Improved Delivery Through Biological Membranes LX: Intradermal Targeting of Acyclovir Using Redox-Based Chemical Drug Delivery Systems

Two types of novel chemical drug delivery systems (CDS's) for acyclovir, A-CDS-1 (based on oxidation, which utilized the 1,4-dihydrotrigonelline moiety) and A-CDS-2 (based on reduction, which utilized the lipoic acid moiety), were designed to create reservoirs of metabolic precursors for the enhanced local delivery of the antiviral agent acyclovir to the skin. They were evaluated in two-compartment diffusion cells using hairless-mouse skin in vitro. This approach could be useful in the treatment of mucocutaneous herpes simplex virus (HSV-1) infection in the epidermal region of the skin. Upon application to the freshly excised hairless-mouse skin, A-CDS-1 was rapidly oxidized to form the quaternary metabolite AQ+, which was extensively localized in the skin. AQ+ then served as a reservoir for the release of the antiviral agent in the skin. A-CDS-1 delivered almost equivalent amounts of acyclovir not only to the skin but also transdermally. On the other hand, A-CDS-2 specifically localized acyclovir delivery to the skin as opposed to transdermal delivery. Due to their redox properties, both CDS's demonstrated significant depot formation of metabolic precursors, thus enhancing intradermal acyclovir delivery. The CDS's exhibited greater skin membrane partition coefficients than the parent underivatized acyclovir and were able to release the antiviral agent in the skin tissue. The CDS's were susceptible to hydrolysis in biological media, resulting in the release of acyclovir under near physiological conditions. Thus, the CDS's can serve to enhance intradermal targeting and delivery of the antiviral agent acyclovir.