Modeling skin permeability to hydrophilic and hydrophobic solutes based on four permeation pathways

Barrier properties of skin originate from low permeability of stratum corneum. The objective of this paper is to compile fundamentally-based analytical expressions that can be used to predict skin permeability to hydrophilic as well as hydrophobic solutes. Solute permeation through four possible routes in stratum corneum including free-volume diffusion through lipid bilayers, lateral diffusion along lipid bilayers, diffusion through pores, and diffusion through shunts was analyzed. Contribution of free-volume diffusion through lipid bilayers was determined using Scaled Particle Theory. This theory relates solute partition and diffusion coefficients to the work required to create cavities in a lipid bilayers to allow solute incorporation and motion. Contribution of lateral lipid diffusion was determined from the literature data. Contribution of pores was estimated using hindered transport theory. This theory assumes that hydrophilic solutes permeate across the skin through imperfections in the lipid bilayers modeled as pores. Finally, contribution of shunts was determined using a simple diffusion model. The model yielded a series of equations to predict skin permeability based on solute radius and octanol-water partition coefficient. Predictions of the model compare well with the experimental data.