Evaluation of particle size distribution of albuterol sulfate hydrofluoroalkane administered via metered-dose inhaler with and without valved holding chambers Courtney Crim, MD; Mark Holmes, BS; Benjamin Lee, PharmD; Robb Cavanaugh, BS; and William Lincourt, BS
Background: Administration of inhaled medications via metered-dose inhaler (MDI) to pediatric patients younger than 4 years usually requires use of a holding chamber or spacer with an attached face mask. Objective: To determine the particle size distribution and overall dose of albuterol from the albuterol sulfate hydrofluoroalkane delivered in conjunction with 2 US-marketed valved holding chambers (VHCs) compared with the dose delivered via MDIs without VHCs. Methods: Cascade impaction methods with high-performance liquid chromatography were used to evaluate the fine particle mass (FPM) of albuterol administered without and with the use of 2 commercially available VHCs. Results: Particle size distributions for the 2 VHCs and the control were similar. The mean FPM values for the 2 VHCs and the control were 32, 28, and 30 g, respectively. Statistical comparison of the FPM shows a similar profile when differences from the albuterol hydrofluoroalkane without a spacer were evaluated. Conclusions: In vitro results obtained under these test conditions demonstrate that all the FPM values for the VHCs tested were within 15% of the control range, a difference that is unlikely to be clinically meaningful. These results do not warrant a change in the recommended dose of albuterol hydrofluoroalkane administered when using the VHCs tested. The use of an MDI in conjunction with a VHC provides a reasonable therapeutic approach for administration of albuterol hydrofluoroalkane to young children and other patients who have difficulty administering the MDI alone. Ann Allergy Asthma Immunol. 2005;94:80–85.
INTRODUCTION Asthma is the most common chronic disease of childhood.1 Estimates indicate that the disease affects 11% of children younger than 18 years, or 7.8 million children in the United States,2 and its prevalence has increased during the past few decades.3 Childhood asthma not only interferes with the child’s daily functioning but also places a considerable burden on the child’s family.4,5 Pressurized metered-dose inhalers (MDIs) are commonly used for the delivery of asthma medications. More than 500 million MDIs are produced worldwide each year.6 Aerosol delivery of therapy offers the advantages of a lower dose of medication relative to systemic therapy and direct delivery of the drug to the target organ.7 Despite recommendations of the National Asthma Education and Prevention Program guidelines,8 no MDI treatment for asthma is currently approved for children younger than 4 years. Jet or ultrasonic nebulizers are most often used for inhaled drug delivery to very young children. However, administraGlaxoSmithKline Inc, Research Triangle Park, North Carolina. This study was supported by GlaxoSmithKline Inc, Research Triangle Park, NC. Received for publication March 26, 2004. Accepted for publication in revised form September 27, 2004.
tion of drugs via a nebulizer is costly, cumbersome, and time-consuming. The variability of the output from different nebulizers,9,10 the higher dose of medication required, and the possible ocular exposure are additional disadvantages of nebulization.11 In addition, the albuterol solution for nebulization is currently approved only for children 2 years and older. The use of valved holding chambers (VHCs) with MDIs is a recommended alternative to nebulization.8 Use of a VHC for drug delivery has the advantages of portability, decreased costs, and decreased oropharyngeal deposition (an advantage that is of even more clinical importance with inhaled corticosteroids than with ␤-agonists) compared with nebulizers.8 Clinical studies7,11 have not demonstrated greater efficacy for nebulized therapy over an MDI plus VHC even in acutely ill patients. Also, VHCs offer advantages to patients who cannot be taught proper inhalation techniques and to patients who have difficulty coordinating the actuation and inhalation required with the use of MDIs. Errors in inhalation technique occur frequently, often leading to improper dosing and lack of asthma symptom control.12–14 In the United States, an albuterol sulfate inhalation aerosol (Ventolin hydrofluoroalkane; Glaxo Wellcome Inc, Research Triangle Park, NC) received marketing approval in April 2001 for the treatment and prevention of bronchospasm in adults and children 4 years and older with reversible obstruc-
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tive airway disease. It is estimated that since the availability of this product through December 31, 2002, there have been approximately 12 million patient-years of exposure. The chlorofluorocarbon propellants are expected to eventually be withdrawn from the market because of their effects on the ozone layer. This phaseout was mandated by the 1987 Montreal protocol, to which the United States was a signatory. Hydrofluoroalkanes have been identified as an acceptable alternative to chlorofluorocarbon propellants because they do not contribute to depletion of the ozone layer and are well tolerated. The AeroChamber Plus (Trudell Medical Group, Plattsburgh, NY) and the OptiChamber (Respironics HealthScan Asthma and Allergy Products, Cedar Grove, NJ) are 2 VHCs commonly used in the United States. Because the VHC seems to be a reasonable therapeutic option for dosing of inhaled medications to pediatric patients, we sought to compare the in vitro characteristics of albuterol administered via these 2 commonly used, commercially available VHCs. This in vitro study was conducted to determine the particle size distribution and overall dose of albuterol available for lung delivery using these 2 VHCs compared with the dose available for delivery via MDI without VHCs. METHODS VHCs Tested The VHCs tested in this study were the AeroChamber Plus and the OptiChamber. The AeroChamber Plus is fitted with various-sized masks. These masks were removed before the testing, and a special rubber adapter/mouthpiece was made to mate the VHC to the throat of the cascade impactor. The special rubber mouthpiece was of similar dimensions to the
