title: Novel Inhaled Combination Powder Containing Amorphous Colistin and Crystalline Rifapentine with Enhanced Antimicrobial Activities against Planktonic Cells and Biofilm of Pseudomonas aeruginosa for Respiratory Infections.
abstract: Colistin has been increasingly used for the treatment of respiratory infections caused by Gram-negative bacteria. Unfortunately parenteral administration of colistin can cause severe adverse effects. This study aimed to develop an inhaled combination dry powder formulation of colistin and rifapentine for the treatment of respiratory infections. The combination formulation was produced by spray-drying rifapentine particles suspended in an aqueous colistin solution. The combination dry powder had enhanced antimicrobial activities against planktonic cells and biofilm cultures of Pseudomonas aeruginosa, with both minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC) values (2 and 4 mg/L, respectively) being half that of pure colistin (MIC 4 mg/L and MBIC 8 mg/L) and 1/16th that of pure rifapentine (MIC 32 mg/L and MBIC 64 mg/L). High aerosol performance, as measured via an Aerolizer device, was observed with emitted doses>89% and fine particle fraction (FPF) total>76%. The proportion of submicron particles of rifapentine particles was minimized by the attachment of colistin, which increased the overall particle mass and aerodynamic size distribution. Using the spray-drying method described here, stable particles of amorphous colistin and crystalline rifapentine were distributed homogeneously in each stage of the impinger. Unlike the colistin alone formulation, no deterioration in aerosol performance was found for the combination powder when exposed to a high relative humidity of 75%. In our previous study, surface coating by rifampicin contributed to the moisture protection of colistin. Here, a novel approach with a new mechanism was proposed whereby moisture protection was attributed to the carrier effect of elongated crystalline rifapentine particles, which minimized contact between hygroscopic colistin particles. This inhaled combination antibiotic formulation with enhanced aerosol dispersion efficiency and in vitro efficacy could become a superior treatment for respiratory infections.
authors.affiliation: †Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
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: †Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.|‡JHL Biotech, Inc., Zhubei City, Hsinchu County 302, Taiwan, R.O.C.
authors.forename: John Gar Yan
authors.initials: JG
authors.lastname: Chan
authors.affiliation: †Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: §Centre for Marine Bio-Innovation and School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
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 on 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 3052, Australia.
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.affiliation: ⊥Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: †Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000737:chemistry; D018441:Biofilms / Q000187:drug effects; D003091:Colistin / Q000008:administration & dosage* / Q000737:chemistry; D004338:Drug Combinations; D004357:Drug Synergism; D058995:Dry Powder Inhalers; D006801:Humans; D008826:Microbial Sensitivity Tests; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D059085:Nasal Sprays; D010316:Particle Size; D010933:Plankton / Q000187:drug effects; D011208:Powders; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D012141:Respiratory Tract Infections / Q000188:drug therapy*; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000890:Anti-Infective Agents; D004338:Drug Combinations; D059085:Nasal Sprays; D011208:Powders; D012293:Rifampin; C018421:rifapentine; D003091:Colistin
keywords: antibiofilm; colistin; combination antibiotics; elongated carrier; inhalable powder formulation; moisture protection; respiratory infection; rifapentine