Synthesis and evaluation of dextran–budesonide conjugates as colon specific prodrugs for treatment of ulcerative colitis

Abstract

Budesonide is a potent glucocorticoid with high affinity for the glucocorticoid receptor, which is now used for the treatment of inflammatory bowel diseases. Current oral formulations of budesonide present low efficacy against ulcerative colitis because of the premature drug release in the upper part of the gastrointestinal tract. The objective of this study was to develop a colon specific delivery system for budesonide to increase the efficacy in the treatment of ulcerative colitis. Dextran–budesonide conjugates were prepared with different molecular weights (MW) of dextran (10,000, 70,000 and 500,000) in the presence of dimethylaminopyridine (DMAP) using succinate spacer. The conjugates were characterized by 1H NMR and IR spectroscopy and elemental analysis. The degree of substitution, aqueous solubility and chemical stability of conjugates in HCl 0.1N, phosphate buffer solutions pH 6.8 and 7.4 were studied. Drug release characteristics of the conjugates were also studied in the presence of the luminal contents of different segments of the rat gastrointestinal tract. Degree of substitution (DS) was dependent on the polymer MW and was 19.33, 14.29 and 11.60 mg/100 mg conjugate for MW 10,000, 70,000 and 500,000, respectively. Solubility of the drug in conjugates of MW 10,000 and 70,000 was increased with respect to the free drug and was dependent on DS. The three conjugates were found to be stable in HCl 0.1N, phosphate buffer solutions pH 6.8 and 7.4 incubated at 37 °C within 6 h and the rate constants for degradation of conjugates to budesonide and budesonide hemisuccinate were less than 0.006 h −1. Less than 10% of the drug was released in contents of the stomach and small intestine, while about two-fold increase was observed after incubating the conjugates with colonic luminal contents. Conjugate prepared by dextran 70,000 showed the most desirable solubility, stability and release properties and could therefore be evaluated in vivo, for potential clinical use in the treatment of ulcerative colitis.