已公布的卡马西平片参比制剂在体内外的相关性研究

In Vitro and in Vivo Correlation of Two Reference Listed Drugs for Carbamazepine Tablets Announced by NMPA

目的 以2家企业、2种规格的卡马西平片作为参比制剂进行体内外相关性研究,指导国内仿制药企业更好地开展仿制药一致性评价工作。方法 测定北京诺华和太阳药业(日本)生产的卡马西平片参比制剂在5种不同溶出介质中的溶出曲线,随后应用Gastro Plus软件建模、人工仿生膜结合Macro Flux^(TM)型药物溶出度与渗透速率测试系统进行体内外相关性研究,预测2家参比制剂的体内生物等效性。结果 2家企业的卡马西平片参比制剂在5种溶出介质中的溶出曲线均不相似,Gastro Plus软件虚拟生物等效性(BE)与溶出-渗透测定结果显示2家制剂在空腹和饱腹2种状态中均存在生物不等效风险。结论 本研究发现2家企业的卡马西平片参比制剂体外溶出不一致,软件建模预测及人工仿生膜技术预测其体内存在生物不等效的风险,对同时生产两种规格制剂的企业而言,可能导致同一企业不同规格的仿制药在一致性评价中存在生物不等效的风险,建议国家药监局确定唯一企业的参比制剂。本研究为卡马西平片参比制剂的选择提供了数据基础,也为窄治疗窗口药物参比制剂的遴选和确定提供参考,同时为仿制药一致性评价提供技术支撑。

OBJECTIVE To study the in vitro and in vivo correlation of reference listed drugs of carbamazepine tablets and better carry out generic drug consistency evaluation.METHODS The dissolution curves of reference listed drugs of carbamazepine tablets produced by Novartis(Beijing) and Sun Pharmaceutical(Japan) Co., Ltd. in five different dissolution media were determined. Then the in vivo and in vitro correlation study was carried out by using Gastro Plus software modeling, and a dissolution-permeation model based on PAMPA(parallel artificial membrane permeability assay) was established using Macro Flux^(TM) for In Vitro Absorption Test Equipment to predict the bioequivalence of the two reference listed drugs.RESULTS The dissolution curves of the reference listed drugs of carbamazepine tablets of the two companies in five dissolution media were not similar. The results of virtual bioequivalence by using GastroPlus software and dissolution-permeation test showed that the two reference listed drugs had the risk of bioequivalence in both fasted and fed conditions.CONCLUSION In this study, it is founded that the dissolution in vitro of the reference preparations of carbamazepine tablets of the two companies was inconsistent, meanwhile software modeling prediction and dissolution-permeation model predicted the risk of non-bioequivalence in vivo. For enterprises that produce two specifications of preparations at the same time, it may lead to the risk of inconsistent results of bioequivalence tests for different specifications in the consistency evaluation of generic drugs. It is suggested that National Medical Products Administration designate reference listed drugs from a single enterprise. This study not only provides a data basis for the selection of reference preparations of carbamazepine tablets, but also provides reference for the selection and determination of reference preparations of drugs with narrow therapeutic windows, and provides technical support for the consistency evaluation of generic drugs.