Synthesis and in vitro transdermal penetration of methoxypoly(ethylene glycol) carbonate and carbamate derivatives of lamivudine (3TC).
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 6'-hydroxy group of lamivudine. Irrespective of the oligomeric series of derivatives (carbamate or carbonate), the aqueous solubility increases as the MPEG chain lengthens 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 penetrate the skin better than the parent drug itself. The use of Pheroid even appeared to significantly retard the skin permeation.
van Heerden
Jaco
J
Pharmaceutical Chemistry, North-West University, Potchefstroom 2520, South Africa.
Breytenbach
Jaco C
JC
N'Da
David D
DD
Breytenbach
J Wilma
JW
du Preez
Jan L
JL
D000279:Administration, Cutaneous; D002219:Carbamates / Q000737:chemistry*; D002254:Carbonates / Q000737:chemistry*; D005260:Female; D006801:Humans; D019259:Lamivudine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry*; D012867:Skin / Q000737:chemistry / Q000187:drug effects; D012869:Skin Absorption / Q000187:drug effects*; D012882:Skin Tests; D012995:Solubility; D013237:Stereoisomerism; D014018:Tissue Distribution
D002219:Carbamates; D002254:Carbonates; D019259:Lamivudine; D011092:Polyethylene Glycols