TPGS修饰的紫杉醇pH敏感脂质体处方优化及制剂学性质的考察

Formulation optimization and characterization of paditaxe-loaded pH-sensitive liposomes modified with tocopheryl polyethylene glycol 1000 succinate

目的筛选生育酚聚乙二醇琥珀酸盐(tocopheryl polyethylene glycol 1000 succinate,TPGS)与紫杉醇(paclitaxe,PTX)的质量比例,对TPGS修饰的PTX p H敏感脂质体进行处方优化及制剂学性质的考察。方法采用噻唑蓝(methyl thiazolyl tetrazolium,MTT)法以逆转耐药为指标筛选TPGS与PTX的质量比;采用薄膜分散法制备脂质体,对制剂进行单因素考察,并以包封率、载药量和24 h稳定性(24 h包封率和24 h载药量)为指标,应用星点设计-效应面法对处方及工艺进行优化。测定脂质体的粒径、Zeta电位和体外释药行为。结果 TPGS与PTX的最优质量比例为1:1,制剂的最优处方和工艺确定为m(dioleoyl phosphoethanolamine,DOPE):m(cholesteryl hemisuccinate,CHEMS):m(hydrogenated soybean phospholipids,HSPC)=6:4:2,m(TPGS):m(PTX)=1:1,投药量:1.02 mg,水化时间:12.29 min,水化温度:35℃,超声条件:200 W,5 min。脂质体的包封率为83.54%,载药质量分数为6.52%,24 h包封率和载药质量分数分别为80.03%和5.97%,稳定性良好。脂质体粒径为(115.8±2.03)nm,Zeta电位为(-56.47±1.55)m V。在p H 5.0条件下脂质体释药速率明显增加。结论星点设计成功实现了对处方的优化,且模型预测性良好;最优处方制备的脂质体具有较高的包封率和载药量,粒径较小且分布均匀,体外释放表现出一定的p H敏感性。

Objective To screen the optimal ratio of TPGS to and paclitaxel to against the reverse multiple drug resistance（MDR） in MCF-7/ADR cells.To prepare paclitaxel-loaded pH-sensitive liposomes modified with tocopheryl polyethylene glycol 1 000 succinate and investigate its optimal formulation and pharmaceutical properties.Methods The cytotoxicity of TPGS and PTX to reverse drug-resistance MCF-7/ADR was determined by methyl thiazolyl tetrazoliam（MTT） assay.Liposomes were prepared by film dispersion method,and then Box-Behnken design was applied to optimize the formulation and preparation process of liposomes with encapsulation efficiency,drug loading and stability over 24 h as the index.The particle size,Zeta potential and in vitro release behavior of the liposomes were measured.Results The optimal ratio of TPGS to paclitaxel was 1：1（m：m）.The optimal formulation was composed of 6 mg DOPE,4 mg CHEMS 2 mg HSPC,1.02 mg TPGS and PTX,which was prepared under the hydration temperature of 35℃ for 12.29 min and ultrasonication with the power of 200 W for 5 min.Encapsulation efficiency,drug loading,particle size and Zeta potential of the liposomes were 83.54%,6.52%,（116.5 ±2.03） nm and（-57.3 ±1.55） mV,respectively.In vitro release of PTX from the liposomes in pH 5.0 was significantly faster than that in neutral medium.Conclusions Box-Behnken design was successfully used in the formulation optimization.The optimal formulation and process is suitable for preparation of liposomes with high encapsulation efficiency and drug loading,smaller particle size,appropriate Zeta potential and significant pH sensitivity.