Unsaturated cyclic ureas as new non-toxic biodegradable transdermal penetration enhancers. II. Evaluation study

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Abstract

Thirteen new transdermal penetration enhancers were evaluated with respect to the absorption of indomethacin using shed snake skin of Elaphe obsoleta as a model of the stratum corneum and using Azone as the standard enhancer for comparison. Indomethacin was incorporated into a petrolatum ointment together with the appropriate enhancer. Three of these compounds, (A1), (A2), and (A3), show penetration enhancement at least equal to or better than Azone. Using hairless mouse skin as the model skin, (A1) shows enhancement 3 times better than Azone. Hairless mouse skin is more permeable than snake skin by indomethacin. The low toxicity of the enhancers was demonstrated by the survival of mice which were given s.c. a total of 14 g/kg of (A2). The biodegradability of the enhancers was illustrated by the hydrolysis of (A3) with porcine esterase in isotonic phosphate buffer pH 7.2 at 32° C with a t12 = 7.28 min. A release study of indomethacin for a series of ointments consisting of a variable concentration of indomethacin indicates that the saturated concentration of indomethacin in petrolatum base in the presence of 5% of (A1) is about 0.6% of indomethacin. The release rate of (A1) from an ointment made of 1% of indomethacin, 5% (A1), and 94% petrolatum base was 4.34 μg/min12/cm2. Electron micrograph study on shed snake skin treated with (A1) demonstrated that (Al) interacted with the skin, making a marked morphological change in the skin.

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