Posted by CDs enhance drug permeation across biomembranes predominantly through physicochemical and mass-transfer mechanisms rather than by disrupting membrane integrity or altering water structure. Hydrophilic CDs do not readily permeate lipophilic membranes and therefore do not function as classical chemical penetration enhancers. Instead, their effect on permeation is indirect and arises from modulation of drug solubility, maintenance of free-drug concentration, and facilitation of diffusion within the aqueous boundary layer. For lipophilic drugs with limited aqueous solubility, the increase in total drug flux from an aqueous suspension across the UWL–membrane barrier is attributable to an increase in the flux of the D/CD complex as its concentration rises. After diffusing through the UWL, drug molecules are released from the complex at the lipophilic membrane surface due to dilution and partitioning processes. Although the donor phase is saturated with drug, the aqueous layer immediately adjacent to the membrane remains unsaturated because of the relatively slow diffusion of free drug across the unsteered water layer (UWL) and the continuous partitioning of free drug into the membrane. When CD is present in excess of that required to solubilize the drug, the free-drug concentration at the membrane surface decreases, leading to reduced thermodynamic activity and diminished partitioning into the membrane. Consequently, CD-mediated enhancement is most pronounced when UWL resistance exceeds membrane resistance, particularly for poorly soluble, highly permeable (BCS Class II) drugs. The effect is concentration-dependent and typically exhibits a maximum, since excessive CD lowers the free-drug fraction and shifts the rate-limiting step to membrane partitioning. Overall, a mechanistic framework grounded in thermodynamic activity and diffusional resistance analysis provides a rational basis for predicting when CDs will enhance drug delivery across biomembranes.
Schematic drawing showing how a drug permeates from a drug-saturated aqueous CD solution through a membrane barrier consisting of an UWL and a lipophilic membrane.
Phatsawee Jansook, Thorsteinn Loftsson (2027) Drug permeation through biomembranes: Mechanism of cyclodextrin-mediated enhancement. Journal of Drug Delivery Science and Technology 127, 108861. https://doi.org/10.1016/j.jddst.2026.108861