title: A comparative study of a range of polymeric microspheres as potential carriers for the inhalation of proteins.
abstract: The aim of this study was to compare protein-loaded inhalable microparticles manufactured using a range of biocompatible polymers including hydroxypropyl cellulose (HPC), chitosan, hyaluronic acid, alginate, gelatin, ovalbumin and poly(lactide-co-glycolide) (PLGA). Spray-drying was used to prepare microparticles containing bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC). Particles of respirable size and high protein loading were obtained. No evidence of BSA degradation was seen from PAGE analysis. The microparticles were mixed with mannitol as a carrier and powder aerosolization was assessed with a multi-dose dry powder inhaler (DPI) using a multi-stage cascade impactor. The mass median aerodynamic diameter (MMAD) ranged between 2.9 and 4.7 microm. Potential polymer toxicity in the lungs was compared by impinging the particles on Calu-3 monolayers and assessing the cytotoxicity, induction of cytokine release, changes in transepithelial permeability and electrical resistance. No toxic effects were observed with most of the polymers though some evidence of compromised cell monolayer integrity was seen for PLGA and ovalbumin. PLGA and gelatin microparticles caused a significant increase in IL-8 release. Of the polymers studied, PLGA showed the greatest toxicity. Certain polymers showed particular promise for specific protein delivery needs in the lungs, such as HPC to improve flow properties, sodium hyaluronate for controlled release, and chitosan and ovalbumin for systemic delivery.
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, York House, York Street, Dublin 2, Ireland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Sivadas
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Rourke
authors.forename: Aoife
authors.initials: A
authors.lastname: Tobin
authors.forename: Vivienne
authors.initials: V
authors.lastname: Buckley
authors.forename: Zeibun
authors.initials: Z
authors.lastname: Ramtoola
authors.forename: John G
authors.initials: JG
authors.lastname: Kelly
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hickey
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Cryan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003890:Desiccation; D004337:Drug Carriers; D004355:Drug Stability; D005079:Excipients; D019793:Fluorescein; D005456:Fluorescent Dyes; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010316:Particle Size; D011108:Polymers; D011506:Proteins / Q000008:administration & dosage* / Q000737:chemistry; D013778:Tetrazolium Salts; D013844:Thiazoles; D014867:Water / Q000032:analysis
chemical_list: D000336:Aerosols; D016207:Cytokines; D004337:Drug Carriers; D005079:Excipients; D005456:Fluorescent Dyes; D011108:Polymers; D011506:Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014867:Water; C022616:thiazolyl blue; D019793:Fluorescein