Penetration Enhancers for Human Skin: Mode of Action of 2-Pyrrolidone and Dimethylformamide on Partition and Diffusion of Model Compounds Water, n-Alcohols, and Caffeine

Abstract

Penetration-enhancing solvents may modify diffusional routes through the stratum corneum and the partitioning of drugs into these pathways. To investigate the mechanisms of action of enhancers, steady-state fluxes were measured in vitro for polar methanol, nonpolar octanol, and an intermediate compound, caffeine, selected as model penetrants; human stratum corneum conditioned on both sides with water or accelerants (2-pyrrolidone or dimethylformamide solutions) was used. We determined partition, permeability, and apparent diffusion coefficients, and derived the standard free energy of transfer of the methylene group from water to stratum corneum (-423 cal mol-1); less negative values were obtained for transfer from 2-pyrrolidone solutions. We conclude that for these model compounds, and taking a fully hydrated membrane as a standard: (a) 2-pyrrolidone enhances permeation through the polar route of the skin by increasing the diffusivity, and reduces passage through the nonpolar route by decreasing diffusivity and partitioning, (b) dimethylformamide promotes polar route absorption by raising diffusivity and partitioning and reduces nonpolar absorption by decreasing both parameters, and (c) for caffeine, the markedly increased absorption (15-fold) caused by dimethylformamide is associated with damage to the membrane.