Pulmonary Pharmacology & Therapeutics 18 (2005) 151153

www.elsevier.com/locate/ypupt

Short communication

In vitro comparison of nebulised budesonide (Pulmicort Respulesw)

and beclomethasone dipropionate (Clenilw per Aerosol)*
A. Vaghia, E. Bergb,*, S. Liljedahlb, J.O. Svenssonb
a
Azienda Ospedaliera G. Salvini, Garbagnate, Italy
AstraZeneca R&D, Scheelvagen 2, Lund S-221 87, Sweden

Received 3 August 2004; revised 15 October 2004; accepted 23 October 2004

Abstract
This study compared the in vitro performance of two inhaled corticosteroid products for nebulisation, Pulmicort Respulesw (budesonide
0.5 mg/mL) and Clenilw per Aerosol (beclomethasone dipropionate (BDP) 0.4 mg/mL). Each product was used in combination with three
different nebulisers (2 mL/test, 5 min run time) and the dose to the lungs was determined according to standard methods. The shape of the
suspended particles in each product was studied using scanning electron microscopy (SEM). Overall, a higher fine particle dose was achieved
with Pulmicort Respulesw versus Clenilw per Aerosol, with estimated dose to the lungs of 814 and 36% of nominal dose, respectively.
SEM showed that budesonide particles were small, typically w23 mm in diameter, whereas those of BDP were needle-shaped and up to
w10 mm long. The more favourable particle shape and size of suspended budesonide may explain the higher fine particle dose with Pulmicort
Respulesw versus Clenilw per Aerosol.
q 2004 Elsevier Ltd. All rights reserved.

1. Introduction
The use of inhaled corticosteroids such as budesonide
and beclomethasone dipropionate (BDP) represents the
cornerstone of asthma management [1], enabling many
asthmatic patients who are otherwise limited by their
disease to enjoy a near normal or normal lifestyle. These
agents are available in different formulations, from metereddose and dry powder inhalers to products for nebulisation, to
meet the diverse requirements of the heterogeneous
population of asthmatic patients. However, one potential
limitation of such product diversity is that differences in
formulation technology can impact upon drug delivery to
the lungs [2], which may lead to potential differences in
clinical response. Comparative studies are therefore important to determine the performance characteristics of available
products for inhalation treatment of asthma, as any
differences may have implications for clinical efficacy.
*

This study was supported by AstraZeneca R&D, Lund, Sweden.

* Corresponding author. Tel.: C46 46 336162; fax: C46 46 337168.
E-mail address: elna.berg@astrazeneca.com (E. Berg).

1094-5539/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pupt.2004.10.004

The aim of the present study, therefore, was to compare

the in vitro performance of two inhaled corticosteroid
products for nebulisation, namely Pulmicort Respulesw
(budesonide 0.5 mg/mL; AstraZeneca) and Clenilw per
Aerosol (BDP 0.4 mg/mL; Chiesi).

2. Methods
Different conventional jet nebuliser devices were used in
this study to simulate the types of conditions under which
the study products may be administered in routine practice.
Three nebulisers were used (experiments performed in
triplicate): Cirrusw (relatively small droplet size 23 mm;
Intersurgical), Pari LC Plusw (medium droplet size 45 mm;
Pari), and Omron COMP Air Elite NE-C21w (large droplet
size 68 mm; Medel; in Italy marketed as Clenny). The
Cirrusw and Pari LC Plusw nebulisers were used with a
compressor (Pari Masterw; Pari), whereas the Omron
nebuliser has a built-in compressor. Each nebuliser was
connected to a breathing simulator (Pari Compasw; Pari);
experimental conditions were: tidal volume, 500 mL;

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A. Vaghi et al. / Pulmonary Pharmacology & Therapeutics 18 (2005) 151153

pore size 0.2 mm. A piece of the filter with residue was cut
out, fixed to a metal holder, sputtered with gold and studied
in a SEM, JEOL JSM-5200 scanning microscope, operated
at 15 kV. Representative micrographs of the drug particles,
the residue on the filter, were recorded digitally.

3. Results and discussion

Fig. 1. In vitro particle size distribution (meanGSD) for Pulmicort

Respulesw (budesonide) and Clenilw per Aerosol (beclomethasone
dipropionate (BDP)) expressed as a percentage of the nominal dose when
administered using three different nebuliser devices.

frequency, 15 breaths/min; and 1:1 inhalation to exhalation

ratio (i.e. 2 s inhalation, 2 s exhalation). These settings were
in accordance with the CEN-standard for nebuliser testing
[3]. Each nebuliser was charged with 2 mL product and run
for 5 min, after which the amount of drug on the inhalation/
exhalation filters and contained within the nebuliser residue
was quantified using established methods.
The test was performed as described in the European
Standard, except that clinical formulations were used
instead of sodium fluoride [3]. Budesonide and BDP were
quantified by liquid chromatography (LC) method, using
internal standard (fluocinolone acetonide), ethanol/water
(43:57) mobile phase, a Supelcosil LC-18 column (5 mm
particles, 5!0.46 cm), and UV detection at 254 nm.
Particle size distribution of the nebulised suspensions
was evaluated in tandem experiments using an Andersen
impactor with the nebuliser outlets centred into the USPthroat (23 mm overlap).
The shape and size of the suspended particles in the two
products was investigated by scanning electron microscopy
(SEM). In brief, a container with suspension was shaken,
opened and transferred to a glass beaker. While stirring,
0.2 mL of Clenilw or 0.4 mLw of Pulmicort suspension was
filtered through an isopore polycarbonate membrane filter,

