1996 Fiscal Year Final Research Report Summary
Improvement of Pharmaceutical Properties of Protein Drugs by Bioadaptable Cyclodextrins
| Project/Area Number |
07672464
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Faculty of Pharmaceutical Sciences, Kumamoto University |
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Principal Investigator |
UEKAMA Kaneto Kumamoto University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (90040328)
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| Co-Investigator(Kenkyū-buntansha) |
IRIE Tetsumi Kumamoto University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (60150546)
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| Project Period (FY) |
1995 – 1996
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| Keywords | insulin / cyclodextrin / self-association / surface adsorption / aggregation / absorption rate control / long-acting injection |
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| Research Abstract |
Self-association of insulin molecules into oligomers and macromolecular aggregates leads to complications in the development of long-term insulin therapeutic systems and limits the rate of subcutaneous absorption. In his study, therefore, the effects of hydrophilic cyclodextrins (CyDs) on the aggregation of bovine insulin in aqueous solution and its adsorption onto hydrophobic surfaces were investigated. Furthermore, this study addressed how the complexation of insulin with CyDs could impact upon the pharmacokinetic and pharmacodynamic behavior of the insulin when given subcutaneously to rats. Of the CyDs tested, maltosyl-beta-CyD (G2-beta-CyD) was found to be the most potent inhibitor of insulin aggregation and of its adsorption onto the surface of glass and polypropylene tubes. The sulfobutyl ether of beta-CyD (SBE-beta-CyD) showed different effects on the insulin aggregation, depending on the degree of substitution of sulfobutyl group : i.e., the inhibition at relatively low substitution (SBE4-beta-CyD) and acceleration at higher substitution (SBE7-beta-CyD). Differential scanning calorimetry, electrospray ionization mass spectrometry, and 1H-nuclear magnetic resonance spectroscopic studies revealed that hydrophilic CyDs interact with insulin in a varying manner, modifying the self-association and adsorption behavior of the peptide. In vivo studies indicated that a proper use of the CyD derivatives in subcutaneous insulin injection could be effective in designing rapid or long-acting preparations, thus offering an improvement in patient comfort.
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