title: A novel dry powder inhalable formulation incorporating three first-line anti-tubercular antibiotics.
abstract: Treatment for tuberculosis (TB) using the standard oral antibiotic regimen is effective but inefficient, requiring high drug dosing and lengthy treatment times. Three concurrent first-line antibiotics recommended by the World Health Organization (WHO) guidelines are pyrazinamide, rifampicin and isoniazid. Combining these antibiotics in a novel formulation for dry powder inhalation (DPI) may facilitate rapid and efficient resolution of local and systemic infection. However, spray-dried individually, these antibiotics were found to be physically unstable. A solution of the three antibiotics, at the WHO-recommended ratio, was spray-dried. The collected powder was assessed by a series of in vitro methods to investigate aerosol performance, particle physico-chemical characteristics and dissolution profile. Particles obtained were spherical with a surface composed primarily of rifampicin, as identified by TOF-SIMS. A mass median aerodynamic diameter of 3.5 ± 0.1 μm and fine particle fraction (<5 μm) of 45 ± 3% indicated excellent aerosol performance. The combination powder was differentiated by the presence of rifampicin dihydrate and the delta polymorph of pyrazinamide. Quantitative analysis indicated individual particles contained the three antibiotics at the expected proportions (400:150:75 w/w). This excipient-free triple antibiotic DPI formulation could be used as a significant enhanced treatment for TB.
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: jcha5503@uni.sydney.edu.au.
authors.forename: John Gar Yan
authors.initials: JG
authors.lastname: Chan
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: kim.chan@sydney.edu.au.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
authors.affiliation: Ian Wark Research Institute, The University of South Australia, Mawson Lakes, Australia. Electronic address: clive.prestidge@unisa.edu.au.
authors.forename: Clive A
authors.initials: CA
authors.lastname: Prestidge
authors.affiliation: Ian Wark Research Institute, The University of South Australia, Mawson Lakes, Australia. Electronic address: John.Denman@unisa.edu.au.
authors.forename: John A
authors.initials: JA
authors.lastname: Denman
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: paul.young@sydney.edu.au.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Young
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: daniela.trani@sydney.edu.au.
authors.forename: Daniela
authors.initials: D
authors.lastname: Traini
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000737:chemistry; D000904:Antibiotics, Antitubercular / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D058995:Dry Powder Inhalers / Q000379:methods; D005079:Excipients / Q000737:chemistry; D010316:Particle Size; D011208:Powders / Q000737:chemistry*
chemical_list: D000336:Aerosols; D000904:Antibiotics, Antitubercular; D005079:Excipients; D011208:Powders