Controlled release of nifedipine from mucoadhesive tablets of its inclusion complexes with beta-cyclodextrin

Mucoadhesive tablets formulated with nifedipine (N) alone and its inclusion complexes with beta-cyclodextrin (betaCD) and the mucoadhesive polymers sodium carboxy methylcellulose and carbopol were investigated with a view to the design of oral controlled release tablets of nifedipine. As nifedipine is practically insoluble in water and aqueous fluids, its complexation with betaCD was investigated to improve its solubility and dissolution rate. Complexation of nifedipine with betaCD has markedly enhanced the solubility and dissolution rate of nifedipine. The phase solubility studies indicated the formation of a N-betaCD inclusion complex with a stability constant of 121.9 M(-1). A 20.6 fold increase in the dissolution rate of nifedipine was observed with N-betaCD (1:2) solid inclusion complex. Mucoadhesive tablets formulated employing nifedipine alone gave very low dissolution, whereas those formulated employing its betaCD inclusion complexes gave slow, controlled and complete release spread over a period of 12 h. Drug release from these tablets followed zero order kinetics up to 85-90% release and the release was diffusion controlled. Good controlled release two layered tablet formulations of nifedipine, satisfying the theoretical sustained release requirements based on its pharmacokinetics, were developed using its inclusion complexes with betaCD.     

Effect of low-molecular-weight beta-cyclodextrin polymer on release of drugs from mucoadhesive buccal film dosage forms

We investigated the effect of low-molecular-weight beta-cyclodextrin (beta-CyD) polymer on in vitro release of two drugs with different lipophilicities (i.e., lidocaine and ketoprofen) from mucoadhesive buccal film dosage forms. When beta-CyD polymer was added to hydroxypropylcellulose (HPC) or polyvinylalcohol (PVA) film dosage forms, the release of lidocaine into artificial saliva (pH 5.7) was reduced by 40% of the control. In contrast, the release of ketoprofen from the polymer film was enhanced by addition of beta-CyD polymer to the vehicle. When lidocaine and ketoprofen was incubated with beta-CyD polymer in the artificial saliva, concentration of free lidocaine molecules decreased in a beta-CyD polymer concentration-dependent manner. The association constant with beta-CyD polymer was 6.9+/-0.6 and 520+/-90 M(-1) for lidocaine and ketoprofen, respectively. Retarded release of the hydrophilic lidocaine by beta-CyD polymer might be due to the decrease in thermodynamic activity by inclusion complex formation, whereas enhanced release of the lipophilic ketoprofen by the beta-CyD polymer might be due to prevention of recrystallization occurring after contacting the film with aqueous solution. Thus, effects of low-molecular-weight beta-CyD polymer to the drug release rate from film dosage forms would vary according to the strength of interaction with and the solubility of active ingredient.     

Controlled dual release of basic fibroblast growth factor and indomethacin from heparin-conjugated polymeric micelle

This work describes the development of heparinized polymeric micelle as a novel injectable carrier for the dual drug delivery that can simultaneously release basic fibroblast growth factor (bFGF) and indomethacin (IMC), which can promote the regeneration of damaged tissue and prevent the inflammatory response after implantation. Tetronic-PCL-heparin for the preparation of heparinized polymeric micelle was synthesized by introducing PCL as a biodegradable linkage on Tetronic, following the conjugation of heparin. The mean diameter of the formed TCH micelle was around 114 nm and increases in the micelle size after single and dual drug loading were observed. Loading efficiencies of IMC and bFGF were 30.9% and 70.5%, respectively. In vitro dual drug release profiles from TCH micelles were investigated. IMC was more slowly released from dual drug-loaded micelle over 3 weeks as compared with single drug-loaded one. bFGF was released over 2 months in a controlled manner. Therefore, the release profile results support that TCH micelle could not only incorporate a hydrophobic drug into the core but also bind with bFGF to heparin that exists on its outer shell. The TCH micelle will have enhanced therapeutic effects on the target site which may be required the multi-function of drugs to use.     

Controlled release of bovine serum albumin from chitosan membranes in vitro

Chitosan membranes loaded with bovine serum albumin (BSA; BSA/chitosan membranes) were prepared by either oven-drying or lyophilization. The encapsulation of BSA was mostly >80%. Controlled release of BSA from the membranes into phosphate-buffered saline (PBS; pH 7.4) was determined with Coomassie brilliant blue at different time periods. The highest cumulative amount of released BSA was 17.30% after 20 days. The optimized chitosan concentration was found to range from 10 to 20 g/l. The most favorable drying temperature for the membrane preparation was 55°C. And membranes made by lyophilization were more porous and uniform than those made by oven-drying.     

