多索茶碱渗透泵型控释片和缓释骨架片的研究

【作者】 郭晓蕾；

【导师】 何仲贵； 孙淑英；

【作者基本信息】 沈阳药科大学 ， 药物制剂， 2001， 硕士

【摘要】 本文以多索茶碱作为模型药物，在考察各辅料、药物及包衣膜基本性质的基础上，选用聚氧乙烯（PEO）、羧甲基纤维素钠（CMCNa）、羟丙基甲基纤维素（HPMC）及KCl、NaCl等为辅料与药物制成具有含药层和推挽层的双层片心，以醋酸纤维素（CA）/聚乙二醇6000（PEG6000）为包衣材料，制备了多索茶碱渗透泵型控释片，并以HPMC作为骨架材料制备了多索茶碱缓释骨架片。 本文对多索茶碱渗透泵型控释片作了系统研究。首先考察了影响本品释药的因素。其中，含药层载药量、促渗透聚合物用量、推挽层片重等因素对释药有较明显的影响；含药层片重、促渗透聚合物的种类、推挽层组成及一定范围内的释药孔径对释药影响不大。利用正交试验，选定包衣膜厚度、增塑剂PEG的用量及分子量三个因素三个水平，以药物释放度及其与时间的相关系数两个指标的综合评分作为评价指标，优化筛选了包衣膜处方，通过调节增塑剂PEG的用量、包衣膜的厚度等因素，使本品在12或24小时内保持零级释药。同时对该片剂的释药机制作了初步考察，膜内外渗透压差和推挽层产生的推动力是药物释放的主要动力。初步稳定性试验结果表明，在高温高湿条件下，本品外观变化较大，应40℃以下密闭保存。 考察了影响多索茶碱缓释骨架片释药的因素。结果表明，HPMC的种类和用量、填充剂乳糖的用量对其释药有显著影响，通过调节HPMC的用量，可使本品在12或24小时内保持连续缓慢释放。初步稳定性试验结果表明，在高温高湿条件下，本品质量稳定。 本文以国产多索茶碱速释片作为对照，对多索茶碱缓释骨架片和渗透泵型控释片进行了人体相对生物利用度和药动学初步研究。结果表明：单剂量口服多索茶碱300mg，三种制剂（速释片、缓释骨架片和渗透泵型控释片）的药—时曲线下面积分别为5.67、5.51、6.01（μg/ml）·h，达峰时间分别为1.5、4.0、5.7h，最大血药浓度分别为2.57、0.69、0.48μg/ml。缓释 沈阳药科大学硕士学位论文 摘要骨架片对速释片的相对生物利用度为97．2％，渗透泵型控释片为105．9％，两种制剂具有良好的体内外相关性。更多还原

【Abstract】 In this paper doxophylline was selected as the model drug to prepare the osmotic pump tablet and matrix tablet. On the basis of the pre-formulation research about the properties of doxophylline, excipients and cellulose acetate (CA) free film, polyethylene oxide (PEO),carboxymethylcellulose sodium (CMCNa), hydroxypropylmethylcellulose (HPMC), potassium chloride and sodium chloride were used to make the two-layer tablet core coated with the CA coating comprising with 10% polyethylene glycol 6000 (PEG6000).And HPMC was selected as the matrix material to prepare the sustained-release tablet. The system research of the doxophylline osmotic pump controlled-release tablet was made mainly. The effect of some factors on the drug release from the osmotic pump tablet was investigated. The result was the content of drug in the core tablet, the content variation of osmopolymers and the mass of the push-pull layer had significant influence on the drug release; but the sort of osmopolymers, the mass of the drug layer, the composition of the push-pull layer and the size of orifice for drug delivery had not. According to the experimental design of orthogonal test, coating thickness, the PEG sorts and content variation in the coating solution were selected as the causal factors. The linear correlation coefficient of the accumulative drug release amount and time (r) and the accumulative drug release amount (F%) were used as the evaluation standard to optimize the coating formulation. The zero-order release of the drug from the osmotic pump tablet could sustain to 12 or 24 hours with the thickness of coating varying. The result of the drug release mechanism study indicated that the drug release was mainly modulated by the osmotic pressure difference between inside and outside of the coating and the swelling force of the push-pull layer of the core tablet. The osmotic pump tablets were unstable under high temperature or humidity circumstance. The effect of some factors on the drug release from the HPMC sustained- release matrix tablet was investigated. The result was the viscosity and content variation of HPMC and the content variation of additive had significant influence on the drug release. The drug release from the matrix tablet could sustain to 12 or 24 hours with the content of HPMC varying. The matrix tablets were stable under high temperature or humidity circumstance. Using the immediate release tablet as the reference, the pharmacokinetics 3 of doxophylline sustained-release tablet and osmotic pump controlled-release tablet were studied, The result indicated that after p.o. 300mg doxophylline, AUC~.,. of the three formulations in turn were 5.67, 5.51, 6.01 (~ig/ml)h; Tm were 1.5, 4.0, 5.7 h; Cm were 2.57, 0.69, 0.48 ~tg/ml. The relative bioavailability of the sustained-release tablet was 97.2% and that of the osmotic pump controlled-release tablet was 105.9%. The drug release from the two kinds of tablets was equal in vitro and in vivo.更多还原