基于体外溶出的格列美脲片人体生物等效性预测研究

Study on the prediction of bioequivalence of glimepiride tablets in human based on its dissolution in vitro

目的开发与格列美脲片体内溶出行为相关的体外溶出方法,并预测两种片剂的人体生物等效性。方法采用GastroPlusTM软件建立格列美脲片人体药代动力学(PK)模型;基于模型预测原研片剂在人体中的溶出行为;以预测结果指导体外溶出方法开发;通过虚拟生物等效性试验,利用体外溶出数据预测B、C两种格列美脲片的人体生物等效性(BE)结果;利用比格犬BE进行佐证。结果模型的准确性与可靠性良好;原研片剂在人体胃肠道中呈线性溶出,于2 h时溶出完全;流通池开环模式(pH 7.0缓冲液,14 mL·min-1)可基本模拟格列美脲片在人体中的溶出行为;经虚拟生物等效性试验,预测B与原研片剂生物等效,而C与其不等效;比格犬BE试验结果与人体虚拟BE结果一致。结论基于体外溶出数据,预测格列美脲片人体生物等效性的方法具有一定可行性。

Objective To develop in vivo-correlated in vitro dissolution method for glimepiride tablets, and predict the bioequivalence of two glimepiride tablets in human. Methods Glimepiride tablet PK model in human was built using GastroPlusTM software. The in vivo dissolution behaviors of reference tablets were predicted based on the model. The model prediction results were used to guide in vitro dissolution development. The bioequivalence of two glimepiride tablets(B and C) in human was predicted using in vitro dissolution data by virtual bioequivalence trials. Bioequivalence trials of two glimepiride tablets(B and C) in Beagle dogs were conducted to provide proof for human prediction results. Results The accuracy and applicability of the model were good. Glimepiride reference tablets were predicted to dissolve linearly in human gastrointestinal tract, and dissolve completely in 2 hours. Flow-through cell method in open-loop mode(pH 7.0 buffer at the flow rate of 14 mL·min-1) could generally simulate in vivo dissolution in human for glimepiride tablets. After virtual bioequivalence trials, B was predicted to be bioequivalent to reference in human, while C was bioinequivalent to reference. Bioequivalence results in Beagle dogs were consistent with prediction results in human. Conclusion The method of predicting bioequivalence of glimepiride tablets in human based on in vitro dissolution data is feasible.