Skip to main content

Advertisement

SpringerLink
Log in

Combined Inhaled Salbutamol and Mannitol Therapy for Mucus Hyper-secretion in Pulmonary Diseases

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the β2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, whilst mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray-dried samples, containing therapeutically relevant doses of SS and MA, were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally, the formulations were evaluated for their effects on cell viability and transport across air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distributions and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10−6 and MA 10−3 M gave a significant increase in cilia beat frequency whilst simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and the ability to increase ciliary beat frequency for improving the mucociliary clearance in patients suffering from hyper-secretory diseases, whilst simultaneously acting on the underlying smooth muscle.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

REFERENCES

  1. Barker AF. Bronchiectasis. N Engl J Med. 2002;346(18):1383–93.

    Article  PubMed  Google Scholar 

  2. Murray TS, Egan M, Kazmierczak BI. Pseudomonas aeruginosa chronic colonization in cystic fibrosis patients. Curr Opin Pediatr. 2007;19(1):83.

    Article  PubMed  Google Scholar 

  3. Barker AF, Couch L, Fiel SB, Gotfried MH, Ilowite J, Meyer KC, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med. 2000;162(2):481–5.

    Article  CAS  PubMed  Google Scholar 

  4. Geller DE. Aerosol antibiotics in cystic fibrosis. Respir Care. 2009;54(5):658–70.

    Article  PubMed  Google Scholar 

  5. Yang Y, Tsifansky MD, Shin S, Lin Q, Yeo Y. Mannitol-guided delivery of ciprofloxacin in artificial cystic fibrosis mucus model. Biotechnol Bioeng. 2011;108(6):1441–9.

    Article  CAS  PubMed  Google Scholar 

  6. Anderson P. Emerging therapies in cystic fibrosis. Ther Adv Respir Dis. 2010;4(3):177–85.

    Article  CAS  PubMed  Google Scholar 

  7. Wood AJJ, Ramsey BW. Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med. 1996;335(3):179–88.

    Article  Google Scholar 

  8. Brannan JD, Anderson SD, Perry CP, Freed-Martens R, Lassig AR, Charlton B. The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir Res. 2005;6(1):144.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Robinson M, Daviskas E, Eberl S, Baker J, Chan HK, Anderson S, et al. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. Eur Respir J. 2001;14(3):678–85.

    Article  Google Scholar 

  10. Hasani A, Toms N, O’Connor J, Dilworth J, Agnew J. Effect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma. Respir Med. 2003;97(6):667–71.

    Article  CAS  PubMed  Google Scholar 

  11. Fazio F, Lafortuna C. Effect of inhaled salbutamol on mucociliary clearance in patients with chronic bronchitis. Chest. 1981;80(6 Suppl):827–30.

    Article  CAS  PubMed  Google Scholar 

  12. Bennett WD. Effect of β-adrenergic agonists on mucociliary clearance. J Allergy Clin Immunol. 2002;110(6, Supplement):S291–7.

    Article  CAS  PubMed  Google Scholar 

  13. Mortensen J, Hansen A, Falk M, Nielsen I, Groth S. Reduced effect of inhaled beta 2-adrenergic agonists on lung mucociliary clearance in patients with cystic fibrosis. CHEST J. 1993;103(3):805–11.

    Article  CAS  Google Scholar 

  14. Robinson M, Bye PTB. Mucociliary clearance in cystic fibrosis. Pediatr Pulmonol. 2002;33(4):293–306.

    Article  PubMed  Google Scholar 

  15. Ong HX, Traini D, Bebawy M, Young PM. Epithelial profiling of antibiotic controlled release respiratory formulations. Pharm Res. 2011;28(9):2327–38.

    Article  CAS  PubMed  Google Scholar 

  16. Haghi M, Young PM, Traini D, Jaiswal R, Gong J, Bebawy M. Time-and passage-dependent characteristics of a Calu-3 respiratory epithelial cell model. Drug Dev Ind Pharm. 2010;36(10):1207–14.

    Article  CAS  PubMed  Google Scholar 

  17. Ong HX, Traini D, Salama R, Anderson SD, Daviskas E, Young PM. The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia. Mol Pharm. 2013;10(8):2915–24.

    Article  CAS  PubMed  Google Scholar 

  18. Devalia J, Sapsford R, Rusznak C, Toumbis M, Davies R. The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells, in vitro. Pulm Pharmacol. 1992;5(4):257–63.

