论文总字数：24048字

摘 要

塞来昔布（Celecoxib）为第一个特异性Cox-2抑制剂，2000年在中国市场正式上市，是新一代具有抗炎，镇痛和退热作用的非甾体抗炎药（NSAIDs）。由于其在阻止前列腺素（PG）的产生时能够选择性抑制COX-2环氧化酶，但同时不会抑制与保护胃肠粘膜相关的COX-1的表达，进而达到比传统非甾体抗炎药较低的不良反应。然而长期口服易产生诸如胃肠道毒性、胃粘膜溃疡出血等负面影响，而且药物溶解度低，口服后无法达到在胃肠管中完全润湿并溶解，抑制了该药物的进一步吸收。

实验针对药物在生物药剂学分类中处于ClassⅡ低溶解高渗透药物，将药物制备成微乳液以提高药物水溶解度并利用其较高的油水分配系数的特性制备塞来昔布纳米微乳凝胶剂，提高药物体外透皮渗透以及生物利用度。本课题系统进行了塞来昔布微乳凝胶剂（MBGs）的药代动力学研究，主要对以下内容进行研究：

1、塞来昔布微乳制备、质量评价及含量测定

本文采用低能乳化法制备塞来昔布微乳，综合伪三元相图法，溶解度法以及微乳透皮动力学参数的测定选择三乙酸甘油酯为微乳体系的油相，吐温-80为体系的表面活性剂，二乙二醇单甲醚为助乳化剂，制备所得微乳呈淡黄色澄清透明液体，稀释后平均粒径，黏度以及粒子形态均符合微乳特征，结果表明塞来昔布微乳凝胶在抗炎效果上与市售凝胶有较好的一致性评价。

2、塞来昔布微乳凝胶家兔体内初步药代动力学研究

本文建立了塞来昔布在家兔血浆中含量测定的高效液相色谱法，实验表明检测方法专属性，回收率，准确度均符合要求。通过自制纳米乳凝胶与市售塞来昔布胶囊进行家兔体内初步药代动力学研究，结果显示，自制塞来昔布微乳凝胶相对于市售胶囊具有更好的生物利用度。

关键词：塞来昔布；微乳凝胶；响应面分析；透皮给药；药代动力学

ABSTRACT

Celecoxib, the specific Cox-2 inhibitors,first was developed form the Sears company in USA, and it was imported to the Chinese market in 2000. As a new generation of non-steroidal anti-inflammatory drugs (NSAIDs), it has effects in anti-inflammatory, analgesic and antipyretic. When the prostaglandin (PG) is generated, celecoxib is able to inhibit COX-2 cyclooxygenase selectively. Meanwhile the expression of COX-1 was not inhibited that is in accord with the protection of mucosa in gastrointestinal. Compared to the conventional non-steroidal anti-inflammatory drugs, celecoxib has lower gastrointestinal adverse reactions. However, long-term oral is easy to produce negative effects such as gastrointestinal toxicity, gastric ulcer bleeding. After oral administration celecoxib can not be completely wetted and dissolved in the gastrointestinal tube due to the low solubility. So we need further study in that drug.

Celecoxib is included to the ClassⅡin Biopharmaceutics Classification that respected to high penetration of low dissolved drugs. In our research we focus on the improvement of the water solubility of the drug using microemulsion technology. With its characteristic of high water partition coefficient preparation, we intend to the preparation of microemulsion-based organogels(MBGs) to enhance in vitro transdermal penetration and bioavailability of the drug. We did the research mainly on the following.

1. Preparation of celecoxib nanoemulsion and Establishment of the quality study of celecoxib microemulsion-based organogels

Celecoxib nanoemulsion is prepared by the method of low-energy emulsification. The composition of celecoxib nanoemulsion is determined through pseudoternary phase diagrams, solubility method and transdermal kinetic parameters. glycerol triacetate, Tween-80 and diethylene glycol monomethyl ether were used as oil phase, emulsifier and co-emulsifier,respectively. The celecoxib nanoemulsion we prepared is showed as the clea ryellowish and transparent liquid. The microemulsion characteristics are feasible such as average particle diameter of the system after diluted, viscosity, and particle morphology, which showed that effects are in good agreement with the commercial gels.

2. Pharmacokinetic studies in rabbits of celecoxib microemulsion-based organogels

HPLC method was developed for assay of celecoxib in plasma. The results showed that plasma endogenous material are non-interference to the content assay of celecoxib. The test-to-reference ratio for C_max and AUC_0–t demonstrates the better bioavailability of celecoxib microemulsion-based organogels compared to the commercial formulations.

Keywords: Celecoxib, microemulsion-based organogels, response surface analysis, transdermal release, pharmacokinetics

目 录

摘 要 I

ABSTRACT II

第一章 文献综述 1

1.1 塞来昔布的概述 1

1.1.1 塞来昔布简介 1

1.1.2 塞来昔布药理作用机制 2

1.1.3 塞来昔布药代动力学研究 2

1.2 立题依据及主要研究内容 3

1.2.1立题依据 3

1.2.2本课题研究内容 3

第二章 塞来昔布的制备及含量测定 5

2.1 实验材料 5

2.1.1 仪器 5

2.1.2 试药 5

2.2 实验部分 6

2.2.1 塞来昔布微乳凝胶制备 6

2.2.2含量测定 6

2.3 结果与讨论 7

2.3.1含量测定 7

2.4 本章小结 10

第三章 塞来昔布微乳凝胶的质量评价 12

3.1 实验材料 12

3.1.1 仪器 12

3.1.2 试药 12

3.2 实验部分 13

3.2.1塞来昔布微乳凝胶理化性质评价 13

3.2.2塞来昔布微乳凝胶生物学评价 14

3.3 结果与讨论 14

3.3.1塞来昔布微乳凝胶理化性质评价 14

3.3.2塞来昔布微乳凝胶生物学评价 17

3.4 本章小结 18

第四章 塞来昔布微乳凝胶剂家兔体内药代动力学研究 20

4.1 实验材料 20

4.1.1 仪器 20

4.1.2 试药 20

4.1.3 动物 21

4.2 实验方法 21

4.2.1 血浆药物浓度测定方法的建立 21

4.3 结果与讨论 23

4.3.1专属性试验 23

4.3.2标准曲线 24

4.3.3方法回收率与精密度 24

4.3.4提取回收率 25

4.3.5定量下限 25

4.3.6家兔体内药代动力学实验结果 26

4.4 本章小结 27

第五章 结论与展望 28

5.1 结论 28

5.2 展望 28

参考文献 29

致 谢 31

第一章 文献综述

1.1 塞来昔布的概述

1.1.1 塞来昔布简介

塞来昔布是环氧酶-2（COX-2）高选择性抑制剂，是第一个新一代COX-2抑制剂，能阻止炎性前列腺素类物质的产生，达到抗炎镇痛及退热作用^[1]；能有效治疗类风湿性关节炎和骨关节炎，强效缓解关节炎的疼痛和炎症^[2]；还可以预防多种恶性肿瘤，如前列腺癌、肠道癌及口腔恶性肿瘤等的发生^[3-5]。有研究表明与传统非甾体抗炎药相比，治疗量的塞来昔布对COX-1 几乎不抑制，使由于抑制COX 而引起的胃肠道不良反应的发生率显著下降^[6-8]。目前在市场上主要以塞来昔布胶囊为主，为了避免胃肠道的刺激问题和首过效应，增强药效，本实验设计了塞来昔布纳米微乳凝胶剂，并对塞来昔布微乳药代动力学做进一步研究

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