title: Soluplus® as an effective absorption enhancer of poorly soluble drugs in vitro and in vivo.
abstract: As many new active pharmaceutical ingredients are poorly water soluble, solubility enhancers are one possibility to overcome the hurdles of drug dissolution and absorption in oral drug delivery. In the present work a novel solubility enhancing excipient (Soluplus®) was tested for its capability to improve intestinal drug absorption. BCS class II compounds danazol, fenofibrate and itraconazole were tested both in vivo in beagle dogs and in vitro in transport experiments across Caco-2 cell monolayers. Each drug was applied as pure crystalline substance, in a physical mixture with Soluplus®, and as solid solution of the drug in the excipient. In the animal studies a many fold increase in plasma AUC was observed for the solid solutions of drug in Soluplus® compared to the respective pure drug. An effect of Soluplus® in a physical mixture with the drug could be detected for fenofibrate. In vitro transport studies confirm the strong effect of Soluplus® on the absorption behavior of the three tested drugs. Furthermore, the increase of drug flux across Caco-2 monolayer is correlating to the increase in plasma AUC and C(max)in vivo. For these poorly soluble substances Soluplus® has a strong potential to improve oral bioavailability. The applicability of Caco-2 monolayers as tool for predicting the in vivo transport behavior of the model drugs in combination with a solubility enhancing excipient was shown. Also the improvement of a solid dispersion compared to physical mixtures of the drugs and the excipient was correctly reflected by Caco-2 experiments. In the case of fenofibrate the possible improvement by a physical mixture was demonstrated, underscoring the value of the used tool as alternative to animal studies.
authors.affiliation: Biopharmaceutics and Pharmaceutical Technology, Saarland University, 66123 Saarbrücken, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Linn
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Collnot
authors.forename: Dejan
authors.initials: D
authors.lastname: Djuric
authors.forename: Katja
authors.initials: K
authors.lastname: Hempel
authors.forename: Eric
authors.initials: E
authors.lastname: Fabian
authors.forename: Karl
authors.initials: K
authors.lastname: Kolter
authors.forename: Claus-Michael
authors.initials: CM
authors.lastname: Lehr
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D003613:Danazol / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D005079:Excipients / Q000737:chemistry*; D005260:Female; D011345:Fenofibrate / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D017964:Itraconazole / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D012995:Solubility
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D011145:Polyvinyls; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D017964:Itraconazole; D011092:Polyethylene Glycols; D003613:Danazol; D011345:Fenofibrate