standard rubber mouthpiece used for inhalation. The OptiChamber has an integrated mouthpiece that was fitted directly into the standard rubber mouthpiece adapters used for MDIs on the cascade impactor throat. Six of each spacer type were analyzed, and each spacer was evaluated with a different albuterol hydrofluoroalkane inhaler. In addition to the spacer testing, an albuterol hydrofluoroalkane control (an MDI without a spacer) was assessed with every set of analyses so that the effect of the VHCs on the fine particle mass (FPM) could be evaluated. As detailed in the manufacturers’ patient leaflets, the VHCs were washed before use to help reduce static. The VHCs were rinsed for 20 minutes with agitation in 4 L of warm water containing 1 mL of concentrated washing detergent. The VHCs were then rinsed in clean warm water to remove the detergent and were allowed to air dry overnight. The instructions in the patient leaflets included with each spacer were used in conjunction with the cascade impaction methods to ensure that the VHCs and inhalers were handled in the same way a patient would use them. Cascade Impaction All cascade impactor determinations were made using a standard Andersen cascade stack (Graseby Andersen, Smyrna, GA), a metal throat (GlaxoSmithKline design), and a modified inlet cone. A stand was used to place constant pressure on the impactor to prevent vacuum loss and promote consistency. Figure 1 presents the setups for the cascade stack, modified inlet cone, and inhaler for the AeroChamber Plus and OptiChamber VHCs. Ventolin hydrofluoroalkane (albuterol sulfate inhalation aerosol) (lot number 1ZP2507) was used for drug delivery.
Figure 1. Setups for the cascade stack, modified inlet cone, and inhaler for the AeroChamber Plus (left) and OptiChamber (right) valved holding chambers.
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This formulation differs from the hydrofluoroalkane 134a formulation Proventil (3M Pharmaceuticals, St Paul, MN), which contains ethanol and oleic acid as co-solvents; these co-solvents are not used in the GlaxoSmithKline hydrofluoroalkane 134a formulation. If the inhalers had not been test fired, each inhaler was inverted and shaken for no less than 5 seconds before 4 test fires were actuated to waste. There was no wait between actuations for the priming shots. The MDI canisters were then removed from the actuator, the valve stems were wiped, and the canisters were placed into clean actuators. After establishing a flow of approximately 28.3 L/min (ie, the flow rate used to calibrate the cascade impaction stack according to the manufacturer’s instructions) through the cascade impactor, the correct rubber mouthpiece was attached to the throat of the impactor and the VHC was inserted into the mouthpiece. The inhaler was then shaken while inverted for no less than 5 seconds and then inserted into the end of the VHC. An actuation was delivered by fully depressing the canister. The canister was then left in place for 60 seconds. The inhaler was removed and shaken for not less than 5 seconds. This procedure was repeated for 5 complete actuations. The flow through the cascade impactor remained at 28.3 L/min continuously throughout the firing of the 5 actuations. One minute after the final actuation, the pump was turned off and the inhaler was removed and reweighed before washing down the actuator, canister, VHC, and cascade impactor with methanol for albuterol determination. The shot weight was calculated on 9 actuations (including the 4 priming actuations). Stages 3, 4, and 5 of the cascade impactor collect particle sizes ranging from 4.7 to 1.1 m in diameter, a range considered ideal for deposition and retention in the small human airways. For this reason, results of stages 3, 4, and 5 of the cascade impactor are considered the standard for the delineation of particle distribution for albuterol. The results from these stages are the most conservative measures of the particle size distribution of albuterol from the 2 VHCs and are the most sensitive in detecting differences in particle distribution across the different spacer devices. Statistical Analyses All analyses were performed on the total of stages 3, 4, and 5 for each cascade impactor determination of any given VHC type or control inhaler. Each VHC type was compared with the albuterol hydrofluoroalkane control by constructing a 95% confidence interval for the difference in mean FPM reported in micrograms and for the difference in mean FPM reported as a percentage of total FPM. The 95% confidence intervals were constructed using the t test. Mean FPM for each VHC type and for the albuterol hydrofluoroalkane control, the difference in mean FPM, and the standard error of the difference were also determined.
