Transdermal delivery of drugs anti enhancement of percutaneous absorption

This paper describes 1) the drug delivery through the skin to produce syste mic effects, 2) the enhancement of percutaneous absorption by absorption en hancers, heating and complex formation, 3) the mechanism for the enhancemen t effect by enhancers, 4) the percutaneous absorption of peptides, and 5) t he pharmacokinetic analysis for percutaneous absorption. 1,3-Dinitroglyceri n, indomethacin (IND) and many drugs were efficiently absorbed via rat and rabbit skins in the presence of some enhancers, and using a microporous mem brane therapeutic plasma concentrations were maintained for a long time. En hancement of percutaneous absorption by the complex formation with fatty ac id was observed for propranolol (PL) in vitro and in vivo. Heating at 42-45 degrees C also enhanced the percutaneous absorption dramatically, with dec reased activation energies. The following mechanisms for the enhancement ef fect 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 cornifi ed 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 throug h the skin in the presence of some enhancers and specific inhibitors, with no proteolytic degradation. The pharmacokinetic model with two parallel abs orption processes, lipidic and aqueous pore transport pathways, in skin cou ld 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 describ e well the steady-state flux of peptides.