Pulmonary Pharmacology & Therapeutics (1997) 10, 211–214 PULMONARY PHARMACOLOGY & THERAPEUTICS
Lung Delivery of Salbutamol Given by Breath Activated Pressurized Aerosol and Dry Powder Inhaler Devices B. J. Lipworth∗, D. J. Clark Department of Clinical Pharmacology, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK
SUMMARY: Poor inhalation technique is prevalent in asthmatics using standard metered dose inhalers (MDI). Both dry powder inhalers (DPI) and breath activated MDIs offer a solution to this problem. Our aim was to compare the lung delivery of salbutamol from two DPIs, Diskhaler and Diskus (Accuhaler), and the Easi-Breathe breath activated MDI. Ten healthy volunteers mean (SEM) age 24.0 years (1.7) were studied in a randomized single (investigator) blind crossover design. Single 1200 lg nominal doses of salbutamol via Diskhaler and Diskus (6 sequential 200 lg puffs) and Easi-Breathe (12 sequential 100 lg puffs) were given over 6 min. Mouth rinsing was performed after every inhalation sequence. Lung delivery was evaluated by measuring the early lung absorption profile of salbutamol at 5, 10, 15 and 20 min after inhalation, with calculation of peak (Cmax) and average over 20 min (Cav) concentration (ng/ml). Both the Diskhaler and the Easi-Breathe produced significantly greater salbutamol Cmax and Cav than Diskus (as mean and 96% CI for difference vs. Diskus): [Cmax] Diskus 3.22 vs. Diskhaler 4.35 (95% CI 0.19 to 2.08), vs. Easi-Breathe 3.98 (95% CI −0.18 to 1.71). [Cav] Diskus 2.62 vs. Diskhaler 3.95 (95% CI 0.52 to 2.14), vs. Easi-Breathe 3.52 (95% CI 0.09 to 1.71). For Cav this amounted to a 1.51-fold difference (95% CI 1.35 to 1.68) between Diskhaler vs. Diskus, and a 1.36-fold difference (95% CI 1.03 to 1.69) for Easi-Breathe vs. Diskus. In conclusion we found that, in vivo, the Diskus DPI produced significantly lower lung delivery for the same nominal dose of salbutamol than either Diskhaler DPI or the Easi-Breathe pressurised aerosol. This shows that breath activated inhaler devices may have different in vivo deposition characteristics for delivering the same drug. 1997 Academic Press Limited
KEY WORDS: Salbutamol, Bioavailability, Deposition, Breath activated, Dry powder inhaler, Pressurized metered dose aerosol, Chlorofluorocarbon.
An important clinical issue with short-acting bagonists, such as salbutamol, is whether significant differences exist between inhaler devices in the first few minutes after inhalation, as this might conceivably influence the acute bronchodilator response. The pharmacokinetic profile of unchanged salbutamol in the first 20 min after inhalation represents the bioavailability from the lung but not the gastrointestinal tract, with the latter moiety contributing 0.3% to the overall bioavailability from an inhaled dose over this time period.6,7 This is because the gastrointestinal absorption occurs much later than lung absorption, and there is no buccal absorption of salbutamol.8 Hence this method may be applied to compare the deposition from different inhaler devices.9–12 As far as we are aware, there is no published data available comparing the lung deposition of salbutamol from the Diskhaler and the Diskus (Accuhaler), and we were therefore interested in establishing whether
