Transdermal delivery of heparin by skin electroporation

Therapeutic uses of compounds produced by biotechnology are presently limited by the lack of noninvasive methods for continuous administration of biologically-active macromolecules. Transdermal delivery would be an attractive solution, except macromolecules have not previously been delivered clinically across human skin at therapeutic rates. To increase transport of a highly-charged macromolecule (heparin), high-voltage pulses believed to cause electroporation were applied to skin. Using this approach, transdermal heparin transport across human skin in vitro occurred at therapeutic rates (100-500 micrograms/cm2h), reported to be sufficient for systemic anticoagulation. In contrast, fluxes caused by low-voltage iontophoresis having the same time-averaged current were an order of magnitude lower. Heparin transported across the skin was biologically active, but with only one eighth the anticoagulant activity of heparin in the donor compartment due to preferential transport of small (less active) heparin molecules. Flux, activity, and transport number data together suggest that high-voltage pulsing creates transient changes in skin microstructure which do not occur during iontophoresis. Safety issues are discussed.