    Article  CAS  PubMed  Google Scholar 

  19. Labiris N, Dolovich M. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Phamacol. 2003;56(6):588–99.

    Article  CAS  Google Scholar 

  20. Adi H, Young PM, Chan H-K, Agus H, Traini D. Co-spray-dried mannitol–ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease. Eur J Pharm Sci. 2010;40(3):239–47.

    Article  CAS  PubMed  Google Scholar 

  21. Haghi M, Traini D, Bebawy M, Young PM. Deposition, diffusion and transport mechanism of dry powder microparticulate salbutamol, at the respiratory epithelia. Mol Pharm. 2012;9(6):1717–26.

    Article  CAS  PubMed  Google Scholar 

  22. Palacio M, Cuffini S, Badini R, Karlsson A, Palacios S. Solid-state characterization of two polymorphic forms of R-albuterol sulfate. J Pharm Biomed Anal. 2007;43(4):1531–4.

    Article  CAS  PubMed  Google Scholar 

  23. Shariare M, de Matas M, York P. Effect of crystallisation conditions and feedstock morphology on the aerosolization performance of micronised salbutamol sulphate. Int J Pharm. 2011;415(1):62–72.

    Article  CAS  PubMed  Google Scholar 

  24. Begat P, Young PM, Edge S, Kaerger JS, Price R. The effect of mechanical processing on surface stability of pharmaceutical powders: visualization by atomic force microscopy. J Pharm Sci. 2003;92(3):611–20.

    Article  CAS  PubMed  Google Scholar 

  25. Heng D, Lee SH, Kwek JW, Ng WK, Chan H-K, Tan RB. Assessing the combinatorial influence of climate, formulation and device on powder aerosolization using the Taguchi experimental design. Powder Technol. 2012;226:253–60.

    Article  CAS  Google Scholar 

  26. Tee S, Marriott C, Zeng X, Martin G. The use of different sugars as fine and coarse carriers for aerosolised salbutamol sulphate. Int J Pharm. 2000;208(1):111–23.

    Article  CAS  PubMed  Google Scholar 

  27. Young PM, Edge S, Traini D, Jones MD, Price R, El-Sabawi D, et al. The influence of dose on the performance of dry powder inhalation systems. Int J Pharm. 2005;296(1):26–33.

    Article  CAS  PubMed  Google Scholar 

  28. Ong HX, Traini D, Young PM. Pharmaceutical applications of the Calu-3 lung epithelia cell line. Expert Opin Drug Deliv. 2013;0(0):1–16.

    CAS  Google Scholar 

  29. Hirsh AJ. Altering airway surface liquid volume: inhalation therapy with amiloride and hyperosmotic agents. Adv Drug Deliv Rev. 2002;54(11):1445–62.

    Article  CAS  PubMed  Google Scholar 

  30. McDougall CM, Blaylock MG, Douglas JG, Brooker RJ, Helms PJ, Walsh GM. Nasal epithelial cells as surrogates for bronchial epithelial cells in airway inflammation studies. Am J Respir Cell Mol Biol. 2008;39(5):560.

    Article  CAS  PubMed  Google Scholar 

  31. Rutland J, Cole PJ. Nasal mucociliary clearance and ciliary beat frequency in cystic fibrosis compared with sinusitis and bronchiectasis. Thorax. 1981;36(9):654–8.

    Article  CAS  PubMed  Google Scholar 

  32. Andersen I, Camner P, Jensen PL, Philipson K, Proctor DF. A comparison of nasal and tracheobronchial clearance. Arch Environ Health. 1974;29(5):290–3.

    Article  CAS  PubMed  Google Scholar 

  33. Yaghi A, Zaman A, Dolovich MB. The direct effect of hyperosmolar agents on ciliary beating of human bronchial epithelial cells. J Aerosol Med Pulm Drug Deliv. 2012;25(2):88–95.

    Article  CAS  PubMed  Google Scholar 

  34. Daviskas E, Anderson SD, Eberl S, Chan HK, Young IH, Seale JP. Effects of terbutaline in combination with mannitol on mucociliary clearance. The Eur Respir J. 2002;20(6):1423–9.

    Article  CAS  Google Scholar 

  35. Duchateau GS, Merkus FW, Zuidema J, Graamans K. Correlation between nasal ciliary beat frequency and mucus transport rate in volunteers. Laryngoscope. 1985;95(7):854–9.

    Article  CAS  PubMed  Google Scholar 

  36. Boek WM, Graamans K, Natzijl H, van Rijk PP, Huizing EH. Nasal mucociliary transport: new evidence for a key role of ciliary beat frequency. Laryngoscope. 2002;112(3):570–3.

    Article  PubMed  Google Scholar 

  37. Anderson SD, Brannan J, Spring J, Spalding N, Rodwell LT, Chan K, et al. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med. 1997;156(3):758–65.

