title: A novel enzymatic technique for limiting drug mobility in a hydrogel matrix.
abstract: An oral colon specific drug delivery platform has been developed to facilitate targetted release of therapeutic proteins as well as small molecule drugs. A simple enzymatic procedure is used to modify the molecular architecture of a lightly chemically crosslinked galactomannan hydrogel as well as a model drug-galactomannan oligomer conjugate, fluoroisocynate (FITC) tagged guar oligomer, to entrap the model drug. The enzyme-modified hydrogel retains the drug until it reaches the colonic environment where bacteria secrete enzymes (namely beta-mannanase) to degrade the gel and release the drug molecule. Laser scanning confocal microscopy combined with fluorescence recovery after photobleaching is used to quantify the diffusion of the drug conjugate. The diffusion coefficient of solutes in the lightly crosslinked galactomannan hydrogel is approximately equal to the diffusion coefficient in the guar solution for simple diffusional drug loading. After drug loading, alpha-galactosidase treatment generates additional physical crosslinks in the hydrogel matrix as well as between the drug-oligomer conjugate and the hydrogel, which reduces diffusion of the drug-oligomer conjugate significantly. Degradation of the hydrogel by beta-mannanase results in a slow and controlled rate of FITC-guar oligomer diffusion, which generates an extended release profile for the model drug.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Burke
authors.forename: Jung O
authors.initials: JO
authors.lastname: Park
authors.forename: Mohan
authors.initials: M
authors.lastname: Srinivasarao
authors.forename: Saad A
authors.initials: SA
authors.lastname: Khan
mesh_terms: D001234:Aspergillus niger / Q000201:enzymology; D003432:Cross-Linking Reagents / Q000737:chemistry; D031293:Cyamopsis / Q000201:enzymology; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005685:Galactans / Q000737:chemistry; D005690:Galactose / Q000031:analogs & derivatives; D020100:Hydrogels / Q000737:chemistry*; D007700:Kinetics; D008351:Mannans / Q000737:chemistry; D008970:Molecular Weight; D053149:Plant Gums; D012995:Solubility; D014025:Titanium / Q000737:chemistry; D000519:alpha-Galactosidase / Q000737:chemistry*; D044902:beta-Mannosidase / Q000737:chemistry*
chemical_list: D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005685:Galactans; D020100:Hydrogels; D008351:Mannans; D053149:Plant Gums; C012990:galactomannan; D014025:Titanium; C007894:guar gum; D000519:alpha-Galactosidase; D044902:beta-Mannosidase; D016650:Fluorescein-5-isothiocyanate; D005690:Galactose