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(Chest. 2002;122:510-516.)
© 2002 American College of Chest Physicians

Lung Deposition of Hydrofluoroalkane-134a Beclomethasone Is Greater Than That of Chlorofluorocarbon Fluticasone and Chlorofluorocarbon Beclomethasone*

A Cross-over Study in Healthy Volunteers

Chet L. Leach, PhD; Patricia J. Davidson, MS; Bruce E. Hasselquist, PhD and Robert J. Boudreau, MD, PhD

* From 3M Pharmaceuticals (Dr. Leach and Ms. Davidson), St. Paul; and the Department of Radiology (Drs. Hasselquist and Boudreau), University of Minnesota, Minneapolis, MN.

Correspondence to: Chet L. Leach, PhD, Inhale Therapeutic Systems, 150 Industrial Rd, San Carlos, CA 94070-6256; e-mail: cleach{at}inhale.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To compare the lung deposition of radiolabeled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) with chlorofluorocarbon fluticasone propionate (CFC-FP) and chlorofluorocarbon beclomethasone (CFC-BDP).

Design: Six-day, open-label, nonrandomized, crossover study.

Setting: Clinical research laboratory.

Participants: Nine healthy, nonsmoking, adult volunteers.

Interventions: On each study day, participants inhaled one or two puffs of 99mTc-labeled HFA-BDP, CFC-FP, or CFC-BDP. All products delivered 50 µg per puff ex-valve. Subjects used a respiratory training and monitoring device to meet predefined, standardized inhalation patterns. Immediately after inhalation of radiolabeled study drug, planar gamma camera images were obtained.

Measurements and results: Radiolabeled HFA-BDP had a higher deposition in the lungs (53% ex-actuator) compared with CFC-FP (12 to 13%) and CFC-BDP (4%). Conversely, CFC-FP and CFC-BDP had a much higher distribution to the oropharynx (72 to 78%, and 82%, respectively) than HFA-BDP (29%). HFA-BDP was deposited evenly throughout the lungs, while CFC-FP and CFC-BDP deposition was primarily in the large central and intermediate airways. Andersen particle size sampling gave mass median aerodynamic diameters for HFA-BDP, CFC-FP, and CFC-BDP of 0.9 µm, 2.0 µm, and 3.5 µm, respectively.

Conclusions: Lung deposition was greater with HFA-BDP compared with CFC-FP and CFC-BDP. Deposition values appeared to be related to the particle size distribution of each inhaler, with the smaller particles of HFA-BDP providing the greatest lung deposition and least oropharyngeal deposition.

Key Words: beclomethasone dipropionate • chlorofluorocarbon-free propellant • fluticasone propionate • hydrofluoroalkane • lung deposition • 99mTc aerosol


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled corticosteroids are well-established anti-inflammatory therapies for the prophylactic treatment of asthma, recommended in national treatment guidelines as first-line therapy in persistent disease.1 Asthma is an inflammatory disease affecting the whole of the bronchial tree, from the large central airways down to the small peripheral airways.2 3 Steroid receptors, the site of action of inhaled corticosteroid therapy, are likewise located throughout the bronchial tree.4 An optimal therapeutic response with inhaled anti-inflammatory treatment would, therefore, be obtained with a product that reaches the large and small airways of the lung. With the development of imaging techniques such as gamma scintigraphy, it is possible to quantify the amount of radiolabeled drug delivered from a metered-dose inhaler (MDI) that is deposited in the lungs and its distribution throughout the airways.

