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

肽类/蛋白质类药物（如胰岛素）的鼻内吸收受到粘膜纤毛清除或酶降解引起的系统前消除以及有限的粘膜渗透性的严重限制。因此，本研究的目的是研究亲水性环糊精（CyD）衍生物在胰岛素鼻用制剂中的潜在用途，以及防止胰岛素自缔合和表面吸附。获得的结果如下。(1)甲基化环糊精被发现是比母体和羟丙基化环糊精更有效的吸收促进剂。光谱观察表明，胰岛素与环糊精包合络合物的范围似乎对鼻吸收促进作用的重要性较小。CyDs增加大鼠鼻粘膜的通透性，可能通过与膜表面的脂质和/或二价阳离子的相互作用。此外，胰岛素在大鼠鼻匀浆中的酶促降解也被发现。 ...更多信息 被CyDs抑制。多元回归分析表明，鼻粘膜通透性增加和蛋白水解减少协同促进胰岛素的吸收。(2)初步探讨了2-羟丙基-β-环糊精（2-HP-β-CYD）在设计含亲脂性吸收促进剂1-[2-（癸硫基）乙基]氮杂环戊烷-2-酮（HPE-101）的胰岛素鼻用制剂中的应用。当大鼠经鼻给予胰岛素时，.使用溶于2-HP-β-CyD中的HPE-101显示血清免疫活性胰岛素水平显著增加和显著的低血糖，这可能是通过促进HPE-101转移到鼻粘膜中。这些结果表明，HPE-101和亲水性CyDs的组合可用于设计更有效和更安全的肽/蛋白质药物鼻内给药系统。(3)由于胰岛素主要以单体状态具有生物活性，因此本研究还试图通过添加CyDs来克服胰岛素自缔合和表面吸附现象。发现亲水性CyD如麦芽糖基-β-CyD和2-HP-β-CyD与胰岛素溶液显著降低了胰岛素自缔合和在玻璃和聚合物表面上的吸附。对胰岛素溶液的圆二色性（CD）分析表明，CyD可以促进胰岛素从某些高分子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

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