The long-term objective of the proposed research is to understand the mechanism of alteration in skin barrier properties by iontophoresis in order to develop transdermal drug delivery systems for macromolecules, including polypeptide hormones. Initiation of current flow across the skin causes a rapid decrease in resistance of the membrane to achieve a new lower value. Voltage-induced effects, which decrease the electrical resistance and proportionally increase the flux of both ionic permeants and polar, non-ionic solutes, suggest that these effects are primarily electric field induced pore formation. However, physical presence of electric field induced pores in the HSC has not been demonstrated. The overall hypothesis to be evaluated is that skin resistance changes are due to ions in the media changing the number of ions in the skin and formation of pores during iontophoresis. To test these hypotheses, we propose studies with the following Specific Aims: 1) To determine the effect of a constant D.C. voltage (200-10,000 mV), concentration, and type of electrolytes on the resistance (conductivity) of the HSC; 2a) To characterize topographical (structural) changes in the HSC in real time at sub-micrometer to nanometer levels using AFM; and 2b) to determine the number and size of field-induced pores per unit surface area during iontophoresis using AFM. We believe that the proposed research will significantly enhance our basic understanding about alterations in skin by iontophoresis for non-invasive delivery of macromolecules, including polypeptide hormones such as human growth hormone and insulin.
