Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Eur J Pharm Biopharm. 2013 Nov;85(3 Pt B):1293-9. doi: 10.1016/j.ejpb.2013.05.018. Epub 2013 Jun 11.
The purpose of this study was to investigate the interaction of 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 2,6-dimethyl-β-cyclodextrin (DMβCD) with the lipophilic drug nifedipine and to investigate the subsequent solubility-permeability interplay. Solubility curves of nifedipine with HPβCD and DMβCD in MES buffer were evaluated using phase solubility methods. Then, the apparent permeability of nifedipine was investigated as a function of increasing HPβCD/DMβCD concentration in the hexadecane-based PAMPA model. The interaction with nifedipine was CD dependent; significantly higher stability constant was obtained for DMβCD in comparison with HPβCD. Moreover, nifedipine displays different type of interaction with these CDs; a 1:1 stoichiometric inclusion complex was apparent with HPβCD, while 1:2 stoichiometry was apparent for DMβCD. In all cases, decreased apparent intestinal permeability of nifedipine as a function of increasing CD level and nifedipine apparent solubility was obtained. A quasi-equilibrium mass transport analysis was developed to explain this solubility-permeability interplay; the model enabled excellent quantitative prediction of nifedipine's permeability as a function of CD concentrations. This work demonstrates that when using CDs in solubility-enabling formulations, a trade-off exists between solubility increase and permeability decrease that must not be overlooked. This trade-off was found to be independent of the type of CD-drug interaction. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.
本研究旨在考察亲脂性药物硝苯地平与 2-羟丙基-β-环糊精（HPβCD）和 2,6-二甲基-β-环糊精（DMβCD）的相互作用，并研究随后的溶解度-渗透性相互作用。采用相溶解度法评价硝苯地平与 HPβCD 和 DMβCD 在 MES 缓冲液中的溶解度曲线。然后，在基于十六烷的 PAMPA 模型中，考察硝苯地平的表观渗透随 HPβCD/DMβCD 浓度增加的变化情况。与硝苯地平的相互作用与 CD 有关；与 HPβCD 相比，DMβCD 获得了更高的稳定常数。此外，硝苯地平与这些 CD 显示出不同类型的相互作用；与 HPβCD 明显形成 1:1 化学计量的包合络合物，而与 DMβCD 则形成 1:2 化学计量的络合物。在所有情况下，随着 CD 水平的增加和硝苯地平表观溶解度的增加，硝苯地平的表观肠道渗透性均降低。建立了准平衡质量传递分析来解释这种溶解度-渗透性相互作用；该模型能够极好地定量预测硝苯地平的渗透性随 CD 浓度的变化。本工作表明，在使用 CD 增加溶解度的配方中，溶解度的增加与渗透性的降低之间存在权衡，不可忽视。这种权衡与 CD-药物相互作用的类型无关。本文提出的传输模型有助于在溶解度和渗透性之间取得适当的平衡，以实现最佳的整体吸收。
