盐酸伊伐布雷定缓释微丸的制备工艺及其药动学研究  

Research on the preparation and pharmacokinetics of ivabradine hydrochloride sustained-release pellets

作　　者：李翰铭 尹虹 张金伟 吴燕 邢佳丽 刘雨欣 赵利刚 LI Hanming;YIN Hong;ZHANG Jinwei;WU Yan;XING Jiali;LIU Yuxin;ZHAOLigang(School of Pharmacy,North China University of Science and Technology,Tangshan 063210,China;Tangshan Key Laboratory of Novel Preparations and Drug Release Technology,Tangshan 063000,China)

机构地区：[1]华北理工大学药学院,河北唐山063210 [2]唐山市新型药物制剂与释药技术重点实验室,河北唐山063000

出　　处：《沈阳药科大学学报》2024年第7期875-882,共8页Journal of Shenyang Pharmaceutical University

基　　金：河北省“青年拔尖人才”项目;华北理工大学杰出青年基金项目(JQ201713)。

摘　　要：目的制备盐酸伊伐布雷定缓释微丸,考察其载药率、体外释放度及其在大鼠体内的药动学特征。方法采用流化床包衣法制备盐酸伊伐布雷定缓释微丸,以载药率为评价指标,通过正交试验设计优化载药层工艺参数,以体外释放度为评价指标,通过响应面实验设计优化缓释层处方。健康雄性SD大鼠随机分成2组:盐酸伊伐布雷定缓释微丸组和盐酸伊伐布雷定片组,单次给药后,测定不同时间点的血药浓度,运用Das20软件计算药动学参数。结果载药层处方:盐酸伊伐布雷定原料药075 g、羟丙基甲基纤维素180 g、水40 g,流化床工艺参数:进风量13 m^(3)·h^(-1)、进风温度50℃、雾化压力12 bar、蠕动泵流速09 mL·min^(-1);缓释层处方:乙基纤维素78%、聚乙二醇400091%、柠檬酸三乙酯20%。平均载药率924%,12 h累计释放度为9237%;盐酸伊伐布雷定缓释微丸较普通片剂的相对生物利用度为13559%。结论盐酸伊伐布雷定缓释微丸制备工艺重现性良好,体内外缓释效果明显,生物利用度显著提高,为盐酸伊伐布雷定缓释制剂的研究提供了基础。Objective To prepare ivabradine hydrochloride sustained-release pellets,and to investigate their drug loading rate,in vitro release and pharmacokinetics in rats.Methods Ivabradine hydrochloride sustained-release pellets were prepared by the fluidized bed coating method.With the drug loading rate as the evaluation index,the process parameters of the drug loading layer were optimized by orthogonal test design,The formulation of sustained-release layer was optimized by response surface methodology.Healthy male SD rats were randomly divided into two groups:ivabradine hydrochloride sustained-release pellets group and ivabradine hydrochloride tablets group.After single administration,the blood drug concentrations were measured at different time points,and the pharmacokinetic parameters were calculated using Das20 software.Results The prescription of drug carrier layer:075 g ivabradine hydrochloride API,180 g hydroxypropyl methylcellulose and 40 g water.The technological parameters of fluidized bed:inlet air volume of 13 m^(3)·h^(-1),inlet air temperature at 50℃,atomization pressure at 12 bar,flow rate of peristaltic pump 09 mL·min^(-1);The formulation of sustained-release layer 78%ethyl cellulose,91%polyethylene glycol 4000 and 20%triethyl citrate.The average drug loading rate was 924%,and the cumulative release rate was 9237%after 12 h.The relative bioavailability of ivabradine hydrochloride sustained-release pellets was 13559%compared with tablets.Conclusion The preparation process of ivabradine hydrochloride sustained-release pellets has good reproducibility,obvious sustained-release effect in vivo and in vitro,and significantly improved bioavailability,which provides a basis for the study of ivabradine hydrochloride sustained-release preparations.

关 键 词：盐酸伊伐布雷定 缓释微丸 流化床 正交试验 响应面试验设计 药动学 

分 类 号：R94[医药卫生—药剂学]