High Efficiency Delivery of Surfactant Aerosols to Infants without Intubation

目前新生儿的表面活性剂替代疗法是通过气管内插管实现的， 液体团注。提出了高效递送雾化的表面活性剂作为改进的技术。 在无创通气的情况下， (NIV)是首选的呼吸支持策略。雾化表面活性剂的主要限制目前是 肺部给药效率非常低（通常约1%），给药时间长（网状雾化器约3小时）， 将表面活性剂分布到肺泡区域。 本研究的目的是开发有效递送雾化吸入的制剂和装置。 使用鼻-肺（N2 L）途径将表面活性剂输送到婴儿的肺中，从而避免插管。实现 高效肺递送，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，并含有表面活性剂和吸湿剂， 赋形剂雾化颗粒的初始小尺寸允许有效地渗透通过新的纳米颗粒。 分娩装置和婴儿上呼吸道。在初级颗粒中包含吸湿性赋形剂促进了 气溶胶尺寸在气道内增加并且在肺泡区域中有效沉积。这种方法 我们的小组成功地用于改善成人中的N2 L气雾剂递送。气溶胶就会产生 使用新的EEG表面活性剂粉末制剂以及新的低流量和低体积干粉 使用计算流体动力学（CFD）的组合开发和优化的吸入器， 原型设计和体外实验。新的表面活性剂气溶胶的功能将在表面活性剂 消耗动物模型，并与液体滴注进行比较。提出了以下目标，以发展这一 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增强生长（EEG）制剂， 有效地雾化，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。开发和优化用于产生和向婴儿施用表面活性剂气雾剂的装置 使用非侵入性鼻-肺（N2 L）途径并实现高效肺递送。 具体目标3。调整N2 L气雾剂输送装置并测试婴儿的EEG表面活性剂气雾剂功效- 在氧合、肺分布和组织学方面，将大小雪貂模型与表面活性剂滴注进行比较。 结果和影响。成功地输送雾化表面活性剂将避免相关的副作用 在已经受损的婴儿气道中滴注。高效的N2 L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，改善表面活性剂输送到 肺泡区域也可以帮助治疗其它肺部疾病，例如肺炎和病毒性细支气管炎。

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.