Permeation Mechanism of Caffeine and Naproxen through in vitro Human Epidermis: Effect of Vehicles and Penetration Enhancers

Background/Aims: The mechanisms by which permeation enhancers increase human skin permeation of caffeine and naproxen were assessed in vitro. Methods: Active compound solubility in the vehicles and in the stratum corneum (SC), active compound flux across epidermal membranes and uptake of active and vehicle components into the SC were measured. The effect of vehicle pH on the permeation of caffeine and naproxen was also determined. Results: Oleic acid and eucalyptol significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous controls. Naproxen permeation was increased from vehicles with pH presenting more ionized naproxen. Caffeine maximum flux enhancement was associated with an increase in caffeine SC solubility and skin diffusivity, whereas for naproxen a penetration enhancer/vehicle-induced increase in solubility in the SC correlated with an increase in maximum flux. SC solubility was related to experimentally determined active uptake, which was in turn predicted by vehicle uptake and active compound solubility in the vehicle. Conclusion: A permeation enhancer-induced alteration in diffusivity, rather than effects on SC solubility, was the main driving force behind increases in permeation flux of the hydrophilic molecule caffeine. For the more the lipophilic molecule naproxen, increased SC solubility drove the increases in permeation flux. (C) 2019 S. Karger AG, Basel