药学论文复方布洛伪麻缓释微丸胶囊的研究.doc
复方布洛伪麻缓释微丸胶囊的研究 复方布洛伪麻缓释微丸胶囊的研究 The Study on the Compound Sustained-Released Pellets of Pseudoephedrine Hydrochloride and Ibuprofen 【摘要】 本文以盐酸伪麻黄碱(Pseudoephedrine Hydrochloride，PSE)和布洛芬(Ibuprofen，IBU)为模型药物，利用流化床设备分别制备体外缓释12小时的布洛芬缓释微丸和盐酸伪麻黄碱缓释微丸，将二者按处方比例混合制备复方布洛伪麻缓释微丸胶囊，并对体内药物动力学进行研究。建立复方缓释微丸的含量测定、释放度测定的HPLC检测方法。以粉体学参数和产率为考察指标，采用Hasaan转换求得“归一值”，利用盐酸二甲双胍代替PSE进行含药丸芯的单因素考察，确定理想的含药丸芯处方和工艺参数。利用正交试验考察包衣处方参数，并使用SPSS软件对正交试验数据进行方差分析，确定PSE缓释微丸最佳的包衣参数为：包衣增重为50，抗黏剂用量为30，以Eudragit? RS为骨架和包衣材料制备盐酸伪麻黄碱膜控骨架杂化型缓释微丸。利用单因素考察试验和正交试验，确定IBU缓释微丸最佳的工艺处方参数为：喷雾风量为0.4MPa，喷雾速率为5mL·min-1，进口温度为50，主药与骨架材料比例为12，以Surelease?为骨架材料及黏合剂，制备布洛芬骨架型缓释微丸。讨论两种缓释微丸的释药机理并对释药曲线拟合，结果表明PSE微丸释药行为符合Higuchi动力学方程，IBU缓释微丸释药行为符合一级动力学方程。对复方布洛伪麻缓释微丸胶囊的Beagle犬体内药物动力学进行了研究。以高效液相胶束色谱法(HPLMC)测定PSE和IBU Beagle犬体内血药浓度，隔室模型拟合结果表明自制复方缓释微丸和市售普通复方片在体内符合单室模型。药动学参数计算结果表明：与市售复方普通片相比，自制复方缓释微丸中两种药物的Tmax后移，Cmax明显降低。统计矩分析方法计算结果表明，与市售复方普通片相比，自制缓释微丸PSE和IBU的MRT显著延长。自制复方缓释微丸对市售复方普通片的相对生物利用度PSE为92.18，IBU为115.47。采用统计学方法判定，自制复方缓释微丸与市售复方普通片的生物利用度等效，体内外相关性良好【Abstract】 In this paper, Pseudoephedrine Hydrochloride and Ibuprofen were selected as the model drugs to prepare compound sustained-release pellets by fluidized bed. The HPLC method of assay, dissolution. Micromeritics parameters, yield were employed to optimize the formulation and technolgy parameters by single factor and the total score of dissolution was used in the orthogonal test to determine the best formulation. The data of testing result was dealed with by SPSS statistical software, and the optimized formulation and technique parameters were obtained. Eudragit? RS and Surelease? aqueous dispersions were used to prepare membrane-matrix hybrid sustained-release pellet of Pseudoephedrine Hydrochloride and matrix sustained-release pellet of Ibuprofen as coating material ,matrix material and adhesives respectively. According to the ratio of Pseudoephedrine Hydrochloride and Ibuprofen in designed formulation, the Pseudoephedrine Hydrochloride sustained-release pellets and Ibuprofen sustained-release pellets were mixed evenly and filled into capsule.The drug release character and mechanism from different sustained-release pellets were studied.Finally, the pharmacokinetic study of compound Pseudoephedrine Hydrochloride and Ibuprofen sustained-release pellets was performed. With the commercial compound