| Risperidone is already listed in China's atypical antipsychotics. Because of its positive effects of improving the positive and negative symptoms of schizophrenia and less adverse drug reactions such as extra pyramidal reactions and inhibition of motor function, risperidone attracted much attention as a first-line antipsychotic. In this paper, pharmacokinetics and relative bioavailability of risperidone dispersible tablets produced by ZH Pharmaceutical Factory in health were studied with risperidone tablets produced by Xi'an-Janssen Pharmaceutical Co. as a standard reference formulation.Objective:To establish a High Performance Liquid Chromatography Mass Spectrometry (HPLC-MS) method to monitor the concentration of risperidone in human plasma samples, to clarify its pharmacokinetics profiles in health body, and evaluate the bioequivalence of risperidone dispersible tablets produced by ZH Pharmaceutical Factory and risperidone tablets produced by Xi'an-Janssen Pharmaceutical Co. to provide scientific ground for safe and reasonable clinical application. Methods:We established a HPLC-MS assay for determining the concentration of risperidone in human plasma. Chromatographic conditions:The analytical column was ACQUITY UPLCTM BEH C18(2.1×50mm,1.7μm) (Waters Co. USA). The mobile phase consisted of a mixture of acetonitrile and 0.01mol-L-1 ammonium acetate adjusted to PH 3.4 with formic acid. The flow rate was 0.2mol-L-1. The MS conditions were as follows:Measure method:MRM; ionization:ESI; ion polarity; (Positive). Then the concentration of risperidone in human plasma can be determined with the established method of HPLC-MS.The crossover experimental design has been used in this study.20 subjects were randomly divided into 2 groups (n=10) to respectively oral risperidone reference preparation and test preparation of the same dose (2mg) in the two cycles. The medication was given to each subject 2 times, with the interval was 12 days. The whole process includes the 2 cycles. Venous blood samples (3ml each) were collected into tubes containing heparin respectively before the drug administration and 0.25, 0.5,0.75,1,1.5,2,3,5,8,11,14,24hours after. The samples were spun immediately after the collection and the plasma samples were stored at-20℃until assayed. All the proceedings of the experiment were accompanied by doctors and nurses for safe. We used the already established HPLC-MS method for the determination of risperidone in plasma concentration time.The plasma concentration-time data were disposed with DAS2.1.1 program. The concentration-time curve was drawn according to the data of plasma concentration (C) and time (T) of each subject. The peak concentration (Cmax) and the peak time (Tmax) of risperidone were determined from the respective observed concentration-time data. The areas under the curve (AUC) were calculated by the linear trapezoidal method. To evaluate the bioequivalence of the two preparations, and analysis of variance of the pharmacokinetic parameters Cmax,AUC0-t and were done after logarithmic transformation, simultaneously two one-side test were done.Results:The linear range was 0.66-42.24μg·L-1 and the lower limit of quantification was 0.66μg·L-1. The relative recoveries were in the range of 87.50%-104.00%. The intra-and inter-RSD were both less than 15%. Moreover, it has been proved that risperidone was stable and meet the requirements of biological sample analysis under various conditions such as room temperature, freeze-thaw, long-term frozen.A total of 18 subjects completed the testing process. The results showed that the main pharmacokinetics parameters of risperidone reference formulation and test formulation were as follows:Cmax were (14.03±6.54)μg·L-1 and (13.77±7.73)μg·L-1; Tmax were (1.36±0.71) h and (1.17±0.81)h; T1/2 were (3.59±1.69)h and (3.87±1.78)h; AUC0-t were (66.02±46.79)μg·h·L/1 and (73.05±59.85)μg·h·L/1; AUC0-∞, were (71.26±48.00)μg·h·L-1 and (78.97±63.48)μg·h·L-1; Respectively, the relative bioavailability of F0-t and F0-∞were (107.1±22.6)% and (107.5±25.2)%.AUC0-t and AUQ0-∞between risperidone reference formulation and test formulation were analyzed with a statistic analysis of ANOVA, the results showed that there was no significance. At the same time, they were analyzed with a statistic analysis of two one-side t-test. The confidence zone of [1-2α] was respectively during 94.5%-116.6% and 93.8%-117.2%. Both of them were during 85%-125%. AUC0-t and A UC0-∞of the two formulations were bioequivalent. It shows that there was no significance between ln(Cmax) of the two formulations after they were analyzed with a statistic analysis of ANOVA. On the other hand, they were analyzed with a statistic analysis of two one-side t-test. The result showed that confidence zone of [1-2α] was respectively during 82.9%-112.2% and 70%-143%. Both of them were during 70%-143%, the results show that 1n(Cmax) of the two formulations also met the bioequivalence. The test of Tmax of the two risperidone formulations with the non-parametric test (paired Wilcoxon method) showed that that there was no significance between them. It was to say that they were bioequivalent. All the results of the statistical analysis showed that risperidone in the two formulations are bioequivalent.Conclusion:1. The method of HPLC-MS established in this experiment is accurate and sensitive, simple and repeatable. It is fully applicable to the studies of pharmacokinetics and bioequivalence of risperidone.2. Risperidone dispersible tablets produced by ZH Pharmaceutical Factory and risperidone tablets produced by Xi'an-Janssen Pharmaceutical Co. had the similar pharmacokinetic parameters and they were bioequivalent. |
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