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Mechanisms of action of skin penetration enhancers/retarders: Azone and analogues

1996; Elsevier BV; Volume: 141; Issue: 1-2 Linguagem: Inglês

10.1016/0378-5173(96)04609-1

1873-3476

Jonathan Hadgraft, James Peck, Dafydd G. Williams, W. Pugh, Geoffrey Allan,

Contact Dermatitis and Allergies

The modifying effect of Azone and five analogues on diffusion of metronidazole through isolated stratum corneum (SC) is reported. All enhance diffusion except N-0915, which is a retarder. Enhancement ratios (amount penetrating with modifier/amount from control) at 40 min are Azone 6.7; N-0539 6.4; N-0253 3.4; N-0721 1.4; N-0131 1.1; N-0915 0.2. The sulphur analogue of Azone (N-0721) is much less effective than Azone itself, and the short hydrocarbon chain in N-1031 renders it ineffective. Similar results using diethyl m-toluamide as penetrant suggest that this effect of N-0195 is non-specific. Azone expands while N-0915 condenses monolayers of dipalmitoyl phosphatidylcholine (DPPC). The phase transition temperature (Tm) at ∼40°C of multilamellar DPPC liposomes is lowered by the enhancers in rank order of their enhancing abilities, while N-0915 increases Tm. Thus, modifier activity might be related to fluidising effect on lipid lamellae. A mechanism of modifier action based on alteration of the lateral bonding within SC lipid lamellae is proposed, based on molecular modelling of Azone and N-0915 and their hydrogen bonding capacities to cerebrosides.