RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Performance of Pressurized Metered-Dose Inhalers at Extreme Temperature Conditions CHELSEA M. D. MORIN, JAMES W. IVEY, JORDAN T. F. TITOSKY, JONATHAN D. SUDERMAN, JASON S. OLFERT, REINHARD VEHRING, WARREN H. FINLAY Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta Received 16 June 2014; revised 1 August 2014; accepted 11 August 2014 Published online 22 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24145 ABSTRACT: The performance of pressurized metered-dose inhalers (pMDIs) under a variety of temperature conditions was investigated. The effects of both inhaler temperature and ambient temperature were considered. The inhaler temperature ranged from −13.0◦ C to 41.7◦ C and the ambient temperature ranged from −12.0◦ C to 41.7◦ C. The in vitro lung dose was measured for four widely available pMDIs: AiromirTM , QVARTM , Symbicort , and Ventolin . The in vitro lung dose through an Alberta Idealized Throat was measured by gravimetric assay, which was verified by UV spectroscopic assay. A decrease in the in vitro lung dose was observed for all evaluated pMDIs when ambient temperature and device temperature were simultaneously reduced, decreasing on average by 70% at the coldest temperatures, whereas increasing on average by 25% at the elevated temperature condition. In vitro lung dose is strongly dependent on both inhaler C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J temperature and ambient temperature with the tested pMDIs. Pharm Sci 103:3553–3559, 2014 Keywords: temperature; pressurized metered-dose inhaler (pMDI); aerosols; microparticles; in vitro models; pulmonary drug delivery; AiromirTM ; stability; QVARTM ; Symbicort ; Ventolin R
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INTRODUCTION Pressurized metered-dose inhalers (pMDIs) are widely used for treating and controlling asthma and chronic obstructive pulmonary disease.1 pMDIs are typically formulated as either solutions or suspensions. Solution pMDIs consist of a drug in a solubilized state and may contain dissolved excipients and cosolvents. Suspension pMDIs consist of a drug in a solid phase, suspended in a propellant. Surfactants may be added to reduce particle aggregation but are typically insoluble in the pure propellant, necessitating the addition of a cosolvent, such as ethanol.1 It is well known that propellant droplet formation is influenced by device parameters including actuator orifice diameter and valve size, as well as drug formulation parameters such as composition, concentration, propellant type, cosolvent, and vapor pressure inside the canister.2,3 Increases in orifice diameter lead to higher plume momentum,3 which in turn leads to increased oropharyngeal deposition.4 Propellant choice and cosolvent content determine the vapor pressure within the canister at any given temperature, and an increase in vapor pressure increases evaporation rate after atomization.5 Increasing vapor pressure also produces a finer atomized droplet distribution.3 Overall, increased vapor pressure leads to a decrease in extrathoracic deposition and an increase in lung deposition.6 In vitro tests of pMDI delivery efficiency, such as cascade impaction, have thoroughly explored the effects of manipulating the aforementioned device parameters. Such tests are typically Abbreviations used: pMDI, pressurized metered-dose inhaler; MMAD, mass median aerodynamic diameter; RH, relative humidity. Correspondence to: Warren H. Finlay (Telephone: +780-492-4707; Fax: +780492-2200; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 103, 3553–3559 (2014)
C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association
performed under controlled laboratory conditions, but there are a number of environmental factors, which also influence delivery efficiency, including temperature and humidity.7–11 In order to obtain results under realistic use conditions, external factors influencing droplet formation and delivery must also be considered. The effect of reduced temperature on pMDI performance has previously been studied, but in a limited manner. In an early study of pMDIs with chlorofluorocarbon propellant, Wilson et al.7 showed that as the device temperature decreases, the vapor pressure inside the canister also decreases, leading to a larger initial mass median diameter when actuated in ambient conditions. They also found the actuated dose increased at lower temperatures and proposed increased propellant density at lower temperatures as a potential explanation. Stein and Cocks8 showed that the mass median aerodynamic diameter (MMAD) of commercially available solution and suspension pMDIs, including QVARTM and Ventolin , increased with decreased device temperature. They concluded that the MMAD of solution pMDIs increased as a result of an increase in the atomized droplet size, and the MMAD of suspension pMDIs increased as a result of a larger number of propellant droplets containing multiple particles of the dispersed phase (so-called multiplets). Because the frequency of multiplets is related to the propellant droplet size distribution,12 Stein and Cocks8 essentially showed that cold inhalers produce coarser droplet size distributions compared with warmer inhalers. The effects of increasing inhaler temperature have also been investigated, albeit in a limited way.9–11,13 Shemirani et al.9 tested pMDIs equilibrated to ambient conditions and observed an increase in lung dose fraction for a BDP HFC 134a formulation with an increase in ambient temperature. Hoye11 also tested pMDIs at increased temperatures, but it is not clear whether they were tested at elevated ambient temperature or R
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at room temperature. They observed a decrease in the amount of drug leaving the device as well as a decrease in the MMAD as temperature increased. The two competing mechanisms led to an 85.2% increase in respirable mass for Ventolin with an increase from 4◦ C to 60◦ C. Nithyanandan et al. studied the effects of exposing pMDIs to high temperatures (50◦ C) and found that other than higher susceptibility to damage by mechanical stresses, if the inhalers were allowed to equilibrate to room temperature, their performance was not detrimentally affected. To our knowledge, no studies investigating both the separate and combined effects of device temperature and ambient temperature have been conducted. Oropharyngeal and lung deposition are influenced by initial droplet size distribution, velocity distribution, and evaporation rates, all of which may be affected by device or ambient temperature.5 Therefore, the influence of both device temperature and ambient temperature on the in vitro lung dose was studied with four commercially available pMDIs. The distinction between device and ambient temperature is of practical importance, as pMDIs may not always be in thermal equilibrium with the environments in which they are utilized. R
EXPERIMENTAL Materials
chamber. The relative humidity (RH) in the chamber was thus less than 1% for all in vitro lung dose testing. The environmental chamber consisted of a glove box inside of a second glove box. Dry air was supplied to the outer chamber to avoid ice formation on the outer walls of the inner chamber, which would have limited the view into the chamber, and to help maintain a constant inner chamber temperature. In order to achieve the coldest testing conditions, the air was also run through a secondary heat exchanger filled with dry ice. The use of dry air avoided particle size changes due to humidity, which has previously been shown to have an effect on the in vitro lung dose.9 In Vitro Testing Apparatus The equipment configuration is shown schematically in Figure 1. All testing was conducted using the Alberta Idealized Throat.25,26 The throat model was cleaned by wiping it with ethanol, spraying it with silicone (Molykote Silicone 557, Dow Corning, Midland, Michigan), and allowing it to dry. The temperature on the surface of the throat model was maintained at 36.3◦ C (SD F = 2.9◦ C) using heat tape (BSAT051004, Briskheat, Columbus, Ohio). The temperature was measured using a thermocouple (50416-T, Cooper Atkins, Middlefield, Connecticut) and read off a panel meter (765-TF, Jenco Instruments Inc., San Diego, California) connected to the thermocouple.
