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Highfield, United Kingdom

Buchmann N.A.,Monash University | Buchmann N.A.,University of Federal Defense Munich | Duke D.J.,Monash University | Shakiba S.A.,Monash University | And 8 more authors.
Pharmaceutical Research | Year: 2014

Purpose: Non-volatile agents such as glycerol are being introduced into solution-based pMDI formulations in order to control mean precipitant droplet size. To assess their biopharmaceutical efficacy, both microscopic and macroscopic characteristics of the plume must be known, including the effects of external factors such as the flow generated by the patient's inhalation. We test the hypothesis that the macroscopic properties (e.g. spray geometry) of a pMDI spray can be predicted using a self-similarity model, avoiding the need for repeated testing.Methods: Glycerol-containing and glycerol-free pMDI formulations with matched mass median aerodynamic diameters are investigated. High-speed schlieren imaging is used to extract time-resolved velocity, penetration and spreading angle measurements of the pMDI spray plume. The experimental data are used to validate the analytical model.Results: The pMDI spray develops in a manner characteristic of a fully-developed steady turbulent jet, supporting the hypothesis. Equivalent glycerol-containing and non glycerol-containing formulations exhibit similar non-dimensional growth rates and follow a self-similar scaling behaviour over a range of physiologically relevant co-flow rates.Conclusions: Using the proposed model, the mean leading edge penetration, velocity and spreading rate of a pMDI spray may be estimated a priori for any co-flow conditions. The effects of different formulations are captured in two scaling constants. This allows formulators to predict the effects of variation between pMDIs without the need for repeated testing. Ultimately, this approach will allow pharmaceutical scientists to rapidly test a number of variables during pMDI development. © 2014 Springer Science+Business Media New York. Source


Haghi M.,University of Sydney | Bebawy M.,University of Technology, Sydney | Colombo P.,University of Parma | Forbes B.,Kings College London | And 4 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2014

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 (∼1000 ng or ∼2000 ng of the formulation) or equivalent particle number (1000 ng of BDP in the glycerol-containing versus 2000 ng 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 2 h was faster when delivered in glycerol-free particles, 465.01 ng ± 95.12 ng of the total drug (20.99 ± 4.29%; BDP plus active metabolite) transported across the cell layer, compared to 116.17 ng ± 3.07 ng (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.© 2013 Elsevier B.V. All rights reserved. Source


Paggiaro P.,University of Pisa | Patel S.,Chiesi Ltd | Nicolini G.,Chiesi Farmaceutici S.p.A. | Pradelli L.,AdRes Health Economics and Outcomes Research | And 2 more authors.
Respiratory Medicine | Year: 2013

Background GINA guideline recommends stepping down treatment of asthma patients where control is achieved. The aim of this analysis was to estimate the costs and health outcomes associated with step down of controlled patients on high dose fluticasone/salmeterol (FP/S 1000/100 μg daily) to either medium dose FP/S (500/100 μg) dry powder or extrafine beclometasone/formoterol (BDP/F 400/24 μg) pMDI in three European countries. Methods A patient-level simulation Markov model was constructed to enable the simulation of three comparative arms (FP/S 1000/100, FP/S 500/100, BDP/F 400/24). Transition probabilities and healthcare resources consumption were derived from a multinational clinical trial comparing BDP/F 400/24 μg vs. FP/S 500/100 μg as step down therapy in asthma. Direct costs and health state utilities were sourced from public source and published literature. The analysis was conducted from a health system perspective, based on six months horizon. Probabilistic sensitivity analyses were conducted. Results The ICER (Incremental Cost-Effectiveness Ratio) associated with high dose dry powder FP/S 1000/100 μg vs. extrafine BDP/F 400/24 μg was above 70,000 GBP and 200,000 €/QALY (Quality Adjusted Life Years). An ICER of 29,000 GBP/QALY and above 30,000 €/QALY was associated with medium dose dry powder FP/S 500/100 μg vs. BDP/F 400/24 μg. Conclusions It was found that maintaining controlled patients on high dose FP/S is not cost-effective. Extrafine BDP/F 400/24 μg daily can be considered to be a cost-effective option in the countries analyzed to maintain control of asthmatic patients stepped down from high dose FP/S 1000/100 μg daily dry powder or suspension formulations. Source


Zhu B.,University of Sydney | Traini D.,University of Sydney | Lewis D.A.,Chiesi Ltd | Young P.,University of Sydney
Colloids and Surfaces A: Physicochemical and Engineering Aspects | Year: 2014

The aerosol performance, physical properties and formation process of two corticosteroids (beclomethasone dipropionate and fluticasone propionate) and caffeine (active pharmaceutical ingredients: APIs) from ethanol-based pressurized metered dose inhaler solution formulations, containing various ethanol fractions, were evaluated using cascade impaction, thermal analysis and scanning electron microscopy. In general, the final aerosol particle size distribution (post USP induction port) was unaffected by ethanol concentration (mass median aerodynamic diameter and geometric standard deviation values for each formulation were independent of ethanol concentration (%, w/w) in the initial formulation). However, ethanol concentration directly affected the percentage of particles that passed the USP induction, resulting in a significant decrease in fine particle fraction, across all formulations, as ethanol was increased. Thus it can be concluded that particle size is governed by initial droplet diameter and API concentration, while performance is governed by drying time. The physico-chemical properties and morphology of the dried API particles, collected from cascade impactor stages, showed that the solid state was related to the glass transition temperature (Tg) and, to some extent, the saturated hydrofluoroalkane propellant (HFA)/ethanol solubility of the APIs. The low Tg API caffeine, with high HFA solubility resulted in crystalline particles, while the high Tg corticosteroids were amorphous. Furthermore, the final structure of the particles was dependent on the ethanol concentration and drying kinetics after initial droplet formation. This study has shown that the solid-state physico-chemical properties and morphology of particles is intrinsically linked to the API properties and drying kinetics of the propellant/co-solvent. These variations in aerosol efficiency, particle morphology and solid-state characteristics may have direct effects on drug efficacy and bioavailability after deposition in the lung. © 2013 . Source


Buttini F.,University of Parma | Miozzi M.,University of Parma | Miozzi M.,Chiesi Ltd | Balducci A.G.,University of Parma | And 5 more authors.
International Journal of Pharmaceutics | Year: 2014

Solution composition alters the dynamics of beclomethasone diproprionate (BDP) particle formation from droplets emitted by pressurised metered dose inhalers (pMDIs). The hypothesis that differences in inhaler solutions result in different solid particle physical chemistry was tested using a suite of complementary calorimetric techniques. The atomisation of BDP-ethanol solutions from commercial HFA-pMDI produced aerodynamically-equivalent solid particle aerosols. However, differences in particle physico-chemistry (morphology and solvate/clathrate formation) were detected by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and supported by hot stage microscopy (HSM). Increasing the ethanol content of the formulation from 8 to 12% (w/w), which retards the evaporation of propellant and slows the increase in droplet surface viscosity, enhanced the likelihood of particles drying with a smooth surface. The dissolution rate of BDP from the 12% (w/w) ethanol formulation-derived particles (63% dissolved over 120 min) was reduced compared to the 8% (w/w) ethanol formulation-derived particles (86% dissolved over 120 min). The addition of 0.01% (w/w) formoterol fumarate or 1.3% (w/w) glycerol to the inhaler solution modified the particles and reduced the BDP dissolution rate further to 34% and 16% dissolved in 120 min, respectively. These data provide evidence that therapeutic aerosols from apparently similar inhaler products, including those with similar aerodynamic performance, may behave non-equivalently after deposition in the lungs. © 2014 Elsevier B.V. Source

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