Design of Hyaluronic Acids Hydrogels as a Long-term Implant and Those Application for Endometriosis Therapy

透明质酸水凝胶作为长期植入物的设计及其在子宫内膜异位症治疗中的应用

• 批准号: 13558106
• 负责人: YUI Nobuhiko
• 金额: $ 5.63万
• 依托单位: Japan Advanced Institute of Science and Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13558106/
• 关键词: Hyaluronic acid; Endometriosis; Steroids; Hydrogels; Release; Hyaluronidase; Cysts; Erosion; 薬物放出; 滅菌; 3次元架橋; アルキルアンモニウム; 抗原性物質除去; イオンコンプレックス; 架橋

Endometriosis is a disease caused by algomenorrhea, coital pain, and agenesis. According to a lot of epidemiological surveys, it is thought that 5-10% of reproductive-age women infected the endometriosis. This disease often forms cysts in ovary. Oral administration and hypodermic injection of danazol and GnRH analogues have been tried to cure the endometriosis. However, those drugs cause adverse effects such as liver dysfunction, agenesis, dropsy, headache, and so on. From this perspective, local release of danazol at uterus is expected to improve the side effects. Here, we report on hydrophobically modified hyalumnic acid (HA) for injectable hydrogels and local release of danazol. Biodegradable properties of HA at uterus may lead to controlled release of danazol without causing inflammations. Stearoyl HA (StHA) and glutaryl HA (GlHA) were synthesized and evaluated in terms of danazol loading, enzymatic degradation, danazol release, and those effects on a model rat.Viscosity of StHA in … More the presence of 100 unit/ml hyaluronidase (HAase) was not changed at 160 min after adding the HAase. Viscosities of GlHA and HA under the same condition were decreased to 50 % of the initial value at 161 and 120 min after adding the HAase, respectively. These results suggest that chemical modification of HA by stearoyl and glutaryl groups suppressed the accessibility of HAase to the HA backbone. Especially, longer alkyl chains of StHA was effective for suppressing the accessibility of HAase to the HA backbone. The introduced hydrophobic groups contribute to the increased solubility of danazol. GlHA seemed to be more hydrophobic domains because of its high DS. In both systems, the concentration of danazol in plasma was below 10 hg/ml through the experimental period. This value is below 1/20 of the concentration of danazol in plasma via oral administration.Concentration of danazol in the cysts was also measured. In both StHA and GlHA systems, the concentrations of danazol in the cysts are about 10 μg/g(at 1st week). At 2 nd week, it decreased to 1μg/g in the StHA system, while it remained 8 μg/g in the GlHA system. These results indicate that almost all the danazol in the StHA system was disappeared from cysts by the 2 nd week. From these results, it is suggested that burst release of danazol increased the concentration of danazol in cysts by the 1 st week. On the other hand, the low concentration at 2 nd week in StHA system is presumably due to slow release of danazol in relation to slower degradation of StHA than that of GlHA. The effect of local injecting the danazol solubilized StHA system on cysts was observed by microscopic image. Atrophy of whole cells was observed after injecting at 4 th weeks, although such an atrophy of cells without injection was not observed. Taking the result of danazol concentration in plasma and cysts into account, the released danazol was absorbed directly in cysts without inhibiting hypothalamo-hypophysial functions. Less

