title: Effects of Surface Composition on the Aerosolisation and Dissolution of Inhaled Antibiotic Combination Powders Consisting of Colistin and Rifampicin.
abstract: Colistin is often the only effective antibiotic against the respiratory infections caused by multidrug-resistant Gram-negative bacteria. However, colistin-resistant multidrug-resistant isolates have been increasingly reported and combination therapy is preferred to combat resistance. In this study, five combination formulations containing colistin (COL) and rifampicin (RIF) were prepared by spray drying. The lowest minimum inhibitory concentration (MIC) value against Pseudomonas aeruginosa PAO1 was measured for the formulation of COL/RIF = 4:1 with relatively high emitted doses (over 80%) and satisfactory fine particle fractions (over 60%). Data from X-ray photoelectron spectroscopy (XPS) and nano-time-of-flight secondary ion mass spectrometry (ToF-SIMS) showed the surfaces of particles were mainly covered by rifampicin even for the formulation with a mass ratio of COL/RIF = 4:1. Because colistin is hygroscopic and rifampicin is hydrophobic, moisture absorption of combination formulations was significantly lower than the pure colistin formulation in the dynamic vapour sorption results. To investigate the dissolution characteristics, four dissolution test methods (diffusion Franz cell, modified Franz cell, flow-through and beaker methods) were employed and compared. The modified Franz cell method was selected to test the dissolution behaviour of aerosolised powder formulations to eliminate the effect of membrane on dissolution. The results showed that surface enrichment of hydrophobic rifampicin neither affected aerosolisation nor retarded dissolution rate of colistin in the combination formulations. For the first time, advanced surface characterisation techniques of XPS and ToF-SIMS have shown their capability to understand the effect of surface composition on the aerosolisation and dissolution of combination powders.
authors.affiliation: Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Wang
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia.|Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907-2091, USA.
authors.forename: Qi Tony
authors.initials: QT
authors.lastname: Zhou
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Si-Ping
authors.initials: SP
authors.lastname: Sun
authors.affiliation: Ian Wark Research Institute, University of South Australia, Mawson Lakes, South Australia, 5095, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Denman
authors.affiliation: CSIRO Manufacturing, Bayview Avenue, Clayton, Victoria, 3168, Australia.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Gengenbach
authors.affiliation: Centre for Marine Bio-Innovation and School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia.|Department of Microbiology, Genetics of Biofilms Unit, Institut Pasteur, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barraud
authors.affiliation: Centre for Marine Bio-Innovation and School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia.|Singapore Centre for Environmental Life Sciences Engineering, and the School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rice
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. my@farma.ku.dk.
authors.forename: Mingshi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia. kim.chan@sydney.edu.au.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry*; D003091:Colistin / Q000008:administration & dosage / Q000737:chemistry*; D058995:Dry Powder Inhalers / Q000379:methods; D008826:Microbial Sensitivity Tests / Q000379:methods; D010316:Particle Size; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology; D012141:Respiratory Tract Infections / Q000188:drug therapy; D012293:Rifampin / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility; D013499:Surface Properties / Q000187:drug effects
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D012293:Rifampin; D003091:Colistin
keywords: colistin; combination antibiotics; dry powder inhaler; respiratory infection; rifampicin