The four pMDIs tested were AiromirTM (lot #GNJ017A, Medicis now Valeant, Laval, Quebec, Canada), QVARTM (lot #GNG058A, Medicis now Valeant), Symbicort (lot #3000598C00 and 3000702C00, AstraZeneca Inc., Mississauga, Ontario, Canada) and Ventolin (lot #3ZP5854, GlaxoSmithKline Inc., Mississauga, Ontario, Canada). The labeled dosage and composition along with the measured actuator orifice diameter and MMADs from the literature are listed in Table 1. The orifice diameters were measured using pin gauges (Starrett, Athol, Massachusetts). The values reported are the upper and lower bounds for the diameter and were limited to the steps in size of successive pin gauges. R
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Environmental Controls Inhalers were tested in a controlled environmental chamber. Compressed, dry air with a dew point temperature of –67◦ C flowed through a heat exchanger with a 50:50 ethylene glycol– water (volume basis) working fluid and into the environmental
Figure 1. Equipment used for experimental setup, showing components both within and outside of environmental chamber.
Table 1. Summary of Reported Data from Product Monographs and Prescribing Information,14–17 Room Temperature MMADs from Literature, and Measured Actuator Orifice Diameters Device Drug and metered dose (:g) Format Excipient(s) Propellant Orifice diameter (mm) MMAD (:m)
AiromirTM
QVARTM
SymbicortR
VentolinR
Salbutamol sulfate (100) Suspension Ethanol and oleic acid HFC 134a 0.20–0.28
Beclomethasone dipropionate (100) Solution Ethanol
Budesonide (160)/formoterol (4.5) Suspension Povidone K25 and PEG 1000 HFC 227ea 0.36–0.38
Salbutamol sulfate (100) Suspension None
1.84–1.9718,19
1.0–1.120,21
HFC 134a 0.20–0.28
3.3a –3.7b
22,23
HFC 134a 0.48–0.51 2.05–2.418,23,24
All label dosages listed are metered doses according to Canadian convention, except Symbicort , which is the ex-actuator dose according to USA convention. a MMAD for formoterol fumarate. b MMAD for budesonide. R
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Custom mouthpiece adaptors were utilized to secure the pMDIs to the front of the throat model. The throat outlet was attached to a filter holder (XX4404700, Millipore, Billerica, Massachusetts) with a modified top plate that the throat model was fitted directly into to capture all particles emitted. The particles were collected on filters (Pallflex Emfab TX40HI20-WW, lot #T14418GW, Pall Corporation, Port Washington, New York). The filter holder was connected to a flow meter (4043E, TSI, Shoreview, Minnesota), critical flow controller (TPK 2000, Copley Scientific Limited, Nottingham, UK), and vacuum pump (0523–101Q-G582DX, Gast, Benton Harbor, Michigan) in series. The flow controller was programmed to produce a square breath profile of six second duration at 30 standard L/min. Dosing actuations were performed immediately upon commencement of the breath profile.
tion, Copley Scientific Limited), and humidity readings at low temperatures were verified by measuring the dew point temperature of the air with a second humidity and temperature indicator (MI70, Vaisala, Helsinki, Finland) and probe (HMP77B, Vaisala). A waste shot was actuated from each inhaler inside the chamber directly onto a waste filter prior to testing. For all testing conditions where the inhalers were at a different temperature than the environment, a waste shot was actuated outside of the chamber before handing the inhaler into the chamber and immediately conducting testing. In order to cool down the inhalers to approximately –10◦ C for actuation in a 20◦ C environment, the inhalers were left in a completely sealed bag that was half submerged in a cooling bath set at –10◦ C. The setup allowed the inhalers to reach their required temperature while providing access to easily remove each inhaler just prior to testing.
Inhaler Testing Ten waste shots were actuated to prime the inhalers following no-use periods of 2 weeks or longer. A single waste shot was further actuated from each inhaler immediately prior to testing. The actuator was left depressed and the inhaler was shaken 10 times to ensure adequate mixing of active ingredient, propellant, and excipient before release. The inhalers were tested under eight testing conditions, altering both the inhaler temperature and the temperature of the environmental chamber. The test matrix of all testing conditions is provided in Table 2. Four actuations from each AiromirTM , QVARTM , and Ventolin inhaler were used for each test, whereas a single actuation was used from each Symbicort inhaler. For tests requiring multiple actuations, the inhaler was shaken again following the first actuation (with the actuator depressed) and after fitting the inhaler back into its adaptor, a second breath profile was initialized for the second actuation. This process was repeated twice so that the particles from four total actuations were collected onto the filter. Approximately 30 s elapsed between actuations to minimize the effect of time between actuations on the results.27 A single throat model was utilized for multiple determinations; a maximum of five determinations totaling no more than 20 actuations was permitted before the throat model was removed and cleaned. For conditions in which the inhalers were at the same temperature as the environment, the inhalers were equilibrated inside the environmental chamber for a minimum of 30 min. The temperature and humidity inside the chamber were measured with a temperature and humidity sensor (TPK 2000 opR
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Gravimetric Assay Upon completion of the required number of actuations, the filter with the collected dose was removed from the setup and stored in a Petri dish until it was equilibrated for weighing. The total mass deposited on the filters was considered to be the in vitro lung dose. All filters were allowed to equilibrate to laboratory conditions (21.1 ± 1.6◦ C, 13.8 ± 5.3% RH) for a minimum of 24 h prior to measurement of tare weight or sample weight. The gravimetric assay was carried out using an ultrabalance (UMX2, Mettler Toledo, Greifensee, Switzerland). The filters were treated with an antistatic device (Zerostat 3, Milty, Hertfordshire, UK) immediately prior to weighing to minimize variation due to electrostatic charge. The gravimetric assay data were normalized to room temperature and verified by comparison with UV spectroscopic chemical assay (Hewlett Packard, Greely, Colorado). Budesonide was collected through two extractions: first with 25 mL of methanol, followed by 5 mL of methanol. Beclomethasone dipropionate was collected through two extractions, each with 10 mL of methanol. Methanol extracts were then filtered through syringe-driven filters with a pore size of 2 :m (SLAP02550, Millipore) and measured at wavelengths of 244 and 238 nm for budesonide and beclomethasone dipropionate, respectively, using a diode array UV–vis spectrophotometer (8452A, Hewlett Packard). Salbutamol sulfate was extracted under sonication for 1 min from filters using 10 mL of deionized ultra-filtered water; extracts were filtered through 0.45 :m
