阿立哌唑缓释微球的工艺优化及体内药动学研究

目的:制备阿立哌唑缓释微球,使用星点设计-效应面法优化工艺,并对其体内血药浓度进行分析。方法:采用乳化溶剂挥发法制备阿立哌唑微球;以油相二氯甲烷体积、水相聚乙烯醇质量分数及乳化转速为自变量,以微球的平均粒径、跨距、载药量、包封率、产率及突释量为因变量,对制备工艺进行优化,并对优化后的工艺进行验证。采用HPLC法测定家兔血浆中药物浓度。结果:最佳工艺为二氯甲烷体积1.62mL,聚乙烯醇质量分数1.91%,乳化转速2 161 r.min-1;按优化工艺制备的微球外观圆整、流动性好;平均粒径为41.54μm,跨距为1.01,载药量为18.82%,包封率为75.39%,产率为85.17%,突释为1.68%。自制微球制剂在家兔体内d 1有少量的突释,d 5～d 20维持较稳定的血药浓度,缓慢释放,之后浓度开始下降。结论:所优化的制备工艺重现性好,简单易行;星点设计-效应面法优化微球制备工艺预测性良好,所制备的微球具有较好的体外缓释特性;阿立哌唑缓释微球在家兔体内缓慢释放,该释药行为达到了预期的目的。

Optimization and pharmacokinetics of the sustained release microspheres of aripiprazole

Objective: To prepare the sustained release microspheres of aripiprazole,to optimize the formulation by central composite design-response surface methodology,and to evaluate the pharmacokinetics of aripiprazole in rabbits.Methods: Emulsification-solvent evaporation method was used to prepare aripiprazole microspheres.The volume of CH2Cl2,polyvinyl alcohol(PVA) concentration and speed of mechanical stirring were listed as three independent variables;the dependent variables were mean diameter,span,durg content,encapsulation efficiency,yield and initial release.The central composite design-response surface methodology was constructed to optimize the formulations,and the optimized formulation was validated.HPLC method was used for the determination of aripiprazole in rabbit plasma.Results: The optimized preparation conditions were as follows: the volume of CH2Cl2 1.62 mL;PVA mass concentration 1.91%(m∶m);speed of mechanical stirring 2 161 r·min-1.In these conditions,the prepared microspheres were spherical in their morphology,and the mean diameter of the microspheres was 41.54 μm with span of 1.01.Drug content,encapsulation efficiency,yield and initial releases of aripiprazole microspheres were 18.82%,75.39%,85.17% and 1.68%,respectively.The microspheres had an obvious property of sustained release.After administration in rabbits,there was little burst release in the first day,plasma concentration of aripiprazole was steady from the fifth day to the twentieth day,and thereafter the drug concentrations declined.Conclusion: The preparing method is reproducible and easy,so is suitable to prepare aripiprazole microspheres.Central composite design-response surface methodology is successfully applied in optimization of preparing aripiprazole-loaded sustained-release microspheres.Aripiprazole can be slowly released from the microspheres in vivo as we expected.