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, while 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 an 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 distribution 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, while 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 ability to increase the ciliary beat frequency for improving the mucociliary clearance in patients suffering form hyper secretory diseases, whilst simultaneously acting on the underlying smooth muscle.