Effective Delivery of Pharmaceutical Aerosols during Non-Invasive Ventilation

描述（由申请人提供）：无创通气（NIV）是目前患有呼吸功能不全、睡眠呼吸暂停、慢性阻塞性肺疾病（COPD）和更严重的急性和慢性呼吸衰竭的患者的标准护理形式。接受NIV治疗的患者通常有潜在的呼吸和全身疾病，可以用药物气雾剂有效治疗。雾化治疗同时与NIV允许持续通气支持。然而，NIV期间给药效率非常低（为初始剂量的1-7%），导致剂量变异性大、副作用增加和药物浪费。本研究的目的是开发气溶胶给药系统，该系统可以使用冷凝生长方法显着改善NIV期间肺部药物沉积。将考虑三种无创通气技术：(1)使用套管接口的热湿高流量治疗（HFT），(2)通过鼻套管的氧气低流量治疗（LFT），以及(3)通过面罩的无创正压通气（NPPV）。冷凝生长概念从产生和输送亚微米气溶胶（100 - 900 nm）开始，以减少输送管道、患者界面和额外胸腔气道中的沉积和损失。气溶胶与饱和或过饱和的热气流和/或包含吸湿赋形剂一起递送，以促进冷凝生长，导致气溶胶大小和肺沉积增加。具体来说，增强凝聚生长（ECG）是通过在气道入口处或气道内将气溶胶与加湿气流结合来实现的，而增强赋形剂生长（EEG）是由输送联合药物和吸湿赋形剂亚微米颗粒组成的。气溶胶输送系统的开发和优化将基于并发的体外实验和在真实的胸外气道模型中的计算模拟。为了开发这种新的呼吸道药物递送策略，提出了以下具体目标。具体目标1：开发一种有效的呼吸道药物输送系统，用于基于增强凝聚生长（ECG）的鼻高频通气。具体目标2：开发一种有效的呼吸药物输送技术，用于基于增强赋形剂生长（EEG）的低流量鼻插管氧气系统。具体目标3：基于ECG和EEG的结合，开发一种有效的用于NPPV的呼吸药物递送方法。通过NIV系统和胸外鼻气道输送亚微米气溶胶，然后随着冷凝物的增长增加气溶胶的大小，有望显著减少沉积损失。使用这一概念的结果是，可以减少剂量的可变性，同时实现几乎完全的肺保留，这是有效使用许多当前和下一代医用气溶胶所必需的。

DESCRIPTION (provided by applicant): Non-invasive ventilation (NIV) is currently a form of standard care for patients suffering from respiratory insufficiency, sleep apnea, chronic obstructive pulmonary disease (COPD) and more severe acute and chronic respiratory failure. Patients receiving NIV typically have underlying respiratory and systemic conditions that can be effectively treated with pharmaceutical aerosols. Administration of aerosol therapy simultaneously with NIV allows for continuous ventilation support. However, drug delivery efficiency to patients during NIV is very low (1-7% of the initial dose), resulting in high dose variability, increased side effects, and wasted medication. The objective of this study is to develop aerosol drug delivery systems that can significantly improve pulmonary drug deposition during NIV using a condensational growth approach. Three non-invasive ventilation techniques will be considered: (1) high-flow therapy (HFT) with heat and humidity using a cannula interface, (2) oxygen low-flow therapy (LFT) through a nasal cannula, and (3) non-invasive positive pressure ventilation (NPPV) through a face mask. The condensational growth concept begins with generating and delivering initially submicrometer aerosols (100 - 900 nm) to minimize deposition and loss in the delivery lines, patient interface, and extra thoracic airways. The aerosol is delivered with a saturated or supersaturated warm airstream and/or with the inclusion of hygroscopic excipients in order to foster condensational growth, leading to increased aerosol size and pulmonary deposition. Specifically, enhanced condensational growth (ECG) is achieved by combining the aerosol with a humidified airstream at the entrance to or within the airways, while enhanced excipient growth (EEG) consists of delivering combination drug and hygroscopic excipient submicrometer particles. Development and optimization of the aerosol delivery systems will be based on concurrent in vitro experiments and computational simulations in realistic models of the extra thoracic airways. In order to develop this novel respiratory drug delivery strategy, the following specific aims are proposed. Specific Aim 1: Develop an effective respiratory drug delivery system for use during nasal HFT based on enhanced condensational growth (ECG). Specific Aim 2: Develop an effective respiratory drug delivery technique for use with a low-flow nasal cannula oxygen system based on enhanced excipient growth (EEG). Specific Aim 3: Develop an effective respiratory drug delivery methodology for use with NPPV based on a combination of ECG and EEG. By delivering a submicrometer aerosol through the NIV system and extra thoracic nasal airways, and then increasing aerosol size with condensational growth, significant reductions in depositional losses are expected. As a result of using this concept, reduced variability in dose can be achieved together with near full lung retention, which is necessary for the effective use of many current and next-generation medical aerosols. PUBLIC HEALTH RELEVANCE: Patients receiving non-invasive ventilation (NIV) for respiratory support frequently need pharmaceutical aerosols to treat conditions like asthma, COPD, pulmonary hypertension, lung infections, and cystic fibrosis. However, 90% or more of the drug never reaches the patient's lungs due to deposition and loss in the NIV delivery system and nasal airways, which wastes potentially expensive medication and increases side effects. The overall goal of this project is to develop a novel technology for the efficient delivery of pharmaceutical aerosols during NIV that minimizes depositional losses in the delivery system and nasal airways and maximizes drug delivery to the lungs.