目的 制备柚皮素胶束温敏凝胶（naringenin micelles-loaded thermosensitive gel，NMTG），评价其生物安全性和抗炎活性，并考察其对苯扎氯铵诱导干眼症（dry eye disease，DED）大鼠的治疗作用。方法 采用薄膜分散法制备柚皮素胶束（naringenin micelles，NM），并对其外观、粒径、ζ电位、透射电子显微镜（scanning electron microscopy，TEM）、包封率和载药量、稳定性等进行质量评价。以泪液稀释前、后NMTG相变温度T_gel和T_{atd gel}为考察指标，优选泊洛沙姆188（Poloxamer 188，P188）和泊洛沙姆407（Poloxamer 407，P407）的用量，将最优用量的P188和P407溶于NM中形成NMTG；研究其生物安全性、抗炎活性和对苯扎氯铵诱导DED大鼠的治疗作用。结果 制备的NM外观澄清透明，TEM观察NM呈类球形，平均粒径为（21.56±0.16）nm，多分散指数（polydispersity index，PDI）为0.053±0.033，ζ电位为（-18.63±1.94）mV，包封率为（73.96±0.24）%，载药量为（7.34±0.38）%，在14 d内稳定性良好。以P188、P407用量分别为5.29%和16.24%制得最佳NMTG；NMTG具有良好的生物安全性和抗炎活性，并且药效学实验证明NMTG对DED大鼠具有良好的治疗作用。结论 成功制备NMTG，提高柚皮素溶解度以使其具有良好的DED治疗作用，将为柚皮素在眼部应用的新适应证提供支持，并为柚皮素新剂型的开发提供候选方案。

Objective To prepare naringenin micelles-loaded thermosensitive gel (NMTG), evaluate its biological safety and anti-inflammatory activity, and investigate its therapeutic effects on dry eye disease (DED) induced by benzalkonium chloride (BAC) in rats. Methods Naringenin micelles (NM) were prepared by the thin-film dispersion method. Quality evaluations of the prepared NM included appearance, particle size, ζ potential, transmission electron microscopy, encapsulation efficiency, drug loading and stability. Concentrations of Poloxamer 188 (P188) and Poloxamer 407 (P407) were optimized based on the phase transition temperatures (T_gel and T_{atd gel}) of NMTG before and after dilution with tear fluid. Optimal concentrations of P188 and P407 were dissolved in NM to form NMTG. Biological safety, anti-inflammatory activity, and therapeutic effects on BAC-induced DED rats were investigated. Results Prepared NM was clear and transparent. Transmission electron microscopy showed near-spherical particles with an average particle size of (21.56 ± 0.16) nm, a polydispersity index (PDI) value of 0.053 ± 0.033, and a ζ potential of (-18.63 ± 1.94) mV. Encapsulation efficiency and drug loading were (73.96 ± 0.24)% and (7.34 ± 0.38)%, respectively, and the stability was good within 14 d. The optimal NMTG was achieved with concentrations of 5.29% P188 and 16.24% P407. NMTG demonstrated good biological safety and anti-inflammatory activity. Pharmacological experiments indicated that NMTG showed favorable therapeutic effects on DED rats. Conclusion The successful preparation of NMTG improve the solubility of naringenin, which endow it with good DED therapeutic effects. This will provide support for new indications of naringenin in ocular applications and offer candidate solutions for the development of new naringenin dosage forms.

R283.6

山东省自然科学基金项目（ZR2019BH070）；济宁医学院大学生创新创业训练计划项目重点项目（cx2024018z）