论文总字数：19101字

摘 要

醋酸奥曲肽（octreotide acetate）是一种八肽的生长抑素类似物（somotostatin analogue，SSA），在药学和医学领域上有很多应用。然而奥曲肽在人体内半衰期短，在人体内只有1-2h，因此制备成具有缓释效果的微球制剂可以使其用药范围更加广泛简易。理想的PLGA微球制剂应具有合理的高药物包封率、高载药量和药物缓释性。增加药物的载药量，最小化初始释放量，减小甚至是避免微球的高突释是非常有必要的。

本研究通过提高内水相中醋酸奥曲肽药物浓度（2.5g/ml）来提高微球的载药量并有效控制微球突释。实验结果证明，高内水相药物浓度使得内水相的粘度达到一个较高的值，阻碍了醋酸奥曲肽的扩散，因此微球的突释得到了很好的控制（9.36%）。此外还考察了高内水相微球相对于普通微球在体外释放和体内释放的释放曲线。结果显示：高内水相微球在体外释放过程中，突释现象小，释放量稳定且28天可以达到百分之八十；体内释放第一天血药浓度仅有50pg/μl，并且在28天的释放中内水相高的微球可以维持一个更高更稳定的血药浓度。

实验验证增加内水相醋酸奥曲肽浓度制得高内水相粘度的微球，可以得到突释更小缓释效果更好的醋酸奥曲肽PLGA微球。

关键字： 醋酸奥曲肽 突释 生长抑素类似物 PLGA微球

Preparation of low burst - release octreotide acetate sustained - release microspheres

ABSTRACT

The acetic acid peptide (octreotide acetate) is one of the eight peptide somatostatin analogues (somotostatin analogue, SSA), has many applications in the fields of pharmacy and medicine. However, octreotide has a short half-life in human body and only lasts for 1.5-2h in human body. Therefore, the preparation of microspheres with sustained release effect can make the drug range more extensive and simple.High drug encapsulation efficiency over the PLGA microsphere preparation should have a reasonably high drug loading and drug release properties. It is necessary to increase the drug load, minimize the initial release, and reduce or even avoid the high sudden release of microspheres.

In this study, the drug loading of microspheres was increased and the microspheres were effectively controlled by increasing the concentration of octreotide acetate (2.5 g/ml) in the aqueous phase. The experimental results show that the concentration of the high internal aqueous phase makes the viscosity of the internal aqueous phase reach a higher value, which hinders the diffusion of octreotide acetate, so the burst release of the microspheres is well controlled (9.36%). Also investigated the release profile of the microspheres aqueous phase with respect to the normal high release microspheres in vitro and in vivo release. The results showed that during the in vitro release of high internal aqueous microspheres, the burst release phenomenon was small, and the release amount reached 80%; the blood concentration on the first day of in vivo release was only 50pg/μl, and in the 28-day release. Microspheres with a high internal phase can maintain a higher and more stable blood concentration.

Experiments have shown that increasing the concentration of octothelin in the aqueous phase to obtain the microspheres with high internal phase viscosity can obtain octreotide acetate PLGA microspheres with better burst release and better sustained release.

Key words: octreotide acetate initial burst somotostatin analogue

PLGA microsphere

目录

摘要 Ⅰ

ABSTRACT Ⅱ

第一章 绪论 1

1.1醋酸奥曲肽 1

1.1.1生长激素抑制因子其类似物 1

1.1.2 醋酸奥曲肽概述 1

1.2醋酸奥曲肽微球缓释剂应用 2

1.3 PLGA微球缓控释制剂的制备工艺 2

1.3.1 微球研究现状 2

1.3.2 PLGA简介及优点 3

1.3.3 微球制备方法 4

1.3.4制备工艺和原料药性质对微球特性的影响 6

1.3.5 控制药物释放 7

1.4本论文研究思路 8

第二章 实验内容和方法 9

2.1试验材料 9

2.2试验仪器 9

2.3微球制备 10

2.3.1内水相配置 10

2.3.2中油相配置 10

2.3.3外水相配置 11

2.3.4磷酸缓冲溶液（PBS）制备 11

2.3.5初乳的制备 11

2.3.6复乳的制备，微球的洗涤和收集 11

2.3.7冻干 12

2.3.8微球的保存 13

2.4微球特性考察 13

2.4.1微球表征 13

2.4.2 体外突释情况考察 14

2.4.3微球体外释放实验 15

2.4.4微球体内释放 15

第三章 实验结果与讨论 16

3.1微球表征 16

3.1.1微球电镜扫描图 16

3.1.2 微球粒径测量结果 17

3.1.3微球有机溶剂残余量，粘度和载药量结果 19

3.2微球突释 20

3.3体外释放试验考察结果 21

3.4体内释放试验结果与讨论 21

第四章 实验结论与展望 23

参考文献 24

致谢 27

第一章 绪论

1.1醋酸奥曲肽

1.1.1生长激素抑制因子其类似物

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