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 acco mplished 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 kinet ics of pre-loaded hydrocortisone from GGP hydrogels into buffer solutions w ith, or without GG degrading enzymes (alpha-galactosidase and beta-mannanas e) and (b) direct measurements of the polymers' degradation in the cecum of conscious rats. The effect of GG diet on alpha-galactosidase and beta-mann anase activity in the cecum of the rat and GGP degradation was also measure d. It was found that the product GGP-0.1 (loosely crosslinked with 0.1 equi valents of STMP) was able to prevent the release of 80% of its hydrocortiso ne load for at least 6 h in PBS, pH=6.4. When a mixture of alpha-galactosid ase and beta-mannanase was added to the buffer solution, an enhanced hydroc ortisone release was observed. In-vivo degradation studies in the rat cecum showed that despite the chemical modification of GG, it retained its enzym e-degrading properties in a crosslinker concentration-dependent manner. Eig ht days of GG diet prior to the study increased alpha-galactosidase activit y 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 t he degradation of the different GGP products. The overall alpha-galactosida se activity in the rat cecum was found to be extracellular, while the activ ity of beta-mannanase was found to be bacterial cell-wall associated. It is concluded that because CG crosslinked with STMP can be biodegraded enzymat ically 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 deli very. (C) 2000 Elsevier Science B.V. All rights reserved.