【摘要】 目的:采用计算机模拟技术结合平行人工膜渗透模型（the parallel artificial membrane permeability assay, PAMPA）,指导国产富马酸比索洛尔片生物等效性豁免的研究。方法:首先利用DDDplus^TM软件评估富马酸比索洛尔片中主成分（active pharmaceutical ingredient, API）及辅料的物理参数对其溶出行为的影响;第2步采用Gastroplus^TM软件的群体模拟实验,模拟药物在体内具有不同释放速率(t_85%=15～120 min)时的体内吸收情况,计算出不影响生物等效性的释放速率范围;第3步测定国产富马酸比索洛尔片、富马酸比索洛尔原料、参比制剂的膜渗透曲线,评估辅料对渗透速率的影响,预测其生物等效性。结果:DDDplus^TM模拟结果显示主成分的粒径、各辅料的量和粒径发生变化时,富马酸比索洛尔片的体外溶出行为未发生变化;群体模拟结果显示该药物只要在90 min内完全溶出就能满足与参比制剂生物等效;在空腹肠模拟液中,膜渗透速率曲线显示辅料不影响药物的膜渗透,受试制剂与参比制剂渗透速率基本一致,ρ_max和AUC_0→t无明显差异。结论:计算机模拟技术和平行人工膜渗透模型的结果能为富马酸比索洛尔片的生物等效性豁免提供数据支撑。更多还原

【Abstract】 Objective:To evaluate the biowaiver of domestic bisoprolol fumarate tablets using computer simulations and parallel artificial membrane permeability assay（PAMPA）. Methods: First, DDDplus^TM software was used to evaluated the effects of physical parameters of API and excipients on dissolution behavior of bisoprolol fumarate tablets. Second, population simulation using Gastroplus^TM software was used to predict the absorption behavior of the drug with different release rates(t_85%=15～120 min) and obtain the release rate range which had no effect on bioequivalence. Third, the membrane permeation curves of domestic bisoprolol fumarate tablets, bisoprolol fumarate raw material and reference preparation were determined to evaluate the influence of excipients on permeation rate and predict their bioequivalence. Results: The results of DDDplus^TM simulation indicated that the in vitro dissolution behavior of bisoprolol fumarate tablets did not change when the particle size of API and excipients, or the amount of excipients, or the particle size of excipients changed. The results of population simulation revealed that the drug preparation could be bioequivalent to the reference preparation as long as it was completely dissolved in 90 minutes. In the jejunum model solution, the membrane permeation rate curve showed that excipients did not affect the membrane permeation behavior of the drug, and the test preparation is bioequivalent with the reference preparation. There was no significant difference in ρ_max and AUC_0→t. Conclusion: The application of computer simulations and PAMPA can provide evidence for the biowaiver study of bisoprolol fumarate tablets.更多还原