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Purpose: To investigate if pulmonary delivery of low molecular weight heparin (LMWH) formulated with tetradecyl-beta-maltoside (TDM) or dimethyl-beta-cyclodextrin (DMbetaCD) could be a feasible alternative to subcutaneous injections for the treatment of pulmonary embolism., Methods: The pulmonary absorption of two LMWHs and unfractionated heparin formulated with TDM or DMbetaCD was studied in cell culture and rodent model. The in vitro study was performed by measuring the transport of radiolabeled enoxaparin and mannitol across human bronchial epithelial cells (Calu-3) in the presence or absence of varying concentrations of TDM or DMbetaCD. The changes in transepithelial electrical resistance (TEER) and enoxaparin metabolic stability were also investigated using Calu-3 cells. In vivo absorption studies were performed by measuring plasma anti-factor Xa activity after pulmonary administration of enoxaparin, dalteparin, or unfractionated heparin to anesthetized rats., Results: In vitro experiments conducted in Calu-3 cells suggest that the addition of TDM or DMbetaCD to the apical chamber results in a significant increase in 3H-enoxaparin and 14C-mannitol permeability and a decrease in TEER across the Calu-3 cell monolayer. Enoxaparin incubated in Calu-3 cell extracts was stable for 8 h. In vivo studies indicate that both TDM and DMbetaCD enhance pulmonary absorption of LMWH. However, TDM was found to be more potent than DMbetaCD in both in vitro transport and in vivo absorption studies., Conclusions: TDM and DMbetaCD enhance pulmonary absorption of LMWH both in vitro and in vivo, with TDM being more efficacious than DMbetaCD. Both agents increase drug transport by acting mainly on the membrane rather than interacting with the drug.