Substituted Amylose as a Matrix for Sustained Drug Release

Purpose. Amylose derivatives form an important group of polymers, and many of them can be used as drug sustained-release systems. Methods. Substituted amylose can be prepared in a 1-step reaction with substituent(s) in a basic medium. The substituents can be represented as (A—R), where (A) serves an epoxy, halide or suitable organic or inorganic function reacting with hydroxyl groups located on the amylose chain, and (R) is an organic radical. Results. The present work shows the synthesis of different polymers and the effect of different (A) and/or (R) and their different degrees of substitution (n) on the sustained drug release from matrix tablets prepared by direct compression. Conclusions. SA polymers are interesting excipients for the preparation of controlled drug release tablets.     

磷酸川芎嗪骨架片的研制及其体外释药

采用直接压片法制备了以卡波姆为骨架材料的磷酸川芎嗪缓释片。其体外释放曲线12h内符合Higuchi方程,2－8h接近零级。药物释放速率随卡波姆用量增多而减慢,并受卡波姆类型、释药介质pH的影响。     

以HPMC为骨架的盐酸丁螺环酮缓释片的制备

以HPMC单用或与卡波姆934p合用，制备盐酸丁螺环酮缓释片并进行体外释放度的测定。结果表明本品可持续释药24h，且加入卡波姆比单用HPMC为骨架具有更好的缓释效果。     

硫酸伪麻黄碱凝胶骨架型缓释片的制备与释放度试验

目的 研制硫酸伪麻黄碱缓释片并对其释放度的影响因素进行考察，方法 以羟丙甲纤维者（HPMC）为骨架材料制备硫酸伪麻黄碱凝胶骨架型缓释片，采用紫外分光光度法测定体外硫酸伪麻黄碱，并对缓释片进行释放度试验，结果 HPMC用量增加时释放速度变慢。磷酸氢钙用量增加时片削可压性得以改善．结论 该制刺缓释效果良好。     

氢溴酸高乌甲素亲水凝胶骨架片的制备及体外释放

目的为了减少给药次数,方便患者,并提高镇痛效果,制备氢溴酸高乌甲素亲水凝胶骨架片,优化制剂处方,并探讨释放机制。方法以羟丙甲纤维素(HPMC)为骨架材料,乳糖、微晶纤维素(MCC)、淀粉为填充剂,硬脂酸镁为润滑剂制备氢溴酸高乌甲素骨架片,考察各因素对药物释放度的影响,筛选优化处方,并拟合讨论其释放机制。结果 HPMC的用量及分子量,微晶纤维素和硬脂酸镁的用量对药物释放有显著影响。所制缓释片无突释现象,缓释周期12 h,根据拟合方程,药物释放符合一级释放模型,其释放既有扩散,又有骨架溶蚀。结论本方法制备的氢溴酸高乌甲素缓释片工艺简单,生产成本低,且具有良好的释放性能。     

Formulation Design,Optimization and Pharmacodynamic Evaluation of Sustained Release Mucoadhesive Microcapsules of Venlafaxine HCl

The objective of present research work was to design and characterize the venlafaxine HCl-loaded sodium alginate-based mucoadhesive microcapsules by ionic gelation technique using HPMC K100M as mucoadhesive polymer. The Placket-Burman Design was applied for preliminary screening of the formulations and systematic optimization by using Box-Behnken Design. The prepared microcapsules were characterized for drug content, entrapment efficiency, micromeritic properties, particle size, swelling index, mucoadhesive strength, in vitro drug release and in vivo antidepressant activity. FTIR and differential scanning calorimetry studies showed no incompatibility. Surface morphology studies revealed spherical nature of the prepared microcapsules. In vitro drug release studies revealed sustained release by diffusion mechanism. Further, the microcapsules were effective in reducing the depression induced by forced swimming test in Sprague-Dawley rats compared to the pure drug. The microcapsules were found to be stable under accelerated stability conditions, which suggest them as better alternative delivery systems for enhanced therapeutic efficacy of antidepressant drug, venlafaxine HCl.     

马来酸氟吡汀缓释片的研制及体外释放特性考察

目的：采用羟丙甲基纤维素（HPMC）作为亲水凝胶骨架材料,制备马来酸氟吡汀缓释片,并考察其体外释放特性。方法：通过单因素试验,分剐考察了HPMC、乳糖用量对马来酸氟吡汀缓释片释放速率的影响;以体外释放度为评价指标优选处方的最佳组成和比例。结果：马来酸氟吡汀缓释片的释放速度随处方中HPMC含量增加而减慢,随乳糖用量增多而加快;释放介质对马来酸氟吡汀的释放速率也有明显影响,而释放度测定方法、转速对马来酸氟吡汀缓释片的释放速率无明显影响。结论：本品处方组成合理,制备工艺稳定。制备的马来酸氟吡汀缓释片,体外释药曲线显示有明显的缓释作用,属于零级释放。     

