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Synergistic Antibiotic Combination Powders of Colistin and Rifampicin Provide High Aerosolization Efficiency and Moisture Protection

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Abstract

For many respiratory infections caused by multidrug-resistant Gram-negative bacteria, colistin is the only effective antibiotic despite its nephrotoxicity. A novel inhaled combination formulation of colistin with a synergistic antimicrobial component of rifampicin was prepared via co-spray drying, aiming to deliver the drug directly to the respiratory tract and minimize drug resistance and adverse effects. Synergistic antibacterial activity against Acinetobacter baumannii was demonstrated for the combination formulation with high emitted doses (96%) and fine particle fraction total (FPFtotal; 92%). Storage of the spray-dried colistin alone formulation in the elevated relative humidity (RH) of 75% resulted in a substantial deterioration in the aerosolization performance because the amorphous colistin powders absorbed significant amount of water up to 30% by weight. In contrast, the FPFtotal values of the combination formulation stored at various RH were unchanged, which was similar to the aerosolization behavior of the spray-dried rifampicin-alone formulation. Advanced surface chemistry measurements by XPS and ToF-SIMS demonstrated a dominance of rifampicin on the combination particle surfaces, which contributed to the moisture protection at the elevated RH. This study shows a novel inhalable powder formulation of antibiotic combination with the combined beneficial properties of synergistic antibacterial activity, high aerosolization efficiency, and moisture protection.

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ACKNOWLEDGMENTS

HKC acknowledges the Australian Research Council (ARC, grant DP120102778 and DP0985367) for the financial support of this study. JL is a National Health and Medical Research Council (NHMRC) Senior Research Fellow. QTZ is supported by an NHMRC Early Career Fellowship. The authors are grateful for the scientific and technical assistance of the Australian Microscopy & Microanalysis Research Facility at the Australian Centre for Microscopy and Microanalysis, The University of Sydney and the Ian Wark Research Institute, University of South Australia. Capsugel Australia is acknowledged for the kind donation of the capsules.

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Authors and Affiliations

  1. Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia

    Qi (Tony) Zhou & Hak Kim Chan

  2. CSIRO Materials Science and Engineering, Bayview Avenue, Clayton, VIC, Australia

    Thomas Gengenbach

  3. Ian Wark Research Institute, University of South Australia, Mawson Lakes, SA, Australia

    John A. Denman

  4. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Heidi H. Yu & Jian Li

Authors
  1. Qi (Tony) Zhou
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  2. Thomas Gengenbach
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  4. Heidi H. Yu
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  5. Jian Li
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  6. Hak Kim Chan
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Correspondence to Hak Kim Chan.

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Zhou, Q.(., Gengenbach, T., Denman, J.A. et al. Synergistic Antibiotic Combination Powders of Colistin and Rifampicin Provide High Aerosolization Efficiency and Moisture Protection. AAPS J 16, 37–47 (2014). https://doi.org/10.1208/s12248-013-9537-8

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