| 李睿,周谡,朱鸿雁,张志超,方静,顾敏旸,季之雯,唐黎明.盐酸溴己新中杂质N-(2-硝基)-N-环己基-N-甲胺的遗传毒性评价[J].中国药事,2021,35(9):1024-1028 |
| 盐酸溴己新中杂质N-(2-硝基)-N-环己基-N-甲胺的遗传毒性评价 |
| Genotoxicity Evaluation of the Impurity N-(2-nitro)-N-cyclohexyl-Nmethylamine in Bromhexine Hydrochloride |
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| DOI：10.16153/j.1002-7777.2021.09.009 |
| 中文关键词: 盐酸溴己新 N-(2-硝基)-N-环己基-N-甲胺 (Q)SAR 遗传毒性杂质 Mini-Ames 试验 |
| 英文关键词: bromhexine hydrochloride N-(2-nitro)-N-cyclohexyl-N-methylamine (Q)SAR genotoxicity impurities mini-Ames |
| 基金项目: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) |
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| 中文摘要: |
| 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。 |
| 英文摘要: |
| 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. |
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