1-ALKYLAZACYCLOALKAN-2-ONE ESTERS AS PRODRUGS OF INDOMETHACIN FOR IMPROVED DELIVERY THROUGH HUMAN SKIN

1-Alkylazacycloalkan-2-one esters of indomethacin were synthesized and assayed to determine their stability in aqueous media, their susceptibility to undergoing in vitro enzymatic hydrolysis and their flux through excised human skin. 1-Methylazacycloalkan-2-one esters of indomethacin (I-IV) proved unstable in aqueous media while 1-ethylazacycloalkan-2-one esters (V-VIII) were much more stable. Esters V-VIII were readily hydrolyzed in vitro by porcine esterase and penetrated excised human skin better than the parent drug. The lipophilic index was determined by means of HPLC for esters I-VIII. Plotting the flux through the skin of esters V-VIII against their lipophilic index resulted in a parabolic relationship, the maximum being ester VI.