Effect of Processing Methods and Heat Treatment on the Formation of Wax Matrix Tablets for Sustained Drug Release

The objective of this study was to evaluate the effects of processing methods and heat treatment on matrix formation and subsequent drug release from wax matrix tablets for controlled release. Phenylpropanolamine hydrochloride (PPA) and Compritol® were processed with appropriate diluent(s) using either dry blending (DB), wet granulation (WG), partial melt granulation (PMG), or melt granulation (MG). Then the tablets were heat-treated at 80°C. Particle size distribution and compressibility, along with drug release, tablet micro-morphology, wettability, porosity, and tortuosity were investigated. The drug release was different for the four processing methods even though the tablet formulation was identical. Heat treatment further retarded drug release and its effect was related to the previous manufacturing processes. Scanning Electron Microscopy (SEM) showed that heat treatment redistributed the wax and formed a film-like structure covering drug and excipients. The contact angle of tablets made from DB, WG, and PMG methods increased after heat treatment, while that of tablets made from DB, WG, and PMG methods increased after heat treatment, while that of tablets made from MG remained constant. Tablet tortuosity calculated from drug release rate constants increased dramatically after heat treatment. Drug release from the wax tablets with or without heat treatment was best described by the Higuchi equation. Different processing methods produced different matrix structures that resulted in different drug release rates. Heat treatment retarded drug release mainly by increasing tortuosity of the matrix. Contact angle measurement and SEM analysis indicated that heat treatment caused the wax to melt, redistribute, coat the drug and diluents, and form a network structure.     

醋氯芬酸缓释片和普通片体内外释药行为的相关性研究

目的对比研究醋氯芬酸缓释片和普通片的体外释放行为和Beagle犬体内的药动学,分析体内、体外释药行为的相关性。方法以紫外分光光度法测定两药的体外释放度,利用反相高效液相色谱法测定不同时间Beagle犬血浆中药物浓度,用DAS2.0统计软件计算有关药动学参数,Loo-Riegelman法计算体内吸收百分数,并对体内外相关性进行评价。结果醋氯芬酸缓释片体外恒速释放14h累积释放百分率在95%以上,普通片和缓释片的主要药动学参数达峰时间（tmax）为（2.833±1.169）h和（12.800±0.980）h,血浆半衰期（t1/2）为（2.650±0.261）h和（6.859±6.029）h,峰浓度（Cmax）为（23.457±8.881）μg/mL和（5.674±1.903）μg/mL,药时曲线下面积（AUC0-∞）为（113.171±16.529）μg.h/mL和（128.295±118.601）μg.h/mL,且体内外相关性较好。结论醋氯芬酸缓释片血药浓度平稳,与普通片相比可较长时间保持有效血药浓度。     

Sustained Release of Acetaminophen from Heterogeneous Matrix Tablets: Influence of Polymer Ratio,Polymer Loading,and Co-active on Drug Release

ABSTRACT

The aim of this research was to investigate the effect of pseudoephedrine (PE), polymer ratio, and polymer loading on the release of acetaminophen (APAP) from hydroxypropyl methyl cellulose (HPMC)/polyvinylpyrrolidone (PVP) matrices. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and PVP were compressed into tablets at varying compression forces ranging from 2000 to 6000 lb. In vitro drug release from the matrix tablets was determined and the results correlated with those of tablet water uptake and erosion studies. Drug release from the formulations containing both APAP and PE was slower than those containing only APAP (P < 0.05, F = 3.10). Drug release from tablets formulated with APAP only showed an initial burst at pH 1.16 or 7.45, and at high total polymer loading (≥ 9.6%). Formulations containing both APAP and PE showed slower drug release at pH 1.16 than at pH 7.45. At pH 1.16, a decline in the percentage of APAP released occurred after 18 hours. This was due to the hydrolysis of APAP to p-aminophenol. The drug dissolution data showed good fit to the Korsmeyer and Peppas model, and the values of the release exponents ranged from 0.20 to 0.62, indicating a complex drug release pattern. Tablet erosion studies indicated that the amount of APAP released was linearly related to the percentage of tablet weight loss. The kinetics of tablet water uptake was consistent with a diffusion and stress relaxation controlled mechanism. Overall, the results of this study indicated that PE, as a co-active in the formulation, modified the matrix, and hence retarded APAP release.     

Formulation and Evaluation of Dextromethorphan Hydrobromide Sustained Release Tablets

Sustained release (SR) matrix tablets of dextromethorphan hydrobromide were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. A complete cross-over bioavailability study of the optimized formulation of the developed sustained tablets and marketed immediate release tablets was performed on six healthy male volunteers. The extent of absorption of drug from the SR tablets was significantly higher than that for the marketed dextromethorphan hydrobromide tablet because of lower elimination rate and longer half-life.     

