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(Chest. 2001;119:1018-1020.)
© 2001 American College of Chest Physicians

Comparative In Vivo Lung Delivery of Hydrofluoroalkane-Salbutamol Formulation Via Metered-Dose Inhaler Alone, With Plastic Spacer, or With Cardboard Tube*

Stephen J. Fowler, MB, ChB; Andrew M. Wilson, MB ChB; Ewen A. Griffiths, BSc and Brian J. Lipworth, MD

* From the Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.

Correspondence to: Brian J. Lipworth, MD, Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK; e-mail: b.j.lipworth{at}dundee.ac.uk


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To compare the lung delivery of chlorofluorocarbon-free salbutamol via a pressurized metered-dose inhaler (pMDI) alone, a pMDI with a small-volume plastic spacer, and a pMDI with a cardboard tube.

Design: A randomized, single (investigator)-blind, three-way, crossover study.

Setting: The Asthma and Allergy Research Group, Ninewells Hospital, University of Dundee, Dundee, Scotland, UK.

Participants: Twelve healthy volunteers aged 16 to 65 years.

Interventions: The subjects were administered 400 µg of salbutamol via a pMDI alone, via a pMDI plus a small-volume plastic spacer, or via a pMDI plus a cardboard tube.

Measurements and results: Blood samples for plasma salbutamol concentrations were taken at 5 min, 10 min, and 20 min after inhalation, to measure lung bioavailability as a surrogate for relative lung dose. The addition of the plastic spacer resulted in a significantly higher maximal plasma salbutamol concentration (CMAX) and average plasma salbutamol concentration (CAV) than the pMDI used alone. This amounted to a 1.48-fold (32%) difference (95% confidence interval [CI], 1.03 to 2.13) for CMAX and a 1.42-fold (30%) difference (95% CI, 1.01 to 2.00) for CAV. There was no significant difference in the CMAX or CAV comparing the addition of the cardboard tube with the plastic spacer or the pMDI alone.

Conclusions: Using a chlorofluorocarbon-free pMDI with a plastic spacer produced statistically, but not biologically, significant greater lung delivery of salbutamol. If a spacer is required for reasons other than increasing delivered drug dose, then the addition of a readily available cardboard tube will fulfill many of the required functions with no expense to the patient.

Key Words: hydrofluoroalkane • inhaler • salbutamol • spacer


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Spacer devices are prescribed for three main reasons when administering inhaled ß2-agonists: as a holding chamber to obviate poor technique and coordination with a pressurized metered-dose inhaler (pMDI), to negate the "cold-Freon" effect on the oropharynx, or to improve drug delivery to the lungs. Spacers may be used for delivering salbutamol either for everyday maintenance therapy or in the setting of acute severe asthma instead of a nebulizer.1

We therefore evaluated a readily available, simple cardboard tube (approximately 10 cm in length by 4 cm in width; volume, 115 mL), as found in the center of a toilet-paper roll, and a polycarbonate small-volume (145 mL) spacer (AeroChamber; 3M Pharmaceuticals; Loughborough, UK). With chlorofluorocarbon pMDIs currently being phased out, we chose to use a hydrofluoroalkane-134a (HFA) formulation of salbutamol with the two spacer devices. We compared the lung deposition from the devices using the early pharmacokinetic profile of salbutamol in the first 20 min after inhalation, which represents bioavailability from the lungs.2 In this situation, there is no need to administer oral charcoal to block gut absorption, as the fraction absorbed from the GI tract contributes 0.3% to the overall bioavailability over the first 30 min after inhalation.3


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Twelve healthy volunteers (mean [SE] age, 23 [1.4] years) were studied in a randomized, crossover fashion. The study was single (investigator) blind in terms of the statistical analysis. Ethical approval was obtained from the Tayside Committee on Medical Research Ethics. Volunteers were administered 400 µg of the HFA formulation of salbutamol (100 µg per actuation) via a pMDI alone, via a pMDI with the cardboard tube, or via a pMDI with the plastic spacer. The volunteers were instructed to hold the pMDI in one end of the cardboard tube, placing the other end against their mouth. Inhaler techniques for the pMDI alone and with the plastic spacer were according to the instructions of the manufacturers. The plastic spacer was prewashed in detergent and drip-dried before use, and preprimed with 50 actuations of the salbutamol pMDI to reduce the static charge.

