title: The formulation of a pressurized metered dose inhaler containing theophylline for inhalation.
abstract: BACKGROUND
  Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP.
  
  
  METHODS
  Aerosol performance was assessed using Andersen Cascade Impaction (ACI). Solubility of TP in HFA 134/ethanol mixture was measured and morphology of the particles analyzed with a scanning electron microscope (SEM). Calu-3 cell viability, epithelial cell transport and inflammatory-response assays were conducted to study the impact of the formulation on lung epithelial cells.
  
  
  RESULTS
  The mass deposition profile of the formulation showed an emitted dose of 250.04±14.48μg per 5 actuations, achieving the designed nominal dose (50μg/dose). SEM showed that the emitted particles were hollow with spherical morphology. Approximately 98% of TP was transported across Calu-3 epithelial cells and the concentration of interleukin-8 secreted from Calu-3 cells following stimulation with tissue necrosis factor-α (TNF-α) resulted in significantly lower level of interleukin-8 released from the cells pre-treated with TP (1.92±0.77ng·ml(-1) TP treated vs. 8.83±2.05ng·ml(-1) TNF-α stimulated, respectively).
  
  
  CONCLUSIONS
  The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW 2037, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW 2037, Australia; School of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia.
authors.forename: Mehra
authors.initials: M
authors.lastname: Haghi
authors.affiliation: Avans University of Applied Science, Breda, The Netherlands.
authors.forename: Mary
authors.initials: M
authors.lastname: Goud
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW 2037, Australia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Young
authors.affiliation: Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW 2037, Australia. Electronic address: daniela.traini@sydney.edu.au.
authors.forename: Daniela
authors.initials: D
authors.lastname: Traini
mesh_terms: D000280:Administration, Inhalation; D000335:Aerosol Propellants / Q000737:chemistry; D000336:Aerosols; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000737:chemistry; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004867:Equipment Design; D000431:Ethanol / Q000737:chemistry; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry; D018836:Inflammation Mediators / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D036501:Metered Dose Inhalers; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D011312:Pressure; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013806:Theophylline / Q000008:administration & dosage* / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D005466:Fluorocarbons
chemical_list: D000335:Aerosol Propellants; D000336:Aerosols; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D000431:Ethanol; D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D016209:Interleukin-8; D013806:Theophylline; D014409:Tumor Necrosis Factor-alpha; C508606:CXCL8 protein, human; C094049:apaflurane; D005466:Fluorocarbons
keywords: Chronic obstructive pulmonary disease; Pressurized metered dose inhaler; Theophylline; Toxicity