title: Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy. [Corrected].
abstract: Tuberculosis is the most serious infectious disease caused by a single organism, Mycobacterium tuberculosis (Mtb). The standard of care is a protracted and complex drug treatment regimen made more complicated and of longer duration by the incidence of multiple and extensively drug resistant disease. Pulmonary delivery of aerosols as a supplement to the existing regimen offers the advantage of delivering high local drug doses to the initial site of infection and most prominent organ system involved in disease. Pyrazinamide is used in combination with other drugs to treat tuberculosis. It is postulated that the action of pyrazinoic acid (POA), the active moiety of pyrazinamide, may be enhanced by local pH adjustment, when presented as a salt form. POA was prepared as leucine (POA-leu) and ammonium salts (POA-NH4), spray dried, and characterized in terms of physicochemical properties (melting point, crystallinity, moisture content), aerodynamic performance (aerodynamic particle size distribution, emitted dose), and in vitro inhibitory effect on two mycobacteria (Mtb and Mycobacterium bovis). Particles were prepared in sizes suitable for inhalation (3.3 and 5.4 μm mass median aerodynamic diameter and 61 and 40% of the aerodynamic particle size distribution less than 4.46 μm, as measured by inertial impaction, for POA-leu and POA-NH4, respectively) and with properties (stoichiometric 1:1 ratio of salt to drug, melting points at ∼180 °C, with water content of <1%) that would support further development as an inhaled dosage form. In addition, POA salts demonstrated greater potency in inhibiting mycobacterial growth compared with POA alone, which is promising for therapy.
authors.affiliation: †RTI International, Research Triangle Park, North Carolina 27709, United States.
authors.forename: P G
authors.initials: PG
authors.lastname: Durham
authors.affiliation: †RTI International, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †RTI International, Research Triangle Park, North Carolina 27709, United States.
authors.forename: N
authors.initials: N
authors.lastname: German
authors.affiliation: †RTI International, Research Triangle Park, North Carolina 27709, United States.
authors.forename: N
authors.initials: N
authors.lastname: Mortensen
authors.affiliation: §St George's Hospital, University of London, London SW17 0QT, U.K.
authors.forename: J
authors.initials: J
authors.lastname: Dhillon
authors.affiliation: §St George's Hospital, University of London, London SW17 0QT, U.K.
authors.forename: D A
authors.initials: DA
authors.lastname: Mitchison
authors.affiliation: ∥Department of Medical Microbiology, University of Pretoria, Hatfield 0028, South Africa.
authors.forename: P B
authors.initials: PB
authors.lastname: Fourie
authors.affiliation: †RTI International, Research Triangle Park, North Carolina 27709, United States.
authors.forename: A J
authors.initials: AJ
authors.lastname: Hickey
mesh_terms: D000280:Administration, Inhalation; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000737:chemistry; D003890:Desiccation; D058995:Dry Powder Inhalers; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry; D059085:Nasal Sprays; D010316:Particle Size; D033362:Powder Diffraction; D011718:Pyrazinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D012492:Salts / Q000008:administration & dosage / Q000737:chemistry; D014376:Tuberculosis / Q000188:drug therapy*; D014961:X-Ray Diffraction
chemical_list: D000995:Antitubercular Agents; D059085:Nasal Sprays; D012492:Salts; D011718:Pyrazinamide; C005296:pyrazinoic acid
keywords: antimycobacterial activity; pulmonary drug delivery; pyrazinoic acid salts; spray drying; therapeutic aerosols; tuberculosis