Transdermal penetration of acyclovir in the presence and absence of terpenes

Abstract

Acyclovir is an antiviral drug used in the treatment and prevention of herpes simplex and varicella-zoster viral infections. The major problem in the transdermal delivery of acyclovir is the permeation in sufficient amounts to deeper layers of the skin and into the systemic circulation. Acyclovir is a hydrophilic substance with a low partition coefficient, resulting in poor penetration through the excellent barrier of the skin, the stratum corneum. In an attempt to enhance the transdermal permeability of acyclovir, the aim of this study was to employ terpenes as possible penetration enhancers. Terpenes are constituents of natural essential oils, with widespread medicinal use including in aromatherapy. The terpenes used in this study were 1,8-cineole, limonene, menthol, menthone, and 13-myrcene. Terpenes are not only used as penetration enhancers, but are even more often present in drugs and cosmetics. Limited studies have been done concerning the penetration of terpenes through the skin. Thus, not only the effect of the terpenes on the penetration of acyclovir, but also the penetration of the terpenes themselves were studied. The influence of acyclovir on the penetration of the terpenes was also determined. In vitro permeation experiments were performed on human skin using Franz diffusion cells. The skin was pretreated with a 5 % solution of the terpene in ethanol and left for 30 minutes to enable ethanol evaporation and terpene incorporation into the skin. Saturated aqueous solutions of acyclovir (pH 7.4) were added in the donor compartment before and after skin pre-treatment. The acyclovir concentration retrieved from the receptor compartment of the Franz cells was analyzed by HPLC. The amount of terpene that penetrated were semi-quantitatively determined by GC. Penetration of acyclovir was significantly enhanced by two terpenes, viz. 1,8-cineole and menthol. The extent of enhancement was, however, not large enough to be of clinical use. The enhancement in acyclovir penetration observed upon ethanol pre-treatment alone, or in the presence of limonene, menthone or ~-myrcene, was not significant. Penetration enhancement of acyclovir by the terpenes was in accordance with previous studies, which postulated better enhancement of hydrophilic drugs by hydrophilic terpenes. Large percentages of the terpenes with log P values within the optimum log P range (1 - 3) penetrated, as was found with menthone and menthol. Penetration decreased accordingly as the log P, and thus lipophilicity, increased. Stratum corneum retention is regarded as the most plausible explanation for this phenomenon. In the case of 1,8-cineole, enhancer pooling in the stratum corneum could be a possible reason for its poor penetration. Acyclovir significantly influenced the penetration profiles of some of the terpenes, but no clear explanation could be given.