Controlled release of huperzine A from biodegradable microspheres: In vitro and in vivo studies

This paper describes the effect on Sun Protection Factor (SPF) of the combination of inorganic and organic filters in sunscreen products as determined by an in vitro method. O/W emulsions containing inorganic filters, such as titanium dioxide and zinc oxide, combined with 18 EU-authorized UV-B organic filters were tested. SPF measurements were carried out using a spectrophotometer equipped with an integrating sphere.

This study observed a synergic effect when titanium dioxide was combined with either anisotriazine or octyldimethylPABA. The combination of zinc oxide with 11 UV-B organic filters also exhibited a similar synergy; however, the measured SPF was systematically lower than the protection factor achieved with titanium dioxide.     

盐酸索他洛尔生物黏附微球的体外释药及黏附性能研究

目的考察盐酸索他洛尔生物黏附微球的体外释药特性并评价其黏附性能。方法采用高效液相色谱法测定释放介质与微球中盐酸索他洛尔含量,并以滞留率为指标考察微球的黏附特性。结果盐酸索他洛尔生物黏附微球30min累积释药百分率达30％,4h释药达90％;离体法与在体法测得微球胃黏膜上的滞留率分别为87．60±2．8％与60．2％±9．8％。结论盐酸索他洛尔高效液相色谱测定方法简便、可靠,与盐酸索他洛尔普通片相比,盐酸索他洛尔生物黏附微球具有一定缓释特性,且其在离体与在体模型中黏附性能良好。     

吲哚美辛缓释片制备工艺及体外溶出特性的研究

目的：采用新型骨架材料甲壳胺制备吲哚辛缓释片。方法：单因素考察法考察工艺因素如压力及甲壳胺粒度对缓释作用的影响,利用正交设计优化处方。结果：甲壳胺粒度小于１５４μｍ 时,抗张强度在（４ ．０ ±１０ ．０）ｋｇ 范围内,对甲壳胺缓释作用无明显影响,当抗张强度大于１３ｋｇ ,时,药物释放明显减慢,优化后的处方可达到美国药典ⅩⅩⅡ版对缓释制剂体外溶出的要求。结论：该片剂处方合理,制备工艺简单易行,适合工业化大生产。     

Controlled release of nifedipine from gelatin microspheres and microcapsules: in vitro kinetics and pharmacokinetics in man

Nifedipine was embedded in a gelatin matrix to develop a prolonged release dosage form. The effects of polymer/drug ratio, size of the beads, cross-linking with formaldehyde and ethylcellulose coating of the gelatin microspheres on the in vitro release rate of the drug were investigated. The data were analysed according to different laws that can govern the release mechanism: first-order, Higuchi square root of time, spherical matrix and zero-order. The in vitro release kinetics of nifedipine from gelatin microspheres were mainly first-order; from formaldehyde hardened gelatin microspheres, complied with the diffusion model for a spherical matrix, and from ethylcellulose-coated gelatin microspheres, obeyed zero-order kinetics. These findings suggest the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system. The pharmacokinetic parameters of nifedipine, after administration of a single oral dose of nifedipine-loaded hardened gelatin microspheres to volunteers, suggest that the preparation can be considered as a sustained release delivery system for nifedipine.     

Controlled release of nifedipine from gelatin microspheres and microcapsules: in vitro kinetics and pharmacokinetics in man

Abstract

Nifedipine was embedded in a gelatin matrix to develop a prolonged release dosage form. The effects of polymer/drug ratio, size of the beads, cross-linking with formaldehyde and ethylcellulose coating of the gelatin microspheres on the in vitro release rate of the drug were investigated. The data were analysed according to different laws that can govern the release mechanism: first-order, Higuchi square root of time, spherical matrix and zero-order. The in vitro release kinetics of nifedipine from gelatin microspheres were mainly first-order; from formaldehyde hardened gelatin microspheres, complied with the diffusion model for a spherical matrix, and from ethylcellulose-coated gelatin microspheres, obeyed zero-order kinetics. These findings suggest the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system. The pharmacokinetic parameters of nifedipine, after adminstration of a single oral dose of nifedipine-loaded hardened gelatin microspheres to volunteers, suggest that the preparation can be considered as a sustained release delivery system for nifedipine.     

In vitro drug liberation and kinetics of sustained release indomethacin suppository

The aim of this study was to formulate sustained release (SR) suppositories containing indomethacin (IND) microspheres. In the first part of the study, IND microspheres were prepared by solvent evaporation method. Ethyl cellulose was used as polymer. Shape and surface characteristics, particle size and size distribution of microspheres were determined. The effect of drug: polymer ratio and stirring rate on microsphere formation, average particle size, drug loading capacity and in vitro IND release were investigated. The highest drug loading capacity was found with 1:1 drug-polymer ratio. Stirring rate caused insignificant effect on drug loading capacity but particle size. Increase in stirring rate resulted in a decrease in particle size. In the second part, SR suppositories were formulated by incorporating IND microspheres having the highest drug loaded. The bases used were PEG mixtures (400:1500:4000) and Witepsol H15. Qualitative controls and IND assay on the suppositories were carried out. The drugs released were evaluated by in vitro dissolution tests. Comparative results of SR suppositories containing IND microspheres with that of conventional ones showed that the former has sustained effect up to 480 min in vitro. Release results were evaluated kinetically and the data was fitted (Bt)(a) kinetics.     

