Improvement of Pharmaceutical Properties of Protein Drugs by Bioadaptable Cyclodextrins

胰岛素分子自我结合成低聚物和大分子聚集体导致长期胰岛素治疗系统发展的并发症，并限制了皮下吸收的速度。因此，在他的研究中，研究了亲水性环糊精（CyDs）对牛胰岛素在水溶液中的聚集及其在疏水表面上的吸附的影响。此外，本研究还探讨了胰岛素与CyDs的络合如何影响大鼠皮下注射胰岛素的药代动力学和药效学行为。在测试的cyd中，麦芽糖基- β - cyd （g2 - β - cyd）被发现是胰岛素聚集及其在玻璃管和聚丙烯管表面吸附的最有效抑制剂。β - cyd的磺基丁基醚（sbe - β - cyd）对胰岛素聚集的影响因磺基丁基取代程度的不同而不同，即在较低取代时（sbe4 - β - cyd）有抑制作用，在较高取代时（sbe7 - β - cyd）有加速作用。差示扫描量热法、电喷雾电离质谱法和1h核磁共振光谱研究表明，亲水性CyDs以不同的方式与胰岛素相互作用，改变了肽的自结合和吸附行为。体内研究表明，在皮下胰岛素注射中适当使用CyD衍生物可以有效地设计快速或长效制剂，从而改善患者的舒适度。

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.