propylene glycol (as co-surfactant), 33% Tween®80 (as surfactant) and 40% distilled water, which was tested for viscosity and rheological behavior. The prepared tretinoin microemulsion showed pseudoplastic-thixotropic behavior. The profile of drug release follows zero order kinetics. The optimized tretinoin microemulsion showed enhanced in-vitro release profile compared to the commercial gels and creams. PMID:24523740

Pharmaceutical quality of "party pills" raises additional safety concerns in the use of illicit recreational drugs.

PubMed

Young, Simon A; Thrimawithana, Thilini R; Antia, Ushtana; Fredatovich, John D; Na, Yonky; Neale, Peter T; Roberts, Amy F; Zhou, Huanyi; Russell, Bruce

2013-06-14

To determine the content and release kinetics of 1-benzylpiperazine (BZP) and 1-(3-trifluoromethyl-phenyl)piperazine (TFMPP) from "party pill" formulations. From these data, the possible impact of pharmaceutical quality upon the safety of such illicit formulations may be inferred. The amount of BZP and TFMPP in party pill formulations was determined using a validated HPLC method. The in-vitro release kinetics of selected party pill brands were determined using a USP dissolution apparatus (75 rpm, 37.5 degrees Celsius). The release data were then fitted to a first order release model using PLOT software and the time taken to achieve 90% release reported. Many of the tested party pill brands contained amounts of BZP and TFMPP that varied considerably from that stated on the packaging; including considerable TFMPP content in some brands not labelled to contain this drug. Dissolution studies revealed that there was considerable variability in the release kinetics between brands; in one case 90% release required >30 minutes. Lack of quality control in party pill manufacture may have led to the toxic effects reported by users unaware of the true content and release of drug from pills. More stringent regulation in the manufacture and quality control of "new generation party pills" is essential to the harm reduction campaign.

Control-release microcapsule of famotidine loaded biomimetic synthesized mesoporous silica nanoparticles: Controlled release effect and enhanced stomach adhesion in vitro.

PubMed

Li, Jing; Wang, Hongyu; Yang, Baixue; Xu, Lu; Zheng, Nan; Chen, Hongtao; Li, Sanming

2016-01-01

In the present work, control-release microcapsule of famotidine (FMT) loaded biomimetic synthesized mesoporous silica nanoparticles (B-MSNs) was developed, and controlled release effect and stomach adhesion of this formulation in vitro were mainly investigated. B-MSN was previously synthesized and it was amorphous mesoporous nanoparticles with helical channels. Cytotoxicity of B-MSN was studied using human breast cancer cells (MCF-7) and the result indicated that cytotoxicity of B-MSN can be neglected. After loading FMT into B-MSN, specific surface area, pore volume and pore diameter of B-MSN were obviously reduced. In vitro dissolution test showed that B-MSN had the ability to slow down FMT release for 15 min. In order to prolong controlled release effect and remained the advantage of B-MSN (improve drug stability due to its rigid silica framework), the combined application of control-release microcapsule (using cellulose and hydroxypropyl methylcellulose K15M as excipients) with B-MSN was designed. It was obvious that newly designed formulation significantly controlled FMT release with Fickian diffusion mechanism and showed enhanced stomach adhesion in vitro, which has significant value in widening the application of B-MSN in formulation design. Copyright © 2015 Elsevier B.V. All rights reserved.

Formulation and In-vitro Evaluation of Tretinoin Microemulsion as a Potential Carrier for Dermal Drug Delivery.

