Transdermal iontophoresis of dexamethasone sodium phosphate in vitro and in vivo: effect of experimental parameters and skin type on drug stability and transport kinetics.

Abstract

The aim of this study was to investigate the cathodal iontophoresis of dexamethasone sodium phosphate (DEX-P) in vitro and in vivo and to determine the feasibility of delivering therapeutic amounts of the drug for the treatment of chemotherapy-induced emesis. Stability studies, performed to investigate the susceptibility of the phosphate ester linkage to hydrolysis, confirmed that conversion of DEX-P to dexamethasone (DEX) upon exposure to samples of human, porcine and rat dermis for 7 h was limited (82.2+/-0.4%, 72.5+/-4.8% and 78.6+/-6.0% remained intact) and did not point to any major inter-species differences. Iontophoretic transport of DEX-P across dermatomed porcine skin (0.75 mm thickness) was studied in vitro as a function of concentration (10, 20, 40 mM) and current density (0.1, 0.3, 0.5 mA cm(-2)) using flow-through diffusion cells. Increasing concentration of DEX-P from 10 to 40 mM resulted in a approximately 4-fold increase in cumulative permeation (35.65+/-23.20 and 137.90+/-53.90 microg cm(-2), respectively). Good linearity was also observed between DEX-P flux and the applied current density (i(d); 0.1, 0.3, 0.5 mA cm(-2); J(DEX) (microg cm(2) h(-1))=237.98 i(d)-21.32, r(2)=0.96). Moreover, separation of the DEX-P formulation from the cathode compartment by means of a salt bridge - hence removing competition from Cl(-) ions generated at the cathode - produced a 2-fold increase in steady-state iontophoretic flux (40 mM, 0.3 mA cm(-2); 20.98+/-7.96 and 41.82+/-11.98 microg cm(-2) h(-1), respectively). Pharmacokinetic parameters were determined in Wistar rats (40 mM DEX-P; 0.5 mA cm(-2) for 5h with Ag/AgCl electrodes and salt bridges). Results showed that DEX-P was almost completely converted to DEX in the bloodstream, and significant DEX levels were achieved rapidly. The flux across rat skin in vivo (1.66+/-0.20 microg cm(-2) min(-1)), calculated from the input rate, was not statistically different from the flux obtained in vitro across dermatomed porcine skin (1.79+/-0.49 microg cm(-2) min(-1)). The results suggest that DEX-P delivery rates would be sufficient for the management of chemotherapy-induced emesis.

• Authors: J Cázares-Delgadillo, C Balaguer-Fernández, A Calatayud-Pascual, A Ganem-Rondero, D Quintanar-Guerrero, A C López-Castellano, V Merino, Y N Kalia
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 75 Issue 2 Pg. 173-8 (Jun 2010) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 20332024 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Glucocorticoids
• dexamethasone 21-phosphate
• Dexamethasone

Topics

• Administration, Cutaneous
• Animals
• Antineoplastic Agents (adverse effects)
• Dexamethasone (administration & dosage, analogs & derivatives, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Stability
• Glucocorticoids (administration & dosage, pharmacokinetics)
• Humans
• Hydrolysis
• Iontophoresis
• Male
• Rats
• Rats, Wistar
• Skin (metabolism)
• Skin Absorption
• Species Specificity
• Swine
• Time Factors
• Vomiting (chemically induced, prevention & control)