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）与 具有功能失调的肺表面活性剂系统；但是，表面活性剂替代疗法的大型临床试验具有 在这个人群中没有成功。在这些失败的试验中，用于表面活性剂输送的方法 是液体推注，通常需要插管，使用大液体量（〜500 mL），然后 机械通气通常在ARDS的进展后期。成功的干粉气管合成肺 表面活性剂产品将提供早期表面活性剂给药的优势，可能在需要之前 用于侵入性机械通气（IMV），快速和高剂量向肺泡区域递送并改善 与基于初步动物模型发现的滴注相比，功效。 这项研究的目的是合成肺表面活性剂干粉气溶胶产品的临床前开发 （包括交付策略，配方和设备），用于管理低氧血症或 在接收不同的通风模式的同时，以快速，高效和安全的方式受到直接肺损伤的ARDS 支持。将开发和优化气溶胶输送策略和设备，以高效气溶胶 高流量鼻套管（HFNC）治疗期间的给药，无创正压通气（NPPV） 和IMV。高效的气溶胶给药将通过高度分散喷雾剂的组合来启用 干粉配方，新的阳性干粉吸入器（DPI）和赋形剂增强的生长 （EEG）气溶胶输送策略。将建立气雾化性能和肺输送效率，并 使用现实的体外实验和计算流体动力学（CFD）的同时进行优化 造型。将实施动物实验（在大鼠中）以确定适当水平的表面活性剂 蛋白类似物和评估铅合成表面活性剂干粉制剂的体内功效 直接肺损伤的模型。该项目的具体目标如下： 特定目的1。开发一种合成表面活性剂干粉气溶胶配方，可以轻松分散到 空气量低的小颗粒气雾剂，表现出吸湿性生长并实现稳定的产品存储。 特定目的2。制定和优化表面活性剂交付策略和设备，以实现安全，高效和 对接受HFNC，NPPV或IMV的成年人的快速气溶胶给药。 特定目的3。测试用动物施用的铅合成表面活性剂制剂的功效 使用急性肺损伤的体内大鼠模型（ALI）模仿细菌感染，病毒的版本 感染和呼吸机诱导的肺损伤。 结果和影响。拟议的进步直接解决了与以前的多种失败机制有关 灌输和雾化（液体和粉末）表面活性剂，对于制成雾化表面活性剂是必不可少的 低氧血症或ARDS的治疗，可以选择早期治疗的成年人可行选择。