{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T22:14:49Z","timestamp":1773353689904,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics13010012","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T12:19:51Z","timestamp":1608725991000},"page":"12","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Johanna","family":"Michael","sequence":"first","affiliation":[{"name":"Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Bessa de Sousa","sequence":"additional","affiliation":[{"name":"Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Conway","sequence":"additional","affiliation":[{"name":"IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erick","family":"Gonzalez-Labrada","sequence":"additional","affiliation":[{"name":"IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodolphe","family":"Obeid","sequence":"additional","affiliation":[{"name":"IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Tevini","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8266-5513","authenticated-orcid":false,"given":"Thomas","family":"Felder","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgit","family":"Hutter-Paier","sequence":"additional","affiliation":[{"name":"QPS Neuropharmacology, 8074 Grambach\/Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Horst","family":"Zerbe","sequence":"additional","affiliation":[{"name":"IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Paiement","sequence":"additional","affiliation":[{"name":"IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludwig","family":"Aigner","sequence":"additional","affiliation":[{"name":"Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria"},{"name":"QPS Neuropharmacology, 8074 Grambach\/Graz, Austria"},{"name":"Austrian Cluster of Tissue Regeneration Affiliation, 1200 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1038\/sj.emboj.7601341","article-title":"The orphan receptor GPR17 identified as a new dual uracil nucleotides\/cysteinyl-leukotrienes receptor","volume":"25","author":"Ciana","year":"2006","journal-title":"EMBO J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1517\/14656566.5.3.679","article-title":"A review of montelukast in the treatment of asthma and allergic rhinitis","volume":"5","author":"Nayak","year":"2004","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1001\/archinte.158.11.1213","article-title":"Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: A multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group","volume":"158","author":"Reiss","year":"1998","journal-title":"Arch. Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1007\/s11095-008-9642-z","article-title":"Dynamic Dissolution Testing To Establish In Vitro\/In Vivo Correlations for Montelukast Sodium, a Poorly Soluble Drug","volume":"25","author":"Okumu","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3389\/fphar.2016.00299","article-title":"Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies","volume":"7","author":"Thompson","year":"2016","journal-title":"Front. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1183\/09031936.98.11061232","article-title":"Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma. Montelukast Asthma Study Group","volume":"11","author":"Noonan","year":"1998","journal-title":"Eur. Respir. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/FPC.0b013e32831bd98c","article-title":"Absorption of montelukast is transporter mediated: A common variant of OATP2B1 is associated with reduced plasma concentrations and poor response","volume":"19","author":"Mougey","year":"2009","journal-title":"Pharm. Genom."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1177\/0091270010374472","article-title":"Effect of Citrus Juice and SLCO2B1 Genotype on the Pharmacokinetics of Montelukast","volume":"51","author":"Mougey","year":"2011","journal-title":"J. Clin. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.3109\/10717544.2016.1170247","article-title":"Montelukast medicines of today and tomorrow: From molecular pharmaceutics to technological formulations","volume":"23","author":"Barbosa","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.drudis.2018.09.008","article-title":"The leukotriene signaling pathway: A druggable target in Alzheimer\u2019s disease","volume":"24","author":"Michael","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1369\/jhc.2008.951855","article-title":"Increased 5-Lipoxygenase Immunoreactivity in the Hippocampus of Patients With Alzheimer\u2019s Disease","volume":"56","author":"Ikonomovic","year":"2008","journal-title":"J. Histochem. Cytochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40478-020-00989-4","article-title":"Microglia depletion diminishes key elements of the leukotriene pathway in the brain of Alzheimer\u2019s Disease mice","volume":"8","author":"Michael","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Grinde, B., Schirmer, H., Eggen, A.E., Aigner, L., and Engdahl, B. (2020). A possible effect of montelukast on neurological aging examined by the use of register data. Int. J. Clin. Pharm., 1\u20138.","DOI":"10.1007\/s11096-020-01160-8"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12979-017-0102-7","article-title":"Prescription database analyses indicates that the asthma medicine montelukast might protect against dementia: A hypothesis to be verified","volume":"14","author":"Grinde","year":"2017","journal-title":"Immun. Ageing"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.2174\/1874205X01711010007","article-title":"Case Series Using Montelukast in Patients with Memory Loss and Dementia","volume":"11","author":"Rozin","year":"2017","journal-title":"Open Neurol. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.4103\/0975-7406.76478","article-title":"Mucoadhesive drug delivery systems","volume":"3","author":"Shaikh","year":"2011","journal-title":"J. Pharm. Bioal. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"466","DOI":"10.5731\/pdajpst.2012.00877","article-title":"Drug Delivery from the Oral Cavity: A Focus on Mucoadhesive Buccal Drug Delivery Systems","volume":"66","author":"Shinkar","year":"2012","journal-title":"Pda J. Pharm. Sci. Technol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.ijpharm.2015.08.038","article-title":"Mucoadhesive oral films: The potential for unmet needs","volume":"494","author":"Silva","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal beta-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer\u2019s Disease Mutations: Potential Factors in Amyloid Plaque Formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8466","DOI":"10.1038\/ncomms9466","article-title":"Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug","volume":"6","author":"Marschallinger","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1002\/bmc.3114","article-title":"Sensitive LC-MS\/MS-ESI method for simultaneous determination of montelukast and fexofenadine in human plasma: Application to a bioequivalence study","volume":"28","author":"Muppavarapu","year":"2014","journal-title":"Biomed. Chromatogr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3797\/scipharm.1002-07","article-title":"Method Development and Validation of Montelukast in Human Plasma by HPLC Coupled with ESI-MS\/MS: Application to a Bioequivalence Study","volume":"78","author":"Challa","year":"2010","journal-title":"Sci. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/3454212","article-title":"Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases","volume":"2017","author":"Gelosa","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1111\/cns.12596","article-title":"Cysteinyl Leukotrienes and Their Receptors: Emerging Therapeutic Targets in Central Nervous System Disorders","volume":"22","author":"Ghosh","year":"2016","journal-title":"CNS Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/21658","article-title":"Characterization of the human cysteinyl leukotriene CysLT1 receptor","volume":"399","author":"Lynch","year":"1999","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1046\/j.1365-2222.2001.00969.x","article-title":"Clinical safety and tolerability of montelukast, a leukotriene receptor antagonist, in controlled clinical trials in patients aged > or = 6 years","volume":"31","author":"Storms","year":"2001","journal-title":"Clin. Exp. Allergy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1159\/000366164","article-title":"Montelukast-Induced Adverse Drug Reactions: A Review of Case Reports in the Literature","volume":"94","author":"Calapai","year":"2014","journal-title":"Pharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1183\/09031936.00092812","article-title":"Nightmares induced by montelukast in children and adults","volume":"40","author":"Cereza","year":"2012","journal-title":"Eur. Respir. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00341","DOI":"10.1002\/prp2.341","article-title":"Adverse drug reactions of montelukast in children and adults","volume":"5","author":"Haarman","year":"2017","journal-title":"Pharm. Res. Perspect."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chu, J., Li, J.G., and Pratic\u00f2, D. (2013). Zileuton Improves Memory Deficits, Amyloid and Tau Pathology in a Mouse Model of Alzheimer\u2019s Disease with Plaques and Tangles. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070991"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1016\/j.ajpath.2010.12.032","article-title":"Pharmacologic blockade of 5-lipoxygenase improves the amyloidotic phenotype of an Alzheimer\u2019s disease transgenic mouse model involvement of gamma-secretase","volume":"178","author":"Chu","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.biopsych.2013.04.009","article-title":"5-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer\u2019s disease","volume":"74","author":"Giannopoulos","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1016\/j.neurobiolaging.2014.05.016","article-title":"Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer\u2019s disease mice","volume":"35","author":"Lauretti","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1007\/s12035-018-1124-7","article-title":"Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway","volume":"56","author":"Giannopoulos","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.phrs.2019.02.025","article-title":"Improvement of fiber connectivity and functional recovery after stroke by montelukast, an available and safe anti-asthmatic drug","volume":"142","author":"Gelosa","year":"2019","journal-title":"Pharm. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.phrs.2015.02.001","article-title":"Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: An isobolographic analysis","volume":"94","author":"Fleck","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"869","DOI":"10.12659\/MSM.892932","article-title":"Montelukast Inhibits Pentylenetetrazol-Induced Seizures in Rats","volume":"21","author":"Cevik","year":"2015","journal-title":"Med. Sci. Monit."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1007\/s13311-020-00836-3","article-title":"The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies","volume":"17","author":"Marschallinger","year":"2020","journal-title":"Neurotherapeutics"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/1\/12\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:48:47Z","timestamp":1760179727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/1\/12"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,23]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["pharmaceutics13010012"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13010012","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.11.06.371500","asserted-by":"object"}]},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,23]]}}}