Table 2. Testing Conditions Specifying both Inhaler and Environmental Temperature Ranges as well as Number of Replicates for Each Test and Number of Devices Used per Test Number of Replicates, n (Number of Devices, nd ) Target Inhaler Temperature ± Range, TI (◦ C) –10.0 ± 3.0 0.0 ± 1.4 10.0 ± 1.3 21.0 ± 1.1 40.0 ± 1.6
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Target Ambient Temperature ± Range, TA (◦ C) –10.0 21.0 0.0 10.0 –10.0 0.0 21.0 40.0
± ± ± ± ± ± ± ±
2.4 1.5 1.4 1.3 2.0 2.0 1.1 1.6
AiromirTM
QVARTM
SymbicortR
VentolinR
5 (5) 5 (5) 5 (5) 5 (5) 4 (4) 5 (5) 5 (5) 5 (5)
4 (4) 5 (5) 5 (5) 4 (4) 5 (5) 5 (5) 4 (4) 5 (5)
5 (3) 5 (3) 5 (3) 5 (3) 4 (3) 5 (3) 10 (6) 5 (3)
5 (5) 3 (1) 5 (5) 5 (5) 4 (4) 5 (5) 5 (5) 5 (5)
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syringe-driven filters (SLHA033SS, Millipore) and then measured at a wavelength of 274 nm using a diode array UV–vis spectrophotometer (8452A, Hewlett Packard). The UV spectroscopic chemical assay was carried out for two experimental conditions, when both the inhaler and environment were equilibrated at –10◦ C and 20◦ C, and the data were then compared with the normalized data from the gravimetric assay. As expected, there was excellent agreement between the normalized data from the two types of assays. The agreement was confirmed using a linear fit with a y-intercept of 0, which gave coefficients of determination of 0.823, 0.853, 0.943, and 0.974 for QVARTM , AiromirTM , Symbicort , and Ventolin , respectively. R
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Shot Weight Testing The effect of device temperature on shot weight was assessed. Inhalers were equilibrated at 40◦ C, 21◦ C, and –10◦ C for a minimum of 2 h prior to testing. Inhalers at 40◦ C were equilibrated in an incubator (Isotemp, Thermo Fisher Scientific Inc., Waltham, Massachusetts), 21◦ C inhalers were equilibrated on a lab bench, and –10◦ C inhalers were sealed in foil pouches and immersed in the reservoir of a circulating bath (Model A-40, Anova Industries, Stafford, Texas). Two priming shots were actuated to waste immediately prior to testing. Three shot weight determinations were performed for each inhaler at each temperature point. The change in mass for each single shot was determined using an analytical balance (ME204E, Mettler Toledo); for –10◦ C inhalers, priming and shot weight tests were conducted in a custom glove box with a dry ( 0.1). R
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Figure 3. Mean in vitro lung dose relative to measured in vitro lung dose at room temperature conditions, 21.3◦ C (F = 0.6◦ C), for AiromirTM , QVARTM , SymbicortR , and VentolinR pMDIs. The environment was kept at room temperature while inhaler temperature was varied. Error bars represent 1 SD and dashed lines represent a ±20% dose margin.
Devices at room temperature, 21.3◦ C (F = 0.6◦ C), were then actuated into environments with ambient temperatures of approximately –10◦ C and 0◦ C. The results compared with devices at room temperature actuated into a room temperature environment are shown in Figure 4. A significant reduction in the in vitro lung dose was observed for AiromirTM and Ventolin (p < 0.05). No significant change in the in vitro lung dose was observed for either QVARTM or Symbicort (p > 0.1). R
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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Figure 4. Mean in vitro lung dose relative to measured in vitro lung dose at room temperature conditions, 21.3◦ C (F = 0.6◦ C), for AiromirTM , QVARTM , SymbicortR , and VentolinR pMDIs. Inhalers were kept at room temperature for all tests while ambient temperature was varied. Error bars represent 1 SD and dashed lines represent a ±20% acceptable dose margin.
Testing conditions in which the largest changes in performance were observed, that is, –10◦ C inhalers actuated in a –10◦ C environment and 20◦ C inhalers actuated in a –10◦ C environment, were then repeated with the addition of a common, commercially available holding chamber (AeroChamber , Trudell Medical InternationalTM , London, UK; Ontario, Canada), but no improvement in in vitro lung dose was measured. Shot weight data are summarized in Table 3. For all tested inhalers, shot weight increased as the inhaler temperature decreased. R
DISCUSSION When a pMDI is actuated during in vitro lung dose testing as conducted here, drug may deposit in the valve stem, on the actuator, in the throat model, or on the collection filter. Wilson et al.7 showed that the “released dose” from CFC pMDIs increased with decreased canister temperature and proposed
Table 3.
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increased formulation density as a possible explanation; in that work, the actuator deposition was included in the “released dose.” The results of our shot weight experiment show that the shot weight also increases as inhaler temperature is reduced; this implies that the metered dose will increase. Therefore, the observed reductions in in vitro lung dose are attributable to increased device or throat deposition and not to a decrease in metered dose. The percent change in shot weight at 40◦ C and –10◦ C varied with inhaler type, possibly due to differences in formulation of each pMDI or due to thermally induced changes in geometry, including valve components and seals. Furthermore, it should be noted that the total number of doses in the inhaler’s life will decrease when actuated at low inhaler temperature due to the increased shot weight. The portion of the emitted dose depositing in the lungs is governed by the aerodynamic diameter distribution and momentum distribution of the aerosol.4,28 Ambient temperature and inhaler temperature may affect both the aerodynamic diameter and the momentum distribution, but through separate mechanisms. As the inhaler temperature decreases, the vapor pressure of the propellant decreases.29 Decreased vapor pressure provides less energy for atomization, resulting in a coarser droplet size distribution.2 Larger droplets, which contain more dissolved or suspended material or both, take longer to evaporate and produce a coarser particle size distribution.12 Longer evaporation times and coarser aerosols are both expected to increase throat deposition, reducing the in vitro lung dose. As the ambient temperature decreases, the evaporation rate of the expelled aerosol also decreases.4 It is therefore possible that at low ambient temperatures the volatile components of the aerosol have not completely evaporated upon entering the throat, and thus may have greater inertia and a larger aerodynamic diameter than fully evaporated, dry particles. Particles with higher inertia and larger aerodynamic diameters have a greater tendency to deposit on the throat, thus decreasing in vitro lung dose.25 Appreciable differentiation in performance across the tested inhaler types is observed in Figures 2–4. Given the complexity of aerosol generation, evolution, and deposition in pMDIs, and the large number of device, formulation, and environmental variables in the experiments, direct and simple correlation of the in vitro lung dose to independent variables is not possible with the current data. However, qualitative observations can be drawn that may explain why some inhalers are more susceptible to loss of in vitro lung dose at lower temperatures than others.
