title: Bioavailability enhancement of itraconazole-based solid dispersions produced by hot melt extrusion in the framework of the Three Rs rule.
abstract: Solid dispersion formulations made of itraconazole (ITZ) and Soluplus® (polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer abbreviated SOL) were produced using hot melt extrusion. Since ITZ possesses a water solubility of less than 1ng/mL, the aim of this work was to enhance the aqueous solubility of ITZ, and thereby improve its bioavailability. The three formulations consisted of a simple SOL/ITZ amorphous solid dispersion (ASD), an optimized SOL/ITZ/AcDiSol® (super-disintegrant) ASD and an equimolar inclusion complex of ITZ in hydroxypropyl-β-cyclodextrin (substitution degree=0.63, CD) with SOL. The three formulations were compared in vitro and in vivo to the marketed product Sporanox®. The in vitro enhancement of dissolution rate was evaluated using a biphasic dissolution test. In vitro dissolution results showed that all three formulations had a higher percentage of ITZ released than Sporanox® with the following ranking: SOL/ITZ/CD>SOL/ITZ/AcDiSol®>SOL/ITZ>Sporanox®. The bioavailability of these four formulations was evaluated in rats. The bioanalytical method was optimized so that only 10μL of blood was withdrawn from the rats using specific volumetric absorptive microsampling devices. This enabled to keep the same rats during the whole study, which was in accordance with the Three Rs rules (reduction, refinement and replacement). Furthermore, this technique allowed the suppression of inter-individual variability. Higher Cmaxand AUC were obtained after the administration of all three formulations compared to the levels after the use of Sporanox® as follows: SOL/ITZ/AcDiSol®>SOL/ITZ/CD>SOL/ITZ>Sporanox®. The inversion in the ranking between SOL/ITZ/CD and SOL/ITZ/AcDiSol® made impossible the establishment of an in vitro-vivo correlation. Indeed, very different release rates were obtained in vitro and in vivo for the two optimized formulations. These results suggest that ITZ would be protected inside the core of the SOL micelles even during the absorption step at the intestine, while some agents present in the intestinal fluids could displace ITZ from the hydrophobic cavity of CD by competition.
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hopital, Avenue Hippocrate 15, 4000, Liege, Belgium. Electronic address: jthiry@ulg.ac.be.
authors.forename: Justine
authors.initials: J
authors.lastname: Thiry
authors.affiliation: Laboratory for the Analysis of Medicines, CIRM, University of Liège, Quartier Hopital, Avenue Hippocrate 15, 4000, Liege, Belgium.
authors.forename: Miranda G M
authors.initials: MG
authors.lastname: Kok
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hopital, Avenue Hippocrate 15, 4000, Liege, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Collard
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hopital, Avenue Hippocrate 15, 4000, Liege, Belgium.
authors.forename: Antoine
authors.initials: A
authors.lastname: Frère
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hopital, Avenue Hippocrate 15, 4000, Liege, Belgium.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Krier
authors.affiliation: Laboratory for the Analysis of Medicines, CIRM, University of Liège, Quartier Hopital, Avenue Hippocrate 15, 4000, Liege, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Fillet
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hopital, Avenue Hippocrate 15, 4000, Liege, Belgium.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Evrard
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005079:Excipients / Q000737:chemistry; D007408:Intestinal Absorption / Q000187:drug effects; D017964:Itraconazole / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D005079:Excipients; D008823:Micelles; D011108:Polymers; D011145:Polyvinyls; D047392:beta-Cyclodextrins; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017964:Itraconazole; D011092:Polyethylene Glycols
keywords: And solid dispersion; Bioavailability enhancement; Biphasic dissolution test; Cyclodextrin; Volumetric absorptive microsampling devices