Controlled release of growth hormone from thermosensitive triblock copolymer systems: In vitro and in vivo evaluation

The purpose of this study was to design injectable controlled release polymer formulations for growth hormone using triblock copolymer PLGA-PEG-PLGA (MW 1400-1000-1400). Porcine growth hormone (pGH) formulations were prepared by adding pGH into 30% (w/v) aqueous solution of triblock copolymer. pGH concentrations in the released samples were determined using a standard MicroBCA method. In vitro release studies demonstrated that there were no initial burst of pGH from both formulations containing a low dose (0.12%, w/v) and a high dose (0.42%, w/v) of pGH. In vivo absorption study of pGH in rabbits showed that constant serum levels of exogenous pGH (3-7 ng/mL from high dose and 2-4 ng/mL from low dose) were detected for nearly 4 weeks from delivery systems upon single subcutaneous injection. The absolute bioavailability of pGH enhanced from the thermosensitive polymer-based systems, which was approximately 5-15-fold those of subcutaneous aqueous solution. MTT assay and light microscopy were used to investigate the in vitro and in vivo biocompatibility of thermosensitive polymer delivery systems, respectively. Both in vitro and in vivo results support the biocompatible nature of these polymer delivery systems. Thus, the triblock copolymer used in this study was able to control the release of incorporated pGH in vitro and in vivo for longer duration and the delivery system was biocompatible.     

Controlled release chitosan microspheres of mirtazapine: In vitro and in vivo evaluation

The purpose of the study was to formulate and evaluate controlled release chitosan microspheres of mirtazapine (MTZ) to improve the bioavailability by altering the pharmacokinetic profiles of the drug. Chitosan microspheres were prepared to prolong the release of the drug into the systemic circulation. Microspheres were prepared by a single water in oil (w/o) emulsion technique varying the chitosan/drug ratio, stirring speed and concentration of the crosslinking agent (glutaraldehyde). Drug-polymer compatibility studies were carried out using fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The microspheres were evaluated for encapsulation efficiency, particle size, surface morphology, swelling index, in vitro release, as well as erosion and in vivo studies in rats. The FT-IR and DSC studies revealed no interaction between drug and polymer. The encapsulation efficiency of different formulation varied from 53 ± 1.2% to 78 ± 1.5%. The mean particle size of the optimized formulation F-14 was 106.4 ± 0.5 μm. Surface morphology revealed that chitosan microspheres were discrete and spherical in shape with a porous surface. The release of MTZ from chitosan microspheres was rapid up to 4 h, and then it was continuously and slowly released up to 48 h. Optimized formulation (F-14) was found to be stable under accelerated storage conditions based on International Conference on Harmonisation guidelines. Pharmacokinetic studies revealed that the optimized formulation showed significant increases in systemic exposure (AUC = 177.70 ± 7.39 μg·h/mL), half-life (4.72 ± 0.46 h) and reduced clearance (0.009 ± 0.0001 L/h) compared to pure drug administration. Hence, the present study demonstrates that controlled release formulation of MTZ microspheres using chitosan can improve pharmacokinetic profiles of MTZ.     

氟康唑眼药膜的研制及体外释放特性

目的 :制备氟康唑眼药膜。方法 :研究制剂的制备工艺 ,建立质量标准 ,采用紫外分光光度法测定制剂中氟康唑的含量 ,进行眼药膜体外释放特性的研究。结果 :制剂制备工艺简单 ,质量便于控制 ,眼药膜中氟康唑的回收率为 (99.2 1± 0 .30 ) % ;氟康唑眼药膜在生理氯化钠溶液中 4h释放 76 .7% ,T50 为 2 0min ,Td 为 53min。结论 :氟康唑眼药膜可以满足临床需要     

Transdermal nicotine mixed natural rubber-hydroxypropylmethylcellulose film forming systems for smoking cessation: in vitro evaluations

Abstract

Novel film forming polymeric dispersions for transdermal nicotine delivery were prepared from deproteinized natural rubber latex (DNRL) blended with hydroxypropylmethylcellulose (HPMC) and dibutyl phthalate (DBP) or glycerin (GLY) as plasticizer. The preliminary molecular compatibility of ingredients was observed by Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffractometry characterizations. All film forming polymeric dispersions were elegant in appearance and smooth in texture without agglomeration. Their pH was 7–8. In addition, their viscosity and spreadability showed good characteristics depended on HPMC and plasticizers blended. The transparent in situ dry films with good strength and elasticity were also confirmed by peeling-off. The nicotine release from them revealed an initial fast release that was similar to the release from a concentrated nicotine solution, and followed by slow release pattern from the in situ films. GLY blended formulation produced a higher amount of nicotine permeation through the in vitro pig skin than DBP blends. Ethanol mixing also enhanced nicotine permeation, but it affected the integrity of in situ films. The nicotine release and skin permeation kinetics were by a diffusion mechanism that was confirmed by the Higuchi's model. These formulations were safe without producing any severe skin irritation. However, for the stability they needed to be stored at 4?°C in tightly sealed containers.     

