Transdermal delivery of drugs and enhancement of percutaneous absorption

Abstract

This paper describes 1) the drug delivery through the skin to produce systemic effects, 2) the enhancement of percutaneous absorption by absorption enhancers, heating and complex formation, 3) the mechanism for the enhancement effect by enhancers, 4) the percutaneous absorption of peptides, and 5) the pharmacokinetic analysis for percutaneous absorption. 1,3-Dinitroglycerin, indomethacin (IND) and many drugs were efficiently absorbed via rat and rabbit skins in the presence of some enhancers, and using a microporous membrane therapeutic plasma concentrations were maintained for a long time. Enhancement of percutaneous absorption by the complex formation with fatty acid was observed for propranolol (PL) in vitro and in vivo. Heating at 42-45 degrees C also enhanced the percutaneous absorption dramatically, with decreased activation energies. The following mechanisms for the enhancement effect by enhancers were found: a) an increase in the fluidity of the stratum corneum lipids and reduction in the diffusional resistance to permeants, b) the removal of intercellular lipids and dilation between adherent cornified cells, c) an increase in the thermodynamic activity of drugs in vehicles, d) the exfoliation of stratum corneum cell membranes, the dissociation of adherent cornified cells and elimination of the barrier function. Peptides such as enkephalin, elcatonin and insulin were effectively absorbed through the skin in the presence of some enhancers and specific inhibitors, with no proteolytic degradation. The pharmacokinetic model with two parallel absorption processes, lipidic and aqueous pore transport pathways, in skin could adequately describe the percutaneous absorption of IND, PL and valproic acid. With peptides, a kinetic model including zero-order input rate, first-order permeation rate and first-order degradation rate was able to describe well the steady-state flux of peptides.