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

利用肺泡区域靶向气雾剂技术向啮齿动物输送尼古丁

• 批准号: 8525015
• 负责人: XUESI Max SHAO
• 金额: $ 50.61万
• 依托单位: AFASCI, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525015
• 关键词: Acute; Aerosols; Air; Air Pressure; Alveolar; Animal Model; Animal Testing; Animals; Applications Grants; Behavior; Behavioral; Blood; Blood Circulation; Breathing; Caliber; Cessation of life; Chronic; Cigarette; Circadian Rhythms; Cocaine; Computer software; Computers; Cookbook; Dependence; Deposition; Detection; Development; Devices; Disease; Dosage Forms; Dose; Drug Addiction; Drug Administration Routes; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Generations; Goals; Heroin; Human; Immobilization; Infusion Pumps; Intake; Label; Laboratories; Light; Lung; Manuals; Marijuana; Marketing; Measures; Methods; Monitor; Mus; National Institute of Drug Abuse; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nose; Oral; Performance; Pharmaceutical Preparations; Phase; Plasma; Play; Positron-Emission Tomography; Property; Protocols documentation; Psychological reinforcement; Radioactive; Rattus; Receptor Activation; Reinforcement Schedule; Rodent; Role; Schedule; Seizures; Self Administration; Series; Simulate; Sleep; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Smoker; Smoking; Smoking Behavior; Subcutaneous Injections; System; Tail; Technology; Time; Tissues; Tobacco; Tobacco use; Toxic effect; Toxicology; Translating; Tremor; United States National Institutes of Health; Venous; Ventilatory Depression; Withdrawal; cigarette smoking; cigarette smoking; desensitization; design; disability; drug of abuse; drug reinforcement; in vivo; meetings; novel; novel therapeutics; operation; prototype; public health relevance; research study; response; scale up; sensor; software development; software systems; vapor

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.

描述（由申请人提供）：我们已完成的SBIR I期项目（R43 DA 031578）是对NIH PA 11 -096、PHS 2011-02“NIDA 2下SBIR/STTR资助申请的综合征集”的回应，“药物滥用研究替代药物给药剂型的开发”。“我们开发了一种针对肺泡区域的雾化/吸入方法，用于向啮齿动物输送尼古丁，并开发了带有专门软件的设备，使这种新方法能够有效使用。在仅鼻用装置和自由移动暴露室中，气溶胶液滴尺寸分布均在可吸入直径范围内。通过物理模拟香烟烟雾的特性，气雾吸入在动脉和静脉血液中产生类似于人类吸烟的PK特征的尼古丁PK。这种非侵入性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量的尼古丁快速递送到体循环中，并诱导剂量依赖性行为反应。第二阶段项目的目标是将原型转化为商业化产品-“AeroDeliver（R）"。三个具体目标如下：目标1。开发和扩大一体化气雾剂吸入系统的商业产品系列，包括鼻暴露装置和自由移动暴露室。我们将创建集成的硬件和软件，并扩展到同时运行16个AeroDeliver（R）系统。目标二。进一步开发针对慢性间歇性尼古丁暴露的新型肺泡区域靶向雾化吸入方法，并通过动物试验进行验证。将使用动物试验和测量血浆尼古丁浓度（模拟中度至重度吸烟者的PK特征）对器械和方案进行评价和确认。我们将通过正电子发射断层扫描（PET）和放射性标记的尼古丁气雾剂验证尼古丁气雾剂在体内肺中的沉积。目标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例。该系统将有积极和消极的杠杆（大鼠）或鼻子戳传感器（小鼠）的性能选择。该系统还将执行固定比率（FR）和渐进比率（PR）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使用当前市售设备的传统静脉内尼古丁自我给药方法进行比较。在进行动物测试时，我们亦会制订一套标准化的实验守则，方便比较不同实验室的结果。我们的产品-AeroDeliver（R）系统将成为尼古丁成瘾、毒理学、致畸性和烟草相关疾病研究的强大工具包，并最终促进新的治疗发现。此外，这些工具包用于大麻、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。