Nicotine delivery to rodent with lung alveolar region-targeted aerosol technology

描述(由申请人提供)：我们完成的SBIR第一阶段项目(R43 DA031578)是对NIH PA11-096，PHS 2011-02“NIDA 2下的SBIR/STTR赠款申请的综合征集”的响应，NIDA 2“为药物滥用研究开发替代药物给药剂型”。我们已经开发了一种针对肺泡区的尼古丁向啮齿动物输送的气雾剂/吸入方法，并开发了具有专门软件的设备，使这种新方法能够有效地使用。在只有鼻子的装置和自由移动的曝光室中，气溶胶液滴的尺寸分布都在可呼吸的直径范围内。通过物理模拟香烟烟雾的特性，雾化吸入在动脉和静脉血液中产生尼古丁PK，类似于人类吸烟的PK曲线。这种非侵入性的方法克服了目前尼古丁输送方法的局限性。我们已经证明，这种新的方法和装置能够将可控数量的尼古丁快速输送到体循环中，并诱导剂量依赖的行为反应。这一第二阶段项目的目标是将原型转化为商业化产品--“AeroDeliver(R)”。具体目标如下：目标1.开发和扩大集成气雾剂吸入系统的商业产品系列，包括仅靠鼻子的曝光装置和可自由移动的曝光室。我们将创建集成的硬件和软件，并扩大规模，同时运行16个AeroDeliver(R)系统。目的2.进一步发展针对慢性间歇性尼古丁暴露的新型肺泡区靶向雾化吸入方法，并通过动物实验进行验证。该设备和方案将通过动物试验和测量血浆尼古丁浓度来评估和验证，这些浓度模拟了中等到重度吸烟者的PK曲线。我们将通过放射性标记尼古丁气溶胶的正电子发射断层扫描(PET)来验证体内尼古丁气溶胶在肺部的沉积。目的3.在药物依赖和强化研究中建立尼古丁气雾剂自我给药范式。该系统将有正负杠杆(用于大鼠)或鼻戳传感器(用于小鼠)，以供性能选择。该系统还将执行固定比率(FR)和累进比率(PR)的加固计划。我们将在啮齿动物实验中对该系统进行评估，并将其操作和结果与常规静脉注射进行比较。使用目前可用的商业设备的尼古丁自我给药方法。在动物测试过程中，我们还将开发一本带有标准化方案的实验《食谱》，以便于比较不同实验室产生的结果。我们的产品-AeroDeliver(R)系统将成为研究尼古丁成瘾、毒理学、致畸性和烟草相关疾病的强大工具包，并最终促进新的治疗发现。此外，这些工具包被用于大麻、可卡因和海洛因等其他滥用药物的巨大潜力将扩大我们产品的市场规模。

DESCRIPTION (provided by applicant): Our completed SBIR Phase I project (R43 DA031578) was in response to NIH PA11-096, PHS 2011-02 'Omnibus solicitation for SBIR/STTR Grant Application' under NIDA 2, "Development of Alternate Drug Delivery Dosage Forms for Drugs Abuse Studies." We have developed an alveolar region-targeted aerosol/inhalation method for nicotine delivery to rodents and developed devices with specialized software that enable this new method to be used effectively. In both the nose-only device and free-moving exposure chambers, the aerosol droplet size distribution is within the respirable diameter range. By physically imitating the properties of cigarette smoke, aerosol inhalation produces nicotine PK in both the arterial and venous blood resembling the PK profile of humans smoking cigarettes. This noninvasive method overcomes the limitations of current nicotine delivery methods. We have demonstrated that this novel method and device enable rapid delivery of a controllable amount of nicotine into systemic circulation and induces dose-dependent behavioral responses. The goal of this Phase II project is to translate the prototypes into commercialized products-"AeroDeliver(R)". Three Specific Aims are as follows: Aim 1. Develop and scale up a commercial product series of integrated aerosol inhalation systems including nose-only exposure devices and free-moving exposure chambers. We will create the integrated hardware and software, and scale up to simultaneously operate 16 AeroDeliver(R) systems. Aim 2. Further develop the novel alveolar region-targeted aerosol inhalation method for chronic intermittent nicotine exposure and validate it with animal testing. The device and protocol will be evaluated and validated using animal testing and by measuring plasma nicotine concentrations that simulate the PK profile in moderate to heavy human smokers. We will verify nicotine aerosol deposition in the lungs in vivo by positron emission tomography (PET) with radioactive labeled nicotine aerosol. Aim 3. Establish nicotine aerosol self-administration paradigms in drug dependence and reinforcement studies. The system will have positive and negative levers (for rats) or nosepoke sensors (for mice) for performance choice. The system will also perform fixed ratio (FR) and progressive ratio (PR) reinforcement schedules. We will evaluate the system in rodent experiments and compare the operation and results with conventional i.v. nicotine self-administration methods that use currently available commercial devices. In the course of animal testing, we will also develop an experimental "cookbook" with standardized protocols to facilitate comparison of results generated by different laboratories. Our products -AeroDeliver(R) system will be a powerful toolkit for studies of nicotine addiction, toxicology, teratogenicity and tobacco-related diseases, and ultimately, for facilitation of new therapeutic discovery. Furthermore, the significant potential for these toolkits to be used for other drugs of abuse such as marijuana, cocaine, and heroin will expand the market size for our products.