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

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 (T-m) at similar to 40 degrees C of multilamellar DPPC liposomes is lowered by the enhancers in rank order of their enhancing abilities, while N-0915 increases T-m. 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.