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Absorption Mechanism Study of Insulin-Bile Acid Complex for the Oral Delivery

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Authors
K.A.FoyezMahmud
Advisor
Victor C. Yang
Major
분자의학 및 바이오제약학과
Issue Date
2012-02
Publisher
서울대학교 대학원
Description
학위논문 (석사)-- 서울대학교 대학원 : 분자의학 및 바이오제약학과, 2012. 2. Victor C. Yang.
Abstract
Diabetes is regarded one of the leading causes of death in the world. Since the discovery, insulin is an indispensable treatment option for the treatment of diabetes. To avoid the burden of repeated subcutaneous injections and to improve insulins pharmacokinetics, oral administration is still a better option to deliver insulin. The objective of the present investigation was to demonstrate the absorption mechanism process of insulin with the physical complexation of Nα-Deoxycholyl-L-lysyl-methylester (DCK) for the oral delivery. In our study, we use DCK (1:10 ratio) as a bile acid enhancer for delivering insulin orally. By making complex with DCK, the lipophilicity was greatly increased without changing the secondary structure of insulin. In Caco-2 cell line, 90% uptake of insulin/DCK complex was observed. By visualizing actin and zonula occluden-1 protein, the complex was observed to interact with tight junction proteins. However, most of the drug was distributed in cytoplasm of Caco-2 cell. The permeability study demonstrated that insulin/DCK complex was better transported across Caco-2 monolayers. The possible transport route of insulin/DCK for oral administration might be: (1) paracellular transport via transient opening of tight junctions in reversible manner which was confirmed by western blotting, (2) transcellular transport (passive diffusion) via the intestinal barrier in Caco-2 monolayer. Moreover, in ASBT transfected MDCK and ASBT over-expressed SK-BR-3 cell line, the insulin/DCK complex showed interaction with ASBT and also showed absorption through few extent of passive diffusion, which also supports the dual transportation nature of the insulin/DCK complex. In bile acid transporter inhibition study, using sodium taurocholate, it showed gradual decrease in uptake when concentration (0-200 µM) of sodium taurocholate was increased. We also observed no absorption via endocytosis process. In rat intestine model, the highest absorption of insulin complex was observed at 1 h in jejunum followed by ileum at 2-4 h. From this result, we concluded that insulin showed initial absorption in jejunum, due to passive diffusion and tight junction interruption. But in ileum, the absorption pattern was very steady for a longer period due to active interaction with ileal apical bile acid transporters. This data showed the great potential for the clinical application for oral delivery of insulin.
Language
eng
URI
https://hdl.handle.net/10371/154951

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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Theses (Master's Degree_분자의학 및 바이오제약학과)
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