硝苯地平缓释片体内外相关性模型的建立与评估

Develop and Evaluate the in vitro-in vivo Correlation Model of Nifedipine Extendedrelease Tablets

目的建立和评价硝苯地平缓释片体内外相关性(IVIVC)的模型。方法筛选不同处方片剂的体外释放条件,采用高效液相色谱(HPLC)法测定其累积释放百分率(Fd);液相色谱串联-质谱(LC-MS/MS)法测定健康志愿者单剂量口服两种不同释放速率的硝苯地平缓释片后的血药浓度,利用Wagner-Nelson方程计算累积吸收百分率(Fa)。结果两种制剂体外释放与体内累积吸收相关性均良好,用与硝苯地平控释片生物等效的制剂,创建IVIVC模型:Fa=0.831 4 Fd+0.005 2,r=0.980 8(P<0.01);用另一种制剂对其模型进行外部预测能力的评估:AUC0～24和Cmax的预测误差分别为3.2%,3.5%。结论 IVIVC模型具有良好的预测硝苯地平缓释片体内吸收的能力,为硝苯地平缓释片质量标准制订提供依据。

Objective To develop and evaluate the in vitro-in vivo correlation model（IVIVC） of nifedipine extended- release tablets. Methods A release condition that distinguished different formulations was screened and the accumulated release rate （Fd） of nifedipine extended-release tablets was determined by HPLC. The plasma drug level of healthy volunteers after single oral dose of nifedipine extended-release tablets with different release rates were determined by LC-MS/MS. The accumulated absorption percentage （Fa） was calculated by the equation of Wagner-Nelson. Results Our study showed that good correlation appeared between in vitro release and in vivo absorption of the two formulations. The formulation which was bioequivalent to Adalat GITS was used to create a IVIVC model： Fa = 0. 831 4 Fd＋0. 005 2, r=0. 980 8, P=0. 0006 （P〈 0.01 ）. Another formulation was used to estimate the prediction error externally of the model, and the prediction error was： PE% （ AUC0-24 ） = 3.2%, PE% （ Cmax ） = 3.5%. Conclusion The IVIVC model can well forecast the characteristics of the in vivo absorption of nifedipine extended-release tablets effectively, which provides the basis for making product quality standards.