The Synergistic Effect of Iontophoresis or Electroporation and Microneedles on the Skin Permeation of High Molecular Weight Compounds

Abstract

Microneedle pretreatment has been introduced to increase skin permeability for several compounds by creating micron-scale pathways across the skin’s stratum corneum layer. In order to further enhance the skin permeability by microneedle pretreatment, several skin penetration-enhancing strategies have been developed such as a combination of microneedle system with iontophoresis or electroporation. The synergic effect of the combination of microneedle pretreatment and iontophoresis was evaluated for the potential to further increase skin permeation of drugs. Fluorescein isothiocyanate (FITC)-dextrans (FDs) (FD-4, FD-10, FD-40, FD-70, and FD-2000; average molecular weight of 4.3, 9.6, 42.0, 71.2, and 200.0 kDa) were used as models for high molecular weight compounds, and deuterium oxide (D2O) was used as a model for low molecular weight compounds in order to evaluate the effect of microneedle pretreatment and iontophoresis on their skin permeation in vitro using excised hairless rat skin. The combination of microneedle pretreatment and subsequent iontophoresis application significantly enhanced the cumulative amount and the flux of FDs compared to microneedle pretreatment alone or iontophoresis alone, whereas no synergistic effect was found in increasing the cumulative amount and the flux of D2O. On the other hand, the combination of microneedle pretreatment and electroporation was developed in order to enhance the delivery of macromolecular drugs to the deep skin tissues, the so-called in-skin electroporation (IN-SKIN EP). FITC-dextran (FD-4; average molecular weight, 4.3 kDa) was selected as a model high molecular weight compound. In vitro skin permeation experiments showed that the IN-SKIN EP provided a significantly higher skin penetration-enhancing effect for FD-4 than microneedles alone or ON-SKIN EP (conventional EP treatment). These results suggest that the combination of iontophoresis or electroporation with microneedle pretreatment may be a useful means to further increase skin permeation of high molecular weight compounds.