摘要
目的以一种新型两亲性大分子材料普鲁兰多糖接枝聚乳酸(pullulan-grafted-poly(D,L-lactide),PPLA)为载体材料,制备普鲁兰多糖接枝聚乳酸紫杉醇(paclitaxel,PTX)大分子胶束(PPLAPTX),以期降低紫杉醇的不良反应。方法采用薄膜水化法制备PPLA-PTX,以粒径、粒径分布(particle distribute index,PDI)、载药量(drug loading,DL)、包封产率(encapsulation efficiency,I.E)为指标,应用单因素联合星点设计效应面法,对胶束的处方及工艺进行优化,采用多元线性回归及二项式拟合,预测较优参数。对按照最优处方所制备的PPLA-PTX的结构特性和制剂学性质进行表征,并以紫杉醇注射液(PTX-solution,PTX-S)为对照,考察PPLA-PTX的体内毒性。结果二次多项式非线性回归模型是描述因素与指标关系的最佳模型,紫杉醇在PPLA-PTX中以分子或无定型形式存在,根据所得优化处方制得共聚物胶束的包封产率约为86.39%,载药量质量分数约为7.58%,透射电镜下粒子呈圆形均匀分布,采用马尔文激光粒度仪测定胶束粒径约为117.7 nm,PDI值0.158,Zeta电位为-3.43 mV,PPLA-PTX体外释放分为两阶段,第一阶段(0~4 h)符合Higuchi释放动力学,第二阶段(4~12 h)符合一级释放动力学。小鼠体内毒性实验表明,PPLAPTX的给药剂量为PTX-S的1.8倍时,前者的小鼠存活率为70%,后者全部死亡,连续给药7 d,前者的白细胞数约为后者的1.6倍,给药结束后7 d,PPLA-PTX组白细胞数回升至生理盐水组的83%。结论通过单因素与星点设计效应面法对处方和工艺优化,成功制备了普鲁兰多糖接枝聚乳酸紫杉醇大分子胶束,其粒径小而均匀,且具有较高的载药量和包封产率,与PTX-S相比,其具有更高的耐受剂量,更低的骨髓毒性,具有潜在的研究价值。
Objective To prepare and optimize the physical properties of paclitaxel based on pullulan-graftedpoly（D,L-lactide）,in order to avoid the use of Cremophor EL and reduce the toxicity.Methods PPLA-PTX was prepared by film hydration method.Single-factor experiment combined with central composite design response surface methodology was applied to optimize the micelle formulation and the preparation technology with particle size,drug loading and incorporation efficiency as responses.Data were simulated using multiple linear regression and second-order polynomial equation.The optimum formulation＇ s pharmaceutical properties were evaluated via DSC transmission electron microscope and dynamic light scattering.The HPLC method was applied to determine the drug concentration,and the drug loading,incorporation efficiency and in vitro release profile were further calculated.The KM mice were taken to evaluate the toxicity of PPLA-PTX in vivo.Results The drug was dispersed in the graft copolymer of molecular state or non-crystalline.The micelle prepared according to the optimized results showed drug loading and incorporation efficiency were 7.58% and 86.39%,respectively.The methodology of preparation allowed the formation of spherical nanometric（particle size 117.7 nm）,homogeneous（PDI0.158） and negatively charged（-3.43 mV）.The in vitro release profile was accord with Higuchi（0-4 h）and first-order（4-12 h） release model,separately.The in vivo toxicity of PPLA-PTX was much lower than PTX-S even the dose was 1.8 fold of the later,the survival of the two groups was 70%and 0,respectively.At the 7th day,the WBC concentration of PPLA-PTX was 1.6 fold of the PTX-S group,and recovered to83%of saline group 7 days after administration.Conclusions Single factor experiment combined with central composite design response surface methodology are applicable for formulation and preparation optimization of PPLA-PTX.The prepared micelle has small and uniform particle size,higher drug loading and incorporation efficiency.The lower toxicity and higher tolerance dose indicate that PPLA-PTX has a significant potential in cancer treatment.
出处
《沈阳药科大学学报》
CAS
CSCD
北大核心
2017年第4期275-284,共10页
Journal of Shenyang Pharmaceutical University
关键词
普鲁兰多糖接枝聚乳酸
紫杉醇
大分子胶束
单因素
星点设计效应面法
毒性
pullulan-grafted-poly（D L-lactide） paclitaxel polymer micelle single factor central composite design response surface toxicity
