Heparin Containing Microparticles for Pulmonary Delivery

描述(申请人提供)：血栓栓塞症在心血管疾病的发病机制中起主要作用。低分子肝素(LMWHs)是预防的首选药物。一般来说，低分子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希望的给药途径。然而，吸入后进入肺的药物处置受到诸如制剂、空气动力学、粘液纤毛清除、吸收机制、组织隔离等因素的限制。因此，目前低分子肝素的给药方式(如皮下注射、皮下注射)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，这些疾病存在昼夜节律。克服上述问题的一种方法是开发含有不同速率/时间释放的大孔微粒(LPM)的药物用于肺部给药。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)，我们预制了含有不同释放速率的LPM的肝素。 我们的假设是，含有LPM的低分子肝素制剂可以更有效地提供所需的每日预防性剂量的抗凝剂，且副作用比S.C.注射。这一假说的基本原理是基于这样一个概念，即肝素-LPM可以避免巨噬细胞的快速清除，并增强肺部药物的输送。基于这一假设，我们提出了两个具体的目标：1)评价含肝素的LPM的稳定性和空气动力学；2)评价含肝素的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在大鼠肺中的生物利用度：(I)降低巨噬细胞摄取的低分子肝素，(Ii)减少粘液纤毛清除的粘附性聚合物，以及(Iii)吸收促进剂。我们还将进行组织学、出血和细胞毒性研究，以进行安全性评估。这项赠款是一项重点计划，将有助于确定第一个时间依赖型肝素输送系统，以改进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.