普瑞巴林缓释片体外释放度及比格犬体内药代动力学研究

In vitro release and in vivo pharmacokinetics in Beagle dogs of pregabalin sustained-release tablets

目的对自制普瑞巴林缓释片和原研制剂Lyrica®CR的体外释放度、释放机制以及剂量倾泻进行评价。进一步以Beagle犬为模型考察自制制剂与原研制剂的体内药代动力学情况。方法以美国辉瑞公司的普瑞巴林缓释片(Lyrica®CR)为原研制剂,使用自动溶出仪进行体外释放行为评价,采用相似因子(f2)法进行原研制剂与自制制剂体外释放相似度分析,并拟合体外释放方程评价其释药机制。综合美国、欧洲、中国的相关指导原则对制剂进行剂量倾泻研究。最后比较了自制制剂与原研制剂在Beagle犬的体内药代动力学参数。结果自制制剂与原研制剂在五种释放介质中f2均>80,在含乙醇的释放介质中无突释现象。自制制剂与原研制剂的药动学参数Tmax分别为(6.00±2.19)和(4.00±2.19)h,Cmax分别为(19.35±11.43)和(17.25±7.77)μg/ml,AUC0-t分别为(340.37±220.66)和(281.65±196.25)h·μg/ml。结论本研究自制制剂与原研制剂在五种介质中释放曲线相似,药物呈缓慢释放无剂量倾泻现象,体外释放机制相似。自制制剂与原研制剂在比格犬体内各药代动力学参数差异均无统计学意义,相对生物利用度达80%以上。

Objective To evaluate the in vitro release degree,release mechanism and dose dumping of test tablet and refer⁃ence tablet Lyrica®CR.The in vivo pharmacokinetics of the test tablet and the reference tablet were further investigated using the Bea⁃gle dog as a model.Methods With Pfizer's pregabalin sustained-release tablets(Lyrica®CR)as the reference listed drug,the in vi⁃tro release behavior was evaluated using an automatic dissolution apparatus,and similarity factor(f2)method was used to analyze the in vitro release similarity between the reference tablet and the test tablet.The in vitro release equation was fitted to evaluate the drug re⁃lease mechanism.Study was conducted on dose dumping of preparations based on the relevant guiding principles of the United States,Europe and China.Finally,the pharmacokinetic parameters of the test tablet and the reference tablet in Beagle dogs were compared.Results The f2 of the test tablet and the reference tablet were more than 80 in all five release media,and there was no sudden release in the release medium containing ethanol.The pharmacokinetic parameters of the reference tablet and the test tablet were as follows:The Tmax was(6.00±2.19)and(4.00±2.19)h,the Cmax was(19.35±11.43)and(17.25±7.77)μg/ml,and the AUC0-t was(340.37±220.66)and(281.65±196.25)h·μg/ml for the reference tablet and the test tablet,respectively.Conclusion In this study,the re⁃lease curve of the test tablet was similar to that of the reference tablet in the five media.The drug was released slowly without sudden re⁃lease,and the release mechanism in vitro was similar.There was no significant difference in pharmacokinetic parameters between the test tablet and the reference tablet in beagle dogs,and the relative bioavailability was more than 80%.