Bioequivalence Of Nifedipine Controlled-release Tablets In Healthy Volunteers

Objective:To evaluate the bioequivalence and safety of nifedipine controlled-release tablets（specification:30mg）produced by a domestic pharmaceutical company in healthy volunteers.Methods:A high sensitivity and rapid HPLC-MS/MS method was developed for the analysis of human plasma samples.The samples were pre-treated by acetonitrile precipitation method,and the Capcell PAK ADME column（5μm,2.1×50 mm）was used to separate the samples.The internal standard was nifedipin-d₆.The Mobile Phase A and B were water and acetonitrile respectively,and the needle solution was 50%acetonitrile solution.The compounds were eluted by gradient elution（0 min,30%B;0.6 min,90%B;1.6 min,90%B;1.7 min,30%B;3.0 min,stop）.ESI source was used to ionize and the positive ions were monitored by multiple reaction monitoring mode.DP,CE and CXP values are 30,26 and 10V,respectively.This clinical trial followed the single-center,double-cycle,double-cross design method,and has the characteristics of randomicity and openness.A total of 24 volunteers were recruited and divided into fasting and postprandial groups.The cleaning period was 7 days.Volunteers were instructed to take nifedipine controlled release tablets（30mg）for test preparation and reference preparation.Plasma samples were detected by HPLC-MS/MS,and bioequivalence and safety were evaluated.Results:The linear range of HPLC-MS/MS method established in this experiment was 0.2～100 ng/m L,and the linear relationship was good.Precision and accuracy experiments,matrix effect and extraction recovery experiments and stability experiments all meet the requirements.All the 24 volunteers successfully completed the experiment without shedding.The pharmacokinetic parameters of the subjects in the fasting group were as follows:T_max was 12.79 h and 9.32 h,C_max was 22.8 ng/m L and 21.6 ng/m L,AUC_0-t was 664 h*ng/m L and 569h*ng/m L,AUC_0-∞was 686 h*ng/m L and 609 h*ng/m L.The pharmacokinetic parameters of postprandial group were as follows:T_maxwas 8.03 h and 8.01 h,C_max was 28.2 ng/m L and 26.5 ng/m L,AUC_0-t was572 h*ng/m L and 478 h*ng/m L,AUC_0-∞was 576 h*ng/m L and 481h*ng/m L.In the fasting trial,the incidence of adverse events was 16.7%for the test preparation and 41.7%for the reference preparation.In the postprandial trial,the incidence of adverse events was 16.7%for the test preparation and 25%for the reference preparation.All of the adverse events were grade 1,and all of the volunteers recovered or were in remission（except those lost to follow-up）.Conclusion:An accurate and rapid HPLC-MS/MS method was established for the determination of nifedipine in human plasma.After analysis and statistical treatment,the plasma samples produced in the postprandial group test showed that the tested agent met the bioequivalence requirements;The bioequivalence of the test preparation in the fasting group needs further experimental verification.The tested preparations used in the fasting and postprandial groups showed good safety.