盐酸替罗非班注射液质量一致性评价研究

发布时间：2018-07-08 16:02

本文选题：盐酸替罗非班 + 质量研究　；参考：《成都中医药大学》2014年硕士论文

【摘要】：盐酸替罗非班(Tirofiban Hydrochloride),化学名为N-正丁基磺酰基-0-[4-(4-哌啶基)丁基]-L-酪氨酸盐酸盐一水合物,是一种非肽类血小板表面糖蛋白GPⅡb/Ⅲa受体拮抗剂,临床常用于治疗急性冠状脉综合症,包括不稳定性心绞痛或非Q波心肌梗死患者,以及行径皮腔内冠状动脉成形术或动脉粥样斑块切除术的患者。本课题的主要目的是研制与市售品质量一致的盐酸替罗非班注射液。质量源于设计(Quality by Design, QbD),为了缩小自制盐酸替罗非班注射液与原研产品之间的差距,该课题对原料药的稳定性、注射液处方设计、注射液工艺路线的确定、自制产品的质量等进行了详细的考察,具体内容如下： 1、盐酸替罗非班注射液相关的基础研究盐酸替罗非班注射液相关的基础研究主要包括用于制剂的原料药与辅料的研究。原料药的研究主要包括强制降解试验以及影响因素试验,用于初步考察原料药的稳定性,结果发现其耐受性好,对热相对稳定。同时根据其质量属性对制剂进行风险评估,为制剂工艺研究提供依据；辅料的研究主要包括氯化钠、氢氧化钠以及活性炭的研究。 2、盐酸替罗非班注射液的工艺研究影响仿制药与原研产品质量的关键因素为制剂因素,因此本实验对盐酸替罗非班注射液的工艺进行了详细的研究,主要包括两个方面：(1)剂型的选择、规格、处方中主药与辅料的组成与用量；(2)配制过程中的各种关键工艺参数的考察,包括药液的PH范围,最佳配液温度,活性炭的用量,产品残氧量,灭菌条件及包材的相容性的考察。 3、盐酸替罗非班注射液的质量标准研究由于盐酸替罗非班注射液未收载于药典之中,因而只有查阅相关文献及标准对其质量进行评价。参考盐酸替罗非班氯化钠注射液注册试行标准(YBH12132004)和盐酸替罗非班注射液进口注册标准(JX20080265),本课题着重对其专属性检查项(有关物质、含量、异构体)的检查方法进行了优化与验证,最终确定的了有关物质的检查方法为以乙腈为流动相A,0.025mol/L KH2P04溶液(三乙胺调pH至6.8)-乙腈(80：20)为流动相B,进行如下梯度洗脱：T (min)/B(V/V)0/100,10/95,20/94,20/94,30/81,50/81,55／100；含量HPLC检测方法为以0.025mol/L KH2PO4溶液(三乙胺调pH至6.8)-乙腈(78：22)为流动相等度洗脱；异构体的检测方法为正己烷-异丙醇-甲醇-7二胺-冰醋酸(300：400：300：3：3)。对于其他的如pH值、不溶性微粒等均采用2010年版药典附录规定方法进行检测,未专门进行考察。 4、盐酸替罗非班注射液与原研产品的质量一致性研究为了考察自制酸替罗非班注射液与原研品(艾卡特)的区别,本实验做了以下几个方面考察：(1)比较中试产品与原研品在有关物质,pH,含量,外观性状等方面的差异(2)考察自制产品与肝素钠配伍试验,观察结果是否与市售品配伍试验结果描述一致(3)将中试产品与原研产品同置于影响因素试验、加速试验、长期试验条件下进行考察,比较二者有关物质,pH,含量,外观性状等方面的差异。
[Abstract]:Tirofiban (Tirofiban Hydrochloride), a chemical named N- n-butyl sulfonyl -0-[4- (4- piperidine) butyl]-L- tyrosine monohydrate, is a non peptide platelet surface glycoprotein GP II b/ III a receptor antagonist. It is commonly used in the treatment of acute coronary vein syndrome, including unstable angina or non Q wave myocardial infarction. Dead patients, and patients with percutaneous transluminal coronary angioplasty or atheromatectomy. The main purpose of this project is to develop Tirofiban Hydrochloride Injection that is in line with the quality of the market products. The quality is based on the design (Quality by Design, QbD), in order to narrow the gap between the homemade Tirofiban Hydrochloride Injection and the original product. In this subject, the stability of the API, the design of the injection prescription, the determination of the injection process route and the quality of the homemade products were investigated in detail. The specific contents are as follows:
1, the basic research related to Tirofiban Hydrochloride Injection
The basic research related to Tirofiban Hydrochloride Injection mainly includes the study of raw materials and excipients used for preparation. The research of the API mainly includes the forced degradation test and the influence factor test, which is used to investigate the stability of the API initially. The results show that the drug is well tolerated and the heat is relatively stable. Risk assessment is to provide basis for preparation process research; the study of excipients mainly includes sodium chloride, sodium hydroxide and activated carbon.
2, research on the process of Tirofiban Hydrochloride Injection
The key factors affecting the quality of generic drugs and original products are preparation factors. Therefore, this experiment has carried out a detailed study on the process of Tirofiban Hydrochloride Injection, including two aspects: (1) the selection of the dosage forms, the specifications, the composition and dosage of the main drugs and excipients in the prescription, and (2) the investigation of the key technological parameters in the preparation process, It includes the PH range of the liquid medicine, the optimum temperature of the solution, the amount of activated carbon, the oxygen content of the product, the sterilization condition and the compatibility of the package.
3, research on the quality standard of Tirofiban Hydrochloride Injection
Since Tirofiban Hydrochloride Injection has not been collected in the Pharmacopoeia, it has only consulted the relevant documents and standards to evaluate its quality. With reference to the Tirofiban hydrochloride Sodium Chloride Injection registration test standard (YBH12132004) and the Tirofiban Hydrochloride Injection import registration standard (JX20080265), this topic focuses on its specificity inspection items ( The inspection method of material, content and isomer was optimized and verified. The final determination method of the related substances was the liquid phase A with acetonitrile, 0.025mol/L KH2P04 solution (three ethylamine pH to 6.8) - acetonitrile (80:20) as the mobile phase B, and the following gradient elution was made: T (min) /B (V/V) 0/100,10/95,20/94,20/94,30/81,50/81,55 / 100 The content HPLC detection method is 0.025mol/L KH2PO4 solution (three ethylamine pH to 6.8) - acetonitrile (78:22) as the flow equality; isomer detection method is hexane - isopropanol - methanol, -7 two amine - glacial acetic acid (300:400:300:3:3). For other such as pH value, insoluble particles, and so on using the 2010 Edition of the Pharmacopoeia appendix The method was tested, and no special investigation was carried out.
4, quality consistency between Tirofiban Hydrochloride Injection and original research products
In order to investigate the difference between the self-made acid tirobiban injection and the original research product (Eckart), the experiment was studied in the following aspects: (1) to compare the differences between the pilot products and the original products in the related substances, pH, content, and appearance characters (2) to investigate the compatibility test of home-made products and hepatin sodium, and whether the observation results were compatible with the market products. The fruit description is consistent (3) the pilot products are placed in the influence factor test, the accelerated test and the long-term test conditions are carried out to compare the differences in the related substances, pH, content and appearance properties of the two parties.
【学位授予单位】：成都中医药大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R927.1

【参考文献】