In this study we sought to compare the in vitro

performance characteristics of two available corticosteroid-containing products for nebulisation, namely Pulmicort
Respulesw (budesonide) and Clenilw per Aerosol (BDP).
Analysis of inhalation filters showed that for both products,
drug deposition (mean (SD)) was lowest for Cirrusw
(budesonide, 12 (1)% of nominal dose; BDP, 10 (2)% of
nominal dose) and highest for the Omron nebuliser
(budesonide, 29 (2)% of nominal dose; BDP, 37 (1)% of
nominal dose). The corresponding values for the Pari LC
Plusw was 27 (3)% (BDP) and 27 (1)% (budesonide) of
nominal dose. These findings are consistent with the droplet
size produced by each nebuliser, from relatively small with
Cirrusw to large with the Omron nebuliser. For both
products, the exhaled amount as a percentage of nominal
dose was comparable for the Cirrusw and Pari LC Plusw
nebulisers (1113%). Data are not available for the Omron
nebulizer as it cannot be connected to an exhalation filter.
As expected, the major proportion of added drug was
retained in the nebuliser device and was comparable for the
two products (Cirrusw, w75%; Pari LC Plusw, w55%; and
Omron, w50%). The remainder was accounted for by loss
to the environment as a result of nebuliser leakage.
In vitro findings for particle size distribution for the two
products evaluated with the three nebuliser devices are
summarised in Fig. 1. Overall, dose quality (% of dose in the
respirable range i.e. !5 and!3 mm) was highest for
Cirrusw and lowest for the Omron nebuliser, irrespective
of administered product. In all cases the fine particle dose
(!5 mm) was higher for Pulmicort Respulesw (budesonide)
than for Clenilw per Aerosol (BDP), the difference being
even more pronounced for the fraction !3 mm (Table 1).
Combining these results with those for the dose on the
inhalation filter it was possible to estimate comparative

Table 1
Summary of in vitro findings (mean [SD]) for particle size distribution of Pulmicort Respulesw (budesonide) and Clenilw per Aerosol (beclomethasone
dipropionate (BDP)) following administration by three nebuliser devices
Nebuliser
Cirrusw

Particles !5 mm (%)a
Particles !3 mm (%)a
MMAD (mm)

Pari LC Plusw

Omron COMP Air Elite NE-C21w

BDP

Budesonide

BDP

Budesonide

BDP

Budesonide

54 (6.3)
23 (3.7)
4.8 (0.5)

71 (4.4)
47 (4.3)
3.3 (0.2)

23 (3.9)
7 (1.1)
7.5 (0.5)

51 (4.9)
32 (4.9)
4.5 (0.6)

8 (1.0)
2 (0.3)
10.0 (0.1)

26 (1.7)
14 (2.0)
7.4 (0.1)

MMAD, mass median aerodynamic diameter.

a
Expressed as a percentage of dose to impactor.

A. Vaghi et al. / Pulmonary Pharmacology & Therapeutics 18 (2005) 151153

153

Respulesw (49 versus 12% for Clenilw per Aerosol).

Given that there is a clear relationship between particle size
and lung deposition and, in turn, clinical effect [4], such
findings indicate that the two products may differ in terms of
clinical efficacy and comparative studies, using doseresponse or dose-reduction designs in symptomatic asthma
patients, are warranted. Such studies should be of high
quality and involve a dose-response or dose-titration phase
rather than attempt to draw conclusions from comparing
individual doses [5].
Scanning electron micrograph analysis showed that
budesonide particles were small, typically about 23 mm
in diameter, whereas those of BDP were needle-shaped and
up to about 10 mm long (Fig. 2). This difference in particle
size is the most probable explanation for the difference in
particle size distribution and drug disposition between the
two products, as outlined above.
In summary, the findings of this study with two
corticosteroid-containing productions for nebulisation treatment of asthma show that there are differences in the fine
particle dose produced by different nebulisers. However, a
higher fine particle dose is consistently achieved with
Pulmicort Respulesw (budesonide) versus Clenilw per
Aerosol (BDP), contributing to a higher estimated dose to
the lungs. This difference is most likely due to a more
favourable particle shape and size of suspended budesonide,
and further studies are warranted to determine whether this
may contribute to improved clinical efficacy.

References
Fig. 2. Scanning electron micrographs of suspended budesonide and
beclomethasone dipropionate particles in the Pulmicort Respulesw and
Clenilw per Aerosol products (micrographs taken August 2003).

doses to the lungsthis was the amount of drug on the

inhalation filter in percentage of nominal dose (reported in
first paragraph under Section 3)!the fraction !5 mm (or
3 mm) from Table 1. Across the three nebulisers, Pulmicort
Respulesw (budesonide) achieved an estimated dose to the
lungs (!5 mm) of 814% compared with 36% of nominal
dose for Clenilw per Aerosol (BDP). Thus, Pulmicort
Respulesw will deliver 23 times more drug to the lungs
than Clenilw per Aerosol. Looking at the dose in droplets !
3 mm, this difference was 27-fold in favour of Pulmicort

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