Post-inhalation cough with therapeutic aerosols: Formulation considerations

Area of Science:

• Pharmacology
• Respiratory Medicine
• Drug Delivery Systems

Background:

• Cough is a common side effect of inhaled therapeutics, impacting patient adherence and treatment efficacy.
• The incidence and severity of post-inhalation cough are influenced by various factors including drug properties, formulation characteristics, and delivery device design.

Purpose of the Study:

• To review and assess the factors contributing to post-inhalation cough associated with therapeutic aerosols.
• To identify strategies for mitigating cough through modifications in drug design, formulation, and device engineering.

Main Methods:

• Literature review of studies investigating cough reflex triggered by inhaled medications.
• Analysis of dose-response relationships and physicochemical properties of aerosols influencing cough.

Main Results:

• Cough incidence is generally low (<5%) for inhaled drugs with doses under 1 mg, common in asthma and COPD treatments.
• Cough incidence significantly increases with higher doses (approaching 100 mg) due to alterations in airway epithelial lining fluid composition (e.g., osmolality, pH).
• Individual cough response is linked to sensitization to mechanical/chemical stimuli, often exacerbated by lung inflammation from the drug, formulation, or underlying disease.

Conclusions:

• Cough reflex sensitivity is a key determinant of post-inhalation cough.
• Modifying drug and excipient properties to maintain neutral, insoluble forms can limit cough induced by epithelial lining fluid changes.
• Strategic design of drugs, formulations, and delivery devices offers a viable approach to minimize cough in aerosol therapy.