Transdermal Delivery of Dideoxynucleoside‐type Anti‐HIV Drugs. 1. Stability Studies for Hairless Rat Skin Permeation

Abstract

The stability of dideoxynucleoside‐type anti‐HIV drugs in solution when in contact with hairless rat skin was investigated in order to study the feasibility of their transdermal delivery. The freshly excised dorsal region of hairless rat skin was mounted on Valia‐Chien skin permeation cells, and both epidermis (donor) and dermis (receptor) were extracted with isotonic phosphate buffer (pH 7.4) at 37°C for 24h. Zalcitabine (DDC), didanosine (DDI), and zidovudine (AZT) were found to be stable in the extract of the epidermis at 37°C for at least 30h. However, DDC and DDI degraded in the extract of the dermis following first‐order kinetics at both 25 and 37 °C, while AZT was stable at 37°C for at least 30h. The degradation mechanism(s) of DDC and DDI was (were) studied by analyzing HPLC chromatograms and by evaluating the drug stability in the extract which was filtered to remove any microbes. An unidentified peak produced by DDC in the dermis extract did not appear when the drug was added to the filtered extract, which suggested a bacterial degradation of DDC. On the other hand, DDI was unstable even in the filtered extract and produced a degradation product which corresponded to hypoxanthine, which suggested that a cutaneous enzyme is also involved in the degradation of DDI. DDC was stabilized by the addition of 0.01% (w/v) of an antibacterial agent, such as thimerosal or gentamicin, in the receptor solution, while DDI was stabilized by 0.01% (w/v) purine nucleoside phosphorylase inhibitor,i.e.,p‐chloromercuri‐benzoic acid. These results show the importance of stability studies when designing skin permeation experiments using hairless rat since compounds with similar chemical structures can have different stability profiles when in contact with hairless rat skin.