Formulation development and in-vitro evaluation of a polysaccharide-based colon-specific drug delivery system (CSDDS) for the treatment of inflammatory bowel disease.

摘要

Inflammatory bowel disease (IBD) is a chronic digestive disorder of the small and large intestines and refers to two major clinical conditions: Crohn's disease (CD) and ulcerative colitis (UC).; The objective of this dissertation is to develop a locally effective colon-specific therapeutic system in the form of a multiparticulate oral formulation that might provide an improved efficacy with a significant reduction in dose and systemic toxicity and improved quality of life for the treatment of IBD. The model drug was azathioprine (AZA).; As the first part of the investigation, various preformulation studies were carried out that were necessary to understand the physico-chemical behavior of AZA in solid and solution states.; The pH-solubility profile in Britton-Robinson (BR) buffer systems confirmed the weakly acidic behavior of AZA and provided two key physicochemical parameters: the intrinsic solubility (Si) and ionization constant (pKa). Overall, the results of preformulation studies indicated that solubility characteristics and metabolic instability in the simulated GI fluids is not expected to be a rate-limiting factor for the oral delivery of AZA.; In the formulation development studies, a series of microencapsulation techniques were investigated for their potential to deliver the required dose. To satisfy these interests, ionotropic gelation was used as a technique of choice because of its propensity to interact with ionic polysaccharides such as gellan gum. Studies revealed that azathioprine exists in amorphous state in the bead formulation and undergoes significant biodegradation in the presence of galactomannanase and the effects of galactomannanase is concentration-dependent rather time-dependent.; To retard drug release in the stomach and achieve a pH-dependent release at colonic pH of 7.4, a polymethacrylate-based coating procedure was developed and optimized.; The results of in vitro studies indicated that coating beads with Eudragit S-100 or with FS-30D has significant retarding effect in SGF. In addition, the in-vitro release profiles of beads (both uncoated and coated) were found to be significantly affected by the presence of galactomannanase (0.015 g/ml) in the dissolution media. (Abstract shortened by UMI.)