HMG-CoA还原酶抑制剂SIPI-4887的处方前和制剂初步研究（英文）  

Preformulation and Preliminary Pharmaceutics Study of SIPI-4887, an HMG-Co A Reductase Inhibitor

作　　者：柴鸿宇 李丹丹[1] 高大林 杨晶晶[1] 赵雁[1] 柴旭煜[1] 陶涛[1] 

机构地区：[1]中国医药工业研究总院药物制剂国家工程研究中心,上海201203

出　　处：《中国医药工业杂志》2017年第12期1704-1715,共12页Chinese Journal of Pharmaceuticals

摘　　要：SIPI-4887是他汀类候选药物,能有效降低脂蛋白胆固醇,但由于其溶解度较低,制剂难度较大。本试验主要研究了其理化性质,并初步设计了能提高其溶解度和生物利用度的给药系统系统。处方前研究主要包括SIPI-4887的溶解度、log D、吸收速率常数(K_a)和表观渗透系数(P_(app))的测定,并观察到它具有肝肠循环现象。在此基础上,使用自微乳化载药系统(SMEDDS)和固体分散体(SD)对其进行了初步制剂学及药动学研究。两种制剂的最优处方分别为:自乳化系统含中链甘油三酯(30%)、Cremophor EL(55%)、Transcutol HP(15%)和另外加入的5%药物;固体分散体中药物和Soluplus(PVCL-PVAc-PEG)质量比为1∶9,采用热熔挤出(HME)制备。体外释放研究表明自微乳化和固体分散体制剂能不同程度地提高SIPI-4887的溶解度。大鼠体内药动学研究表明,自微乳和固体分散体制剂与其2.5%DMSO/2.5%Tween-80溶液相比能增加SIPI-4887的口服生物利用度。SIPI-4887, an HMG-CoA reductase inhibitor, is an effective cholesterol-lowering agent with poor water solubility and low bioavailability. This work aimed to investigate the physicochemical properties of SIPI-4887,and develop preliminary drug delivery systems to improve the solubility and oral bioavailability of SIPI-4887. Solubility,logD, absorption rate constant （Ka） and apparent permeability coefficients （Papp） of SIPI-4887 were determined using classic methods, and the enterohepatic cycle phenomenon of SIPI-4887 was discovered. Based upon these researches, the self-microemusifying drug delivery system （SMEDDS） and the solid dispersion （SD） were chosen to do further pharmaceutical study. The optimized formulation of SMEDDS was medium chain triglyceride （MCT, 30%）, Cremophor EL （55%）, and Transcutol HP （15%） with 5% active pharmaceutical ingredients （API） added in, and that of SD was drug and Soluplus （PVCL-PVAc-PEG） with a mass ratio of 1∶9, using hot melt extrusion （HME）. The solubility of SIPI-4887 was increased in SMEDDS and SD at various degrees. The dissolution study in vitro showed that SIPI-4887 in SMEDDS and SD could quickly dissolve in water and pH 6.8 phosphate buffer. Pharmacokinetic experiment in rats demonstrated that SMEDDS and SD could improve the oral absorption of SIPI-4887 compared with its 2.5% DMSO/2.5% Tween-80 solution. The research results in this paper have promised that SIPI-4887-SMEDDS or SIPI-4887-SD can serve as a practical oral preparation for the treatment of hyperlipemia.

关 键 词：HMG-COA还原酶抑制剂 自微乳给药系统 固体分散体 溶解度 生物利用度 

分 类 号：R944.9[医药卫生—药剂学]