title: Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs.
abstract: The aim of the study is to increase the bioavailability of itraconazole (ITRA) using nanosized cocrystals prepared via wet milling of ITRA in combination with dicarboxylic acids. Wet milling was used in order to create a nanosuspension of ITRA in combination with dicarboxylic acids. After spray-drying and bead layering, solid state was characterized by MDSC, XRD, Raman and FT-IR. The release profiles and bioavailability of the nanococrystalline suspension, the spray-dried and bead layered formulation were evaluated. A monodisperse nanosuspension (549±51nm) of ITRA was developed using adipic acid and Tween®80. Solid state characterization indicated the formation of nanococrystals by hydrogen bounds between the triazole group of ITRA and the carboxyl group of adipic acid. A bioavailability study was performed in dogs. The faster drug release from the nanocrystal-based formulation was reflected in the in vivo results since Tmax of the formulations was obtained 3h after administration, while Tmax of the reference formulation was observed only 6h after administration. This fast release of ITRA was obtained by a dual concept: manufacturing of nanosized cocrystals of ITRA and adipic acid via wet milling. Formation of stable nanosized cocrystals via this approach seems a good alternative for amorphous systems to increase the solubility and obtain a fast drug release of BCS class II drugs.
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
authors.forename: Lieselotte
authors.initials: L
authors.lastname: De Smet
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Saerens
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: De Beer
authors.affiliation: Applied and Analytical Chemistry, Hasselt University, Diepenbeek, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Carleer
authors.affiliation: Applied and Analytical Chemistry, Hasselt University, Diepenbeek, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Adriaensens
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Bocxlaer
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium. Electronic address: Chris.Vervaet@UGent.be.
authors.forename: Chris
authors.initials: C
authors.lastname: Vervaet
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Remon
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D003460:Crystallization; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D017964:Itraconazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D013499:Surface Properties; D014961:X-Ray Diffraction
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D017964:Itraconazole
keywords: Cocrystals; Dicarboxylic acids; Itraconazole; Nanosuspension; Poorly water soluble drugs; Wet milling