Investigation of flux variability associated with human epidermal membrane iontophoresi

Transdermal drug delivery has been one of the alternatives to traditional oral drug delivery because of its many advantages. However, for transdermal drug delivery, physical methods and/or chemical enhancers often need to be used to enhance human skin permeability. Among these enhancement methods, iontophoresis has been one of the most extensively studied techniques because of its potential for delivering of drug molecules or extracting endogenous materials at a constant and/or programmable rate. The application of this promising technique, however, is hindered because of the issue of large flux variabilities and our lack of understanding of the mechanisms causing these variabilities.;The first topic of the present dissertation deals with the quantification of the contribution of pore induction during human skin iontophoresis by measuring changes in skin electrical resistance. It was found that skin resistance changes could be used to predict the contribution from electroporation only when the size of the background electrolyte ions matched those of the permeants. Larger or smaller size background electrolyte ions would cause either positive or negative deviations from the modified Nernst-Planck model predictions. These results also indicated that there was a pore size distribution change relative to the pre-existing pores when a constant voltage direct current was applied and that the average pore size became larger as a result of iontophoresis.;In order to deal with the flux variability observed in the traditional constant direct current iontophoresis, a technique has been developed in which the skin electrical resistance is maintained constant by adjusting the applied alternating current (AC) voltages. Constant permeant fluxes with less inter- and intrasample variability compared with the conventional constant direct current iontophoresis were obtained under this constant skin conductance conditions. From the mechanistic standpoint, changes in the transport properties during constant current DC iontophoresis indicate that changes in the membrane parameters such as porosity, effective pore size, and/or pore surface charge density may occur during the conventional constant current direct current (DC) iontophoresis. The results of the constant conductance AC iontophoresis transport studies suggest that this method effectively maintains the membrane parameters that affect transport at more constant values, providing for significantly less flux variability.;A systematic study was also conducted at different target skin resistances to more fully understand human skin transport behavior under the constant conductance conditions. The results showed that: (1) with the constant conductance alternating current (CCAC) protocol, it is possible to reduce the HEM electrical resistance to various target levels, even as low as 0.8 kO cm2, and to maintain the specific resistance level constant throughout the flux experiment; (2) permeant fluxes are proportional to skin electrical resistance; and (3) from passive transport experiments under the CCAC conditions, the effective HEM pore size was found to increase somewhat as the HEM target resistance was reduced.