目的 基于羧甲基壳聚糖（carboxymethyl chitosan，CMC）-氧化透明质酸（oxidized hyaluronic acid，OHA）的自组装行为，构建一种用于局部递送难溶性药物的pH响应型纳米乳水凝胶给药系统。方法 采用自乳化法制备丹参酮II_A（tanshinone Ⅱ_A，Tan II_A）纳米乳，通过平衡溶解度的考察和伪三元相图的绘制优化纳米乳处方，对纳米乳进行理化性质考察。高碘酸钠氧化法制备OHA，以成胶时间为指标优选CMC和OHA的浓度。将OHA溶解于纳米乳中与CMC溶液自组装形成Tan II_A纳米乳水凝胶（CMC-OHA/Tan II_A-NBHs）。对得到的CMC-OHA/Tan II_A-NBHs进行理化性质和体外抑菌活性评价。结果 优化处方可制备得到O/W型Tan II_A纳米乳，粒径为（52.18±0.15）nm，PDI为0.165±0.012。自组装得到的CMC-OHA/Tan II_A-NBHs具有良好的稳定性、酸响应性和药物缓释性能。抑菌圈实验表明CMC-OHA/Tan II_A-NBHs体外可显著抑制痤疮丙酸杆菌和金黄色葡萄球菌的生长。结论 CMC-OHA/Tan II_A-NBHs制备方法简便、稳定性好，可以有效改善难溶性药物的体外溶出行为，为纳米乳局部递送难溶性药物提供了新的思路和方法。

Objective To construct a pH-responsive nanoemulsion hydrogel drug delivery system based on the self-assembly behavior of carboxymethyl chitosan (CMC)-oxidized hyaluronic acid (OHA) for the topical delivery of in poor solubility drugs. Methods The optimum prescription of nanoemulsion was determined according to the amount of tanshinone Ⅱ_A (Tan II_A) dissolved in various excipients and the pseudo-ternary phase diagram and the physicochemical properties of the nanoemulsion were investigated. Furthermore, OHA was prepared by sodium periodate oxidation and the concentration of CMC and OHA is optimized by using the gel formation time as an indicator. CMC-OHA Tan II_A nanoemulsion-based hydrogels (CMC-OHA/Tan II_A-MBHs) were prepared by dissolving OHA in nanoemulsion and self-assembling the mixture with CMC solution. Physicochemical properties and in vitro antibacterial activity of CMC-OHA/Tan II_A-MBHs were observed and detected. Results The mean particle size of the prepared Tan II_A nanoemulsion was (52.18 ±0.21) nm and PDI was 0.165 ±0.012. The in vitro evaluation results showed CMC-OHA/Tan II_A-NBHs had good centrifugal stability, light stability, pH responsiveness, and sustained-release properties. The bacterial inhibition ring test showed that CMC-OHA/TanII_A-NBHs could significantly inhibit the growth of Propionibacterium acnes and Staphylococcus aureus in vitro. Conclusion With the advantages of simple preparation and good stability, CMC-OHA/Tan Ⅱ_A-MBHs could effectively improve the in vitro dissolution behavior of insoluble drugs, providing a new idea and method for topical delivery of poorly soluble drugs by nanoemulsion.

R283.6

国家自然科学基金面上项目（81873092）