What makes flunisolide different among inhaled corticosteroids used for nebulization: a close look at the role of aqueous solubility

  • Ahmad Kantar | kantar@centropediatricotosse.com Pediatric Cough and Asthma Center, Istituti Ospedalieri Bergamaschi, University and Research Hospitals, Bergamo, Italy.


Evidence-based management of bronchial asthma and wheezing in children and adults recommends the employment of inhaled corticosteroids (ICSs). Difficulty in using some inhalation devices for ICS delivery, such as pressurized metered-dose and dry-powder inhalers, is common among young children and in the elderly, and for that reason, they are replaced with nebulizers. We reviewed comparative studies that evaluated funisolide with other ICSs currently available on the market, including beclomethasone dipropionate, fluticasone propionate, and budesonide. Moreover, we assessed the physicochemical properties of these ICSs in determining drug fate in the lung. Data indicate that the flunisolide output in respirable particles by any type of pneumatic nebulizer (traditional, open breath or breath-enhanced) is superior to the output of other ICSs. This is principally attributed to the higher water solubility of flunisolide. Furthermore, in vivo simulation studies demonstrate that the intersubject variability of the inhaled dose among asthmatic children was much greater for suspensions of fluticasone propionate and beclomethasone dipropionate than for those of flunisolide. The physicochemical properties and pharmacokinetic profile of flunisolide favor its employment in nebulization.



PlumX Metrics


Download data is not yet available.


Derendorf H, Nave R, Drollmann A, Cerasoli F, Wurst W. Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur Respir J 2006;28:1042-50. DOI: https://doi.org/10.1183/09031936.00074905

Hubner M, Hochhaus G, Derendorf H. Comparative pharmacology, bioavailability, pharmacokinetics, and pharmacodynamics of inhaled glucocorticosteroids. Immunol Allergy Clin North Am 2005;25:469-88. DOI: https://doi.org/10.1016/j.iac.2005.05.004

Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, et al. Device selection and outcomes of aerosol therapy: evidence- based guidelines: American College of Chest Physicians/ American College of Asthma, Allergy, and Immunology. Chest 2005;127:335-71. DOI: https://doi.org/10.1378/chest.127.1.335

Vermeire P. European trends in inhalation therapy. Eur Respir Rev 1994;4:89-91.

Lavorini F, Corrigan CJ, Barnes PJ, Dekhuijzen PR, Levy ML, Pedersen S, et al. Retail sales of inhalation devices in European countries: so much for a global policy. Respir Med 2011;105:1099-103. DOI: https://doi.org/10.1016/j.rmed.2011.03.012

Melani AS. Nebulized corticosteroids in asthma and COPD. An Italian appraisal. Respir Care 2012;57:1161-74. DOI: https://doi.org/10.4187/respcare.01414

Daley-Yates PT. Inhaled corticosteroids: potency, dose equivalence and therapeutic index. Br J Clin Pharmacol 2015;80:372-80. DOI: https://doi.org/10.1111/bcp.12637

Derendorf H, Hochhaus G, Meibohm B, Mo¨llmann H, Barth J. Pharmacokinetics and pharmacodynamics of inhaled corticosteroids. J Allergy Clin Immunol 1998;101:S440-6. DOI: https://doi.org/10.1016/S0091-6749(98)70156-3

Lipworth BJ. Clinical pharmacology of corticosteroids in bronchial asthma. Pharamcol Ther 1993;58:173-209. DOI: https://doi.org/10.1016/0163-7258(93)90049-J

Fabbri L, Burge PS, Croonenborgh L, Warlies F, Weeke B, Ciaccia A, et al. Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. Thorax 1993;48:817-23. DOI: https://doi.org/10.1136/thx.48.8.817

Ayres JG, Bateman ED, Lundback B, Harris TA. High dose fluticasone propionate, 1 mg daily versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma. Eur Respir J 1995;8:579-86.

Agertoft L, Pedersen S. A randomised, double-blind dose reduction study to compare the minimal effective dose of budesonide Turbohaler and fluticasone propionate Diskhaler. J Allergy Clin Immunol 1997;99:773-80. DOI: https://doi.org/10.1016/S0091-6749(97)80011-5

Yiallouros PK, Milner AD, Conway E, Honour JW. Adrenal function and high dose inhaled corticosteroids for asthma. Arch Dis Child 1997;76:405-10. DOI: https://doi.org/10.1136/adc.76.5.405

Lönnebo A, Grahnén A, Jansson B, Brundin RM, Ling-Andersson A, Eckernäs SA. An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers. Eur J Clin Pharmacol 1996;49:459-63. DOI: https://doi.org/10.1007/BF00195931

