Transdermal penetration enhancers in rabbit pinna skin: Duration of action, skin irritation, and in vivo/in vitro comparison

Abstract

Irritation of the skin by chemical penetration enhancers may limit the use of these compounds in transdermal drug delivery. Biodegradable enhancers like dodecyl N,N-dimethylamino acetate (DDAA) have been synthesized previously to decrease the duration of action and toxicity of the enhancers. We studied the reversibility and extent of penetration enhancement and skin irritation by DDAA, Azone, and n-dodecanol in rabbit pinna skin using timolol and propranolol as penetrants. Also, in vitro and in vivo permeabilities of the drugs with and without enhancers were compared. Drug concentrations in diffusion chambers and rabbit plasma were determined using HPLC and radio receptor assay, respectively. Skin irritation was measured with a chromameter. DDAA and Azone caused approximately equal transdermal penetration enhancement of model drugs in vitro but the potency of n-dodecanol was lower. In vivo, Azone was the most irritating enhancer in rabbit pinna skin. Both enhancer effects and skin irritation by DDAA were reversed in 4 days, while the effects of Azone and n-dodecanol lasted longer. Thus, it is possible to affect the duration of skin alteration by enhancer design. Propranolol was more irridating than timolol in rabbit pinna skin in vivo. Percutaneous permeability of propranolol in vivo, calculated from pharmacokinetic parameters, was considerably greater than its in vitro permeability coefficient. In contrast, in vitro and in vivo permeability coefficients of timolol were comparable. The increased permeation of propranolol in vivo may be due to skin irritation, because in vivo permeability coefficients correlated with associated skin irritation.