RESULTS Particle size distributions for the AeroChamber Plus and OptiChamber were similar across all stages of the cascade impactor when analyzed by high-performance liquid chromatography (Fig 2). In addition, the particle size distributions for both VHCs were similar to the distribution of the control MDI without a spacer. The profiles of cumulative mass percentages of particles based on aerodynamic diameter for all VHCs were similar and comparable to that of the control (Fig 3). Stages 3, 4, and 5 of the cascade impactor collected most (ⱖ95%) of the drug deposited in the impactor. The FPM results for these stages were similar across the various VHCs tested (Table 1). The mean FPM values for the AeroChamber, the OptiChamber, and the control were 32, 28, and 30 g, respectively. When the differences in fine particle fraction from the albuterol MDI control were compared, some variability between VHCs became apparent (Fig 4). The AeroChamber Plus had a difference in mean values from the albuterol control for FPM that included zero. Compared with the albuterol control, the OptiChamber demonstrates a slight decrease in FPM. This is consistent for FPM in micrograms and for FPM as a percentage of the total. However, all of the FPM values were within 15%, and the differences were not deemed to be clinically significant. DISCUSSION This study was intended to determine whether the use of 2 commercially available VHCs in conjunction with a pressurized MDI changed the FPM characteristics of inhaled albuterol hydrofluoroalkane aerosol. The primary reason for performing this in vitro work in conjunction with the various spacer devices was to determine the overall dose available for delivery to the patient and whether the different VHCs changed the FPM and, hence, whether there was a need to modify the dose given to pediatric patients when VHCs were used. The present study demonstrated similar results for all
Figure 2. Particle size distributions for the 2 valved holding chambers (VHCs) and the control.
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Figure 3. Cumulative mass percentage of particles based on aerodynamic diameter for the 2 valved holding chambers (VHCs) and the control.
VHCs tested under these standard test conditions compared with the control. Although there were slight differences in FPM among the VHCs tested, these differences were not significant enough to warrant a change in the recommended dose administered. Particles in the 1- to 5-m range are considered to have the greatest likelihood of depositing in small conducting airways and alveoli. However, this finding is based on data in healthy adult volunteers. It has been suggested that aerosol particles that measure 1 to 2 m may provide the greatest lung dose to negotiate the small airways of infants.7 Therefore, it is important to consider the particle size distribution within this range when assessing the comparability of the various VHCs and the comparability to the MDI alone (ie, the control). This study demonstrated that both VHCs significantly reduced the throat dose of albuterol without reducing the amount of drug available for inhalation into the airways of young children. Although FPM values across the VHCs tested were similar and comparable to that delivered via the MDI alone, other factors need to be considered when selecting VHCs for clinical use. Barry and O’Callaghan15 evaluated the effect of a delay of up to 20 seconds between actuation and sampling. In their study, all spacers tested had a lower recovery of drug after a delay between MDI actuation and sampling (P ⬍ .001). The drug recovery half-lives were approximately 15 seconds for beclomethasone and 8 to 10 seconds for fluticasone propionate irrespective of the spacer studied. In addition, the volumes of the spacers tested in this study are different: 149 mL for the AeroChamber Plus and 218 mL for the OptiChamber. The OptiChamber has an integrated mouthpiece, and the AeroChamber Plus has face masks available in various sizes. Differences in the valve design, thickness, and resultant opening pressure also exist across these devices. These differences in VHC volumes, geometric design, and valve performance, coupled with a smaller tidal volume and relatively larger dead space in young children, could result in a prolonged time taken for the drug to empty from the VHC. This effectively introduces a “delay” between actuation and drug delivery, which may result in less drug being available for inhalation. Evaluation of these and other
