IN-VITRO EVALUATION OF A SERIES OF AZONE ANALOGS AS DERMAL PENETRATION ENHANCERS .2. (THIO)AMIDES

The sorption promoting ability of nine Azone (N-dodecylazacycloheptan-2-one) analogs was tested against the model drug, hydrocortisone 21-acetate using a hairless mouse skin model in vitro. The synthesis of these compounds is presented. The enhancers were applied in propylene glycol, 1 h prior to the application of the steroid which was applied as a saturated suspension in the same vehicle. All but enhancers 3-5, 8, and 9 were applied at 0.4 M. The remaining enhancers (all solids) were applied at their respective saturation solubilities. Flux, receptor concentrations, and skin accumulation of hydrocortisone acetate were measured over 24 h and compared with controls (no enhancer) and three model enhancers: Azone (N-dodecylazacycloheptan-2-one), 2-pyrrolidinone, and N-methyl-2-pyrrolidinone. Pre-treatment of skin with the Azone analogs markedly increased penetration and skin retention of the steroid. The greatest enhancement of flux was observed for 2, where flux increased 53.8-fold over control and 2.76-fold over Azone; receptor concentrations were 35.37-fold and skin retentions 1.6-fold higher than control. Compound 1 gave the greatest skin retention enhancement ratio (ER) (2.2 over control) of the series, while 2-pyrrolidinone produced an ER of 3.2, and Azone 1.5 compared with controls at an ER of 1.0.