Cutaneous iontophoresis of μ-conotoxin CnIIIC-A potent Nav1.4 antagonist with analgesic, anaesthetic and myorelaxant properties

Cutaneous iontophoretic delivery of mu-conotoxin CnIIIC (XEP), a potent peptide antagonist of the Na(v)1.4 sodium channel, was investigated using porcine ear skin and validated using human abdominal skin. Initial results demonstrated that cutaneous deposition of XEP following iontophoresis was superior to passive delivery and increased with current density. XEP deposition after iontophoresis at 0.1, 0.3 and 0.5 mA/cm(2) for 2 h and 4 h was 22.4 +/- 0.4, 34.5 +/- 1.4, 57.4 +/- 7.6 mu g/cm(2) and 30.6 +/- 5.4, 53.9 +/- 17.2, 90.9 +/- 30.8 mu/cm(2), respectively (cf. corresponding passive controls -9.8 +/- 1.1 and 16.9 +/- 1.0 mu/cm(2)). Moreover, tape-stripping studies showed that XEP was mainly adsorbed on the skin surface when administered passively. Co-iontophoresis of acetaminophen demonstrated that XEP was present in the skin as it significantly reduced convective solvent flow as evidenced by the similar to 7-fold decrease in acetaminophen permeation. Shorter duration iontophoresis (15, 30 and 60 min) was performed and the effect of current density (0.1, 0.3 and 0.5 mA/cm(2)) and concentration (0.1 and 1 mM) investigated. Skin deposition of XEP was already quantifiable after iontophoresis for 15 min at the lower concentration. There was no statistically significant difference between XEP deposition in porcine and human skin. Confocal laser scanning microscopy enabled post-iontophoretic visualization of FITC-labelled XEP in the epidermis. (C) 2016 Elsevier B.V. All rights reserved.