LC-MS法研究地尔硫卓缓释片的人体生物等效性

HPLC-MS method to investigate the bioequivalence of diltiatem extended action tablets

目的建立测定人血浆中地尔硫卓浓度的HPLC-MS方法,并研究健康受试者单次口服地尔硫卓缓释片的生物等效性。方法 20名男性健康受试者采用随机交叉的方法口服受试制剂和参比制剂各180 mg,采用HPLC-MS法测定人血浆中地尔硫卓的浓度,估算地尔硫卓的药动学参数及两种制剂的人体生物等效性。结果血浆中地尔硫卓的最低定量限为0.4 ng/ml,在0.4～400ng/ml范围内线性关系良好,批内及批间精密度RSD均小于15%。受试制剂与参比制剂的各主要药动学参数:tmax分别为(22.3±7.3)h和(23.0±6.5)h,Cmax分别为(54.32±25.73)ng/ml和(55.63±27.19)ng/ml,t1/2分别为(8.8±2.5)h和(9.9±4.4)h,AUC0-60分别为(1 465.3±686.3)ng.h/ml和(1 539.6±692.9)ng.h/ml。对受试制剂和参比制剂的药动学参数Cmax、AUC0-216、AUC0-经对数转换后,先用双交叉实验设计的方差分析后进行双向单侧t检验及[1-2α]%可信区间判断,经对数转换后的Cmax、AUC0-60、AUC0-的[1-2α]%可信区间为88.5%～108.1%、88.7%～102.1%和86.0%～100.2%,差异无统计学意义。结论两种制剂生物等效。

Objective To establish an HPLC-MS method the determination of diltiatem and to investigate the bioequivalence in Chinese healthy volunteers.In a randomized,crossover study.Methods 20 healthy male volunteers were orally administrated with diltiatem extended action tablets（test sample and reference sample） 180 mg.The plasma concentration of diltiatem was determined by HPLC-MS method.The pharmacokinetic parameters were calculated and the bioequivalence was evaluated.Results The LLOQ of the HPLC-MS method for diltiatem in plasma was 0.4 ng/ml and the calibration curve was linear over the range of 0.4~400 ng/ml.The intra-and inter-run standard deviation was less than 15%.The main pharmacokinetic parameters of the test and reference drugs were as follows ： tmax（22.3±7.3） h and（23.0±6.5） h,Cmax（54.32±25.73） ng·ml-1 and（55.63±27.19） ng·ml-1,t1 /2（8.8±2.5）h and（9.9±4.4） h,AUC0-60（1 465.3±686.3） ng·h·ml-1 and（1 539.6±692.9） ng·h·ml-1.The confidence interval（%） of Cmax、AUC0-60、AUC 0-are 88.5%~108.1%、88.7%~102.1% and 86.0%~100.2% through logarithmic transformation,Tmax was not statistically significant through non-parametric test.Conclusion Two formulations were bioequivalent.