Development of High-performance Cyclic-oligosaccharide-Based Peptide/protein Delivery System Having Biodegradable Characteristics

本研究研究了各种β-环糊精衍生物（β-CyDs）的多功能特性、生物学特性和包合特性，预测了肽/蛋白类药物的新型药物载体。所得结果如下：(1)在不同链长（C_1-C_<12 b>）的酰基化β-CyDs中，每o -丁烷基和每o -valery-β-CyDs形成了透明的粘接片状膜，没有任何化学交联。这些膜在透皮给药系统中作为一种具有高生物适应性的储存库型载体，从而延长了硝酸异山梨酯、莫西多明、醋酸布丝林、胰岛素等水溶性药物的释放时间。(2)磺基丁基醚β-CyD是一种聚阴离子型高水溶性CyD衍生物，在CyD和磺酸之间有疏水丁基间隔，与模型肽胰岛素有强相互作用。这种相互作用显著抑制胰岛素的聚集和酶降解，导致大鼠皮下注射胰岛素后具有高生物利用度和降糖作用。(3)研究了6-O-（4-O-α- d -葡萄糖醛基）- d -葡萄糖基-β- cyd （GUG-β- cyd）对重组人生长激素（rhGH）聚集的影响，并与亲水性cyd进行了比较。结果表明，GUG-β- cyd与rhGH的熔融球状中间体暴露的疏水表面相互作用，降低了蛋白质-蛋白质相互作用，从而抑制了胍、voltexing和热变性等各种化学和物理刺激诱导的聚集。此外，GUG-β-CyD与基本药物有很强的相互作用，可能是氯丙嗪和肉桂嗪等基本药物的安全增溶剂和/或稳定剂。由于本研究开发的CyD衍生物具有较高的生物适应性，因此它们可以在肠外和非肠外给药中作为蛋白质和肽药物的药物载体。

This study dealed with the investigation of the multi-funtional properties, biological properties, and inclusion properties of various β-cyclodextrin derivativess (β-CyDs), anticipating the novel drug carriers for peptide/protein drugs. Results obtained were as follows;(1) Among various acylated β-CyDs with different chain lengths (C_1-C_<12>), per-O-butanoyl and per-O-valery-β-CyDs formed transparent, adhesive sheet-like films without any chemical cross-linkings. These films worked as a reservoir-type carrier with high bioadaptability in transdermal delivery system, thus prolonging the release of water-soluble drugs including peptide drugs, such as isosorbide dinitrate, molsidomine, buserelin acetate and insulin.(2) Sulfobutyl ether β-CyD, a polyanionic highly water-soluble CyD derivative with a hydrophobic butyl spacer between CyD and the sulfonate, strongly interacted with a model peptide, insulin. This interaction significantly inhibited both aggregation and enzymatic degradation of insulin, leading the high bioavailability and hypoglycaemic effect of insulin after subcutaneous administration in rats.(3) Effect of 6-O-(4-O-α-D-Glucuronyl)-D-glucosyl-β-CyD (GUG-β-CyD) on the aggregation of recombinant human growth hormon (rhGH) was studied and compared with hydrophilic CyDs. The results indicated that GUG-β-CyD interacts with the exposed hydrophobic surfaces of the molten globule-like intermediates of rhGH and reduces the protein-protein interaction, resulting in the inhibition of aggregations induced by various chemical and physical stimulus such as guanidine-, voltexing- and thermal-denaturations. Moreover, GUG-β-CyD interacted strongly with basic drugs, and may be useful as a safe solubilizer and/or stabilizer for basic drugs such as chlorpromazine and cinnarizine.Since the CyD derivatives developed here have higher bioadaptability, they can be useful as drug carries for protein and peptide drugs in both parenteral and nonparenteral adminstrations.