Treating severe asthma in the small airways with a highly efficient and penetrating inhaled dry powder

使用高效、渗透性吸入干粉治疗小气道严重哮喘

• 批准号: 10080247
• 负责人: Bryce Beverlin II
• 金额: $ 124.75万
• 依托单位: QUENCH MEDICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080247
• 关键词: 3-Dimensional; Adrenal Cortex Hormones; Aerosols; Anti-Inflammatory Agents; Asthma; Budesonide; Caliber; Canis familiaris; Characteristics; Clinical; Clinical Research; Consensus; Data; Deposition; Development; Devices; Disease; Dose; Drug Delivery Systems; Drug Exposure; Emergency Situation; Excipients; Exhalation; FDA approved; Formulation; Foundations; Funding; Goals; Grant; Growth; Hospitals; Human; In Vitro; Inflammation; Inhalation; Inhalation Toxicology; Inhalators; Investigational Drugs; Investigational New Drug Application; Lead; Legal patent; Leucine; Life; Lung; Medicine; Methods; Modeling; National Heart, Lung, and Blood Institute; Oral cavity; Particle Size; Pathway interactions; Performance; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharyngeal structure; Phase; Powder dose form; Preparation; Production; Publications; Pulmonary Inflammation; Pulmonology; Quality Control; Research; Rod; Rodent Model; Safety; Series; Small Business Innovation Research Grant; Sodium Chloride; Structure; Study models; Symptoms; Techniques; Technology; Testing; Toxicology; Translations; Universities; Validation; Virginia; Wettability; airway inflammation; asthmatic; asthmatic patient; base; chemical stability; cost; drug development; efficacy study; efficacy testing; fine particles; first-in-human; good laboratory practice; human study; improved; in silico; in vitro Model; in vitro testing; in vivo; novel; particle; practice setting; pre-clinical; preclinical efficacy; preclinical study; prevent; prototype; side effect; stability testing; submicron

Project Summary / Abstract Uncontrolled inflammation in the small airways remains a major unmet need in clinical pulmonology. Severely asthmatic patients suffer from life-threatening symptoms and exacerbations requiring costly emergency hospital treatments. Although asthma patients are prescribed large numbers of inhalers, these current devices deliver very little medication into the lungs, with often less than 1% being deposited into small airways, which remain untreated. Therefore, we are developing a new method of delivering medication to the small airways which will perform significantly better than current products, including extra-fine formulations. We will create a novel dry powder formulation containing budesonide, a well-studied and FDA approved corticosteroid medication and a hygroscopic excipient (inactive ingredient) resulting in an excipient enhanced growth (EEG) formulation. This EEG formulation will be able to uniquely treat inflammation in small airways in order to significantly reduce related symptoms of severe asthma. By creating extra-fine submicron and micrometer sized drug powder particles combined with a hygroscopic excipient, the particles are able to avoid depositing in the throat and grow hygroscopically during inhalation to an optimal size to target the small airways with high efficiency. Hygroscopic growth of the particles is essential to prevent exhalation of these small particles and to allow targeted deposition in the small airways. The powder formulation will be delivered by a high efficiency dry powder inhaler including a novel 3D rod array structure that was demonstrated to best disaggregate carrier-free powder formulations. These new formulation and inhaler combinations have been shown to achieve emitted doses greater than 75%, fine particle fractions (<5 µm in size) of greater than 90% and initial mass median aerodynamic diameters (MMAD) less than 1.5 µm, which result in mouth-throat depositional losses of less than 5%. The high efficiency drug delivery will increase drug deposition in untreated lung regions and reduce systemic drug exposure compared to current devices, including extra-fine formulations. We have previously demonstrated feasibility by manufacturing and testing a series of dry powder formulations for chemical stability, physicochemical characteristics, and aerosol performance in a realistic airway in-vitro model in order to identify pharmaceutically acceptable formulations. From these studies, we have selected the lead formulation to move forward in this Phase II effort. We will produce adequate amounts of the lead formulation in order to conduct pre-clinical efficacy tests and IND-enabling toxicology tests to demonstrate the safety of our novel budesonide formulation. Pre- clinical proof of safety will allow for first-in-human testing, the next major phase of development toward significantly controlling symptoms of severe asthma. The translation of this technology into a clinically beneficial product will revolutionize drug delivery and symptom control for severe asthma patients by delivering medicine to currently untreated regions of the airways.

项目摘要 /摘要 小气道中的不受控制的炎症仍然是临床肺病学的主要未满足需求。 严重哮喘患者患有威胁生命的症状和恶化，需要昂贵的紧急情况 医院治疗。尽管哮喘患者处方大量继承，但这些当前设备 将很少的药物输送到肺部，通常不到1％的人沉积到小气道中， 保持未经治疗。因此，我们正在开发一种向小气道输送药物的新方法 它的性能将比当前产品（包括超细公式）的性能要好得多。我们将创建一个 新型的干粉配方奶粉，其中包含布德索尼，经过良好研究和FDA认可的皮质类固醇药物 以及吸湿性赋形剂（无活性剂），导致赋形剂增强的生长（EEG）公式。 该脑电图将能够在小气道中唯一处理炎症，以显着减少 严重哮喘的相关症状。通过创建超细量子和微米大小的药粉 颗粒与吸湿赋形剂结合在一起，颗粒能够避免沉积在喉咙中并生长 吸入期间，以高效率对小气道瞄准的最佳尺寸。吸湿性 颗粒的生长对于防止这些小颗粒的呼气至关重要，并允许靶向沉积 在小气道中。粉末配方将通过高效率干粉吸入器传递 一种新型的3D杆阵列结构，该结构被证明是最好分解无载体粉末配方的。 这些新的配方和吸入器组合已显示出大于75％的发射剂量， 大于90％和初始质量质量平均空气动力学直径的细粒子分数（<5 µm） （MMAD）小于1.5 µm，导致口throat沉积损失小于5％。高效率 药物输送将增加未经治疗的肺部区域的药物沉积并减少全身药物暴露 与当前的设备（包括超细配方）相比。我们以前已经证明了 制造和测试一系列用于化学稳定性的干粉配方，物理化学 在逼真的气道内电体模型中的特征和气溶胶性能，以便在药物上识别 可接受的公式。从这些研究中，我们选择了铅公式来向前推进 第二阶段的努力。我们将产生足够数量的铅公式以进行临床前效率 测试和成熟的毒理学测试，以证明我们新型布德索尼尼德公式的安全性。 pre 临床安全证明将允许首次人类测试，这是下一个主要发展阶段 明显控制严重哮喘的症状。将该技术转换为临床上有益的 产品将通过送药来彻底改变严重哮喘患者的药物输送和症状控制 目前未经处理的航空区域。