目的 采用星点设计-效应面法优化天山雪莲提取物(Saussureae Involucratae Herba extract,SIHE)-复合磷脂脂质体(composite phospholipid liposome,CPL)的制备工艺,并考察其体外释药规律。方法 采用硫酸铵梯度法制备SIHE-CPL,通过单因素试验考察磷酸盐缓冲液pH值、药脂比(质量比)和磷脂与胆固醇质量比对平均粒径和多分散指数(PDI)的影响。基于单因素,应用星点设计考察磷脂用量、胆固醇用量2个因素对平均粒径、PDI、Zeta电位和包封率的影响,对结果进行多元线性和二项式方程拟合,用效应面法预测最佳处方,并考察其体外释放特征(动态透析法),用傅里叶红外光谱(FTIR)和X射线衍射光谱(XRD)研究SIHE-CPL的光谱特征及分子表征。结果 二项式非线性拟合方程优于多元线性回归方程,理论预测值与实测值偏差较小,预测性良好。在最佳制备工艺条件下,SIHE-CPL的平均粒径为(102.7±5.1)nm,PDI为0.154±0.017,Zeta电位为(-28.4±2.2)mV,绿原酸的包封率为(87.68±2.57)%,芦丁的包封率为(84.18±2.97)%,SIHE和SIHE-CPL的体外释放规律均符合一级动力学方程,FTIR和XRD验证了SIHE-CPL的形成。结论 SIHE-CPL具有较低的平均粒径、PDI和较高的Zeta电位、包封率,星点设计-效应面法可以准确快速地优化SIHE-CPL的制备工艺。

Objective To optimize the preparation of Saussureae Involucratae Herba extract(SIHE)-composite phospholipid liposome(CPL) by the central composite design-response surface methodology(CCD-RSM) and to investigate the in vitro release of drugs. Methods The method of ammonium sulfate transmembrane gradients was adopted to prepare SIHE-CPL. The single factor experiments were used for the key experimental factors and their test ranges. Based on the single factor experiments, with the size of SIHE-CPL, polymey disperse index(PDI), encapsulation efficiency(EE), and Zeta potential as dependent variables, central composite design was adopted to optimize the preparation technology by taking the content of phospholipid and the content of cholesterol as independent variables, test results were fitted by multiple linear and binomial nonlinear equations, and optimum formulation was selected by RSM, then the in vitro release behavior of the drug was studied by method of dynamic dialysis. Infrared(IR) spectroscopy and X-ray diffraction(XRD) pattern were used to analyze the spectroscopic properties of SIHE-CPL. Results The second-order polynomial equation was superior to the linear one, the observed values agreed well with model predicted values. The optimal process conditions were as follows:Size of SIHE-CPL was(102.7±5.1) nm, PDI was 0.154±0.017, EE of chologenic acid and rutin was(87.68±2.57)% and(84.18±2.97)%, Zeta potential was(-28.4±2.2) mV, SIHE-CPL and solution of SIHE were both accorded with the first order model, and IR analysis and XRD proved the formation of SIHE-CPL. Conclusion The size and PDI of SIHE-CPL are low, the EE and Zeta potential of SIHE-CPL are high. CCD-RSM could be successfully used to optimize the prescription of SIHE-CPL.

国家自然科学基金资助项目(81260681)