1-ethylazacycloalkan-2-one indomethacin esters as new oral prodrugs: chemical stability, enzymatic hydrolysis, anti-inflammatory activity and gastrointestinal toxicity

In the present study two 1-ethylazacycloalkan-2-one indomethacin esters were evaluated for the potential use as prodrugs for oral delivery. These derivatives were assayed to determine 'in vitro' their stability in pH 7.4 phosphate buffer and in simulated gastric fluid and their susceptibility in undergoing enzymatic cleavage in rat plasma. Besides their anti-inflammatory and analgesic activity and gastrointestinal toxicity after oral administration in rodents were evaluated. The prodrugs were found to be stable both in pH 7.4 phosphate buffer and in simulated gastric fluid, and readily hydrolyzed by rat plasma esterase activity. When tested in the carrageenan-induced edema in the rat paw, both esters showed an anti-inflammatory activity, following chronic administration, similar to that of indomethacin, although at higher doses; interestingly, they were significantly less irritating to the gastric mucosa than the parent drug. Furthermore, in the mouse acetic acid-induced writhing assay, the prodrugs exhibited, following acute administration, a good analgesic activity. In conclusion, the present evaluation indicates that the two tested esters represent potentially useful indomethacin prodrugs for oral administration since they: (1) are stable in aqueous solution and in simulated gastric fluid; (2) are readily hydrolyzed in rat plasma; (3) retain the anti-inflammatory and analgesic activity of the parent drug; and (4) notably inhibit the gastrointestinal irritation induced by indomethacin. (C) 1997 Elsevier Science B.V.