劳拉西泮片的关键质量属性研究

Study on the critical quality attributes of Lorazepam tablets

目的对国产劳拉西泮片的关键质量属性进行分析,为该品种现行质量标准的完善以及质量风险控制提供依据。方法在了解国内劳拉西泮片整体质量状况的基础上,以问题为导向,围绕安全性和有效性,选择片剂的有关物质、溶出度等质控关键点开展研究。结果通过对原料杂质谱的分析,确认USP杂质C(Ch P杂质Ⅱ)为劳拉西泮最主要的降解杂质,同时确定了该杂质的来源;Ch P现行标准有关物质检查方法能够有效分离已知及未知杂质,且杂质的定量方法合理;斑马鱼胚胎发育毒性结果显示杂质C的神经毒性较劳拉西泮强;对现行标准溶出度检查法进行了优化;国产制剂与进口制剂在体外溶出特性方面存在一定差别。结论国产劳拉西泮片的整体质量状况良好,但与进口制剂间仍存在一定的差距,应提高生产工艺的稳定性。现行标准基本上能够实现对本品关键指标的控制,但溶出度检查项有待优化,以提高对不同质量产品的区分度。

Objective The critical quality attributes of domestic Lorazepam tablets were analyzed, in order to improve the current quality standard and provide direct ground for quality risk control. Methods On the basis of evaluating the whole quality status of domestic Lorazepam tablets, several exploratory researches were carried out using problem-oriented approach. It involved in the related substances and dissolution. Results By investigation of the impurity profile, Lorazepam related compound C was considered to be the critical impurity of Lorazepam, and the source and the degradation pathway were discussed. The current quality standard can effectively separate the known and the unknown impurities, and the quantitative methods for impurities were rational. Moreover, the effect of Lorazepam and its related compound B and C on cell proliferation has no significant difference, but the toxicity of Lorazepam related compound C on zebrafish embryos were strongest than that of Lorazepam and related compound B. The method of dissolution was optimized and it was found that there were some differences between domestic and imported preparations in dissolution characteristics in vitro. Conclusion The overall quality of domestic Lorazepam tablets was satisfied, but there was still the certain gap between domestic and imported preparations. The stability of production process should be improved, and it was suggested to optimize the dissolution test to improve the differentiation of different quality products.