目的:研究华法林钠的生物药剂学特征, 利用计算机模拟技术研究药物体外溶出与体内吸收的相关性, 比较研究华法林钠片仿制制剂与参比制剂（reference listed drug, RLD）的溶出行为。方法:通过测定华法林钠在不同pH介质中的溶解性与平行人工膜渗透性模型（the parallel artificial membrane permeability assay, PAMPA）渗透性, 分析研究了药物的生物药剂学特征; 绘制药物制剂在多种介质中的溶出曲线, 比较研究华法林钠片仿制药与RLD的溶出行为一致性; 基于RLD的溶出曲线数据, 利用计算机技术模拟研究华法林钠片体外溶出与体内吸收的相关性。结果:华法林钠的溶解性随pH的升高而增大; 渗透性随pH的升高而降低, 华法林钠的生物药剂学分类为BCSⅡ类, 即低溶解度, 高渗透性药物。仿制制剂A 的溶出行为与RLD相似度较高, 仿制制剂B与RLD不相似。华法林钠片在pH 6.8的介质中的体外溶出与体内吸收之间显示出较高的相关性。结论:华法林钠片在pH 1.2、pH 4.5与pH 6.8介质中的溶出曲线可作为特征溶出曲线。本研究结果可以为药物制剂处方筛选与生物药剂学分类判定提供新的研究方法和思路。
Objective：To study biopharmaceutics character of warfarin sodium. To compare the dissolution behavior of warfarin sodium tablets, and investigate dissolution and absorption correlation of warfarin sodium tablets. Methods：Testing the solubility and permeability of warfarin sodium in different pH media, and the biopharmaceutical characteristics of warfarin sodium tablets were studied and analyzed. The dissolution curves of warfarin sodium tablets in different media were plotted. The dissolution behavior of warfarin sodium tablets was studied and compared. Based on the data of reference listed drug (RLD) dissolution curves in vitro, the correlation between dissolution and absorption of warfarin sodium tablets was studied by computer simulation. Results：The solubility of warfarin sodium increased with the increase of pH value. However, the permeability decreased with the increase of pH value. warfarin sodium was classified as BCS Ⅱ (low solubility and high permeability drugs). The dissolution of warfarin sodium RLD tablets was similar in four media. The dissolution behavior of generic A was similar to that of reference, and that of generic B was not similar to that of reference. The dissolution and absorption of warfarin sodium tablets in pH 6.8 showed a high correlation. Conclusion：The dissolution curves of warfarin sodium tablets in media of pH 1.2, pH 4.5 and pH 6.8 can be used as the characteristic dissolution curves of the preparation. This study can provide reference for drug formulation screening, biopharmaceuticals classification determination and bioequivalence risk assessment.
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