PubMed

Mortazavi, Seyed Alireza; Pishrochi, Sanaz; Jafari Azar, Zahra

2013-01-01

In this study, tretinoin microemulsion has been formulated based on phase diagram studies by changing the amounts and proportions of inactive ingredients, such as surfactants, co-surfactants and oils. The effects of these variables have been determined on microemulsion formation, particle size of the dispersed phase and release profile of tretinoin from microemulsion through dialysis membrane. In released studies, static Franz diffusion cells mounted with dialysis membrane were used. Sampling was conducted every 3 h at room temperature over a period of 24 h. The amount of released drug was measured with UV-spectrophotometer and the percentage of drug released was calculated. Based on the results obtained, the oil phase concentration had a proportional effect on particle size which can consequently influence on drug release. The particle size and the amount of released drug were affected by the applied surfactants. The components of the optimized microemulsion formulation were 15% olive oil, 12% propylene glycol (as co-surfactant), 33% Tween(®)80 (as surfactant) and 40% distilled water, which was tested for viscosity and rheological behavior. The prepared tretinoin microemulsion showed pseudoplastic-thixotropic behavior. The profile of drug release follows zero order kinetics. The optimized tretinoin microemulsion showed enhanced in-vitro release profile compared to the commercial gels and creams.

In vitro-in vivo correlation for nevirapine extended release tablets.

PubMed

Macha, Sreeraj; Yong, Chan-Loi; Darrington, Todd; Davis, Mark S; MacGregor, Thomas R; Castles, Mark; Krill, Steven L

2009-12-01

An in vitro-in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC-MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin. A Double Weibull model optimally fits the in vitro data. A unit impulse response (UIR) was assessed using the fastest ER formulation as a reference. The deconvolution of the in vivo concentration time data was performed using the UIR to estimate an in vivo drug release profile. A linear model with a time-scaling factor clarified the relationship between in vitro and in vivo data. The predictability of the final model was consistent based on internal validation. Average percent prediction errors for pharmacokinetic parameters were <10% and individual values for all formulations were <15%. Therefore, a Level A IVIVC was developed and validated for nevirapine extended release formulations providing robust predictions of in vivo profiles based on in vitro dissolution profiles. Copyright 2009 John Wiley & Sons, Ltd.

Synthesis and characterization of antibacterial dental monomers and composites

PubMed Central

Xu, Xiaoming; Wang, Yapin; Liao, Sumei; Wen, Zezhang T.; Fan, Yuwei

2012-01-01

The objective of this study is to synthesize antibacterial methacrylate and methacrylamide monomers and formulate antibacterial fluoride-releasing dental composites. Three antibacterial methacrylate or methacrylamide monomers containing long-chain quaternary ammonium fluoride, 1,2-methacrylamido-N,N,N-trimethyldodecan-1-aminium fluoride (monomer I), N-benzyl-11-(methacryloyloxy)-N,N-dimethylundecan-1-aminium fluoride (monomer II), and methacryloxyldecylpyridinium fluoride (monomer III) have been synthesized and analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The cytotoxicity test and bactericidal test against Streptococcus mutans indicate that antibacterial monomer II is superior to monomers I and III. A series of dental composites containing 0–6% of antibacterial monomer II have been formulated and tested for degree of conversion (DC), flexure strength, water sorption, solubility, and inhibition of S. mutans biofilms. An antibacterial fluoride-releasing dental composite has also been formulated and tested for flexure strength and fluoride release. The dental composite containing 3% of monomer II has a significant effect against S. mutans biofilm formation without major adverse effects on its physical and mechanical properties. The new antibacterial monomers can be used together with the fluoride-releasing monomers containing a ternary zirconiun- fluoride chelate to formulate a new antibacterial fluoride- releasing dental composite. Such a new dental composite is expected to have higher anticaries efficacy and longer service life. PMID:22447582

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.

Preparation and In vitro Evaluation of Naproxen Suppositories

PubMed Central

Hargoli, S.; Farid, J.; Azarmi, S. H.; Ghanbarzadeh, S.; Zakeri-Milani, P.

