A lidocaine dry powder inhaler to modulate cough: particle engineering and human proof-of-concept.

Chronic cough remains a major unmet clinical need, particularly in patients with refractory or unexplained disease. This study aimed to develop a spray-dried dry powder inhaler formulation of lidocaine hydrochloride capable of targeting deposition to the upper and central airways, where cough receptors are mainly located, while minimizing deep lung delivery and systemic exposure. Lidocaine was incorporated into sodium hyaluronate, selected as a mucoadhesive and release-modifying excipient. The effects of polymer molecular weight, drug-to-polymer ratio, and spray-drying parameters on the key quality attributes of the formulation were investigated. Low-molecular-weight sodium hyaluronate at a 20:80 lidocaine-to-polymer ratio produced amorphous microparticles with appropriate solid-state characteristics and controlled dissolution behaviour. Optimization identified a lead formulation with a median particle size of 8.9 µm and a non-respirable fraction of about 85%, supporting preferential deposition in the tracheobronchial region. Aerodynamic performance assessed using a Next Generation Impactor and an anatomically realistic mouth-throat model confirmed efficient delivery with limited fine particle deposition. Compared with raw lidocaine, the optimized formulation showed slower in vitro release, consistent with drug incorporation within the polymer matrix. In a randomized, single-blind, crossover proof-of-concept study in healthy volunteers, inhalation of 8 mg lidocaine powder significantly increased cough threshold at 15 and 30 min versus placebo, without clinically relevant safety concerns, bronchoconstriction, or impairment of the gag reflex. These findings show that particle engineering can enable regional airway targeting of lidocaine by dry powder inhalation and support the potential of this approach as a rapid, on-demand antitussive strategy.