IONTOPHORESIS OF A MODEL PEPTIDE ACROSS HUMAN SKIN IN-VITRO - EFFECTSOF IONTOPHORESIS PROTOCOL, PH, AND IONIC-STRENGTH ON PEPTIDE FLUX ANDSKIN IMPEDANCE

This study deals with effects of electrical (current density, frequenc y and duty cycle) and chemical (buffer pH and ionic strength) conditio ns on the flux of the octapeptide, 9-desglycinamide, 8-arginine vasopr essin (DGAVP), through dermatomed human skin. A pulsed constant curren t was applied during iontophoresis. The anode faced the anatomical sur face of the skin samples inside the diffusion cells. The resistive and capacitative components of the equivalent electrical circuit of human skin could be calculated by fitting the voltage response to a bi-expo nential equation. The skin resistance prior to iontophoresis varied be tween 20 and 60 k Omega.cm(2). During iontophoresis a decrease of skin resistance and an increase of the series capacitances was observed, w hich were most pronounced during the first hour of iontophoresis; ther eafter both quantities gradually levelled off to an apparent steady st ate value. The reduction of the resistance during iontophoresis increa sed non-linearly with increasing current density between 0.013-0.64 mA .cm-(2). The steady state resistance and capacitances did not vary sig nificantly with frequency and duty cycle of the current pulse. There w as no pH dependence of skin resistance at steady state. Between pH 4 a nd 10, the steady state peptide flux had a bell-shaped pH-dependence w ith a maximum of 0.17 nmol.cm(-2).h(-1) at pH 7.4, which is close to t he I.E.P. of the peptide. Lowering the ionic strength from 0.15 to 0.0 15 M NaCl increased the steady state flux at pH 5 and pH 8 by a factor 5 to 0.28 +/- 0.21 and 0.48 +/- 0.37 nmol.cm(-2).h(-1), respectively. Together these observations suggested that DGAVP is transported predo minately by volume flow. At pH 6, at which 65% of the peptide carried a net single positive charge, the steady state flux increased with inc reasing current density (0.013-0.64 mA.cm(-2)) from O.11 +/- 0.03 to 0 .19 +/- 0.04 nmol.cm(-2).h(-1). Skin permeability during passive diffu sion preceding iontophoresis at pH 6.0 was 2.9 +/- 0.6 10(-7) cm.h(- 7). In accordance with theoretical predictions based on the Nernst-Pla nck equation, to which a volume flow term was added, the flux was prop ortional to the mean voltage across the skin between 0.013 and 0.32 mA .cm(-2).h(-1). Variation of frequency or duty cycle did not result in significantly different peptide transport rates. From these studies it is concluded that DGAVP can be transported iontophoretically through human skin. The pH- and ionic strength-dependence of the iontophoretic peptide flux suggests that transport of DGAVP mainly occurs by volume flow. Furthermore, the flux of DGAVP appears to be controlled by the applied voltage rather than by the current density, as predicted by th e Nernst-Planck equation.