Preclinical development of a synthetic lung surfactant dry powder aerosol for hypoxemia or acute respiratory distress syndrome patients receiving different modes of ventilation support

用于接受不同通气支持模式的低氧血症或急性呼吸窘迫综合征患者的合成肺表面活性剂干粉气雾剂的临床前开发

• 批准号: 10658610
• 负责人: P. Worth Longest
• 金额: $ 75.83万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658610
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adolescent; Adult; Aerosols; Affect; Air; Air Pressure; Alveolar; Alveolus; Animal Experiments; Animal Model; Animals; Area; Bacterial Infections; Bacterial Pneumonia; Bolus Infusion; COVID-19; Cannulas; Chemical Surfactants; Chest; Child; Childhood; Clinical; Clinical Trials; Contusions; Development; Device or Instrument Development; Devices; Dose; Dryness; Early treatment; Edema; Epithelial Cells; Excipients; Exhalation; Exhibits; Failure; Formulation; Gases; Goals; Growth; Hour; Human; Hypoxemia; In Vitro; Infant; Inflammation; Inhalation; Inhalators; Intubation; Lead; Leukocytes; Liquid substance; Lung; Mechanical ventilation; Methods; Modeling; Near Drowning; Nebulizer; Nose; Outcome; Patients; Performance; Periodicity; Phospholipids; Population; Powder dose form; Procedures; Production; Proteins; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants; Radiation Injuries; Rattus; Source; Stress; Support System; Surfactant therapy; System; Technology; Treatment Cost; Ventilator-induced lung injury; Viral Pneumonia; Virus Diseases; Wettability; aerosolized; alveolar epithelium; analog; aspirate; comparative efficacy; cost; cytokine; design; efficacy testing; experience; experimental study; fungal pneumonia; improved; in vivo; lung injury; meter; mortality; particle; peptide analog; pharmacologic; preclinical development; pressure; surfactant; surfactant deficiency; surfactant production; surfactant replacement therapy; ventilation

Hypoxemia and acute respiratory distress syndrome (ARDS) arising from direct lung injury are associated with a dysfunctional lung surfactant system; however, large clinical trials of surfactant replacement therapy have been unsuccessful in this population. The method employed for surfactant delivery in these unsuccessful trials was liquid bolus instillation, which often requires intubation, use of large liquid volumes (~500 ml) and subsequent mechanical ventilation often late in the progression of ARDS. A successful dry powder aerosol synthetic lung surfactant product would provide the advantages of early surfactant administration, potentially before the need for invasive mechanical ventilation (IMV), rapid and high dose delivery to the alveolar region, and improved efficacy compared with instillation based on preliminary animal model findings. The goal of this study is the preclinical development of a synthetic lung surfactant dry powder aerosol product (including delivery strategies, formulations and devices) for administration to adults experiencing hypoxemia or ARDS from direct lung injury in a rapid, efficient and safe manner while receiving different modes of ventilation support. Aerosol delivery strategies and devices will be developed and optimized for high efficiency aerosol administration during high flow nasal cannula (HFNC) therapy, noninvasive positive pressure ventilation (NPPV) and IMV. High efficiency aerosol administration will be enabled by a combination of a highly dispersible spray- dried powder formulation, a new positive-pressure dry powder inhaler (DPI), and an excipient enhanced growth (EEG) aerosol delivery strategy. Aerosolization performance and lung delivery efficiency will be established and optimized using a concurrent approach of realistic in vitro experiments and computational fluid dynamics (CFD) modeling. Animal experiments (in rats) will be implemented to determine appropriate levels of the surfactant protein analog and assess in vivo efficacy of the lead synthetic surfactant dry powder formulation in different models of direct lung injury. Specific aims of the project are as follows: Specific Aim 1. Develop a synthetic surfactant dry powder aerosol formulation that can be easily dispersed into a small particle aerosol with low air volume, exhibit hygroscopic growth, and enable stable product storage. Specific Aim 2. Develop and optimize surfactant delivery strategies and devices that enable safe, efficient and rapid aerosol administration to adults receiving HFNC, NPPV or IMV. Specific Aim 3. Test the efficacy of the lead synthetic surfactant formulations administered with an animal- version of the air-jet DPI using in vivo rat models of acute lung injury (ALI) mimicking bacterial infection, viral infection, and ventilator-induced lung injury. Outcomes and Impact. The proposed advances directly address multiple previous failure mechanisms related to instilled and aerosolized (liquid and powder) surfactants and are necessary to make aerosolized surfactant therapy for hypoxemia or ARDS with the option of early treatment a viable option in adults.

直接肺损伤引起的低氧血症和急性呼吸窘迫综合征（ARDS）相关 肺表面活性物质系统功能失调；然而，表面活性剂替代疗法的大型临床试验已经 在这个人群中并不成功。这些不成功的试验中用于表面活性剂输送的方法 是液体推注，通常需要插管、使用大量液体（约 500 毫升）以及随后的操作 机械通气通常出现在 ARDS 进展的晚期。成功的干粉气雾剂合成肺 表面活性剂产品将提供早期表面活性剂施用的优势，可能在需要之前 用于有创机械通气 (IMV)，快速、高剂量输送至肺泡区域，并改进 根据初步动物模型研究结果与滴注效果进行比较。 本研究的目标是合成肺表面活性剂干粉气雾剂产品的临床前开发 （包括递送策略、制剂和装置）用于向患有低氧血症或 在接受不同通气模式的同时，以快速、高效和安全的方式因直接肺损伤而导致急性呼吸窘迫综合征 (ARDS) 支持。将开发和优化气雾剂输送策略和设备以实现高效气雾剂 高流量鼻插管 (HFNC) 治疗、无创正压通气 (NPPV) 期间给药 和IMV。通过结合高度分散的喷雾剂，可以实现高效的气雾剂给药 干粉配方、新型正压干粉吸入器 (DPI) 和促进生长的赋形剂 （脑电图）气雾剂输送策略。将建立气雾化性能和肺部输送效率，并 使用现实体外实验和计算流体动力学 (CFD) 的并行方法进行优化 造型。将进行动物实验（大鼠）以确定表面活性剂的适当水平 蛋白质类似物并评估先导合成表面活性剂干粉制剂在不同环境中的体内功效 直接肺损伤模型。该项目的具体目标如下： 具体目标 1. 开发一种合成表面活性剂干粉气雾剂配方，可轻松分散到 低风量的小颗粒气溶胶，表现出吸湿性增长，并可实现稳定的产品储存。 具体目标 2. 开发和优化表面活性剂输送策略和设备，以实现安全、高效和 对接受 HFNC、NPPV 或 IMV 的成人进行快速气雾剂给药。 具体目标 3. 测试给动物施用的先导合成表面活性剂制剂的功效 使用模拟细菌感染、病毒感染的急性肺损伤 (ALI) 体内大鼠模型的喷气 DPI 版本 感染和呼吸机引起的肺损伤。 结果和影响。所提出的进展直接解决了先前的多个相关故障机制 用于滴注和雾化（液体和粉末）表面活性剂，并且是制造雾化表面活性剂所必需的 对于成人来说，早期治疗是治疗低氧血症或 ARDS 的可行选择。