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Skin permeability of drugs was evaluated based on the hydrodynamic pore theory. Four polar solutes were used, with differing molecular sizes--ethylene glycol, 1,3-butylene glycol, antipyrine and sucrose--and isosorbide dinitrate was also selected as a lipophilic drug. The skin permeations of solvent (D2O) and one of these drugs were measured simultaneously under various osmotic pressures to calculate the reflection coefficient. The clearance of isosorbide dinitrate was independent of the solvent flux, whereas a linear relationship was obtained between the solvent flux and the clearance of each hydrophilic drug except for sucrose. The reflection coefficient of the hydrophilic drugs increased with increasing molecular radius. These results suggest that the convective flow contributes significantly to the total skin permeability of hydrophilic drugs and that the extent of contribution decreases with increasing molecular size of the drugs. The pore radius of the skin barrier could be estimated from the reflection coefficient of the hydrophilic drugs and the resulting value was compared with that for the other absorption sites, jejunum, rectum, and nose. The apparent water influx was also compared to assess the volume occupied by the pores. The pore radius and apparent influx of skin were lower than those for the other absorption sites, which is apparently one reason for low skin permeability of drugs, especially hydrophilic drugs.

A physiological pharmacokinetic model describing the absorption and disposition of topically applied drugs was proposed, and the effect of various pharmacokinetic and physiological parameters on the drug delivery into the targeted muscle was simulated. The proposed model consists of vehicle, and stratum corneum, viable epidermis and muscle below the application and reference sites, and plasma, each joined with transfer clearance and plasma flow. Indomethacin concentrations in tissues and plasma after topical application to rats could be explained by the model. Most indomethacin delivered into the underlying muscle was via direct penetration. The model simulation showed that the increase in plasma clearance and clearance between viable skin and muscle, and the decrease in application area and plasma flow rate into viable skin and muscle would promote the targeting efficacy of topically applied drugs to the underlying muscle.