Development of a self-emulsifying formulation that reduces the food effect for torcetrapib
Development of a self-emulsifying formulation that reduces the food effect for torcetrapib
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DOI：
10.1016/j.ijpharm.2007.09.015
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发表时间：
2008-03-03
影响因子：
5.8
通讯作者：
Erhart, L. C.
中科院分区：
文献类型：
--
作者：
Perlman, M. E.;Murdande, S. B.;Erhart, L. C.
Torcetrapib 是一种高亲脂性 (Clog P=7.45) 和水不溶性胆固醇酯转移蛋白 (CETP) 抑制剂，开发用于治疗动脉粥样硬化。自乳化药物递送系统 (SEDDS) 配方已被开发出来，以减少使用中链甘油三酯 (MCT) 软胶囊的早期临床试验中观察到的食物效应，并增加每粒胶囊的剂量。 MCT/三醋精/聚山梨酯 80/Capmul MCM (20/30/20/30) (MTPC) 增加了狗的禁食暴露量，因此在 90 mg 剂量下将食物效应从 5 倍降低到 3 倍。自乳化制剂还加速吸收并通常降低变异性。使用亲脂性 GRAS 共溶剂三醋精可使每粒胶囊的剂量增加 2 倍。对于在狗身上评估的三种吸收表现出显着差异的制剂，乳液液滴大小似乎没有发挥显着作用。吸收确实随着 Cremophor RH40 含量的增加而增加，并且在 50% Cremophor RH40 下，没有食物效应（30 mg）。高极性表面活性剂含量也会导致较差的剂量比例，而 MTPC 则具有良好的剂量比例。正在进行体外脂肪分解研究，以帮助了解 torcetrapib SEDDS 吸收的体外/体内关系。 (C) 2007 Elsevier B.V. 保留所有权利。
Torcetrapib is a highly lipophilic (Clog P=7.45) and water insoluble cholesteryl ester transfer protein (CETP) inhibitor developed for the treatment of atherosclerosis. Self-emulsifying drug delivery system (SEDDS) formulations have been developed to reduce the food effect observed in early clinical trials using medium chain triglyceride (MCT) softgels and to increase the dose per capsule. MCT/Triacetin/Polysorbate 80/Capmul MCM (20/30/20/30) (MTPC) increased fasted exposure and thus reduced the food effect from 5- to 3-fold in dogs at a dose of 90 mg. Self-emulsifying formulations also accelerated absorption and generally decreased variability. Use of the lipophilic, GRAS cosolvent triacetin allowed a 2-fold increase in the dose per capsule. For the three formulations evaluated in dogs that showed significant differences in absorption, emulsion droplet size did not appear to play a significant role. Absorption did increase with Cremophor RH40 content, and at 50% Cremophor RH40 there was no food effect (at 30 mg). High polar surfactant content also resulted in poor dose proportionality, while there was good dose proportionality for MTPC. Studies of in vitro lipolysis are being conducted to aid in understanding the in vitro/in vivo relationships for torcetrapib SEDDS absorption. (C) 2007 Elsevier B.V. All rights reserved.