Average Shot Weight and SD at Inhaler Temperatures of –10◦ C, 21◦ C, and 40◦ C
Inhaler Type
Number of Inhalers Tested
Number of Replicates/Inhaler at Each Temperature
1 3 3 2
3 3 3 3
AiromirTM QVARTM SymbicortR VentolinR
Percentage Change Relative to 21◦ C (%)
Average Shot Weight ± SD (mg) –10◦ C 30.1 66.1 86.9 79.9
± ± ± ±
1.6 1.7 3.4 2.0
21◦ C 26.6 61.0 74.3 73.1
± ± ± ±
1.6 0.2 0.5 0.3
40◦ C
–10◦ C
40◦ C
± ± ± ±
13 8 17 9
–10 –9 –9 –6
23.9 55.5 67.9 68.6
1.7 1.2 2.0 1.8
The number of inhalers tested varied due to limited availability of test material. Where more than one inhaler was tested, the reported average and SD are for the pooled data and thus encompass interinhaler variability as well as shot-to-shot variability. DOI 10.1002/jps.24145
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In Figure 3, where inhaler temperature is varied while ambient temperature is held at 21◦ C, both Symbicort and Ventolin show a large reduction in in vitro lung dose at –10◦ C relative to their room temperature values. AiromirTM also loses some of the in vitro lung dose at –10◦ C, whereas QVARTM shows no such loss. As per Table 1, QVARTM is the only solution pMDI represented and produces a finer aerosol (MMAD = 1.0—1.1 :m) at room temperature than the other pMDIs. Thus, though the initial droplet size distributions of all the tested pMDIs are expected to coarsen as the inhaler temperature is reduced, QVARTM may have a greater buffer against loss of in vitro lung dose to throat deposition at low inhaler temperature. In Figure 4, the effect of ambient air temperature on in vitro lung dose is most pronounced in the case of Ventolin . Because larger actuator orifice diameters have been shown to result in increased aerosol momentum and oropharyngeal deposition,30 it is likely that the aerosol emitted from Ventolin has greater momentum than the other pMDIs. As the ambient air temperature is reduced, the droplet evaporation rate is expected to decrease. Thus, reducing ambient temperature may result in increased momentum of the spray at the entrance of throat model relative to the room temperature case and consequently an increase in throat deposition. Although this mechanism is expected to impact all of the tested pMDIs, Ventolin may be especially susceptible due to the already greater momentum of its aerosol plume. When both inhaler and ambient temperature are changed simultaneously, as shown in Figure 2, it is expected that both the initial droplet diameter distribution and the evaporation rate will change. It is therefore unsurprising that reducing inhaler and ambient temperature together result in the greatest reduction in in vitro lung dose for all tested pMDIs. Furthermore, the results in Figure 2 are not predicted by simple superposition or multiplication of the relative effects of inhaler temperature and ambient temperature, demonstrating the complexity of the physics involved. R
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CONCLUSIONS The results of this study demonstrate that the performance of pMDIs is strongly dependent on both inhaler temperature and ambient temperature. The in vitro lung dose was reduced at low temperatures for both HFC 227ea and HFC 134a formulations, but the largest reduction at equilibrated low inhaler and ambient temperatures was measured for the tested HFC 227ea formulation. The observed decreases in the in vitro lung dose are likely largely due to increases in oropharyngeal deposition by the mechanisms mentioned above, though we cannot rule out some influence of device deposition. In vitro lung doses outside of a ±20% dose range also occurred when ambient and inhaler temperatures were elevated to 40◦ C, as shown in Figure 2. The increases in in vitro lung doses are likely due to reductions in throat deposition; some of the same mechanisms discussed for the cold temperature conditions may be responsible, with opposite direction of effect. As the particle size distributions of the pMDI aerosols were not measured in this study, this is a valuable topic for future work and should further illuminate some of the underlying mechanisms responsible for changes in performance as device and ambient temperatures vary. No tested pMDIs were able to maintain their room temperature in vitro lung dose at the coldest tested equilibrated amMorin et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3553–3559, 2014
bient and inhaler temperatures (–10◦ C). Consideration should be given to the effect of temperature when designing pMDIs if it is desirable to minimize the effect of environmental temperature on lung dose. Smaller actuator orifice diameters, smaller MMADs, or propellants with lower boiling points may help to maintain the lung dose at either decreased ambient temperatures or decreased inhaler temperatures.
REFERENCES 1. Newman SP. 2005. Principles of metered-dose inhaler design. Respir Care 50:1177–1190. 2. Stein SW, Myrdal PB. 2006. The relative influence of atomization and evaporation on metered dose inhaler drug delivery efficiency. Aerosol Sci Technol 40:335–347. 3. Clark AR. 1991. Metered atomization for respiratory drug delivery. Ph.D. Thesis. Loughborough: Loughborough University of Technology. 4. Finlay WH. 2001. Mechanics of inhaled pharmaceutical aerosols— An introduction. San Diego, California: Academic Press. 5. Smyth HD. 2003. The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers. Adv Drug Deliv Rev 55:807–828. 6. Newman SP, Moren F, Pavia D, Corrado O, Clarke SW. 1982. The effects of changes in metered volume and propellant vapour pressure on the deposition of pressurized inhalation aerosols. Int J Pharm 11:337– 344. 7. Wilson AF, Mukai DS, Ahdout JJ. 1991. Effect of canister temperature on performance of metered-dose inhalers. Am Rev Respir Dis 143:1034–1037. 8. Stein SW, Cocks PM. 2013. Size distribution measurements from metered dose inhalers at low temperatures. In RDD Europe 2013; Dalby RN, Byron PR, Peart J, Suman JD, Young PM, Traini D, Davis Healthcare International Publishing, River Grove, IL. Eds. Vol. 2. pp 203–208. 9. Shemirani FM, Hoe S, Lewis D, Church T, Vehring R, Finlay WH. 2013. In vitro investigation of the effect of ambient humidity on regional delivered dose with solution and suspension MDIs. J Aerosol Med Pulm Drug Deliv 26:215–222. 10. Lange CF, Finlay WH. 2000. Overcoming the adverse effect of humidity in aerosol delivery via pressurized metered-dose inhalers during mechanical ventilation. Am J Respir Crit Care Med 161:1614–1618. 11. Hoye WL. 2005. Effects of extreme temperatures on drug delivery of albuterol sulfate hydrofluoroalkane inhalation aerosols. Am J Health Syst Pharm 62:2271–2277. 12. Sheth P, Stein SW, Myrdal PB. 2013. The influence of initial atomized droplet size on residual particle size from pressurized metered dose inhalers. Int J Pharm 455:57–65. 13. Nithyanandan P, Hoag SW, Dalby RN. 2007. The analysis and prediction of functional robustness of inhaler devices. J Aerosol Med 20:19–37. 14. Val Can LP. 2013. Airomir product monograph. Accessed, at: http://webprod5.hc-sc.gc.ca/dpd-bdpp/dispatch-repartition.do?lang = eng. Last access date December 2nd, 2013. 15. Val Can LP. 2013. QVAR product monograph. Accessed, at: http://webprod5.hc-sc.gc.ca/dpd-bdpp/info.do?code = 65701&lang = eng. 16. AstraZeneca LP. 2010. Symbicort prescribing information. Accessed, at: http://www.accessdata.fda.gov/scripts/cder/ drugsatfda/index.cfm?fuseaction = Search.DrugDetails. 17. GlaxoSmithKline Inc. 2013. Ventolin product monograph. Accessed, at: http://webprod5.hc-sc.gc.ca/dpd-bdpp/dispatch-repartition.do?lang = eng. 18. Martin AR, Finlay WH. 2005. The effect of humidity on the size of particles delivered from metered-dose inhalers. Aerosol Sci Technol 39:283–289. 19. Taylor G, Bains BK, Birchall JC. 2013. Application of an abbreviated Andersen viable sampler for assessing pMDI nucleic acid formulations. J Aerosol Med Pulm Drug Deliv 26:A-1–A-69. DOI 10.1002/jps.24145
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20. Mitchell JP, Nagel MW, Wiersema KJ, Doyle CC. 2003. Aerodynamic particle size analysis of aerosols from pressurized metered-dose inhalers: Comparison of Andersen 8-stage cascade impactor, next generation pharmaceutical impactor, and model 3321 aerodynamic particle sizer aerosol spectrometer. AAPS PharmSciTech 4:425–433. 21. Leach CL, Davidson PJ, Boudreau RJ. 1998. Improved airway targeting with the CFC-free HFA–beclomethasone metered-dose inhaler compared with CFC–beclomethasone. Eur Respir J 12:1346–1353. 22. Adi H, Young PM, Traini D. 2012. Co-deposition of a triple therapy drug formulation for the treatment of chronic obstructive pulmonary disease using solution-based pressurised metered dose inhalers: MDI triple therapy for COPD. J Pharm Pharmacol 64:1245–1253. 23. Chambers F, Ludzik A. 2009. In vitro drug delivery performance of a new budesonide/formoterol pressurized metered-dose inhaler. J Aerosol Med Pulm Drug Deliv 22:113–120. 24. Terzano C. 2001. Pressurized metered dose inhalers and add-on devices. Pulm Pharmacol Ther 14:351–366. 25. Zhang Y, Gilbertson K, Finlay WH. 2007. In vivo–in vitro comparison of deposition in three mouth–throat models with Qvar R and Turbuhaler R inhalers. J Aerosol Med 20:227–235.
