Predicting the solubility-permeability interplay when using cyclodextrins in solubility-enabling formulations: Model validation

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• 作者：Jonathan M. Miller ; Arik Dahan ; ^{arikd@bgu.ac.il}
• 关键词：Low-solubility drugs ; Cyclodextrins ; Solubility&ndash ; permeability interplay ; Solubility&ndash ; permeability tradeoff ; Intestinal permeability ; Oral drug delivery
• 刊名：International Journal of Pharmaceutics
• 出版年：2012
• 期刊代码：24_03785173
• 类别：pha
• 出版时间：1 July, 2012
• 卷：430
• 期：1-2
• 页码：388-391
• 文件大小：475 K

摘要

Although the extraordinary solubility advantage afforded by cyclodextrins has led to their widespread use as pharmaceutical solubilizers, several reports have emerged that cyclodextrins may also reduce the apparent permeability of the drug. With the purpose to investigate this solubility-permeability interplay, we have recently developed a mathematical mass transport model that quantitatively explains the impact of molecular complexation on the intestinal permeability. This model enabled excellent quantitative prediction of progesterone P_eff as a function of HP尾CD concentrations in several experimental methods. The purpose of the present study was to challenge the predictive capabilities of this mathematical model, assessing whether the model allows the prediction of literature permeability data, as a model validation method. The mass-transport model was applied to carbamazepine and hydrocortisone, and the predicted permeability (P_eff, P_m and P_aq) vs. HP尾CD concentration were plotted. Excellent agreement was obtained between literature experimental permeability and the predicted P_eff values for both compounds at all of the HP尾CD concentrations tested. The presented validated model that considers the opposing effects of the formulation on the solubility and the permeability, can lead to a more efficient and intelligent use of molecular complexation strategies; the formulator will be able to a priori strike the optimal solubility-permeability balance to maximize and facilitate the overall oral drug absorption.