Inhaled dopamine agonists for late stage Parkinsonism

描述（由申请人提供）：许多帕金森病晚期患者会经历急性不动期（“关闭”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，如果通过注射迅速进入血流，可以迅速中止“关闭”期。然而，这种形式的治疗的效用是有限的，由于其侵入性和许多晚期帕金森病患者无法自我管理注射。 该项目的目的是开发一种吸入装置，以方便，非侵入性的方式将多巴胺激动剂快速输送到血流中。我们已经开发了一种新的药物递送技术，其涉及加热药物，使得它们蒸发，但不降解，随后冷却并冷凝成适合于通过吸入全身递送的小颗粒气溶胶。在该提案的第一阶段，我们已经构建了一种能够产生几种多巴胺激动剂的纯气溶胶的手持设备，证明了这些气溶胶在体外的生物活性，并证实了气溶胶的粒径适合于通过深肺吸入进行全身递送。在该资助的第二阶段，我们将证明吸入性多巴胺激动剂在动物模型中迅速逆转帕金森病症状，并将进行所有临床前工作，以启动吸入性多巴胺激动剂治疗晚期帕金森病的临床开发。成功完成这些目标将使我们能够进入I期临床试验，该试验将由外部投资者、FDA孤儿药开发基金和/或与一家大型制药公司合作提供资金。最终FDA批准吸入多巴胺激动剂产品用于治疗晚期帕金森氏症的运动波动，将大大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.