Lung Delivery of Nebulized Tissue Plasminogen Activator

描述(由申请人提供)：急性呼吸窘迫综合征(ARDS)在美国每年折磨数万人，并与显著的死亡率有关。目前，还没有有效的治疗方法，目前正在研究的前瞻性治疗方法也不太乐观。一种独特的抗炎剂(蛋白质)可以减少中性粒细胞活性氧簇(ROS)介导的肺部炎症动物模型中的损伤，已经被发现，并代表了一种潜在的可行的ARDS治疗方法。因此，这项研究和药物开发计划的广泛的、长期的目标是开发一种独特的、局部的(肺靶向)疗法，这种疗法将有效地降低与ARDS相关的死亡率。这一第一阶段应用的目的是通过开发一种将维持雾化过程并充分分布到人体呼吸道的药物配方，在人类身上证明这一策略的原理。为此，本项目的具体目标是：1)研制该制剂，使其适合局部雾化吸入，同时保持活性。通过添加不同浓度的表面活性剂，可以得到最佳配方。配方活动将包括对蛋白质稳定性、空气动力学颗粒大小和生物功能的评估。蛋白质稳定性将通过总蛋白质回收率和结构完整性来衡量。颗粒大小将使用级联撞击器确定，生物活性将通过试剂抑制中性粒细胞ROS产生的能力来量化；2)在人类肺复制模型中表征雾化制剂试剂的呼吸沉积。这一目的是为了产生更多的支持性证据，以证明人类配方的原理。为了实现这一目标，由特定目标#1的可行性标准确定的每一种可行的配方都将被雾化成人类肺的复制品。将使用由人类身体制作的主铸模复制的高保真人类肺复制品，其中包括五到九代的支气管。铸型的小气道和肺泡区的沉积是由穿过上游气道并收集在泡沫过滤器上的材料模拟的。在这两个特定目标下进行的工作的结果将确定这种新的和新的制剂的雾化配方的可行性，并作为第二阶段应用和随后的产品商业化的基础

DESCRIPTION (provided by applicant): Acute respiratory distress syndrome (ARDS) afflicts tens of thousands of individuals annually in the United States and is associated with significant mortality. Presently, there is no effective treatment and little optimism exists for prospective therapies currently under investigation. A unique antiinflammatory agent (protein) that reduces neutrophil reactive oxygen species (ROS)-mediated injury in an animal model of lung inflammation has been identified and represents a potentially viable therapy for ARDS. Therefore, the broad, long-term objectives of this research and drug development program are to develop a unique, localized (lung-targeted) therapy that will be effective in reducing the mortality associated with ARDS. The purpose of this phase I application is to prove the principle of this strategy in man by developing a drug formulation that will sustain the nebulization process and distribute adequately into the human respiratory tract. To this end, the specific aims of this project are to: 1) formulate the agent to make it suitable for local pulmonary delivery via nebulization while retaining activity. Optimal formulation will be derived by the addition of varying concentrations of surfactant. The formulation activities will include an assessment of protein stability, aerodynamic particle size, and biological function. Protein stability will be measured by total protein recovery and structural integrity. Particle size will be determine using a cascade impactor and biological activity will be quantified by the ability of the agent to inhibit neutrophil ROS production; 2) characterize the respiratory deposition of a nebulized formulation of the agent in a human lung replica model. This aim is designed to generate additional supportive evidence to prove the principle of the formulation in man. To accomplish this aim, each viable formulation, as determined by the feasibility criteria of specific aim #1, will be nebulized into a human lung replica. A high-fidelity human lung replica reproduced from a master cast made from a human cadaver which includes five to nine generations of bronchi will be utilized. Deposition in the small airways and alveoli regions of the cast is simulated by material that passes through the upstream airways and is collected on foam filters. The results of the work performed in both specific aims will determine the feasibility of the nebulized formulation of this new and novel agent as well as serve as the basis for a phase II application and the subsequent commercialization of the product