    Article  CAS  PubMed  Google Scholar 

  38. Leuppi JD, Brannan JD, Anderson SD. Bronchial provocation tests: the rationale for using inhaled mannitol as a test for airway hyperresponsiveness. Swiss Med Wkly. 2002;132(13/14):151–8.

    PubMed  Google Scholar 

  39. Fujimoto N, Zhao C, Shichi H. The effects of prostaglandins E2 and F2α on porcine ciliary muscle cells in culture. Curr Eye Res. 1995;14(12):1155–63.

    Article  CAS  PubMed  Google Scholar 

  40. Ma X, Cheng Z, Wang Y, Unruh H, Stephens NL, Laviolette M. Changes in biophysical and biochemical properties of single bronchial smooth muscle cells from asthmatic subjects. Am J Physiol Lung Cell Mol Physiol. 2002;283(6):L1181–9.

    CAS  PubMed  Google Scholar 

  41. Pang I-H, Shade DL, Tamm E, DeSantis L. Single-cell contraction assay for human ciliary muscle cells. Effect of carbachol. Invest Ophthalmol Vis Sci. 1993;34(5):1876–9.

    CAS  PubMed  Google Scholar 

  42. Oldenburg PJ, Wyatt TA, Sisson JH. Ethanol attenuates contraction of primary cultured rat airway smooth muscle cells. Am J Respir Cell Mol Biol. 2010;43(5):539–45.

    Article  CAS  PubMed  Google Scholar 

  43. Govindaraju V, Michoud M-C, Ferraro P, Arkinson J, Safka K, Valderrama-Carvajal H, et al. The effects of interleukin-8 on airway smooth muscle contraction in cystic fibrosis. Respir Res. 2008;9(1):76.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kume H, Hall IP, Washabau RJ, Takagi K, Kotlikoff MI. Beta-adrenergic agonists regulate KCa channels in airway smooth muscle by cAMP-dependent and -independent mechanisms. The J Clin Investig. 1994;93(1):371–9.

    Article  CAS  Google Scholar 

  45. Salathe M. Effects of β-agonists on airway epithelial cells. J Allergy Clin Immunol. 2002;110(6):S275–81.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

A/Professor Traini is the recipient of an Australian Research Council Future Fellowship (project number FT12010063). A/Professor Young is the recipient of an Australian Research Council Future Fellowship (project number FT110100996). This project was supported by ARC-Linkage grant no. LP100100451. The authors would also like to acknowledge Lynn Moir for her expert advice on the smooth muscle contraction studies.

Author information

Authors and Affiliations

  1. Respiratory Technology, Woolcock Institute of Medical Research, 431 Glebe Point Road, Sydney, NSW, 2037, Australia

    Hui Xin Ong, Daniela Traini, Giulia Ballerin & Paul M. Young

  2. Department of Chemical and Pharmaceutical Sciences, The University of Ferrara, Ferrara, Italy

    Giulia Ballerin & Santo Scalia

  3. Concord Repatriation General Hospital, Sydney, Australia

    Lucy Morgan & Lachlan Buddle

  4. Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia

    Daniela Traini & Paul M. Young

  5. Sydney Medical School-Concord Clinical School, University of Sydney, Sydney, NSW, Australia

    Lucy Morgan

Authors
  1. Hui Xin Ong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Traini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giulia Ballerin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucy Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lachlan Buddle
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Santo Scalia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul M. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul M. Young.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

Spray drying conditions for single mannitol (MA) and co-spray-dried mannitol/salbutamol sulphate (SS). (DOCX 51 kb)

Supplementary Fig. 1

Particle size distribution of single spray-dried mannitol (MA) and co-spray-dried salbutamol sulphate with mannitol (SS/MA) measured using laser diffraction. Data represents the mean ± SD of at least three replicate experiments. (JPEG 214 kb)

Supplementary Fig. 2

The effect of SS and MA on Calu-3 cells viability after 72-h drug exposure. The data represented the mean ± SD of at least three separate determinations. (JPEG 357 kb)

Supplementary Fig. 3

Transepithelial electrical resistance (TEER) of Calu-3 cells after transport experiments. Data represents the mean ± SD of at least three separate determinations. (JPEG 167 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ong, H.X., Traini, D., Ballerin, G. et al. Combined Inhaled Salbutamol and Mannitol Therapy for Mucus Hyper-secretion in Pulmonary Diseases. AAPS J 16, 269–280 (2014). https://doi.org/10.1208/s12248-014-9560-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-014-9560-4

KEY WORDS

Search

Navigation