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，通过气管插管和 液体推注。提出了高效的雾化表面活性剂作为改进的技术 在无创通气的情况下，表面活性剂的气道分布并防止气管插管 （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 非常低的肺输送效率（通常约为1％），较长的递送时间（网状雾化器约3小时）和差 表面活性剂到肺泡区域的分布。 这项研究的目的是开发有效递送的配方和设备 使用鼻向肺（N2L）路线到婴儿肺的表面活性剂，从而避免插管。实现 将使用高效率肺输送，赋形剂增强的增长（EEG）方法 亚微米颗粒是通过喷雾干燥形成的，并含有表面活性剂和吸湿性 赋形剂。最初的小尺寸雾化颗粒可以通过新的有效穿透 递送装置和婴儿上部气道。将吸湿性赋形剂纳入主要颗粒中 气溶胶大小在气道内部增加，并在肺泡区域有效沉积。这种方法是 我们小组成功地利用了成人的N2L气溶胶递送。气溶胶将产生 使用新的EEG表面活性剂粉末配方以及新的低流量和低量干粉 吸入器是使用计算流体动力学（CFD）组合开发和优化的，快速 原型和体外实验。新表面活性剂气溶胶的功能将在表面活性剂中进行评估 耗尽动物模型，并与液体滴注进行比较。提出了以下目的来开发这一点 新的治疗方法： 特定目的1。开发一种可以是肺表面活性剂的赋形剂增强的生长（EEG）表述 有效雾化，气道内空气动力学大小的增加并保持表面活性剂功能。 特定目标2。开发和优化一种为婴儿生成和给予表面活性剂气溶胶的设备 使用无创鼻向肺（N2L）路线并实现高效率肺输送。 具体目标3。适应N2L气溶胶递送装置并测试婴儿中的EEG表面活性剂气溶胶功效 大小雪貂模型与表面活性剂的滴注相比，就氧合，肺部分布和组织学而言。 结果和影响。成功递送气溶剂表面活性剂将避免相关的副作用 在已经受到损害的婴儿气道中滴注。有效的N2L交付将允许扩大使用 NIV呼吸支持技术，从而避免了与插管和液体相关的更大风险 推注滴注。除了婴儿的呼吸窘迫综合征外，还改善了表面活性剂的递送 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。