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
Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada.
Pharmaceutics. 2020 Dec 23;13(1):12. doi: 10.3390/pharmaceutics13010012.
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.
白三烯受体拮抗剂孟鲁司特（MTK）是一种已获批准用于治疗哮喘和过敏性鼻炎的药物。现有的孟鲁司特市售片剂形式表现出不一致的吸收和生物利用度，这部分解释了人群中存在相当比例的孟鲁司特低反应者和无反应者。除此之外，片剂对于吞咽困难的患者来说并非最佳剂型，例如，在患有神经退行性疾病（如阿尔茨海默病）的患者中可见，而阿尔茨海默病是一种对孟鲁司特重新利用越来越感兴趣的疾病。这一点以及对提高生物利用度的需求促使我们对孟鲁司特进行重新配方。我们的目标是开发一种具有良好安全性和改善药理学特性的粘膜粘附孟鲁司特薄膜，即在人类以及阿尔茨海默病小鼠模型中具有改善的生物利用度概况。我们测试了孟鲁司特粘膜粘附薄膜的溶出度，并评估了在小鼠急性和慢性口服给药后的药物暴露和动力学。此外，我们在人体中进行了I期分析，其中包括与市售片剂形式的比较以及脑脊液中孟鲁司特水平的定量分析。在临床1a期研究中，新型孟鲁司特薄膜与市售片剂相比，生物利用度有显著提高。此外，脑脊液（CSF）中存在可测量量的孟鲁司特。在小鼠中，急性和慢性暴露后，血清和脑脊液中均以剂量依赖性方式检测到孟鲁司特。孟鲁司特的粘膜粘附薄膜是片剂给药的一种有前景的替代方案。口服薄膜可能会降低哮喘患者的无反应率，并且可能是孟鲁司特在其他疾病中重新利用的一个有趣产品。由于我们在临床前模型以及临床研究中证明了血脑屏障（BBB）的渗透性，孟鲁司特口服薄膜可能会用作治疗急性和慢性神经退行性疾病（如痴呆症和中风）的药物。
