Pharmacokinetics Study Of Domestic Carvedilol Dispersible Tablet

Carvedilol is a nonselectiveβ-receptor blocking andα₁-adrenergic receptor blocking agent and it also has vasodilating properties that are attributed mainly to its blocking activity at receptors.Carvedilol is applied for treatment of hypertension and angina pectoris.It is also used to reduce mortality in patients with left ventricular dysfunction following myocardial infarction in plasma.Carvedilol was also approved for the treatment of congestive heart failure.It was overturned the recognition thatβ-receptor blockings were prohibitted to be used in heart failure.So it was awarded America New Drug Prize in 2008.The tablets and capsules of carvedilol have already been on sale,but dispersible tablet haven't on market yet.The first domestic dispersible tablet of carvedilol is designed for convenient oral and quick absorption. Compared with tablets and capsules of carvedilol on sale,more and more patients will be satisfied with dispersible tablet because of its excellent quality and reasonable price.In the following study,we have set up the method of determination of carvedilol in human plasma by LC-MS/MS in this experiment.Then we investigate the pharmacokinetics of carvedilol with reference in healthy volunteers'body for bioequiavailabilty analyse and clinical application of the drug. 1.Establishment the method for determination of carvedilol in plasma with LC-MS/MSCarvedilol was determinated by LC-MS/MS with hydrochloride terazosin as internal standard.The method was corroborated according to acceptance criteria of industrial guidance for the bioanalytical method validation,including examination of method specificity,standard curve preparation,base effect investigation,absolute rate of recovery,relative rate of recovery as well as stability investigation.2.Investigation of pharmacokinetics for Carvedilol in human plasmaBefore study,this project was approved by ethics committee of the First Hospital,Zhejiang University,College of medicine.Twenty healthy volunteers were included.According to 2×2 crossover trial design,these subjects were administrated 12.5mg carvedilol orally before meal.4ml of venous blood sample were withdrawn, centrifuged for 15min at 4000rpm and the plasma was preserved at -20℃in PP tube. The time for collection of each dose were before administration and 0.25,0.5,0.75,1,2,3,4,6,8,10,12,24,48h after administration.The concentration of carvedilol in plasma was determinated by LC-MS/MS.C_max,t_max were calculated.Regression curve was made by the end drug concentration in plasma,and the slope K_e and t_1/2 was calculated.The A UC_0-t was calculated with trapezia method.AUC_0-iμf=AUC_0-t+C_t /K_e.The main parameters of carvedilol was analysed by DAS 2.0 software.The main pharmacokinetics parameters were subjected variance analysis and Student t-test after logarithm transition,and the 90%believe section was calculated.T_max was statistical managed by non-parametric method.The statistical meaning of variance between preparation,individuals,periods was analysed,and bioequiavailability was evaluated.The results indicated that:(1) a high recover efficency,degree of precision and degree of accuracy was obtained.The LC-MS/MS method had a high sensitivity(having low quantitation limits as 0.36 ng·mL^-1),specificity,linear correlation,consistent to bio-sample analysis requirement.(2)healthy subjects were administrated dispersible carvedilol or reference preparation,the blood samples were determined by LC-MS/MS and the pharmacokinetics data was calculated:t_max were (0.93±0.51) h and(0.93±0.50) h,C_max were(51.99±21.69) ng·mL^-1 and (58.21±35.30) ng·mL^-1,AUC_0-t were(194.60±87.28) ng·mL^-1·h and (203.62±105.55) ng·mL^-1·h,AUC_0-∞ were(197.93±87.95) ng·mL^-1·h and (207.01±105.71) ng·mL^-1·h,t_1/2(ke) were(3.06±0.62) h and(2.79±0.47) h,K_e were (0.2558±0.0468) h^-1 and(0.2351±0.0490) h^-1,MRT were(4.32±2.24) h and (3.70±1.79) h,respectively.The relative bioavailability of the test formulation was (104.73±18.36)%.After double and half t-test,the test statistics were exceeded t_0.05(20) =1.706.90%confidece interval of AUC_0-t and C_max were 96.3%～110.6%and 90.8%～122.0%.With non parametric method,the two preparations had no difference.The statistical analysis showed that the two formulations had no significant deviation.(3) Safety evaluation:The experiment was surveilled by staff and no oobvious adverse reactions was found.The biochemical indicators of the tested healthy volunteers had no difference between pre-experiment and post-experiment.Conclusion:the concentration of carvedilol in plasma was determined by LC-MS/MS,the mothod was accurate,sensitive and convenient,was able to be suitable for pharmacokinetic study and other routine bioequivalence studies.The investigation of pharmacokinetics properties indicated that after administration orally, there's no difference compared with reference preparation,which is consistent with reference.Therefore,when the preparation was used in clinic,the drug dose should be adjusted according to the sick,such as once per day or twice per day,in order to guarantee the availability and security.