A rifapentine-containing inhaled triple antibiotic formulation for rapid treatment of tubercular infection.
OBJECTIVE
The potential for rifapentine-containing oral therapeutic regimens to significantly shorten the current six-month anti-tubercular treatment regimen is confounded by high plasma protein binding of rifapentine. Inhaled aerosol delivery of rifapentine, a more potent anti-tubercular antibiotic drug, in combination with other first-line antibiotics may overcome this limitation to deliver a high drug dose at the pulmonary site of infection.


METHODS
A formulation consisting of rifapentine, moxifloxacin and pyrazinamide, with and without leucine, was prepared by spray-drying. This formulation was assessed for its physico-chemical properties, in vitro aerosol performance and antimicrobial activity.


RESULTS
The antibiotic powders, with and without leucine, had similar median aerodynamic diameters of 2.58 ± 0.08 μm and 2.51 ± 0.06 μm, with a relatively high fine particle fraction of 55.5 ± 1.9% and 63.6 ± 2.0%, respectively. Although the powders were mostly amorphous, some crystalline peaks associated with the δ polymorph for the spray-dried crystalline pyrazinamide were identified.


CONCLUSIONS
Stabilisation of the powder with 10% w/w leucine and protection from moisture ingress was found to be necessary to prevent overt crystallisation of pyrazinamide after long-term storage. In vitro biological assays indicated antimicrobial activity was retained after spray-drying. Murine pharmacokinetic studies are currently underway.
Respiratory Technology Group Woolcock Institute of Medical Research & Discipline of Pharmacology Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia.
John Gar Yan
JG
Chan
Anneliese S
AS
Tyne
Angel
A
Pang
Hak-Kim
HK
Chan
Paul M
PM
Young
Warwick J
WJ
Britton
Colin C
CC
Duke
Daniela
D
Traini
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D033362:Powder Diffraction; D011208:Powders; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy*
D000336:Aerosols; D000904:Antibiotics, Antitubercular; D011208:Powders; D012293:Rifampin; C018421:rifapentine