Synthesis and chemical stability of glucocorticoid-dextran esters: potential prodrugs for colon-specific delivery☆

Dextran ester prodrugs have been proposed as a means of delivering drug to the colon. In this study, methylprednisolone and dexamethasone were covalently attached to dextran (Mw = 72 600) by the use of a succinate linker. In addition, dexamethasone was attached by glutaric acid to investigate the effect of linker molecule on hydrolysis kinetics. The kinetics of degradation of the hemiesters and corresponding dextran conjugates were measured as a function of pH and temperature. Intramolecular migration of the linker molecule from the 21- to the 17-position on the glucocorticoid occurred in all three hemiesters, although to a greater extent in methylprednisolone-hemisuccinate. The dextran conjugates were also incubated at 37°C, pH 6.8 and the chemical degradation half-lives were as follows: dexamethasone-succinate-dextran 75 h; dexamethasone-glutarate-dextran 103 h and methylprednisolone-succinate-dextran 82 h. Incubation of dexamethasone-21-hemisuccinate with rat gastrointestinal (GI) tract luminal contents indicated that the hemiester is hydrolyzed throughout the GI tract. Greatest esterase activity, however, was found in the small intestine. By contrast, little drug (< 3%) was released from dexamethasone-succinate-dextran during incubation with small intestinal contents despite the high esterase activity. Dexamethasone and dexamethasone-21-hemisuccinate were released at faster rates during incubation with cecum and colon contents. This combination of chemical stability and selective enzyme-mediated drug release in the large intestine indicates that these dextran prodrugs have potential in colon-specific delivery of glucocorticoids.