Alkylglycoside Mediated Pulmonary Delivery of Heparins

说明(申请人提供)：从历史上看，肝素一直被用作治疗深静脉血栓形成(DVT)的抗凝剂。DVT是一种毁灭性的疾病，每年影响200万美国人，估计其中60万人会发生肺血栓，这是一种致命的并发症，每年导致20万人死亡。最近，低分子肝素(LMWHs)已被用作普通肝素的替代品，用于治疗DVT和肺栓塞。然而，在非卧床环境中广泛使用低分子肝素的主要限制是要求通过疼痛的皮下注射给药。这项建议旨在验证这样一种假设，即肺途径可以提供一种可行的、非侵入性的和有效的低分子肝素给药方法。在这方面，依诺肝素将由一系列烷基糖苷组成，这是一个较新的非离子表面活性剂家族，并将在麻醉大鼠模型中考察这些制剂的安全性和有效性。将进行第一系列实验，以确定能够有效促进低分子肝素的肺吸收的最佳吸收促进剂。在活体大鼠模型中，将通过测量血浆抗因子Xa活性来评估喉镜下气管显影后经肺途径给药的低分子肝素的吸收。一旦确定了最佳吸收促进剂，依诺肝素制剂将与其他低分子肝素进行比较，以确定其中一种低分子肝素比其他低分子肝素更适合肺部给药。我们将在大鼠颈静脉血栓形成模型上研究该制剂对深静脉血栓的治疗效果。这些制剂的安全性将通过研究该制剂对呼吸道粘液纤毛清除功能的影响来确定。将进行支气管肺泡灌洗，以确定因接触优化配方而可能在肺内发生的细胞和生化变化。该项目的长期目标是：i)开发一种低分子肝素肺给药配方，可用于安全有效地控制深静脉血栓形成和肺栓塞；以及ii)评价烷基糖苷促进低分子肝素肺吸收的机制。

DESCRIPTION (provided by applicant): Historically, heparin has been used as an anticoagulant for the treatment of deep vein thrombosis (DVT), a devastating disease that affects two million Americans annually and an estimated 600,000 of which develop pulmonary embolism, a fatal complication resulting in 200,000 deaths a year. Recently, low molecular weight heparins (LMWHs) have been used as an alternative to unfractionated heparins in the treatment of DVT and pulmonary embolism. However, the main limitation to the broader utilization of LMWHs in an ambulatory setting is the requirement of administering the drug by painful subcutaneous injections. This proposal is designed to test the hypothesis that pulmonary route can provide a viable, noninvasive, and efficacious means of administering LMWHs. In this regard, enoxaparin will be formulated with a series of alkylglycosides, a newer family of nonionic surfactants, and the safety and efficacy of the formulations will be investigated in anesthetized rat model. The first series of experiments will be conducted to determine the optimal absorption enhancer that can effectively enhance pulmonary absorption of LMWHs. Absorption of LMWHs, administered via pulmonary route after laryngoscopic visualization of the trachea, will be evaluated by measuring plasma anti-factor Xa activity in vivo rat model. Once an optimal absorption enhancer is identified, enoxaparin formulations will be compared with other LMWHs to determine if one of the LMWHs is better suited than the others for pulmonary delivery. The efficacy of the proposed formulation in the treatment of DVT will be investigated in rat jugular vein thrombosis model. The safety of the formulations will be determined by studying the effect of the formulation on mucociliary clearance function of the respiratory tract. Bronchoalveolar lavage will be conducted to determine cellular and biochemical changes that may occur in the lung due to exposure to the optimized formulation. The long-term goals of this project are i) to develop a formulation for pulmonary delivery of LMWHs that can be used to provide safe and effective control of deep vein thrombosis and pulmonary embolism and ii) to evaluate the mechanism by which alkylglycosides enhance pulmonary absorption of LMWHs.