PulmicortRespule VsBeclomethasone 2005-Vaghi

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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

aAzienda Ospedaliera G. Salvini, Garbagnate, Italy

bAstraZeneca 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 metered-

dose 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 tothe lungs [2], which may lead to potential differences in

clinical response. Comparative studies are therefore import-

ant to determine the performance characteristics of available

products for inhalation treatment of asthma, as any

differences may have implications for clinical efficacy.

The aim of the present study, therefore, was to comparethe 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 intriplicate): 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;

1094-5539/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.

doi:10.1016/j.pupt.2004.10.004

Pulmonary Pharmacology & Therapeutics 18 (2005) 151153

www.elsevier.com/locate/ypupt

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

* Corresponding author. Tel.:C46 46 336162; fax: C46 46 337168.

E-mail address: [email protected] (E. Berg).
http://www.elsevier.com/locate/ypupthttp://www.elsevier.com/locate/ypupt


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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 USP-

throat (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,

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

In this study we sought to compare the in vitro

performance characteristics of two available corticoster-

oid-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 LCPlusw 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,w

50%). The remainder was accounted for by lossto 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 inFig. 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 Pari LC Plusw Omron COMP Air Elite NE-C21w

BDP Budesonide BDP Budesonide BDP Budesonide

Particles !5 mm (%)a 54 (6.3) 71 (4.4) 23 (3.9) 51 (4.9) 8 (1.0) 26 (1.7)

Particles !3 mm (%)a 23 (3.7) 47 (4.3) 7 (1.1) 32 (4.9) 2 (0.3) 14 (2.0)

MMAD (mm) 4.8 (0.5) 3.3 (0.2) 7.5 (0.5) 4.5 (0.6) 10.0 (0.1) 7.4 (0.1)

MMAD, mass median aerodynamic diameter.a Expressed as a percentage of dose to impactor.

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.

A. Vaghi et al. / Pulmonary Pharmacology & Therapeutics 18 (2005) 151153152


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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) fromTable 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, PulmicortRespulesw 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

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 dose-

response or dose-reduction designs in symptomatic asthma

patients, are warranted. Such studies should be of highquality 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 treat-ment 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

[1] Global Initiative for Asthma. Workshop report: strategy for asthma

management and prevention (updated 2002). Scientific information and

recommendations for asthma programs. NIH publication No. 02-3659.

Bethesda, MD: National Institutes for Health; 2002.

[2] Thorsson L, Edsbacker S, Conradson TB. Lung deposition of

budesonide from Turbuhaler is twice that from a pressurized metered

dose inhaler (pMDI). Eur Respir J 1994;7:183944.

[3] European Standard, E N 135441. Respiratory therapy equipment, part

1: nebulizing systems and their components. Brussels, Belgium:

European Committee for Standardization; 2001.

[4] Pauwels R, Newman S, Borgstrom L. Airway deposition and airway

effects of antiasthma drugs delivered from metered-dose inhalers. Eur

Respir J 1997;10:212738.

[5] Beasley R, Sterk PJ, Kerstjens HAM, Decramer M. Comparative

studies of inhaled corticosteroids in asthma. Eur Respir J 2001;17:

57980.

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).

A. Vaghi et al. / Pulmonary Pharmacology & Therapeutics 18 (2005) 151153 153

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PulmicortRespule VsBeclomethasone 2005-Vaghi