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

用于接受不同通气支持模式的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: 10704308
• 负责人: P. Worth Longest
• 金额: $ 71.94万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704308
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Adult; Aerosol Drug Therapy; Aerosols; Air; Alveolar; Alveolus; Animal Experiments; Animal Model; Animals; Antibiotics; Antiviral Agents; Bacterial Infections; Bacterial Pneumonia; Bolus Infusion; COVID-19; COVID-19 pandemic; Cannulas; Catheters; Chemical Surfactants; Chest; Clinical Research; Clinical Trials; Contusions; Deposition; Development; Devices; Dose; Edema; Epithelial; Excipients; Exhalation; Exhibits; Failure; Formulation; Goals; Growth; Hour; Hypoxemia; In Vitro; Infant; Inhalation; Inhalators; Intubation; Lead; Liquid substance; Lung; Mechanical ventilation; Methods; Modeling; Near Drowning; Nebulizer; Neonatal Respiratory Distress; Nose; Outcome; Patients; Pediatric Acute Respiratory Distress Syndrome; Performance; Pharmacology; Phospholipids; Population; Powder dose form; Process; Production; Proteins; Pulmonary Inflammation; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants; Radiation Injuries; Rattus; Recovery; Respiration; Source; Support System; Surfactant therapy; System; Time; Translating; Tube; Ventilator-induced lung injury; Viral Pneumonia; Virus Diseases; Wettability; analog; base; comparative efficacy; cost; design; efficacy testing; endotracheal; experience; experimental study; fungal pneumonia; healing; improved; in vivo; lung injury; mortality; particle; peptide analog; preclinical development; pressure; prevent; pulmonary function; surfactant; surfactant production; surfactant replacement therapy; targeted treatment; ventilation

Acute respiratory distress syndrome (ARDS) arising from direct lung injury is 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 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 ARDS or hypoxemia 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 and efficient 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. For patients receiving noninvasive ventilation, dry powder surfactant therapy is intended to halt deteriorating lung function and prevent progression to IMV. If IMV is required, early dry powder surfactant administration is intended to minimize further lung injury and enable more rapid and reliable extubation.

由直接肺损伤引起的急性呼吸窘迫综合征（ARDS）与功能失调有关 肺表面活性物质系统；然而，表面活性剂替代疗法的大型临床试验并未成功 在这个人群中。在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 滴注，需要插管、使用大量液体（约 500 毫升）以及随后的机械注射 通气通常出现在 ARDS 进展的晚期。一种成功的干粉气雾剂合成肺表面活性剂 该产品将提供早期表面活性剂给药的优势，可能在需要侵入性治疗之前 机械通气 (IMV)、快速高剂量输送至肺泡区域并提高疗效 与基于初步动物模型研究结果的滴注进行比较。 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 （包括给药策略、制剂和装置）用于给患有急性呼吸窘迫综合征（ARDS）或 在接受不同模式的治疗时，以快速、有效和安全的方式因直接肺损伤引起的低氧血症 通风支持。将开发和优化气雾剂输送策略和设备以实现高效率 高流量鼻插管 (HFNC) 治疗期间的气雾剂给药、无创正压通气 (NPPV) 和 IMV。高效气雾剂给药将通过高度分散的组合来实现 喷雾干燥粉末配方、新型正压干粉吸入器 (DPI) 和增强型赋形剂 生长（脑电图）气雾剂输送策略。雾化性能和肺部输送效率将 使用现实体外实验和计算流体的并行方法进行建立和优化 动力学 (CFD) 建模。将进行动物实验（在大鼠中）以确定适当的水平 表面活性剂蛋白类似物并评估先导合成表面活性剂干粉制剂的体内功效 在不同的直接肺损伤模型中。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，实现安全高效 对接受 HFNC、NPPV 或 IMV 的成人进行气雾剂给药。 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。对于接受无创通气的患者，适用干粉表面活性剂治疗 阻止肺功能恶化并防止进展为 IMV。如果需要IMV，早期干粉表面活性剂 给药的目的是最大限度地减少进一步的肺损伤，并实现更快速、更可靠的拔管。