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）是相关的 肺表面活性物质系统功能失调;然而，表面活性物质替代疗法的大型临床试验 在这个群体中没有成功。在这些不成功的试验中用于表面活性剂递送的方法 是液体推注，这通常需要插管，使用大量液体（约500 ml）和随后的 机械通气通常在ARDS进展的后期。一种成功的干粉气溶胶合成肺 表面活性剂产品将提供早期表面活性剂施用的优点，可能在需要之前 用于有创机械通气（IMV），快速和高剂量递送到肺泡区域， 基于初步动物模型发现，与滴注相比的功效。 本研究的目的是临床前开发的合成肺表面活性剂干粉气雾剂产品 （包括递送策略、制剂和装置），用于向经历低氧血症或 在接受不同通气模式的同时，以快速、有效和安全的方式治疗直接肺损伤所致的ARDS 支持.将开发和优化气雾剂输送策略和装置，以实现高效气雾剂 高流量鼻插管（HFNC）治疗期间的给药，无创正压通气（NPPV） 还有IMV。高效的气雾剂给药将通过高度分散的喷雾剂- 干粉制剂，一种新的正压干粉吸入器（DPI）和一种赋形剂促进生长 (EEG)气溶胶递送策略。将确定雾化性能和肺输送效率， 使用现实的体外实验和计算流体动力学（CFD）的并行方法进行优化 建模将进行动物实验（大鼠）以确定表面活性剂的适当水平 蛋白质类似物，并评估在不同条件下，先导合成表面活性剂干粉制剂的体内功效。 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制剂， 具有低空气体积的小颗粒气溶胶，表现出吸湿性增长，并能够稳定地储存产品。 具体目标2。开发和优化表面活性剂输送策略和装置，以实现安全、高效和 接受HFNC、NPPV或IMV的成人快速气雾剂给药。 具体目标3。测试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、病毒感染和急性肺损伤（ALI）的体内大鼠模型的空气喷射DPI版本 感染和呼吸机引起的肺损伤。 结果和影响。所提出的进步直接解决了以前的多个故障机制， 滴注和雾化（液体和粉末）表面活性剂，并且是制备雾化表面活性剂所必需的 低氧血症或ARDS的早期治疗是成人的可行选择。