The AAPS Journal

, Volume 16, Issue 2, pp 269–280 | Cite as

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

  • Hui Xin Ong
  • Daniela Traini
  • Giulia Ballerin
  • Lucy Morgan
  • Lachlan Buddle
  • Santo Scalia
  • Paul M. Young
Research Article

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.

KEY WORDS

cilia responce epithelia transport lung delivery mannitol salbutamol smooth muscle responce 

Notes

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.

Supplementary material

12248_2014_9560_MOESM1_ESM.docx (51 kb)
Supplementary Table 1 Spray drying conditions for single mannitol (MA) and co-spray-dried mannitol/salbutamol sulphate (SS). (DOCX 51 kb)
12248_2014_9560_Fig11_ESM.jpg (214 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)

12248_2014_9560_Fig12_ESM.jpg (357 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)

12248_2014_9560_Fig13_ESM.jpg (167 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)

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Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Hui Xin Ong
    • 1
  • Daniela Traini
    • 1
    • 4
  • Giulia Ballerin
    • 1
    • 2
  • Lucy Morgan
    • 3
    • 5
  • Lachlan Buddle
    • 3
  • Santo Scalia
    • 2
  • Paul M. Young
    • 1
    • 4
  1. 1.Respiratory Technology, Woolcock Institute of Medical ResearchSydneyAustralia
  2. 2.Department of Chemical and Pharmaceutical SciencesThe University of FerraraFerraraItaly
  3. 3.Concord Repatriation General HospitalSydneyAustralia
  4. 4.Discipline of Pharmacology, Sydney Medical SchoolThe University of SydneySydneyAustralia
  5. 5.Sydney Medical School-Concord Clinical School, University of SydneySydneyAustralia

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