In vitro evaluation of N-acyllactam esters of indomethacin as dermal prodrugs

Indomethacin N-acyllactam esters 1-6 were synthesized and assayed to determine their water and isopropylmyristate (IPM) stability, susceptibility to undergoing in vitro enzymatic hydrolysis and flux through excised human skin. Esters 1-6 showed poor stability in phosphate buffer pH 7.4 while they were stable in IPM over a period of 48 h. All the prodrugs, apart from derivative 6, were readily hydrolyzed by porcine esterase, Derivative 6, which possessed the greatest stability in phosphate buffer, was slowly hydrolyzed by esterases. Since esters 1-6 were poorly stable in water their skin permeation was determined using IPM as a vehicle. Esters 1-3 proved to permeate the skin better than indomethacin while esters 4-6 provided smaller (4 and 5) or similar indomethacin cumulative amount permeated through the skin over 24 h compared to the parent drug. Therefore, in this investigation only the derivatives (1-3) which showed increased lipophilicity and water solubility compared to the parent provided a moderate enhancement of in vitro indomethacin skin permeation.