Lue Bena-Marie, Nielsen Flemming Seier, Magnussen Thomas, Schou Hanne Mette, Kristensen Kim, Jacobsen Lene Orup, Müllertz Anette
Department of Pharmaceutics and Analytical Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
Eur J Pharm Biopharm. 2008 Jun;69(2):648-57. doi: 10.1016/j.ejpb.2007.12.013. Epub 2007 Dec 25.
The usefulness of selected biorelevant dissolution media (BDM) to predict in vivo drug absorption was studied. Dissolution profiles of solid formulations of a poorly soluble model compound were compared in BDM simulating fasted and two levels of fed state. A non-physiologically relevant medium containing the cationic surfactant, cetrimide, was also investigated. All the media studied were capable of differentiating between the formulations employed, with formulation A consistently ranking high and formulations C and D ranking low. An in vivo dog study was carried out and an attempt was made to obtain a level A correlation between the plasma absorption curves and in vitro dissolution curves, using non-linear regression software. The in vitro-in vivo correlation (IVIVC) models developed indicated that fed state media (BDM 3) containing high levels of both bile salts (BS) and lipolysis products (LP) were best able to predict in vivo pharmacokinetic parameters (Cmax and AUC) with prediction errors lower than 10%. Overall, design and use of appropriate media for in vitro dissolution is extremely important. This study demonstrates the potential of physiologically relevant media containing both BS and LP for use in formulation and early drug development.
研究了选定的生物相关溶出介质（BDM）预测体内药物吸收的有效性。在模拟禁食和两种进食状态水平的BDM中比较了难溶性模型化合物固体剂型的溶出曲线。还研究了一种含有阳离子表面活性剂西曲溴铵的非生理相关介质。所研究的所有介质都能够区分所用的剂型，其中制剂A始终排名靠前，制剂C和D排名靠后。进行了一项体内犬类研究，并尝试使用非线性回归软件在血浆吸收曲线和体外溶出曲线之间获得A级相关性。所建立的体外-体内相关性（IVIVC）模型表明，含有高水平胆汁盐（BS）和脂解产物（LP）的进食状态介质（BDM 3）最能预测体内药代动力学参数（Cmax和AUC），预测误差低于10%。总体而言，设计和使用合适的体外溶出介质极其重要。本研究证明了含有BS和LP的生理相关介质在制剂和早期药物开发中的应用潜力。