米诺环素亲水凝胶型缓释骨架片的制备及体外释放度考察

目的:制备米诺环素亲水凝胶型缓释骨架片并考察其体外释放度。方法:采用粉末直接压片工艺制备缓释片;采用紫外分光光度法测定其释放度,同时考察羟丙基甲基纤维素(HPMC)的不同规格、用量以及不同释药条件对药物释放速率的影响。结果:所制制剂为黄色片剂,检查项符合2005年版《中国药典》中的相关规定。试验确定了以HPMCK100为缓释骨架材料,处方用量为32%;不同释放介质与释放装置对药物的释放均有显著影响。释放规律符合Higuchi方程。结论:该制剂处方工艺简单,体外释放度测定方法准确易行,制剂具有明显的缓释效果。     

高于饱和装填量时的平板混合药膜体系释放动力学模型

针对最一般的情况建立了Ｃｄ＞Ｃｓ时的混合药膜的释放动力学模型,用拉氏变换求得了解析解,该模型可通过相应简化而获得一些特定情况的解;用５－氟脲嘧啶／ＥＶＡＬ混合药膜体系的释放实验数据对所提出的模型进行了验证并与Ｈｉｇｕｃｈｉ模型进行了比较。结果表明：在中等装填量的情况下如：１５.５＜Ｃｄ＜１２３.６ｍｇ·ｃｍ(－３)时,本文模型与实验数据符合的很好,预测精度比Ｈｉｇｕｃｈｉ模型高,特别是在Ｃｄ＜１５．５ｍｇ·ｃｍ(－３)时;这两个模型均不能较好描述较高装填量的情况,如Ｃｄ＞２１０ｍｇ．ｃｍ(－３),这种情况我们在别处已经作过讨论（８,９）。     

Development of Dividable One-Step Dry-Coated Tablets (Dividable-OSDRC) and Their Evaluation as a New Platform for Controlled Drug Release

PURPOSE: The purpose of this study is to develop novel dividable coated tablets that retain their characteristics even after they are divided. METHODS: We prepared dividable one-step dry-coated tablets (dividable-OSDRC) using our own manufacturing process with double structure punches. The release pattern of the dividable-OSDRC with hydroxypropyl methylcellulose (HPMC) or methacrylic acid copolymer LD (Eudragit) as an outer layer was investigated before and after the division, and dissolution profiles were statistically compared using difference factor f1 and similarity factor f2. RESULTS: The dividable-OSDRC with HPMC for sustained-release (compression pressure, 150 MPa; crashing strength, 6.1 N; friability, 0.05%; CV of divided tablet weight, 7.8%) showed statistically equivalent release patterns between the one-half and the whole (f1, 13.9; f2, 55.5) and between the one-half and the two-halves (5.5, 72.5). The surface area of the tablets affected the sustained-release profiles. Furthermore, the tablets made with Eudragit LD for timed-release (150 MPa. 12.8 N, 0.18%, 9.6%) also showed approximated release patterns before and after the division. CONCLUSIONS: We proved that dividable-OSDRC maintain their release characteristics after they are divided. We conclude that the dividable-OSDRC could be used as a new platform for the controlled release of drugs.     

骨架片在缓释给药系统中应用

本文研究的主要内容是骨架片作为一种有效的缓释给药系统的基本信息。骨架片是用来调节药物释放最常用的方法。骨架片受到广泛的欢迎,而且是治疗的首选,因为它能提高患者的顺应性,减少药物剂量和副作用,还能增加安全性。不同的聚合物材料能够被用来设计出适宜的释放曲线,并提供一个可行的和一致性的生产模式。     

Evaluation of Solubilizers in the Drug Release Testing of Hydrophilic Matrix Extended-Release Tablets of Felodipine

The drug release of felodipine, a water-insoluble drug, was tested by using sodium lauryl sulphate (SLS), polyoxyethylene 20 sorbitan monooleate (Tween) or cetyltrimethylammonium bromide (CTAB) in the test medium as solubilizers. Three slightly different felodipine extended-release (ER) tablets 10 mg based on the gel matrix principle were evaluated under different solubilizer concentrations, agitation intensities and pH. These tablets were also tested in a bioavailability study together with an oral solution. All three solubilizers substantially enhanced the drug solubility and sink conditions were obtained. The choice of solubilizer affected the drug release rate. This is most probably due to physico-chemical interactions between the gel-forming agent and the solubilizers. All in vitro test conditions provided a good correlation (r² = 0.94 – 0.97) to in vivo dissolution, as determined by moment analysis. However, a much steeper in vitro/in vivo relationship was obtained for SLS compared to Tween and CTAB reflecting an inferior discrimination between the tablets by use of this anionic solubilizer.     