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characteristics of the VHCs are beyond the scope of this evaluation. A further caveat of this in vitro trial is that most children aged 1 to 3 years will use the VHCs with a face mask that covers the nose and mouth. Nasal inhalation through a mask has been shown to reduce airway delivery compared with inhaling through a mouthpiece.16 Thus, the in vitro delivered dose is likely to be an overestimate of the actual dose delivered. However, this same issue exists for nebulizer delivery, and clinical trials have demonstrated efficacy for delivery with a face mask. The use of MDIs with spacers provides multiple advantages over alternative administration methods. The results of a placebo-controlled, double-blind trial conducted by Leversha and colleagues17 showed that the albuterol MDI and spacer combination is a cost-effective alternative to albuterol nebulizer for the delivery of inhaled medications to young children aged 1 to 4 years. In that study, patients and parents preferred the spacer to the nebulizer. Delgado and colleagues18 showed that albuterol administered by MDI with a spacer was as effective as nebulizers for the emergency department treatment of wheezing in children 2 years or younger. Chou and colleagues19 demonstrated that albuterol with spacers may be an effective alternative to nebulizers for the treatment of children with acute asthma exacerbation in the emergency department. A recent review20 of 13 trials in adults and children concluded that MDIs with spacers were at least as effective as nebulizers for ␤-agonist administration, and the use of MDIs with spacers in children resulted in shorter stays in emergency departments and smaller increases in pulse rates. Although no clinical trials have directly compared long-term controller therapy by nebulizer and MDI plus VHC in young children, comparisons of recent trials of inhaled corticosteroids administered by the 2 methods suggest similar efficacy.21,22 Nebulizers have several disadvantages compared with the MDI and spacer combination. Nebulizers are noisy and require a child to sit still for extended periods. Nebulizers have been shown to deliver, at best, 10% of the prescribed drug to the lungs,23 and the output varies considerably from different nebulizers.9 Nebulizers are also more complicated to operate and maintain, and jet nebulizers require a source of compressed air. Preparation of medications to be administered requires added handling and dilution that may increase the possibility of contamination of the product or administration of incorrect dosages. In contrast, MDI and spacer combinations are more efficient and require a shorter time to deliver the dose compared with nebulization. Spacer and MDI combinations are also more compact and easily portable. Based on these advantages, it is not surprising that guidelines on asthma management have supported the wider use of spacer devices.24 In a recent editorial,25 it was stated that these devices, with or without face masks, have now displaced nebulizers as the first line of drug delivery to children. In conclusion, the VHCs studied significantly reduce large particles delivered without impairing availability of the dose in
Table 1. Comparison of Fine Particle Mass (FPM) (Stages 3, 4, and 5) Valved holding chamber (volume) AeroChamber Plus (149 mL) OptiChamber (218 mL)
FPM, mean, g*
Control FPM, mean, g†
Difference from control, g
SE (95% CI)‡
2.74 (⫺4.5–8.9) 2.74 (⫺8.0–5.4)
Abbreviation: CI, confidence interval. * Total from stages 3, 4, and 5 of the cascade impactor. Represents particle sizes 4.7 to 1.1 m. † Albuterol metered-dose inhaler without a holding chamber. ‡ Standard error of difference between the FPM of the valved holding chamber and the control.
Figure 4. Mean fine particle mass (FPM) (stages 3, 4, and 5) vs the control. Error bars represent 95% confidence intervals for the differences in FPM (vs control).
the respirable range for young children so that the MDI plus VHC is a reasonable alternative in these patients. REFERENCES 1. Centers for Disease Control and Prevention. Measuring childhood asthma prevalence before and after the 1997 redesign of the National Health Interview Survey—United States. MMWR Morb Mortal Wkly Rep. 2000;49:908 –911. 2. Blackwell DL, Tonthat L. Summary health statistics for U.S. children: National Health Interview Survey, 1999. Vital Health Stat 10. 2003;210:207–212. 3. Epidemiology and Statistics Unit, American Lung Association. Trends in Asthma Morbidity and Mortality. New York, NY: American Lung Association; March 2003. 4. American Lung Association. ALA Asthma Survey 1998. Available at: http://www.lungusa.org/asthma/merck_summary.html. Accessed March 26, 2004. 5. Mahajan P, Stahl E, Arledge T. Quality of life in pediatric asthma patients treated with fluticasone propionate and impact on daily activities of their parents. Pediatr Asthma Allergy Immunol. 1998;12:21–28. 6. McDonald KJ, Martin GP. Transition to CFC-free metered dose inhalers: into the new millennium. Int J Pharm. 2000;201: 89 –107. 7. Cole CH. Special problems in aerosol delivery: neonatal and pediatric considerations. Respir Care. 2000;45:646 – 651. 8. National Heart, Lung, and Blood Institute. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health; April 1997. NIH
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22. Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M, Walton-Bowen K. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics. 1999;103:414 – 421. 23. Everard ML, Clark AR, Milner AD. Drug delivery from jet nebulizers. Arch Dis Child. 1992;67:586 –591. 24. British Thoracic Society. British guidelines on asthma management: 1995 review and position statement. Thorax. 1997;52(Suppl):S1–S24.
25. O’Callaghan C. Barry PW. Asthma drug delivery devices for children [editorial]. BMJ. 2000;320:664. Requests for reprints should be addressed to: Courtney Crim, MD GlaxoSmithKline Inc Five Moore Dr Research Triangle Park, NC 27709 E-mail: [email protected]
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