Transdermal delivery of vancomycin hydrochloride: influence of chemical and physical permeation enhancers.

Abstract

Topical and transdermal delivery of vancomycin hydrochloride (VH), a broad-spectrum peptide antibiotic, is a challenge because of its high molecular weight (1485.7 Da) and hydrophilicity (log P -3.1). The objective of this study was to investigate the feasibility of delivering VH into and across the skin using permeation enhancement techniques. Skin permeation studies were performed using Franz diffusion cell apparatus in the excised porcine skin model. The influence of co-treatment and pre-treatment of chemical permeation enhancers (oleic acid and palmitic acid) on permeation of VH across intact and tape-stripped skin was evaluated. In addition, continuous anodal iontophoresis was applied to enhance the skin permeation of VH. The mechanism of skin permeation enhancement by palmitic acid was investigated using FTIR spectroscopy, impedance spectroscopy, and thermal analysis techniques. Pharmacokinetic analysis was performed after the topical application of VH formulations in Sprague Dawley rats. Results from permeation studies showed that VH did not passively permeate across the intact skin after 48 h, whereas the cumulative amount of VH permeated across the tape-stripped skin was found to be 854±67 µg/cm2. A combination of tape-stripping and chemical enhancers resulted in enhancing the cumulative amount of VH permeated across the skin by 2- and 10-fold with oleic acid and palmitic acid application, respectively. Similarly, 2 and 12 h pre-treatment of tape-stripped skin with palmitic acid enhanced the flux of VH across the skin by 1.7- and 5-fold, respectively. It was found that tape-stripping and the palmitic acid application would provide greater VH permeation compared with 0.31 mA/cm2 iontophoresis application. Thermal analysis and impedance spectroscopic analysis showed that palmitic acid interacts with epidermal lipids to enhance VH permeation. Pharmacokinetic analysis after topical application showed that the Cmax and mean residence time increased by 3-fold with the application of VH and palmitic acid on tape-stripped skin compared with free VH on intact skin. Taken together, VH can be delivered through the topical route using a combination of chemical enhancer and tape-stripping to treat local and systemic bacterial infections.