权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Heparin Containing Microparticles for Pulmonary Delivery

用于肺部输送的含肝素微粒

基本信息

批准号：
7413520
负责人：
Bi-Botti Celestin Youan
金额：
$ 1.6万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7413520
关键词：
Accounting Acute myocardial infarction Adverse effects Anticoagulants Applications Grants Asthma Behavior Biological Availability Biological Preservation Biotechnology Blood Breathing Caliber Cardiovascular Diseases Cause of Death Chemical Structure Circadian Rhythms Clinic Clinical Research Condition Daily Deposition Disease Dose Drug Administration Routes Drug Controls Drug Delivery Systems Drug Formulations Emulsions Enhancers Exhibits Future Generations Genes Goals Grant Healthcare Hematological Disease Hemorrhage Hemostatic Agents Heparin Home environment Hour Human Hypertension In Vitro Ingestion Inhalators Injection of therapeutic agent Insulin Intravenous Invasive Kinetics Knowledge Laboratories Low-Molecular-Weight Heparin Lung Lung diseases Malignant Neoplasms Medicine Methods Modeling Molecular Weight Monitor Morbidity - disease rate Mucociliary Clearance Nose Oral Outpatients Pain Pathogenesis Patients Pattern Peptides Personal Satisfaction Pharmaceutical Preparations Pharmacotherapy Physiological Play Polymers Powder dose form Pregnancy Prevention Preventive Property Prophylactic treatment Proteins Pulmonary Embolism Range Rate Rattus Research Research Personnel Respiratory Mucosa Risk Role Route Safety Self Care Solvents Standards of Weights and Measures Stroke Subcutaneous Injections System Testing Therapeutic Therapeutic Agents Thromboembolism Thrombophilia Thrombosis Time Tissues Toxic effect United States Venous Warfarin Water Work absorption base biodegradable polymer compliance behavior concept controlled release cytotoxicity design disability evaporation expectation hazard improved in vivo innovation interest irritation lung Carcinoma macrophage mortality novel particle programs prophylactic respiratory size subcutaneous success uptake

项目摘要

Thromboembolism plays a major role in the pathogenesis of cardiovascular diseases. Low molecular weight heparins (LMWHs) are agents of choice for the prevention. Generally, LMWHs and biotechnology drugs present a poor oral bioavailability. Pulmonary delivery is the most promising route of administration for these agents. However, drug disposition into the lung following inhalation is limited by factors such as, formulation aerodynamics, mucociliary clearance, absorption mechanism, tissue sequestration. Therefore, current delivery methods of LMWHs (eg. subcutaneous injection, s.c.) are invasive, present some hazards (eg. pain/bleeding) and are not patient compliant. Moreover, it is now well-established that a circadian rhythm exists in these diseases. One approach to overcome the foregoing problems is to develop drug containing large porous microparticles (LPM) with different rate/time-release for pulmonary delivery. Using biodegradable and nonbiodegradable polymers, and three heparins (3,000, 6,000 and 17.000MW), we have preformulated heparin containing LPM with different release rates. Our hypothesis is that formulation of LMWHs containing LPM, which can be administered by pulmonary route can more efficiently deliver the required daily preventive dose of anticoagulant with less side effects than s.c. injection. The rationale for this hypothesis is based on the concept that heparin-LPM could avoid rapid clearance by macrophages and enhance pulmonary drug delivery. Based on this hypothesis, we propose two Specific Aims: 1) evaluate the stability and aerodynamics of heparin containing LPM, and 2) evaluate the bioavailability and bioactivity of the heparin containing LPM by pulmonary route. In Aim#1, we will assess particle stability, and aerodynamics in a cascade impactor to optimize formulation variables. In Aim#2, we will use three strategies to enhance LMWHs bioavailability in rat lungs: (i) LPM to reduce macrophage uptake, (ii) mucoadhesive polymer to reduce mucociliary clearance, and (iii) absorption enhancer. We will also perform histological, bleeding and cytotoxicity studies for safety estimation. This grant is a focused plan that will contribute to the identification of the first time-dependent heparin delivery system for improved pharmacotherapy of thrombosis via the lung.

血栓栓塞在心血管疾病的发病机制中起着重要作用。低分子重质肝素（LMWH）是预防的选择试剂。一般来说，低分子量物质和生物技术药物的口服生物利用度差。肺部给药是最有前途的给药途径对于这些代理商。然而，吸入后药物在肺中的分布受到以下因素的限制，制剂空气动力学、粘膜纤毛清除、吸收机制、组织隔离。因此，我们认为， LMWH的当前递送方法（例如，皮下注射，s.c.）是侵入性的，存在一些危险（例如：疼痛/出血），并且患者不依从。此外，现在已经确定，昼夜节律这些疾病都存在节律性。克服上述问题的一种方法是开发药物含有用于肺部递送的具有不同速率/时间释放的大多孔微粒（LPM）。使用生物可降解和非生物可降解聚合物和三种肝素（3，000，6，000和17.000 MW），我们具有不同释放速率的含有预先配制的肝素的LPM。我们的假设是含有LPM的LMWH制剂，其可以通过以下方式施用：肺途径可以更有效地提供所需的每日预防剂量的抗凝剂，副作用比s.c.注射该假设的基本原理是基于肝素-LPM 可以避免巨噬细胞的快速清除并增强肺部药物递送。基于此假设，我们提出了两个具体的目的：1）评价肝素的稳定性和空气动力学含肝素的LPM的生物利用度和生物活性，以及2）通过以下方法评价含肝素的LPM的生物利用度和生物活性：肺部途径在目标1中，我们将评估级联撞击器中的颗粒稳定性和空气动力学，优化配方变量。在目标#2中，我们将使用三种策略来提高LMWH的生物利用度，大鼠肺：（i）LPM以减少巨噬细胞摄取，（ii）粘膜粘附聚合物以减少粘膜纤毛清除，和（iii）吸收促进剂。我们还将进行组织学，出血和细胞毒性安全性评估研究。这项赠款是一项重点突出的计划，将有助于确定第一个时间依赖性肝素输送系统，用于改善经肺血栓形成的药物治疗。