目的 制備托法替尼醇質(zhì)體溫敏凝膠（Tof-ES-TG），考察其對潰瘍性結(jié)腸炎（UC）模型小鼠的治療作用。方法 薄膜分散法制備托法替尼醇質(zhì)體（Tof-ES）。根據(jù)單因素實(shí)驗(yàn)結(jié)果，選擇磷脂與膽固醇用量比、脂藥比、水化體積為Tof-ES主要影響因素，采用Tof-ES包封率、載藥量和粒徑的總評歸一值（OD）為評價指標(biāo)，應(yīng)用Box-Behnken設(shè)計(jì)-效應(yīng)面法優(yōu)化Tof-ES處方，泊洛沙姆188和泊洛沙姆407作為基質(zhì)將Tof-ES制備成Tof-ES-TG。透射電鏡（TEM）觀察微觀外貌。透析法考察體外釋藥行為，并對Tof-ES-TG進(jìn)行流變學(xué)研究。采用葡聚糖硫酸鈉建立UC模型，實(shí)驗(yàn)動物分為對照組、模型組、美沙拉嗪（陽性藥，0.5 g·kg^-1）組、Tof-TG（50 mg·kg^-1）組及Tof-ES-TG低、高劑量組（25、50 mg·kg^-1），測定疾病活動指數(shù)（DAI）、結(jié)腸長度、結(jié)腸濕質(zhì)量、結(jié)腸指數(shù)和腸黏膜損傷評分評價藥效，蘇木精-伊紅（HE）染色觀察結(jié)腸病理變化。結(jié)果 Tof-ES最佳處方為磷脂與膽固醇用量比12.5∶1，脂藥比9.6∶1，水化體積16.0 mL。Tof-ES形態(tài)為橢圓形或球形，包封率、載藥量、粒徑和$\zeta$電位分別為（84.02±1.11）%、（7.64±0.17）%、（182.41±7.52）nm和（-18.16±0.40）mV。TofES-TG釋藥行為符合Weibull模型，24 h累積釋放率為85.71%，流變學(xué)研究顯示Tof-ES-TG具有固體彈性性質(zhì)。體內(nèi)實(shí)驗(yàn)結(jié)果表明，與Tof-TG組相比，Tof-ES-TG高劑量組DAI評分和腸黏膜損傷評分顯著性下降，結(jié)腸長度、結(jié)腸指數(shù)和結(jié)腸濕質(zhì)量顯著性增加，治療效果顯著（P＜0.05、0.01）。與美沙拉嗪組相比，Tof-ES-TG高劑量組胸腺指數(shù)極顯著性升高，脾臟指數(shù)極顯著性下降，UC模型小鼠胸腺和脾臟的修復(fù)效果顯著提高。結(jié)論 Tof-ES-TG制備工藝穩(wěn)定，緩釋特征明顯，極大提高了Tof對結(jié)腸炎模型小鼠的治療作用，值得進(jìn)一步開發(fā)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

南省科技攻關(guān)項(xiàng)目（242102310469）；河南省教