星点设计-效应面法优化丹参酮ⅡA脂微球处方工艺研究及质量评价

Technology research and quality assessment on prescription of tanshinone Ⅱ A lipid microspheres by central composite design-response surface method

目的:采用星点设计法,以平均粒径、稳定性常数及包封率为考察指标,优化丹参酮ⅡA脂微球处方。方法:以平均粒径、稳定性常数及包封率为评价指标,考察了蛋黄卵磷脂用量(A)、泊洛沙姆用量(B)、大豆油占油相总量的百分比(C)对丹参酮ⅡA脂微球制剂性质的影响。用二项式拟合建立指标与因素之间的数学关系,根据评价指标的最佳数学模型描绘效应面,经效应面法预测最佳处方,并进行预测分析。按照优化的处方制备丹参酮ⅡA脂微球,并对其进行常规的质量评价研究。结果:各指标的二项式方程拟合较好,平均粒径、稳定性常数和包封率的相关系数分别为0.97,0.92,0.84,可信度较高。优化后的处方为:蛋黄卵磷脂1.38 g,F68 0.19 g,LCT 2 g,MCT 18 g,优化处方各指标和目标值接近。按优化处方制备的丹参酮ⅡA脂微球的平均粒径为203 nm,粒径分布为0.1,ζ电位为36,包封率为93%,载药量为0.8 mg·m L-1;室温条件下避光放置7个月,其粒径、ζ电位、载药量、包封率、p H未见明显变化。结论:星点设计-效应面法适用于脂微球乳剂的处方优化,所建立的数学模型预测性良好;优化后的丹参酮ⅡA脂微球符合药剂学要求。

OBJECTIVE To optimize prescription of tanshinone ⅡA lipid microspheres by central composite design method,and evaluate the quality. METHODS Mean particle size,stability constant and encapsulation efficiency of lipid microspheres were determined to investigate concentration of egg yolk lecithin and poloxamer and percentage of soybean oil in oil phase which might impact properties of tanshinone ⅡA lipid microspheres. Mathematic relation between index and factor was constructed by binomial expression,according to the best mathematical model of evaluation indicators to describe response surface. Then response surface method was used to predict the best prescription to be analyzed. Optimized prescription was used to prepare tanshinone ⅡA lipid microspheres to evaluate its quality. RESULTS Each index of binomial equation fitted well. Correlation coefficients of mean particle size,stability constant and encapsulation efficiency were 0. 97,0. 92 and 0. 84,respectively,with a higher credibility. Optimized prescription： egg yolk lecithin 1. 38 g,F68 0. 19 g,LCT 2 g,MCT 18 g. All indexes of optimized prescription were similar to target values. Mean particle size of tanshinone ⅡA prepared by optimized prescription was 203 nm,particle size distribution 0. 1,ζ potential 36,encapsulation efficiency 93%,drug-loading rate 0. 8 mg·mL^- 1. No obvious changes were observed in these parameters after storage for 7 months. CONCLUSION Central composite design-response surface method can apply to optimize prescription of lipid emulsion microspheres. The predictability of mathematical model is good,and optimized tanshinoneⅡA lipid microspheres meet pharmacy requirements.