论文总字数：18055字

摘 要

盐酸厄洛替尼属于小分子酪氨酸激酶抑制剂，是4-氨苯基哇哩琳类的抗肿瘤药，可以直接作用于表皮生长因子受体(epidermal growth factor receptor EGFR)，可以阻断EGFR，切断了细胞内的酪氨酸激酶的磷酸化过程，进而达到抗肿瘤的作用^[1]。盐酸厄洛替尼由于其在水中溶解度不高（0.4mg/mL），这导致其口服生物利用度很低。因此，要想提高药物的口服生物利用度，就必须增强盐酸厄洛替尼的水溶性。本课题是研究了一种新型的具有水溶性的载体材料（PVP类、PEG类）和盐酸厄洛替尼制成固体分散体的药物^[2]，替代原药物。本文系统地研究了PEG6000与PVP对盐酸厄洛替尼的包蔽作用，具体内容有：理化性质、设置体外分析的方法、固体分散体制备及表征。

1. 理化性质的研究^[3]

根据盐酸厄洛替尼的理化性质，并参考相关文献，所选取的检测波长为247nm。分别在25°C和37°C的条件下，将盐酸厄洛替尼于水、甲醇、乙酸乙酯、乙腈、0.5%十二烷基硫酸酸钠（0.5%SLS）、0.1mol/mL盐酸溶液中在48h内保持稳定。检测盐酸厄洛替尼在高湿度、高温度、空气、强光照等条件下的稳定性。

1. 体外分析方法的建立

使用高效液相色谱法对于盐酸厄洛替尼的体外溶出度及制剂含量进行测定，此方法的各项指标均符合要求，该方法操作简便，且准确可靠。

关键词：厄洛替尼、非小细胞肺癌、表皮生长因子受体、固体分散体、靶向治疗

Erlotinib hydrochloride solid dispersion preparation

ABSTRACT

Erlotinib hydrochloride erlotinib is a small molecule tyrosine kinase inhibitor, belonging

to 4 - amino phenyl wow miles Lin a kind of antitumor drug, can direct role in epidermal growth factor receptor (EGFR) and through the inhibition of EGFR and cut off the intracellular tyrosine tyrosine kinase phosphorylation process, so as to achieve the role of anti tumor. Erlotinib hydrochloride due to its high solubility in water (0.4mg/mL), which leads to its oral bioavailabil-

-ity is very low. Therefore, in order to improve the oral bioavailability of drugs, we must enhance the erlotinib hydrochloride soluble. In this paper, we study a new water soluble carrier material (polyethylene glycol, poly dimensional ketones) and erlotinib hydrochloride imatinib made of solid dispersions of drugs, to replace the original drugs. The PEG6000 and PVP on erlotinib hydrochloride for Nepal package shielding effect, the specific content: physical and chemical properties, in vitro analysis method is established, the preparation and characterization of the system studied in the thesis.

1. the physical and chemical properties of the study

The effects of acid erlotinib for physicochemical properties, refer to the relevant literature and standard, 247nm is selected as the detection wavelength. At 25℃and 37℃ , hydrochloric acid erlotinib erlotinib in water, ethyl acetate, acetonitrile, 0.5% sodium dodecyl sulfate acid sodium 0.5%SLS, 0.1mol/mL hydrochloric acid solution within 48h remained stable. Erlotinib hydrochloride in high stability, high temperature, air humidity, under the condition of Intense light etc.

2.Establishment of in vitro analysis method

Using high performance liquid chromatography (HPLC) method for erlotinib hydrochlo-

-ride imatinib in vitro dissolution and drug content were determined, the indicators are in line

with the requirements, the method has the advantages of simple operation, accurate and reliable.

Keywords: erlotinib, non-small cell lung cancer, epidermal growth factor receptor, solid dispersion,targeted therapy

目录

摘 要 II

ABSTRACT II

第一章 文献综述 1

1.1 研究背景 1

1.2 盐酸厄洛替尼的概述 1

1.2.1盐酸厄洛替尼理化性质 1

1.2.2盐酸厄洛替尼药理作用机制 2

1.2.3药代动力学 2

1.3 固体分散体的研究进度 3

1.3.1固体分散体的应用 3

1.4固体分散体的制备方法 4

1.4.1熔融法 5

1.4.2溶剂法 5

1.4.3溶剂-熔融法 5

1.4.4机械分散法 6

1.4.5溶剂喷雾干燥法或冷冻干燥法 6

第二章 盐酸厄洛替尼理化性质研究 7

2.1 前言 7

2.2 实验部分 7

2.2.1实验材料与仪器 7

2.2.3溶液稳定性试验 9

2.2.4盐酸厄洛替尼原料药的性质检查 10

2.2.5盐酸厄洛替尼原料药的含量检查 10

2.3 结果与讨论 10

2.3.1检测波长的选取 10

2.3.2溶液稳定性试验 11

2.3.3盐酸厄洛替尼原料药的稳定性 12

2.3.4有关物质检查 12

2.4 本章小结 12

2.4.1检测波长的选择 12

2.4.2溶液稳定性试验 12

2.4.3盐酸厄洛替尼原料药的稳定性 13

第三章 盐酸厄洛替尼固体分散体的制备及表征 13

4.1 前言 13

4.2 实验部分 13

4.2.1实验材料与仪器 13

4.2.2固体分散体的制备 14

4.2.3 固体分散体的鉴定 15

4.2.4相溶解度曲线的研究 15

4.2.5溶解度测定 15

4.3 实验结果与讨论 16

4.3.1载药量的测定 16

4.3.2红外光谱分析 16

4.3.3差示扫描量热法分析 16

4.3.4 X-射线衍射法分析 16

4.3.5 相溶解度测定分析 16

4.3.6固体分散体增溶性分析 17

4.4 本章小结 17

4.4.1盐酸厄洛替尼固体分散体的制备 17

4.4.2固体分散体的表征 17

4.4.3相溶解度测定分析 17

4.4.4溶解度测定 18

第四章结论与展望 18

4.1结论 18

4.2展望 18

参考文献…………………………………………………………………………19

第一章 文献综述

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