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

本文对β-环糊精衍生物（β-CyDs）的多功能特性、生物学特性、包合特性等进行了研究，以期为肽/蛋白类药物的新型药物载体提供参考。结果表明：（1）在不同链长（C_1-C_2）的酰化β-CyDs中<12>，全O-丁酰基和全O-缬酰基β-CyDs形成透明的、粘性的片状膜，没有发生任何化学交联。这些膜在透皮给药系统中作为一种具有高生物适应性的缓释型载体，从而延长了包括肽类药物在内的水溶性药物的释放，如硝酸异山梨酯、么西多明、醋酸布舍瑞林和胰岛素。(2)磺丁基醚β-CyD是一种聚阴离子型高水溶性CyD衍生物，在CyD和磺酸盐之间具有疏水丁基间隔基，与模型肽胰岛素有很强的相互作用。这种相互作用显著抑制胰岛素的聚集和酶降解，导致大鼠皮下给药后胰岛素的高生物利用度和降血糖作用。(3)研究了6-O-（4-O-α-D-葡萄糖醛酸基）-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的熔融球状中间体的疏水表面相互作用，减少蛋白质-蛋白质相互作用，从而抑制由胍变性、变性和热变性等各种化学和物理刺激诱导的聚集。此外，GUG-β-CyD与碱性药物有较强的相互作用，可作为氯丙嗪、桂利嗪等碱性药物的安全增溶剂和/或稳定剂，具有较高的生物适应性，可作为蛋白质和多肽类药物的载体，用于胃肠外和非胃肠外给药。

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.