INTRODUCTION Poor inhaler technique is a common problem with asthmatics, particularly when using metered-dose inhalers (MDI).1–3 To overcome this problem breath activated MDIs have been developed. In one study there was a three-fold increase in salbutamol delivery, from 7% to 21% comparing a breath activated pressurized aerosol with a standard metered-dose inhaler, in patients with poor inhaler technique.4 Another solution is to utilize dry powder inhalers (DPI), which are also by design, breath activated. Dry powder inhalers have the additional advantage of being chlorofluorocarbon (CFC) free, and as CFC containing inhalers are to be phased out in the near future this type of inhaler is likely to play an increasingly prominent role in asthma control.5 ∗ Author for correspondence. 1094–5539/97/040211+04 $25.00/0/pu970093
1997 Academic Press Limited
B. J. Lipworth and D. J. Clark
METHODS Ten healthy volunteers mean (SEM) age 24.0 years (1.7), FEV1 103.2% (2.5) predicted, were studied in a randomized single (investigator) blind crossover design. Single 1200 lg nominal doses of salbutamol via Diskhaler or Diskus (Accuhaler) (Allen & Hanbury’s, Uxbridge, UK) (six sequential 200 lg puffs) and EasiBreathe (Allen & Hanbury’s, Uxbridge, UK) (12 sequential 100 lg puffs) were given over 6 min. Mouth rinsing was performed after every inhalation sequence to obviate gastrointestinal absorption. The subjects were studied on 3 days each separated by 1 week. They were carefully instructed in inhalation technique as described by the manufacturers literature. Plasma salbutamol (ng/ml) was measured at 5, 10, 15 and 20 min. Systemic b2-responses were measured as plasma potassium, tremor and heart rate taken at baseline, 5, 10, 15 and 20 min (all measurements made with the subject supine). The study was approved by the Tayside Committee for Medical Ethics and informed consent as obtained from all subjects.
MEASUREMENTS Finger tremor was measured with an accelerometer transducer (Entran, Ealing, UK).13 Heart rate was measured from standard lead II of an electrocardiogram monitor. Plasma potassium was assayed by flame photometry using an IL943 analyser (Instrumentation Laboratory Ltd, Warrington, UK). The intra-assay and interassay values for analytical imprecision were 0.41% and 1.04% respectively. Plasma salbutamol was assayed by high performance liquid chromatography (HLPC), the extraction process using silica adsorption with chromotography followed by reverse phase ion pair HPLC and electrochemical detection. The analytical imprecision for plasma salbutamol was 7.8% (intraassay) and 6.7% (interassay). The HPLC detection limit for salbutamol was 0.2 ng/ml. Statistical analysis The results were analysed by using the ‘Statgraphics’ statistical software package (STSC Software Publishing Group, Rockville, USA). Salbutamol levels were calculated as peak (Cmax) and average (Cav) over
4.5 Plasma salbutamol (ng/ml)
the more modern Diskus would differ significantly in terms of salbutamol lung bioavailability. We also studied the Easi-Breathe pressurized aerosol device, which offers a CFC containing breath activated alternative to the dry powder inhalers.
3 2.5 2 1.5 1 0.5 0 25 (b)
Heart rate (beats/min)
10 15 Minutes
Fig. 1 Values are shown for mean plasma salbutamol concentration (a) and for the increase in heart rate (0–20 min) after inhalation of salbutamol (b). The average (Av) for all time points (0–20 min) is also shown with SEM. Asterisk denotes a significant difference between either Diskhaler or Easi-Breathe compared with Diskus P<0.05. Key: Χ Diskhaler; Β EasiBreathe, Μ Diskus.
0–20 minutes. For all parameters, comparisons were made by multifactorial analysis of variance (MANOVA) and Duncan’s multiple range testing was used to establish where there differences were significant. A probability value of P<0.05 (two-tailed) was considered as being of significance.
