非模型依赖多变量置信区间法用于药品体外溶出评价的探讨

目的 在口服固体制剂仿制药体外溶出相似性评价研究中，针对批内溶出量相对标准偏差（RSD）较大、无法满足相似因子（f₂）法适用条件的情况，验证非模型依赖多变量置信区间法在溶出曲线相似性评价中的使用区别。方法 参考FDA和CFDA发布的《口服固体制剂溶出度试验技术指导原则》，使用两种不同的非模型依赖多变量置信区间法，即Bootstrap统计验证方法（BS）和Mahalanobis distance多变量分析法（MD）对模拟的参比制剂与仿制制剂溶出数据相似性进行评价。结果 利用BS法得出仿制批与参比批的f₂预期值（f₂^*）=59.965，大于50。MD法得到参比批次间多变量统计矩最大值是1.559 4，并将其确定为相似性限度，仿制批与参比批多变量置信区间90%上限为2.656 7，大于相似限度。结论 采用BS法评价体外溶出具备相似性，而采用MD评价方法则不具备相似性。因此，对于同一组数据，选用不同的评价方式可能会得出不同的结论。

Exploration on evaluation of model independent multivariate confidence region procedure used for drug dissolution in vitro

Objective In the study of evaluation of consistency for in vitro dissolution of oral solid dosage forms of generics, we verified the differences of non-model dependent multivariable confidence interval method for evaluating the similarity of dissolution profiles in the case of with significantly different in within-batch dissolution profile RSD which was unable to apply f₂ approach. Method According to Guidance for Industry:Immediate Release Solid Oral Dosage Forms (released by FDA and CFDA), we used two different model independent multivariate confidence region procedure, i.e. Bootstrap statistical verification method (BS) and Mahalanobis distance multivariable analysis method (MD), to evaluate the similarity of dissolution data of reference product and generic product. Results For BS, the f₂^* is 59.965, f₂^*>50. For MD, the maximum of inter-batch multivariable statistic moment of reference product is 1.559 4, indicated that the reference product and generic product had similar quality. However, the inter-batch 90% upper limits between reference drug and generic drug was 2.656 7, which was larger than similar limit. Conclusion It was showed that reference product and generic product were similar when BS method was used. In contrast, MD method indicated that they were different. Therefore, different evaluation methods may result in contrary conclusions for the same data.