舒林酸亲水凝胶缓释骨架片的研究

【作者】 张晓明；

【导师】 何仲贵；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2009， 硕士

【摘要】 舒林酸为非甾体抗炎药,用于治疗各类风湿、类风湿性关节炎、骨关节炎等,疗效确切,副作用小。其为前体药物,无药理活性,只有代谢为舒林酸硫醚与舒林酸硫砜时,其中的舒林酸硫醚具有药理活性,发挥药效。舒林酸半衰期短,为7.8小时,制成缓释制剂可减少服药次数和血药浓度波动,降低副作用。目前国内外只有日服两次的普通片,尚无任何缓释剂型。本文采用羟丙基甲基纤维素(HPMC)为基本骨架材料,联合应用填充剂预胶化淀粉,研制了日服一次,一次两片,每片片重500 mg的舒林酸缓释片。其最优处方为每片含200 mg舒林酸,20%HPMCK4M,34%乳糖,5%预胶化淀粉,1%硬脂酸镁,以3%PVP的80%乙醇为黏合剂。该方法制备工艺简单,易于进行工业化生产。同时我们参照中国药典(2005年版),美国药典(USP26版),英国药典(2002版)中舒林酸普通片的标准考察出舒林酸缓释片的含量测定方法与释放度的测定方法(以PH7.2PBS为溶出介质)。本文在制剂处方前研究和预实验的基础上,以体外药物释放为筛选指标,选用Kollidon(?)SR、羟丙甲纤维素(HPMC)、海藻酸钠、海藻酸丙二醇酯、微晶纤维素、乳糖、预胶化淀粉、低取代羟丙基纤维素等主要辅料,从处方因素和工艺因素方面详细考察了各种因素对药物释放行为的影响,在此基础上制备了舒林酸骨架缓释片。对自制骨架缓释片质量因素考察结果表明,其受体外释放条件影响较小,释放均一性、工艺重现性良好；有关释药机理研究显示药物体外释放过程为非Fick扩散(0.45<n=0.7804<0.89),即药物扩散与骨架溶蚀的共同作用结果。由影响因素考察实验可知,自制舒林酸缓释片受高湿影响较大,故本品应密闭保存。以市售普通片为对照,对舒林酸自制缓释片进行了家犬体内药物动力学研究。采用双周期双交叉实验设计,以高效液相色谱法对6只健康家犬体内血药浓度进行测定。单剂量给药实验结果为,市售普通片与自制缓释片的血药浓度曲线下面积AUC0-24(μg·h／ml)分别为19.75±8.93和15.08±11.23、最大血药浓度Cmax(μg／ml)分别为4.46±3.95和5.18±5.38、达峰时间Tmax(h)分别为0.42±0.13和1.75±0.76,相对生物利用度为83.8±53.7%。结果表明体内缓释效果存在一定差异。更多还原

【Abstract】 Sulindac is a non-steroidal anti-inflammatory drug with less side effects and higher efficacy which is widely used for the treatment of various types of rheumatism, rheumatoid arthritis, osteoarthritis, etc. Sulindac is a precursor drug of no pharmacological activity metabolized only in the colon. Among the metabolites is sulindac sulfide which is pharmacological activity, sulindac sulfide has a short half-life of 7.8 hours, that makes it suitable for preparing extended release formulations in order to reduce the side effects by decreasing the times of medication and blood concentration fluctuations. At present, there are sulindac tablets taken two times a day both in domestic and international market, but no extended release formulations have been developed yet. In this research, we prepared sulindac extended release tablets that only need to be taken one time a day, hydroxypropylmethylcellulose (HPMC) was used as main skeleton material, and amylum pregelatinisatum as disintegrant, each tablet weights 500mg and two tablets make a dose. Optimal formula contains 200mg Sulindac, 20%HPMCK4M,34%lactose,5% amylum pregelatinisatum,1% magnesium stearate each tablet, using 3% PVP in 80% ethanol solution as adhesives. The preparation of sulindac extended release tablet is easy and suitable for industrial production. According to methods of assaying and realse rate determination for sulindac tablet on Chinese Pharmacopoeia (edition2005), the United States Pharmacopoeia (edition USP26) and British Pharmacopoeia (edition 2002), we studied our examination of the contents by HPLC and RP-HPLC. During the examination, pH7.2PBS was used as dissolution medium.Based on studies of formulas and pretreatment, in vitro drug release behavior was considered the screening indicators of the products. After studying influences on drug release behavior from formula factors to processing factors, we prepared sulindac extended release tablet, choosing excipients including KollidonRSR、hydroxypropylmethylcellulose (HPMC)、sodium alginate、Propylene Glycol Alginate、Microcrystalline cellulose、lactose、amylum pregelatinisatum、low-substituted hydroxypropyl cellulose, etc. Results of investigation of influencing factor suggest that in vitro drug release conditions have little effect on the product which possesses good release uniformity and excellent reproducibility. Studies on drug release mechanism indicate the release of drug in sulindac extended release tablet to be non-Ficker proliferation (0.45<n=0.7804<0.89), that means both drug proliferation and skeleton dissolution contribute to the drug release. Also, high humidity has a great influence on the stability of sulindac extended release tablet, so the product needs to be kept sealed.With the commercial sulindac tablets as the reference, the in vivo pharmacokinetics of self-prepared sulindac extended release tablet was studied with four dogs. Double-cycle and double-crossover tests was designed and HPLC method was employed to detect the blood drug level in dogs administered with single dose. The pharmacokinetic parameters of the reference and test tablets were as follows:AUC0-24(μg·h/ml) were 19.75±8.93 and 15.08±11.23, respectively; Cmax (μg/ml) were 4.46±3.95 and 5.18±5.38, individually; Tmax(h) were 0.42±0.13 and 1.75±0.76 separately. The relative bioavailability was 83.8±53.7%.更多还原