title: Synergistic combination dry powders for inhaled antimicrobial therapy: formulation, characterization and in vitro evaluation.
abstract: In combination antimicrobial therapy, the desired outcome is to broaden the antimicrobial spectrum and to achieve a possible synergistic effect. However, adverse antagonistic species may also emerge from such combinations, leading to treatment failure with serious consequences. It is therefore imperative to screen the drug candidates for compatibility and possible antagonistic interactions. The aim of this work was to develop a novel synergistic dry powder inhaler (DPI) formulation for antimicrobial combination therapy via the pulmonary route. Binary (ciprofloxacin hydrochloride and gatifloxacin hydrochloride, SD-CIP/GAT) and ternary (ciprofloxacin hydrochloride, gatifloxacin hydrochloride, and lysozyme, SD-CIP/GAT/LYS) combinations were prepared via spray-drying on a BUCHI® Nano Spray Dryer B-90. The powder morphologies were spherical with a slightly corrugated surface and all within the respirable size range. The powders yielded fine particle fractions (of the loaded dose) of over 40% when dispersed using an Aerolizer® at 60 L/min. Time-kill studies carried out against the respiratory tract infection-causing bacteria Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia, and Acinetobacter baumannii at 1 × the minimum inhibitory concentration (MIC) over 24h revealed no antagonistic behavior for both the binary and ternary combinations. While the interactions were generally found to be indifferent, a favorable synergistic effect was detected in the dual combination (SD-CIP/GAT) when it was tested against P. aeruginosa bacteria.
authors.affiliation: Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: Sie Huey
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, National University Hospital, Singapore, 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), Singapore, Singapore. Electronic address: desmond_heng@ices.a-star.edu.sg.
authors.forename: Desmond
authors.initials: D
authors.lastname: Heng
authors.affiliation: Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: Wai Kiong
authors.initials: WK
authors.lastname: Ng
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, 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), Singapore, Singapore; Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, 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; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004357:Drug Synergism; D058995:Dry Powder Inhalers / Q000379:methods; D011208:Powders / Q000737:chemistry* / Q000494:pharmacology*; D012141:Respiratory Tract Infections / Q000188:drug therapy
chemical_list: D000890:Anti-Infective Agents; D011208:Powders