Investigation on the synergistic effect of a combination of chemical enhancers and modulated iontophoresis for transdermal delivery of insulin

Purpose: The main objective of this study was to assess the flux enhancement of insulin transdermally by utilizing a complex of chemical enhancers in combination with modulated iontophoresis. Methods: The experiments were performed on porcine epidermis model under three different circumstances, namely, (a) 1-hour modulated iontophoresis alone; (b) pretreatment with vehicle and chemical enhancer combinations and (c) combination of (a) and (b). The mechanism of action of the enhancers was studied using infra-red spectra by derivative and curve-fitting techniques and Confocal laser scanning microscopy. The efficacy of the optimized combination was tested in vivo in streptozocin-diabetic Wistar rats. Results: A blend of 1,8 cineole, oleic acid and sodium deoxycholate in propylene glycol : ethanol (7:3) resulted in 45% enhancement, when permeation was performed in combination with iontophoresis as compared to the latter alone. In-depth analysis of infra-red spectra revealed that each of the enhancers acted differentially on lipid-protein domains of the stratum corneum thereby supporting the observed synergism. Movement of fluorescently labeled insulin depicted highlighted follicular regions and paracellular accumulation of the probe after iontophoresis and chemical enhancer treatment respectively. Presence of the fluorescent peptide in these regions 4 hour after treatment with the combination reinforced the results of the permeation studies. Finally the combination of modulated iontophoresis with chemical enhancer blend resulted in lowering of blood glucose for 8 hour in vivo. Conclusions: The study proved the applicability of modulated iontophoresis with chemical pretreatment in delivering insulin transdermally.