In vitro characterization and pharmacokinetics in mice following pulmonary delivery of itraconazole as cyclodextrin solubilized solution

Wei Yang, Keat Theng Chow, Bo Lang, Nathan P. Wiederhold, Keith P. Johnston, Robert O. Williams

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

This study aims to make a 2-hydroxypropyl-β-cyclodextrin (HPβCD) solubilized itraconazole (ITZ) solution (i.e., HPβCD-ITZ) suitable for pulmonary delivery by nebulization, and compare pharmacokinetics of inhaled nebulized aerosols of HPβCD-ITZ versus a colloidal dispersion of ITZ nanoparticulate formulation (i.e., URF-ITZ). Solid state characterizations of lyophilized HPβCD-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 HPβCD. Nebulized aerosols of both HPβCD-ITZ and colloidal dispersion of URF-ITZ were confirmed suitable for deep lung delivery. Single doses of the nebulized aerosols (equivalent to 5.3 mg ITZ/mL in 5 mL) in mice produced similar ITZ lung depositions and pharmacokinetic profiles, with ITZ lung levels of approximately 4 μg/g wet lung weight upon completion of nebulization and remained above 0.5 μg/g at 24 h. HPβCD-ITZ demonstrated faster systemic absorption of ITZ across lung epithelium than URF-ITZ, with tmax values of 1.5 and 3.0 h, and AUC0-∞ 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.

Original languageEnglish (US)
Pages (from-to)336-347
Number of pages12
JournalEuropean Journal of Pharmaceutical Sciences
Volume39
Issue number5
DOIs
StatePublished - Mar 18 2010

Keywords

  • Aerosol
  • Cyclodextrin
  • Nanoparticle
  • Permeability across mucosal membrane
  • Poorly water-soluble drug
  • Pulmonary delivery

ASJC Scopus subject areas

  • Pharmaceutical Science

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