Deposition of fenoterol from pressurized metered dose inhalers containing hydrofluoroalkanes Stephen Newman, PhD,a Gary Pitcairn, PhD,a Karen Steed, MPhil,a Aleck Harrison, BSc,b and Jürgen Nagel, PhDc Nottingham and Bracknell, United Kingdom, and Ingelheim, Germany The imaging technique of gamma scintigraphy has been used to quantify the total amount of drug deposited in the lungs and the pattern of regional lung deposition, for formulations of Berodual (Boehringer Ingelheim GmbH) delivered from pressurized metered dose inhalers formulated with chlorofluorocarbons, and with hydrofluoroalkane-134a or -227. Data were expressed as the mass of fenoterol deposited in the lungs from the Berodual formulations. All the formulations tested gave a whole lung deposition less than 20% of the metered (exvalve) dose. The mass of fenoterol deposited in the lungs for a solution formulation containing hydrofluoroalkane-134a was inversely proportional to the actuator nozzle diameter. The data suggest that the total and regional lung deposition of hydrofluoroalkane-based pressurized aerosol formulations is highly product-specific and that changes in bioavailability can be brought about by varying both the constituents of the formulation and the design of the actuator. (J Allergy Clin Immunol 1999;104:S253-7.) Key words: Bronchodilators, asthma therapy, drug deposition, pressurized metered dose inhaler
After the ban placed on the production of chlorofluorocarbon propellants under the Montreal Protocol, many new formulations for pressurized metered dose inhalers (pMDIs) containing hydrofluoroalkanes have been described.1 Some of these novel hydrofluoroalkane-based products are intended to have the same drug delivery characteristics as the chlorofluorocarbon-based products that they are replacing,2 although other products have been formulated in such a way that they deliver a greater percentage of each dose to the lungs compared with their chlorofluorocarbon-based counterparts.3 Information on the deposition of hydrofluoroalkane-based pMDI formulations in the respiratory tract has hitherto been limited. Leach et al4 have reported lung depositions averaging 4% and 51% of the delivered dose for chlorofluorocarbon and hydrofluoroalkane formulations of beclomethasone dipropionate. However, in another study, the lung depositions of the antimicrobial agent fusafungine averaged only 3% of the dose for both chlorofluorocarbon and From aPharmaceutical Profiles Limited, Nottingham, United Kingdom; bBoehringer Ingelheim Ltd, Bracknell, United Kingdom; and cBoehringer Ingelheim GmbH, Ingelheim, Germany. Reprint requests: S.P. Newman, PhD, Pharmaceutical Profiles Ltd, 2 Faraday Building, Highfields Science Park, Nottingham NG7 2QP, United Kingdom. Copyright © 1999 by Mosby, Inc. 0091-6749/99 $8.00 + 0 1/0/102887
Abbreviations used P/C: Peripheral to central lung zone deposition ratio pMDI: Pressurized metered dose inhaler
hydrofluoroalkane formulations.5 Lung depositions of 19% and 23% of the metered dose were found for hydrofluoroalkane formulations of triamcinolone acetonide and flunisolide, respectively.6,7 These data suggest that the deposition of drugs from hydrofluoroalkane-based pMDIs is highly formulation specific. This paper reports the deposition in the respiratory tract of novel hydrofluoroalkane formulations of Berodual (Boehringer Ingelheim), which has been assessed with the imaging technique of gamma scintigraphy.8,9 The mass of fenoterol deposited in the lungs and oropharynx from each formulation was quantified. The objectives of the study were (1) to compare the deposition patterns in the human respiratory tract of Berodual pMDIs formulated with chlorofluorocarbons and hydrofluoroalkane-134a and hydrofluoroalkane-227 and (2) to assess the effect of actuator nozzle diameter on the deposition pattern of a solution formulation of Berodual containing hydrofluoroalkane134a.
MATERIAL AND METHODS Formulations The contents of the formulations tested are shown qualitatively in Table I. The chlorofluorocarbon and hydrofluoroalkane-227 formulations were suspensions, although the hydrofluoroalkane-134a formulation was a solution with ethanol as a cosolvent. Formulations of Berodual contained 50 µg fenoterol and 20 µg ipratropium bromide per metered (exvalve) dose.