2013-01-01

The aim of this work was to develop the best formulations for naproxen suppositories. The effects of different bases and surfactants on the physicochemical characteristics of the suppositories were determined by several tests such as weight variation, melting point, assay, hardness, and release rate. All formulations met the standard criteria for tested physicochemical parameters; weight variation (97-112%), content uniformity (97-105%), melting point (4.66-8.7 min) and hardness tests (>5400 g). Based on release rate studies, hydrophilic, and lipophilic bases without surfactants were not suitable bases for naproxen suppository. Amongst the formulations containing surfactants only Witepsol H15 with 0.5% w/w of Tween 80 and Witepsol W35 with 0.5% of cetylpyridinium chloride were suitable and released nearly complete drug during 30 and 60 min, respectively. This study demonstrates the effects of incorporation of known agents on the in vitro release characteristics of naproxen suppository. PMID:24019561

Preparation, characterization and optimization of sildenafil citrate loaded PLGA nanoparticles by statistical factorial design

PubMed Central

2013-01-01

Background and the aim of the study The objective of the present study was to formulate and optimize nanoparticles (NPs) of sildenafil-loaded poly (lactic-co-glycolic acid) (PLGA) by double emulsion solvent evaporation (DESE) method. The relationship between design factors and experimental data was evaluated using response surface methodology. Method A Box-Behnken design was made considering the mass ratio of drug to polymer (D/P), the volumetric proportion of the water to oil phase (W/O) and the concentration of polyvinyl alcohol (PVA) as the independent agents. PLGA-NPs were successfully prepared and the size (nm), entrapment efficiency (EE), drug loading (DL) and cumulative release of drug from NPs post 1 and 8 hrs were assessed as the responses. Results The NPs were prepared in a spherical shape and the sizes range of 240 to 316 nm. The polydispersity index of size was lower than 0.5 and the EE (%) and DL (%) varied between 14-62% and 2-6%, respectively. The optimized formulation with a desirability factor of 0.9 was selected and characterized. This formulation demonstrated the particle size of 270 nm, EE of 55%, DL of 3.9% and cumulative drug release of 79% after 12 hrs. In vitro release studies showed a burst release at the initial stage followed by a sustained release of sildenafil from NPs up to 12 hrs. The release kinetic of the optimized formulation was fitted to Higuchi model. Conclusions Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method. Characterization of optimum formulation, provided by an evaluation of experimental data, showed no significant difference between calculated and measured data. PMID:24355133

Trehalose limits BSA aggregation in spray-dried formulations at high temperatures: implications in preparing polymer implants for long-term protein delivery.

PubMed

Rajagopal, Karthikan; Wood, Joseph; Tran, Benjamin; Patapoff, Thomas W; Nivaggioli, Thierry

2013-08-01

Polymer implants are promising systems for sustained release applications but their utility for protein delivery has been hindered because of concerns over drug stability at elevated temperatures required for processing. Using bovine serum albumin (BSA) as a model, we have assessed whether proteins can be formulated for processing at elevated temperatures. Specifically, the effect of trehalose and histidine-HCl buffer on BSA stability in a spray-dried formulation has been investigated at temperatures ranging from 80°C to 110°C. When both the sugar and buffer are present, aggregation is suppressed even when exposed to 100°C, the extrusion temperature of poly(lactide-co-glycolide) (PLGA), a bioresorbable polymer. Estimation of aggregation rate constants (k) indicate that though both trehalose and histidine-HCl buffer contribute to BSA stability, the effect because of trehalose alone is more pronounced. BSA-loaded PLGA implants were prepared using hot-melt extrusion process and in vitro release was conducted in phosphate buffered saline at 37°C. Comparison of drug released from implants prepared using four different formulations confirmed that maximal release was achieved from the formulation in which BSA was least aggregated. These studies demonstrate that when trehalose and histidine-HCl buffer are included in spray-dried formulations, BSA stability is maintained both during processing at 100°C and long-term residence within implants. Copyright © 2013 Wiley Periodicals, Inc.

Release of a wound-healing agent from PLGA microspheres in a thermosensitive gel.

