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Open AccessArticle

Inhalable Dry Powder of Bedaquiline for Pulmonary Tuberculosis: In Vitro Physicochemical Characterization, Antimicrobial Activity and Safety Studies

1
School of Pharmacy, University of Otago, Dunedin 9054, New Zealand
2
Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0533, USA
3
Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(10), 502; https://doi.org/10.3390/pharmaceutics11100502
Received: 11 August 2019 / Revised: 9 September 2019 / Accepted: 23 September 2019 / Published: 1 October 2019
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
Bedaquiline is a newly developed anti-tuberculosis drug, conditionally approved by the United States Food and Drug Administration (USFDA) for treating drug-resistant tuberculosis in adults. Oral delivery of bedaquiline causes severe side effects such as increased hepatic aminotransferase levels and cardiac arrhythmias (prolongation of QT-interval). This study aimed to develop inhalable dry powder particles of bedaquiline with high aerosolization efficiency to reduce the side-effects of oral bedaquiline. Bedaquiline (with or without l-leucine) powders were prepared using a Buchi Mini Spray-dryer. The powders were characterized for physicochemical properties and for their in vitro aerosolization efficiency using a next-generation impactor (NGI). The formulation with maximum aerosolization efficiency was investigated for physicochemical and aerosolization stability after one-month storage at 20 ± 2 °C/30 ± 2% relative humidity (RH) and 25 ± 2 °C/75% RH in an open Petri dish. The cytotoxicity of the powders on A549 and Calu-3 cell-lines was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The powders were also evaluated for antimicrobial activity against Mycobacterium tuberculosis. The aerodynamic diameter of the l-leucine-containing powder was 2.4 µm, and the powder was amorphous in nature. The aerosolization efficiency (fine-particle fraction) of l-leucine-containing powder (fine-particle fraction (FPF): 74.4%) was higher than the bedaquiline-only powder (FPF: 31.3%). l-leucine containing powder particles were plate-shaped with rough surfaces, but the bedaquiline-only powder was spherical and smooth. The optimized powder was stable at both storage conditions during one-month storage and non-toxic (up to 50 µg/mL) to the respiratory cell-lines. Bedaquiline powders were effective against Mycobacterium tuberculosis and had a minimal inhibitory concentration (MIC) value of 0.1 µg/mL. Improved aerosolization may help to combat pulmonary tuberculosis by potentially reducing the side-effects of oral bedaquiline. Further research is required to understand the safety of the optimized inhalable powder in animal models. View Full-Text
Keywords: bedaquiline; inhalation; formulation; spray-drying; dry powder; tuberculosis bedaquiline; inhalation; formulation; spray-drying; dry powder; tuberculosis
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MDPI and ACS Style

Momin, M.A.M.; Rangnekar, B.; Sinha, S.; Cheung, C.-Y.; Cook, G.M.; Das, S.C. Inhalable Dry Powder of Bedaquiline for Pulmonary Tuberculosis: In Vitro Physicochemical Characterization, Antimicrobial Activity and Safety Studies. Pharmaceutics 2019, 11, 502. https://doi.org/10.3390/pharmaceutics11100502

AMA Style

Momin MAM, Rangnekar B, Sinha S, Cheung C-Y, Cook GM, Das SC. Inhalable Dry Powder of Bedaquiline for Pulmonary Tuberculosis: In Vitro Physicochemical Characterization, Antimicrobial Activity and Safety Studies. Pharmaceutics. 2019; 11(10):502. https://doi.org/10.3390/pharmaceutics11100502

Chicago/Turabian Style

Momin, Mohammad A.M.; Rangnekar, Bhamini; Sinha, Shubhra; Cheung, Chen-Yi; Cook, Gregory M.; Das, Shyamal C. 2019. "Inhalable Dry Powder of Bedaquiline for Pulmonary Tuberculosis: In Vitro Physicochemical Characterization, Antimicrobial Activity and Safety Studies" Pharmaceutics 11, no. 10: 502. https://doi.org/10.3390/pharmaceutics11100502

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