【作者】 施悦；

【导师】 戚雪勇；

【作者基本信息】 江苏大学 ， 制药工程（专业学位）， 2022， 硕士

【摘要】 类风湿性关节炎作为自身免疫性疾病的一种,患病人数全球人数众多,致死率高,被列为全球致残危害疾病之一。因此类风湿性关节炎的药物研究非常重要。在传统治疗药物的基础上,Janus kinase(JAK激酶)抑制剂开始用于治疗自身免疫性疾病。枸橼酸托法替布片于2017年在我国批准上市,用于治疗类风湿性关节炎。相较于传统的治疗药物,枸橼酸托法替布片的最大优点是不良反应程度更低。此药具有良好的市场前景。《中国药典》暂未收载本品种,本文对枸橼酸托法替布片进行了多方面的质量研究。论文第一部分对枸橼酸托法替布进行了介绍。包括枸橼酸托法替布的分子结构、理化性质和临床应用情况,为后续研究提供基础。论文第二部分建立了枸橼酸托法替布片的HPLC含量测定方法,研究了枸橼酸托法替布的色谱行为,并对含量测定方法进行了方法学验证。验证内容包括系统适用性、专属性(强制降解试验)、精密度(重复性和中间精密度)、准确度、溶液稳定性和方法耐用性。论文第三部分建立了枸橼酸托法替布片的微生物限度检查方法,对检查方法进行了适用性预试验和完整验证。确定了用平皿法进行需氧菌、霉菌和酵母菌总数的计数,用常规法对控制菌大肠埃希菌进行计数。并对三批枸橼酸托法替布片样品进行了微生物限度的检查,结果均未检出。论文第四部分根据枸橼酸托法替布片的处方工艺以及口服给药途径的特点,确定了本文对分类1和分类2A类元素杂质(即砷(As)、镉(Cd)、汞(Hg)、铅(Pb)、钴(Co)、镍(Ni)、钒(V)这七种元素杂质)进行研究和质量评估,建立了ICP-MS的方法并进行了方法学验证。同时对三批枸橼酸托法替布片进行了金属元素检测,结果均未检出。论文第五部分建立了枸橼酸托法替布原料药中8种金属元素(即砷(As)、镉(Cd)、汞(Hg)、铅(Pb)、钴(Co)、镍(Ni)、钒(V)、钯(Pd))的方法,并进行方法学的验证,验证结果均符合标准。钯常常作为脱氢反应的催化剂用于枸橼酸托法替布原料药的合成中。钯颗粒非常细小,在药物精制中难于清除彻底,会导致依然有少量钯残留于药物中,对枸橼酸托法替布的质量产生重大的影响。故本文对枸橼酸托法替布原料药增加了钯的元素检查研究,同时对七批供试品进行检测,结果均低于各元素的限度要求。更多还原

【Abstract】 As a kind of autoimmune diseases,rheumatoid arthritis has a large number of patients all over the world and has a high fatality rate.It is listed as one of the crippling diseases in the world.Therefore,drug research for rheumatoid arthritis is very important.Janus kinase(JAK)inhibitors have been used to treat autoimmune diseases based on the traditional treatment drugs.Tofacitinib Citrate tablets have been approved for the treatment of rheumatoid arthritis in China from 2017.Compared with traditional treatment drugs,the biggest advantage of Tofacitinib Citrate is that the degree of adverse reactions is lower.This medicine has a good market prospect.Tofacitinib Citrate tablets have not been regulated in The Chinese Pharmacopoeia,so we studied the various quality research of Tofacitinib Citrate tablets.In the first part,we introduced the information of Tofacitinib Citrate to providing a basis for follow-up research,including the molecular structure,physicochemical properties and clinical application of Tofacitinib Citrate.In the second part,we established the HPLC method for the determination of Tofacitinib Citrate,studied the chromatographic behavior and we also verified the method for the determination of the content.The verification content included system suitability,specificity,precision(repeatability and intermediate precision),accuracy,solution stability and method ruggedness.In the third part,the microorganism limited inspecting method of Tofacitinib Citrate was established,and the applicability of the inspection method was pre-tested and fully verified.Determined to use the plate method to count the total number of aerobic bacteria,moulds and yeasts,and use the conventional method to count the control bacteria Escherichia coli.Three batches of Tofacitinib Citrate tablets were tested for microbial limits,and none of them were detected.In the fourth part,according to the prescription technology of Tofacitinib Citrate tablets and the characteristics of oral route of administration,we established and verified an ICP-MS method to determine seven element impurities in the classification 1 and 2A element impurities,including arsenic(As),cadmium(Cd),tribute(Hg),lead(Pb),cobalt(Co),nickel(Ni),vanadium(V).At the same time,three batches of Tofacitinib Citrate tablets were tested for seven elements,and all were not detected.In the fifth part,the method for determining the content of 8 metal elements in Tofacitinib Citrate API was established,including arsenic(As),cadmium(Cd),tribute(Hg),lead(Pb),cobalt(Co),nickel(Ni),vanadium(V),palladium(Pd),and the method was verified.The verification results meet the standards.Palladium is often used as a catalyst for dehydrogenation reaction in the synthesis of Tofatinib Citrate API.Palladium particles are very small and difficult to remove completely in drug refining,which will lead to a small amount of palladium remaining in the drug.That will have a significant impact on the quality of Tofatinib Citrate.Therefore,in this paper,palladium was added to the API of Tofatinib Citrate.At the same time,seven batches of Tofatinib Citrate API were tested,all of which were below the limit requirements of each elements.更多还原