Synthesis and In Vitro Properties of Dexamethasone 21-Sulfate Sodium as a Colon-Specific Prodrug of Dexamethasone

ABSTRACT

We synthesized dexamethasone 21-sulfate sodium (DS) as a colon-specific prodrug of dexamethasone and investigated its properties. Introduction of a sulfate group to dexamethasone lowered the apparent partition coefficient from 52.5 to 0.27 in 1-octanol/pH 6.8 phosphate buffer at 37°C. DS was stable on incubation with buffer solutions of varied pH or with the upper intestinal contents of rats at 37°C for 24 h. On incubation with the cecal contents, DS was hydrolyzed by producing dexamethasone over 80% of the dose at 10 h. When DS was incubated with the cecal contents collected from trinitrobenzenesulfonic acid (TNBS)-induced colitic rats, the degree of prodrug hydrolysis and production of dexamethasone amounted to 70% of healthy rats. In comparison with prednisolone, hydrocortisone, and cortisone, dexamethasone was stable against bioinactivation by the cecal contents, a desirable property for the development of a colon-specific prodrug. These results demonstrated that DS might be delivered specifically to the colon as an intact form to produce dexamethasone in high yield, suggesting DS as a potential colon-specific prodrug of dexamethasone.

KEYWORDS:

• Colon-specific prodrug of glucocorticoid
• Dexamethasone
• Sulfatase
• Dexamethasone 21-sulfate sodium
• Inflammatory bowel disease