目的 通过星点设计-效应面法优化负载和厚朴酚（honokiol，HNK）的当归多糖（Angelica sinensis polysaccharide，ASP）-小檗碱（berberine，Ber）聚合物胶束（ASP-SS-Ber/HNK）的处方工艺并考察其制剂学性质。方法 HPLC法测定HNK的含量；采用薄膜水化法制备ASP-SS-Ber/HNK，在单因素实验的基础上，以粒径、载药量以及包封率为评价指标，对载药比、水化温度和水化时间进行处方工艺筛选，采用星点设计-效应面法进行3因素3水平的实验，分析结果得出最优处方工艺并对其进行验证；使用透射电子显微镜（TEM）和粒径仪观察测定ASP-SS-Ber/HNK形态、平均粒径和ζ电位，通过体外释药对该载药系统进行评价并考察其稳定性。结果 优化得到的ASP-SS-Ber/HNK最佳处方工艺：当归多糖-小檗碱载体（ASP-SS-Ber）与HNK的投药量分别为5.00 mg和0.71 mg、水化温度为30℃、水化时间为100 min。采用最优处方制得的负载HNK的胶束制剂对HNK的载药量为（9.22±0.42）%，包封率为（71.77±1.20）%；胶束平均粒径为（44.38±2.95）nm；ζ电位接近于（—10.32±1.26）mV。在含有谷胱甘肽（GSH为10 mmol/L）的体外释放介质中72 h累积释放率达到80.2%；12 h的吸光度维持在0.29±0.01，连续7 d内的粒径稳定在（45.14±0.67）nm，ζ电位稳定在（—10.46±0.60）mV。结论 星点设计-效应面法所建立的模型精度高，可用于ASP-SS-Ber/HNK胶束制剂的处方优化。

Objective To optimize the prescription process of Angelica sinensis polysaccharide (ASP)-berberine (Ber) micelle loaded with honokiol (HNK) (ASP-SS-Ber/HNK) by central composite design-response surface method and investigate its formulation properties.Methods The content of HNK was determined by HPLC; ASP-SS-Ber/HNK was prepared by thin film hydration method. On the basis of single factor experiment, particle size, drug loading and encapsulation rate were used as the evaluation index to screen the prescription process for drug loading ratio, hydration temperature and hydration time. Central composite design-response surface method was used to carry out three factors and three levels experiment, and the results were analyzed to get the optimal prescription process and verify it. The morphology, average particle size and ζ potential of ASP-SS-Ber/HNK were observed and determined by transmission electron microscope and particle size analyzer, and the drug delivery system was evaluated by in vitro drug release and its stability was examined. Results The optimal preparation process was as follow:the dosage of A. sinensis polysaccharide- berberine carrier (ASP-SS-Ber) and HNK was 5.00 mg and 0.71 mg, the hydration temperature was 30℃, and the hydration time was 100 min. The compound loaded with HNK micelles prepared by the optimum formulation had the loading capacity of (9.22 ±0.42)% and entrapment rate of honokiol was (71.77 ±1.20)%; the average particle size of the micellar preparation was (44.38 ±2.95) nm and the ζ potential was close to (−10.32 ±1.26) mV. The cumulative release amount in in vitro release medium containing glutathione (GSH was 10 mmol/L) reached 80.2% in 72 h; the absorbance for 12 h was maintained at (0.29 ±0.01)%, the particle size was stabilized at (45.14 ±0.67)% for seven consecutive days, and the potential was stabilized at (−10.46 ±0.60) mV. Conclusion The model established by central composite design-response surface method had high accuracy and could be used to optimize the formulation of ASP-SS-Ber/HNK micelle preparations.

R283.6

齐齐哈尔市科技攻关项目（LHYD-2021001）；国家自然科学基金项目（82174097）