子宫内膜异位症是一种由痛经、性交疼痛和发育不全引起的疾病。据大量的流行病学调查，认为育龄妇女中有5-10%感染子宫内膜异位症。这种疾病通常在卵巢中形成囊肿。达那唑和GnRH类似物的口服和皮下注射已被尝试用于治疗子宫内膜异位症。但这些药物会引起肝功能异常、发育不全、水肿、头痛等不良反应，从这个角度来看，达那唑在子宫局部释放有望改善其副作用。在这里，我们报告疏水改性透明质酸（HA）的注射水凝胶和达那唑的局部释放。HA在子宫内的生物降解特性可能导致达那唑的控释而不引起炎症。合成了硬脂酰HA（StHA）和戊二酰HA（GlHA），并根据达那唑负载、酶促降解、达那唑释放以及对模型大鼠的那些影响进行了评价。 ...更多信息 在加入透明质酸酶（HAase）后160分钟，100单位/ml透明质酸酶（HAase）的存在没有改变。在相同条件下，加入HA酶后，GlHA和HA的粘度分别在161和120 min时降至初始值的50%。这些结果表明，化学修饰的HA的硬脂酰基和戊二酰基抑制HA酶的HA骨架的可及性。特别是，较长的烷基链的StHA是有效的抑制HA酶的HA骨架的可及性。引入的疏水基团有助于增加达那唑的溶解度。由于GlHA的DS高，因此其似乎是更疏水性的结构域。在这两个系统中，达那唑在血浆中的浓度低于10微克/毫升，通过实验期间。该值低于口服达那唑血药浓度的1/20。在StHA和GlHA系统中，孢囊中达那唑的浓度约为10 μg/g（在第1周）。第2周时，StHA系统中的蛋白质含量降至1μg/g，而GlHA系统中的蛋白质含量仍为8 μg/g。这些结果表明，到第2周，StHA系统中几乎所有的达那唑从包囊中消失。从这些结果可以看出，达那唑的爆发释放在第1周增加了孢囊中达那唑的浓度。另一方面，在StHA系统中第2周的低浓度可能是由于达那唑的缓慢释放，这与StHA的降解比GlHA的降解慢有关。通过显微镜观察局部注射达那唑增溶StHA系统对包囊的作用。注射后第4周观察到全细胞萎缩，但未注射时未观察到这种细胞萎缩。结合丹那唑在血浆和包囊中的浓度结果，丹那唑释放后直接被包囊吸收，不抑制下丘脑-垂体功能。少

项目成果

Development of local application of drugs for endometrosis therapy

子宫内膜异位症局部应用治疗药物的开发

• 发表时间: 2005
• 期刊: Nippon Ishikai Zattushi 134
• 作者: K.Murakami;M.Inoue;N.Yui
• 通讯作者: N.Yui

Y.Kumashiro, T.Ooya, W.K.Lee, N.Yui: "Enzymatic degradation of semi-IPN hydrogels based on N-isopropylacrylamide and dextran at a specific temperature range"Macromol. Rapid Commun.. 23. 407-410 (2002)

Y.Kumashiro、T.Ooya、W.K.Lee、N.Yui：“在特定温度范围内基于 N-异丙基丙烯酰胺和葡聚糖的半互穿网络水凝胶的酶促降解”Macromol。

N.Yui, K.Park, R.J.Mrsny: "Reflexive Polymers and Hydrogels : Understanding and Designing Fast-Responsive Polymeric Systems"CRC. 350 (2004)

N.Yui、K.Park、R.J.Mrsny：“反射聚合物和水凝胶：理解和设计快速响应聚合物系统”CRC。

Dextran hydrogels containing poly(N-isopropylacrylamide) as grafts and cross-linkers exhibiting enzymatic regulation at specific temperature range

含有聚（N-异丙基丙烯酰胺）作为接枝物和交联剂的葡聚糖水凝胶在特定温度范围内表现出酶促调节

• 发表时间: 2004
• 期刊: Macromol.Rapid.Commun. 25
• 作者: Y.Kumashiro;T.Ooya;N.Yui
• 通讯作者: N.Yui

Poly(ethylene glycol) hydrogels cross-linked by hydrolyzable polyrotaxane containing hydroxyapatite particles as scaffolds for bone regeneration

• DOI: 10.1163/156856205774576664
• 发表时间: 2005-01
• 期刊: Journal of Biomaterials Science, Polymer Edition
• 作者: Mariko Fujimoto;M. Isobe;S. Yamaguchi;T. Amagasa;A. Watanabe;T. Ooya;N. Yui