PubMed

Machado, H A; Abercrombie, J J; You, T; Deluca, P P; Leung, K P

2013-01-01

The purpose of this research was to develop a topical microsphere delivery system in a thermosensitive 20% poloxamer 407 gel (Pluronic F127) to control release of KSL-W, a cationic antimicrobial decapeptide, for a period of 4-7 days for potential application in combat related injuries. KSL-W loaded microsphere formulations were prepared by a solvent extraction-evaporation method (water-oil-water), with poly (D,L-lactic-co-glycolic acid) (PLGA) (50 : 50, low-weight, and hydrophilic end) as the polymeric system. After optimization of the process, three formulations (A, B, and C) were prepared with different organic to water ratio of the primary emulsion while maintaining other components and manufacturing parameters constant. Formulations were characterized for surface morphology, porous nature, drug loading, in vitro drug release, and antimicrobial activity. Microspheres containing 20% peptide with porous surfaces and internal structure were prepared in satisfactory yields and in sizes varying from 25 to 50 μm. Gels of 20% Pluronic F127, which were liquid at or below 24.6°C and formed transparent films at body temperature, were used as carriers for the microspheres. Rheological studies showed a gelation temperature of 24.6°C for the 20% Pluronic F127 gel alone. Gelation temperature and viscosity of formulations A, B, and C as a function of temperature were very close to those of the carrier. A Franz diffusion cell system was used to study the release of peptide from the microspheres suspended in both, phosphate-buffered saline (PBS) and a 20% Pluronic F127 gel. In vitro release of greater than 50% peptide was found in all formulations in both PBS and the gel, and in one formulation there was a release of 75% in both PBS and the gel. Fractions collected from the release process were also tested for bactericidal activity against Staphylococcus epidermidis using the broth microdilution method and found to provide effective antimicrobial activity to warrant consideration and testing in animal wound models for treating combat-related injuries.

Antipsoriatic and Anti-inflammatory Studies of Berberis aristata Extract Loaded Nanovesicular Gels

PubMed Central

Nimisha; Rizvi, Dilshad Ali; Fatima, Zeeshan; Neema; Kaur, Chanchal Deep

2017-01-01

Objective: Novel nanovesicular gel of Berberis aristata extract was developed and evaluated for its anti-inflammatory and antipsoriatic activity. Materials and Methods: Transferosomes were prepared using soya phosphatidylcholine and edge activators (Tween 80, Span 80, and sodium deoxycholate) by a modified lipid film hydration technique using rotary evaporator and evaluated for various parameters. The quantification and standardization of extract have been carried out using its alkaloid content as berberine as biomarker. Topical application of imiquimod (IMQ) (immune modifier) on the shaved back of mice developed psoriasis-like inflammation followed by histopathological study of inflamed skin. Results: The size of transferosomes was in the range of 265–345 nm whereas polydispersity index ranges from 0.10 to 0.63, and for zeta potential, it was from −19.3 to −43.3 mV. Transferosomes were further added to Carbopol 934P for gel formation and subsequently evaluated for their physicochemical properties. Their efficacy against inflammation, IMQ-induced psoriasis, and skin sensitivity was compared with conventional formulation (commercial formulation-Angle Gloss, Phytolab Pvt. Ltd.). Percent inhibition of edema by transferosomal gel (55.76%) was more as compared to conventional gel of extract (33.5%) found out by Carrageenan-induced paw edema method. Primary irritation index was found to be <0.4 inferring its safe use for topical formulation. Conclusion: Histopathological report showed that, in psoriasis-induced animal treated with topical application of extract loaded transferosomal gel showed a marked reduction in thickness of epidermis, length of rete ridges as compared to conventional gel formulation. It can be inferred that B. aristata extract loaded transferosomal gel can function as potential anti-inflammatory and antipsoriatic formulation. SUMMARY The objective of the present research work was to prepare Berberis aristata extracts (roots, ethanolic 70%v/v) loaded transferosomal gel, to perform in vitro characterization and in vivo evaluation of their efficacy against inflammation as well as imiquimod (IMQ)-induced psoriasis in animalsThe remarkable enhancement in the in vitro release efficiency of B. aristata extract loaded transferosomal gel resulted in improved anti-inflammatory activity. The prepared novel formulation of B. aristata has also shown its efficacy against IMQ-induced psoriasis. Abbreviations used: SPC: Soyaphosphatidylcholine, PDI: Polydispersity index, IMQ: Imiquimod, EA: Edge activator, BE: Berberine, TEM: Transmission electron microscopy, PBS: Phosphate buffered saline, H and E: Hematoxylin and eosin, ZP: Zeta potential, EE: Entrapment efficiency. PMID:29142419