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26. Stapleton KW, Guentsch E, Hoskinson MK, Finlay WH. 2000. On the suitability of k-epsilon turbulence modelling for aerosol deposition in the mouth and throat: A comparison with experiment. J Aerosol Sci 31:739–749. 27. Hautmann J, Godoy SE, Marshik P, Chand R, McConville J, Krishna S, Krishna S, Muttil P. 2013. Effect of time between actuation on the dose variability for three metered dose inhalers. In RDD Europe 2013; Dalby RN, Byron PR, Peart J, Suman JD, Young PM, Traini D, Eds. Vol. 2. pp 429–434. 28. Ivey JW, Lewis D, Church T, Finlay WH, Vehring R. 2014. A correlation equation for the mass median aerodynamic diameter of the aerosol emitted by solution metered dose inhalers. Int J Pharm 465:18–24. 29. Williams RO III, Liu J. 1998. Influence of formulation additives on the vapor pressure of hydrofluoroalkane propellants. Int J Pharm 166:99–103. 30. Lewis D, Meakin B, Brambilla G. 2006. New actuators versus old: Reasons and results for actuator modifications for HFA solution MDIs. In Respiratory drug delivery 2006; Dalby RN, Byron PR, Peart J, Suman JD, Farr S, Eds. Richmond, Virginia: Virginia Commonwealth University, pp 101–110.
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Performance of Pressurized Metered-Dose Inhalers at Extreme Temperature Conditions CHELSEA M. D. MORIN, JAMES W. IVEY, JORDAN T. F. TITOSKY, JONATHAN D. SUDERMAN, JASON S. OLFERT, REINHARD VEHRING, WARREN H. FINLAY Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta Received 16 June 2014; revised 1 August 2014; accepted 11 August 2014 Published online 22 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24145 ABSTRACT: The performance of pressurized metered-dose inhalers (pMDIs) under a variety of temperature conditions was investigated. The effects of both inhaler temperature and ambient temperature were considered. The inhaler temperature ranged from −13.0◦ C to 41.7◦ C and the ambient temperature ranged from −12.0◦ C to 41.7◦ C. The in vitro lung dose was measured for four widely available pMDIs: AiromirTM , QVARTM , Symbicort , and Ventolin . The in vitro lung dose through an Alberta Idealized Throat was measured by gravimetric assay, which was verified by UV spectroscopic assay. A decrease in the in vitro lung dose was observed for all evaluated pMDIs when ambient temperature and device temperature were simultaneously reduced, decreasing on average by 70% at the coldest temperatures, whereas increasing on average by 25% at the elevated temperature condition. In vitro lung dose is strongly dependent on both inhaler C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J temperature and ambient temperature with the tested pMDIs. Pharm Sci 103:3553–3559, 2014 Keywords: temperature; pressurized metered-dose inhaler (pMDI); aerosols; microparticles; in vitro models; pulmonary drug delivery; AiromirTM ; stability; QVARTM ; Symbicort ; Ventolin R
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INTRODUCTION Pressurized metered-dose inhalers (pMDIs) are widely used for treating and controlling asthma and chronic obstructive pulmonary disease.1 pMDIs are typically formulated as either solutions or suspensions. Solution pMDIs consist of a drug in a solubilized state and may contain dissolved excipients and cosolvents. Suspension pMDIs consist of a drug in a solid phase, suspended in a propellant. Surfactants may be added to reduce particle aggregation but are typically insoluble in the pure propellant, necessitating the addition of a cosolvent, such as ethanol.1 It is well known that propellant droplet formation is influenced by device parameters including actuator orifice diameter and valve size, as well as drug formulation parameters such as composition, concentration, propellant type, cosolvent, and vapor pressure inside the canister.2,3 Increases in orifice diameter lead to higher plume momentum,3 which in turn leads to increased oropharyngeal deposition.4 Propellant choice and cosolvent content determine the vapor pressure within the canister at any given temperature, and an increase in vapor pressure increases evaporation rate after atomization.5 Increasing vapor pressure also produces a finer atomized droplet distribution.3 Overall, increased vapor pressure leads to a decrease in extrathoracic deposition and an increase in lung deposition.6 In vitro tests of pMDI delivery efficiency, such as cascade impaction, have thoroughly explored the effects of manipulating the aforementioned device parameters. Such tests are typically Abbreviations used: pMDI, pressurized metered-dose inhaler; MMAD, mass median aerodynamic diameter; RH, relative humidity. Correspondence to: Warren H. Finlay (Telephone: +780-492-4707; Fax: +780492-2200; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 103, 3553–3559 (2014)
C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association
performed under controlled laboratory conditions, but there are a number of environmental factors, which also influence delivery efficiency, including temperature and humidity.7–11 In order to obtain results under realistic use conditions, external factors influencing droplet formation and delivery must also be considered. The effect of reduced temperature on pMDI performance has previously been studied, but in a limited manner. In an early study of pMDIs with chlorofluorocarbon propellant, Wilson et al.7 showed that as the device temperature decreases, the vapor pressure inside the canister also decreases, leading to a larger initial mass median diameter when actuated in ambient conditions. They also found the actuated dose increased at lower temperatures and proposed increased propellant density at lower temperatures as a potential explanation. Stein and Cocks8 showed that the mass median aerodynamic diameter (MMAD) of commercially available solution and suspension pMDIs, including QVARTM and Ventolin , increased with decreased device temperature. They concluded that the MMAD of solution pMDIs increased as a result of an increase in the atomized droplet size, and the MMAD of suspension pMDIs increased as a result of a larger number of propellant droplets containing multiple particles of the dispersed phase (so-called multiplets). Because the frequency of multiplets is related to the propellant droplet size distribution,12 Stein and Cocks8 essentially showed that cold inhalers produce coarser droplet size distributions compared with warmer inhalers. The effects of increasing inhaler temperature have also been investigated, albeit in a limited way.9–11,13 Shemirani et al.9 tested pMDIs equilibrated to ambient conditions and observed an increase in lung dose fraction for a BDP HFC 134a formulation with an increase in ambient temperature. Hoye11 also tested pMDIs at increased temperatures, but it is not clear whether they were tested at elevated ambient temperature or R