RESULTS Both the Diskhaler and the Easi-Breathe produced significantly greater salbutamol Cmax and Cav than Diskus, as shown in Figure 1 and Table 1 (as mean and 95% CI for difference vs. Diskus): [Cmax] Diskus 3.22 vs. Diskhaler 4.35 (95% CI 0.19 to 2.08), vs. Easi-Breathe 3.98 (95% CI −0.18 to 1.71). [Cav] Diskus 2.62 vs. Diskhaler 3.95 (95% CI 0.52 to 2.14), vs. EasiBreathe 3.52 (95% CI 0.09 to 1.71). This amounted to a 1.51-fold difference (95% CI 1.35 to 1.68) between Diskhaler and Diskus in Cav, and a 1.36-fold difference (95% CI 1.15 to 1.56) for Cmax. Comparing EasiBreathe and Diskus we found a 1.36-fold difference
Lung Delivery of Salbutamol
Table 1 Average and maximal values for plasma salbutamol, fall in plasma potassium and increase in heart rate (mean and 95% CI for mean) Salbutamol (ng/ml)
Delta potassium (mmol/l)
Delta heart rate (beats/min)
Diskhaler Easi-Breathe Diskus
3.95∗ (3.50 to 4.40) 3.52∗ (3.07 to 3.97) 2.62 (2.17 to 3.07)
0.52∗ (0.38 to 0.67) 0.40 (0.26 to 0.55) 0.30 (0.15 to 0.44)
19.9∗ (14.3 to 25.5) 20.4∗ (14.8 to 26.0) 10.4 (4.8 to 16.0)
Diskhaler Easi-Breathe Diskus
4.35∗ (3.82 to 4.88) 3.98∗ (3.45 to 4.51) 3.22 (2.68 to 3.74)
0.63∗ (0.48 to 0.79) 0.49 (0.33 to 0.65) 0.37 (0.22 to 0.53)
25.2 (18.6 to 31.8) 27.7∗ (21.2 to 34.3) 16.7 (10.1 to 23.3)
Diskhaler Easi-Breathe Diskus
15 (5 to 20) 10 (5 to 10) 10 (5 to 20)
15 (10 to 20) 20 (15 to 20) 15 (10 to 20)
15 (10 to 20) 10 (5 to 20) 10 (5 to 20)
∗ Asterisks denotes where either Diskhaler or Easi-Breathe are significantly different from Diskus P<0.05. Values are also shown for tmax as median and range.
(95% CI 1.03 to 1.69) for Cav and a 1.24-fold difference (95% CI 0.98 to 1.50) for Cmax. There were no significant differences in Cmax or Cav between Diskhaler and Easi-Breathe. Similar differences were found for the systemic b2responses of heart rate and potassium (Table 1) For tremor the same trend was seen, however, the differences were not significant (mean values, log units); average: Diskhaler (0.55), Easi-Breathe (0.48), Diskus (0.47).
DISCUSSION We found that for the same nominal dose of salbutamol the more modern Diskus (Accuhaler) dry powder inhaler produced significantly lower lung bioavailability than the Diskhaler dry powder device, which amounted to a 1.51-fold difference in Cav. Likewise, the Easi-Breathe breath activated MDI also produced greater lung bioavailability than the Diskus amounting to a 1.36-fold difference in Cav. This illustrates that breath activated inhaler devices may have different in vivo deposition characteristics for delivering the same drug. We would advocate a degree of caution in extrapolating our pharmacokinetic data in healthy volunteers to what happens in asthmatic patients in terms of the clinical efficacy response. The evaluation of the early lung absorption profile is likely to represent peripheral delivery of salbutamol. In this respect we have previously shown in asthmatics that when comparing two different nebulisers, improved in vitro delivery of respirable particles was mirrored by similar differences in the early lung absorption profile of salbutamol, and was associated with an improved bronchodilator response.14 It is interesting to contrast the salbutamol pharmacokinetic profile with the dynamic systemic b2responses, not only looking at where differences exist,
but also the magnitude and variance of the differences. On inspecting the confidence intervals for the different inhalers it is evident that the variance for salbutamol responses is less than for dynamic responses. This illustrates the point that plasma salbutamol measures are more sensitive at detecting differences in bioavailability between inhaler devices than using dynamic b2-responses. We have also previously demonstrated this in a study comparing salbutamol metered-dose aerosol and dry powder inhalers using the same study design as described above, with the exception that we only measured dynamic responses at 20 min.10 We found that even when there was a significant 1.32-fold difference in salbutamol Cav between CFC free and CFC containing aerosol devices, the dynamic b2-responses measured at 20 min were not statistically significant, although they did follow the same trend. In the present study we evaluated the eight-place Diskhaler for salbutamol. In an abstracted study evaluating the pharmacokinetics of fluticasone propionate from Diskus and four-place Diskhaler, both devices were found to produce comparable lung delivery.15 This disparity in results emphasises the importance of evaluating specific drug and device combinations. We believe that these results address an important clinical issue with short acting b2-agonists, that is, their initial lung delivery profile and onset of action, which may be relevant to inhaler use during an episode of acute bronchoconstriction. Our results confirm that, even as early as 5 min after inhalation, that significant differences are seen between these inhalers with both pharmacokinetic and dynamic b2-responses. However, the explanation as to why the more modern Diskus delivers less salbutamol than the Diskhaler remains unclear. Further studies are also required to evaluate whether such differences in peripheral lung deposition translate into similar differences in bronchodilator response, particularly in patients with impaired peripheral aerosol delivery due to severe airway obstruction.