Oral Delivery of DMAB-Modified Docetaxel-Loaded PLGA-TPGS Nanoparticles for Cancer Chemotherapy

NASA Astrophysics Data System (ADS)

Chen, Hongbo; Zheng, Yi; Tian, Ge; Tian, Yan; Zeng, Xiaowei; Liu, Gan; Liu, Kexin; Li, Lei; Li, Zhen; Mei, Lin; Huang, Laiqiang

2011-12-01

Three types of nanoparticle formulation from biodegradable PLGA-TPGS random copolymer were developed in this research for oral administration of anticancer drugs, which include DMAB-modified PLGA nanoparticles, unmodified PLGA-TPGS nanoparticles and DMAB-modified PLGA-TPGS nanoparticles. Firstly, the PLGA-TPGS random copolymer was synthesized and characterized. DMAB was used to increase retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability. Nanoparticles were found to be of spherical shape with an average particle diameter of around 250 nm. The surface charge of PLGA-TPGS nanoparticles was changed to positive after DMAB modification. The results also showed that the DMAB-modified PLGA-TPGS nanoparticles have significantly higher level of the cellular uptake than that of DMAB-modified PLGA nanoparticles and unmodified PLGA-TPGS nanoparticles. In vitro, cytotoxicity experiment showed advantages of the DMAB-modified PLGA-TPGS nanoparticle formulation over commercial Taxotere® in terms of cytotoxicity against MCF-7 cells. In conclusion, oral chemotherapy by DMAB-modified PLGA-TPGS nanoparticle formulation is an attractive and promising treatment option for patients.

Investigation into the Effect of Ethylcellulose Viscosity Variation on the Drug Release of Metoprolol Tartrate and Acetaminophen Extended Release Multiparticulates-Part I.

PubMed

Mehta, R; Teckoe, J; Schoener, C; Workentine, S; Ferrizzi, D; Rajabi-Siahboomi, A

2016-12-01

Ethylcellulose is one of the most commonly used polymers to develop reservoir type extended release multiparticulate dosage forms. For multiparticulate extended release dosage forms, the drug release is typically governed by the properties of the barrier membrane coating. The ICH Pharmaceutical Development Guideline (ICH Q8) requires an understanding of the influence of critical material attributes and critical process parameters on the drug release of a pharmaceutical product. Using this understanding, it is possible to develop robust formulations with consistent drug release characteristics. Critical material attributes for ethylcellulose were evaluated, and polymer molecular weight variation (viscosity) was considered to be the most critical attribute that can impact drug release. To investigate the effect of viscosity variation within the manufacturer's specifications of ethylcellulose, extended release multiparticulate formulations of two model drugs, metoprolol tartrate and acetaminophen, were developed using ETHOCEL™ as the rate controlling polymer. Quality by Design (QbD) samples of ETHOCEL Std. 10, 20, and 100 Premium grades representing the low, medium, and high molecular weight (viscosity) material were organically coated onto drug layered multiparticulates to a 15% weight gain (WG). The drug release was found to be similar (f 2  > 50) for both metoprolol tartrate and acetaminophen multiparticulates at different coating weight gains of ethylcellulose, highlighting consistent and robust drug release performance. The use of ETHOCEL QbD samples also serves as a means to develop multiparticulate dosage formulations according to regulatory guidelines.

Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation

PubMed Central

Yasir, Mohd; Sara, Udai Vir Singh

2014-01-01

In the present study, haloperidol (HP)-loaded solid lipid nanoparticles (SLNs) were prepared to enhance the uptake of HP to brain via intranasal (i.n.) delivery. SLNs were prepared by a modified emulsification–diffusion technique and evaluated for particle size, zeta potential, drug entrapment efficiency, in vitro drug release, and stability. All parameters were found to be in an acceptable range. In vitro drug release was found to be 94.16±4.78% after 24 h and was fitted to the Higuchi model with a very high correlation coefficient (R2=0.9941). Pharmacokinetics studies were performed on albino Wistar rats and the concentration of HP in brain and blood was measured by high performance liquid chromatography. The brain/blood ratio at 0.5 h for HP-SLNs i.n., HP sol. i.n. and HP sol. i.v. was 1.61, 0.17 and 0.031, respectively, indicating direct nose-to-brain transport, bypassing the blood–brain barrier. The maximum concentration (Cmax) in brain achieved from i.n. administration of HP-SLNs (329.17±20.89 ng/mL, Tmax 2 h) was significantly higher than that achieved after i.v. (76.95±7.62 ng/mL, Tmax 1 h), and i.n. (90.13±6.28 ng/mL, Tmax 2 h) administration of HP sol. The highest drug-targeting efficiency (2362.43%) and direct transport percentage (95.77%) was found with HP-SLNs as compared to the other formulations. Higher DTE (%) and DTP (%) suggest that HP-SLNs have better brain targeting efficiency as compared to other formulations. PMID:26579417

PEGylated lipid nanocapsules with improved drug encapsulation and controlled release properties.

PubMed

Hervella, Pablo; Alonso-Sande, Maria; Ledo, Francisco; Lucero, Maria L; Alonso, Maria J; Garcia-Fuentes, Marcos

2014-01-01

Drugs with poor lipid and water solubility are some of the most challenging to formulate in nanocarriers, typically resulting in low encapsulation efficiencies and uncontrolled release profiles. PEGylated nanocapsules (PEG-NC) are known for their amenability to diverse modifications that allow the formation of domains with different physicochemical properties, an interesting feature to address a drug encapsulation problem. We explored this problem by encapsulating in PEG-NC the promising anticancer drug candidate F10320GD1, used herein as a model for compounds with such characteristics. The nanocarriers were prepared from Miglyol(®), lecithin and PEG-sterate through a solvent displacement technique. The resulting system was a homogeneous suspension of particles with size around 200 nm. F10320GD1 encapsulation was found to be very poor (<15%) if PEG-NC were prepared using water as continuous phase; but we were able to improve this value to 85% by fixing the pH of the continuous phase to 9. Interestingly, this modification also improved the controlled release properties and the chemical stability of the formulation during storage. These differences in pharmaceutical properties together with physicochemical data suggest that the pH of the continuous phase used for PEG-NC preparation can modify drug allocation, from the external shell towards the inner lipid core of the nanocapsules. Finally, we tested the bioactivity of the drug-loaded PEG-NC in several tumor cell lines, and also in endothelial cells. The results indicated that drug encapsulation led to an improvement on drug cytotoxicity in tumor cells, but not in non-tumor endothelial cells. Altogether, the data confirms that PEG-NC show adequate delivery properties for F10320GD1, and underlines its possible utility as an anticancer therapy.

Influence of Polymer Type on the Physical Properties and Release Profile of Papaverine Hydrochloride From Hard Gelatin Capsules.

PubMed

Polski, Andrzej; Iwaniak, Karol; Kasperek, Regina; Modrzewska, Joanna; Sobótka-Polska, Karolina; Sławińska, Karolina; Poleszak, Ewa

