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Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration

Mycobacterium tuberculosis (M.tb) has infected one-quarter of the world’s population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant M.tb strains coupled w...

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Autores principales: Maloney, Sara E., Stewart, Ian E., Podell, Brendan K., Gary, Hadley E., Mecham, Jeffrey B., Berube, Bryan J., Baldwin, Susan L., Coler, Rhea N., Hickey, Anthony J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10220837/
https://www.ncbi.nlm.nih.gov/pubmed/37242512
http://dx.doi.org/10.3390/ph16050729
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author Maloney, Sara E.
Stewart, Ian E.
Podell, Brendan K.
Gary, Hadley E.
Mecham, Jeffrey B.
Berube, Bryan J.
Baldwin, Susan L.
Coler, Rhea N.
Hickey, Anthony J.
author_facet Maloney, Sara E.
Stewart, Ian E.
Podell, Brendan K.
Gary, Hadley E.
Mecham, Jeffrey B.
Berube, Bryan J.
Baldwin, Susan L.
Coler, Rhea N.
Hickey, Anthony J.
author_sort Maloney, Sara E.
collection PubMed
description Mycobacterium tuberculosis (M.tb) has infected one-quarter of the world’s population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant M.tb strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against M.tb while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline’s poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below <5 µm), suitable for inhalation therapies. Furthermore, the use of a 2-hydroxypropyl-β-cyclodextrin excipient allowed a molecular dispersion of bedaquiline in an aqueous solution for liquid instillation. Both delivery modalities were successfully administered to Hartley guinea pigs for pharmacokinetic analysis and were well-tolerated by the animals. Intrapulmonary liquid delivery of bedaquiline led to adequate serum absorption and appropriate peak serum concentrations of the drug. The liquid formulation was superior in systemic uptake compared to the powder formulation. The predominant route via which M.tb bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for M.tb.
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spelling pubmed-102208372023-05-28 Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration Maloney, Sara E. Stewart, Ian E. Podell, Brendan K. Gary, Hadley E. Mecham, Jeffrey B. Berube, Bryan J. Baldwin, Susan L. Coler, Rhea N. Hickey, Anthony J. Pharmaceuticals (Basel) Article Mycobacterium tuberculosis (M.tb) has infected one-quarter of the world’s population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant M.tb strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against M.tb while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline’s poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below <5 µm), suitable for inhalation therapies. Furthermore, the use of a 2-hydroxypropyl-β-cyclodextrin excipient allowed a molecular dispersion of bedaquiline in an aqueous solution for liquid instillation. Both delivery modalities were successfully administered to Hartley guinea pigs for pharmacokinetic analysis and were well-tolerated by the animals. Intrapulmonary liquid delivery of bedaquiline led to adequate serum absorption and appropriate peak serum concentrations of the drug. The liquid formulation was superior in systemic uptake compared to the powder formulation. The predominant route via which M.tb bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for M.tb. MDPI 2023-05-11 /pmc/articles/PMC10220837/ /pubmed/37242512 http://dx.doi.org/10.3390/ph16050729 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Maloney, Sara E.
Stewart, Ian E.
Podell, Brendan K.
Gary, Hadley E.
Mecham, Jeffrey B.
Berube, Bryan J.
Baldwin, Susan L.
Coler, Rhea N.
Hickey, Anthony J.
Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration
title Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration
title_full Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration
title_fullStr Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration
title_full_unstemmed Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration
title_short Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration
title_sort preparation strategies of the anti-mycobacterial drug bedaquiline for intrapulmonary routes of administration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10220837/
https://www.ncbi.nlm.nih.gov/pubmed/37242512
http://dx.doi.org/10.3390/ph16050729
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