Phosphated crosslinked guar for colon-specific drug delivery II. In vitro and in vivo evaluation in the rat

Targeting of drugs to the colon, following oral administration, can be accomplished by the use of modified, biodegradable polysaccharides as vehicles. In a previous study, a crosslinked low swelling guar gum (GG) hydrogel was synthesized by reacting it with trisodium trimetaphosphate (STMP). in the present study the functioning of GG crosslinked products (GGP) as possible colon-specific drug carriers was analyzed by studying (a) the release kinetics of pre-loaded hydrocortisone from GGP hydrogels into buffer solutions with, or without GG degrading enzymes (alpha-galactosidase and beta-mannanase) and (b) direct measurements of the polymers' degradation in the cecum of conscious rats. The effect of GG diet on alpha-galactosidase and beta-mannanase activity in the cecum of the rat and GGP degradation was also measured. It was found that the product GGP-0.1 (loosely crosslinked with 0.1 equivalents of STMP) was able to prevent the release of 80% of its hydrocortisone load for at least 6 h in PBS, pH=6.4. When a mixture of alpha-galactosidase and beta-mannanase was added to the buffer solution, an enhanced hydrocortisone release was observed. In-vivo degradation studies in the rat cecum showed that despite the chemical modification of GG, it retained its enzyme-degrading properties in a crosslinker concentration-dependent manner. Eight days of GG diet prior to the study increased alpha-galactosidase activity in the cecum of the rat three-fold, compared to its activity without the diet. However, this increase in the enzyme activity was unable to improve the degradation of the different GGP products. The overall alpha-galactosidase activity in the rat cecum was found to be extracellular, while the activity of beta-mannanase was found to be bacterial cell-wall associated. It is concluded that because CG crosslinked with STMP can be biodegraded enzymatically and is able to retard the release of a low water-soluble drug, this polymer could potentially be used as a vehicle for colon-specific drug delivery. (C) 2000 Elsevier Science B.V. All rights reserved.