积雪草酸自组装胶束的构建及其大鼠体内药动学研究

Preparation and pharmacokinetic study of asiatic acid loaded chitosan-deoxycholic acid polymeric micelles in rats

目的以两亲性材料壳聚糖-去氧胆酸聚合物为载体制备积雪草酸(AA)自组装胶束(AA-CS-DCA PMs),并研究胶束在大鼠体内的药动学特点。方法采用超声分散法构建AA-CS-DCA PMs,采用包封率、载药量、粒径、Zeta电位等指标对胶束进行表征,通过体外释放考察胶束的释药特性。进一步建立清醒大鼠胆汁引流模型,采用柱前衍生化HPLC方法测定胆汁中药物质量浓度,并通过达峰时间(t_(max))、峰浓度(C_(max))、药物排泄速率-时间曲线下面积(AUC0~t)评价口服胶束的体内药动学特点。结果所构建的载药胶束粒径为(70.5±9.8)nm,Zeta电位为(38.4±0.8)mV;药物AA包封率为(77.8±1.2)%,载药量达到(11.7±0.2)%;体外释放试验中,药物没有明显的突释现象,具有缓释特征。载药胶束经胆汁排泄的C_(max)(26.05±3.04)μg/h是对照组(原料药)(9.19±1.12)μg/h的2.8倍,tmax显著延长(2 h vs 1 h),体内消除明显减慢,其消除半衰期t_(1/2)(2.68±1.71)h是对照组(1.49±0.38)h的1.8倍。反映药物吸收程度的生物利用度AUC_(0～t),与对照组相比提高了200%[(99.05±12.83)μg vs(33.56±8.33)μg]。结论 AA经自组装胶束包封后,体内药物水平明显提高,作用时间延长,极大提高了AA的口服生物利用度。

Objective To prepare asiatic acid（AA） loaded chitosan-deoxycholic acid self-assembled micelles（AA-CS-DCA PMs） adopting chitosan-deoxycholic acid（CS-DCA） as carriers and investigate its pharmacokinetic characteristics in rats.Methods AA-CS-DCA PMs were prepared by ultrasonic dispersion method.The characteristics of micelles were evaluated by the distribution of particle size,Zeta potential,drug loading,encapsulation efficiency,and in vitro release.Model of bile drainage was established in conscious rats and pre-column derivatization HPLC method was used to determine the concentration of AA in bile.Moreover,the pharmacokinetics characteristics of AA-CS-DCA PMs in vivo was evaluated by tmax,Cmax and AUC_（0-t）.Results The particle size was（70.5 ± 9.8） nm,the Zeta potential was（38.4 ± 0.8） mV,and encapsulation efficiency and drug loading were（77.8 ± 1.2）% and（11.7 ± 0.2）%,respectively.The in vitro release profile showed a sustained release property.In vivo study showed that Cmax of AA-CS-DCA group（26.05 ± 3.04） μg/h was 2.8 times higher than that of the control group（9.19 ± 1.12） μg/h; The tmax of AA-CS-DCA PMs group prolonged significantly（P〈0.05） in biliary excretion（2 h vs 1 h） and the elimination half-life t_（1/2） was 1.8 times of the control group [（2.68 ± 1.71） h vs（1.49 ± 0.38 h）].In addition,the AUC_（0-24 h） which reflected the degree of drug absorption increased by 200% compared with the control group [（99.05 ± 12.83） μg vs（33.56 ± 8.33） μg].Conclusion The chitosan-deoxycholic acid self-assembled micelles can raise the concentration of AA and prolong the retention time in vivo,which effectively improve the oral bioavailability of AA.