title: Effect of solubilizing excipients on permeation of poorly water-soluble compounds across Caco-2 cell monolayers.
abstract: The purpose of this study was to evaluate the effects of solubilizing excipients on Caco-2 transport parameters of poorly water-soluble NCEs (new chemical entities), and determine their permeability class under the BCS guidance (Biopharmaceutics Classification System). The effect of solubilizing excipients on soluble donor concentration of Sch 56592, Sch-X and Sch-Y was estimated. The transport of reference compounds and NCEs was studied across Caco-2 monolayers in absence or presence of solubilizing agents. The Caco-2 permeability of reference compounds showed good correlation with their extent of human oral absorption data. Sch 56592, Sch-X and Sch-Y exhibited high baseline Caco-2 permeability (>10(-5) cm/s). Povidone (1%) improved soluble donor concentration and flux of Sch 56592 by 40%. Other solubilizing excipients predominantly improved Sch 56592 soluble donor concentration, with either no change or a decrease in flux. With Sch-X, 1% povidone, pluronic F68, gelucir 44/14, and 3:2 propylene glycol/Tween-80 markedly improved soluble donor concentration, while increasing Sch-X flux by 40-65%. The soluble donor concentration of Sch-Y was also enhanced by excipients; however, only 1% pluronic F68 and PEG 300 increased Sch-Y flux by 35-50%. Sch 56592, Sch-X and Sch-Y are low solubility-high permeability compounds under the BCS guidance. For such poorly water-soluble NCEs, solubilizing excipients should be carefully screened based on their effects on solubility profiles and membrane transport.
authors.affiliation: Formulation Research, Schering-Plough Research Institute, Kenilworth, NJ, USA. pratik_saha@fmc.com
authors.forename: P
authors.initials: P
authors.lastname: Saha
authors.forename: J H
authors.initials: JH
authors.lastname: Kou
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002927:Cimetidine / Q000737:chemistry / Q000493:pharmacokinetics; D004110:Diltiazem / Q000737:chemistry / Q000493:pharmacokinetics; D005079:Excipients / Q000494:pharmacology*; D005663:Furans; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects*; D009281:Naphthalenes; D010672:Phenytoin / Q000737:chemistry / Q000493:pharmacokinetics; D010880:Piperidines; D020442:Poloxamer / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011205:Povidone / Q000494:pharmacology; D011433:Propranolol / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D014230:Triazoles / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000470:Alkaloids; D005079:Excipients; D005663:Furans; D007093:Imidazoles; D009281:Naphthalenes; D010880:Piperidines; D014230:Triazoles; D020442:Poloxamer; C104509:gelucire 44-14; D011092:Polyethylene Glycols; D010672:Phenytoin; C101425:posaconazole; D002927:Cimetidine; D011433:Propranolol; D004110:Diltiazem; D011205:Povidone; C048172:himbacine