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Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice

The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low-...

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Autores principales: Michael, Johanna, Bessa de Sousa, Diana, Conway, Justin, Gonzalez-Labrada, Erick, Obeid, Rodolphe, Tevini, Julia, Felder, Thomas, Hutter-Paier, Birgit, Zerbe, Horst, Paiement, Nadine, Aigner, Ludwig
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822410/
https://www.ncbi.nlm.nih.gov/pubmed/33374646
http://dx.doi.org/10.3390/pharmaceutics13010012
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author Michael, Johanna
Bessa de Sousa, Diana
Conway, Justin
Gonzalez-Labrada, Erick
Obeid, Rodolphe
Tevini, Julia
Felder, Thomas
Hutter-Paier, Birgit
Zerbe, Horst
Paiement, Nadine
Aigner, Ludwig
author_facet Michael, Johanna
Bessa de Sousa, Diana
Conway, Justin
Gonzalez-Labrada, Erick
Obeid, Rodolphe
Tevini, Julia
Felder, Thomas
Hutter-Paier, Birgit
Zerbe, Horst
Paiement, Nadine
Aigner, Ludwig
author_sort Michael, Johanna
collection PubMed
description The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low- and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering from dysphagia, for example, seen in patients with neurodegenerative diseases such as Alzheimer’s disease, a disease with increasing interest in repurposing of MTK. This, and the need for an improved bioavailability, triggered us to reformulate MTK. Our aim was to develop a mucoadhesive MTK film with good safety and improved pharmacological features, i.e., an improved bioavailability profile in humans as well as in a mouse model of Alzheimer’s disease. We tested dissolution of the MTK mucoadhesive film and assessed pharmacoexposure and kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I analysis in humans, which included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid. The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical Phase 1a study. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF). In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose-dependent manner. The mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate Blood-Brain-Barrier (BBB) penetrance in a preclinical model, as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke.
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spelling pubmed-78224102021-01-23 Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice Michael, Johanna Bessa de Sousa, Diana Conway, Justin Gonzalez-Labrada, Erick Obeid, Rodolphe Tevini, Julia Felder, Thomas Hutter-Paier, Birgit Zerbe, Horst Paiement, Nadine Aigner, Ludwig Pharmaceutics Article The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low- and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering from dysphagia, for example, seen in patients with neurodegenerative diseases such as Alzheimer’s disease, a disease with increasing interest in repurposing of MTK. This, and the need for an improved bioavailability, triggered us to reformulate MTK. Our aim was to develop a mucoadhesive MTK film with good safety and improved pharmacological features, i.e., an improved bioavailability profile in humans as well as in a mouse model of Alzheimer’s disease. We tested dissolution of the MTK mucoadhesive film and assessed pharmacoexposure and kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I analysis in humans, which included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid. The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical Phase 1a study. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF). In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose-dependent manner. The mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate Blood-Brain-Barrier (BBB) penetrance in a preclinical model, as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke. MDPI 2020-12-23 /pmc/articles/PMC7822410/ /pubmed/33374646 http://dx.doi.org/10.3390/pharmaceutics13010012 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Michael, Johanna
Bessa de Sousa, Diana
Conway, Justin
Gonzalez-Labrada, Erick
Obeid, Rodolphe
Tevini, Julia
Felder, Thomas
Hutter-Paier, Birgit
Zerbe, Horst
Paiement, Nadine
Aigner, Ludwig
Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice
title Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice
title_full Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice
title_fullStr Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice
title_full_unstemmed Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice
title_short Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice
title_sort improved bioavailability of montelukast through a novel oral mucoadhesive film in humans and mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822410/
https://www.ncbi.nlm.nih.gov/pubmed/33374646
http://dx.doi.org/10.3390/pharmaceutics13010012
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