Treatment of Pain by Drug Aerosol Inhalation

描述（由申请人提供）：突破性疼痛是一种令人恐惧的症状，在疾病的某个阶段折磨着大多数癌症患者。其特征在于快速发作，疼痛强度在几分钟内达到极度痛苦的水平，持续时间短（中位持续时间约为30分钟）。虽然常用，但由于其延迟起效和作用持续时间长，口服阿片类药物不能充分缓解爆发性疼痛，并且经常在疼痛消退后导致过量的血浆药物浓度，从而引起不良反应。最近批准的口服经粘膜芬太尼产品已在商业上取得成功，相对于口服阿片类药物，略微加速了突破性疼痛治疗的开始。然而，对于具有最小副作用的更快起效治疗仍然存在大量未满足的需求。该提案的目标是开发一种用于快速全身递送芬太尼（一种强效阿片类镇痛药）的吸入装置，用于治疗突破性疼痛。该吸入装置应用了Alexza MDC开创的新技术，以产生适合通过肺部深部全身递送的纯芬太尼气雾剂。初步的动物研究表明，使用我们的技术，可以快速、IV样、全身性地将几种FDA批准的药物输送给狗。在第一阶段，我们将证明将这种气雾剂生成技术纳入手持式多剂量输送设备的可行性，该设备具有确保患者安全并最大限度地减少阿片类药物滥用和转移的功能。在第二阶段，我们将在动物毒理学研究中确定芬太尼吸入的安全性，设计和制造用于临床试验的设备，并在人类使用我们的设备之前完成所有产品测试。在资助期结束时，我们将准备启动多剂量装置的人体测试。FDA最终批准我们的芬太尼产品将使癌症患者能够更有效地缓解突破性疼痛，从而提高他们的整体生活质量。此外，用于快速全身递送的安全、方便的多剂量装置平台可能会在临床实践中找到其他有价值的应用。

DESCRIPTION (provided by applicant): Breakthrough pain is a feared symptom afflicting the majority of cancer patients at some point in their illness. It is characterized by rapid onset, with pain intensity reaching excruciating level within several minutes, and brief duration (median duration approximately 30 minutes). Although commonly used, due to their delayed onset and long duration of action, oral opioids do not relieve breakthrough pain adequately and often result in excess plasma drug concentration after the pain has subsided, thus introduce adverse effects. A recently approved oral transmucosal fentanyl product has been commercially successful by marginally accelerating the onset of breakthrough pain treatment relative to oral opioids. However, there remains a substantial unmet need for a faster onset treatment with minimal side effects. The goal of this proposal is to develop an inhalation device for rapid systemic delivery of fentanyl, a potent opioid analgesic, for the treatment of breakthrough pain. The inhalation device applies a novel technology pioneered by Alexza MDC to generate a pure fentanyl aerosol appropriate for systemic delivery through the deep lung. Preliminary animal studies have shown rapid, IV-like, systemic delivery of several FDA-approved drugs to dogs using our technology. In Phase I of this grant, we will demonstrate the feasibility of incorporating this aerosol generation technology into a handheld, multi-dose delivery device with features ensuring patient safety and minimizing opioid abuse and diversion. In Phase II, we will determine the safety of fentanyl inhalation in animal toxicology studies, design and manufacture devices for use in clinical trials, and complete all product testing required prior to human use of our device. By the end of the grant period, we will be ready to initiate human testing of the multi-dose device. Eventual FDA approval of our fentanyl product will allow cancer patients to relieve breakthrough pain more effectively, thus improving their overall quality of life. In addition, the secure, convenient multi-dose device platform for rapid systemic delivery will likely find other valuable applications in clinical practices.