Beclomethasone dipropionate has been in use for almost 30 years as inhaled asthma medication. With the traditional chlorofluorocarbon formulation (chlorofluorocarbon beclomethasone dipropionate [CFC-BDP]), < 10% of the dose of medication released from the MDI is deposited in the lungs,5 and deposition is primarily in the large central airways. Beclomethasone dipropionate has been reformulated in a chlorofluorocarbon-free propellant: hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) [QVAR; 3M Pharmaceuticals; St. Paul, MN].6 In this formulation, beclomethasone dipropionate is in solution rather than in suspension as with CFC-BDP, resulting in an extrafine aerosol of medication. The smaller particle size, along with a softer, more gentle spray,7 has resulted in improved lung deposition, with 50 to 60% of the emitted dose deposited throughout the airways.5 8

As well as improving the delivery systems of inhaled corticosteroids, there have been efforts to improve the steroid molecule itself, chiefly through stronger receptor binding. Fluticasone propionate was introduced in the 1990s, and is one of the most potent inhaled steroids currently available, having more potent anti-inflammatory effects than beclomethasone dipropionate.9 10 Fluticasone propionate is available in a chlorofluorocarbon formulation (chlorofluorocarbon fluticasone propionate [CFC-FP]) and also an hydrofluoroalkane-134a formulation (hydrofluoroalkane-134a fluticasone propionate [HFA-FP]), in response to the mandated phaseout of chlorofluorocarbon-based inhalers stipulated by the Montreal Protocol in 1994.11 The objective of this study was to compare the lung deposition of radiolabeled CFC-FP, HFA-BDP, and CFC-BDP.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subject Selection and Training
Men and women from 18 to 55 years of age, between 155 cm and 190 cm in height, and within 25% of normal body weight for their height and frame size were eligible for inclusion in the study. Subjects were required to have abstained from tobacco for at least 1 year and have a < 10-pack-year smoking history. Subjects were also required to have an FEV1 at the screening visit >= 90% of predicted normal. In addition, women were required to have a negative urine pregnancy test result and be using a medically acceptable means of birth control.

Subjects were excluded from the study if they had received a dose of radiation during participation in clinical trials or diagnostic radiography within the previous 12 months (routine chest, sinus, dental, or minor trauma radiographs were permitted). Other exclusion criteria included a history of alcohol or substance abuse within the previous 2 years, use of study medication within 4 weeks prior to the screening visit, any current acute infection or an upper or lower respiratory tract infection within 2 weeks prior to the screening visit, and a recent history of significant respiratory system disease including asthma, chronic bronchitis, and emphysema.

Nine subjects were trained to inhale from a placebo MDI in a reproducible manner using a real-time respiratory biofeedback device developed by 3M Pharmaceuticals. The subject observed, on a computer screen, a visual display of breath pattern (ie, inspiration time, actuation time, and breath-hold time). The device enabled subjects to reproduce a particular inhalation pattern. The subjects were instructed to exhale to their maximum comfortable level prior to inhaling the dose. The target inhalation pattern was as follows: 0.3-s actuation time, inspiration duration of 2 to 4 s, followed by a 10-s breath hold. After training, subjects had to demonstrate the reproducibility of their inspiratory flow pattern using the respiratory training device, as well as demonstrating satisfactory technique in the use of the MDI.

Study Design and Procedures
This was a phase I, open-label, nonrandomized crossover study. Subjects attended a screening visit, a 133Xe scan visit, 6 study days, and a poststudy visit. On study days 1 to 5, deposition of radiolabeled HFA-BDP, CFC-BDP, and CFC-FP was analyzed and compared. CFC-FP was evaluated on 2 separate study days, while HFA-BDP and CFC-BDP were evaluated on 1 separate study day each. On the remaining study days, other investigations were performed, the results of which are not reported here.

At the screening visit, subjects were evaluated to determine whether they met the inclusion and exclusion criteria. A 133Xe scan was performed (if a scan had not been performed within the past 2 years) to obtain a posterior ventilation image, which enabled the lung edge and central, intermediate, and peripheral lung regions to be defined.

On each of the study days, subjects inhaled 99mTc-labeled HFA-BDP, CFC-FP, or CFC-BDP. Each of the inhalers were primed after final assembly and used the same day without further priming. Subjects were instructed to take one or two puffs of radiolabeled drug (all products delivered 50 µg per puff ex-valve) from the MDI. The number of puffs required was calculated from the amount of radioactivity provided by each actuation and the amount of radioactivity needed for gamma camera imaging. Subjects used the respiratory training device to meet the predefined, standardized inhalation patterns. The subject was required to exhale into a low-resistance filter that trapped any exhaled radiolabeled drug.

