Effective Delivery of Pharmaceutical Aerosols during Non-Invasive Ventilation

描述(申请人提供)：无创呼吸机(NIV)目前是呼吸功能不全、睡眠呼吸暂停、慢性阻塞性肺疾病(COPD)以及更严重的急性和慢性呼吸衰竭患者的一种标准护理形式。接受NIV治疗的患者通常有潜在的呼吸系统和全身疾病，可以用药物气雾剂有效地治疗。雾化吸入治疗与NIV同时进行，可实现持续的通风支持。然而，在NIV期间，给药效率非常低(初始剂量的1-7%)，导致剂量变异性高，副作用增加，浪费药物。本研究的目的是开发气雾剂给药系统，利用凝聚生长方法显着改善NIV期间的肺部药物沉积。将考虑三种无创通气技术：(1)使用插管界面的热和湿度的高流量疗法(HFT)，(2)通过鼻管的氧气低流量疗法(LFT)，以及(3)通过面罩的无创正压通气(NPPV)。凝聚式增长的概念始于最初产生和输送亚微米气雾剂(100-900 nm)，以将输送管道、患者界面和胸外呼吸道中的沉积和损失降至最低。气雾剂以饱和或过饱和的暖气流和/或含有吸湿性辅料的方式输送，以促进凝结生长，从而导致气溶胶尺寸增大和肺沉积。具体地说，增强型凝聚生长(CG)是通过将气雾剂与呼吸道入口处或呼吸道内的增湿气流结合起来实现的，而增强型赋形剂生长(EEG)则是通过输送组合药物和吸湿性赋形剂亚微米颗粒来实现的。气雾剂输送系统的开发和优化将基于同时进行的体外实验和在现实的胸外呼吸道模型中的计算模拟。为了开发这一新的呼吸道给药策略，提出了以下具体目标。具体目标1：开发一种基于增强型凝聚性生长(ECG)的有效呼吸道给药系统，用于鼻腔HFT。具体目标2：开发一种有效的呼吸道给药技术，用于基于增强型辅料生长(EEG)的低流量鼻插管供氧系统。具体目标3：开发一种有效的呼吸系统药物给药方法，用于基于心电和脑电的NPPV。通过NIV系统和胸外鼻腔输送亚微米气雾剂，然后随着凝结生长增加气雾剂尺寸，沉积损失有望显著减少。使用这一概念的结果是，可以减少剂量的可变性，同时实现近全肺滞留，这对于有效使用许多当前和下一代医用气雾剂是必要的。

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.