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1、 密 级： 学校代码：10075 分类号： 学 号：20091166 理学硕士学位论文 阿替洛尔缓释骨架片的研制 学位申请人： 李聚坤 指 导 教 师 ： 张 娜 胡连栋 副教授 学 位 类 别 ： 理学硕士 学 科 专 业 ： 药物化学 授 予 单 位 ： 河北大学 答 辩 日 期 ： 二一二年六月 Classified Index: CODE: 10075CODE: 10075 U.D.C.: NO: 20091166NO: 20091166 A Dissertation for the Degree of M. Science The Preparation of Atenolol Su
2、stained Release Matrix Tablets Candidate : Li Jukun Supervisor : Zhang Na Associate Prof. Hu Liandong Academic Degree Applied for : Master of Science Specialty : Pharmaceutical Chemistry University : Hebei University Date of Oral Examination : June, 2012 摘 要 I 摘 要 阿替洛尔(Atenolol，ATN)为肾上腺素受体阻滞剂，临床上主要用
3、于治疗高血压、 心绞痛、心律失常和青光眼等。但该药普通制剂口服生物利用度低、个体差异大，易引 起血药浓度峰谷现象，不能起到平稳的降压效果。为了解决上述问题，因此本文以乙基 纤维素（EC）和十六醇作为缓释材料，制备了阿替洛尔缓释骨架片。 本文对 ATN 在油相、水相中的平衡溶解度进行了测定，并建立了 UV 法来测定阿 替洛尔骨架片的释放度。该法操作简便，并满足该研究的各项分析要求。 在处方研究中， 以缓释骨架片在 012 h 的释放度为考察指标， 并考察了处方因素和 工艺因素对 ATN 缓释骨架片释放度的影响；并且在此基础上采用星点设计效应面法 优化处方， 筛选出最优处方， 制成了阿替洛尔缓释骨
4、架片。 其最优处方为： EC (20 mpa.s) 为缓释阻滞剂，十六醇为辅助缓释辅料，加入一定量的硬脂酸镁以粉末直接压片法来制 备缓释片。按照优化处方制备的缓释片在 12 h 内释放度达到 80 %以上。 此外还考察了 ATN 缓释骨架片的释药机理，并采用零级模型、一级模型、Higuchi 模型和 Ritger-Peppas 模型等方程对制剂的体外释放曲线进行了模型拟合。结果表明， 释放曲线符合 Higuchi 方程，r = 0.991；同时也符合 Ritger-Peppas 方程，r = 0.976，最终 判断缓释片的释药机理为非纯 Ficks 扩散机制， 即为药物扩散和骨架溶蚀协同作用的
5、结 果，其中扩散机制起主要作用。 关键词 阿替洛尔 缓释骨架片 乙基纤维素 十六醇 星点设计-效应面优化法 Abstract II Abstract Atenolol (ATN) belongs to the -receptor blocker, which has the main effect on hypertension, angina, arrhythmia and glaucoma and so on. However, the common dosage form of the drug has a low bioavailability and the individual d
6、ifference is severe, which is easy to cause the blood concentration peak valley phenomenon. It cannot obtain a stable effect on the anti-hypertension. In order to deal with the problems mentioned above, EC and hexadecanol were taken as basic materials to prepare the ATN sustained release matrix tabl
7、ets in this paper. In this study, a UV method was used for the determination of the equilibrium solubility of atenolol in oil and aqueous phase. According to the literature, UV spectrophoto- metry was adopted for the determination of ATN during the study of drug release rate. These methods were accu
8、rate and quick which could meet the requirement of the analysis perfectly. Basing on the studies of the influencing factors in formulation and manufacture on the release profile, optimal formulation modified to release drug over 12 h was obtained by central composition designresponse surface optimiz
9、ation method and the optimal formula- tion of the ATN sustained release tablet was screened. The best formulation includes EC as the retard and hexadecanol as an assistant adjuvant which has sustained release effect together with the magnesium stearate. ATN sustained release matrix tablets were prep
10、ared by direct compression method and the cumulated release rate achieved was over 80 %. The release mechanism of ATN was studied by comparing zero-order model, first-order model, Higuchi model and Ritger-Peppas model et al. Release data were in good linearization with the Higuchi equation with corr
11、elation coefficient r value of 0.991. The release data were also in accordance with Ritger-Peppas equation with correlation coefficient r value of 0.976, indicating that drug diffusion was the prevailing release mechanism with erosion as a supplementary release mechanism. Key words Atenolol Sustaine
12、d-release matrix tablets EC Hexadecanol Central composition design-response surface methodology 目 录 III 目 录 第 1 章 绪 论.1 1.1 缓释制剂概述 .1 1.1.1 缓释制剂定义 .1 1.1.2 研制缓释制剂的意义 .1 1.1.3 缓释制剂的发展及现状 .2 1.1.4 缓释制剂的分类 .2 1.2 缓释材料 EC 概述.3 1.3 星点设计-效应面优化法 .4 1.4 模型药物-阿替洛尔简介 .5 1.4.1 阿替洛尔的药理特性 .5 1.4.2 药理作用与机理 .6 1.4.3 阿替洛尔的安全性与剂量 .6 1.4.4 本课题的研究内容及意义 .6 第 2 章 阿替洛尔缓释骨架片处方前研究.7 2.1 实验部分 .7 2.1.1 仪器和试药 .7 2.1.2 阿替洛尔平衡溶解度的测定 .7 2.1.3 阿替洛尔油水分配系数的测定 .9 2.2 结果与讨论 .11 2.3 本章小结 .11 第 3 章 阿替洛尔缓释片体外分析方法的建立.
