Evaluation of membrane-retentive pro-drugs to increase duration of effect to enable once-a-day dosing of inhaled muscarinic M3 receptor antagonists

吸入是治疗药物进入肺部的一种日益重要的给药方式。在不同的治疗领域，“一天一次”治疗的医疗、商业和实际需求仍未得到满足，而目前的一些治疗方法缺乏这一需求。在某些情况下，每天一次治疗是可能的，但这种方法可能涉及过量服药，以提供所需的作用时间。一个负面的问题通常是由于最初的药物暴露高于预期而产生的副作用。拟议的项目涉及通过亲药物方法对现有药物进行化学修饰。活性药物在靶点以受控方式释放，药理作用持续时间明显长于传统方法。这一概念将通过各种测试剂的迭代设计和合成以及体外和体内的药物代谢测试进行临床前测试，以证明所需的延长持续时间是实现的。

Inhalation is an increasingly important delivery approach of therapeutic agents to the lung. There remains an unmet medical, commercial and practical need for 'once-a-day' treatment in various therapeutic areas and this is lacking for some current therapies. Once daily treatment is possible in some cases, but this approach can involve over-dosing to give the required duration of action. A negative issue is often side-effects due to initial higher than desired drug exposure. The proposed project involves chemically modifying current drugs via a pro-drug approach. The active drug will be released in a controlled manner at the target site, so the duration of pharmacological effect will be significantly longer than the traditional approach. The concept will be tested pre-clinically with the iterative design and synthesis of various test agents and drug metabolism tests in vitro and in vivo to prove that the required extension of duration is realised.