High Efficiency Delivery of Surfactant Aerosols to Infants without Intubation

无需插管即可高效向婴儿输送表面活性剂气雾剂

• 批准号: 9889160
• 负责人: Michael Hindle
• 金额: $ 72.37万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889160
• 关键词: 3-Dimensional; Adult; Adult Respiratory Distress Syndrome; Aerosols; Alveolar; Animal Model; Bolus Infusion; Catheters; Cerebrum; Chronic lung disease; Continuous Positive Airway Pressure; Deposition; Devices; Dose; Edema; Ensure; Excipients; Ferrets; Formulation; Fostering; Goals; Growth; Hand; Histology; Hour; Hypotension; Hypoxia; In Vitro; Infant; Inflammation; Inhalators; Intracranial Hemorrhages; Intratracheal Intubation; Intubation; Liquid substance; Lung; Lung infections; Mechanical ventilation; Methods; Modeling; Mucous body substance; Nebulizer; Nose; Outcome; Penetration; Perfusion; Phospholipids; Pneumonia; Powder dose form; Premature Infant; Pulmonary Surfactants; Rattus; Respiration; Respiratory physiology; Risk; Rod; Rodent; Route; Structure; System; Techniques; Testing; Therapeutic; Time; Tube; Viral Bronchiolitis; Wettability; aerosolized; airway inflammation; base; effective therapy; efficacy testing; endotracheal; experimental study; fine particles; hemodynamics; improved; lung injury; neonate; novel therapeutic intervention; particle; prevent; prototype; respiratory; respiratory distress syndrome; side effect; simulation; surfactant; surfactant function; surfactant replacement therapy; symptomatic improvement; ventilation

Surfactant replacement therapy in neonates is currently achieved through endotracheal intubation and liquid bolus instillation. High efficiency delivery of aerosolized surfactant is proposed as a technique to improve airway distribution of the surfactant and prevent endotracheal intubation in cases where noninvasive ventilation (NIV) is the preferred respiratory support strategy. Primary limitations of aerosolized surfactants are currently very low lung delivery efficiencies (typically ~1%), long delivery times (~3 hours for mesh nebulizers), and poor distribution of the surfactant to the alveolar region. The goal of this study is to develop formulations and devices for the effective delivery of aerosolized surfactants to the lungs of infants using the nose-to-lung (N2L) route thereby avoiding intubation. To achieve high efficiency lung delivery, the excipient enhanced growth (EEG) approach will be used in which submicrometer particles are formed through spray drying and contain the surfactant and a hygroscopic excipient. The initial small size of the aerosolized particles allows for effective penetration through the new delivery device and infant upper airways. Inclusion of the hygroscopic excipient in the primary particles fosters aerosol size increase inside the airways and effective deposition in the alveolar region. This approach was successfully employed by our group to improve N2L aerosol delivery in adults. The aerosol will be generated using new EEG surfactant powder formulations together with new low-flow and low-volume dry powder inhalers, which are developed and optimized using a combination of computational fluid dynamics (CFD), rapid prototyping, and in vitro experiments. Functionality of the new surfactant aerosol will be assessed in surfactant depletion animal models and compared with liquid instillation. The following aims are proposed to develop this new therapeutic approach: Specific Aim 1. Develop an excipient enhanced growth (EEG) formulation of a lung surfactant that can be efficiently aerosolized, increase in aerodynamic size within the airways, and maintain surfactant function. Specific Aim 2. Develop and optimize a device for generating and administering surfactant aerosols to infants using the noninvasive nose-to-lung (N2L) route and achieving high efficiency lung delivery. Specific Aim 3. Adapt the N2L aerosol delivery device and test EEG surfactant aerosol efficacy in an infant- size ferret model compared with surfactant instillation in terms of oxygenation, lung distribution and histology. Outcomes and Impact. Successful delivery of aerosolized surfactant will avoid the side effects associated with instillation in already compromised infant airways. Efficient N2L delivery will allow for expanded use of NIV respiratory support techniques, thereby avoiding the greater risks associated with intubation and liquid bolus instillation. In addition to respiratory distress syndrome in infants, improved surfactant delivery to the alveolar region may also aid the treatment of other lung conditions such as pneumonia and viral bronchiolitis.

目前，新生儿的表面活性剂替代疗法是通过气管插管和 液体推注。提出了雾化表面活性剂的高效输送作为改善 表面活性剂的气道分布，并在无创通气的情况下防止气管插管 (NIV) 是首选的呼吸支持策略。目前雾化表面活性剂的主要局限性是 肺部输送效率极低（通常约为 1%）、输送时间长（网状雾化器约为 3 小时）以及较差 表面活性剂向肺泡区域的分布。 本研究的目标是开发有效输送雾化剂的配方和装置 使用鼻到肺（N2L）途径将表面活性剂输送到婴儿的肺部，从而避免插管。达到 高效肺部输送，将使用赋形剂增强生长（EEG）方法，其中 亚微米颗粒通过喷雾干燥形成，含有表面活性剂和吸湿剂 赋形剂。雾化颗粒的初始尺寸较小，可以有效渗透新的颗粒 输送装置和婴儿上呼吸道。初级颗粒中包含吸湿性赋形剂促进 气道内气溶胶尺寸增加，并在肺泡区域有效沉积。这种方法是 我们小组成功地采用该技术来改善成人 N2L 气雾剂的输送。将会产生气溶胶 使用新的脑电图表面活性剂粉末配方以及新的低流量和低体积干粉 吸入器是结合计算流体动力学 (CFD)、快速 原型设计和体外实验。新型表面活性剂气雾剂的功能将在表面活性剂中进行评估 耗竭动物模型并与液体滴注进行比较。为发展这一目标，提出以下目标 新的治疗方法： 具体目标 1. 开发一种肺表面活性剂的赋形剂促进生长 (EEG) 配方，可 有效雾化，增加气道内的空气动力学尺寸，并保持表面活性剂功能。 具体目标 2. 开发并优化一种用于产生并向婴儿施用表面活性剂气溶胶的装置 使用无创鼻到肺（N2L）途径并实现高效肺部输送。 具体目标 3. 采用 N2L 气雾剂输送装置并测试婴儿脑电图表面活性剂气雾剂功效 大小雪貂模型与表面活性剂滴注在氧合、肺分布和组织学方面的比较。 结果和影响。成功输送雾化表面活性剂将避免相关的副作用 滴注到已经受损的婴儿呼吸道中。高效的 N2L 输送将允许扩大使用 NIV 呼吸支持技术，从而避免与插管和液体相关的更大风险 推注。除了婴儿呼吸窘迫综合征外，还改善了表面活性剂向婴儿的输送 肺泡区域还可能有助于治疗其他肺部疾病，例如肺炎和病毒性细支气管炎。