2015-01-01

The capsule is one of the most important solid dosage forms in the pharmaceutical industry. It is easier and faster to produce than a tablet, because it requires fewer excipients. Generally, capsules are easy to swallow and mask any unpleasant taste of the substances used while their release profiles can be easily modified. Papaverine hydrochloride was used as a model substance to show different release profiles using different excipients. The main aim of the study was to analyze the impact of using different polymers on the release profile of papaverine hydrochloride from hard gelatin capsules. Six series of hard gelatin capsules containing papaverine hydrochloride as a model drug and different excipients were made. Then, the angle of repose, flow rate, mass flow rate and volume flow rate of the powders used for capsule production were analyzed. The uniform weight and disintegration time of the capsules were studied. The dissolution study was performed in a basket apparatus, while the amount of papaverine hydrochloride released was determined spectrophotometrically at 251 nm. Only one formula of powder had satisfactory flow properties, while all formulas had good Hausner ratios. The best properties were from powder containing polyvinylpyrrolidone 10k. The disintegration time of capsules varied from 1:30 min to 2:00 min. As required by Polish Pharmacopoeia X, 80% of the active substance in all cases was released within 15 minutes. The capsules with polyvinylpyrrolidone 10k were characterized by the longest release. On the other hand, capsules containing microcrystalline cellulose had the fastest release profile. Using 10% of different polymers, without changing the other excipients, had a significant impact on the physical properties of the powders and papaverine hydrochloride release profile. The two most preferred capsule formulations contained either polyvinylpyrrolidone 10k or microcrystalline cellulose.

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

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

PubMed

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

2007-06-01

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

Substituted amylose matrices for oral drug delivery

NASA Astrophysics Data System (ADS)

Moghadam, S. H.; Wang, H. W.; Saddar El-Leithy, E.; Chebli, C.; Cartilier, L.

2007-03-01

High amylose corn starch was used to obtain substituted amylose (SA) polymers by chemically modifying hydroxyl groups by an etherification process using 1,2-epoxypropanol. Tablets for drug-controlled release were prepared by direct compression and their release properties assessed by an in vitro dissolution test (USP XXIII no 2). The polymer swelling was characterized by measuring gravimetrically the water uptake ability of polymer tablets. SA hydrophilic matrix tablets present sequentially a burst effect, typical of hydrophilic matrices, and a near constant release, typical of reservoir systems. After the burst effect, surface pores disappear progressively by molecular association of amylose chains; this allows the creation of a polymer layer acting as a diffusion barrier and explains the peculiar behaviour of SA polymers. Several formulation parameters such as compression force, drug loading, tablet weight and insoluble diluent concentration were investigated. On the other hand, tablet thickness, scanning electron microscope analysis and mercury intrusion porosimetry showed that the high crushing strength values observed for SA tablets were due to an unusual melting process occurring during tabletting although the tablet external layer went only through densification, deformation and partial melting. In contrast, HPMC tablets did not show any traces of a melting process.

Recent advancement of gelatin nanoparticles in drug and vaccine delivery.

PubMed

Sahoo, Nityananda; Sahoo, Ranjan Ku; Biswas, Nikhil; Guha, Arijit; Kuotsu, Ketousetuo

2015-11-01

Novel drug delivery system using nanoscale materials with a broad spectrum of applications provides a new therapeutic foundation for technological integration and innovation. Nanoparticles are suitable drug carrier for various routes of administration as well as rapid recognition by the immune system. Gelatin, the biological macromolecule is a versatile drug/vaccine delivery carrier in pharmaceutical field due to its biodegradable, biocompatible, non-antigenicity and low cost with easy availability. The surface of gelatin nanoparticles can be modified with site-specific ligands, cationized with amine derivatives or, coated with polyethyl glycols to achieve targeted and sustained release drug delivery. Compared to other colloidal carriers, gelatin nanoparticles are better stable in biological fluids to provide the desired controlled and sustained release of entrapped drug molecules. The current review highlights the different formulation aspects of gelatin nanoparticles which affect the particle characteristics like zeta potential, polydispersity index, entrapment efficacy and drug release properties. It has also given emphasis on the major applications of gelatin nanoparticles in drug and vaccine delivery, gene delivery to target tissues and nutraceutical delivery for improving the poor bioavailabity of bioactive phytonutrients. Copyright © 2015 Elsevier B.V. All rights reserved.