Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
PLoS One. 2013 Jul 16;8(7):e68237. doi: 10.1371/journal.pone.0068237. Print 2013.
The purpose of this study was to investigate the impact of oral cyclodextrin-based formulation on both the apparent solubility and intestinal permeability of lipophilic drugs. The apparent solubility of the lipophilic drug dexamethasone was measured in the presence of various HPβCD levels. The drug's permeability was measured in the absence vs. presence of HPβCD in the rat intestinal perfusion model, and across Caco-2 cell monolayers. The role of the unstirred water layer (UWL) in dexamethasone's absorption was studied, and a simplified mass-transport analysis was developed to describe the solubility-permeability interplay. The PAMPA permeability of dexamethasone was measured in the presence of various HPβCD levels, and the correlation with the theoretical predictions was evaluated. While the solubility of dexamethasone was greatly enhanced by the presence of HPβCD (K1:1 = 2311 M(-1)), all experimental models showed that the drug's permeability was significantly reduced following the cyclodextrin complexation. The UWL was found to have no impact on the absorption of dexamethasone. A mass transport analysis was employed to describe the solubility-permeability interplay. The model enabled excellent quantitative prediction of dexamethasone's permeability as a function of the HPβCD level. This work demonstrates that when using cyclodextrins in solubility-enabling formulations, a tradeoff exists between solubility increase and permeability decrease that must not be overlooked. This tradeoff was found to be independent of the unstirred water layer. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.
本研究旨在探究口服环糊精制剂对亲脂性药物表观溶解度和肠道渗透性的影响。在不同 HPβCD 浓度下测量亲脂性药物地塞米松的表观溶解度。在大鼠肠灌流模型和 Caco-2 细胞单层中，在有无 HPβCD 的情况下测量药物的渗透性。研究了非搅拌水层 (UWL) 在地塞米松吸收中的作用，并开发了简化的质量传递分析来描述溶解度-渗透性相互作用。在存在各种 HPβCD 浓度的情况下测量地塞米松的 PAMPA 渗透性，并评估与理论预测的相关性。虽然 HPβCD 的存在极大地提高了地塞米松的溶解度 (K1:1 = 2311 M(-1))，但所有实验模型均表明，环糊精络合后药物的渗透性明显降低。发现 UWL 对地塞米松的吸收没有影响。采用质量传递分析来描述溶解度-渗透性相互作用。该模型能够出色地定量预测地塞米松的渗透性随 HPβCD 浓度的变化。本研究表明，在使用环糊精增加溶解度的制剂时，必须注意溶解度增加和渗透性降低之间的权衡，不能忽视这一点。这种权衡与非搅拌水层无关。本文提出的传输模型可以帮助达到适当的溶解度-渗透性平衡，从而实现最佳的整体吸收。
