Improvement of Stability and Nasal Absorption of Peptide/Protein Drugs by Cyclodextrin Derivatives

环糊精衍生物改善肽/蛋白质药物的稳定性和鼻吸收

• 批准号: 02671055
• 负责人: UEKAMA Kaneto Ph. D.
• 金额: $ 1.47万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02671055/
• 关键词: Peptide; protein drugs; Insulin; Enhanced nasal absorption; Hypoglycemia; Proteolytic degradation; Insulin aggregation; Cyclodextrin derivatives; Lipophilic absorption enhancer; メチル化シクロデキストリン; 酢酸ブセレリン

Nasal absorption of peptide/protein drugs such as insulin has been severely restricted by the presystemic elimination due to mucociliary clearance or enzymatic degradaion and by the limited mucosal membrane permeability. The objective of this study, therefore, is to investigate the potential use of hydrophilic cyclodextrin (CyD) derivatives in the nasal preparation of insulin, and prevention of insulin self-association and surface adsorption. The results obtained were as follows.(1) Methylated cyclodextrins were found to be more potent absorption enhancers than parent and hydroxypropylated CyDs. Spectroscopic observations indicated that the scope of inclusion complexation of insulin with cyds appeared to be of minor importance in the nasal absorption enhancement. CyDs increased the permeability of rat nasal mucosa, perhaps through the interaction with lipids and/or divalent cations on the membrane surface. In addition, the enzymatic degradation of insulin in- rat nasal homogenates was … More suppressed by CyDs. Multiple regression analysis suggested that the increased nasal membrane permeability and reduced proteolysis contributed synergistically to the absorption enhancement of insulin.(2) Possible use of 2-hydroxypropyl- beta -cyclodextrin (2-HP- beta -CYD) was preliminarily investigated in designing nasal preparation of insulin involving lipophilic absorption enhancer 1-[2- (decylthio) -ethyl]azacyclopentane-2-one (HPE-101). When insulin was administered nasally to rats, a simultanqp. . u's use of HPE-101 solubilized in 2-HP- beta-CyD showed a prominent increase in serum immunoreacive insulin levels and a marked hypoglycemia, probably through the facilitated transfer cit HPE-101 into the nasal mucosa. These results suggest that a combination of HPE-101 and hydrophilic CyDs is useful for designing mote effective and safer nasal delivery system of peptide/protein drugs.(3) Since insulin is biologically active mainly in the monomeric state, this study also attempted to overcome the insulin self-association and surface adsorption phenomena by the addition of CyDs. It was found that the hydrophilic CyDs such as maltosyl-beta-CyD and 2-HP-beta-CyD to insulin solution significantly reduced both insulin self-association and adsorption onto glass and polymeric surfaces. The analysis of circular dichroic (CD) behavior of insulin solution indicated that CyD may facilitate the conformational transition of insulin from some higher aggregates to monomeric state, decreasing antiparallel beta-structure of insulin. Less

由于纤毛粘膜清除或酶降解引起的全身前消除以及有限的粘膜通透性，胰岛素等肽/蛋白药物的鼻腔吸收受到严重限制。因此，本研究的目的是探讨亲水环糊精（CyD）衍生物在鼻腔胰岛素制备中的潜在应用，以及胰岛素自结合和表面吸附的预防。所得结果如下：(1)甲基化环糊精比亲本和羟丙基环糊精具有更强的吸收促进作用。光谱观察表明，胰岛素与cyds的包合范围在鼻吸收增强中似乎不太重要。CyDs增加了大鼠鼻黏膜的通透性，可能是通过与膜表面的脂质和/或二价阳离子相互作用。此外，CyDs对大鼠鼻匀浆中胰岛素的酶降解有明显的抑制作用。多元回归分析表明，鼻膜通透性增加和蛋白水解减少对胰岛素吸收增强有协同作用。(2)初步探讨了使用2-羟丙基- β -环糊精（2- hp - β - cyd）设计含亲脂吸收促进剂1-[2-（癸硫）-乙基]氮杂环戊烷-2- 1 （HPE-101）的鼻用胰岛素制剂的可能性。当给大鼠鼻腔注射胰岛素时，使用2-HP- β - cyd溶解的HPE-101后，血清免疫反应性胰岛素水平显著升高，血糖明显降低，这可能是通过将HPE-101转移到鼻黏膜。这些结果表明，HPE-101与亲水性CyDs的结合可用于设计更有效、更安全的多肽/蛋白药物鼻腔给药系统。(3)由于胰岛素主要在单体状态下具有生物活性，本研究也试图通过添加cyd来克服胰岛素的自结合和表面吸附现象。研究发现，麦芽糖基- β - cyd和2- hp - β - cyd对胰岛素溶液的亲水性明显降低了胰岛素在玻璃和聚合物表面的自结合和吸附。胰岛素溶液的圆二向性（CD）行为分析表明，CyD可能促进胰岛素从一些高聚集体向单体状态的构象转变，减少胰岛素的反平行β结构。少

项目成果

Kaneto Uekama: "Modification of Drug Release by Cyclodextrin Derivatives.in D.Duchene (Ed.),New Trends in Cyclodextrins and Derivatives" Editions de Sante, 38 (1991)

Kaneto Uekama：“环糊精衍生物对药物释放的修饰。D.Duchene（编辑），环糊精和衍生物的新趋势”Editions de Sante，38（1991）

Kaneto Uekama: "Modification of Drug Ralease by Cyclodextrin Eerivatives.in D.Duchene(Ed.),New Trends in Cyclodextrins and Derivatives" Editions de Sante, 38 (1991)

Kaneto Uekama：“环糊精衍生物对药物释放的修饰。D.Duchene（编辑），环糊精和衍生物的新趋势”Editions de Sante，38（1991）

Tetsumi Irie: "Enhancing Effects of Cyclodextrins on Nasal Absorption of Insulin in Rats" International Journal of Pharmaceutics. (1992)

Tetsumi Irie：“环糊精对大鼠胰岛素鼻吸收的增强作用”国际药剂学杂志。

Kaneto Uekama: "Pharmaceutical Uses of Cyclodextrin Derivatives." High Performance Biomaterials, A Comprehensive Guide to Medical and Pharmaceutical Applications. Technomic Publishing Co. Inc.18 (1991)

Kaneto Uekama：“环糊精衍生物的制药用途。”

Fumitoshi Hirayama: "Biopharmaceutical Evaluation of MaltosylーβーCylodextrin as a Parenteral Erug Carrier." S.T.P.Pharma Sciences. 1. 397-402 (1991)

Fumitoshi Hirayama：“麦芽糖基-β-环糊精作为肠外药物载体的生物制药评价。S.T.P.Pharma Sciences。”1. 397-402 (1991)