Grahnén A, Eckernäs SA, Brundin RM, Ling-Andersson A. An assessment of the systemic activity of single doses of inhaled fluticasone propionate in healthy volunteers. Br J Clin Pharmacol 1994;38:521-5. DOI: https://doi.org/10.1111/j.1365-2125.1994.tb04393.x

Grahnén A, Jansson B, Brundin RM, Ling-Andersson A, Lönnebo A, Johansson M, et al. A dose-response study comparing suppression of plasma cortisol induced by fluticasone propionate from Diskhaler and budesonide from Turbohaler. Eur J Clin Pharmacol 1997;52:261-7. DOI: https://doi.org/10.1007/s002280050287

Thorsson L, Dahlström K, Edsbäcker A, Källén A, Paulson J, Wirén JE. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol 1997;43:155-61. DOI: https://doi.org/10.1046/j.1365-2125.1997.d01-1425.x

Boorsma M, Andersson N, Larsson P, Ullman A. Assessment of the relative systemic potency of inhaled fluticasone and budesonide. Eur Respir J 1996;9:1427-32. DOI: https://doi.org/10.1183/09031936.96.09071427

Clark DJ, Grove A, Cargill RI, Lipworth BJ. Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients. Thorax 1996;51:262-6. DOI: https://doi.org/10.1136/thx.51.3.262

Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997;52:55–8. DOI: https://doi.org/10.1136/thx.52.1.55

Derom E, Van Schoor J, Verhaeghe W, Vincken W, Pauwels R. Systemic effects of inhaled fluticasone propionate and budesonide in adult patients with asthma. Am J Respir Crit Care Med 1999;160:157-61. DOI: https://doi.org/10.1164/ajrccm.160.1.9805106

Brutsche MH, Brutsche IC, Munavvar M, Langley SJ, Masterson CM, Daley-Yates PT, et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000;356:556-61. DOI: https://doi.org/10.1016/S0140-6736(00)02581-2

Möllman H, Wagner M, Meibohm B, Hochhaus G, Barth J, Stöckmann R, et al. Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration. Eur J Clin Pharmacol 1998;53:459-67. DOI: https://doi.org/10.1007/s002280050407

Yanai M, Hatazawa J, Ojima F, Sasaki H, Itoh M, Ido T. Deposition and clearance of inhaled 18FDG powder in patients with chronic obstructive pulmonary disease. Eur Respir J 1998;11:1342-8. DOI: https://doi.org/10.1183/09031936.98.11061342

Melchor R, Biddiscombe M, Mak V, Short M, Spiro S. Lung deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction. Thorax 1993;48:506-11. DOI: https://doi.org/10.1136/thx.48.5.506

Niven RW. Atomization and nebulizers. In: Hickey AJ, editor. Inhalation aerosol: Physical and biological basis for therapy. New York: Marcel Dekker; 1996. p. 273-312.

O'Callaghan C, Barry PW. The science of nebulised drug delivery. Thorax 1997;52:531-44. DOI: https://doi.org/10.1136/thx.52.suppl_2.31

Dalby RN, Tiano SL, Hickey AJ. Medical devices for the delivery of therapeutic aerosols to the lungs. In: Hickey AJ, editor. Inhalation aerosol: Physical and biological basis for therapy. New York: Marcel Dekker; 1996. p 441-73.

Dhand R. Nebulizers that use a vibrating mesh or plate with multiple apertures to generate aerosol. Respir Care 2002;47:1406-146. discussion 1416-8.

Fink JB, Simmons R. Nebulization of steroid suspension: an in vitro evaluation of the Aeroneb®Go nebulizer and the Pari®LC+ nebulizers. Chest 2004;126:816S-7. DOI: https://doi.org/10.1378/chest.126.4_MeetingAbstracts.816S-b

Amani A, York P, Chrystyn H, Clark BJ. Evaluation of a nanoemulsion-based formulation for respiratory delivery of budesonide by nebulizers. AAPS Pharm Sci Tech 2010;11:1147-51. DOI: https://doi.org/10.1208/s12249-010-9486-9

Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev 2000;45:89-121. DOI: https://doi.org/10.1016/S0169-409X(00)00103-4

Kamin W, Schwabe A, Krämer I. Inhalation solutions: which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers. J Cyst Fibros 2006;5:205-13. DOI: https://doi.org/10.1016/j.jcf.2006.03.007

Melani AS. Effects on aerosol performance of mixing of either budesonide or beclomethasone dipropionate with albuterol and ipratropium bromide. Respir Care 2011;56:319-26. DOI: https://doi.org/10.4187/respcare.00955

