pH敏感型紫杉醇胶束的工艺优化

Formulation optimization of pH sensitive micelle loaded with paclitaxel

目的:优化pH敏感型紫杉醇胶束的处方及工艺。方法:用制备的pH敏感型壳聚糖衍生物,N-辛基-N(2-羧基环己甲酰基)-壳聚糖(OCCC),通过透析法包载紫杉醇(PTX),并采用单因素考察-中心面复合设计(central composite design,CCD)优化了载药胶束杉醇的制备工艺。选择胶束的载药量(drug loading rate),包封产率(entrapment efficiency),粒径(parti-cle size)以及多分散指数(polydispersity index,PI)为考察指标,考察药载比(PTX/OCCC),药物浓度,载体浓度,透析时间等因素对工艺的影响。并对结果进行线性方程和二次多项式方程拟合,效应面法选取最佳工艺条件进行预测分析。结果:从复相关系数上看,各指标二项式拟合方程均优于多元线性回归方程,优选的最佳条件为药载比为0.98,载体质量浓度为3.0mg·mL-1,模型预测载药量为35.52%,包封产率71.91%。冻干胶束配伍稳定性研究表明与0.9%生理盐水溶液配伍稳定。结论:中心面复合设计适用于pH敏感型紫杉醇胶束的工艺优化,所建立的数学模型预测性良好。

OBJECtIVE To optimize the formulation of pH sensitive mieelle loaded with paclitaxel. METHODS A series of pH-sensitive graft copolymer, N-oetyl-N-（2earboxyl-cyclohexametheny 1）ehitosan derivatives were synthesized and encapsulated PTX by dialysis method. Several factors（ratio of PTX/OCCC, OCCC concentration, PTX concentration and dialysis time） were investigated in the process of micelle preparation by the single-factor study. With central composite design （CCD）, the optimized formulation of PTX-load OCCC micelle was obtained. Then the results of linear equation and quadratic polynomial equation were fitting and the response surface method was used to select the optimum condition for predictive analysis. RE-SULTS According to multiple correlation coefficient, the indicators were better than the binominal equation fitting multiple linear regression, the best condition for optimization was the PTX/OCCC 0. 98, the OCCC concentration 3.0 mg·mL ^-1. The predicted drug loading was 35.52% and the entrapment efficiency was 71.91%. The compatible stability experiment showed that the freeze-drying micelle should be resolved with normal saline other than dextrose solution. CONCLUSION The central composite design and response surface method was useful for the optimization of preparing of pH sensitive micelle loaded with paclitaxel.