TRANSDERMAL PENETRATION ENHANCERS IN RABBIT PINNA SKIN - DURATION OF ACTION, SKIN IRRITATION, AND IN-VIVO IN-VITRO COMPARISON

Irritation of the skin by chemical penetration enhancers may limit the use of these compounds in transdermal drug delivery. Biodegradable en hancers like dodecyl N,N-dimethylamino acetate (DDAA) have been synthe sized previously to decrease the duration of action and toxicity of th e enhancers. We studied the reversibility and extent of penetration en hancement and skin irritation by DDAA, Azone, and n-dodecanol in rabbi t pinna skin using timolol and propranolol as penetrants. Also, in vit ro and in vivo permeabilities of the drugs with and without enhancers were compared. Drug concentrations in diffusion chambers and rabbit pl asma were determined using HPLC and radio receptor assay, respectively . Skin irritation was measured with a chromameter. DDAA and Azone caus ed approximately equal transdermal penetration enhancement of model dr ugs in vitro but the potency of n-dodecanol was lower. In vivo, Azone was the most irritating enhancer in rabbit pinna skin. Both enhancer e ffects and skin irritation by DDAA were reversed in 4 days, while the effects of Azone and n-dodecanol lasted longer. Thus, it is possible t o affect the duration of skin alteration by enhancer design. Propranol ol was more irritating than timolol in rabbit pinna skin in vivo. Perc utaneous permeability of propranolol in vivo, calculated from pharmaco kinetic parameters, was considerably greater than its in vitro permeab ility coefficient. In contrast, in vitro and in vivo permeability coef ficients of timolol were comparable. The increased permeation of propr anolol in vivo may be due to skin irritation, because in vivo permeabi lity coefficients correlated with associated skin irritation.