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

开发具有生物降解特性的高性能环状低聚糖基肽/蛋白质递送系统

基本信息

批准号：
12557206
负责人：
UEKAMA Kaneto
金额：
$ 8.32万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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.

本研究对不同的β-环糊精衍生物(β-CyDS)的多功能性质、生物学性质和包合性质进行了研究，以期成为多肽/蛋白质类药物的新型药物载体。研究结果如下：(1)在不同链长的酰化β-β中，Per-O-丁酰基和Per-O-Valery-Cyds形成透明粘连的片状薄膜，无任何化学交联。这些薄膜作为具有高度生物适应性的储备型载体应用于经皮给药系统，从而延长了包括多肽药物如硝酸异山梨酯、莫西多明、醋酸丁酯和胰岛素在内的水溶药物的释放。(2)磺丁基醚β-Cyd是一种多阴离子高度水溶性的Cyd衍生物，在Cyd和磺酸盐之间具有疏水丁基间隔，与模型肽胰岛素强相互作用。这种相互作用显著抑制了胰岛素的聚集和酶降解，导致胰岛素在大鼠皮下注射后具有较高的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CyDS进行了比较。结果表明，GUG-β-CyD与重组人生长激素熔融的球状中间体的疏水表面相互作用，减少了蛋白质与蛋白质的相互作用，从而抑制了各种化学和物理刺激(如胍、卷曲和热变性)引起的聚集。此外，GUG-β-Cyd与基础药物有很强的相互作用，可作为氯丙嗪、桂利嗪等基础药物的安全增溶剂和/或稳定剂。由于所开发的Cyd衍生物具有较高的生物适应性，因此可作为蛋白质和多肽药物的药物载体，用于静脉和非肠道给药。