目的 优化大黄素（Emo）与小檗碱（Ber）壳聚糖双载药纳米粒的制备工艺和处方，并考察其稳定性及溶出度。方法 以壳聚糖（CS）为载体，三聚磷酸钠（TPP）为交联剂，采用离子交联法包载大黄素/羟丙基-β-环糊精（HP-β-CD）和小檗碱，得到载药纳米粒（Emo/HP-β-CD-Ber-CS NPs），以粒径和多分散指数（PDI）为自变量，运用总评归一值（OD）法进行数据处理，采用Box-Behnken效应面法优化处方并进行验证。最后对纳米粒的最佳冻干条件进行筛选，考察保护剂种类和用量。并对制剂进行表征和溶出度考察。结果 优化得到的最佳制备工艺为壳聚糖与TPP质量比为3：1，小檗碱与载体质量比为0.166：1，Emo/HP-β-CD与载体质量比为0.2：1。测得Emo/HP-β-CD-Ber-CS NPs的平均粒径为（178.0±2.0） nm，PDI为0.187±0.006，平均OD值为0.953 6，实测值与预测值接近。大黄素和小檗碱的载药量分别为0.34%和0.95%。稳定性考察结果表明，纳米粒胶体溶液在9 d内以4℃储存物理性质稳定，以6%葡萄糖为保护剂制得的冻干制剂效果较好，复溶迅速，再分散后的平均粒径为（161.8±4.8） nm，PDI为0.263±0.047。体外释放研究表明载药纳米粒冻干粉溶解度和溶出度显著提高。结论 Box-Behnken效应面法所建立的模型能较好的用于Emo/HP-β-CD-Ber-CS NPs制剂的处方优化，精度高，预测效果较好，且Emo/HP-β-CD-Ber-CS NPs制备工艺稳定可行。

Objective To optimize the preparation process and formulation of emodin (Emo) and berberine (Ber) chitosan (CS) dual drug-loaded nanoparticles, and investigate its stability and dissolution. Methods Using CS as the carrier and sodium tripolyphosphate (TPP) as the cross-linking agent, emodin/hydroxypropyl-β-cyclodextrin (HP-β-CD) and Ber were encapsulated by ion cross-linking method to obtain drug-loaded nanoparticles (Emo/HP-β-CD-Ber-CS NPs). Then, with particle size and polydispersity index (PDI) as independent variables, data processing was performed using the overall desirability value method, and the Box-Behnken effect surface method was used to optimize the prescription and verify it. Finally, a preliminary screening of the optimal freeze-drying conditions of the nanoparticles was carried out,and the type and dosage of lyoprotectants was investigated. Results The optimized preparation process was as follows:mass ratio of TPP to CS was 3:1, Ber to carrier was 0.166:1, and Emo/HP-β-CD to carrier was 0.2:1. The measured average particle size was (178.0 ±2.0) nm, PDI was 0.187 ±0.006, and the average OD value was 0.953 6. The measured value was close to the predicted value. The drug loading of Emo and Ber were 0.34% and 0.95, respectively. Stability investigation showed that the nanoparticles colloidal solution was physically stable when stored at 4℃ within 9 d. And the freeze-dried formulation prepared with 6% glucose as the protective agent had better effect and rapid reconstitution. The average particle size after redispersion was (161.8 ±4.8) nm,and PDI was 0.263 ±0.047. In vitro release studies have shown that the solubility and dissolution of drug-loaded nanoparticle freeze-dried powder were significantly improved.Conclusion The model established by the Box-Behnken response surface method can be used to optimize the formulation of Emo/HP-β-CD-Ber-CS NPs with high accuracy and good prediction effect. And the preparation process of Emo/HP-β-CD-Ber-CS NPs is stable and feasible.

R283.6

四川省科技厅项目（2019YFS0113）；国家中医药管理局项目（2018YZ03002）；四川省科技厅苗子工程委员会（2020095）