Analysis of skin penetration enhancing effect of drugs by ethanol-water mixed systems with hydrodynamic pore theory

Skin permeation of drugs from ethanol-water mixed systems was evaluated by the hydrodynamic pore theory. Two model drugs of similar molecule size and different polarities, isosorbide dinitrate (ISDN) and antipyrine (ANP) were used, and the relationship between drug clearance and solvent flux through excised hairless rat skin was investigated with a variety of ethanol concentrations (20-100%) in water to calculate the reflection coefficient (delta) of the drugs to the skin. The ISDN clearance was independent of the solvent flux at 20% ethanol, but was dependent on the flux at more than 40% ethanol. Linear relationships. were obtained between the ANP clearance and the solvent flux at all ethanol concentrations. These results suggest high contribution of convective flow with the solvent to the total skin permeability of both drugs. Skin must be delipidized by a high concentration of ethanol in water, thus the barrier function of the stratum corneum to overall permeation of the drugs was reduced. The apparent pore radius of skin estimated from the delta value of ANP differed according to the ratio of ethanol and water in the systems: 100% ethanol was maximum (1.89 +/- 1.24 nm) followed by 0% ethanol (0.98 +/- 0.60 nm) and the mixed solutions had a mean value of 0.42-0.50 nm.