Study visits were separated by at least 72 h. Inhaler technique was reinforced and the inhalations performed under supervision at each visit. At each visit, a 5-mL blood sample was taken with the subjects supine at 5 min, 10 min, and 20 min after inhalation for measurement of plasma salbutamol concentration.

Salbutamol Assay
Plasma salbutamol was assayed by high-performance liquid chromatography (HPLC). The extraction process used silica adsorption with chromatography followed by reverse-phase ion pair HPLC and electrochemical detection. The analytical imprecision for plasma salbutamol (at 5 ng/mL) was 7.8% (intra-assay) and 6.7% (interassay). The HPLC detection limit for salbutamol was 0.2 ng/mL.

Statistical Analysis
It was considered that a twofold (50%) increase in the maximal plasma salbutamol concentration (CMAX), the primary end point, represented a clinically relevant improvement in relative lung dose. The study was therefore powered at the 80% level in order to detect a 50% difference in salbutamol concentration with the sample size of 12 volunteers using a crossover design with the {alpha} error set at 0.05 (two tailed). Salbutamol concentrations were calculated as CMAX and average salbutamol concentration (CAV) over 5 to 20 min. The results were analyzed using software (Statgraphics; STSC Software Publishing Group; Rockville, MD). Comparisons were made by analysis of variance followed by Bonferroni’s multiple-range testing (set at 95% confidence limits) to establish where the differences were significant. In order not to confound the {alpha} error, a probability value of p < 0.05 (two tailed) was considered significant. The time profile for subject 10 after administration of salbutamol from the pMDI alone (after rechecking) was as follows: concentration at 5 min, 2.8 ng/mL; concentration at 10 min, 13.0 ng/mL; and concentration at 20 min, 3.3 ng/mL. This middle reading meant that the CMAX and CAV for this subject were well outside the range of the distribution for the other 11 subjects. We therefore excluded these data from the analysis.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The plastic spacer produced significantly (p < 0.05) higher salbutamol CMAX and CAV than the pMDI used alone (Fig 1 , 2 ). This amounted to a geometric mean 1.48-fold (32%) difference (95% confidence interval [CI], 1.03 to 2.13) for CMAX and a 1.42-fold (30%) difference (95% CI, 1.01 to 2.00) for CAV. There was no significant difference in the CMAX or CAV comparing the cardboard tube to the plastic spacer or to the pMDI alone. For the plastic chamber vs the cardboard tube, this amounted to a 1.22-fold (18%) difference (95% CI, 0.84 to 1.76) for CMAX and a 1.21-fold (17%) difference (95% CI, 0.86 to 1.71) for CAV. For the cardboard tube vs pMDI alone, there was a 1.22-fold (18%) difference (95% CI, 0.84 to 1.75) for CMAX and a 1.17-fold (15%) difference (95% CI, 0.83 to 1.64) for CAV.



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  		Figure 1.. Time profile for geometric CAV. CAV is also shown with 95% CI. Closed circles = HFA-pMDI alone; open squares = HFA-pMDI plus plastic spacer; closed triangles = HFA-pMDI plus cardboard tube. * = pMDI plus plastic spacer (p < 0.05) from pMDI alone.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The 32% difference in the HFA-salbutamol relative lung dose (as CMAX) with the plastic spacer may be clinically relevant for patients with more severe asthma, where a 400-µg dose represents the steep part of the dose-response curve for bronchodilatation.4 We have shown2 that a prewashed, unprimed 750-mL spacer resulted in a 2.0-fold (50%) increase in relative lung dose as CMAX compared to HFA-salbutamol via pMDI alone, while a prewashed, unprimed plastic spacer (AeroChamber) produced a 1.3-fold (23%) increase, also in healthy volunteers. The effect of spacer priming may have improved the relative lung dose in the present study (32%) by reducing static charge in the plastic spacer.5 6 Our data contrast with in vitro impactor data with HFA-salbutamol, where adding the plastic spacer had no significant impact on respirable dose delivery.7 8 This reinforces the importance of the real-life patient-device interaction, which cannot be evaluated by in vitro experiments.

