Excipient enhanced aerosol particle formulations and inhaler development for impr

赋形剂增强气雾剂颗粒配方和吸入器开发以提高效果

基本信息

批准号：
8089550
负责人：
Michael Hindle
金额：
$ 22.43万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089550
关键词：
Address Adverse effects Aerosols Affect Albuterol Sulfate Alveolar Alveolar sac Animals Area Artificial nanoparticles Benchmarking Benign Blood Circulation Blood capillaries Breathing Budesonide Bypass Caliber Characteristics Charge Control Groups Cystic Fibrosis Deposition Development Devices Disadvantaged Dose Drug Delivery Systems Drug Formulations Economics Effectiveness Electrostatics Engineering Ensure Evaluation Excipients Exhalation Exhibits Exubera Future Gene Delivery Generations Generic Drugs Goals Growth Guidelines Human Humidity In Vitro Inhalation Therapy Inhalators Insulin Joints Lung Lung diseases Malignant neoplasm of lung Medicine Methods Modality Modeling Modification Morphology Oral Oral cavity Outcome Particle Size Peptides Performance Pharmaceutical Preparations Pharmacologic Substance Pharyngeal structure Physical condensation Powder dose form Process Property Relative (related person)Research Activity Respiratory System Respiratory Tract Infections Respiratory tract structure Route Site Sodium Chloride Solutions Surface System Systemic disease Systemic infection Techniques Technology Testing Tracheobronchial Upper respiratory tract Vaccines Water Weight Wettability Xylitol aerosolized base capillary design gene therapy improved in vitro testing in vivo insight iterative design nanoparticle nanosized new technology next generation particle performance tests public health relevance research study respiratory simulation small molecule solid state sugar wasting water vapor

项目摘要

DESCRIPTION (provided by applicant): Pharmaceutical nanoparticles have failed to leverage their unique aerosol drug delivery potential for the treatment of local and systemic diseases due to poor pulmonary deposition efficiency. Because of their submicrometer size, aerosolized nanoparticles can potentially overcome many of the problems associated with traditional inhalation therapy if their lung deposition can be significantly increased. In order to make many next- generation inhaled medications a viable drug delivery alternative, utilizing the full potential of nanoparticles for increased lung delivery and decreased inter- and intra-subject variability are of critical importance. The goal of this project is to address the challenges facing inhaled nanoparticle delivery by developing aerosol formulations that can ensure efficient targeted nanoparticle lung deposition. This concept consists of engineering dry powder nanoparticle aerosols containing a model drug and a hygroscopic excipient. The engineered nanoparticles will be delivered in the size range of 100 - 900 nm in order to minimize mouth- throat deposition and maximize drug payload. After bypassing the upper airways, the natural humidity in the lungs will cause the hygroscopic excipient to accumulate water, increasing the size and weight of the nanoparticles. The increased aerodynamic diameter of the particles will then ensure increased lung deposition rather than exhalation of the aerosol and can potentially be used to target the site of deposition. To achieve this goal, the following specific aims are proposed: Specific Aim 1: Generate and characterize engineered pharmaceutical nanoparticles consisting of drug and a hygroscopic excipient to be used in the excipient enhanced growth (EEG) studies. Specific Aim 2: Evaluate nanoparticle growth in conjunction with upper and lower lung deposition of the engineered aerosol using concurrent CFD modeling and in vitro testing. Specific Aim 3: Evaluate and optimize a dry powder inhaler (DPI) design for nanoparticle dispersion and delivery using a quantitative analysis and design approach. By delivering nanoparticles past the mouth-throat and then increasing their aerosol size through excipient enhanced hygroscopic growth, significant reductions in upper airway deposition are expected. As a result of using this concept, reduced variability in dose can be achieved together with near full lung retention, which are necessary for the effective use of many next-generation pharmaceutical aerosols. PUBLIC HEALTH RELEVANCE: The inhalation of pharmaceutical nanoparticles may offer many unique advantages compared to conventional delivery methods for the treatment of respiratory diseases, systemic conditions and to unlock the potential use of the lungs to deliver vaccines and gene therapy. However, the current methods used to administer these next-generation nanoparticle pharmaceuticals to the lungs are often inefficient, which can significantly reduce drug effectiveness, increase unwanted side effects, and make dosing difficult to control. The overall goal of this project is to develop a novel technology for the efficient delivery of inhaled nanoparticles that minimizes deposition in the mouth and throat while maximizing deposition in the lungs.

描述（由申请人提供）：由于肺部沉积效率差，药物纳米粒子未能利用其独特的气雾剂药物输送潜力来治疗局部和全身疾病。由于其亚微米尺寸，如果雾化纳米颗粒的肺部沉积能够显着增加，那么它们就有可能克服与传统吸入疗法相关的许多问题。为了使许多下一代吸入药物成为可行的药物输送替代方案，充分利用纳米粒子的潜力来增加肺部输送并减少受试者间和受试者内的变异性至关重要。该项目的目标是通过开发可确保高效靶向纳米颗粒肺部沉积的气雾剂配方来解决吸入纳米颗粒输送面临的挑战。该概念包括工程干粉纳米颗粒气雾剂，其中含有模型药物和吸湿性赋形剂。工程纳米粒子将以 100 - 900 nm 的尺寸范围输送，以最大限度地减少口腔沉积并最大限度地提高药物有效负载。绕过上呼吸道后，肺部的自然湿度会导致吸湿性赋形剂积聚水分，从而增加纳米颗粒的尺寸和重量。颗粒的空气动力学直径的增加将确保增加肺部沉积而不是气溶胶的呼出，并且可以潜在地用于瞄准沉积部位。为了实现这一目标，提出了以下具体目标：具体目标 1：生成并表征由药物和吸湿性赋形剂组成的工程药物纳米粒子，用于赋形剂增强生长 (EEG) 研究。具体目标 2：使用并行 CFD 建模和体外测试来评估纳米颗粒的生长以及工程气溶胶的上肺和下肺沉积。具体目标 3：使用定量分析和设计方法评估和优化纳米颗粒分散和输送的干粉吸入器 (DPI) 设计。通过将纳米颗粒输送通过口腔，然后通过赋形剂增强吸湿性生长来增加其气溶胶尺寸，预计会显着减少上呼吸道沉积。使用这一概念的结果是，可以减少剂量的变异性，同时实现近乎完全的肺滞留，这对于有效使用许多下一代药物气雾剂是必要的。公共卫生相关性：与传统的递送方法相比，吸入药物纳米颗粒可能具有许多独特的优势，可用于治疗呼吸系统疾病、全身性疾病，并释放肺部用于递送疫苗和基因治疗的潜在用途。然而，目前用于向肺部施用这些下一代纳米颗粒药物的方法通常效率低下，这会显着降低药物有效性，增加不需要的副作用，并使剂量难以控制。该项目的总体目标是开发一种新技术，用于有效输送吸入的纳米颗粒，最大限度地减少在口腔和喉咙的沉积，同时最大限度地增加在肺部的沉积。