Synergistic effect of chemical penetration enhancer and iontophoresis on transappendageal transport of oligodeoxynucleotides

Gap junction protein connexin43 (Cx43) specific antisense oligodeoxynucleotides (AsODN) have been shown to improve a number of inflammatory conditions and may therefore offer a novel strategy for persistent pain management. However, for such molecules to be clinically effective, delivery challenges owing to the molecules' high molecular weight, negative charge and hydrophilicity have to be overcome. In this study, the effect of various chemical penetration enhancers and cathodal iontophoresis on transdermal delivery was evaluated. Initial skin permeation studies revealed only a slight increase in the passive flux of the model anionic drug sodium fluorescein using limonene/ethanol. Applying cathodal iontophoresis, the amount of the model drug permeated through untreated skin was tripled, while a combination of chemical and physical penetration enhancement resulted in a fourfold increase in the fluorescein amount permeated. However, even the synergistic effect of limonene/ethanol and iontophoresis was insufficient to achieve complete permeation of Cy3-labeled Cx43 AsODN across the entire skin thickness. Instead, molecules were trapped in the epidermis or permeated deeply into the hair follicles. These results suggest that the synergistic effect of chemical and physical penetration enhancement increases intradermal delivery of oligonucleotides but is insufficient to deliver such large molecules across intact skin. (C) 2012 Elsevier B.V. All rights reserved.