Radiolabeling validation The radionuclide technetium 99m was used to radiolabel the formulations, by the method for pMDIs previously described in detail elsewhere.10,11 Briefly, the radiolabel was extracted out of the aqueous phase in methyl-ethyl-ketone, which was then evaporated in an empty canister. The contents of a filled canister containing the appropriate formulation was added at below –60°C, and a valve was crimped in place. Validation experiments12,13 were conducted to compare the distributions of fenoterol and 99mTc within the stages of a multistage liquid impinger operated at 60 L/min for each of the 3 formulations. These data showed that the radiolabel was a valid marker for fenoterol across the full range of particle-size bands. In addition, the distributions of fenoterol before labeling (unlabeled drug) and after labeling (labeled S253
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C FIG 1. Radiolabeling validation data for (A) chlorofluorocarbon product, (B) hydrofluoroalkane-134a product, and (C) hydrofluoroalkane227 product. Distributions of drug before labelling (unlabelled drug), drug after labeling (labeled drug), and radiolabel are shown for each formulation in a multistage liquid impinger operated at 60 L/min. The impinger comprised a 90-degree inlet “throat”, 4 impaction stages (S1 to S4), and a wash bottle acting as a final filter.
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TABLE I. Formulations of Berodual tested CFC product
Drug suspensions CFCs-11, -12, -114 Sorbitan trioleate
Drug solutions HFA-134a Ethanol Water; citric acid
Drug suspensions HFA-227 Isopropyl myristate
CFC, chlorofluorocarbon; HFA, hydrofluoroalkane.
drug) were identical. The radiolabeling validation data for the 3 formulations are shown in Fig 1. Because it proved difficult to quantify accurately the amounts of ipratropium bromide recovered from each impinger stage, radiolabeling validation for this drug could not be performed. For this reason, the scintigraphic results are expressed in terms of the deposition of fenoterol, which is the drug present in larger amounts in each formulation.
In vivo studies In the in vivo deposition studies, 2 metered doses were delivered on each study day (total, 100 µg fenoterol and 40 µg ipratropium bromide; together, 10 MBq 99mTc). The inhalers were connected in series with a pMDI-compact spirometer (Vitalograph; Buckingham, United Kingdom), so that inhaled flow rate and inhaled volume could be recorded. The pMDI was fired by an observer during inhalation. After a 10-second breathhold, the subject exhaled through a low-resistance filter to collect exhaled aerosol. Anterior and posterior lung images and a lateral oropharyngeal image were taken immediately after inhalation, together with images of the actuator and the exhaled air filter, with the use of a gamma camera (General Electric Maxi; Milwaukee, Wis) connected to a data processing system (Park Medical; Farnborough, United Kingdom). The geometric mean lung and stomach counts were calculated, and data were corrected for the attenuation of gamma rays by tissue, as previously described.14 After this correction, counts from lungs, stomach, oropharynx, actuator, and exhaled air filter were summed, and the percentage of deposition at each site was determined by expressing the count from each site as a percentage of the summed count. Results were expressed as mass of fenoterol deposited by assuming a metered dose of 100 µg fenoterol. Regional lung deposition was quantified by dividing the lungs into peripheral, intermediate, and central lung zones,15 the lung borders for each subject having been defined from a Krypton 81m lung ventilation scan. The ratio of deposition in the peripheral lung zone to that in the central lung zone (P/C ratio) was calculated.15
RESULTS AND DISCUSSION Study 1 Ten healthy volunteers (5 male) with normal lung function took part in the study that was designed as a 3-way cross-over comparison of chlorofluorocarbon and hydrofluoroalkane-134a and hydrofluoroalkane-227 formulations. Results are shown in Table II. Mean lung depositions averaged 8.0 ± 3.3 µg, 13.4 ± 5.5 µg, and 8.8 ± 7.7 µg fenoterol, respectively, for the 3 formulations, with the difference between chlorofluorocarbon and hydrofluoroalkane-134a being statistically significant. Oropharyngeal depositions (mean values, 73.0 µg, 61.7 µg, and 70.4 µg fenoterol) and the P/C ratio (mean values, 1.78, 1.79, and 1.61) did not vary significantly between the study days. A review of the inhalation techniques of the volunteers
TABLE II. Mean (SD) mass of drug deposited in lungs and oropharynx, retained on the actuator, and recovered from the exhaled air filter for CFC and HFA-134a and HFA-227 formulations CFC (µg)
Whole lung Oropharynx Actuator Exhaled air
8.0 (3.3) 73.0 (18.2) 17.7 (17.9) 1.3 (2.6)
13.4 61.7 (12.1) 23.9 (11.0) 1.1 (0.7)
8.8 (7.7) 70.4 (19.0) 19.5 (11.3) 1.4 (1.5)
CFC, chlorofluorocarbon; HFA, hydrofluoroalkane *P < .05 versus chlorofluorocarbon.
showed that several stopped inhaling momentarily as the chlorofluorocarbon pMDI spray was fired (the so-called “cold Freon” effect), which could have resulted in a reduction in the amount of drug deposited in the lungs for the chlorofluorocarbon product. Consequently, it was considered that the lung deposition of the chlorofluorocarbon product was an underestimation of the true lung deposition value that could be achieved with perfect technique.
