Applicability of an Ultrasonic Nebulization System for the Airways Delivery of Beclomethasone Dipropionate in a Murine Model of Asthma
- 208 Downloads
We have assessed the use of an ultrasonic nebulization system (UNS), composed of ultrasonic nebulizer and diffusion dryer filled with charcoal, for the effective delivery of beclomethasone to the airways in a murine asthma model.
Solution of beclomethasone in ethanol was aerosolized using an ultrasonic nebulizer. Passage of the aerosol through a drying column containing charcoal and deionizer produced dry beclomethasone particles. Particles were delivered to BALB/c mice placed in a whole-body exposition chamber 1 h before intranasal challenge with ovalbumine. Efficacy of beclomethasone delivery was evaluated by examining bronchoalveolar lavage fluid (BALF) cytology.
Effect of three UNS system parameters on aerosol particle size was investigated. The critical parameter affecting the size of dry particles was beclomethasone concentration in aerosolized solution and solution flow rate while power level of ultrasonic nebulizer generator had no effect. Administration of beclomethasone at calculated dose of 150 μg/kg to mice significantly decreased total cell number and relative eosinophil number in BALF.
The UNS system produces a monodisperse aerosol that can be used for inhalative delivery of poorly water soluble substances to experimental animals. The UNS system minimizes formulation requirements and allows rapid and relatively simple efficacy and toxicity testing in animals.
Key wordsasthma beclomethasone dipropionate dry powder inhalation delivery mice ultrasonic nebulization system
bronchoalveolar lavage fluid
chronic obstructive pulmonary disease
dry powder inhaler
- FPF(<2.20 μm)
fine particle fraction <2.20 μm aerodynamic diameter
geometric standard deviation
pressurized metered-dose inhaler
ultrasonic nebulization system
This work was supported by PLIVA Research Institute, Inc. Authors wish to thank dr. Michael J. Parnham for critical reading of the manuscript. Authors also wish to thank Ms. Anica Pešut and Milka Horvatinčić and Mr. Željko Osman for their excellent technical assistance.
- 3.N. Pearce, J. Sunyer, S. Cheng, S. Chinn, B. Bjorksten, M. Burr, U. Keil, H. R. Anderson, and P. Burney. Comparison of asthma prevalence in the ISAAC and the ECRHS. ISAAC Steering Committee and the European Community Respiratory Health Survey. International Study of Asthma and Allergies in Childhood. Eur. Respir. J. 16:420–426 (2000).PubMedCrossRefGoogle Scholar
- 5.S. Newman, and S. Clarke. Aerosols in medicine: principles, diagnosis and therapy. In F. Moren, M. Newhouse, and M. Dolovich (eds), Aerosol in Therapy, Elsevier, Amsterdam, 1985.Google Scholar
- 7.A. D. Perera, C. Kapitza, L. Nosek, R. S. Fishman, D. A. Shapiro, T. Heise, and L. Heinemann. Absorption and metabolic effect of inhaled insulin: intrapatient variability after inhalation via the Aerodose insulin inhaler in patients with type 2 diabetes. Diabetes Care 25:2276–2281 (2002).PubMedCrossRefGoogle Scholar
- 21.L. W. Wattenberg, T. S. Wiedmann, R. D. Estensen, C. L. Zimmerman, A. R. Galbraith, V. E. Steele, and G. J. Kelloff. Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipropionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis 21:179–182 (2000).PubMedCrossRefGoogle Scholar
- 25.S. Pham, and T. S. Wiedmann. Production of aerosol particles from organic solutions for respiratory delivery to animals. Pharm. Res. 14:S133 (1997).Google Scholar
- 27.J. P. Mitchell, M. W. Nagel, K. J. Wiersema, and C. C. Doyle. Aerodynamic particle size analysis of aerosols from pressurized metered-dose inhalers: comparison of Andersen 8-stage cascade impactor, next generation pharmaceutical impactor, and model 3321 Aerodynamic Particle Sizer aerosol spectrometer. AAPS PharmSciTech 4:E54 (2003).PubMedCrossRefGoogle Scholar
- 28.A. C. Guyton. The measurements of the respiratory values of laboratory animals. Am. J. Physiol. 150:70–78 (1942).Google Scholar
- 33.M. L. Bartoli, E. Bacci, S. Carnevali, S. Cianchetti, F. L. Dente, A. Di Franco, D. Giannini, M. Taccola, B. Vagaggini, and P. L. Paggiaro. Clinical assessment of asthma severity partially corresponds to sputum eosinophilic airway inflammation. Respir. Med. 98:184–193 (2004).PubMedCrossRefGoogle Scholar
- 37.Operating instrutions for ultrasonic atomizing nozzle systems v1.2, Sono-Tek Co., 2001.Google Scholar
- 43.S. R. Moores, A. Black, B. E. Lambert, P. J. Lindop, A. Morgan, J. Pritchard, and M. Walsh. Deposition of thorium and plutonium oxides in the respiratory tract of the mouse. In S. L. Sanders, F. T. Cross, G. E. Dagle, and J. A. Mahaffey (eds), Proceedings of the Nineteenth Annual Hanford Life Sciences Symposium, Technical Information Center, Department of Energy, Washington, District of Columbia, 1980, pp. 103–118.Google Scholar
- 48.H. Kuss, N. Hoefgen, S. Johanssen, T. Kronbach, and C. Rundfeldt. In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyo xylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration. J. Pharmacol. Exp. Ther. 307:373–385 (2003).PubMedCrossRefGoogle Scholar