Abstract

Purpose: Inadequate skin permeability is the main challenge encountered in the transdermal drug delivery and to solve this problem physical and chemical enhancement techniques are being developed. The purpose of the present investigation is to study the combined effect of two such techniques, iontophoresis and esterification, on the transdermal delivery of metoprolol tartrate. Methods: Two ester prodrugs of metoprolol were synthesized, characterized and studied for physicochemical properties like solubility, partition coefficient
and pKa. Stability studies were performed in acetate buffer (pH 4) and phosphate buffer (pH 6). In vitro permeation studies of metoprolol tartrate and the prodrugs were carried out by anodal iontophoresis (0.5 mA/cm2) through porcine skin using Franz diffusion cell at different donor concentrations (5, 10 and 20 mmol/l). Results: Evaluation of the physicochemical parameters demonstrated a significant increase in lipophilicity and a slight reduction in pKa value of the prodrugs compared to the parent drug. Stability studies showed a higher stability at pH 4 than pH 6. Enhanced permeation was observed with prodrugs in passive permeation at all donor concentrations when compared to parent drug. The iontophoretic fluxes were minimally higher than the passive fluxes though the benefit was moderate at low donor (5 mmol/l) concentration. Both prodrugs approach and iontophoresis enhanced the flux values independently but the combination contributed minimally to flux enhancement. Conclusion: This study concludes that both the approaches, prodrug and iontophoresis, are effective individually rather than in combination.


Keywords:  Metoprolol   Prodrugs   Stability   Transdermal delivery   Iontophoresis