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at room temperature. They observed a decrease in the amount of drug leaving the device as well as a decrease in the MMAD as temperature increased. The two competing mechanisms led to an 85.2% increase in respirable mass for Ventolin with an increase from 4◦ C to 60◦ C. Nithyanandan et al. studied the effects of exposing pMDIs to high temperatures (50◦ C) and found that other than higher susceptibility to damage by mechanical stresses, if the inhalers were allowed to equilibrate to room temperature, their performance was not detrimentally affected. To our knowledge, no studies investigating both the separate and combined effects of device temperature and ambient temperature have been conducted. Oropharyngeal and lung deposition are influenced by initial droplet size distribution, velocity distribution, and evaporation rates, all of which may be affected by device or ambient temperature.5 Therefore, the influence of both device temperature and ambient temperature on the in vitro lung dose was studied with four commercially available pMDIs. The distinction between device and ambient temperature is of practical importance, as pMDIs may not always be in thermal equilibrium with the environments in which they are utilized. R
EXPERIMENTAL Materials
chamber. The relative humidity (RH) in the chamber was thus less than 1% for all in vitro lung dose testing. The environmental chamber consisted of a glove box inside of a second glove box. Dry air was supplied to the outer chamber to avoid ice formation on the outer walls of the inner chamber, which would have limited the view into the chamber, and to help maintain a constant inner chamber temperature. In order to achieve the coldest testing conditions, the air was also run through a secondary heat exchanger filled with dry ice. The use of dry air avoided particle size changes due to humidity, which has previously been shown to have an effect on the in vitro lung dose.9 In Vitro Testing Apparatus The equipment configuration is shown schematically in Figure 1. All testing was conducted using the Alberta Idealized Throat.25,26 The throat model was cleaned by wiping it with ethanol, spraying it with silicone (Molykote Silicone 557, Dow Corning, Midland, Michigan), and allowing it to dry. The temperature on the surface of the throat model was maintained at 36.3◦ C (SD F = 2.9◦ C) using heat tape (BSAT051004, Briskheat, Columbus, Ohio). The temperature was measured using a thermocouple (50416-T, Cooper Atkins, Middlefield, Connecticut) and read off a panel meter (765-TF, Jenco Instruments Inc., San Diego, California) connected to the thermocouple.
The four pMDIs tested were AiromirTM (lot #GNJ017A, Medicis now Valeant, Laval, Quebec, Canada), QVARTM (lot #GNG058A, Medicis now Valeant), Symbicort (lot #3000598C00 and 3000702C00, AstraZeneca Inc., Mississauga, Ontario, Canada) and Ventolin (lot #3ZP5854, GlaxoSmithKline Inc., Mississauga, Ontario, Canada). The labeled dosage and composition along with the measured actuator orifice diameter and MMADs from the literature are listed in Table 1. The orifice diameters were measured using pin gauges (Starrett, Athol, Massachusetts). The values reported are the upper and lower bounds for the diameter and were limited to the steps in size of successive pin gauges. R
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Environmental Controls Inhalers were tested in a controlled environmental chamber. Compressed, dry air with a dew point temperature of –67◦ C flowed through a heat exchanger with a 50:50 ethylene glycol– water (volume basis) working fluid and into the environmental
Figure 1. Equipment used for experimental setup, showing components both within and outside of environmental chamber.
Table 1. Summary of Reported Data from Product Monographs and Prescribing Information,14–17 Room Temperature MMADs from Literature, and Measured Actuator Orifice Diameters Device Drug and metered dose (:g) Format Excipient(s) Propellant Orifice diameter (mm) MMAD (:m)
AiromirTM
QVARTM
SymbicortR
VentolinR
Salbutamol sulfate (100) Suspension Ethanol and oleic acid HFC 134a 0.20–0.28
Beclomethasone dipropionate (100) Solution Ethanol
Budesonide (160)/formoterol (4.5) Suspension Povidone K25 and PEG 1000 HFC 227ea 0.36–0.38
Salbutamol sulfate (100) Suspension None
1.84–1.9718,19
1.0–1.120,21
HFC 134a 0.20–0.28
3.3a –3.7b
22,23
HFC 134a 0.48–0.51 2.05–2.418,23,24
All label dosages listed are metered doses according to Canadian convention, except Symbicort , which is the ex-actuator dose according to USA convention. a MMAD for formoterol fumarate. b MMAD for budesonide. R
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Custom mouthpiece adaptors were utilized to secure the pMDIs to the front of the throat model. The throat outlet was attached to a filter holder (XX4404700, Millipore, Billerica, Massachusetts) with a modified top plate that the throat model was fitted directly into to capture all particles emitted. The particles were collected on filters (Pallflex Emfab TX40HI20-WW, lot #T14418GW, Pall Corporation, Port Washington, New York). The filter holder was connected to a flow meter (4043E, TSI, Shoreview, Minnesota), critical flow controller (TPK 2000, Copley Scientific Limited, Nottingham, UK), and vacuum pump (0523–101Q-G582DX, Gast, Benton Harbor, Michigan) in series. The flow controller was programmed to produce a square breath profile of six second duration at 30 standard L/min. Dosing actuations were performed immediately upon commencement of the breath profile.
tion, Copley Scientific Limited), and humidity readings at low temperatures were verified by measuring the dew point temperature of the air with a second humidity and temperature indicator (MI70, Vaisala, Helsinki, Finland) and probe (HMP77B, Vaisala). A waste shot was actuated from each inhaler inside the chamber directly onto a waste filter prior to testing. For all testing conditions where the inhalers were at a different temperature than the environment, a waste shot was actuated outside of the chamber before handing the inhaler into the chamber and immediately conducting testing. In order to cool down the inhalers to approximately –10◦ C for actuation in a 20◦ C environment, the inhalers were left in a completely sealed bag that was half submerged in a cooling bath set at –10◦ C. The setup allowed the inhalers to reach their required temperature while providing access to easily remove each inhaler just prior to testing.
