High Efficiency Delivery of Surfactant Aerosols to Infants without Intubation

新生儿肺表面活性物质替代治疗目前是通过气管插管和 液体滴注。气雾化表面活性剂的高效输送是一种改进的技术。 无创通气时表面活性物质的气道分布及预防气管插管 (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 肺部给药效率很低(通常为~1%)，给药时间长(网状雾化器约3小时)，而且很差 表面活性物质在肺泡区的分布。 这项研究的目标是开发有效雾化吸入的配方和装置。 使用鼻对肺(N2L)途径将表面活性物质注入婴儿的肺部，从而避免插管。要实现 高效率的肺部给药，将使用赋形剂促进生长(EEG)方法 亚微米颗粒是通过喷雾干燥形成的，含有表面活性物质和吸湿剂 赋形剂。最初的小尺寸气雾化颗粒允许有效地穿透新的 分娩装置和婴儿上呼吸道。吸湿性赋形剂在初级颗粒中的包裹体 气溶胶在呼吸道内增大，并在肺泡区有效沉积。这种方法是 成功地被我们的团队用来改善成人的N2L气雾剂释放。气雾剂就会产生 使用新的脑电表面活性物质粉剂配方和新的低流量、低容量干粉 吸入器，使用计算流体动力学(CFD)的组合开发和优化，快速 原型设计和体外实验。新的表面活性剂气雾剂的功能将在表面活性剂中进行评估 建立耗竭动物模型，并与液体滴注进行比较。为发展这一点，我们提出了以下目标 新的治疗方法： 具体目标1.开发赋形剂促进生长(EEG)的肺表面活性物质配方，该配方可 高效雾化，增加呼吸道内的空气动力学尺寸，并保持表面活性物质的功能。 具体目标2.开发和优化一种产生和给婴儿使用表面活性气雾剂的装置 采用无创鼻对肺(N2L)途径，实现高效率的肺部给药。 具体目标3.改装N2L气雾剂输送装置，并测试婴儿脑电表面活性气雾剂的疗效- 在氧合、肺组织分布和组织学方面比较大白貂模型和表面活性物质滴注模型。 结果和影响。雾化表面活性剂的成功交付将避免相关的副作用 对已经受损的婴幼儿呼吸道进行灌输。高效的N2L交付将允许更多地使用 Niv呼吸支持技术，从而避免了与插管和液体有关的更大风险 滴注。除了婴儿呼吸窘迫综合征外，改善了表面活性物质对 肺泡区也可以帮助治疗其他肺部疾病，如肺炎和病毒性毛细支气管炎。

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.