title: Phosphated crosslinked guar for colon-specific drug delivery. II. In vitro and in vivo evaluation in the rat.
abstract: 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.
authors.affiliation: The Hebrew University of Jerusalem, School of Pharmacy, Faculty of Medicine, P.O. Box 12065, Jerusalem, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Gliko-Kabir
authors.forename: B
authors.initials: B
authors.lastname: Yagen
authors.forename: M
authors.initials: M
authors.lastname: Baluom
authors.forename: A
authors.initials: A
authors.lastname: Rubinstein
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002432:Cecum / Q000201:enzymology / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D005685:Galactans / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006854:Hydrocortisone / Q000008:administration & dosage / Q000493:pharmacokinetics; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008351:Mannans / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D008361:Mannosidases / Q000378:metabolism; D009928:Organ Specificity; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D053149:Plant Gums; D011122:Polyphosphates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D000519:alpha-Galactosidase / Q000378:metabolism; D044902:beta-Mannosidase
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D005685:Galactans; D020100:Hydrogels; D008351:Mannans; D014677:Pharmaceutical Vehicles; D053149:Plant Gums; D011122:Polyphosphates; C007894:guar gum; D008361:Mannosidases; D000519:alpha-Galactosidase; D044902:beta-Mannosidase; C009293:trimetaphosphoric acid; D006854:Hydrocortisone