title: In vitro characterization and pharmacokinetics in mice following pulmonary delivery of itraconazole as cyclodextrin solubilized solution.
abstract: This study aims to make a 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) solubilized itraconazole (ITZ) solution (i.e., HPbetaCD-ITZ) suitable for pulmonary delivery by nebulization, and compare pharmacokinetics of inhaled nebulized aerosols of HPbetaCD-ITZ versus a colloidal dispersion of ITZ nanoparticulate formulation (i.e., URF-ITZ). Solid state characterizations of lyophilized HPbetaCD-ITZ by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) indicated the formation of dynamic inclusion complexes between ITZ and HPbetaCD. Nebulized aerosols of both HPbetaCD-ITZ and colloidal dispersion of URF-ITZ were confirmed suitable for deep lung delivery. Single doses of the nebulized aerosols (equivalent to 5.3mg ITZ/mL in 5 mL) in mice produced similar ITZ lung depositions and pharmacokinetic profiles, with ITZ lung levels of approximately 4 microg/g wet lung weight upon completion of nebulization and remained above 0.5 microg/g at 24h. HPbetaCD-ITZ demonstrated faster systemic absorption of ITZ across lung epithelium than URF-ITZ, with t(max) values of 1.5 and 3.0 h, and AUC(0-infinity) of 2513 and 3717 ng h/mL, respectively. The fast absorption of solubilized ITZ across lung mucosal surface may be due in part to the elimination of the phase-to-phase transition.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Keat Theng
authors.initials: KT
authors.lastname: Chow
authors.forename: Bo
authors.initials: B
authors.lastname: Lang
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.forename: Keith P
authors.initials: KP
authors.lastname: Johnston
authors.forename: Robert O
authors.initials: RO
authors.lastname: Williams
mesh_terms: D000336:Aerosols; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000737:chemistry*; D066298:In Vitro Techniques; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D010316:Particle Size; D012996:Solutions; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000336:Aerosols; D000935:Antifungal Agents; D003505:Cyclodextrins; D012996:Solutions; D017964:Itraconazole