星点设计-效应面法优化斑蝥素纳米结构脂质载体处方工艺

Optimization of prescription process of cantharidin nanostructured lipid carrier by central composite design-response surface methodology

目的将斑蝥毒性成分斑蝥素(CTD)整合在新型纳米载体(纳米结构脂质载体,NLC)中,并优化斑蝥素纳米结构脂质载体(CTD-NLC)处方工艺,从而降低斑蝥素的毒性并增强其靶向性。方法乳化超声分散法制备CTD-NLC,建立透析法测定其包封率,以平均粒径、粒径分布(多分散指数,PDI)、Zeta电位、包封率与载药量为考察指标,采用单因素考察与星点设计-效应面法(CCD-RSM)优化CTD-NLC的处方工艺,多元二次项拟合评价指标与因素间的模型方程,对拟合方程进行方差分析,效应面法预测最优处方。结果优化后的CTD-NLC处方工艺:脂质总量为453.66mg、固体脂质与液体脂质的比例为1∶2、总稳定剂质量浓度为16.9 mg/mL、Pluronic F68与蛋黄卵磷脂(Lipoid E PC S)的比例为3.88∶1、超声30 min(工作2 s、停2 s);所制得的CTD-NLC外观为澄清透明伴有淡蓝色乳光,平均粒径为(85.99±0.49)nm,PDI为0.280±0.002,Zeta电位为(-8.21±0.24)m V,包封率为(98.57±0.05)%,载药量为(0.65±0.01)%。结论 CCD-RSM建立的拟合模型精准可靠,优化后处方制备的CTD-NLC分布集中,包封率高,物理稳定性好,为CTD-NLC的后续体内外研究奠定了制剂基础。

Objective To integrate the toxic component of cantharidin(CTD)into a novel nanostructured lipid carrier(NLC)and optimize the cantharidin nanostructured lipid carrier(CTD-NLC)formulation process to reduce the toxicity of CTD and enhance its targeting.Methods CTD-NLC was prepared by emulsified ultrasonic dispersion method.The encapsulation efficiency was determined by dialysis method.The average particle size,particle size distribution(polydispersity index,PDI),Zeta potential,encapsulation efficiency,and drug loading were taken as indicators.Univariate investigation and central composite design-response surface methodology(CCD-RSM)were used to optimize the prescription process of CTD-NLC.Multivariate quadratic fitting was used to evaluate the model equation between indicators and factors.The fitted equation was analyzed by the variance analysis and the optimal prescription was predicted by the resonse surface.Results The optimized CTD-NLC prescriptions were as follow:mass of total lipid was 453.66 mg,solid to liquid lipid ratio of 1∶2,total stable dose of 16.9 mg/m L,ratio of Pluronic F68 to egg yolk lecithin(Lipoid E PC S)of 3.88∶1,with ultrasound for 30 min(working 2 s,stopping 2 s).The prepared CTD-NLC was clear clarification in appearance with light blue opalescence,the average particle size was(85.99±0.49)nm,PDI was 0.280±0.002,Zeta potential was(-8.21±0.24)mV,encapsulation efficiency was(98.57±0.05)%,and drug loading was(0.65±0.01)%.Conclusion The fitting model established by CCD-RSM is accurate and reliable.The optimized CTD-NLC distribution is concentrated,with high encapsulation efficiency and good physical stability.It lays a foundation for the subsequent in vitro and in vivo studies of CTD-NLC.