Study 2 A second study was conducted to determine the effect of varying the actuator nozzle diameter between 0.2 and 0.3 mm on the deposition of the hydrofluoroalkane-134a formulation and to determine the actuator nozzle diameter that would give a deposition pattern identical to that achieved for the chlorofluorocarbon product (nozzle diameter, 0.6 mm). Nine healthy volunteers (5 male) took part in a 4-way randomized crossover study that compared the hydrofluoroalkane-134a formulation delivered through actuator nozzles with diameters of 0.3 mm, 0.25 mm, and 0.2 mm versus the chlorofluorocarbon formulation. Special care was taken with the training of the subjects with a placebo aerosol to avoid the “cold Freon” effect when the chlorofluorocarbon aerosol was used; dosing did not take place until the investigators were sure that this error in inhalation technique had been eliminated. In this study, lung deposition showed a significant inverse correlation with actuator nozzle diameter for the hydrofluoroalkane134a formulation (Table III), averaging 12.8 ± 4.1 µg, 15.2 ± 5.2 µg, and 18.0 ± 4.9 µg fenoterol for 0.3 mm, 0.25 mm, and 0.2 mm diameter nozzles, respectively. By comparison, lung deposition averaged 15.5 ± 4.5 µg for the chlorofluorocarbon formulation. There were no significant differences in the regional deposition patterns within the lungs for the 4 study legs; the P/C ratios averaged 1.66, 1.42, and 1.51 for the 3 hydrofluoroalkane aerosols and 1.53 for the chlorofluorocarbon formulation. The change in lung deposition with varying nozzle diameter for the hydrofluoroalkane-134a product formulated as a solution is consistent with the observations of Polli et al,16 who showed a reduction in propellant droplet size from pMDIs with decreasing nozzle diameter, which would allow better penetration
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TABLE III. Mean (SD) mass of drug deposited in lungs and oropharynx, retained on the actuator, and recovered from the exhaled air filter for HFA-134a aerosols with 3 different actuator nozzle diameters and for the CFC aerosol HFA (µg) A (0.3 mm)
Whole lung Oropharynx Actuator Exhaled air
12.8 (4.1) 72.6 (6.6) 13.1 (3.4) 1.5 (1.2)
B (0.25 mm)
C (0.2 mm)
15.2 (5.2) 67.9 (8.1)‡ 15.8 (3.3) 1.1 (0.5)
18.0 58.0 (8.2)*† 21.7 (8.3)* 2.2 (1.7)
D (0.6 mm)
15.5 (4.5)‡ 70.3 (4.2)§ 12.6 (2.8) 1.5 (1.6)
CFC, chlorofluorocarbon; HFA, hydrofluoroalkane *P < .01 versus A. †P < .05 versus B. ‡P < .05 versus A. §P < .05 versus C.
into the lungs. Lewis et al 17 showed a significant increase in fine particle mass for beclomethasone dipropionate hydrofluoroalkane–based aerosols formulated as solutions when the actuator nozzle diameter was reduced, although it has been pointed out by Evans et al 18 that these changes in particle size and lung deposition do not necessarily lead to an enhanced therapeutic effect.
ipated that similar whole lung deposition would have been seen had the study been conducted in patients with asthma; although in patients with asthma, poorer penetration into the lung periphery (resulting in lower P/C ratios for all products tested) would have been expected.19,20 The imaging technique of gamma scintigraphy enabled the deposition patterns of novel pMDI formulations to be quantified noninvasively in humans.