Immediately after inhalation of the radiolabeled study drug, planar gamma camera images were obtained with subjects in an upright position. The following 90-s static images were recorded: posterior thorax, anterior thorax, anterior upper abdomen, posterior upper abdomen, left lateral oropharynx, actuator, and filter. The lung outline and associated regions of interest were determined from the xenon scan and then superimposed on the individual subject’s aerosol scan. Radioactive counts in each region studied were then used to calculate the percentage of total counts in the region.

Safety Issues
No subject was to receive > 18.5 megabecquerels (MBq) of radiolabeled study drug on a single study day, and no subject was to receive radiolabeled study drug on more than six occasions. The maximum whole-body radiation dose from the aerosol scans was 4.05 x 103 milligrays (mGy)/MBq x 111 MBq = 0.45 mGy; the maximum lung dose was 6.8 x 102 mGy/MBq x 111 MBq = 7.5 mGy. The maximum whole-body radiation dose from the 133Xe scan was 0.33 mGy, with a lung dose of 2.5 mGy. During the study, safety was assessed using adverse event reporting, vital sign measurements (body temperature, pulse rate, respiratory rate, and sitting BP), and screening and poststudy physical examinations.

Radiolabeling Technique
The radiolabeling technique was modified from the method of Köhler et al.12 99mTc (half-life of 6 h) was obtained from a commercial vendor as Na99mTcO4 (sodium pertechnetate) in saline solution. The solution was placed in a clean 20-mL glass vial with 0.030 mL of 27% ammonia, 0.006 mL of tetraphenylarsonium chloride hydrochloride hydrate (1% solution), and 12 mL of chloroform. The glass vial was capped, shaken for several seconds, and sonicated for 30 s. After sonication, the mixture was passed through a phase-separation filter into an empty aluminum vial. The chloroform was slowly evaporated from the vial under a flow of nitrogen gas. Dry ice was used to cool both the radioactive vial and the vial containing the original test formulation to be labeled. The valve was removed from the test formulation vial, and the formulation was poured into the radioactive vial. A new valve, appropriate for the original test formulation, was crimped onto the radioactive vial and tested for leaks. After being shaken, the mass and activity per actuation were determined using a filter, through which the radiolabeled drug was drawn. The activity of the delivered drug was counted in a well counter, and the valve delivery of the MDI was determined.

Radiolabel Validation
It was necessary to ensure that the mass and activity per actuation were within expected limits for each product. It was also necessary to ensure that the mass distribution of the formulation did not change during the labeling process and that the mass and radiolabel size distributions agreed. The Andersen I ACFM Particle Sizing Sampler (Mark II; Andersen Samplers; Atlanta, GA) and the Quartz Crystal Microbalance (QCM) Cascade Impactor System (California Measurements; Sierra Madre, CA) operated in standard sampling modes were used to determine the particle size distributions from the MDIs.

The QCM provided nearly real-time distributions for the mass and radiolabel on the day of the study. The Andersen sampling provided drug and radiolabel distributions at a later date. Before the labeling procedure was begun, the canister containing the formulation was primed and actuated the appropriate number of times into the QCM and an Andersen Sampler (ie, "before"). After the mass and activity per actuation were determined, the labeled canister was actuated into the QCM and a second Andersen sampler (ie, "after"). The QCM crystals were removed from the impactor, and the radioactivity on each crystal was counted in a gamma counter. The before and after QCM mass distributions were compared with each other and with the radiolabel distribution. If the distributions agreed, the formulation was considered properly labeled for the study. After the radiolabeled canister had decayed to background levels, medication delivery was also tested to ensure that the values were within specification.

Statistical Analysis
Baseline characteristics were summarized for the whole population. Summary statistics were completed for all deposition and safety parameters using the intent-to-treat population. As this was a pilot study, no hypothesis testing was performed.

