Heparin Containing Microparticles for Pulmonary Delivery

血栓栓塞症在心血管疾病的发病机制中起着重要作用。低分子 体重肝素(LMWHs)是预防的首选药物。一般而言，低分子肝素和生物技术 药物的口服生物利用度很差。肺部给药是最有希望的给药途径 对这些特工来说。然而，吸入后进入肺部的药物处置受到以下因素的限制， 配方空气动力学，粘液纤毛清除，吸收机制，组织隔离。因此， 低分子肝素的当前交付方法(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)，并且不符合患者的要求。此外，现在公认的是，昼夜节律 这些疾病存在节律。克服上述问题的一种方法是开发药物 含有大孔微粒(LPM)，具有不同的肺部释放速率/时间。vbl.使用 可生物降解和不可生物降解的聚合物和三种肝素(3,000，6,000和17,000兆瓦)，我们 预先配制的含有不同释放率的LPM的肝素。 我们的假设是，含有LPM的低分子肝素的配方可以通过 经肺途径可以更有效地提供所需的每日预防性剂量的抗凝剂 副作用比S.C.注射。这一假设的理论基础是基于肝素-LPM的概念 可避免巨噬细胞快速清除，增强肺部给药。在此基础上 假设，我们提出了两个具体目标：1)评价肝素的稳定性和空气动力学 2)评价含有LPM的肝素的生物利用度和生物活性 肺进路。在目标1中，我们将评估串级冲击器中的颗粒稳定性和空气动力学，以 优化配方变量。在目标2中，我们将使用三种策略来提高低分子肝素的生物利用度 大鼠肺：(I)LPM减少巨噬细胞摄取；(Ii)粘附性聚合物减少粘液纤毛 清除剂，以及(Iii)吸收促进剂。我们还将进行组织学、出血和细胞毒性试验 安全评估研究。这笔赠款是一项有重点的计划，将有助于确定第一个 时间依赖的肝素给药系统用于改善经肺血栓形成的药物治疗。

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.