Heparin Containing Microparticles for Pulmonary Delivery

描述（由申请人提供）：血栓栓塞在心血管疾病的发病机制中起主要作用。低分子量肝素（LMWH）是预防的首选药物。通常，低分子量肝素和生物技术药物的口服生物利用度较差。肺部给药是这些药物最有前途的给药途径。然而，吸入后药物在肺中的处置受到诸如制剂空气动力学、粘膜纤毛清除、吸收机制、组织隔离等因素的限制。因此，目前LMWH的递送方法（例如皮下注射，s.c.）具有侵入性，存在一些危害（例如疼痛/出血），并且患者不依从。此外，现在已经确定这些疾病存在昼夜节律。克服上述问题的一种方法是开发用于肺部递送的具有不同速率/时间释放的含有大多孔微粒（LPM）的药物。使用可生物降解和不可生物降解的聚合物，以及三种肝素（3，000，6，000和17.000 MW），我们预先配制了含有LPM的肝素，具有不同的释放速率。 我们的假设是，含有LPM的LMWH制剂可以通过肺部途径给药，可以更有效地递送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可以避免被巨噬细胞快速清除并增强肺部药物递送的概念。基于这一假设，我们提出了两个具体目的：1）评价含肝素LPM的稳定性和空气动力学，2）评价含肝素LPM经肺途径的生物利用度和生物活性。在目标#1中，我们将评估级联撞击采样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增强LMWH在大鼠肺中的生物利用度：（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、出血和细胞毒性研究，以评估安全性。这项资助是一项重点计划，将有助于确定第一个时间依赖性肝素输送系统，以改善经肺血栓形成的药物治疗。

DESCRIPTION (provided by applicant): 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 (e.g. subcutaneous injection, s.c.) are invasive, present some hazards (e.g. 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.