Design and evaluation of sustained release mucoadhesive film of sumatriptan succinate containing grafted co-polymer as the platform

PurposeThe primary goal of this research is to improve the bioavailability and efficacy of Sumatriptan succinate by incorporating it in the mucoadhesive film for the treatment of migraine. Mucoadhesive film offers an excellent substitute to deliver the drug in the systemic circulation and eliminate the chance of first-pass metabolism.MethodUsing central composite design (CCD), various formulations were created by incorporating polymer, plasticizer, and water, and an optimized preparation was created using statistical screening. The optimization has been performed by applying a 3⁴ factorial method based on dependent variables such as Drug content (%), Swelling index (%), Folding endurance (Number of times), and Mucoadhesive strength (g).ResultsThe actual experimental values obtained were compared with those predicted by the mathematical models. Formulation S9 was selected as an optimized formulation because it showed the lowest standard deviation between predicted and actual values compared to other formulations. In the case of the S9 formulation, approximately 77.12% of the drug was released within 24 h, but initially, it showed burst release. In addition, the in-vitro release of pure drug suspension showed 99.32% drug release within 2 h. That signified that the developed formulation provides sustained release due to presence of grafted co-polymer.ConclusionFormulation holding drug-loaded grafted film showed decent sustained and controlled drug release characteristics compared to a pure drug suspension. S9 formulation showed better results than other formulations in drug content, swelling index, folding endurance, and mucoadhesive strength, which is further used to treat migraine.     

Controlled release of methotrexate from w/o microemulsion and its in vitro antitumor activity

The objective of this study was to prepare the microemulsion of methotrexate (M-MTX) for oral use and to investigate the suppressive effect of MTX-loaded microemulsion on MCF-7 human breast cancer cells. At the same time this effect of M-MTX was compared with those of a solution of the drug (Sol-MTX). Microemulsion was composed of soybean oil as oil phase, a mixture of Cremophore EL and Span 80 as surfactants, and isopropyl alcohol as co-surfactant, and 0.2 N NaOH as the aqueous phase. MTX was added into microemulsion at the last stage. We clearly demonstrated that M-MTX had a significant cytotoxic effect on breast cancer cell lines and the cytotoxic effect of M-MTX was significantly more than that of solutions (p < 0.05) and IC(50) value for M-MTX was 40 ng/mL. We also examined M-MTX and Sol-MTX on a model biological environmental model. For this purpose a gastrointestinal cell culture model, the Caco-2 cell line, was used to investigate the cytotoxic effects of the polymeric carrier and its effect on the cell monolayer integrity. The differences between the viability of cells for M-MTX and Sol-MTX were significantly different when applied to ANOVA according to 2 x 8 factorial randomized design (p:0.016; for alpha: 0.05, power : 0.695). According to the in vitro cytotoxicity studies, we concluded that when MTX was incorporated into the microemulsion (M-MTX), which is a new drug carrier system, it suppresses tumour cell growth on multiple tumor lines. These results indicate that M-MTX may exert a low cytotoxic effect on normal cells and may be effective as an antitumor agent that induces apoptosis.     

Buffer controlled release of indomethacin from ethylcellulose microcapsules

The rate of release of indomethacin from ethylcellulose microcapsules prepared by coacervation was studied using internal buffer, dibasic sodium phosphate (DSP), to increase the solubility of the core. The dissolution rate of the drug was determined in phosphate buffer solutions of varying pH and concentration. The role of the stagnant diffusion layer at the microcapsule surface was also evaluated by changing the mixing in the dissolution test. Indomethacin release was accelerated considerably with increasing amounts of DSP in the core. DSP increases the pH inside the microcapsules, thus enhancing the release of the acidic drug. Increasing bulk solution pH increased the release rate of indomethacin, the enhancing effect being more pronounced with buffered microcapsules. Neither increasing phosphate concentration of the bulk solution nor increasing mixing of the microcapsules influenced the rate of release of indomethacin from unbuffered capsules. With buffered capsules the increase in phosphate concentration of bulk solution prevented leaching out of internal phosphate increasing the release rate of indomethacin. The release of indomethacin also accelerated slightly with increasing mixing.