Enhancement of transdermal transport of azidothymidine (AZT) with novel terpene and terpene-like enhancers: In vivo-in vitro correlations

Abstract

The transdermal delivery of the anti-AIDS drug, 3′-azido-3′-deoxythymidine (zidovudine or AZT) was studied in vitro and in vivo using the novel chemical enhancers; t-anethole, carvacrol, thymol and linalool. l-menthol was used as a reference enhancer. In vitro studies were carried out in Franz Cells using excised full thickness CD-1 nude mouse and Sprague-Dawley rat skin. The in vivo transdermal bioavailability of AZT was determined in rats using enhancer containing gel formulations. In the in vitro studies, the nude mouse skin transport of AZT was enhanced 24–38 times with 5% enhancer. All the enhancers produced flux values better than or equivalent to l-menthol. The transport of AZT was optimum with 5% enhancer concentrations. AZT transport increased with increased AZT concentration reaching 70 mg/cm 2/24 h using 150 mg/g AZT/2% t-anethole. As a solvent, isopropyl alcohol (IPA) /water (60:40, v / v) yielded better absorption than propylene glycol (PG) /water ( 60:40, v / v) with all enhancers except l-menthol. In the in vitro transport studies, the amount of AZT retained in the skin was independent of the enhancer type or concentration indicating that the mechanism of transport enhancement is due to increased diffusion of the drug in the stratum corneum. The transport of AZT through the excised nude mouse skin was higher than the transport through abdominal or dorsal rat skin. The absolute transdermal bioavailability of AZT in conscious rats was between 0.8–5.0% using the enhancers. Except for a few formulations, the amount and rate of AZT transport in the in vitro studies were higher than the corresponding values in the in vivo studies. Overall, these studies indicate the potential of t-anethole, carvacrol, thymol and linalool as effective transdermal enhancers and the feasibility of delivering significant amounts of AZT through the skin.