title: Dry powder inhaler formulation of high-payload antibiotic nanoparticle complex intended for bronchiectasis therapy: Spray drying versus spray freeze drying preparation.
abstract: Inhaled nano-antibiotics have recently emerged as the promising bronchiectasis treatment attributed to the higher and more localized antibiotic exposure generated compared to native antibiotics. Antibiotic nanoparticle complex (or nanoplex in short) prepared by self-assembly complexation with polysaccharides addresses the major drawbacks of existing nano-antibiotics by virtue of its high payload and cost-effective preparation. Herein we developed carrier-free dry powder inhaler (DPI) formulations of ciprofloxacin nanoplex by spray drying (SD) and spray freeze drying (SFD). d-Mannitol and l-leucine were used as the drying adjuvant and aerosol dispersion enhancer, respectively. The DPI formulations were evaluated in vitro in terms of the (1) aerosolization efficiency, (2) aqueous reconstitution, (3) antibiotic release, and (4) antimicrobial activity against respiratory pathogen Pseudomonas aeruginosa. The SFD powders exhibited superior aerosolization efficiency to their SD counterparts in terms of emitted dose (92% versus 66%), fine particle fraction (29% versus 23%), and mass median aerodynamic diameter (3 μm versus 6 μm). The superior aerosolization efficiency of the SFD powders was attributed to their large and porous morphology and higher l-leucine content. While the SFD powders exhibited poorer aqueous reconstitution that might jeopardize their mucus penetrating ability, their antibiotic release profile and antimicrobial activity were not adversely affected.
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, 637459, Singapore.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Laboratory Medicine, National University Hospital, 119074, Singapore.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Teo
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, 637459, Singapore.
authors.forename: Jia Wei
authors.initials: JW
authors.lastname: Chew
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, 637459, Singapore. Electronic address: kunnong@ntu.edu.sg.
authors.forename: Kunn
authors.initials: K
authors.lastname: Hadinoto
mesh_terms: D000336:Aerosols; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001987:Bronchiectasis / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000494:pharmacology; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D058995:Dry Powder Inhalers; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D007930:Leucine / Q000737:chemistry; D008353:Mannitol / Q000737:chemistry; D053758:Nanoparticles; D010316:Particle Size; D011550:Pseudomonas aeruginosa / Q000187:drug effects
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D005079:Excipients; D008353:Mannitol; D002939:Ciprofloxacin; D007930:Leucine
keywords: Antibiotic nanoparticles; Chronic lung infection; Cystic fibrosis; Dry powder inhaler; Pulmonary drug delivery