Ethics
At the screening visit, the investigator or a designated assistant explained to subjects the nature of the study, its purpose, procedures, expected duration, and the benefits and risks involved in study participation. Subjects were given the opportunity to ask questions and were informed of their right to withdraw from the study at any time. After study procedures were explained, and before the study drug was administered, the subjects signed an informed consent statement.

The study protocol, subject information document, and the informed consent statement were reviewed and approved by an institutional review board: the Human Subjects Committee at the University of Minnesota. The study was conducted in compliance with the Code of Federal Regulations of the US Food and Drug Administration and the revised Declaration of Helsinki (1996).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Study Subjects
Out of 16 subjects screened, 9 subjects (5 men and 4 women) enrolled in and completed the study. Mean FEV1 was 3.8 L (SD, 0.7 L; range, 2.7 to 4.8 L). Mean FEV1 percent predicted was 98.4% (SD, 8.4%; range, 90.2 to 113.3%). Data from the respiratory feedback device demonstrated that mean breath patterns were consistent between study days and that subjects achieved the target breath patterns (Table 1 ).


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  		Table 1. Breath Patterns as Assessed by the Respiratory Feedback Device on Each Study Day*

 
Radiolabeling Validation
Figure 1 shows the radiolabeling validation results for HFA-BDP, CFC-BDP, and CFC-FP. The validation results show that the radiolabeling process did not significantly alter the particle size distribution of the original product, and that the radioactive count distribution matched the mass distribution of the drug after radiolabeling. The particle size distributions from the Andersen sampler gave mass median aerodynamic diameters (MMADs) for HFA-BDP, CFC-FP, and CFC-BDP of 0.9 µm, 2.0 µm, and 3.5 µm, respectively.



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  		Figure 1. Comparisons of the particle size distributions of HFA-BDP (top), CFC-FP (middle), and CFC-BDP (bottom) showing mass before radiolabeling, mass after radiolabeling, and counts after radiolabeling.

 
Deposition
Figure 2 shows the percentage ex-actuator deposition of the three inhaled corticosteroids in the lungs, oropharynx, mediastinum (ie, trachea and esophagus), and abdomen, and the percentage of drug exhaled. Radiolabeled HFA-BDP had a higher deposition in the lungs (53%) compared with CFC-FP (12% and 13% on the respective study days) and CFC-BDP (4%). Conversely, CFC-FP and CFC-BDP had a much higher deposition in the oropharynx (74% and 78% for CFC-FP and 82% for CFC-BDP) than HFA-BDP (29%).



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  		Figure 2. Distribution, as percentage of ex-actuator dose, of radiolabeled HFA-BDP, CFC-FP, and CFC-BDP to the lungs, oropharynx, mediastinum, abdomen, and expiratory filter.

 
Figure 3 shows individual lung scans for each study subject following inhalation of HFA-BDP, CFC-FP, and CFC-BDP. White areas represent the greatest deposition of radiolabeled drug, while light blue areas represent less deposition. It can be seen that HFA-BDP was deposited throughout the lungs of all subjects, while CFC-FP and CFC-BDP were primarily deposited in the large central and intermediate airways.



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  		Figure 3. Gamma scintigraphic lung images of the nine study volunteers after inhalation of radiolabeled HFA-BDP (top), CFC-FP (middle), and CFC-BDP (bottom).

 
Safety
Over the course of the study, no subjects were exposed to > 51 MBq of radioactivity from 99mTc or 777 MBq of radioactivity from the 133Xe scan. Ten adverse events were reported by five subjects: six reports of upper respiratory tract infection, two reports of headache, and one report each of gastritis and pharyngitis. None of the adverse events were considered related to administration of the study drug, and all resolved within 8 days of the last dose of the study. There were no serious adverse events. No subjects withdrew voluntarily or were withdrawn from the study. There were no changes in vital signs or findings on physical examination that were considered clinically meaningful.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, a larger proportion of inhaled HFA-BDP reached the lungs compared with CFC-FP and CFC-BDP. With HFA-BDP, 53% of the ex-actuator dose was deposited in the lungs compared with 12 to 13% for CFC-FP and only 4% for CFC-BDP. Additionally, less HFA-BDP impacted and remained in the oropharynx and was subsequently swallowed compared with CFC-FP and CFC-BDP. Furthermore, HFA-BDP appeared to be deposited evenly throughout the lungs, including the large, intermediate, and small airways, whereas deposition of CFC-FP and CFC-BDP was primarily in the large central and intermediate airways, based on two-dimensional views of an acknowledged three-dimensional object.

