Alkylglycoside Mediated Pulmonary Delivery of Heparins

描述（由申请人提供）：历史上，肝素一直被用作治疗深静脉血栓形成（DVT）的抗凝剂，DVT是一种每年影响200万美国人的毁灭性疾病，估计其中60万人发生肺栓塞，这是一种致命的并发症，每年导致20万人死亡。最近，低分子量肝素（LMWH）已被用作治疗DVT和肺栓塞的普通肝素的替代品。然而，在门诊环境中更广泛使用LMWH的主要限制是需要通过疼痛的皮下注射给药。该建议旨在检验肺途径可以提供一种可行的、非侵入性的和有效的LMWH给药方法的假设。在这方面，依诺肝素将与一系列烷基糖苷（一种较新的非离子表面活性剂家族）一起配制，并将在麻醉大鼠模型中研究制剂的安全性和有效性。将进行第一系列实验以确定可有效增强LMWH肺部吸收的最佳吸收促进剂。通过在大鼠体内模型中测量血浆抗Xa因子活性，评价在喉镜下观察气管后经肺途径给药的LMWH吸收。一旦确定了最佳吸收促进剂，将依诺肝素制剂与其他LMWH进行比较，以确定其中一种LMWH是否比其他LMWH更适合肺部给药。将在大鼠颈静脉血栓形成模型中研究拟定制剂治疗DVT的疗效。将通过研究制剂对呼吸道粘膜纤毛清除功能的影响来确定制剂的安全性。将进行支气管肺泡灌洗，以确定由于暴露于优化制剂而可能在肺中发生的细胞和生化变化。该项目的长期目标是：i）开发一种用于肺部递送LMWH的制剂，该制剂可用于安全有效地控制深静脉血栓形成和肺栓塞; ii）评价烷基糖苷增强LMWH肺部吸收的机制。

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.