title: Highly respirable dry powder inhalable formulation of voriconazole with enhanced pulmonary bioavailability.
abstract: OBJECTIVE
  To develop and characterize a highly respirable dry powder inhalable formulation of voriconazole (VRZ).
  
  
  METHODS
  Powders were prepared by spray drying aqueous/alcohol solutions. Formulations were characterized in terms of particle size, morphology, thermal, moisture responses and aerosolization performance. Optimized powder was deposited onto an air-interface Calu-3 model to assess their uptake across Calu-3 lung epithelia. Optimized formulation was evaluated for stability (drug content and aerosol performance) for 3 months. Additionally, Calu-3 cell viability, lung bioavailability and tissue distribution of optimized formulation were evaluated.
  
  
  RESULTS
  Particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy. Optimized formulation showed irregular morphology, crystalline nature, low moisture sensitivity and was stable for 3 months at room temperature. Leucine did not alter the transport kinetics of VRZ, as evaluated by air-interface Calu-3 model. Formulation was non-cytotoxic to pulmonary epithelial cells. Moreover, lung bioavailability and tissue distribution studies in murine model clearly showed that VRZ dry powder inhalable formulation has potential to enhance therapeutic efficacy at the pulmonary infection site whilst minimizing systemic exposure and related toxicity.
  
  
  CONCLUSIONS
  This study supports the potential of inhaled dry powder VRZ for the treatment of fungal infections.
authors.affiliation: a Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics , National Institute of Pharmaceutical Education and Research (NIPER) , Mohali , India.|b Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School , The University of Sydney , Sydney , Australia.|c Max Planck Institute for Polymer Research , Mainz , Germany.
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.affiliation: b Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School , The University of Sydney , Sydney , Australia.|d School of Pharmacy, Graduate School of Health , University of Technology , Sydney , Australia.
authors.forename: Mehra
authors.initials: M
authors.lastname: Haghi
authors.affiliation: b Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School , The University of Sydney , Sydney , Australia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Young
authors.affiliation: c Max Planck Institute for Polymer Research , Mainz , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kappl
authors.affiliation: b Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School , The University of Sydney , Sydney , Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Traini
authors.affiliation: a Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics , National Institute of Pharmaceutical Education and Research (NIPER) , Mohali , India.
authors.forename: Sanyog
authors.initials: S
authors.lastname: Jain
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000737:chemistry; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D058995:Dry Powder Inhalers; D006801:Humans; D007930:Leucine / Q000737:chemistry; D010316:Particle Size; D011208:Powders / Q000737:chemistry; D020545:Respiratory Mucosa; D065819:Voriconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000336:Aerosols; D000935:Antifungal Agents; D011208:Powders; D007930:Leucine; D065819:Voriconazole
keywords: Leucine; lung bioavailability; pulmonary delivery; spray drying; storage stability; voriconazole (VRZ)