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Bedaquiline containing triple combination powder for inhalation to treat drug-resistant tuberculosis.
Int J Pharm. 2019 Oct 30; 570:118689.IJ

Abstract

Drug-resistant tuberculosis (DR-TB) is an emerging health problem, challenging the effective control of global TB. Current treatment of DR-TB includes administration of multiple anti-TB drugs via oral and parenteral routes for a duration of 20-28 months. High systemic exposure, side effects and lengthy treatment time are problems affecting current treatment. The success rate of current lengthy treatment regimens is generally <50%. Bedaquiline, a new anti-TB drug is synergistic with pyrazinamide and in combination with moxifloxacin accelerates sputum-culture conversion. Therefore, a triple combination of these drugs may have the potential to shorten the treatment time and improve treatment success. Additionally, inhalation of these drugs in combination may be advantageous due to the direct delivery to the lungs, possibly reducing systemic exposure. This study aimed to develop an inhalable triple combination powder of bedaquiline, moxifloxacin and pyrazinamide and study their physicochemical properties and safety. An inhalable (aerodynamic diameter: ≤2.4 µm) triple combination powder of bedaquiline, moxifloxacin and pyrazinamide with 20% w/w of L-leucine was prepared using a Buchi Mini Spray-Dryer. Combination powder consisted of spherical and porous particles. In vitro aerosolization (fine particle fraction, FPF) determined using a next generation impactor (NGI) showed improved FPF as a combination powder (>75.0%) when compared to single drug-only formulations (<45.0%). The powder was non-toxic to A549 and Calu-3 cells up to 100 µg/mL and stable at 30 ± 2% RH and ambient room temperature during one-month storage. This is the first study reporting the development of inhalable triple combination powder of bedaquiline, moxifloxacin and pyrazinamide with high aerosolization efficiency. The improved aerosolization may help to deliver a high dose of these drugs to treat drug-resistant tuberculosis.

Authors+Show Affiliations

School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.School of Pharmacy, University of Otago, Dunedin 9054, New Zealand; Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0533, United States.School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.School of Pharmacy, University of Otago, Dunedin 9054, New Zealand. Electronic address: shyamal.das@otago.ac.nz.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31513868

Citation

Rangnekar, Bhamini, et al. "Bedaquiline Containing Triple Combination Powder for Inhalation to Treat Drug-resistant Tuberculosis." International Journal of Pharmaceutics, vol. 570, 2019, p. 118689.
Rangnekar B, Momin MAM, Eedara BB, et al. Bedaquiline containing triple combination powder for inhalation to treat drug-resistant tuberculosis. Int J Pharm. 2019;570:118689.
Rangnekar, B., Momin, M. A. M., Eedara, B. B., Sinha, S., & Das, S. C. (2019). Bedaquiline containing triple combination powder for inhalation to treat drug-resistant tuberculosis. International Journal of Pharmaceutics, 570, 118689. https://doi.org/10.1016/j.ijpharm.2019.118689
Rangnekar B, et al. Bedaquiline Containing Triple Combination Powder for Inhalation to Treat Drug-resistant Tuberculosis. Int J Pharm. 2019 Oct 30;570:118689. PubMed PMID: 31513868.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bedaquiline containing triple combination powder for inhalation to treat drug-resistant tuberculosis. AU - Rangnekar,Bhamini, AU - Momin,Mohammad A M, AU - Eedara,Basanth Babu, AU - Sinha,Shubhra, AU - Das,Shyamal C, Y1 - 2019/09/09/ PY - 2019/01/21/received PY - 2019/09/01/revised PY - 2019/09/08/accepted PY - 2019/9/13/pubmed PY - 2020/2/13/medline PY - 2019/9/13/entrez KW - Bedaquiline KW - Formulation KW - Inhalation KW - Moxifloxacin KW - Pyrazinamide KW - Tuberculosis SP - 118689 EP - 118689 JF - International journal of pharmaceutics JO - Int J Pharm VL - 570 N2 - Drug-resistant tuberculosis (DR-TB) is an emerging health problem, challenging the effective control of global TB. Current treatment of DR-TB includes administration of multiple anti-TB drugs via oral and parenteral routes for a duration of 20-28 months. High systemic exposure, side effects and lengthy treatment time are problems affecting current treatment. The success rate of current lengthy treatment regimens is generally <50%. Bedaquiline, a new anti-TB drug is synergistic with pyrazinamide and in combination with moxifloxacin accelerates sputum-culture conversion. Therefore, a triple combination of these drugs may have the potential to shorten the treatment time and improve treatment success. Additionally, inhalation of these drugs in combination may be advantageous due to the direct delivery to the lungs, possibly reducing systemic exposure. This study aimed to develop an inhalable triple combination powder of bedaquiline, moxifloxacin and pyrazinamide and study their physicochemical properties and safety. An inhalable (aerodynamic diameter: ≤2.4 µm) triple combination powder of bedaquiline, moxifloxacin and pyrazinamide with 20% w/w of L-leucine was prepared using a Buchi Mini Spray-Dryer. Combination powder consisted of spherical and porous particles. In vitro aerosolization (fine particle fraction, FPF) determined using a next generation impactor (NGI) showed improved FPF as a combination powder (>75.0%) when compared to single drug-only formulations (<45.0%). The powder was non-toxic to A549 and Calu-3 cells up to 100 µg/mL and stable at 30 ± 2% RH and ambient room temperature during one-month storage. This is the first study reporting the development of inhalable triple combination powder of bedaquiline, moxifloxacin and pyrazinamide with high aerosolization efficiency. The improved aerosolization may help to deliver a high dose of these drugs to treat drug-resistant tuberculosis. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/31513868/Bedaquiline_containing_triple_combination_powder_for_inhalation_to_treat_drug_resistant_tuberculosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(19)30734-3 DB - PRIME DP - Unbound Medicine ER -