The effects of salbutamol sulphate and mannitol on ciliary beat frequency: a combined therapy for mucus hyper-secretion in Pulmonary Diseases

Giulia Ballerin, Hui Xin Ong, Lucy Morgan, Brian Oliver, Santo Scalia, Paul M. Young, Daniela Traini

Background: Two of the major characteristics of chronic obstructive pulmonary disease (COPD) are inflammation of the airways and hyper-secretion of mucus. Current therapies to treat these symptoms include bronchodilators and anti-mucolytic therapy. This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator and mannitol, an anti mucolytic, as a potential combination therapy for COPD. This combination was chosen to have an augmented effect on the airways: the SS will act on the β2 receptor for relaxation of smooth muscle, while mannitol will decrease mucus viscosity, consequently enhancing its clearance from the lung. A series of co-spray dried samples, containing therapeutically relevant doses of salbutamol and mannitol were prepared and tested in terms of physico-chemical characteristics. Additionally the formulation was evaluated for its effect on epithelial cell viability, transport and cilia beat frequency.
Methods: Mannitol (MA) with different concentrations of salbutamol sulphate was co-spray dried to obtain dry powders within a respirable range. The ratios (% w/w) were: 100% MA, 99.95% MA : 0.05% SS, 99.9% MA : 0.1% SS and 99.8% MA : 0.2% SS. The particles size and the morphology were analysed using a Mastersizer and scanning electron microscopy (SEM). The toxicity of MA and SS was tested on Calu-3 bronchial epithelial cell lines at different concentrations, using a liquid covered culture.
Results: The dry powder formulations showed a median volume diameter of 3.16 ± 0.46 μm, suitable for inhalation therapy. Toxicity studies have shown that both MA and SS are not toxic to the Calu-3 over the concentration range studied. Furthermore, SS 10-6 M, MA 10-3 M and the combined ratios gave a significant increase in cilia beat frequency compared to the control.
Conclusion: These studies have established that co-spray dried combination formulations of mannitol and salbutamol sulphate can be successfully prepared that have limited toxicity, good aerosol performance and increase the ciliary beat frequency (CBF) for improving the mucociliary clearance in patients, whilst simultaneously acting on the underlying smooth muscle.

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