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

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Abstract

Purpose

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.

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Acknowledgements

This study was supported by the Australian Research Council's Discovery Projects funding scheme (project number DP120100251).

A/Professor Traini is the recipient of an Australian Research Council Future Fellowship (project 475 number FT12010063). A/Professor Young is the recipient of an Australian Research Council Future Fellowship (project number FT110100996). John Chan and Anneliese Tyne are recipients of the Australian Postgraduate Award from the Australian Government. Prof Britton would like to acknowledge financial assistance from the NHMRC (Project Grant 101126 ) and NSW Government through its infrastructure grant to the Centenary Institute.

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Chan, J.G.Y., Tyne, A.S., Pang, A. et al. A Rifapentine-Containing Inhaled Triple Antibiotic Formulation for Rapid Treatment of Tubercular Infection. Pharm Res 31, 1239–1253 (2014). https://doi.org/10.1007/s11095-013-1245-7

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