Alkylmaltoside mediated nasal delivery of low molecular weight Heparin: In vitro and in vivo evaluations
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Abstract
This study is designed to test the hypothesis that alkylmaltosides could be used as efficacious absorption enhancers for nasal delivery of enoxaparin, a low molecular weight heparin. The efficacy of the absorption enhancers was studied by monitoring the changes in plasma anti-factor Xa level after nasal administration of enoxaparin into anesthetized rats. In vivo reversibility study was performed to determine if the effect of the absorption enhancers on nasal membrane is reversible after acute administration of the formulations. Enoxaparin was formulated with alkylmaltosides containing varying alkyl chain lengths (octyl-, decyl-, dodecyl,- and tetradecyl-maltoside) in order to assess the role of hydrophobic chain length on the potency of the absorption enhancers. The mechanisms by which alkylmaltosides enhance permeation of enoxaparin across epithelial cells were investigated by studying the transport of radiolabelled enoxaparin and mannitol across human bronchial epithelial cells. In vitro cytotoxicity and transepithelial electric resistance recovery studies were performed to further assess the toxicity of the agents on epithelial cells. The results demonstrate that alkylmaltosides enhance enoxaparin absorption in a chain length and dose dependent manner. Of the alkylmaltosides tested, tetradecylmaltoside was most efficacious in enhancing nasal absorption of enoxaparin. It was found that the effect of octylmaltoside on nasal membrane diminishes with time and nasal mucosa re-establishes normal physiological barrier to drug absorption. Permeabilities of enoxaparin and mannitol increase in the presence of alkylmaltosides, suggesting that alkylmaftosides enhance nasal absorption of LMWH via paracellular route. Cytotoxicity studies revealed that octylmaltoside is the least toxic to the bronchial epithelial cells. Overall, the results suggest that nasal enoxaparin formulated v/ith alkylmaltosides could be a feasible alternative to subcutaneous enoxaparin.