论文总字数：18942字

摘 要

目前我国的制药行业基本都是以仿制药物为主。我国通过引进原研药，制造出与原研药在药物结构、活性成分、药效、给药途径等方面等效的仿制药，但是仿制药中药物的含量标准与原研药不同，因此我们需要通过药物的一致性评价，不断加快变革创新升级，从而提高中国药品生产水平。细菌内毒素是热原的一种，药品内的内毒素含量超过一定剂量以后，就会对人体有危害。因此加强药物中的内毒素检测也是我国制药行业面临的重要问题。在胞磷胆碱钠原料药一致性评价中，日本药典中的胞磷胆碱钠原料药中并没有关于内毒素检测热原的项目和指标，但是中国药典中有这样的要求。在本课题中，我们需要对日本药品的样品进行检验，然后与中国药品样品进行对照比较。

《中国药典》2015版中规定，我们可以使用凝胶法来进行细菌内毒素检查。经过查阅一些相关的文献资料可以发现：鲎试剂法简单易操作，灵敏度高，抗干扰能力强并且鲎试剂与内毒素会产生凝胶反应。基于这个原理，通过对鲎试剂灵敏度的测试、干扰实验、细菌内毒素的检查和凝胶半定量的实验我们可以来对内毒素进行检测。

实验结果表明：虽然在日本药典中的胞磷胆碱钠原料药中并无内毒素检测热原项目和指标，但是通过对日本药品样品进行检验，然后与中国药品样品进行对照比较以后，我们就会发现：日本药品样品中的内毒素含量（0.25 EU/ml）是符合中国药典中规定的胞磷胆碱钠的限值（0.30 EU/ml）的，而且结果也表明了中国的仿制药水平也已经趋于成熟。

关键词：胞磷胆碱钠 鲎试剂法 热原 内毒素 一致性评价

Study on the consistency assessment of citicoline sodium pyrogen

Abstract

At present, the pharmaceutical industry in China is basically based on generic drugs. In China, through the introduction of original research medicines, we have created generic drugs that are equivalent to the original drugs in terms of drug structure, active ingredients, drug efficacy, and route of administration. However, the standard content of drugs in generic drugs is different from that of the original drugs, so we need to pass drugs. The consistency evaluation will continue to accelerate the reform, innovation and upgrading, so as to increase the level of pharmaceutical production in China. Bacterial endotoxin is a kind of pyrogen. After the endotoxin content in the medicine exceeds a certain dose, it will be harmful to the human body. Therefore, strengthening endotoxin testing in drugs is an important issue facing the pharmaceutical industry in China. In the evaluation of the consistency of citicoline sodium drug substances, there are no items and indicators for the detection of pyrogens in citicoline sodium raw materials in the Japanese Pharmacopoeia, but there are such requirements in the Chinese Pharmacopoeia. In this topic, we need to test samples of Japanese medicines and compare them with Chinese medicine samples.

According to the 2015 edition of the Chinese Pharmacopoeia, we can use the gel method for bacterial endotoxin testing. After reviewing some relevant literature data, it can be found that the limulus reagent method is simple and easy to operate, with high sensitivity, strong anti-interference ability, and a gel reaction between the limulus reagent and endotoxin. Based on this principle, we can detect endotoxins by testing the sensitivity of limulus reagents, interference experiments, bacterial endotoxin tests, and semi-quantitative gel experiments.

The comprehensive results show that although there are no endotoxin detection pyrogens items and indicators in the CMP raw material of the Japanese Pharmacopoeia, after comparing the Japanese medicine samples with Chinese medicine samples, we It will be found that the endotoxin content (0.25 EU/mll) in Japanese pharmaceutical samples is in line with the limit of citicoline sodium (0.30 EU/ml) specified in the Chinese Pharmacopoeia, and the results also indicate the level of generic drugs in China. It has also matured.

Key words: Cticoline sodium ; Helium reagent method ; Pyrogen ; Endotoxin ; Consistency assessment

目 录

摘要 Ⅰ

Abstract Ⅱ

第一章 文献综述 1

1.1胞磷胆碱钠原料药 1

1.1.1胞磷胆碱钠的简介 1

1.1.2胞磷胆碱钠的药理作用 1

1.2 热原 1

1.2.1 热原的定义 1

1.2.2热原的检测方法 2

1.3鲎实验法 2

1.3.1鲎实验法的简介以及背景 2

1.3.2鲎试剂法之凝胶法 3

1.4本课题研究的目的及内容 3

1.4.1本课题研究的目的 4

1.4.2本课题研究的内容 4

第二章 实验方法 6

2.1. 实验材料 6

2.1.3实验前准备 7

2.2.鲎试剂灵敏度的测试 7

2.2.1实验目的 7

2.2.2 实验材料和仪器 7

2.2.3 实验方法 7

2.2.4结果判断 8

2.2.5实验结果计算 9

2.3干扰实验 9

2.3.1 实验目的 9

2.3.2实验试剂和仪器 9

2.3.3实验方法 9

2.3.4实验结果计算 13

2.4细菌内毒素的检测 14

2.4.1实验目的  14

2.4.2实验试剂及仪器 14

2.4.3实验方法 14

2.5凝胶半定量实验 15

2.5.1实验目的 15

2.5.2实验材料和试剂 15

2.5.3实验方法 15

第三章 实验结果与分析 18

3.1鲎试剂灵敏度的测试的结果 18

3.2干扰实验的结果 18

3.3细菌内毒素检查的结果 21

3.4凝胶半定量实验的结果 22

第四章 结论与展望 23

4.1论文结论 23

4.2展望 23

参考文献 24

致谢 26

第一章 文献综述

1.1胞磷胆碱钠原料药

1.1.1胞磷胆碱钠的简介

图1-1 胞磷胆碱钠的结构式

胞磷胆碱钠（Citicoline sodium)为核苷酸衍生物，白色结晶性粉末，可以由磷酸胆碱生物和5'-CMP酶法合成制得^[1]。如图1-2所示：

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