Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery.

Abstract

Mammalian skin owes its remarkable barrier function to its outermost and dead layer, the stratum corneum. Transdermal transport through this region occurs predominantly through intercellular lipids, organized largely in bilayers. Electroporation is the creation of aqueous pores in lipid bilayers by the application of a short (microseconds to milliseconds) electric pulse. Our measurements suggest that electroporation occurs in the intercellular lipid bilayers of the stratum corneum by a mechanism involving transient structural changes. Flux increases up to 4 orders of magnitude were observed with human skin in vito for three polar molecules having charges between -1 and -4 and molecular weights up to slightly more than 1000. Similar flux increases were observed in vivo with animal skin. These results may have significance for drug delivery and other medical applications.Transdermal drug delivery offers a number of potential advantages over conventional methods, such as pills and injections: (i) no degradation due to stomach, intestine, or first pass of the liver, (ii) probable improved patient compliance because of a user-friendly method, and (iii) potential for steady or time-varying controlled delivery (1-4). Nevertheless, very few drugs can be administered transdermally at therapeutic levels, due to the low permeability and lipophilic nature of human skin. As a result, fewer than 10 drugs are now clinically administered transdermally. However, the market for these drugs exceeds one billion dollars in the United States alone, indicating the importance of this delivery method. Therefore, significant enhancement of transdermal drug delivery has the potential for major impact on medicine.

Imaging Regions of Transport Across Human Stratum Corneum during High-Voltage and Low-Voltage Exposures

“…[16][17][18] In contrast, brief (micro-to milliseconds) electric pulses up to a few hundred volts have also been applied to skin. The resulting enhancement may involve transient structural changes within the intercellular bilayers of the stratum corneum 6,[19][20][21][22][23][24][25][26] that are mechanistically similar to electroporation. 27,28 In this investigation, we imaged regions of transport across human stratum corneum during either highvoltage pulsing or iontophoresis using scanning confocal fluorescence microscopy to optically section tissues.…”

“…1,2 Approaches have been investigated to enhance transdermal transport, including application of chemical enhancers, 3 ultrasound, 4 iontophoresis, 5 and most recently, short-duration high-voltage pulses. 6 Of critical importance to understanding transdermal transport is identifying the route(s) by which molecules cross the stratum corneum. Under passive conditions, drugs are believed to diffuse across the stratum corneum following a tortuous intercellular route.…”

A Numerical Model of Skin Electropermeabilization Based on In Vivo Experiments

“…We got the electrical conductivity values and their changes during electroporation from literature and experiments, as well as the electric field values above which tissues are permeabilized. [4][5][6][7][15][16][17][18]25,26 However, getting these values was a difficult task, due to the lack of measurements in this field.…”

A propagating heat wave model of skin electroporation

“…Transdermal drug delivery is enhanced by electroporation of the stratum corneum (SC), the most effective skin barrier to molecules and ions (Prausnitz et al, 1993;Weaver and Chizmadzhev, 1996). Electroporation itself is a non-thermal phenomenon at the level of the cell membrane.…”