title: Engineered sodium hyaluronate respirable dry powders for pulmonary drug delivery.
abstract: Sodium hyaluronate (HYA) warrants attention as a material for inhalation due to its (i) therapeutic potential, (ii) utility as a formulation excipient or drug carrier, and (iii) ability to target lung inflammation and cancer. This study aimed to overcome formulation and manufacturing impediments to engineer biocompatible spray-dried HYA powders for inhalation. Novel methodology was developed to produce HYA microparticles by spray drying. Different types of surfactant were included in the formulation to improve powder respirability, which was evaluated in vitro using cascade impactors. The individual formulation components and formulated products were evaluated for their biocompatibility with A549 respiratory epithelial cells. The inclusion of stearyl surfactants, 5% w/v, produced the most respirable HYA-powders; FPF 59.0-66.3%. A trend to marginally higher respirability was observed for powders containing stearylamine>stearyl alcohol>cetostearyl alcohol. Pure HYA was biocompatible with A549 cells at all concentrations measured, but the biocompatibility of the stearyl surfactants (based on lethal concentration 50%; LC50) in the MTT assay ranked stearyl alcohol>cetostearyl alcohol>stearylamine with LC50of 24.7, 13.2 and 1.8μg/mL, respectively. We report the first respirable HYA powders produced by spray-drying. A lead formulation containing 5% stearyl alcohol was identified for further studies aimed at translating the proposed benefits of inhaled HYA into safe and clinically effective HYA products.
authors.affiliation: Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Martinelli
authors.affiliation: Interdepartmental Center, Biopharmanet-TEC, University of Parma, Viale delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Anna Giulia
authors.initials: AG
authors.lastname: Balducci
authors.affiliation: King's College London, Institute of Pharmaceutical Science, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sonvico
authors.affiliation: King's College London, Institute of Pharmaceutical Science, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Forbes
authors.affiliation: Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: Bettini
authors.affiliation: Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy; King's College London, Institute of Pharmaceutical Science, 150 Stamford Street, London SE1 9NH, UK. Electronic address: francesca.buttini@unipr.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Buttini
mesh_terms: D000280:Administration, Inhalation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004337:Drug Carriers; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011208:Powders / Q000008:administration & dosage / Q000737:chemistry*; D020545:Respiratory Mucosa / Q000187:drug effects; D013501:Surface-Active Agents / Q000009:adverse effects* / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D011208:Powders; D013501:Surface-Active Agents; D006820:Hyaluronic Acid
keywords: Dry powder inhaler; Hyaluronan; Hyaluronic acid; Inhalation toxicology; Particle engineering