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

直接肺损伤引起的急性呼吸窘迫综合征(ARDS)与功能障碍有关 肺表面活性物质系统；然而，表面活性物质替代疗法的大型临床试验并不成功 在这群人中。在这些不成功的试验中，用于表面活性物质输送的方法是液体团注。 滴注，需要插管，使用大容量液体(~500毫升)和随后的机械 机械通气通常发生在ARDS进展的晚期。一种成功的干粉雾化合成肺表面活性物质 产品将提供早期给药表面活性物质的优势，可能在需要侵入性治疗之前 机械通气(IMV)、快速、高剂量的肺泡区给药，提高了疗效 与基于初步动物模型结果的滴注进行比较。 本研究的目标是在临床前开发一种合成肺表面活性物质干粉状气雾剂产品。 (包括给药策略、配方和设备)，供患有ARDS或 以快速、高效和安全的方式接受不同模式的直接肺损伤所致的低氧血症 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)治疗中的雾化吸入，无创正压通气 (NPPV)和IMV。高效率的气雾剂管理将由高度分散的 喷雾干粉制剂、新型正压干粉吸入器(DPI)和增强型赋形剂 增长(EEG)气雾剂交付战略。雾化性能和肺给药效率将 使用现实的体外实验和计算流体并行的方法建立和优化 动力学(CFD)建模。将进行动物实验(在大鼠身上)以确定适当的水平 含铅合成表面活性物质干粉制剂的表面活性蛋白模拟及体内药效评价 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 一种小颗粒气雾剂，风量小，具有吸湿性生长，并能稳定储存产品。 具体目标2.开发和优化表面活性剂输送策略和设备，以实现安全和高效 雾化吸入给接受HFNC、NPPV或IMV的成年人。 具体目标3.测试含铅合成表面活性剂制剂在动物身上的有效性- 使用模拟细菌感染、病毒感染的急性肺损伤(ALI)大鼠体内模型的空气喷射DPI版本 感染和呼吸机引起的肺损伤。 结果和影响。对于接受无创呼吸机治疗的患者，可以采用干粉表面活性物质治疗。 以阻止肺功能恶化并防止进展为IMV。如果需要IMV，早期使用干粉表面活性剂 给药的目的是将进一步的肺损伤降至最低，并使拔管更迅速、更可靠。

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.