title: Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro.
abstract: Two solution-based pressurised metered dose inhaler (pMDI) formulations were prepared such that they delivered aerosols with identical mass median aerodynamic diameters, but contained either beclomethasone dipropionate (BDP) alone (glycerol-free formulation) or BDP and glycerol in a 1:1 mass ratio (glycerol-containing formulation). The two formulations were deposited onto Calu-3 respiratory epithelial cell layers cultured at an air interface. Equivalent drug mass (∼1000ng or ∼2000ng of the formulation) or equivalent particle number (1000ng of BDP in the glycerol-containing versus 2000ng of BDP in the glycerol-free formulation) were deposited as aerosolised particles on the air interfaced surface of the cell layers. The transfer rate of BDP across the cell layer after deposition of the glycerol-free particles was proportional to the mass deposited. In comparison, the transfer of BDP from the glycerol-containing formulation was independent of the mass deposited, suggesting that the release of BDP is modified in the presence of glycerol. The rate of BDP transfer (and the extent of metabolism) over 2h was faster when delivered in glycerol-free particles, 465.01ng±95.12ng of the total drug (20.99±4.29%; BDP plus active metabolite) transported across the cell layer, compared to 116.17ng±3.07ng (6.07±0.16%) when the equivalent mass of BDP was deposited in glycerol-containing particles. These observations suggest that the presence of glycerol in the maturated aerosol particles may influence the disposition of BDP in the lungs.
authors.affiliation: Respiratory Technology, The Woolcock Institute of Medical Research, The University of Sydney, Australia; Discipline of Pharmacology, Faculty Medicine, The University of Sydney, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Haghi
authors.affiliation: Graduate School of Pharmacy Health-Pharmacy, University of Technology Sydney, Sydney, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Bebawy
authors.affiliation: Department of Pharmacy, University of Parma, Parma, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Colombo
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Forbes
authors.affiliation: Chiesi Limited, Chippenham, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Respiratory Technology, The Woolcock Institute of Medical Research, The University of Sydney, Australia; Discipline of Pharmacology, Faculty Medicine, The University of Sydney, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Salama
authors.affiliation: Respiratory Technology, The Woolcock Institute of Medical Research, The University of Sydney, Australia; Discipline of Pharmacology, Faculty Medicine, The University of Sydney, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Traini
authors.affiliation: Respiratory Technology, The Woolcock Institute of Medical Research, The University of Sydney, Australia; Discipline of Pharmacology, Faculty Medicine, The University of Sydney, Australia. Electronic address: paul.young@sydney.edu.au.
authors.forename: P M
authors.initials: PM
authors.lastname: Young
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D001507:Beclomethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005079:Excipients / Q000737:chemistry; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D036501:Metered Dose Inhalers; D008954:Models, Biological; D012995:Solubility; D012996:Solutions; D013810:Therapeutic Equivalency; D014835:Volatilization
chemical_list: D000336:Aerosols; D005079:Excipients; D012996:Solutions; D001507:Beclomethasone; D005990:Glycerol
keywords: Beclomethasone dipropionate; Bioequivalence; Calu-3; Epithelial cell model; Glycerol; Non-volatile excipients; pMDI