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

吸入是一种日益重要的给药方式。在各种治疗领域，“一天一次”治疗的医疗、商业和实际需要仍未得到满足，而目前的一些治疗方法缺乏这种需求。在某些情况下，每日一次治疗是可能的，但这种方法可能涉及过量剂量，以达到所需的作用时间。负面的问题通常是由于最初的药物暴露量高于预期而产生的副作用。拟议的项目包括通过前药物方法对现有药物进行化学修饰。活性药物将在靶点以受控的方式释放，因此药理作用的持续时间将明显长于传统方法。该概念将在临床前通过各种试验剂的迭代设计和合成以及体外和体内药物代谢试验进行测试，以证明实现了所需的持续时间延长。

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.