硫酸吗啡缓释片的不良反应监察与分析

目的 :了解硫酸吗啡控释片的不良反应 ,为临床合理用药提供依据。方法 :对兰州军区总医院肿瘤科 5 7例使用硫酸吗啡缓释片治疗晚期癌症患者不良反应进行系统监察 ,并进行分析。结果 :出现恶心 3 5 .1% ,呕吐 19.3 % ,便秘2 8.0 % ,头昏嗜睡 2 2 .8% ,排尿困难 14 .0 % ,另有 2例出现欣快感 ,未见其他严重的不良反应。结论 :药物不良反应的发生与用药剂量无明显关系而与用药总量有一定关系。     

Effect of Different Polymer Concentration on Drug Release Rate and Physicochemical Properties of Mucoadhesive Gastroretentive Tablets

Mucoadhesive tablets have emerged as potential candidates for gastroretentive drug delivery providing controlled release along with prolonged gastric residence time. Gastroretentive mucoadhesive tablets could result in increased bioavailability due to prolonged gastric residence time. A hydrophilic matrix system was developed as mucoadhesion is achievable on appropriate wetting and swelling of the polymers used. The polymers were so chosen so as to provide a balance between swelling, mucoadhesion and drug release. The polymers chosen were hydroxypropyl methylcellulose K4M, chitosan, and Carbopol 934. The concentrations of these polymers used has a great impact on the physicochemical properties of the resulting formulation. The tablets were formulated using wet granulation method and tranexamic acid was used as the model drug. The prepared tablets were characterized for size, shape, appearance, hardness, friability, weight variation, swelling, mucoadhesion and in vitro drug release. Several batches of tablets were prepared by varying the ratio of hydroxypropyl methylcellulose K4M and Chitosan. The batches having a greater ratio of chitosan showed higher rate of swelling, greater erosion, less mucoadhesion and faster release rate of the drug whereas the batches having greater ratio of hydroxypropyl methylcellulose K4M showed lesser rate of swelling, less erosion, better mucoadhesion and a smaller drug release rate. The level of carbopol was kept constant in all the batches.     

Synthesis and Evaluation of Boronated Chitosan as a Mucoadhesive Polymer for Intravesical Drug Delivery

This work reports the synthesis of boronated chitosan by reacting it with 4-carboxyphenylboronic acid to improve its mucoadhesive properties. Three products with differing extent of boronate conjugation were synthesized and characterized using ¹H NMR, FT-IR, and UV-Vis spectroscopy, and the potential of these polymers to extend the residence time of loaded model drug in the bladder was investigated. ¹H NMR and ninhydrin test were used to evaluate the extent of chitosan modification. Mucoadhesive properties were evaluated using ex vivo flow-through technique on porcine bladder mucosal tissue combined with fluorescent microscopy, where fluorescein sodium was used as a model drug. The mucoadhesive properties of these polymers on porcine bladder mucosa were also studied using tensile test. There was good correlation in the mucoadhesive profiles of the polymers using the flow through and tensile techniques. The degree of chitosan modification had a remarkable influence on their mucoadhesive behavior, and greater mucoadhesion was observed with increased degree of boronation. These chitosan derivatives have the potential as intravesical drug delivery systems to improve bladder therapy.     

Formulation and Evaluation of Hydroxypropyl Methylcellulose-based Controlled Release Matrix Tablets for Theophylline

The objectives of the study were to formulate hydroxypropyl methyl cellulose-based controlled release matrix tablets for theophylline with varying drug:polymer ratios (1:1 and 1:2) and differing tablet hardness (5, 6 and 7 kg/cm(2)), and to evaluate the tablet's physico-chemical properties such as hardness, uniformity of weight, friability, drug content and in vitro drug release. Initially, granules were made by wet granulation technique and evaluated for angle of repose, bulk density, tapped density, bulkiness, compressibility index and hausner ratio. The results indicate good flow property of the granules and thus, the evaluated tablet physical properties were within the acceptable limits. The FT-IR study for the F-6 formulation showed that there was no interaction between the drug and the polymer. In vitro release studies were performed using Disso-2000 (paddle method) in 900 ml of pH 7.4 at 50 rpm. The result indicated that at high drug:polymer ratio (1:2) and hardness value 7 kg/cm(2), prolonged drug release was observed than the low drug: polymer ratio (1:1) and hardness values (5 and 6 kg/cm(2)). The release kinetics was found to follow korsmeyers-peppas model and the mechanism of drug release was by non-fickian or anomalous diffusion. The F-6 formulation was chosen for stability studies. F-6 formulation was stable when it was kept at different temperatures for a period of 6 months.