摘要
目的:对左羟丙哌嗪和羟苯磺酸钙的已知杂质进行遗传毒性评价,并对现行标准杂质限度的合理性进行评价。方法:按照ICH M7指导原则的要求,采用基于专家知识规则的Derek和基于统计学的Sarah两类(Q)SAR评价系统,对左羟丙哌嗪的3个杂质右羟丙哌嗪、苯基哌嗪、缩水甘油,羟苯磺酸钙及其杂质I(氢醌)进行评价和分类。对于确定为遗传毒性杂质的,根据药物临床用量计算杂质的暴露量,并按照遗传毒性杂质相关指导原则的要求,对其标准限度进行评估。结果:右羟丙哌嗪、苯基哌嗪预测结果为阴性,缩水甘油和氢醌预测结果为阳性,且分类为1类。缩水甘油的标准限度低于可接受安全剂量。氢醌的标准限度过高,存在安全隐患。结论:缩水甘油和氢醌为1类遗传毒性杂质,缩水甘油的标准限度合理,氢醌的标准限度应该进一步严格。
Objective：To assess the genotoxicity of impurities in levodropropizine and calcium dobesilate,and to evaluate the limits of these impurities.Methods：According to ICH M7 guidelines,two（Q）SAR prediction methodologies were applied（expert rule-based Derek and statistical-based Sarah）to assess and classify three impurities in levodropropizine（dextrodropropzine,1-phenylpiperazine and glycidol）,calcium dobesilate and its impurity I（hydroquinone）.If any impurity was characterized as genotoxic,the potential exposure was calculated based on the dosage.Then the limit of a genotoxic impurity was evaluated according to guidelines of genotoxic impurities.Results：（Q）SAR evaluation showed that dextrodropropzine and 1-phenylpiperazine were non-mutagenic while glycidol and hydroquinone were positive,both of which were classified as class 1.The limit of glycidol was less than the acceptable intake,while the limit of hydroquinone was too high to ensure the safety of the drug.Conclusion：Glycidol and hydroquinone were class 1 genotoxic impurities.The limit of glycidol in levodropropizine was appropriate.The limit of hydroquinone in calcium dobesilat should be reduced.
出处
《药物分析杂志》
CAS
CSCD
北大核心
2018年第2期354-358,共5页
Chinese Journal of Pharmaceutical Analysis
基金
重大新药创制科技重大专项(2009ZX09313023)
国家药典会2015年
2016年药品标准提高项目
关键词
(定量)构效评价
缩水甘油
氢醌
杂质
遗传毒性杂质
毒理学关注阈值
风险评估
（ quantitative ） structure-actiVity relationships [ （ Q ） SAR ]
glycidol
hydroquinone
impurity
genotoxic impurity
threshold of toxicological concern （~C）
risk assessment
