Synthesis and evaluation of morpholinoalkyl ester prodrugs of indomethacin and naproxen.

Abstract

Morpholinoalkyl esters (HCl salts) of naproxen 1 and indomethacin 3 were synthesized and evaluated in vitro and in vivo for their potential use as prodrugs for oral delivery. Prodrugs were freely soluble in simulated gastric fluid (SGF) and pH 7.4 phosphate buffer and showed a minimum of a 2000-fold increase in solubility over the parent drugs. All prodrugs were more lipophilic than parent drugs as indicated by n-octanol/pH 7.4 buffer partition coefficients but less lipophilic in terms of n-octanol/SGF partition coefficients. Potentiometrically determined pKa's for prodrugs were in the range of 6.89 to 8.62 at 25 degrees C. All prodrugs were quantitatively hydrolyzed to their respective parent drugs by enzymatic and/or by chemical means. An increase in carbon chain length rendered the prodrugs more stable at pH 7.4 but less stable in SGF. The esters were generally found to be hydrolyzed rapidly in rat plasma at 37 degrees C, the half-lives being in the range of 1.2-31.0 min. Based on in vitro results, prodrugs 2c and 4c were chosen to evaluate solid-state stability, in vivo bioavailability, and ulcerogenicity. At elevated temperatures, the solid-state decomposition of 2c and 4c followed biphasic kinetics, with rapid decomposition occurring initially. The prodrugs were 30-36% more bioavailable orally than the parent drugs following a single equimolar solution dose in rats. Prodrugs 2c and 4c were significantly less irritating to gastric mucosa than parent drugs following single-dose and chronic oral administration in rats.