Previous studies have demonstrated the increased lung deposition of HFA-BDP compared with CFC-BDP. In a study of healthy volunteers by Leach et al,5 55 to 60% of HFA-BDP ex-actuator dose was deposited in the lungs, with 29 to 30% deposited in the oropharynx, while CFC-BDP deposition was only 4 to 7% in the lungs and 90 to 94% in the oropharynx. Deposition of HFA-BDP in patients with mild asthma was similar to that in healthy subjects, at 56% in the lungs and 33% in the oropharynx.5 In a further preliminary study8 involving patients with mild-to-moderate asthma, 54% of the dose of HFA-BDP from a breath-actuated device was deposited in the lungs. Planar gamma camera images showed that radiolabeled HFA-BDP was deposited throughout the central, intermediate, and peripheral areas of the lungs. Thus, the results of this study are consistent with the results of previous studies with regard to HFA-BDP deposition. The lung deposition of CFC-FP observed in this study was also consistent with preliminary findings reported by Rahman et al,13 who showed in a study involving eight healthy volunteers that total lung deposition of radiolabeled fluticasone propionate ranged from 10 to 36%, with maximal deposition in central lung regions.

Fluticasone propionate is also available in an hydrofluoroalkane-134a formulation (HFA-FP) as well as a chlorofluorocarbon formulation. The two products have been licensed on a dose-equivalent basis for switching between formulations. However, a study by Wilson et al14 demonstrated that the lung bioavailability and, by implication, lung deposition of CFC-FP was about twofold greater than that of HFA-FP at the same dose, as assessed by markers of adrenal suppression. The use of CFC-FP rather than HFA-FP in the current study, therefore, provided the more stringent comparator.

HFA-BDP has previously been demonstrated to have a smaller particle size compared with CFC-BDP, with MMADs of 1.1 µm and 3.5 to 3.9 µm, respectively.5 15 Particle sizes previously reported for CFC-FP are also larger than those for HFA-BDP, at 2.8 to 3.2 µm.16 The current study confirmed these findings, demonstrating MMADs for HFA-BDP, CFC-FP, and CFC-BDP of 0.9 µm, 2.0 µm, and 3.5 µm, respectively.

Factors other than particle size may influence lung and oropharyngeal deposition. For example, HFA-BDP is emitted with a much lower spray force (approximately 35 mN) compared with CFC-FP or HFA-FP and CFC-BDP (100 to 120 mN).7 Furthermore, the temperature of the spray is warmer for HFA-BDP (approximately 5°C) than for HFA-FP and CFC-BDP (- 20°C).7 Patients may experience a "cold-freon" effect when using traditional chlorofluorocarbon MDIs, although this cold-freon effect has yet to be clearly demonstrated. This effect may be due to the forceful impaction of cold spray on the back of the throat, and may cause the patient to pause inhaling and consequently affect the amount of medication drawn into the lungs. The warmer, gentler spray from the HFA-BDP MDI may decrease the likelihood of the cold-freon effect, allowing more optimal inhalation of medication into the lungs.