O'Callaghan CL, White JA, Jackson JM, Barry PW, Kantar A. Nebulisation of corticosteroid suspensions and solutions with a beta(2) agonist. J Pharm Pharmacol 2008;60:601-5. DOI: https://doi.org/10.1211/jpp.60.5.0005

Tashkin DP. A review of nebulized drug delivery in COPD. Int J Chron Obstruct Pulmon Dis 2016;11:2585-96. DOI: https://doi.org/10.2147/COPD.S114034

Pleasants RA, Hess DR. Aerosol delivery devices for obstructive lung diseases. Respir Care 2018;63:708-33. DOI: https://doi.org/10.4187/respcare.06290

Melani AS, Sestini P, Aiolfi S, Barbato N, Canessa P, De Angelis G, et al. GENebu Project: home nebulizer use and maintenance in Italy. Eur Respir J 2001;18:758-63. DOI: https://doi.org/10.1183/09031936.01.00231701

Wood JA, Wilson RS, Bray C. Changes in salbutamol concentration in the reservoir solution of a jet nebulizer. Br J Dis Chest 1986;80:164-9. DOI: https://doi.org/10.1016/0007-0971(86)90037-9

McCallion ON, Taylor KM, Thomas M, Taylor AJ. Nebulization of fluids of different physicochemical properties with air-jet and ultrasonic nebulizers. Pharm Res 1995;12:1682-8. DOI: https://doi.org/10.1023/A:1016205520044

Högger P, Rohdewald P. Glucocorticoid receptors and fluticasone propionate. Rev. Contemp Pharmacother 1998;9:501-22.

O'Callaghan C, White J, Barry P, Kantar A. Analysis of the output of beclomethasone dipropionate from different nebulisers. Riv Ital Pediatr 2000;26:821-4.

O'Callaghan C, White J, Jackson J, Barry P, Kantar A. The output of flunisolide from different nebulisers. J Pharm Pharmacol 2002;54:565-9. DOI: https://doi.org/10.1211/0022357021778682

O'Callaghan C, White J, Jackson J, Barry PW, Kantar A. Delivery of nebulized budesonide is affected by nebulizer type and breathing pattern. J Pharm Pharmacol 2005;57:787-90. DOI: https://doi.org/10.1211/0022357056190

O'Callaghan C, White JA, Kantar A. Nebulization of corticosteroids to asthmatic children: large variation in dose inhaled. Respirology 2014;19:276-9. DOI: https://doi.org/10.1111/resp.12208

O’Callaghan C. Particle size of beclomethasone dipropionate produced by two nebulisers and two spacing devices. Thorax 1990;45:109-11. DOI: https://doi.org/10.1136/thx.45.2.109

Todd GR. Nebulised fluticasone. Thorax 2000;55:346-47. DOI: https://doi.org/10.1136/thorax.55.4.345c

Storr J, Lenney CA, Lenney W. Nebulised beclomethasone dipropionate in preschool asthma. Arch Dis Child 1986;61:270-3. DOI: https://doi.org/10.1136/adc.61.3.270

Webb MS, Milner AD, Hiller EJ, Henry RL. Nebulised beclomethasone dipropionate suspension. Arch Dis Child 1986;61:1108-10. DOI: https://doi.org/10.1136/adc.61.11.1108

Barry PW, O’Callaghan C. An in vitro analysis of the output of budesonide from different nebulizers. J Allergy Clin Immunol 1999;104:1168-73. DOI: https://doi.org/10.1016/S0091-6749(99)70009-6

Heyder J, Svartengren MU. Basic principles of particle behavior in human respiratory tract. In: Bisgaard H, O'Callaghan C, Smaldone GC, Editors. Drug delivery to the lung. New York: Marcel Dekker; 2002. p. 21-45. DOI: https://doi.org/10.1201/b14022-3

Bäckman P, Adelman H, Petersson G, Jones CB. Advances in inhaled technologies: understanding the therapeutic challenge, predicting clinical performance, and designing the optimal inhaled product. Clin Pharmacol Ther 2014;95:509-20. DOI: https://doi.org/10.1038/clpt.2014.27

Grainger CI, Saunders M, Buttini F, Telford R, Merolla LL, Martin GP, et al. Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence. Mol Pharm 2012;9:563-9. DOI: https://doi.org/10.1021/mp200415g

Riley T, Christopher D, Arp J, Casazza A, Colombani A, Cooper A, et al. Challenges with developing in vitro dissolution tests for orally inhaled products (OIP’s). AAPS Pharm Sci Tech 2012;13:978-89. DOI: https://doi.org/10.1208/s12249-012-9822-3

