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.
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