Session Speaker
Synthesis, Hydrolytic Stability and Transdermal Penetration in Phosphate Buffer of Methoxypoly(ethylene glycol) Carbonate Derivatives of AZT
David Dago

A homologous series of methoxypoly(ethylene glycol) (MPEG) carbonate prodrugs of zidovudine (AZT) and stavudine (d4T) were synthesized, their physicochemical properties assessed and the in vitro penetration through human skin determined. The carbonates were synthesized in a two-step process by coupling the MPEG promoieties of various chain lengths to each drug. In kinetic studies, both carbonate series proved to be stable towards chemical hydrolysis in weakly basic phosphate medium (pH 7.4) at 37°C. The half-lives ranged from 6 to 21 days, and from 6 to 11 days for the AZT and d4T carbonate series, respectively. Irrespective of the series, both the aqueous and the lipid solubilities increase as the chain length increases. Prior to any attempt in vivo, the ability of the carbonates to deliver the parent drugs through excised human skin was evaluated in vitro in the phosphate medium at 37°C. The results showed that regardless of the series, all the derivatives permeated the skin. However, the derivatives with 3 ethylene oxide (EO) units were the most effective permeants of each series. Thus, the skin permeation rate of zidovudine was enhanced with between 1.2 and 4.5 times while that of stavudine was enhanced with between 3.92 and 9.71 times.