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Under the tounge Insulin

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Sublingual Delivery of Insulin: Effects of Enhancers on the Mucosal Lipid Fluidity and Protein Conformation, Transport, and in Vivo Hypoglycemic Activity

           
 The purposes of this study were to evaluate effects of enhancers for sublingual delivering insulin on the mucosal lipid fluidity and protein conformation, transport, and in vivo hypoglycemic activity in normal rats. The effects on sublingual mucosa, and aggregation states of insulin were estimated using fluorescence polarization, and circular dichroism method, respectively. The human immortalized oral epithelial cell monolayer was used for evaluating transport of insulin. Hydroxylpropyl-β-cyclodextrin (HP-β-CD), chitosan, polyethylene–polypropylene glycol, polyoxyethylene lauryl ether, polysorbate 80, egg lecithin, or oleic acid, was used as a penetration enhancer, respectively. The fluidity of sublingual mucosal lipid was markedly reduced by these enhancers excluding polysorbate 80, and the secondary structure of the mucosal proteins was also influenced by these enhancers. The hexamers of insulin were dissociated to monomers only by chitosan, polyoxyethylene lauryl ether, and egg lecithin. Nonetheless, plasma glucose levels in normal rats were significantly lowered after sublingual administration of insulin with an enhancer compared with those without an enhancer at the same time-point. The enhancing effects may be due to one or multiple factors: increasing the mucosal lipid fluidity, directly loosing the tight junction of epithelia, and dissociating the hexamers of insulin to monomers. Among these, the opened tight junction may correlate most with the enhancing effect in the mucosal permeability. Because the aggregates of insulin exist, the dissociation of the aggregates by an enhancer would benefit the permeability.

Chun-Ying Cui1), Wan-Liang Lu1), Lan Xiao1), Shuang-Qing Zhang1), Yan-Bei Huang2), Sheng-Lin Li3), Rui-Juan Zhang1), Gui-Ling Wang1), Xuan Zhang1) and Qiang Zhang4)

1) School of Pharmaceutical Sciences, Peking University
2) School of Basic Medical Sciences, Peking University
3) School of Stomatology, Peking University
4) The State Key Laboratory of Natural and Biomimetic Drugs, Peking University

 

Key wordsinsulin; enhancing mechanism; transport; hypoglycemic activity; sublingual delivery

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