Synthesis of methodxypoly (ethylene glycol) carbonate prodrugs of zidovudine and penetration through human skin in vitro
N'Da, David D.
Breytenbach, Jaco C.
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The aim of this study was to synthesise a series of novel methoxypoly(ethylene glycol) carbonate prodrugs of the antiretroviral drug zidovudine (azidothymidine, AZT) in an attempt to enhance the physicochemical properties for transdermal delivery, which may reduce the severe side-effects and toxicity associated with high oral doses of AZT. Methoxypoly(ethylene glycol) carbonates of AZT were synthesised in two steps: activation of the relevant methoxypoly(ethylene glycol) with p-nitrophenyl chloroformate, followed by reaction with AZT. Analysis of the hydrolytic stability in phosphate buffer at pH 5.0 and 7.4 revealed that all the carbonates were markedly more stable at pH 5.0 than at pH 7.4 (0.01 M), with half-lives ranging from 15 to 44 days at pH 5.0 and from 6 to 24 days at pH 7.4. The potential of the series to penetrate the skin was evaluated in vitro by measuring diffusion through excised abdominal female human skin at pH 5.0. Prodrugs with 1-3 or 8 oxyethylene units in the methoxypoly(ethylene glycol) moiety were found to permeate the skin whereas those with 12 or 17 units did not. The prodrug with eight oxyethylene units was the most effective penetrant, permeating the skin with a mean flux of 53.3 +/- 46.5 nmol/cm2 per h, which is 2.4-10.1 times that of AZT (8.55 +/- 5.3 nmol/cm2 per h). The bioreversible conjugation of the methoxypoly(ethylene glycol) promoiety to AZT appears to be a promising strategy for the transdermal delivery of AZT at a therapeutic dose.