Pseudoephedrine Hydrochloride and Ibuprofen tablet as the reference preparation, the pharmacokinetic study was performed in six Beagle dogs. HPLMC method was employed to detect the drug concentration in plasma of dogs administered with single dose by crossover design. The pharmacokinetic parameters of the test and reference tablets were as follows: AUC0 of Pseudoephedrine Hydrochloride were 14496.35±1556.49 and 15726.28±2014.32 (ng·h·mL-1), Cmax were 1015.27±141.44 and 1981.70±121.12 (ng.ml-1), Tmax were 5.67±1.51 and 2.6±0.38 (h), AUC0 of Ibuprofen were 888.00±43.99 and 768.99±46.91 (g·h·mL-1), Cmax were 84.44±16.43 and 117.02±1:15.9 (g·mL-1),Tmax were 5.17±1.29 and 2.58±0.38 (h).The relative bioavailability of Pseudoephedrine Hydrochloride and Ibuprofen were 92.18% and 115.47%. The two one-sided test results showed that bioavailability of two dosage forms were equivalent. The results of statistical judgment indicated that the in vitro release of compound Pseudoephedrine Hydrochloride and Ibuprofen sustained-release pellets was correlative well with absorption fraction in vivo. 【关键词】 盐酸伪麻黄碱; 布洛芬; 流化床包衣; 缓释微丸; 药物动力学 【Key words】 Pseudoephedrine Hydrochloride; Ibuprofen; fluidizied bed coater; sustained-release pellets; pharmacokinetics 复方布洛伪麻缓释微丸胶囊的研究摘要 11-12 ABSTRACT 12-13 引言 14-20 第一章 复方布洛伪麻缓释微丸胶囊的处方前研究 20-28 1 仪器与材料 20 2 方法与结果 20-27 2.1 紫外最大吸收波长的测定 20-21 2.2 PSE-IBU微丸体外分析方法的建立 21-27 2.2.1 含量测定方法的建立 21-24 2.2.2 释放度测定方法的建立 24-27 3 讨论 27 4 小结 27-28 第二章 盐酸伪麻黄碱缓释微丸的制备 28-47 1 仪器与释药 28 2 方法与结果 28-45 2.1 含药丸芯的制备 28-29 2.2 含药丸芯粉体学性质考察 29-30 2.3 含药丸芯单因素考察 30-36 2.4 盐酸伪麻黄碱缓释微丸的制备 36 2.5 缓释微丸单因素考察 36-40 2.6 缓释微丸制备的正交试验设计 40-44 2.7 释放度重现性 44 2.8 包衣增重重现性 44-45 3 讨论 45-46 4 小结 46-47 第三章 布洛芬缓释微丸的制备 47-66 1 仪器与释药 47-48 2 方法与结果 48-61 2.1 布洛芬缓释微丸的的制备 48 2.2 缓释微丸单因素考察 48-58 2.3 正交试验设计与结果分析 58-61 2.4 释放度重现性 61 2.5 复方布洛伪麻缓释微丸胶囊的制备 61 3 缓释微丸释药机理的探讨 61-65 3.1 包衣缓释微丸释药动力学 62 3.2 释药机理的探讨 62-65 4 讨论 65 5小 结 65-66 第四章 布洛伪麻缓释胶囊Beagle犬体内药物动力学研究 66-85 1 体内分析方法的建立 66-71 1.1 色谱条件 66-67 1.2 贮备液的制备 67 1.3 血浆样品处理 67 1.4 分析方法的确证 67-68 1.5 标准曲线的绘制 68 1.6 方法回收率 68-69 1.7 日内与日间精密度 69-71 2 Beagle犬体内药物动力学研究 71-83 2.1 试验对象 71 2.2 给药方案及采血 71 2.3 血药浓度测定结果 71-74 2.4 两种剂型的药-时曲线比较 74-75 2.5 药物动力学模型拟和及参数计算 75-78 2.6 相对生物利用度计算 78-79 2.7 生物等效性评价 79-81 2.8 统计矩原理在本研究中的应用 81-82 2.9 体内外相关性评价 82-83 3 讨论 83 4 小结 83-85 全文结论 85-86 参考文献 86-90 发表文章目录 90-91 致谢 91
