Inhaled dopamine agonist for late stage Parkinsonism

描述（由申请人提供）：帕金森氏病的晚期通常以运动波动为特征，包括不可预测的和严重致残的完全不动期（“关闭”期）。对“关闭”期最有效的药物治疗是多巴胺激动剂，多巴胺激动剂阿扑吗啡特别有效。然而，阿扑吗啡的口服生物利用度低，治疗指数低，这限制了其临床应用。该提案的目的是开发吸入装置，将阿扑吗啡和至少一种其他多巴胺激动剂药物快速输送到血液中，使患者能够将药物摄入量滴定到最小有效剂量，从而减少副作用。我们公司开发了一种独特的气雾剂生成方法，可以在没有任何赋形剂或添加剂的情况下产生非常小的颗粒，用于有效的肺部深吸入。该技术已被证明可将几种FDA批准的药物快速全身递送至哺乳动物。在第一阶段的资助中，我们将验证我们使用这项技术可靠和可重复地提供治疗量的阿扑吗啡以及至少一种其他多巴胺激动剂化合物的能力。在随后的第二阶段拨款中，我们打算建立一个具有优化的患者界面和完整的动物药代动力学和毒理学研究的输送装置，足以启动人体临床试验。多巴胺受体激动剂吸入装置的最终临床批准将使晚期帕金森病患者能够更有效地控制他们的疾病，从而提高他们的整体生活质量。

DESCRIPTION (provided by applicant): Later stages of Parkinson's disease are often characterized by motor fluctuations that include unpredictable and severely disabling periods of complete immobility ("off" periods). The most effective pharmacological treatments for "off' periods are dopamine agonists, with the dopamine agonist apomorphine especially effective. Apomorphine, however, suffers from low oral bioavailability and a low therapeutic index, which limit its clinical use. The aim of this proposal is to develop inhalation devices that deliver apomorphine and at least one other dopamine agonist drug rapidly into the blood stream, enabling patients to titrate their drug intake to the minimum effective dose, thus reducing side effects. Our company has developed a unique aerosol generation method that produces very small particles for efficient deep lung inhalation without any excipients or entrainers. This technique has already been proven to result in rapid systemic delivery of several FDA-approved drugs to mammals. In this Phase I grant, we will verify our ability to use this technology to deliver reliably and reproducibly a therapeutic amount of apomorphine as well as at least one other dopamine agonist compound. In a subsequent Phase II grant, we intend to build a delivery device with an optimized patient interface and complete animal pharmacokinetic and toxicology studies sufficient to initiate human clinical trials. Eventual clinical approval of a dopamine agonist inhalation device will allow patients with late stage Parkinson's disease to control their Disease more effectively, and thus increases their overall quality of life.