Clinical studies have confirmed that HFA-BDP is effective at half the daily dose compared with CFC-BDP.17 18 19 The study of Busse et al17 investigated the efficacy of HFA-BDP and CFC-BDP at daily doses of 100 µg, 400 µg, and 800 µg, and found that the dose-response curve for change in FEV1 percent predicted was shifted to the left for HFA-BDP compared with CFC-BDP. Analysis revealed that it would take 2.6 times the dose of CFC-BDP to produce the same improvement in FEV1 obtained with HFA-BDP. Subsequent studies demonstrated the equivalence of HFA-BDP, 400 µg/d, compared with CFC-BDP, 800 µg/d,18 and HFA-BDP, 800 µg/d, compared with CFC-BDP, 1,500 µg/d.19 Studies20 21 have also demonstrated that patients whose asthma was stable and well controlled with CFC-BDP can be switched to HFA-BDP at half the daily dose with no loss of asthma control. A long-term study22 confirmed that asthma control was maintained for 12 months after the switch from CFC-BDP (400 to 1,600 µg/d) to HFA-BDP (200 to 800 µg/d).

It is probable that the equivalent efficacy of HFA-BDP at a reduced dose compared with CFC-BDP is a consequence of the increased lung deposition seen with HFA-BDP compared to CFC-BDP. HFA-BDP and HFA-FP, however, have been shown to have equivalent efficacy at the same daily dose in studies that compared HFA-BDP, 400 µg/d, with CFC-FP, 400 µg/d, in patients with moderate asthma, and HFA-BDP, 800 µg, with HFA-FP, 1,000 µg/d, in patients with moderate-to-severe asthma.23 24 25 This is in keeping with observations that fluticasone propionate is effective at half the daily dose of CFC-BDP.26 Fluticasone propionate is a more potent corticosteroid than beclomethasone dipropionate,9 10 with a greater lipophilicity, longer glucocorticoid receptor binding half-life, and longer elimination half-life compared with beclomethasone dipropionate.27 28 Compared with beclomethasone dipropionate, fluticasone propionate has a greater antiinflammatory effect, as assessed by inhibition of T-cell migration and proliferation, inhibition of cytokine and histamine release, attenuation of adhesion molecule expression, and stimulation of inflammatory cell apoptosis and antiprotease release.9 Thus, the more potent antiinflammatory effect of fluticasone propionate in the central airways may offset its poorer peripheral lung deposition compared with HFA-BDP, resulting in equivalent clinical efficacy when the two products are compared at similar dose levels.

In conclusion, this study has demonstrated that lung deposition is greater with HFA-BDP compared with CFC-FP and CFC-BDP. HFA-BDP was distributed diffusely throughout the lungs, while deposition of CFC-FP and CFC-BDP was primarily in the large central and intermediate airways. Deposition values appeared to be related to the particle size distribution of each product, with the smaller particles of HFA-BDP providing the greatest lung deposition and least oropharyngeal deposition.


   Footnotes
 
Abbreviations: CFC-BDP = chlorofluorocarbon beclomethasone dipropionate; CFC-FP = chlorofluorocarbon fluticasone propionate; HFA-BDP = hydrofluoroalkane-134a beclomethasone dipropionate; HFA-FP = hydrofluoroalkane-134a fluticasone propionate; MBq = megabecquerel; MDI = metered-dose inhaler; mGy = milligray; MMAD = mass median aerodynamic diameter; QCM = Quartz Crystal Microbalance

This study was sponsored by 3M Pharmaceuticals, St. Paul, MN.

Dr. Leach was an employee of 3M Pharmaceuticals from 1990 to 2000, during which time the study was conducted. He is no longer employed by 3M. Dr. Leach owned stock in 3M during that period of time and continues to hold a portion of that stock. Since 1993, Ms. Davidson has been an employee of 3M Pharmaceuticals and has owned stock in 3M. Dr. Hasselquist has been an employee of the University of Minnesota since October 1990 and was a paid consultant to 3M during the time the study was conducted. Dr. Hasselquist does not own any stock in 3M or have any other financial interest in the company. Dr. Boudreau was a paid consultant at 3M Pharmaceuticals during the time the study was conducted. Dr. Boudreau does not own any negotiable securities (eg, stocks) in 3M Corporation or its subsidiaries.

Received for publication April 6, 2001. Accepted for publication March 18, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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