论文总字数：27847字

摘 要

格列吡嗪(glipizide)是一种亲脂性弱酸，也是第二代磺酰脲口服降糖药;口服吸收快速完全，无首过作用，体内作用机制是直接刺激胰岛素B细胞的分泌，增加内源性胰岛素释放水平从而降低血糖;临床疗效确切，常用于治疗Ⅱ型糖尿病。

格列吡嗪通常以片剂形式存在。片剂用作口服制剂中的常用剂型。其质量与原料、辅料、处方组成、粒径、颗粒硬度、工艺条件等因素有关。这些因素对于作为质量控制重要指标的溶出度也有着一定影响。因此，溶出度数据可反映片剂的质量;另一方面，溶度出也可以反映身体的吸收和药物功效。

本文主要研究内容如下：

1. 确定溶出度方法。

采用中国药典格列吡嗪片剂溶出度方法用于对参比制剂和待评价制剂进行初步的质量属性考察以及稳定性考察中加速、长期实验的溶出度检查。照溶出度测定法（中国药典2015年版通则0931第一法），溶出介质为500 mL的pH 7.4磷酸盐缓冲液，转速100 r/min，经30min取样，在222nm波长处测定吸光度，计算每片溶出量，限度为标示量的80%，应符合规定。方法学验证表明所建立的方法是可行可靠的、方法稳定且准确度高。

1. 格列吡嗪片的溶出曲线相似性评价方法的建立。

格列吡嗪属BCSⅡ类低溶解高渗透型药物，药物本身在人体内的吸收较好，而在体内的溶出才是影响药物吸收的关键因素，因此，此类药有可能建立较好的体内外相关性，为进一步研究仿制制剂与参比制剂的体外溶出行为是否相似，从而为提高BE试验的成功率提供依据，对溶出曲线进行了多介质、多方面的考察。建立了在四种介质（桨法，50 r/min，900 mL）：pH1.0盐酸溶液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液和水中考察溶出曲线的方法。分别采用ƒ₂相似因子法评价仿制制剂与参比制剂的体外溶出度差异。

1. 格列吡嗪片与原研产品的溶出曲线相似性考察。

通过已建立并验证的一系列溶出度方法，选择以美国辉瑞的同规格Glucotrol®为参比制剂，对海南赞邦制药公司委托的5mg规格格列吡嗪片与参比制剂进行全面的溶出曲线相似性考察。

关键词 格列吡嗪 溶出曲线 f₂相似因子 HPLC

Study on Dissolution Curve of Glipizide Tablets

ABSTRACT

Glipizide is a lipophilic weak acid, for the second generation of sulfonylurea oral hypoglycemic agents; oral absorption quickly and completely, and no first pass, the mechanism of action in vivo is to directly stimulate the secretion of insulin B cells , To promote the release of endogenous insulin and lower blood sugar; clinical efficacy is exact, commonly used in the treatment of type 2 diabetes.

Glipizide is often present as a tablet. The tablet is used as a common dosage form in oral preparation. Its quality is related to the factors such as raw material, excipient, prescription composition, particle size, particle hardness, process conditions and so on. Dissolution is also affected by the above factors as an important index of quality control. Dissolution data can reflect the quality of the tablet; the other hand, dissolution can also reflect the body's absorption and efficacy.

The main contents of this paper are as follows:

1. Establishment of dissolution method.

The dissolution method of glipizide tablets in Chinese Pharmacopoeia was used to investigate the quality properties of the reference preparation and the preparation to be evaluated as well as the stability test. According to the dissolution test method (Chinese Pharmacopoeia 2015 version of Incoterms 0931 first law), the dissolution medium was 500 mL pH 7.4 phosphate buffer solution, the speed of 100 r/min, the sampling time was 30min, determine the absorbance at the wavelength of 222nm, calculate each piece of dissolution, the limit is 80% of the labeled amount, the results should conform to the provisions. The method validation indicated that the method is feasible, reliable, stable and accurate.

2. The establishment of evaluation methods of dissolution curves’ similarity.

Glipizide belongs to BCS II, namely, low solubility but high permeability. As its good absorption in human body, the dissolution in vivo is the key factors affecting the drug absorption, therefore, this kind of medicine is likely to establish a good correlation between in vitro and in vivo. In order to evaluate whether the dissolution behavior of the generic preparation is similar to reference preparation so as to improve the success rate of BE test, the dissolution curves was studied in different mediums and aspects. We have established methods in four different mediums (paddle method, 50 r/min, 900 mL): the dissolution curves of pH1.0 hydrochloric acid solution, pH4.5 acetate buffer, pH6.8 phosphate buffer and water. In this paper, we used ƒ₂ similarity factor to evaluate the difference of dissolution between generic preparation and reference preparation.

3. Study on Similarity of Dissolution Curve of Glipizide Tablets and Original Research Products.

A series of dissolution methods were established and verified by using the same specification Glucotrol® as the reference preparation. The complete elution curve of 5 mg of glipizide tablets and reference preparation was carried out by Hainan Zambo Pharmaceutical Co., Ltd. Similarity investigation.

Key words: Glipizide ;Dissolution curve; f2 similarity factor;HPLC

目录

摘要 I

ABSTRACT I

第一章 绪论 1

1.1 研究背景 1

1.2 研究目的 1

1.3 研究意义 1

1.4 研究内容及思路 3

1.4.1 研究内容 3

1.4.2 研究方法 3

第二章 格列吡嗪片质量标准的研究 4

2.1 引言 4

2.2 仪器与试药 4

2.2.1 实验仪器 4

2.2.2 试药 4

2.2.3 实验试剂 5

2.3 含量测定方法研究 5

2.3.1 方法来源及筛选 5

2.3.2 方法的确立及优化 6

2.3.3 方法学考察与结果 8

2.4 溶出度测定方法研究 13

2.4.1 方法来源及筛选 13

2.4.2 方法的确立及优化 13

2.5 本章小结 14

第三章 溶出曲线研究方法 15

3.1 引言 15

3.2 多种介质中的溶出曲线研究 15

3.2.1 方法来源及筛选 15

3.2.2 溶出曲线测定条件的选择 16

3.2.3 溶出度方法学验证 18

3.3 本章小结 23

第四章 溶出曲线相似性评价 24

4.1 多种介质中的溶出曲线 24

4.2 半片溶出曲线研究 26

参考文献 29

致谢 30

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