Buttini F, Miozzi M, Balducci AC, Royall PG, Colombo P, Brambilla G, et al. Differences in physical chemistry and dissolution rate of solid particle aerosols from solution inhalers. Int J Pharm 2014;465:42-51. DOI: https://doi.org/10.1016/j.ijpharm.2014.01.033

Sakagami M, Li H, Venitz J. In vivo-relevant transwell dish-based dissolution testing for orally inhaled corticosteroid products. Pharm Res 2019;36:95. DOI: https://doi.org/10.1007/s11095-019-2635-2

Wiedmann TS, Bhatia R, Wattenberg LW. Drug solubilization in lung surfactant. J Control Release 2000;65:43-7. DOI: https://doi.org/10.1016/S0168-3659(99)00230-8

Hallman M. Recycling of surfactant: A review of human amniotic fluid as a source of surfactant for treatment of respiratory distress syndrome. Rev Perinat Med 1989;6:197-226.

Derendorf H, Hochhaus G, Krishnaswami S, Möllmann H. Systemic disposition and effects of inhaled corticosteroids. In: Schleimer RP, O'Byrne PM, Szefler SJ, and Brattsand R, editors. Inhaled steroids in asthma. Optimizing effects in the airways. New York: Marcel Dekker; 2002. p. 247-72.

Derendorf H, Hochhaus G, Rohatagi S, Möllmann H, Barth J, Sourgens H, et al. Pharmacokinetics of triamcinolone acetonide after intravenous, oral, and inhaled administration. J Clin Phramacol 1995;35:302-5. DOI: https://doi.org/10.1002/j.1552-4604.1995.tb04064.x

Miller-Larsson A, Mattsson H, Hjertberg E, Dahlbäck M, Tunek A, Brattsand R. Reversible fatty acid conjugation of budesonide: Novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998;26:623-30.

Hochberg RB. Biological esterification of Steroids. Endocr Rev 1998;19:331-48.

Miller-Larsson A, Janssen P, Runstròm A, Brattsand R. Prolonged airway activity and improved selectivity of budesonide possibly due to esterification. Am J Respir Crit Care Med 2000;162:1455-1461. DOI: https://doi.org/10.1164/ajrccm.162.4.9806112

Kelly HW. Comparative potency and clinical efficacy of inhaled corticosteroids. Respir Care Clin N Am 1999;5:537-53.

Kantar A, Carloni M, Kulkarni N, Fedeli D, Falcioni G. Retention of flunisolide in rat lungs after single inhalation. Europ J inflamm 2012;10:127-31. DOI: https://doi.org/10.1177/1721727X1201000116

Mathias NR, Timoszyk J, Stetsko PI, Megill JR, Smith RL. Wall epithelial cells: in vitro/in vivo correlation to predict lung absorption in rats. J Drug Target 2002;10:31-40. DOI: https://doi.org/10.1080/10611860290007504

Tronde A, Norden B, Marchner H, Wendel A-K, Lennernas H, Bengtsson UH. Pulmonary absorption rate and bioavailability of drugs in vivo in rats: structure-absorption relationships and physicochemical profiling of inhaled drugs. J Pharm Sci 2003;92:1216-33. DOI: https://doi.org/10.1002/jps.10386

Bondesson E, Bengtsson T, Nilsson LE, Wollmer P. Effects of sodium taurocholate on the absorption of inhaled Tc-99m- DTPA. Pharm Res 2006;23:2122-8. DOI: https://doi.org/10.1007/s11095-006-9013-6

Kantar A, Mroueh S, Fiocchi A. A reappraisal of the clinical efficacy of nebulized flunisolide in pediatric asthma: the Italian experience. Allergy Asthma Proc 2007;28:671-87. DOI: https://doi.org/10.2500/aap.2007.28.2979

Conflict of interest statement
AK received lecture fees from Valeas, Menarini, Chiesi, Italchimici, Merck Sharp & Dohme, Sanofi and Novartis (Italy). AK is a member of the Editorial Board of Multidisciplinary Respiratory Medicine
Inhaled corticosteroids, flunisolide, nebulization, drug output, particle size
  • Abstract views: 1000

  • PDF: 47
  • HTML: 0
How to Cite
Kantar, A. (2021). What makes flunisolide different among inhaled corticosteroids used for nebulization: a close look at the role of aqueous solubility . Multidisciplinary Respiratory Medicine, 16. https://doi.org/10.4081/mrm.2021.719

Most read articles by the same author(s)