J. Bradley Phipps

Transdermal ion migration

Abstract This chapter will focus on the influence of ion composition on the transdermal delivery of drug species through mammalian skin, due to an applied electric field. The pH of the drug-containing medium is shown to affect drug transport by altering the fraction of charged drug and the permselectivity of skin. The competitive transport of ions having the same charge as the drug ion (co-ions) and those having a charge opposite that of the drug ion (counter-ions), is discussed in detail. A model is derived to predict drug ion flux through a homogeneous non-ionic membrane at constant current, in the presence of one type of co-ion and counter-ion. Model values are compared to experimental data for ion migration through a synthetic aqueous membrane and through excised porcine skin. This comparison suggests that ion transport through pig skin occurs primarily along an aqueous pathway. In addition, a comparison of in vitro and in vivo data for several drug ions as well as comparison of in vivo results for transdermal sodium influx and efflux, suggests that the apparent sodium chloride concentration of the viable epidermis is hypotonic, having a value of about 0.09 M.

Scanning electrochemical microscopy of a porous membrane

Abstract Measurement of the local flux of electroactive ions across a porous membrane using scanning electrochemical microscopy (SECM) is described. SECM consists of rastering a hemispherical microelectrode (∼ 3.0 μm diameter), held at constant electrochemical potential, across the membrane surface and oxidizing (or reducing) electrochemically active species that emerge from membrane pores. The resulting faradaic current is plotted to construct images of ion pathways in the membrane. SECM images resulting from the passive and electrophoretic flux of potassium ferrocyanide through 1.3 μm radius pores in mica are reported.

Scanning Electrochemical Microscopy of Iontophoretic Transport in Hairless Mouse Skin. Analysis of the Relative Contributions of Diffusion, Migration, and Electroosmosis to Transport in Hair Follicles

Scanning electrochemical microscopy (SECM) is used to measure spatially localized diffusive and iontophoretic transport rates in hairless mouse skin. Molecular fluxes within individual hair follicles are quantified by measuring the rate at which redox-active probe molecules emerge from the follicle. The influence of an applied current on the flux of an anion (ascorbate), a cation (ferrocenylmethyltrimethylammonium), and a neutral molecule (acetaminophen) is used to determine the contributions of diffusion, migration, and electroosmosis to iontophoretic transport. The direction of electroosmotic transport is consistent with hair follicles possessing a net negative charge at neutral pH. Electroosmosis results in a modest increase in the transport rate of the neutral molecule (a factor of approximately 2.4x at an iontophoretic current density of 0.1 mA/cm(2)). Larger enhancements in the flux of the electrically charged species are associated with migration. The electroosmotic flow velocity within hair follicles is established to be 0.5 (+/-0.1) microm/s at 0.1 mA/cm(2), independent of the electrical charge of permeant. The net volume flow rate across skin resulting from electroosmosis in hair follicles is estimated to be 0.3 microL/cm(2)h. The results suggest that hair follicles are a significant pathway for electroosmotic solution flow during iontophoresis. The radius of the hair follicle openings in hairless mouse skin is measured to be 21 +/- 5 microm.

Direct imaging of ionic pathways in stratum corneum using scanning electrochemical microscopy

We have used a scanning electrochemical microscope (SECM) to identify the routes of iontophoretic flux of ionic species (Fe2+ and Fe3+) across excised hairless mouse skin. SECM has been used both in the imaging mode, where large two-dimensional areas (∼1 mm2) are surveyed to identify regions of high ionic flux, and in the quantitative single trace mode, where flux profiles over a fixed feature are repeatedly measured along one dimension. SECM images indicate that a significant portion of ion flux occurs through shunt pathways in the skin. Images reveal that the spatial density of shunt pathways is greater than that of hair follicles, by up to an order of magnitude, indicating that hair follicles represent a minor contribution to shunt pathways in the skin. A quantitative comparison of the relative fluxes of Fe2+ and Fe3+ through a single pore indicates that Fe2+ is transported at a significantly larger rate than Fe3+. These data represent, to our knowledge, the first direct, chemical-specific identification of transport pathways in skin.

Visualization and analysis of iontophoretic transport in hairless mouse skin

ABSTRACT Scanning electrochemical microscopy (SECM) is used to measure spatially-localized diffusive and iontophoretic transport rates in hairless mouse skin. Molecular fluxes within individual hair follicles are quantified by measuring the rate at which redox-active probe molecules emerge from the follicle. The influence of an applied current on the flux of an anion (ascorbate), a cation (ferrocenylmethyltri-methylammonium), and a neutral molecule (acetaminophen) is used to estimate the contributions of diffusion, migration, and electroosmosis to iontophoretic transport.