title: 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 (1)H 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 degrees 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.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. varshosaz@pharm.mui.ac.ir
authors.forename: Jaleh
authors.initials: J
authors.lastname: Varshosaz
authors.forename: Jaber
authors.initials: J
authors.lastname: Emami
authors.forename: Naser
authors.initials: N
authors.lastname: Tavakoli
authors.forename: Afshin
authors.initials: A
authors.lastname: Fassihi
authors.forename: Mohsen
authors.initials: M
authors.lastname: Minaiyan
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Ahmadi
authors.forename: Farid
authors.initials: F
authors.lastname: Dorkoosh
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000138:chemical synthesis; D019819:Budesonide / Q000008:administration & dosage* / Q000138:chemical synthesis; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D003106:Colon / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D008297:Male; D008970:Molecular Weight; D011355:Prodrugs; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
chemical_list: D000893:Anti-Inflammatory Agents; D003911:Dextrans; D004337:Drug Carriers; D011355:Prodrugs; D019819:Budesonide; D015761:4-Aminopyridine; C003885:4-dimethylaminopyridine