摘要
目的:评价盐酸溴己新国抽杂质的遗传毒性,为其制定合理限值提供毒理学依据。方法:按照《中国药典》和ICH M7指导原则的要求,采用基于专家知识规则Derek和基于统计学的Sarah的(Q)SAR软件对杂质N-(2-硝基)-N-环己基-N-甲胺进行分类,采用Mini-Ames试验进一步验证预测结果并进一步对杂质进行准确分类,制定合理限度。结果:通过(Q)SAR评估,N-(2-硝基)-N-环己基-N-甲胺为3类杂质;Mini-Ames试验结果显示N-(2-硝基)-N-环己基-N-甲胺在无和有活化系统条件下,各剂量组菌落数均未增加,Mini-Ames试验为致突变阴性。结论:N-(2-硝基)-N-环己基-N-甲胺没有遗传毒性,可按普通杂质制定限值。
Objective: To evaluate the genotoxicity of an impurity in bromhexine hydrochloride and provide a toxicological basis for the establishment of reasonable limits. Methods: The impurity N-(2-nitro)-N-cyclohexylN-methylamine was classified using Derek(expertise-based) and Sarah’s(statistics-based) quantitative structureactivity relationship((Q)SAR) method according to the requirements of the Chinese Pharmacopoeia and the ICH M7 guidelines. The prediction results were verified by mini-Ames test, and the classification and a reasonable limit of the impurity were subsequently accurately determined. Results: N-(2-nitro)-N-cyclohexyl-N-methylamine was classified as Class 3 impurities according to(Q)SAR prediction. The result of the Mini-Ames test showed that N-(2-nitro)-N-cyclohexyl-N-methylamine did not increase the number of revertants in each group with or without the activation system, and the results of the mini-Ames test were negative. Conclusion: N-(2-nitro)-N-cyclohexylN-methylamine was non-genotoxicitic and its limit could be defined as common impurities.
作者
李睿
周谡
朱鸿雁
张志超
方静
顾敏旸
季之雯
唐黎明
Li Rui;Zhou Su;Zhu Hongyan;Zhang Zhichao;Fang Jing;Gu Minyang;Ji Zhiwen;Tang Liming(Shanghai Institute for Food and Drug Control,Shanghai 201203,China)
出处
《中国药事》
CAS
2021年第9期1024-1028,共5页
Chinese Pharmaceutical Affairs
基金
国家药典委员会课题(遗传杂质风险评估关键技术研究)(编号452)。