B. J. Lipworth and D. J. Clark
This study was supported by a University Grant and received no commercial pharmaceutical sponsorship. 10.
REFERENCES 11. 1. Crompton G K. Problems patients having used pressurised aerosol inhalers. Eur J Respir Dis 1982; 63 (Suppl 119): 101–104. 2. Pedersen S. Choice of inhalation therapy in asthmatics. Eur Respir Rev 1994; 4: 86–89. 3. Siafakas N M, Bouros D. Choice of inhalation therapy in adults. Eur Respir Rev 1994; 4: 78–81. 4. Newman S P, Weisz A W B, Talaee N, Clark S W. Improvement of drug delivery with a breath actuated pressurised aerosol for patients with poor inhaler technique. Thorax 1991; 46: 712–716. 5. Partridge MR. Metered-dose inhalers and CFCs: What respiratory physicians need to know. Respir Med 1994; 88: 645–647. 6. Lipworth B J. Pharmacokinetics of inhaled drugs. Br J Clin Pharmacol 1996; 42: 697–705. 7. Chrystyn H, Corlett S A, Silkstone V. Lung bioavailability of generic and innovator salbutamol MDIs. Thorax 1996; 51: 658. 8. Lipworth B J, Clark R A, Dhillon D P, Moreland T A, Struthers A D, Clark G A, McDevitt D G. Pharmacokinetics, efficacy and adverse effects of sublingual salbutamol in
patients with asthma. Eur J Clin Pharmacol 1989; 37: 567–571. Newnham D M, McDevitt D G, Lipworth B J. Comparison of the extrapulmonary b2-adrenoceptor responses and pharmacokinetics of salbutamol given by standard metered dose inhaler and modified actuator devices. Br J Clin Pharmacol 1993; 36: 445–450. Clark D J, Lipworth B J. Lung bioavailability of chlorofluorocarbon containing formulations of salbutamol. Br J Clin Pharmacol 1996; 41: 247–249. Clark D J, Gordon-Smith J, McPhate G, Clark G, Lipworth B J. Lung bioavailability of generic and innovator salbutamol metered dose inhalers. Thorax 1996; 51: 325–326. Clark D J, Lipworth B J. Effect of multiple actuations, delayed inhalation and antistatic treatment on the lung bioavailability of salbutamol via a spacer device. Thorax 1996; 51: 981–984. Lipworth B J, McDevitt D G. Beta-adrenoceptor responses to inhaled salbutamol in normal subjects. Eur J Clin Pharmacol 1989; 36: 239–245. Newnham D M, Lipworth B J. Nebuliser performance, pharmacokinetics, airways and systemic effects of salbutamol given via a novel nebuliser delivery system (Ventstream). Thorax 1994; 49: 762–766. Mackie A E, Falcoz C, McDowell J E, Moss J, Ventresca G P, Bye A. Pharmacokinetics of fluticasone propionate inhaled from the diskhaler and the diskus powder devices in healthy subjects. Br J Clin Pharmacol 1997; 43: 540P–541P.
Date received: 16 April. Date revised: 19 November. Date accepted: 16 December.