Synthesis and In Vitro Transdermal Penetration of Methoxypoly(ethylene glycol) Carbonate and Carbamate Derivatives of Lamivudine (3TC)

Jaco      van Heerden; Jaco      C. Breytenbach; David      D. N'Da; J.      Wilma Breytenbach; Jan      L. du Preez

Abstract

The objective of this study was to determine the in vitro transdermal permeation through the human stratum corneum (SC) of the antiretroviral (ARV) drug lamivudine (3TC) (1) and its synthesised methoxypoly(ethylene glycol) (MPEG) carbamates and carbonates in phosphate buffer solution and with the use of Pheroid™ as delivery system, and to establish a relationship, if any, with selected physicochemical properties. The synthesis and in vitro human skin permeation flux of three N4-methoxypoly(ethylene glycol) carbamates (3)-(5) and three 6-O-methoxypoly(ethylene glycol) carbonates (6)-(8) of lamivudine are reported. The derivatives were synthesised in a two-step process by coupling activated MPEG oligomers of various chain lengths to either the 4-amino or the 6-hydroxy group of lamivudine. Irrespective of the oligomeric series of derivatives (carbamate or carbonate), the aqueous solubility increased as the MPEG chain lengthened while the solubility in octanol (lipophilicity) remained almost constant. Regardless of the mechanism of diffusion, viz. passive (in PBS) or use of enhancer (Pheroid™), no derivative penetrated the skin better than the parent drug itself. The use of Pheroid™ appeared to retard skin permeation.

Keywords: Transdermal permeation, methoxypoly(ethylene glycol) (MPEG), lamivudine (3TC), Pheroid™, aqueous solubility, log P, stratum corneum (SC)

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