title: Utility of gastric-retained alginate gels to modulate pharmacokinetic profiles in rats.
abstract: A gastric-retentive formulation amenable to dosing in rodents has the potential to enable sustained release in a preclinical setting. This may be useful to provide systemic exposure over a longer duration or to increase duration of exposure for compounds with targets localized in the gastrointestinal tract. Previous work has shown that a mixture of 1% sodium alginate and 0.625% karaya gum in the presence of a calcium chelator can form gels in situ that are gastric retained in rats. The aim of this work was to define the physicochemical boundaries of compounds within this technology and their relation to in vivo release using a series of model compounds with high permeability but varying solubility. In vitro data demonstrated a good correlation between solubility and initial release rates from the gels. In vivo studies were conducted in Sprague-Dawley rats to compare the exposure profile of compounds dosed in gel relative to a standard formulation. In vivo data were consistent with trends from the in vitro studies. These data suggest that, in conjunction with an understanding of compound solubility, sodium alginate/karaya gum gels may be a useful tool to modulate exposure profiles in rodent models in a preclinical setting.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. kimberly.foster@bms.com
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Foster
authors.forename: Huadong
authors.initials: H
authors.lastname: Sun
authors.forename: Roderick Marcus
authors.initials: RM
authors.lastname: Fancher
authors.forename: Mirek
authors.initials: M
authors.lastname: Proszynski
authors.forename: George
authors.initials: G
authors.lastname: Dixon
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ford
authors.forename: Georgia
authors.initials: G
authors.lastname: Cornelius
authors.forename: Olafur S
authors.initials: OS
authors.lastname: Gudmundsson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hageman
mesh_terms: D000284:Administration, Oral; D000464:Alginates / Q000737:chemistry*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005753:Gastric Mucosa / Q000378:metabolism; D005782:Gels / Q000737:chemistry; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D007052:Ibuprofen / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010539:Permeability; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000464:Alginates; D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D003692:Delayed-Action Preparations; D005782:Gels; D006603:Hexuronic Acids; D011720:Pyrazoles; D013449:Sulfonamides; D020723:Glucuronic Acid; D008790:Metoprolol; D000068579:Celecoxib; D007052:Ibuprofen
keywords: alginate; drug delivery; formulation; gastroretention; hydrogels; oral absorption; physicochemical properties