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Lewis D.A.,Chiesi Ltd | Young P.M.,University of Sydney | Buttini F.,University of Parma | Church T.,Chiesi Ltd | And 7 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2014

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 (2.4 μm ± 0.1 and 2.5 μm ± 0.2), fine particle dose (≤5 μm; 66 μg ± 6 and 68 μg ± 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 180 min) compared to the glycerol-free particles (58.0% ± 2.9%, over 60 min) 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.© 2013 Elsevier B.V. All rights reserved.


Haghi M.,University of Sydney | Bebawy M.,University of Technology, Sydney | Colombo P.,University of Parma | Forbes B.,King's 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.


PubMed | Chiesi Ltd, Argonne National Laboratory, Monash University and Woolcock Institute of Medical Research and the Discipline of Pharmacology
Type: | Journal: Pharmaceutical research | Year: 2017

Sprays from pressurised metered-dose inhalers are produced by a transient discharge of a multiphase mixture. Small length and short time scales have made the investigation of the governing processes difficult. Consequently, a deep understanding of the physical processes that govern atomisation and drug particle formation has been elusive.X-ray phase contrast imaging and quantitative radiography were used to reveal the internal flow structure and measure the time-variant nozzle exit mass density of 50L metered sprays of HFA134a, with and without ethanol cosolvent. Internal flow patterns were imaged at a magnification of 194pixels/mm and 7759 frames per second with 150ps temporal resolution. Spray projected mass was measured with temporal resolution of 1ms and spatial resolution 6m5m.The flow upstream of the nozzle comprised large volumes of vapour at all times throughout the injection. The inclusion of ethanol prevented bubble coalescence, altering the internal flow structure and discharge. Radiography measurements confirmed that the nozzle exit area is dominantly occupied by vapour, with a peak liquid volume fraction of 13%.Vapour generation in pMDIs occurs upstream of the sump, and the dominant volume component in the nozzle exit orifice is vapour at all times in the injection. The flow in ethanol-containing pMDIs has a bubbly structure resulting in a comparatively stable discharge, whereas the binary structure of propellant-only flows results in unsteady discharge and the production of unrespirable liquid masses.


PubMed | Chiesi Ltd, Argonne National Laboratory, Monash University and University of New South Wales
Type: Journal Article | Journal: Pharmaceutical research | Year: 2016

Drug concentration measurements in MDI sprays are typically performed using particle filtration or laser scattering. These techniques are ineffective in proximity to the nozzle, making it difficult to determine how factors such as nozzle design will affect the precipitation of co-solvent droplets in solution-based MDIs, and the final particle distribution.In optical measurements, scattering from the constituents is difficult to separate. We present a novel technique to directly measure drug distribution. A focused x-ray beam was used to stimulate x-ray fluorescence from the bromine in a solution containing 85% HFA, 15% ethanol co-solvent, and 1 [Formula: see text] / [Formula: see text] IPBr.Instantaneous concentration measurements were obtained with 1ms temporal resolution and 5 [Formula: see text] spatial resolution, providing information in a region that is inaccessible to many other diagnostics. The drug remains homogeneously mixed over time, but was found to be higher at the centerline than at the periphery. This may have implications for oropharyngeal deposition in vivo.Measurements in the dynamic, turbulent region of MDIs allow us to understand the physical links between formulation, inspiration, and geometry on final particle size and distribution. This will ultimately lead to a better understanding of how MDI design can be improved to enhance respirable fraction.


PubMed | Chiesi Ltd, Argonne National Laboratory, Monash University and Woolcock Institute of Medical Research and the Discipline of Pharmacology
Type: Journal Article | Journal: Pharmaceutical research | Year: 2016

Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques.We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays.Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 m. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow.Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.


Shemirani F.M.,University of Alberta | Hoe S.,University of Alberta | Lewis D.,Chiesi Ltd | Church T.,Chiesi Ltd | And 2 more authors.
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2013

Background: Existing literature has shown that high relative humidity (RH) affects in vitro aerosol drug delivery of nebulizer and pressurized metered dose inhaler (pMDI) formulations. The aim of this study is to investigate in vitro mouth-throat deposition and lung delivery of selected solution and suspension pMDI formulations, under a range of RH, temperature, and flow rate conditions. Methods: The Alberta Idealized Throat was connected to a collection filter and placed in an environmental control chamber. The formulations selected were beclomethasone dipropionate (BDP) in 13% w/w ethanol/1.3% w/w glycerol and HFA-134a propellant solution ("BDP HFA134a"), BDP in 13% w/w ethanol and HFA-227 propellant solution ("BDP HFA227"), and Flixotide Evohaler (fluticasone propionate 250 μg/dose in HFA-134a suspension). Each of these pMDI formulations was dispersed into the mouth-throat and filter assembly in triplicate, according to an experimental matrix consisting of the following conditions: air flow rates of 28.3, 60, and 90 L/min; 0%, 35%, and 80% RH; operating temperatures of 20 C and 40 C. Results: There was a general increase in mouth-throat deposition and corresponding decrease in filter deposition (representing lung dose fraction), with increasing RH for both BDP HFA134a and Flixotide pMDIs. Increasing temperature from 20 C to 40 C resulted in decreased mouth-throat deposition and increased lung dose fraction for the solution pMDIs, but generally no effect for the suspension pMDI. Conclusions: Not only is the dose delivery of pMDI formulations affected by environmental conditions (in some cases causing up to 50% reduction in lung delivery), but solution and suspension formulations also behave differently in response to these conditions. These results have implications during dosage form design, testing, and for usage patient use. © 2013, Mary Ann Liebert, Inc.


