Conclusion

Despite great improvement in inhalation drug delivery systems, cough is still a limiting adverse effect affecting patients’ compliance and treatment efficacy as it would reduce the delivered dose. Cough is an important symptom of many respiratory diseases so it may be difficult to distinguish it from the adverse effects caused by the inhalation product. The underlying disease that cause cough and bronchoconstriction may also affect particle deposition and inhalation effort by the patient. Airway acclimatisation and the individual’s response to cough stimulants are also important factors. Since cough can be due to so many confounding factors via direct or indirect effect of the stimulants, one cannot simply make general statements such as powder aerosols being more likely to cause cough than nebulized formulations, or vice versa, even for the same drug molecule. Well-controlled clinical studies specifically designed to address cough would be necessary to identify the underlying cause for cough encountered in patients during aerosol treatment.
In the airways, chemicals may stimulate Aδ or C fibres by changing the acidity, osmolarity, or by directly activating the receptors. The cough receptors in diseased lungs are highly sensitised and can be stimulated easier compared to those in healthy people. Large particles may stimulate the punctate-sensitive cough receptors in large airways and trigger the expiratory reflex. Controlling the particles size of the formulation to <5 µm is necessary for minimising cough so that the particles deposit in the deep lung, where cough receptors are absent. However, such an approach
would need to take into account the site of therapeutic action. Besides particle size, the form of the aerosol, the dose, solid state of the drug, type of excipients, concentration, and pH and tonicity of the formulation should be considered to avoid causing cough. Higher doses of drugs and/or excipients can increase the risk of cough if the inhaled compounds can activate the cough receptors. Air flow characteristics through the inhaler device must be optimised to achieve the maximum aerosol performance and minimum airway irritation due to unwanted particle
deposition. At the same time, the inhaler should be sufficiently simple for patients to operate correctly. Figure 3 summarises these factors in the design and use of inhalation products to avoid causing coughs.