There are other potential advantages to the plastic spacer over the cardboard tube. The AeroChamber device has a one-way valve at the mouthpiece end and a proper seal at the portal for the pMDI actuator. This eliminates drug loss and facilitates the use of the spacer as a holding chamber for tidal breathing (eg, in acute asthma). In contrast, the cardboard tube is open at both ends, which results in a degree of drug wastage and may explain the numerically (but not significantly) lower relative lung dose than the plastic spacer. However, the pMDI and the plastic spacer in this study were used under optimal operating conditions that would be unlikely to occur in real life.

The benefits of a spacer are not confined to increasing lung dose, and in this respect, the cardboard tube is a suitable option. Our results showed that it was certainly no worse in its lung delivery than optimal use of pMDI alone. Other homemade spacer devices have been suggested. In one study,9 a 500-mL plastic bottle was as effective as a conventional spacer at producing acute bronchodilation. We realize that our data were obtained from healthy subjects, although it is likely that while the relative ratios for CMAX would be similar in asthmatic patients, the absolute magnitude of CMAX for each device would be smaller.10

We would therefore suggest that in situations where it is not possible to prescribe a spacer device because of, for example, lack of availability or economic reasons, then the use of a readily available cardboard toilet-paper tube will perform many of the functions required with no detrimental effect on lung delivery.



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  		Figure 2.. Individual values for CMAX also showing geometric mean and 95% CI. * = pMDI plus plastic spacer (p < 0.05) from pMDI alone.

 

   Acknowledgements
 
The authors acknowledge the technical assistance of Mr. Stephen McLaren.


   Footnotes
 
Abbreviations: CAV = mean plasma salbutamol concentration; CI = confidence interval; CMAX = maximal plasma salbutamol concentration; HFA = hydrofluoroalkane-134a; HPLC = high-performance liquid chromatography; pMDI = pressurized metered-dose inhaler

This study was funded by a University of Dundee departmental grant.

Received for publication June 20, 2000. Accepted for publication November 2, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Raimondi, AC, Schottlender, J, Lombardi, D, et al (1997) Treatment of acute severe asthma with inhaled albuterol delivered via jet nebulizer, metered dose inhaler with spacer, or dry powder. Chest 112,24-28[Abstract/Free Full Text]
  2. Lipworth, BJ, Clark, DJ (1998) Early lung absorption profile of non-CFC salbutamol via small and large volume plastic spacer devices. Br J Clin Pharmacol 46,45-48[ISI][Medline]
  3. Chrystyn, H, Corlett, SA, Silkstone, V (1996) Lung bioavailability of generic and innovator salbutamol MDIs [letter]. Thorax 51,658[Medline]
  4. Clark, DJ, Lipworth, BJ (1997) Dose-response of inhaled drugs in asthma: an update. Clin Pharmacokinet 32,58-74[ISI][Medline]
  5. Clark, DJ, Lipworth, BJ (1996) Effect of multiple actuations, delayed inhalation and antistatic treatment on the lung bioavailability of salbutamol via a spacer device. Thorax 51,981-984[Abstract]
  6. Anhoj, J, Bisgaard, H, Lipworth, BJ (1999) Effect of electrostatic charge in plastic spacers on the lung delivery of HFA-salbutamol in children. Br J Clin Pharmacol 47,333-336[CrossRef][ISI][Medline]
  7. Purewal, TS, Patel, N, Warren, DA (1996) The non-CFC metered dose inhaler performance with a spacer device [abstract]. Thorax 51(suppl 3),A75
  8. Barry, PW, O’Callaghan, C (1997) In vitro comparison of the amount of salbutamol available for inhalation from different formulations used with different spacer devices. Eur Respir J 10,1345-1348[Abstract]
  9. Zar, HJ, Brown, G, Donson, H, et al (1999) Home-made spacers for bronchodilator therapy in children with acute asthma: a randomised trial. Lancet 354,979-982[CrossRef][Medline]
  10. Lipworth, BJ, Clark, DJ (1997) Effects of airway calibre on lung delivery of nebulised salbutamol. Thorax 52,1036-1039[Abstract]




This Article
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