基于来氟米特的溶解度、渗透性分析初步预测制剂的生物等效性

Preliminary Prediction of Bioequivalence of Leflunomide Tablets Based on Analysis of Solublility and Permeability

目的探讨来氟米特片溶出曲线差异是否导致体内生物不等效,考察API关键质量参数对生物利用度的影响。方法以赛诺菲(SANOFI)产品为参比制剂,以国内产品为受试制剂,采用马尔文Morphologi G3-ID颗粒表征系统考察制剂崩解液中API粒径分布;采用Pion μDiss药物溶解吸收测试系统,以pH 6.5的未添加牛胆磺酸钠与卵磷脂的模拟人餐前小肠内肠液(FaSSIF)溶液作为溶解介质,在37℃、转速为150 r·min^(-1)分别比较参比制剂、受试制剂及受试制剂活性成分API原料的溶解度与渗透曲线;从3个质量参数考察对药物释放与吸收过程的影响,比较参比制剂与受试制剂之间差异,预测受试制剂的生物利用度,进而预测制剂间是否生物等效。结果参比制剂的粒径Dv 50为17.60μm,受试制剂的粒径Dv 50为79.80μm;受试制剂API的溶解速率与渗透速率均低于参比制剂,约为参比制剂的70%,受试制剂与参比制剂t_(max)基本一致,但ρ_(max)与AUC_(0-t)均低于参比制剂,生物利用度低于参比制剂,约为参比制剂的90%。结论虽然受试制剂与参比制剂溶出曲线不一致,但初步预测其在体内生物等效。

OBJECTIVE To discuss whether the difference in dissolution profile in vitro may cause different bioavailability in vivo and investigate the effects of the key quality parameters of leflunomide on bioavailability.METHODS Using SANOFI product as the reference preparation and domestic product as the test preparation, the disintegration solution of leflunomide tablets was analyze by Morphologi G3-ID automated measurement to get the paricile size and size distribution of the API; using pH 6.5 FaSSIF solution without adding ox-gall sulfonic acid sodium and lecithin as the dissolution medium, the dissolution and permeation profiles of the reference and test preparations and raw material were compared at 37 ℃ with rotate speed of 150 r·min^-1. The influence of quality parameters on the process of API′s release and absorption was investigated, then the difference between the reference and test preparations were compared to preliminarily predict the bioavailability and bioequivalence.RESULTS The particle size Dv（50）of domestic leflunomide tablets was 79.80 μm, while the particle size Dv（50）of the reference product was 17.60 μm; the dissolution rate and penetration rate of the test preparation were about 70% of the the reference preparation, the tmax was basically identical,but the ρmax and AUC0-t were lower than the reference preparation. The bioavailability of the test preparation was about 90% of the reference preparation.CONCLUSION Though the dissolution profile of domestic leflunomide tablets is not identical to the reference preparation, but the two products were predicted to be bioequivalent.