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

Balaguer-Fernández, C
Calatayud-Pascual, A
Ganem-Rondero, A
Quintanar-Guerrero, D
López-Castellano, A C
Merino, V
Published in European journal of pharmaceutics and biopharmaceutics. 2010, vol. 75, no. 2, p. 173-8
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.
Keywords Administration, CutaneousAnimalsAntineoplastic Agents/adverse effectsDexamethasone/administration & dosage/analogs & derivatives/pharmacokineticsDose-Response Relationship, DrugDrug StabilityGlucocorticoids/administration & dosage/pharmacokineticsHumansHydrolysisIontophoresisMaleRatsRats, WistarSkin/metabolismSkin AbsorptionSpecies SpecificitySwineTime FactorsVomiting/chemically induced/prevention & control
PMID: 20332024
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CAZARES DELGADILLO, Jennyfer et al. Transdermal iontophoresis of dexamethasone sodium phosphate in vitro and in vivo: effect of experimental parameters and skin type on drug stability and transport kinetics. In: European journal of pharmaceutics and biopharmaceutics, 2010, vol. 75, n° 2, p. 173-8. doi: 10.1016/j.ejpb.2010.03.011 https://archive-ouverte.unige.ch/unige:22720

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Deposited on : 2012-09-03

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