目的 制备托法替尼醇质体温敏凝胶（Tof-ES-TG），考察其对溃疡性结肠炎（UC）模型小鼠的治疗作用。方法 薄膜分散法制备托法替尼醇质体（Tof-ES）。根据单因素实验结果，选择磷脂与胆固醇用量比、脂药比、水化体积为Tof-ES主要影响因素，采用Tof-ES包封率、载药量和粒径的总评归一值（OD）为评价指标，应用Box-Behnken设计-效应面法优化Tof-ES处方，泊洛沙姆188和泊洛沙姆407作为基质将Tof-ES制备成Tof-ES-TG。透射电镜（TEM）观察微观外貌。透析法考察体外释药行为，并对Tof-ES-TG进行流变学研究。采用葡聚糖硫酸钠建立UC模型，实验动物分为对照组、模型组、美沙拉嗪（阳性药，0.5 g·kg^-1）组、Tof-TG（50 mg·kg^-1）组及Tof-ES-TG低、高剂量组（25、50 mg·kg^-1），测定疾病活动指数（DAI）、结肠长度、结肠湿质量、结肠指数和肠黏膜损伤评分评价药效，苏木精-伊红（HE）染色观察结肠病理变化。结果 Tof-ES最佳处方为磷脂与胆固醇用量比12.5∶1，脂药比9.6∶1，水化体积16.0 mL。Tof-ES形态为椭圆形或球形，包封率、载药量、粒径和$\zeta$电位分别为（84.02±1.11）%、（7.64±0.17）%、（182.41±7.52）nm和（-18.16±0.40）mV。TofES-TG释药行为符合Weibull模型，24 h累积释放率为85.71%，流变学研究显示Tof-ES-TG具有固体弹性性质。体内实验结果表明，与Tof-TG组相比，Tof-ES-TG高剂量组DAI评分和肠黏膜损伤评分显著性下降，结肠长度、结肠指数和结肠湿质量显著性增加，治疗效果显著（P＜0.05、0.01）。与美沙拉嗪组相比，Tof-ES-TG高剂量组胸腺指数极显著性升高，脾脏指数极显著性下降，UC模型小鼠胸腺和脾脏的修复效果显著提高。结论 Tof-ES-TG制备工艺稳定，缓释特征明显，极大提高了Tof对结肠炎模型小鼠的治疗作用，值得进一步开发研究。

Objective To prerare tofacitinib ethanolosome thermosensitive gel (Tof-ES-TG) and investigate its therapeutic effect on ulcerative colitis (UC) model mice.Methods Tofacitinib ethosomes (Tof-ES) was prepared by film dispersion method. Based on the results of single-factor experiments, dosage ratio of phospholipid to cholesterol, dosage ratio of lipids to drug and hydration volume were selected as main influencing factors, overall desirability (OD) of entrapment efficiency, drug loading and particle size were acted as response values, Box-Behnken design-response surface method was used to optimize preparations of Tof-ES, and its micromorphology was observed by transmission electron microscopy (TEM). Poloxamer 188 and poloxamer 407 were used as the matrix to formulate Tof-ES into Tof-ES-TG, drug release in vitro was studied by dialysis method, and rheology of Tof-ES-TG was also studied. UC model was induced by dextran sulfate sodium salt, the experimental animals were divided into normal group, model group, mesalazine (positive drug, 0.5 g·kg^-1) group, Tof-TG (50 mg·kg^-1) group and Tof-ES-TG low and high dose (25, 50 mg·kg^-1) groups. Disease activity index (DAI), colon length, colon wet weight, colon index and intestinal mucosal damage score were measured to evaluate the efficacy, and the colon pathological changes were observed by hematoxylin-eosin (HE) staining.Results Optimal formulations of Tof-ES: phospholipid to cholesterol ratio was 12.5∶1, lipids to drug ratio was 9.6∶1 and a hydration volume was 16.0 mL. Morphology of Tof-ES was elliptical or spherical, with an encapsulation efficiency, drug loading, particle size and ζ potential of Tof-ES is· (84.02 ± 1.11) %, (7.64 ± 0.17) %, (182.41 ± 7.52) nm and (–18.16 ± 0.40) mV, respectively. Drug release behavior of Tof-ES-TG conformed to Weibull model, with a cumulative release rate of 85.71% at 24 h. Rheological studies showed that Tof-ES-TG had solid elastic properties. Compared with Tof-TG group, the DAI score and intestinal mucosal damage score of the Tof-ES-TG high dose group were significantly decreased, and the colon length, colon index and colon wet weight significantly increased, which indicating that therapeutic effects of Tof-ES-TG was better than that of the Tof-TG group(P<0.05, 0.01). Compared with mesalazine group, the thymus index of the Tof-ES-TG high dose group was significantly increased, and the spleen index was significantly decreased, indicating a significant improvement in the repair of the thymus and spleen in UC mod el mice.Conclusion Preparation process of Tof-ES-TG is stable, with obvious sustained-release characteristics, and significantly improves the therapeutic effect of Tof on colitis model mice, which is worthy of further development and research.

R283.6

南省科技攻关项目（242102310469）；河南省教