Ivey J.W.,University of Alberta | Lewis D.,Chiesi Ltd. | Church T.,Chiesi Ltd. | Finlay W.H.,University of Alberta | Vehring R.,University of Alberta
International Journal of Pharmaceutics | Year: 2014

A correlation equation for the mass median aerodynamic diameter (MMAD) of the aerosol emitted by solution metered dose inhalers (MDIs) is presented. A content equivalent diameter is defined and used to describe aerosols generated by evaporating metered dose inhaler sprays. A large set of cascade impaction data is analyzed, and the MMAD and geometric standard deviation is calculated for each datum. Using dimensional analysis, the mass median content equivalent diameter is correlated with formulation variables. Based on this correlation in combination with mass balance considerations and the definition of the aerodynamic diameter, an equation for prediction of the MMAD of an inhaler given the pressure of the propellant in the metering chamber of the MDI valve and the surface tension of the propellant is derived. The accuracy of the correlation equation is verified by comparison with literature results. The equation is applicable to both HFA (hydrofluoroalkane) propellants 134a and 227ea, with varying levels of co-solvent ethanol. © 2014 Elsevier B.V. All rights reserved.


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 .


PubMed | University of Sydney and Chiesi Ltd.
Type: Journal Article | Journal: International journal of pharmaceutics | Year: 2016

Pharmacopoeial methods for measurement of the aerodynamic particle size distribution (APSD) of metered dose inhalers (MDIs) by cascade impaction specify a sampling flow rate of 28.3L/min. However, there is little data within the literature to rationalize this figure, or to support its clinical relevance. In addition, the standard United States Pharmacopoeia Induction Port (USP IP) used for testing is known to inaccurately reflect deposition behavior in the upper airway, further compromising the relevance of testing, for product development. This article describes experimental studies of the effect of sampling flow rate on APSD data gathered using an Andersen Cascade Impactor (ACI). Tests were carried out using two different formulations to assess the influence of formulation composition. In addition, comparative testing with an Alberta Idealised Throat, in place of the USP IP, to ensure more realistic representation of the upper airway. The results show how measured APSD and fine particle dose, the dose than on the basis of size would be expected to deposit in the lung, vary as a function of test methodology, providing insight as to how the testing can be modified towards greater clinical relevance.


Lewis D.A.,Chiesi Ltd. | O'Shea H.,Chiesi Ltd. | Mason F.,Chiesi Ltd. | Church T.K.,Chiesi Ltd.
Aerosol Science and Technology | Year: 2016

The interplay between canister, valve design, formulation, and environmental temperature is crucial to dose retention in metered dose inhalers (MDIs). Previous studies that have utilized MDIs with polymeric capillary retention valves, have shown that exposure to environmental changes can create a temporary temperature gradient between the formulation retained in the metering chamber and the formulation reservoir in the metal canister, which can cause inconsistencies in the dose delivered to the patient. The purpose of this study was to more fully quantify these effects. This was achieved by deliberately varying the temperature difference between inhalers and environment within ranges representative of routine usage, and assessing the resulting loss of prime effect via shot weight and delivered dose testing. The shot weights delivered by three fixed-dose commercial MDIs—Foster®, flutiform® and Seretide®, were investigated under different experimental conditions. Exposure to temperature changes of up to 15°C did not appear to affect unprimed shot weights (USW) or subsequent doses from the Foster product. In contrast, flutiform maintained prime at a temperature differential of 8.6°C, but delivered a low USW following exposure to a ΔT of 15°C under both realistic and controlled conditions. Seretide exhibited loss of prime at lower temperature differentials (ΔT 8.6°C) and a reduction in USW. The results suggest that the inclusion of ethanol in a solution-based formulation may inhibit loss of prime, leading to more robust performance in the face of temperature variations. Delivered dose testing was carried out to assess the effect of loss of prime on the device ability to deliver a dose to within 80–120% of the label claim. The results suggest that the drainage of propellant from the metering chamber of suspension MDIs leaves active pharmaceutical ingredient (API) residue, causing an increase in subsequent doses once the prime has been restored. Taken together, the results provide valuable insight into the likely performance of MDIs subjected to routine daily use, highlighting design and formulation strategies that could be applied to make performance more robust. © 2016 The Author(s). Published with license by American Association for Aerosol Research

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