These data showed that the lung depositions of fenoterol from the hydrofluoroalkane and chlorofluorocarbon formulations tested were broadly comparable, with all the formulations depositing less than 20% of the exvalve dose in the lungs. Lung deposition for the hydrofluoroalkane-227 formulation (mean, 8.8 µg) was lower than that for hydrofluoroalkane-134a (mean, 13.4 µg), but whether this reflects the specific contents of the products tested or an inherent tendency for hydrofluoroalkane-227 formulations to give lower lung deposition than hydrofluoroalkane-134a formulations is unclear. Lung deposition for the chlorofluorocarbon product in study 1 was lower than that for the hydrofluoroalkane134a product, but this was ascribed to suboptimal inhaler technique with the former formulation. The lung deposition data seen in this study are typical of those commonly seen in most previous studies involving pressurized aerosol formulations.8,10,11,19-21 The lung dose achieved with the hydrofluoroalkane134a solution formulation varied according to actuator nozzle diameter, indicating that changes to both formulation and actuator design may be used to control the bioavailability of novel pMDI solution formulations. The results showed that lung deposition from hydrofluoroalkane formulations is not inevitably higher than that from chlorofluorocarbon formulations but is highly formulation and device specific. The chlorofluorocarbon formulation of Berodual and the hydrofluoroalkane formulation of Berodual delivered through a 0.25-mm diameter nozzle were probably equivalent, but data concerning delivery of ipratropium bromide from these inhalers would also be required to confirm this. Although these data were obtained in healthy volunteers, it is antic-
1. Partridge MR, Woodcock AA, Sheffer AL, Wanner A, Rubinfeld A. Chlorofluorocarbon-free inhalers: Are we ready for the change? Eur Respir J 1998;11:1006-8. 2. Smith IJ. The challenge of reformulation. J Aerosol Med 1995;8:S19-S27. 3. Leach CL. Improved delivery of inhaled steroids to the large and small airways. Respir Med 1998;92(suppl):3-8. 4. Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFA-beclomethasone metered dose inhaler compared with CFC-beclomethasone. Eur Respir J 1998;12:1346-53. 5. Steed KP, Hooper G, Brickwell J, Newman SP. The oropharyngeal and lung deposition patterns of a fusafungine MDI spray delivered by HFA 134a propellant or by CFC 12 propellant. Int J Pharm 1995;123:291-3. 6. Newman SP, Richards JC, Pitcairn GR, Rohatagi S, Gillen MS. Improved lung targeting of a novel HFA-based formulation of triamcinolone acetonide delivered by pressurised metered dose inhaler [abstract]. Pharm Sci 1998;1:S-209. 7. Richards JC, Pitcairn GR, Sista S, Mahashabde S, Abramowitz W, Newman SP. A scintigraphic study to assess the deposition of flunisolide delivered by HFA and CFC metered dose inhalers. In: Dalby RN, Byron PR, Farr SJ, editors. Respiratory drug delivery VI. Buffalo Grove, Ill: Interpharm Press; 1998. p. 405-6. 8. Newman SP. Scintigraphic assessment of therapeutic aerosols. Crit Rev Ther Drug Carrier Syst 1993;10:65-109. 9. Newman SP. Scintigraphic assessment of pulmonary delivery systems. Pharmacol Tech 1998;22:78-94. 10. Newman SP, Clark AR, Talaee N, Clarke SW. Pressurized aerosol deposition in the human lung with and without an “open” spacer. Thorax 1989;44:706-10. 11. Newman SP, Weisz AWB, Talaee N, Clarke SW. Improvement of drug delivery with a breath actuated pressurised aerosol for patients with poor inhaler technique. Thorax 1991;46:712-6. 12. Farr SJ. The physicochemical basis of radiolabelling metered dose inhalers with 99mTc. J Aerosol Med 1996;9(suppl):S27-S36. 13. Newman SP. Characteristics of radiolabelled versus unlabelled formulations. J Aerosol Med 1996;9(suppl):S37-S47. 14. Pitcairn GR, Newman SP. Tissue attenuation corrections in gamma scintigraphy. J Aerosol Med 1997;3:187-98. 15. Newman SP, Hirst PH, Pitcairn GR, Clark AR. Understanding regional lung deposition in gamma scintigraphy. In: Dalby RN, Byron PR, Farr SJ, editors. Respiratory drug delivery VI. Buffalo Grove, Ill: Interpharm Press; 1998. p. 9-15.
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16. Polli GP, Grim WM, Bacher FA, Yunker MH. Influence of formulation on aerosol particle size. J Pharmacol Sci 1969;58:484-6. 17. Lewis DA, Johnson S, Meakin BJ, et al. Effects of actuator orifice diameter on beclomethasone dipropionate delivery from a PMDI HFA solution formulation. In: Dalby RN, Byron PR, Farr SJ, editors. Respiratory drug delivery VI. Buffalo Grove, Ill: Interpharm Press; 1998. p. 363-4. 18. Evans AE, Ward S, Prowse K. Respirable fraction and clinical response in relation to orifice size of aerosol inhalers [abstract]. Thorax 1992;47:239P.
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19. Dolovich MB, Ruffin R, Corr D, Newhouse MT. Clinical evaluation of a new demand-inhalation MDI aerosol delivery device. Chest 1983;84:36-41. 20. Melchor R, Biddiscombe MF, Mak VHF, Short MD, Spiro SG. Lung deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airways obstruction. Thorax 1993;48:506-11. 21. Laube BL, Edwards AM, Dalby RN, Creticos PS, Norman PS. The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma. J Allergy Clin Immunol 1998;101:475-83.