Inhaled dopamine agonists for late stage Parkinsonism

描述(由申请人提供)：许多帕金森氏症晚期患者都经历了急性不动的时期(“休止期”)，这大大降低了他们的生活质量。对这些急性“关闭”期最有效的药物治疗是多巴胺激动剂药物，如果通过注射迅速将其输送到血液中，可以迅速终止“关闭”期。然而，这种形式的治疗的有效性是有限的，因为它具有侵袭性，而且许多晚期帕金森病患者无法自我注射。该项目的目的是开发一种吸入器，以方便、非侵入性的方式将多巴胺激动剂快速输送到血液中。我们开发了一种新的药物输送技术，包括加热药物，使其蒸发，但不会降解，然后冷却并浓缩成适合吸入全身输送的小颗粒气雾剂。在该方案的第一阶段，我们构建了一种能够产生几种多巴胺激动剂的纯气雾剂的手持设备，在体外展示了这些气雾剂的生物活性，并证实了气雾剂的颗粒大小适合通过深肺吸入全身给药。在这笔赠款的第二阶段，我们将在动物模型中证明吸入型多巴胺激动剂可以迅速逆转帕金森氏症的症状，并将进行所有临床前工作，以启动用于治疗晚期帕金森病的吸入型多巴胺激动剂的临床开发。成功完成这些目标将使我们能够进入第一阶段临床测试，该阶段将由外部投资者、FDA用于孤儿药物开发的资金和/或与一家主要制药公司的合作伙伴关系提供资金。FDA最终批准吸入性多巴胺激动剂产品用于治疗晚期帕金森氏症的运动波动，这将极大地改善这种严重和常见的神经退行性疾病的治疗。

DESCRIPTION (provided by applicant): Many patients in the later stages of Parkinson's disease experience periods of acute immobility ("off' periods) that substantially decrease their quality of life. The most effective pharmacological treatments for these acute "off' periods are dopamine agonist drugs, which can rapidly abort "off' periods if delivered quickly into the blood stream via injection. The utility of this form of treatment is, however, limited due to its invasiveness and the inability of many late-stage Parkinson's disease patients to self-administer injections. The aim of this project is to develop an inhalation device that delivers dopamine agonists rapidly into the blood stream in a convenient, non-invasive fashion. We have developed a novel drug delivery technology that involves heating drugs such that they vaporize, but do not degrade, and subsequently cool and condense into small particle aerosols suitable for systemic delivery by inhalation. In Phase I of this proposal, we have constructed a handheld device capable of generating pure aerosols of several dopamine agonists, demonstrated the biological activity of these aerosols in vitro, and confirmed that the aerosol's particle size is appropriate for systemic delivery via deep lung inhalation. In Phase II of this grant we will prove that inhaled dopamine agonists rapidly reverse Parkinson's disease symptoms in an animal model and will conduct all pre-clinical work required to initiate clinical development of inhaled dopamine agonist for treatment of late stage Parkinson's disease. Successful completion of these aims will allow us to move into Phase I clinical testing, which will be funded by a combination of outside investors, FDA funds for the development of orphan drugs, and/or a partnership with a major pharmaceutical company. Eventual FDA approval of inhaled dopamine agonist product for treatment of motor fluctuations in late stage Parkinson's will substantially improve the treatment of this serious and common neurodegenerative disease.