Drug permeation through biomembranes: Mechanism of cyclodextrin-mediated enhancement

Abstract

Drug permeation across biological membranes is governed by the interplay between diffusional resistances and thermodynamic driving forces. Cyclodextrins (CDs) are routinely employed in pharmaceutical formulations to enhance the aqueous solubility and stability of poorly water-soluble drugs; however, their influence on membrane permeation remains mechanistically debated. This review examines how CDs modulate drug transport across lipophilic biomembranes, with emphasis on the roles of the unstirred water layer (UWL) and drug thermodynamic activity.

Hydrophilic CDs do not act as classical chemical penetration enhancers because they do not readily partition into lipid membranes. Instead, their effects are indirect and arise from increased drug solubility, maintenance of free-drug concentration, and diffusion of drug/CD complexes within the aqueous boundary layer. CD-mediated enhancement occurs mainly when UWL resistance constitutes a major fraction of the total barrier. Under these conditions, CDs increase flux by facilitating drug transport across the aqueous layer while sustaining the thermodynamic driving force at the membrane surface. In contrast, when membrane resistance dominates or excessive CD lowers free-drug activity, permeation may remain unchanged or decrease.

Evidence from in vitro and in vivo studies, including skin, mucosal tissues, and artificial membranes, supports a unified framework in which permeation depends on the relative contributions of UWL and membrane resistances, drug/CD stability constants, and drug activity at the membrane interface. Maximum flux is typically observed when sufficient CD solubilizes the drug while maintaining saturation and high chemical potential in the donor phase.

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Phatsawee Jansook, Thorsteinn Loftsson, Drug permeation through biomembranes: Mechanism of cyclodextrin-mediated enhancement, Journal of Drug Delivery Science and Technology, Volume 127, Part 1, 2027, 108861, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108861.

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