Topical Delivery of Antiviral Agents: In Vivo/In Vitro Correlations

Abstract

There has been significant progress made during the past ten years in our understanding of drug transport processes in skin and the use of this information in topical and transdermal drug delivery. Physicochemical concepts and methods have been especially valuable in this regard. We have recently developed a method which combines in vitro experiments with hairless mouse skin and theoretical techniques based upon physical chemical relationships for predicting target-site levels of drug delivered by the drugs or prodrugs in various vehicles. A three-layer model was developed (stratum corneum, epidermis and dermis) and validated by independent experiments. In our most recent investigations, target-site predictions were made for the 5’-monoester prodrugs of vidarabine (an antiviral agent) delivered topically into hairless mouse skin with and without the penetration enhancer, Azone (dodecylazacycloheptan-2-one). The 5’-valerate ester of vidarabine was predicted to be the best among five monoester prodrugs. It was, nevertheless, predicted to be only marginally effective (against herpes virus) in sustaining high enough steady-state vidarabine levels in the epidermis when delivered from conventional creams. Efficacy predictions for the 5’-valerate in formulations containing 10 to 20% Azone, suggested that the Azone formulations would be able to sustain much higher steady-state epidermal vidarabine levels (50 to 200 X). The first set of in vivo studies by Dr. W.M. Shannon completed very recently showed that topical treatment with the 5’-valerate prodrug of vidarabine in a conventional cream was only marginally effective in reducing lesion scores and the mortality rates of prodrug of vidarabine in a conventional cream was only marginally effective in reducing lesion scores and the mortality rates of hairless mice infected topically by Herpes Simplex Virus Type I. With Azone in the formulations, the lesion scores were significantly improved and the mortality rate was zero.