title: 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.
authors.affiliation: Institute of Chemical and Engineering Sciences, A(∗)STAR (Agency for Science, Technology and Research), 1, Pesek Road, Jurong Island, Singapore 627833, Singapore; Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore.
authors.forename: Sie Huey
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Teo
authors.affiliation: Institute of Chemical and Engineering Sciences, A(∗)STAR (Agency for Science, Technology and Research), 1, Pesek Road, Jurong Island, Singapore 627833, Singapore. Electronic address: desmond_heng@ices.a-star.edu.sg.
authors.forename: Desmond
authors.initials: D
authors.lastname: Heng
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore; School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Chemical and Engineering Sciences, A(∗)STAR (Agency for Science, Technology and Research), 1, Pesek Road, Jurong Island, Singapore 627833, Singapore.
authors.forename: Wai Kiong
authors.initials: WK
authors.lastname: Ng
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, A15, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
authors.affiliation: Institute of Chemical and Engineering Sciences, A(∗)STAR (Agency for Science, Technology and Research), 1, Pesek Road, Jurong Island, Singapore 627833, Singapore.
authors.forename: Li Teng
authors.initials: LT
authors.lastname: Tan
authors.affiliation: Institute of Chemical and Engineering Sciences, A(∗)STAR (Agency for Science, Technology and Research), 1, Pesek Road, Jurong Island, Singapore 627833, Singapore; Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore. Electronic address: reginald_tan@ices.a-star.edu.sg.
authors.forename: Reginald B H
authors.initials: RB
authors.lastname: Tan
mesh_terms: D000280:Administration, Inhalation; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001424:Bacterial Infections / Q000188:drug therapy / Q000378:metabolism; D058995:Dry Powder Inhalers / Q000379:methods; D006801:Humans; D010316:Particle Size; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000378:metabolism; D013183:Sputum / Q000187:drug effects / Q000382:microbiology; D014961:X-Ray Diffraction
chemical_list: D000900:Anti-Bacterial Agents
keywords: Antiinfectives; Combinatorial therapy; Dry powder inhaler; Mucoactives; Quorum sensing; Synergy