目的 以甘草酸为稳定剂制备新型姜黄素-水飞蓟宾共载纳米给药系统，研究其制剂学性质和稳定机制。方法 采用简易的反溶剂沉淀法制备姜黄素-水飞蓟宾共载纳米混悬剂（curcumin and silybin co-loaded nanosuspension，Cur&Sil-Np），以稳定剂质量浓度、药物质量浓度、稳定剂与药物的比例以及搅拌速度为考察因素，以平均粒径和多分散系数（polydispersity index，PDI）为指标，采用单因素实验优化处方工艺。利用动态光散射法和透射电子显微镜表征Cur&Sil-Np的粒径、分布和形态。为提高Cur&Sil-Np的稳定性，以3%甘露醇为冻干保护剂，通过冷冻干燥法将Cur&Sil-Np制成冻干粉。采用差示扫描量热法和X射线衍射法分析冻干粉中药物的晶型。进一步评价Cur&Sil-Np的体外释放特性和稳定机制。结果 最优处方工艺为甘草酸质量浓度1.5 mg/mL，药物质量浓度8 mg/mL，药物与稳定剂的比例5：3，搅拌转速600 r/min。制备的Cur&Sil-Np的平均粒径为（226.5±11.1）nm，PDI为0.038±0.021，呈均一的圆球形；制备成纳米混悬剂后，药物的晶型发生了改变；体外释放结果显示，Cur&Sil-Np可分别将姜黄素和水飞蓟宾的体外累积溶出率从游离药物的23.3%和15.1%提高至82.7%和70.9%。稳定机制研究发现，静电斥力是甘草酸稳定Cur&Sil-Np的机制之一。结论 天然表面活性剂甘草酸稳定的Cur&Sil-Np制备工艺简便可行、制剂性质良好、释药快速，是一种潜在的新型给药系统。

Objective The nano-drug delivery system co-loaded with curcumin and silybin was prepared with glycyrrhizic acid as stabilizer as well as its pharmaceutical properties and stability mechanism were explored. Methods A curcumin and silybin co-loaded nanosuspension (Cur&Sil-Np) was prepared by anti-solvent precipitation method. The mass concentration of stabilizer, drug concentration, proportion of stabilizer and drug, and stirring speed were used as investigative factors, while particle size and polydispersity index (PDI) were used as indicators. Based on above, the formulation and preparation process of Cur&Sil-Np were optimized by single factor test. Particle size, distribution, and morphology of Cur&Sil-Np were characterized by dynamic light scattering and transmission electron microscopy, respectively. To improve the stability of Cur&Sil-Np, Cur&Sil-Np was lyophilized by freeze-drying method with 3% mannitol as lyophilized protective agent. Both differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were applied to analyze the crystal form of drugs in freeze-dried powder. The dissolution characteristics and stability mechanism of Cur&Sil-Np were further evaluated. Results The optimal process parameters were as follows:the mass concentration of glycyrrhizic acid was 1.5 mg/mL, the drug concentration was 8 mg/mL, the ratio of drug to stabilizer was 5:3, and the stirring speed was 600 r/min. The average particle size and PDI of Cur&Sil-Np were (226.5 ±11.1) nm and 0.038 ±0.021, respectively. Cur&Sil-Np presented a spherical shape with a uniform distribution. The crystal form of drugs in Cur&Sil-Np altered. The cumulative release of curcumin and silybin in Cur&Sil-Np was significantly increased from 23.3% and 15.1% of free drugs to 82.7% and 70.9%, respectively. Moreover, electrostatic repulsion was one of the stabilization mechanisms of Cur&Sil-Np stabilized by glycyrrhizic acid. Conclusion Cur&Sil-Np stabilized by natural surfactant glycyrrhizic acid is a potential new drug delivery system with simple and feasible preparation process, good properties and rapid drug release.

R283.6

国家自然科学基金资助项目（82204633）；中国博士后科学基金资助项目（2021M700550）；四川省自然科学基金资助项目（2022NSFSC0634）；四川省自然科学基金资助项目（2023NSFSC1782）；四川省中医药管理局中医药科研专项（2020JC0038）