Box-Behnken效应面法优化制备主动靶向紫杉醇亚微乳及其体外抗肿瘤活性

Optimization and preparation of paclitaxel loaded sub-emulsion using Box-Behnken design methodology and its in vitro antitumor activities

目的采用Box-Behnken效应面法对紫杉醇亚微乳的处方进行优化从而制备具有稳定性良好的亚微乳。方法分别以中链油质量分数(X1)、磷脂质量分数(X2)、F68质量分数(X3)、油酸质量分数(X4)4个因素作为考察因素,以包封率和粒径为评价指标,采用4因素3水平Box-Behnken效应面设计法筛选SME/PTX的最优处方。采用透析法测定药物的体外释放行为,采用MTT法测定亚微乳对于肿瘤细胞的细胞毒性。结果最优处方工艺条件为X1=12.70,X2=1.95,X3=0.43,X4=0.05,根据最优处方制备的亚微乳的包封率和粒径与预测值存在较小的偏差,证明本方法可用于亚微乳的处方优化。在体外释放实验结果表明紫杉醇亚微乳具有明显的缓释行为。MTT实验结果表明紫杉醇亚微乳对MCF-7和Hep G2细胞的细胞毒性对比原料药组显著增强。结论Box-Behnken效应面法可用于优化制备紫杉醇亚微乳。

Objective To optimize the formulation of paclitaxel sub-emulsion by Box-Behnken design.Methods MCT concentration（ X1）,phospholipids concentration（ X2）,F 68 concentration（ X3） and oleic acid（ X4） were selected as independent variables,and the entrapment efficiency（ Y1） and size（ Y2） as response variables. A Box-Behnken Design for four factors at three levels was used in this study. Dialysis method was used to investigate the drug release behavior and MTT method was used to evaluate its cytotoxicity. Results In the optimized formulation,the optimal condition were X1= 12. 70,X2= 1. 95,X3= 0. 43,X4= 0. 05,respectively. According to the optimal formulation,there was narrowdifference between the predicted value and measured value in EE / % and size,which proves that this method can be used to optimize the formulation of sub-microne mulsion. In the in vitro release assay,paclitaxel loaded sub-micronemulsion showed significantly sustained release behavior. MTT assay demonstrated the formulation have higher cytotoxicity against MCF-7 cells and Hep G2 cells compared with paclitaxel solution. Conclusions Box-Behnken design method is suitable for modeling of paclitaxel loaded sub-micronemulsion.