阿齐沙坦有关物质遗传毒性评估及限度研究

Genotoxicity Assessment and Limit Study of Azilsartan Related Compounds

关键词:  阿齐沙坦  遗传毒性  有关物质  质量标准

Key words:  azilsartan  genotoxicity  related compounds  quality standard

摘要:

目的 分析阿齐沙坦的合成工艺路线,确定起始原料、中间体、副反应产物等有关物质信息,研究有关物质的致突变性,确定有关物质的限度,为质量标准的建立提供依据。方法 检索相关数据库确定有关物质遗传毒性数据,采用2种定量构效关系软件预测杂质的致突变性,根据ICH M7指导原则,对有关物质进行遗传毒性归类,结合相关指导原则制定有关物质限度。结果 筛选出的18个有关物质中,有11个无遗传毒性,可按非遗传毒性杂质进行控制,有7个化合物致突变性预测结果为阳性,需要按遗传毒性杂质进行控制。结论 为保障用药安全,终产品中总杂质的量不得>0.5%,致突变性预测结果为阳性的有关物质单杂最高限度不得>0.001 875%,其他有关物质单杂最高限度不得>0.1%。

Abstract:

OBJECTIVE To analyze the synthetic route of azirsartan, determine the information of starting materials, intermediates, side reaction products and other related compounds, study the mutagenicity of related compounds, determine the limit of related compounds, and provide basis for the establishment of quality standards. METHODS The genotoxicity data of related compounds were determined by searching related databases, and the mutagenicity of impurities was predicted by using two kinds of quantitative structure-activity relationship software. The genotoxicity of related compounds was classified according to ICH M7 guidelines, and the limits of related compounds were determined according to relevant guidelines. RESULTS Among the 18 compounds screened, 11 were non-genotoxic and could be controlled as non-genotoxic impurities, while 7 compounds showed positive mutagenicity prediction results and needed to be controlled as genotoxic impurities. CONCLUSION In order to ensure the safety of drug use, the total impurities in the final product should not >0.5%, the maximum limit of single impurity should not >0.001 875% for related compounds with positive mutagenicity prediction results, and the maximum limit of single impurity for other related compounds should not >0.1%.