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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要小气道中不受控制的炎症仍然是临床肺病学中未满足的主要需求。严重哮喘患者会出现危及生命的症状和病情加重，需要昂贵的紧急治疗尽管哮喘患者需要使用大量吸入器，但这些现有设备仍然在医院进行治疗。向肺部输送的药物非常少，通常只有不到 1% 的药物会沉积到小气道中，这因此，我们正在开发一种向小气道输送药物的新方法。其性能将显着优于现有产品，包括超精细配方。含有布地奈德的新型干粉制剂，布地奈德是一种经过充分研究并经 FDA 批准的皮质类固醇药物和吸湿性赋形剂（非活性成分），形成赋形剂促进生长（EEG）制剂。这种脑电图制剂将能够独特地治疗小气道炎症，从而显着减少通过制造超细的亚微米和微米大小的药物粉末来缓解严重哮喘的相关症状。颗粒与吸湿性赋形剂结合，颗粒能够避免沉积在喉咙中并生长在吸入过程中吸湿至最佳尺寸，以高效率瞄准小气道。颗粒的生长对于防止这些小颗粒的呼出并允许有针对性的沉积至关重要粉末制剂将通过高效干粉吸入器输送，包括一种新颖的 3D 棒阵列结构，已被证明能够最好地分解无载体粉末配方。这些新配方和吸入器组合已被证明可实现大于 75% 的释放剂量，细颗粒部分（尺寸 <5 µm）大于 90% 且初始质量中值空气动力学直径 (MMAD) 小于 1.5 µm，导致口喉沉积损失小于 5%。药物输送会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现有设备相比，包括超精细配方，我们之前已经证明了可行性。制造和测试一系列干粉制剂的化学稳定性、物理化学性能真实气道体外模型中的特性和气雾剂性能，以便进行药物鉴定从这些研究中，我们选择了主要的配方来推进这一工作。我们将生产足够量的先导制剂以进行临床前疗效。测试和 IND 毒理学测试，以证明我们的新型布地奈德制剂的安全性。安全性的临床证明将允许进行首次人体测试，这是开发的下一个主要阶段显着控制严重哮喘的症状将该技术转化为临床有益的成果。该产品将通过输送药物彻底改变严重哮喘患者的药物输送和症状控制目前未治疗的气道区域。