Box-Behnken效应面法优化紫杉醇mPEG-PDLLA纳米粒处方工艺

Optimization of formulation and process of paclitaxel mPEG-PDLLA nanoparticles by Box-Behnken response surface methodology

目的:优化紫杉醇单甲氧基聚乙二醇-聚丙交酯嵌段共聚物[methoxy-poly(ethylene glycol)poly(D,L-lactide)copolymer,mPEG-PDLLA]纳米粒的处方和工艺。方法:采用高压微射流法制备紫杉醇mPEGPDLLA纳米粒。处方优化方面,分别以mPEG-PDLLA的质量浓度、胆酸钠的质量浓度、mPEG-PDLLA与紫杉醇质量比为考察对象,以包封率和载药量为评价指标;工艺优化方面,分别以均质压力、均质次数、均质温度为考察对象,以平均粒径为评价指标,采用Box-Behnken效应面法筛选优化纳米粒的处方和工艺;并考察制得纳米粒的形态、体外释放度和稳定性。结果:优化确定的处方工艺参数:mPEG-PDLLA质量浓度为22.4mg·m L-1、胆酸钠质量浓度为0.2%、mPEG-PDLLA与紫杉醇质量比为5∶1、均质压力为109 MPa、均质次数为6次、均质温度为12.5℃。制得纳米粒的包封率、载药量和平均粒径分别为(90.21±0.99)%,(12.58±0.50)%和(115.4±5.3)nm,实测值与预测值的偏差均小于5%。制得的纳米粒为球形,具明显的缓释效果,在(4±2)℃放置3个月稳定性良好。结论:Box-Behnken效应面法可用来优化紫杉醇mPEG-PDLLA纳米粒的处方和工艺。

Objective：To optimize the formulation and process parameters of paclitaxel methoxy-poly（ethylene glycol） poly（D,L-lactide） copolymer（mPEG-PDLLA） nanoparticles.Methods：The nanoparticles were prepared by the high pressure microfluidization method.To optimize the formulation,mPEG-PDLLA concentration,sodium cholate hydrate concentration and the mass ratio of mPEG-PDLLA to paclitaxel were selected as independent variables,and entrapment efficiency and durg loading as response variables.To optimize the process,homogenization pressure,cycle numbers of homogenization and preparation temperature were selected as independent variables,and mean particle size as response variable.The formulation and process variables were optimized by Box-Behnken response surface methodology.The morphology,release characteristic in vitro and stability were investigated.Results：The optimal formulation and process parameters were as follows：the concentration of mPEG-PDLLA was 22.4 mg·mL^-1,the concentration of sodium cholate hydrate was 0.2%,the mass ratio of mPEG-PDLLA to paclitaxel was 5∶ 1,the homogenization pressure was 109 MPa,the cycle numbers of homogenization was 6,the preparation temperature was 12.5 ℃.The entrapment efficiency,the drug loading and mean particle size were（90.21 ± 0.99） %,（12.58 ± 0.50） %,and（115.4 ± 5.3） nm,respectively.The standard deviations were all less than 5%.The nanoparticles were spherical particles and had a sustained release property.The nanoparticlesstored at（4 ± 2） ℃ for 3 months were stable.Conclusion：The Box-Behnken response surface methodology facilitates the optimization of formulation and process of paclitaxel mPEG-PDLLA nanoparticles.