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重要作用。低分子量肝素（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很差。肺给药是这些药物最有希望的给药途径。然而，吸入后药物进入肺部受到配方空气动力学、纤毛粘膜清除、吸收机制、组织隔离等因素的限制。因此，目前的给药方法（如皮下注射）是侵入性的，存在一些危险（如疼痛/出血），并且不符合患者的要求。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含有不同释放速率/时间的大孔微颗粒（LPM）的药物用于肺给药。使用可生物降解和不可生物降解聚合物，以及三种肝素（3,000,6,000和17.000MW），我们预先配制了含有不同释放率的LPM的肝素。

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.