Inhaler Testing Ten waste shots were actuated to prime the inhalers following no-use periods of 2 weeks or longer. A single waste shot was further actuated from each inhaler immediately prior to testing. The actuator was left depressed and the inhaler was shaken 10 times to ensure adequate mixing of active ingredient, propellant, and excipient before release. The inhalers were tested under eight testing conditions, altering both the inhaler temperature and the temperature of the environmental chamber. The test matrix of all testing conditions is provided in Table 2. Four actuations from each AiromirTM , QVARTM , and Ventolin inhaler were used for each test, whereas a single actuation was used from each Symbicort inhaler. For tests requiring multiple actuations, the inhaler was shaken again following the first actuation (with the actuator depressed) and after fitting the inhaler back into its adaptor, a second breath profile was initialized for the second actuation. This process was repeated twice so that the particles from four total actuations were collected onto the filter. Approximately 30 s elapsed between actuations to minimize the effect of time between actuations on the results.27 A single throat model was utilized for multiple determinations; a maximum of five determinations totaling no more than 20 actuations was permitted before the throat model was removed and cleaned. For conditions in which the inhalers were at the same temperature as the environment, the inhalers were equilibrated inside the environmental chamber for a minimum of 30 min. The temperature and humidity inside the chamber were measured with a temperature and humidity sensor (TPK 2000 opR
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Gravimetric Assay Upon completion of the required number of actuations, the filter with the collected dose was removed from the setup and stored in a Petri dish until it was equilibrated for weighing. The total mass deposited on the filters was considered to be the in vitro lung dose. All filters were allowed to equilibrate to laboratory conditions (21.1 ± 1.6◦ C, 13.8 ± 5.3% RH) for a minimum of 24 h prior to measurement of tare weight or sample weight. The gravimetric assay was carried out using an ultrabalance (UMX2, Mettler Toledo, Greifensee, Switzerland). The filters were treated with an antistatic device (Zerostat 3, Milty, Hertfordshire, UK) immediately prior to weighing to minimize variation due to electrostatic charge. The gravimetric assay data were normalized to room temperature and verified by comparison with UV spectroscopic chemical assay (Hewlett Packard, Greely, Colorado). Budesonide was collected through two extractions: first with 25 mL of methanol, followed by 5 mL of methanol. Beclomethasone dipropionate was collected through two extractions, each with 10 mL of methanol. Methanol extracts were then filtered through syringe-driven filters with a pore size of 2 :m (SLAP02550, Millipore) and measured at wavelengths of 244 and 238 nm for budesonide and beclomethasone dipropionate, respectively, using a diode array UV–vis spectrophotometer (8452A, Hewlett Packard). Salbutamol sulfate was extracted under sonication for 1 min from filters using 10 mL of deionized ultra-filtered water; extracts were filtered through 0.45 :m
Table 2. Testing Conditions Specifying both Inhaler and Environmental Temperature Ranges as well as Number of Replicates for Each Test and Number of Devices Used per Test Number of Replicates, n (Number of Devices, nd ) Target Inhaler Temperature ± Range, TI (◦ C) –10.0 ± 3.0 0.0 ± 1.4 10.0 ± 1.3 21.0 ± 1.1 40.0 ± 1.6
DOI 10.1002/jps.24145
Target Ambient Temperature ± Range, TA (◦ C) –10.0 21.0 0.0 10.0 –10.0 0.0 21.0 40.0
± ± ± ± ± ± ± ±
2.4 1.5 1.4 1.3 2.0 2.0 1.1 1.6
AiromirTM
QVARTM
SymbicortR
VentolinR
5 (5) 5 (5) 5 (5) 5 (5) 4 (4) 5 (5) 5 (5) 5 (5)
4 (4) 5 (5) 5 (5) 4 (4) 5 (5) 5 (5) 4 (4) 5 (5)
5 (3) 5 (3) 5 (3) 5 (3) 4 (3) 5 (3) 10 (6) 5 (3)
5 (5) 3 (1) 5 (5) 5 (5) 4 (4) 5 (5) 5 (5) 5 (5)
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syringe-driven filters (SLHA033SS, Millipore) and then measured at a wavelength of 274 nm using a diode array UV–vis spectrophotometer (8452A, Hewlett Packard). The UV spectroscopic chemical assay was carried out for two experimental conditions, when both the inhaler and environment were equilibrated at –10◦ C and 20◦ C, and the data were then compared with the normalized data from the gravimetric assay. As expected, there was excellent agreement between the normalized data from the two types of assays. The agreement was confirmed using a linear fit with a y-intercept of 0, which gave coefficients of determination of 0.823, 0.853, 0.943, and 0.974 for QVARTM , AiromirTM , Symbicort , and Ventolin , respectively. R
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Shot Weight Testing The effect of device temperature on shot weight was assessed. Inhalers were equilibrated at 40◦ C, 21◦ C, and –10◦ C for a minimum of 2 h prior to testing. Inhalers at 40◦ C were equilibrated in an incubator (Isotemp, Thermo Fisher Scientific Inc., Waltham, Massachusetts), 21◦ C inhalers were equilibrated on a lab bench, and –10◦ C inhalers were sealed in foil pouches and immersed in the reservoir of a circulating bath (Model A-40, Anova Industries, Stafford, Texas). Two priming shots were actuated to waste immediately prior to testing. Three shot weight determinations were performed for each inhaler at each temperature point. The change in mass for each single shot was determined using an analytical balance (ME204E, Mettler Toledo); for –10◦ C inhalers, priming and shot weight tests were conducted in a custom glove box with a dry ( 0.1). R
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Figure 3. Mean in vitro lung dose relative to measured in vitro lung dose at room temperature conditions, 21.3◦ C (F = 0.6◦ C), for AiromirTM , QVARTM , SymbicortR , and VentolinR pMDIs. The environment was kept at room temperature while inhaler temperature was varied. Error bars represent 1 SD and dashed lines represent a ±20% dose margin.
Devices at room temperature, 21.3◦ C (F = 0.6◦ C), were then actuated into environments with ambient temperatures of approximately –10◦ C and 0◦ C. The results compared with devices at room temperature actuated into a room temperature environment are shown in Figure 4. A significant reduction in the in vitro lung dose was observed for AiromirTM and Ventolin (p < 0.05). No significant change in the in vitro lung dose was observed for either QVARTM or Symbicort (p > 0.1). R
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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Figure 4. Mean in vitro lung dose relative to measured in vitro lung dose at room temperature conditions, 21.3◦ C (F = 0.6◦ C), for AiromirTM , QVARTM , SymbicortR , and VentolinR pMDIs. Inhalers were kept at room temperature for all tests while ambient temperature was varied. Error bars represent 1 SD and dashed lines represent a ±20% acceptable dose margin.
