A novel inhaled multi-pronged attack against respiratory bacteria

Abstract

Airway mucus hypersecretion is a common clinical feature of many severe respiratory diseases, and when complicated by a recalcitrant bacterial infection, the whole treatment regimen thereby becomes more challenging and protracted. The accumulation of thickened mucus secretions in the lower airways provides a nutrient-rich breeding ground for bacteria that promotes their growth and limits the ease of effective eradication. Unfortunately, no direct-inhaled dry powder formulation to treat these respiratory mucoid infections more effectively is available commercially. This work therefore seeks to develop a highly-efficacious ternary dry powder inhaler (DPI) formulation (ciprofloxacin hydrochloride (CIP), gatifloxacin hydrochloride (GAT) and ambroxol hydrochloride (AMB)) capable of delivering a novel multi-pronged attack (synergy, quorum quenching and mucociliary clearance) on Pseudomonas aeruginosa, a common respiratory bacteria found in mucoid infections. The powders were prepared via spray drying, evaluated on their aerosol performance via a multi-stage liquid impinger (MSLI) and tested for their efficacies in bacteria-spiked artificial sputum medium (ASM). The optimized particles were of respirable-size (d50 of ∼1.61±0.03μm) and slightly corrugated. When dispersed via an Aerolizer® inhaler at 60L/min, the powder showed concomitant in vitro deposition, minimal capsule, device and throat retention, and highly promising and uniform fine particle fractions (of the loaded dose) of ∼64–69%, which was a vast improvement over the singly-delivered actives. Favourably, when tested on bacteria-spiked ASM, the optimized ternary formulation (with AMB) was more effective at killing bacteria (i.e. faster rate of killing) than just the synergistic antibiotics alone (binary formulation; without AMB). In conclusion, a ternary antibiotic–(non-antibiotic) DPI formulation involving a unique multi-pronged attack mechanism was successfully pioneered and optimized for mucoid infections.