title: Towards the bioequivalence of pressurised metered dose inhalers 1: design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient.
abstract: A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4μm±0.1 and 2.5μm±0.2), fine particle dose (⩽5μm; 66μg±6 and 68μg±2) and fine particle fractions (28%±2% and 30%±1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8%±2.1%, over 180min) compared to the glycerol-free particles (58.0%±2.9%, over 60min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract.
authors.affiliation: Chiesi Limited, Chippenham, UK. Electronic address: d.lewis@chiesi.com.
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, Sydney Medical School, The University of Sydney, Australia. Electronic address: paul.young@sydney.edu.au.
authors.forename: P M
authors.initials: PM
authors.lastname: Young
authors.affiliation: Department of Pharmacy, University of Parma, Parma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Buttini
authors.affiliation: Chiesi Limited, Chippenham, UK.
authors.forename: T
authors.initials: T
authors.lastname: Church
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: Respiratory Technology, The Woolcock Institute of Medical Research, The University of Sydney, Australia; Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Haghi
authors.affiliation: Chiesi Limited, Chippenham, UK.
authors.forename: R
authors.initials: R
authors.lastname: Johnson
authors.affiliation: Chiesi Limited, Chippenham, UK.
authors.forename: H
authors.initials: H
authors.lastname: O'Shea
authors.affiliation: Respiratory Technology, The Woolcock Institute of Medical Research, The University of Sydney, Australia; Discipline of Pharmacology, Sydney Medical School, 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, Sydney Medical School, The University of Sydney, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Traini
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D001507:Beclomethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D005079:Excipients / Q000737:chemistry; D005990:Glycerol / Q000737:chemistry; D036501:Metered Dose Inhalers; D008855:Microscopy, Electron, Scanning; D008954:Models, Biological; D008956:Models, Chemical; D010316:Particle Size; D016062:Porosity; D012995:Solubility; D013499:Surface Properties; D013810:Therapeutic Equivalency; D014835:Volatilization
chemical_list: D000336:Aerosols; D005079:Excipients; D001507:Beclomethasone; D005990:Glycerol
keywords: Aerosol Performance; Beclomethasone dipropionate; Bioequivalence; Glycerol; Non-volatile excipients; pMDI