Ketobemidone prodrugs for buccal delivery.

Abstract

Various carboxylic acid and carbonate esters of the opioid analgesic ketobemidone were prepared and assessed as potential prodrugs with the aim of obtaining a ketobemidone formulation suitable for buccal or sublingual absorption. The chemical stability, enzymatic hydrolysis and lipophilicity characteristics of the esters were studied using HPLC assay procedures. All esters were rapidly hydrolyzed in human plasma, the half-lives ranging between 0.03 and 1.8 min. A marked enzymatic hydrolysis took place in whole human saliva, the half-lives of hydrolysis being in the range 3-295 min. All esters were more lipophilic than the parent ketobemidone, as determined by octanol-buffer partition experiments and by reversed-phase column chromatography. The relatively high resistance of the sterically hindered 3,3-dimethylbutyryl ester to undergo hydrolysis in saliva combined with its facile plasma-enzyme catalyzed conversion and high lipophilicity makes this ester the most promising prodrug candidate for buccal delivery.