Effects Of High-fat Meal On Human Pharmacokinetics And Bioequivalence Of Trospium Chloride Sustained-release Capsules And Dual Release Capsules

Objective:（1）To establish an accurate and reliable Liquid chromatography-tanden mass spectrometry（LC-MS/MS）for determinating the concentration of Trospium Chloride in human plasma.（2）To study the pharmacokinetic effects of two high-fat meals（Chinese-style and western-style）on the single oral test preparation（Trospium Chloride dual release capsule）and the reference preparation（Trospium Chloride sustained-release capsule）in healthy volunteers,and to evaluate the biological equivalence of the two preparations,so as to provide reference data for subsequent clinical studies.（3）To evaluate the tolerance of Trospium Chloride dual release capsule.Methods:（1）To establishe a LC-MS/MS method for determining the concentration of Trospium Chloride in human plasma.（2）The chromatographic column was Venusil XBP C18（2.1×50 mm,5μm）.The mobile phase A was a 0.1%formic acid aqueous solution containing 2 m M ammonium formate,and the phase B was 0.1%methanol formic acid.The flow rate was 0.8 m L/min with gradient elution.Electrospray ion source（ESI）,positive ion scanning mode,multi-response monitoring mode（MRM）were selected.The monitoring ion pairs of trasmonium chloride standard and internal standard were m/z392.4→164.2 and m/z 400.5→172.0,respectively.The methods of selectivity,precision,accuracy,stability and matrix effect were validate d by dilution injection after elutio.（3）The tolerance of Trospium Chloride dual release capsule was evaluated by adverse events,vital signs,physical examination,laboratory examination and 12-lead ECG.Results:（1）The established LC-MS/MS method has good selectivity,and the blank sample has no interference peak at the retention time of Trospium Chloride and internal standard.There is a good linear relationship between the concentration of Trospium Chloride rang of 10-10000 pg/m L.The precision,accuracy,extraction recovery and matrix effect all meet the requirements,and the stability is good.The method is accurate and reliable,and can be used in the study of human pharmacokinetics and bioequivalence of Trospium Chloride.（2）A total of 24 volunteers were enrolled and 22 completed the trial.In Chinese-style high-fat meal group,the main pharmacokinetic parameters of test preparation and reference preparation after a single administration of 11volunteers were as follows:C_maxwere（585.37±494.81）ng/m L and（402.75±197.68）ng/m L,AUC_0-twere（20249.73±13684.20）ng/m L·h and（16589.27±8212.99）ng/m L·h,AUC_0-∞were（21623.00±14076.05）ng/m L·h and（19156.84±9384.16）ng/m L·h,T_maxwere（10.72±5.44）h and(13.272±5.41h,t_1/2were（22.13±4.96）h and（30.18±6.64）h,respectively.The 90%confdence interval（CI）of the geometric mean ratio ratios（Test/Reference）after logarithmic transformation of C_max,AUC_0–tand AUC_0-∞were 96.97%～133.38%,90.36%～125.28%,101.87%～148.79%,respectively.In westen-style high-fat meal group,the main pharmacokinetic parameters of test preparation and reference preparation after a single administration of 11volunteers were as follows:C_maxwere（560.85±274.22）ng/m L and（453.97±205.70）ng/m L,AUC_0-twere（22679.90±9182.23）ng/m L·h and（18771.67±8887.86）ng/m L·h,AUC_0-∞were（27447.67±11742.31）ng/m L·h and（21653.05±10675.04）ng/m L·h,T_maxwere（10.18±2.75）h and（11.64±2.66）h,t_1/2were（35.02±14.57）h and（29.06±8.32）h,respectively.The 90%CI of the geometric mean ratio ratios（Test/Reference）after logarithmic transformation of C_max,AUC_0–tand AUC_0-∞were 106.80%～146.66%,96.70%～166.31%,101.32%～153.87%,respectively.There was a significant difference in t_1/2between the two high-fat meals in the test preparations of Trospium Chloride（p<0.05）.There was no significant difference between the two high-fat meals on the pharmacokinetic parameters of reference preparations（p>0.05）.AUC_0-∞and AUC_0-tin western-style high-fat meals showed differences in dosage form effects（p<0.05）.There were no significant differences in the Tmax of the two preparations between the two high-fat meals by non-parametric tests（p>0.05）.There were no significant differences in the T_maxof the two preparations between the two high-fat meals by non-parametric tests（p>0.05）.（3）All volunteers had no significant abnormalities in various physical examinations,vital signs,laboratory examinations,and electrocardiograms before and after the test,and no adverse reactions occurred throughout the test.Conclusions:（1）The established LC-MS/MS method can accurately determine the concentration of Trospium Chloride in human plasma.（2）In this study,compared with the western-style high-fat meal,the t_1/2of the test preparation was shortened in the Chinese high-fat meal,which was considered to be affected by the proportion of food components or nutrients in the Chinese-style high-fat meal.The dosage form effect of AUC_0-∞and AUC_0–tin western high fat meal were considersd to be related to the diffetent production process of the two preparations.In the two high-fat meals,the geometric mean ratio of 90%CI of the two preparations did not fall within the acceptable bioequivalence range（80.00%～125.00%）,and neither the test preparation nor the reference preparation was equivalent in the two high-fat diets.（3）Trospium Chloride dual release capsule produced by a domestic pharmaceutical company has good tolerance.