IONTOPHORETIC DELIVERY ACROSS THE SKIN - ELECTROOSMOSIS AND ITS MODULATION BY DRUG SUBSTANCES

Purpose. The long-term objective of this research is to understand how the efficiency of iontophoresis depends upon the structural and physi cochemical properties of the administered drug. Specifically, the abil ity of certain drug species to alter the permselective properties of t he skin was examined. Methods. Using conventional in vitro methodology , the inhibition of electroosmotic flow induced by the iontophoresis o f five different beta-blockers (of varying lipophilicity) was examined . The concomitant electrotransport of the most lipophilic species (pro pranolol) and the convective movement of solvent in the anode-to-catho de direction were measured. In addition, the possibility that electroo smosis might be augmented by the delivery of anionic drugs was also co nsidered. Results. Iontophoresis of lipophilic, cationic beta-blockers caused a concentration-dependent inhibition of conventional electroos mosis. The most hydrophilic analogs elicited no effect. As a result of this charge neutralization phenomenon, the optimal concentration for propranolol iontophoresis was significantly less than the maximum achi evable in aqueous solution. Only a very modest improvement in convecti ve solvent flow was induced by the cathodal iontophoresis of anionic c ompounds. Conclusions. The permselectivity of the skin can be altered by drugs which are positively charged and which possess a significant, adjacent hydrophobic surface. The latter seems able to ''anchor'' the molecule in the skin and the counter charge to the membrane's negativ e character ensures a tight association. Both lipophilicity and a posi tive charge are essential-without either, the phenomenon is not observ ed. The conformational flexibility of the drugs studied to-date, howev er, prevents unambiguous conclusions about the three-dimensional natur e of the putative ''binding site''.