目的 研制枸橼酸托法替布控释胶囊,考察释药机制,评价其大鼠体内药动学行为。方法 采用挤出-滚圆法制备枸橼酸托法替布速释微丸;制备丸芯,以乙基纤维素(EC)等为包衣材料,对丸芯采用流化包衣技术制备枸橼酸托法替布缓释微丸;将速释微丸与缓释微丸以一定比例混合,填充胶囊,制备枸橼酸托法替布控释胶囊;测定控释胶囊体外释放度,拟合释放动力学方程,考察释药机制;大鼠口服枸橼酸托法替布、枸橼酸托法替布片和枸橼酸托法替布控释胶囊,采用LC-MS测定枸橼酸托法替布的血药浓度,采用DAS2.0软件计算药动学参数,并进行体内-体外相关性评价。结果 速释微丸最佳处方组成为枸橼酸托法替布-微晶纤维素(MCC)-乳糖-羧甲基淀粉钠(CMS-Na)-水=1.24∶5.92∶11.84∶1.00∶24.6;缓释微丸最佳处方:丸芯为枸橼酸托法替布-MCC-水=10.0∶190.0∶220.0,缓释膜材为5%EC乙醇溶液,包衣增重7.33%;控释胶囊中速释微丸与缓释微丸最佳比例为1∶9;制备的控释胶囊2、6、12、16、24 h释放度分别为11.72%、31.91%、50.03%、66.64%、96.75%,释放速度符合零级动力学方程,释放机制,为扩散和溶蚀双重作用;制备的控释胶囊在水及pH1.0、3.6、5.0、6.8、7.5的缓冲液中释放度差异因子f₁均小于15,相似因子f₂均大于50,相似性好;控释胶囊与原料药、参比制剂主要药动学参数:ρ_max分别为(13.65±1.43) (19.10±2.21)和(39.44±4.43) μg·mL^-1,t_max分别为(0.5±0.042) (1±0.14)和(1±0.12) h,AUC_0-t分别为(394.016±31.45) (105.403±10.21)和(195.728±17.23) μg·h·mL^-1,MRT_0-t分别为(14.947±1.12) (4.634±0.42)和(4.109±0.39) h,CL分别为(0.002±0.000 1) (8.535±0.76)和(4.389±0.37) L·h^-1·kg^-1;体内-体外相关性回归方程为y=1.004 3x+1.383 6,r=0.999 3。结论 枸橼酸托法替布控释胶囊在24 h内呈良好控释特性,体内外相关性好,起效更快、药效延长,生物利用度更高。

OBJECTIVE To develop tofacitinib citrate controlled-release capsule, investigate the release mechanism, and evaluate its pharmacokinetic behavior in rats. METHODS Tofacitinib citrate immediate-release pellets were prepared by extrusion-spheronization method. The pellet cores were prepared, tofacitinib citrate sustained-release pellets were prepared by fluidized coating technology with ethyl cellulose (EC) as the coating material. The immediate-release pellets and the sustained-release pellets were mixed in a certain ratio, and then filled into the capsules to prepare tofacitinib citrate controlled-release capsules. The release in vitro of the controlled-release capsules were determined, the release kinetic equation was fitted and the drug release mechanism was investigated. Rats were orally administered tofacitinib citrate, tofacitinib citrate tablets and tofacitinib citrate controlled-release capsules, the plasma concentration of tofacitinib citrate was determined by LC-MS, the pharmacokinetic parameters were calculated by the DAS 2.0 software, and the correlation between in vivo-in vitro was evaluated. RESULTS The best prescription composition of immediate-release pellets was tofacitinib citrate: microcrystalline cellulose (MCC)-lactose-sodium carboxymethyl starch (CMS-Na)-water=1.24∶5.92∶11.84∶1.00∶ 24.6. The best prescription for sustained-release pellets: the pill cores composition was tofacitinib citrate-MCC-water=10.0∶190.0∶220.0, the sustained-release coating membrane materials was 5% EC ethanol solution, and the coating weight gain was 7.33%. The best ratio of immediate-release pellets to sustained-release pellets in controlled-release capsules was 1∶9. The release rates of the controlled release capsules were 11.72%, 31.91%, 50.03%, 66.64%, and 96.75%, respectively at 2, 6, 12, 16, and 24 h, the release rate conformed to the zero-order kinetic equation, and the release mechanism conformed to Ritger-Peppas equation, belonged to the dual role of diffusion and dissolution. The release rates difference factor f₁ of controlled-release capsules were all less than 15, and the similarity factor f₂ was greater than 50 in water and pH 1.0, 3.6, 5.0, 6.8, 7.5 buffer solutions, and the similarity was good. The main pharmacokinetic parameters of the controlled-release capsule, the bulk drug and the reference preparation were as follows: ρ_max(13.65±1.43) (19.10±2.21) and (39.44±4.43) μg·mL^-1, t_max(0.5±0.042) (1±0.14) and (1±0.12) h, AUC_0-t(394.016±31.45) (105.403±10.21) and (195.728±17.23) μg·h·mL^-1, MRT_0-t(14.947±1.12) (4.634±0.42) and (4.109±0.39) h, CL(0.002±0.000 1) (8.535±0.76) and (4.389±0.37) L·h^{- 1}·kg^-1. The regression equation of the in vivo-in vitro correlation was y=1.004 3x+1.383 6, r=0.999 3. CONCLUSION Tofacitinib citrate controlled-release capsules showed good controlled-release characteristics within 24 h, belonging to a dual-diffusion mechanism of diffusion and erosion, which have good correlations internal and external, with faster onset of action, prolonged efficacy, and higher bioavailability.