A Rifapentine-Containing Inhaled Triple Antibiotic Formulation for Rapid Treatment of Tubercular Infection

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. 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. The antibiotic powders, with and without leucine, had similar median aerodynamic diameters of 2.58 +/- 0.08 mu m and 2.51 +/- 0.06 mu m, 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 delta polymorph for the spray-dried crystalline pyrazinamide were identified. 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.