title: Interest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide.
abstract: To achieve an efficient lung delivery and efficacy, both active ingredient aerosolisation properties and permeability through the lung need to be optimized. To overcome these challenges, the present studies aim to develop cyclodextrin-based spray-dried microparticles containing a therapeutic corticosteroid (budesonide) that could be used to control airway inflammation associated with asthma. The complexation between budesonide and hydroxypropyl-β-cyclodextrin (HPBCD) has been investigated. Production of inhalation powders was carried out using a bi-fluid nozzle spray dryer and was optimized based on a design of experiments. Spray-dried microparticles display a specific "deflated-ball like shape" associated with an appropriate size for inhalation. Aerodynamic assessment show that the fine particle fraction was increased compared to a classical lactose-based budesonide formulation (44.05 vs 26.24%). Moreover, the budesonide permeability out of the lung was shown to be reduced in the presence of cyclodextrin complexes. The interest of this sustained budesonide release was evaluated in a mouse model of asthma. The anti-inflammatory effect was compared to a non-complexed budesonide formulation at the same concentration and attests the higher anti-inflammatory activity reach with the cyclodextrin-based formulation. This strategy could therefore be of particular interest for improving lung targeting while decreasing systemic side effects associated with high doses of corticosteroids. In conclusion, this works reports that cyclodextrins could be used in powder for inhalation, both for their abilities to improve active ingredient aerosolisation properties and further to their dissolution in lung fluid, to decrease permeability out of the lungs leading to an optimized activity profile.
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liège, Belgium. Electronic address: gilles.dufour@ulg.ac.be.
authors.forename: Gilles
authors.initials: G
authors.lastname: Dufour
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liège, Belgium.
authors.forename: William
authors.initials: W
authors.lastname: Bigazzi
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liège, Belgium.
authors.forename: Nelson
authors.initials: N
authors.lastname: Wong
authors.affiliation: APTIS, Chemistry Institute B6a, University of Liege, 4000 Liège, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Boschini
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liège, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: de Tullio
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liège, Belgium.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Piel
authors.affiliation: Laboratory of Tumour and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liege, 4000 Liège, Belgium.
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liège, Belgium.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Evrard
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D019819:Budesonide / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002478:Cells, Cultured; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D010316:Particle Size; D010539:Permeability; D011208:Powders; D012995:Solubility; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000336:Aerosols; D004337:Drug Carriers; D011208:Powders; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D019819:Budesonide
keywords: Budesonide; Cyclodextrins; Microparticules; Powder inhalation; Spray-drying; Sustained delivery