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Development of an inhaled controlled release voriconazole dry powder formulation for the treatment of respiratory fungal infection Sumit Arora, Mehra Haghi, Ching-Yee Loo, Daniela Traini, Paul M Young, and Sanyog Jain Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 29 Apr 2015 Downloaded from http://pubs.acs.org on April 30, 2015
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Molecular Pharmaceutics
Development of an inhaled controlled release voriconazole dry powder formulation for the treatment of respiratory fungal infection Sumit Arora1, 2, Mehra Haghi2, Ching-Yee Loo2, Daniela Traini2, Paul M. Young2, Sanyog Jain1* 1
Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of
Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali) Punjab160062 INDIA 2
Respiratory Technology, Woolcock Institute of Medical Research and Discipline of
Pharmacology, Sydney Medical School, The University of Sydney, NSW 2037, Australia
* Corresponding author - Sanyog Jain Address: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali) Punjab- 160062 INDIA Telephone: 0172-2292055 Fax: 0172-2214692 E-mail:
[email protected],
[email protected] 1 ACS Paragon Plus Environment
Molecular Pharmaceutics
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TABLE OF CONTENTS GRAPHIC For Table of Contents Use Only
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Molecular Pharmaceutics
Abstract The present research aimed to develop and characterise a sustained release dry powder inhalable formulation of voriconazole (VRZ) for invasive pulmonary aspergillosis. The developed formulations were studied for their in vitro release profile, aerosol and physico-chemical properties as well as interactions with lung epithelia in terms of toxicity and transport/uptake. VRZ and VRZ loaded poly lactide microparticles (VLM) were prepared by aqueous/organic cosolvent and organic spray drying respectively.
Powders were characterised using laser
diffraction, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS) and electron microscopy. Aerosol performance was evaluated using an RS01 dry powder inhaler and in vitro cascade impaction. Uptake across Calu-3 lung epithelia was studied, using aerosol deposition of the powder onto cells cultured in an air interface configuration, and compared to dissolution using a conventional dialysis membrane. Additionally, toxicity of VRZ and VLM and the potential impact of transmembrane proteins on uptake were investigated. The particle size and the aerosol performance of spray dried VRZ and VLM were suitable for inhalation purposes. VRZ exhibited a median volume diameter of 4.52 ± 0.07 µm while VLM 2.40 ± 0.05 µm. Spray dried VRZ was crystalline and VLM amorphous as evaluated by DSC and XRPD and both powders exhibited low moisture sorption between 0 and 90% RH (
