Synthesis and investigation of urea compounds as transdermal penetration enhancers

Twelve urea and thiourea compounds were examined for their transdermal penetration enhancing properties in vitro using hairless mouse skin and hydrocortisone as a model drug. Skins were pretreated for 1 h with the enhancer in propylene glycol before application of the drug also in propylene glycol. Enhancement ratios (ER) were calculated for permeability coefficient (P), 24 h receptor concentration (Q₂₄), and skin content of drug (SC) and compared to control values (no enhancer present). Control values for permeability coefficients were 0.71 ± 0.27 cm h^-1, 24 h receptor concentration: 11.9 ± 3.4 μM, and skin content of drug 44.6 ± 18.5 μg g^{- 1}. The most effective enhancer of the series was 1-dodecyl-3-methylthiourea. This enhancer produced the highest values for all three penetration parameters with a permeability coefficient 4.7 ± 1.8 x 10^-4 cm h^-1 (ER(P) 6.6), a 24 h receptor concentration of 62.7 ± 16.3 μM (ER(Q24) 5.3), and a skin content of 90.1 ± 17.7 μg g^-1 (ER(SC) 2.0). A structure- activity relationship was observed in that the thio-substituted analogs were more effective enhancers than the oxygen-containing compounds. Although these compounds show promise as penetration enhancers, further study is needed to determine their effectiveness with other drugs and their irritation potential.