文献类型：期刊文献

中文题名：枸橼酸托法替布控释胶囊的研制及其释药机制和初步药动学研究

英文题名：Preparation,Release Mechanism and Preliminary Pharmacokinetics of Tofacitinib Citrate Controlled-Release Capsules

作者：杨群[1];张锴[2];李晓辉[1];李若琼[1];吴邵杰[1];姚航宇[1];张淑慧[1];骆翔[3]

机构：[1]绍兴文理学院元培学院,浙江绍兴312000;[2]浙江震元健康科技有限公司,浙江绍兴312000;[3]绍兴文理学院化学化工学院,脂溶性维生素浙江省工程研究中心,浙江绍兴312000

年份：2023

卷号：58

期号：13

起止页码：1186

中文期刊名：中国药学杂志

外文期刊名：Chinese Pharmaceutical Journal

收录：CSTPCD、、Scopus、CSCD2023_2024、北大核心、CSCD、PubMed、北大核心2020

基金：2018年绍兴市科技计划项目资助(2018C30009);2021年国家级大学生创新创业训练计划项目资助(202110349014);2019年国家级大学生创新创业训练计划项目资助(201910349006);2020年浙江省十二届大学生生命科学竞赛三等奖项目资助;2018年浙江省大学生科技创新活动计划暨新苗人才计划项目资助(2018R432017);2017年度大学生科技创新项目资助[绍市教高[2017]71号]。

语种：中文

中文关键词：枸橼酸托法替布;控释胶囊;研制;释放机制;药动学;相似性分析;体内外相关性

外文关键词：tofacitinib citrate;controlled-release capsule;preparation;release mechanism;pharmacokinetics;similarity analysis;in vivo and in vitro correlation

中文摘要：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),MRT0-t分别为(14.947±1.12)(4.634±0.42)和(4.109±0.39)h,CL分别为(0.002±0.0001)(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=1.0043x+1.3836,r=0.9993。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。

外文摘要：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),MRT0-t(14.947±1.12)(4.634±0.42)and(4.109±0.39)h,CL(0.002±0.0001)(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=1.0043x+1.3836,r=0.9993.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.