Testing conditions in which the largest changes in performance were observed, that is, –10◦ C inhalers actuated in a –10◦ C environment and 20◦ C inhalers actuated in a –10◦ C environment, were then repeated with the addition of a common, commercially available holding chamber (AeroChamber , Trudell Medical InternationalTM , London, UK; Ontario, Canada), but no improvement in in vitro lung dose was measured. Shot weight data are summarized in Table 3. For all tested inhalers, shot weight increased as the inhaler temperature decreased. R
DISCUSSION When a pMDI is actuated during in vitro lung dose testing as conducted here, drug may deposit in the valve stem, on the actuator, in the throat model, or on the collection filter. Wilson et al.7 showed that the “released dose” from CFC pMDIs increased with decreased canister temperature and proposed
Table 3.
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increased formulation density as a possible explanation; in that work, the actuator deposition was included in the “released dose.” The results of our shot weight experiment show that the shot weight also increases as inhaler temperature is reduced; this implies that the metered dose will increase. Therefore, the observed reductions in in vitro lung dose are attributable to increased device or throat deposition and not to a decrease in metered dose. The percent change in shot weight at 40◦ C and –10◦ C varied with inhaler type, possibly due to differences in formulation of each pMDI or due to thermally induced changes in geometry, including valve components and seals. Furthermore, it should be noted that the total number of doses in the inhaler’s life will decrease when actuated at low inhaler temperature due to the increased shot weight. The portion of the emitted dose depositing in the lungs is governed by the aerodynamic diameter distribution and momentum distribution of the aerosol.4,28 Ambient temperature and inhaler temperature may affect both the aerodynamic diameter and the momentum distribution, but through separate mechanisms. As the inhaler temperature decreases, the vapor pressure of the propellant decreases.29 Decreased vapor pressure provides less energy for atomization, resulting in a coarser droplet size distribution.2 Larger droplets, which contain more dissolved or suspended material or both, take longer to evaporate and produce a coarser particle size distribution.12 Longer evaporation times and coarser aerosols are both expected to increase throat deposition, reducing the in vitro lung dose. As the ambient temperature decreases, the evaporation rate of the expelled aerosol also decreases.4 It is therefore possible that at low ambient temperatures the volatile components of the aerosol have not completely evaporated upon entering the throat, and thus may have greater inertia and a larger aerodynamic diameter than fully evaporated, dry particles. Particles with higher inertia and larger aerodynamic diameters have a greater tendency to deposit on the throat, thus decreasing in vitro lung dose.25 Appreciable differentiation in performance across the tested inhaler types is observed in Figures 2–4. Given the complexity of aerosol generation, evolution, and deposition in pMDIs, and the large number of device, formulation, and environmental variables in the experiments, direct and simple correlation of the in vitro lung dose to independent variables is not possible with the current data. However, qualitative observations can be drawn that may explain why some inhalers are more susceptible to loss of in vitro lung dose at lower temperatures than others.
Average Shot Weight and SD at Inhaler Temperatures of –10◦ C, 21◦ C, and 40◦ C
Inhaler Type
Number of Inhalers Tested
Number of Replicates/Inhaler at Each Temperature
1 3 3 2
3 3 3 3
AiromirTM QVARTM SymbicortR VentolinR
Percentage Change Relative to 21◦ C (%)
Average Shot Weight ± SD (mg) –10◦ C 30.1 66.1 86.9 79.9
± ± ± ±
1.6 1.7 3.4 2.0
21◦ C 26.6 61.0 74.3 73.1
± ± ± ±
1.6 0.2 0.5 0.3
40◦ C
–10◦ C
40◦ C
± ± ± ±
13 8 17 9
–10 –9 –9 –6
23.9 55.5 67.9 68.6
1.7 1.2 2.0 1.8
The number of inhalers tested varied due to limited availability of test material. Where more than one inhaler was tested, the reported average and SD are for the pooled data and thus encompass interinhaler variability as well as shot-to-shot variability. DOI 10.1002/jps.24145
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In Figure 3, where inhaler temperature is varied while ambient temperature is held at 21◦ C, both Symbicort and Ventolin show a large reduction in in vitro lung dose at –10◦ C relative to their room temperature values. AiromirTM also loses some of the in vitro lung dose at –10◦ C, whereas QVARTM shows no such loss. As per Table 1, QVARTM is the only solution pMDI represented and produces a finer aerosol (MMAD = 1.0—1.1 :m) at room temperature than the other pMDIs. Thus, though the initial droplet size distributions of all the tested pMDIs are expected to coarsen as the inhaler temperature is reduced, QVARTM may have a greater buffer against loss of in vitro lung dose to throat deposition at low inhaler temperature. In Figure 4, the effect of ambient air temperature on in vitro lung dose is most pronounced in the case of Ventolin . Because larger actuator orifice diameters have been shown to result in increased aerosol momentum and oropharyngeal deposition,30 it is likely that the aerosol emitted from Ventolin has greater momentum than the other pMDIs. As the ambient air temperature is reduced, the droplet evaporation rate is expected to decrease. Thus, reducing ambient temperature may result in increased momentum of the spray at the entrance of throat model relative to the room temperature case and consequently an increase in throat deposition. Although this mechanism is expected to impact all of the tested pMDIs, Ventolin may be especially susceptible due to the already greater momentum of its aerosol plume. When both inhaler and ambient temperature are changed simultaneously, as shown in Figure 2, it is expected that both the initial droplet diameter distribution and the evaporation rate will change. It is therefore unsurprising that reducing inhaler and ambient temperature together result in the greatest reduction in in vitro lung dose for all tested pMDIs. Furthermore, the results in Figure 2 are not predicted by simple superposition or multiplication of the relative effects of inhaler temperature and ambient temperature, demonstrating the complexity of the physics involved. R
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CONCLUSIONS The results of this study demonstrate that the performance of pMDIs is strongly dependent on both inhaler temperature and ambient temperature. The in vitro lung dose was reduced at low temperatures for both HFC 227ea and HFC 134a formulations, but the largest reduction at equilibrated low inhaler and ambient temperatures was measured for the tested HFC 227ea formulation. The observed decreases in the in vitro lung dose are likely largely due to increases in oropharyngeal deposition by the mechanisms mentioned above, though we cannot rule out some influence of device deposition. In vitro lung doses outside of a ±20% dose range also occurred when ambient and inhaler temperatures were elevated to 40◦ C, as shown in Figure 2. The increases in in vitro lung doses are likely due to reductions in throat deposition; some of the same mechanisms discussed for the cold temperature conditions may be responsible, with opposite direction of effect. As the particle size distributions of the pMDI aerosols were not measured in this study, this is a valuable topic for future work and should further illuminate some of the underlying mechanisms responsible for changes in performance as device and ambient temperatures vary. No tested pMDIs were able to maintain their room temperature in vitro lung dose at the coldest tested equilibrated amMorin et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3553–3559, 2014
bient and inhaler temperatures (–10◦ C). Consideration should be given to the effect of temperature when designing pMDIs if it is desirable to minimize the effect of environmental temperature on lung dose. Smaller actuator orifice diameters, smaller MMADs, or propellants with lower boiling points may help to maintain the lung dose at either decreased ambient temperatures or decreased inhaler temperatures.
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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
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