Controlled transdermal iontophoresis for poly-pharmacotherapy: Simultaneous delivery of granisetron, metoclopramide and dexamethasone sodium phosphate in vitro and in vivo

Iontophoresis has been used to deliver smallmolecules, peptides and proteins into and across the skin. In principle, it provides a controlled, non-invasive method for poly-pharmacotherapy since it is possible to formulate and to deliver-multiple therapeutic agents simultaneously from the anodal and cathodal compartments. The objective of this proof-of-principle study was to investigate the simultaneous anodal iontophoretic delivery of granisetron (GST) and metoclopramide (MCL) and cathodal iontophoresis of dexamethasone sodium phosphate (DEX-P). In addition to validating the hypothesis, these are medications that are routinely used in combination to treat chemotherapy induced emesis. Two preliminary in vitro studies using porcine skin were performed: Study 1 - effect of formulation composition on anodal co-iontophoresis of GST and MCL and Study 2 - combined anodal iontophoresis of GST (10 mM) and MCL (110 mM) and cathodal iontophoresis of DEX-P (40 mM). The results from Study 1 demonstrated the dependence of GST/MCL transport on the respective drug concentrations when co-iontophoresed at 0.3 mA.cm(-2). Although they possess similar physicochemical properties, MCL seemed to be a more efficient charge carrier (J(MCL)=0.0591 * C-MCL vs J(GST)=0.0414 * C-GST). In Study 2, MCL permeation was markedly superior to that of GST (2324.83 +/- 307.85 and 209.83 +/- 24.84 mu g.cm (2), respectively); this was consistent with the difference in their relative concentrations; DEX-P permeation was 336.94 +/- 71.91 mu g.cm(-2). The in vivo studies in Wistar rats 110 mM GST, 110 mM MCL and 40 mM DEX-P (0.5 mA.cm(-2) for 5 h with Ag/AgCl electrodes and salt bridges) demonstrated that significant drug levels were achieved rapidly for each drug. This was most noticeable for dexamethasone (DEX) where relatively constant plasma levels were obtained from the 1 to 5 h time-points; DEX-P was not detected in the plasma since it was completely hydrolyzed to the active metabolite. The calculated input rates in vivo (k01) for GST, MCL and DEX were 0.45 +/- 0.05, 3.29 +/- 0.48 and 1.97 +/- 0.38 mu g.cm(-2).min(-1), respectively. The study confirmed that iontophoresis provided a controlled method for the simultaneous administration of multiple therapeutic agents and that it could be of use for poly-pharmacotherapy in general and more specifically that it was able to deliver different drugs used in the treatment of chemotherapy-induced emesis. (C) 2016 Elsevier B.V. All rights reserved.