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

项目总结/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，病情加重时需要昂贵的急救费用 医院治疗。尽管哮喘患者被规定使用大量的吸入器，但这些现有的设备 只有很少的药物进入肺部，通常只有不到1%的药物沉积在小气道中， 保持不治疗。因此，我们正在开发一种新的方法， 其性能将显著优于现有产品，包括超细制剂。我们将创建一个 一种新的干粉制剂，含有布地奈德，一种经过充分研究和FDA批准的皮质类固醇药物 和吸湿性赋形剂（非活性成分），从而得到赋形剂增强生长（EEG）制剂。 这种EEG制剂将能够独特地治疗小气道中的炎症，以显著减少 严重哮喘的相关症状。通过制造超细亚微米和微米大小的药物粉末 颗粒与吸湿性赋形剂组合，颗粒能够避免在咽喉中沉积并生长， 在吸入过程中吸湿，以达到最佳的尺寸，以高效率靶向小气道。吸湿 颗粒的生长对于防止这些小颗粒的呼出和允许目标沉积是必要的 在小气道中。粉末制剂将通过高效干粉吸入器递送，包括 一种新的3D棒阵列结构，其被证明能最好地解聚无载体粉末制剂。 这些新的制剂和吸入器组合已经显示出达到大于75%的释放剂量， 大于90%的细颗粒部分（尺寸<5 µm）和初始质量中值空气动力学直径 （MMAD）小于1.5 µm，导致咽喉部沉积损失小于5%。高效率 药物递送将增加药物在未治疗的肺区域中的沉积并减少全身药物暴露 与当前的设备相比，包括超细制剂。我们之前已经证明了可行性， 生产和测试一系列干粉制剂的化学稳定性、物理化学性质、 特征和气雾剂性能，以确定药物组合物的药理学特性。 可接受的配方。从这些研究中，我们选择了领先的配方， 第二阶段的努力。我们将生产足量的先导制剂，以进行临床前疗效研究 试验和IND毒理学试验，以证明我们的新布地奈德制剂的安全性。预处理 安全性的临床证明将允许进行首次人体试验，这是下一个主要的发展阶段， 显著控制严重哮喘的症状。将这项技术转化为临床上有益的 产品将彻底改变药物输送和严重哮喘患者的症状控制， 到目前未经治疗的气道区域。

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.