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

• 批准号: 7976385
• 负责人: Michael Hindle
• 金额: $ 18.39万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976385
• 关键词: Address; Adverse effects; Aerosols; Affect; Albuterol Sulfate; Alveolar; Alveolar sac; Animals; Area; Artificial nanoparticles; Arts; 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 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

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，药物纳米颗粒未能利用其独特的气溶胶药物输送潜力来治疗局部和全身性疾病。由于它们的亚微米大小，如果可以显着增加肺部沉积，则雾化的纳米颗粒可能会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递送替代品，利用纳米颗粒的全部潜力增加肺部输送和降低 - 主体间和受试者内变异性至关重要。该项目的目的是通过开发可确保有效的靶向纳米颗粒肺沉积的气溶胶制剂来解决吸入纳米颗粒面临的挑战。这个概念包括工程干粉纳米粒子气溶胶，其中含有模型药物和吸湿性赋形剂。工程的纳米颗粒将在100-900 nm的尺寸范围内交付，以最大程度地减少口腔沉积并最大化药物有效载荷。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，从而增加纳米颗粒的大小和重量。然后，颗粒的空气动力学直径增加将确保肺部沉积增加而不是气溶胶的呼气，并有可能用于靶向沉积部位。为了实现这一目标，提出了以下特定目的：具体目标1：生成和表征由药物和吸湿性赋形剂组成的工程制药纳米颗粒，用于赋形剂增强的生长（EEG）研究。具体目标2：使用并发的CFD建模和体外测试，评估纳米颗粒的生长以及工程气溶胶的上和下肺沉积。特定目标3：使用定量分析和设计方法评估和优化用于纳米颗粒分散和交付的干粉吸入器（DPI）设计。通过将纳米颗粒递送到口throat中，然后通过赋形剂增强的吸湿生长来增加气溶胶的大小，预计上呼吸道沉积会大大减少。通过使用此概念，可以与几乎全肺保留率一起实现剂量变异性，这对于有效使用许多下一代药物气溶胶是必不可少的。 公共卫生相关性：与传统输送方法相比，吸入药物纳米颗粒可能具有许多独特的优势，用于治疗呼吸道疾病，系统状况，并释放肺部潜在使用疫苗和基因疗法。但是，用于对肺部进行这些下一代纳米颗粒药物的当前方法通常效率低下，这可以显着降低药物有效性，增加不必要的副作用并使给药难以控制。该项目的总体目标是开发一种新型技术，用于有效地输送吸入的纳米颗粒，以最大程度地减少口腔和喉咙的沉积，同时最大程度地在肺部沉积。