Iontophoretic transport mechanisms across skin

Iontophoresis is the process of increasing the penetration rate of ions into or through a membrane by the application of an external electric field across the membrane. The Nernst-Planck theory has been used to describe the flux enhancement of ions across membranes during iontophoresis. This theory neglects secondary effects such as convective solvent flow and permeability increases due to membrane alterations which result from the applied field. Therefore, the mechanisms whereby charged and uncharged solutes transport across skin under the influence of an applied electric field were investigated. The modified Nernst-Planck theory, which includes convective solvent flow contributions to the total flux of ions, has been used to describe the flux enhancement of neutral (glucose) and charged (tetraethylammonium ion and salicylate ion) solutes during iontophoresis. Using glucose and a model, net negatively charged membrane (Nuclepore\circler), solvent flow was shown to be in the direction of counterion (cation) movement. An estimate of the solvent flow velocity was obtained from the glucose flux using the modified Nernst-Planck theory. This velocity value was then used to predict the flux enhancements of a monovalent cation and anion. Comparisons between the theoretical prediction and experimental data using tetraethylammonium ion (cation) and salicylate ion (anion) showed good agreement. A physical model was developed to gain a more mechanistic understanding of the solvent flow process. The Poisson-Boltzmann equation, which relates the surface potential to the surface charge density, was solved numerically for the radial electric potential profile within a cylindrical pore. The potential profile was then used with the equations of fluid motion to predict the electro-osmotic velocity. The membrane pore partitioning behavior for the tetraethylammonium and salicylate ions was then predicted at selected ionic strengths using the best estimates of the electrical potential profile. The agreement between experimental and theoretical partition coefficient values was very good. Iontophoretic studies employing human skin demonstrated that there were both electro-osmosis effects and field induced membrane alterations in addition to direct electric field effects on ion transport. Membrane alterations occurred at 1000mV but not at lower voltages. These alterations reversed after removal of the applied voltage. Mannitol flux enhancement in human skin showed only a 20-25% solvent flow contribution to the modified Nernst-Planck flux for monovalent cations and anions. Experiments with tetraethylammonium and salicylate ions were in good agreement with the predictions of the modified Nernst-Planck equation when membrane alteration effects were taken into consideration.