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

Abstract

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.

Statistically Optimized Polymeric Buccal Films of Eletriptan Hydrobromide and Itopride Hydrochloride: An In Vivo Pharmacokinetic Study

“…The data were interpreted at a 95% confidence interval with their standard deviation (SD) calculated as mentioned. The value of p indicated the value of significance where p < 0.05 indicated that data were significant (*), p < 0.01 represented very significant data (**), and p < 0.0001 showed extremely significant data (*** or ****) [79].…”

Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer’s dementia

“…In rodent models, administration of montelukast enhanced neurogenesis, increased blood-brain barrier (BBB) integrity, and reduced neuroinflammation [ 6 , 7 , 36 ], which may be of benefit in the context of accumulated AD pathology. Although montelukast may penetrate the BBB [ 37 ], it is unclear if it enters the brain at concentrations sufficient to have effects in the central nervous system in humans at the doses currently used in asthma treatment. At these concentrations, LTRAs may be acting primarily on the vasculature which may explain the beneficial effects observed in vascular-related cognitive domains such as psychomotor processing speed but not necessarily domains most specific to AD such as memory.…”

“…Taken together, the results show that the leukotriene pathway warrants further investigation in AD treatment, either with currently available LTRAs (e.g., larger dose, increased frequency, or different route of administration) or with new investigational drugs that are targeting this pathway. Recently, a buccal film was produced which may help increase bioavailability of montelukast and achieve higher plasma concentrations [ 37 ]. Further studies are needed, particularly clinical trials, to determine potential efficacy and dose-response relationships between the LTRA use and cognition.…”

Overview about Oral Films in Mental Disorders

“…Montelukast (MTK) is a leukotriene receptor antagonist commonly used to treat chronic asthma, but recently it has also been used in the treatment of Alzheimer’s disease. Recent literature has highlighted the power of this substance to reduce the risk of dementia and to improve cognitive function in patients with dementia [ 42 ]. An MTK OF could therefore be used in the future as a therapeutic product in acute and chronic neurodegenerative diseases.…”