Thermodynamic Study on Enhancement of Percutaneous Penetration of Drugs by Azone^[○!R]

Abstract

The mechanism whereby Azone^[○!R] (AZ, 1-dodecylazacycloheptan-2-one) enhances drug penetration through the hairless rat abdominal skin was investigated thermodynamically. Three kinds of drugs, indomethacin, ibuprofen and sulfanilamide which have similar solubilities in a mixed organic solvent (ethanol-diethylcarbitol, 40 : 60, v/v), were selected to evaluate the drug penetration with or without 5% AZ. Transdermal delivery rates were determined at 27 and 37°C by using an in vitro diffusion cell procedure and the abdominal full-thickness skin of hairless rat. The solubility of each of the three drugs in the solvent with AZ was similar to that without AZ. Ethanol in the vehicle penetrated through the skin prior to the drugs. Activation energies for the skin penetration of the three drugs in the presence of AZ were decreased compared to those in its absence. For all drugs the partition coefficients between the skin and vehicle with AZ were 2-80 times higher than those without it. The activity coefficients of drugs in the presence of AZ in the skin were 2-90 times lower than those without the enhancer. These results suggested that the enhancing effect of AZ was not due to changing the solubility of the drugs in solvents but to increasing the thermodynamic activities and the affinities of the drugs to skin.