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.
Highlights
IntroductionThe novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical Phase 1a study
Leukotriene production is elevated in the Alzheimer’s disease (AD) brain [11,12]; leukotrienes are involved in various aspects of AD pathologies, in particular, neuroinflammation and neuronal cell death, and genetic and pharmacological blockage of leukotrienes in animal models of neurodegenerative diseases, including AD, have demonstrated efficacy in reducing pathology and promoting cognitive functions
We developed a novel MTK oral mucoadhesive film to circumvent the limitations of MTK in its tablet form, tested its stability and dissolution, and performed a Phase I bioavailability and safety study in healthy volunteers, where we assessed MTK pharmacokinetics in serum and cerebrospinal fluid
Summary
The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical Phase 1a study. 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. MTK is freely soluble in water, its solubility increases significantly above pH 7.5 and drastically reduces under acidic conditions normally found in the gastrointestinal tract—in particular, in the stomach [4] This has led to relatively slow and inconsistent absorption into the blood stream, with maximum concentrations occurring between 2 and 4 h following consumption, thereby limiting its use to chronic applications rather than for rapid acute treatment.
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