CN101316864B - 阳离子化透明质酸 - Google Patents
阳离子化透明质酸 Download PDFInfo
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- CN101316864B CN101316864B CN2006800445418A CN200680044541A CN101316864B CN 101316864 B CN101316864 B CN 101316864B CN 2006800445418 A CN2006800445418 A CN 2006800445418A CN 200680044541 A CN200680044541 A CN 200680044541A CN 101316864 B CN101316864 B CN 101316864B
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- hyaluronic acid
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Abstract
本发明提供能够与透明质酸等阴离子性材料形成聚离子络合物的、更接近于人体成分的阳离子性高分子。本发明的阳离子化透明质酸的特征在于:透明质酸的羟基的氢原子的至少一部分被具有季铵阳离子基团的基团取代。该阳离子化透明质酸可以通过使缩水甘油基三烷基卤化铵等阳离子化剂与透明质酸反应来合成。本发明的阳离子化透明质酸在水共存下与透明质酸等形成聚离子络合物。
Description
相关申请
本申请主张2005年12月1日申请的日本国专利申请2005-347501号的优先权,将其并入本申请。
技术领域
本发明涉及向透明质酸中导入了阳离子性基团的阳离子化透明质酸。
背景技术
如下述通式(I)所示,透明质酸是以N-乙酰基-D-葡糖胺和D-葡萄糖醛酸结合的结构为1单元、该单元重复结合的高分子化合物。
[化学式1]
透明质酸因来源于葡萄糖醛酸的羧基的存在而具有聚阴离子的性质。已知利用这种聚阴离子性,通过在水中与聚阳离子性物质混合,可以形成水不溶性聚离子络合物凝胶。
例如,专利文献1中记载了在透明质酸凝胶表面形成阳离子性物质的聚离子络合物膜的内包药物的透明质酸凝胶胶囊。
专利文献2中记载了使用透明质酸与阳离子性聚丙烯酸衍生物的聚离子络合物作为制剂用载体的缓释制剂。
还有人报道了透明质酸在医疗用粘合材料或固定材料、防粘连材料等医疗用材料中的应用(专利文献3~5)。
透明质酸广泛分布于以人为首的机体结合组织中,故生物安全性、生物适应性优异,但人们希望在聚离子络合物的形成中与透明质酸配对的阳离子性物质也具有优异的生物安全性、生物适应性。
作为来源于生物材料的阳离子性高分子,已知有壳多糖的脱乙酰化物脱乙酰壳多糖或氨基化纤维素等,但人们要求开发更接近于人体成分的阳离子性高分子。
专利文献1:日本特开平6-254381号公报
专利文献2:日本特开平7-33682号公报
专利文献3:日本特开2000-5296号公报
专利文献4:日本特开2000-116765号公报
专利文献5:日本特开2002-638号公报
发明内容
发明所要解决的问题
本发明鉴于上述现有技术问题而设,其目的在于提供能够与透明质酸等阴离子性生物适应性材料形成聚离子络合物的、更接近于人体成分的阳离子性高分子。
解决问题的方法
为了解决上述问题,本发明人等尝试向透明质酸中导入季铵阳离子基团,成功得到了阳离子化的透明质酸。并且发现该阳离子化透明质酸和透明质酸在水存在下形成聚离子络合物凝胶,从而完成了本发明。
即,本发明的阳离子化透明质酸,其特征在于:透明质酸的羟基的氢原子的至少一部分被具有季铵阳离子基团的基团所取代。
本发明的阳离子化透明质酸适合由下述通式(1)表示。
[化学式2]
式中,A为氢原子或下述通式(2)所示的取代基,上述取代基的平均取代度为:每1单元透明质酸为0.1以上。
[化学式3]
R1表示可具有羟基的碳原子数为3~5的亚烷基;R2、R3和R4分别表示碳原子数为1~3的烷基。
本发明的阳离子化透明质酸适合使透明质酸与下述通式(3)所示的阳离子化剂反应而得到。
[化学式4]
式中,R2、R3和R4分别表示碳原子数为1~3的烷基;X表示卤原子。
另外,本发明的聚离子络合物的特征在于:其是由上述任一项所记载的阳离子化透明质酸和阴离子性生物适应性材料形成的。适合的阴离子性生物适应性材料的例子有:透明质酸。
本发明的阳离子化透明质酸在水存在下可以和透明质酸等阴离子性材料形成聚离子络合物,可以期待用于以往使用水凝胶的各种用途。例如,阳离子化透明质酸与透明质酸形成的聚离子络合物是水不溶性的水凝胶,其主体是存在于人体的透明质酸,故生物安全性、生物适应性高,适用于医药·医疗·卫生·食品·化妆品领域等。
附图简述
图1是本发明的阳离子化透明质酸(制备例1)的1H-NMR图谱。
实施发明的最佳方式
本发明的阳离子化透明质酸是透明质酸的羟基的氢原子的至少一部分被具有季铵阳离子基团的基团所取代的产物。
本发明的阳离子化透明质酸的适合例子有:具有上述通式(1)所示结构的物质。
通式(1)中,A为氢原子或上述通式(2)所示的取代基。通式(2)所示取代基的平均取代度优选为:每1单元透明质酸为0.1以上,进一步优选为1以上。
通式(2)中,R1表示碳原子数为3~5的亚烷基,但可以具有羟基,适合的例子有:-CH2CH(OH)CH2-。
R2、R3和R4分别表示碳原子数为1~3的烷基。
n为表示聚合度的正整数。对透明质酸的分子量没有特别限定,通常使用分子量为10~300万左右的透明质酸。
本发明的阳离子化透明质酸可以通过使阳离子化剂与透明质酸反应来进行合成。
对作为原料的透明质酸的制造方法没有特别限定。透明质酸例如由鸡冠的肉冠等机体组织中提取、或者利用使用微生物的培养等进行工业生产,其盐(钠盐等)也有市售。在本发明中可以使用透明质酸或其盐。
对阳离子化剂没有特别限定,只要是具有季铵阳离子基团和与透明质酸的羟基反应的基团的化合物即可。另外,阳离子化剂的量可以根据所需取代度来适当设定。通常每1单元透明质酸优选使用0.1倍以上(摩尔比)、进一步优选使用1倍以上(摩尔比)的阳离子化剂。
适合的阳离子化剂的例子有:上述通式(3)所示的缩水甘油基三烷基卤化铵。
通式(3)中,R2、R3和R4分别表示碳原子数为1~3的烷基。X表示卤原子,其例子有:Cl、Br、I等,优选为Cl。具体例子有:缩水甘油基三甲基氯化铵、缩水甘油基三乙基氯化铵、缩水甘油基三丙基氯化铵等。
使用缩水甘油基三烷基卤化铵作为阳离子化剂时,优选在碱的存在下进行反应。碱的例子有:氢氧化钠或氢氧化钾等碱金属氢氧化物;氢氧化钙、氢氧化镁等碱土金属氢氧化物;乙二胺、三乙胺或三甲胺等有机胺,优选为氢氧化钠。
作为溶剂,通常适合使用水,但只要不特别妨碍反应,也可以使用其他溶剂。
反应温度根据原料或目标取代度来适当设定,通常为20~50℃,优选为25~40℃。高温下有时会进行透明质酸的水解而低分子化,因此当不希望低分子化时需要注意。
反应结束后,向反应液中添加醇或丙酮等阳离子化透明质酸的不良溶剂,使阳离子化透明质酸沉淀。根据需要进一步进行洗涤、干燥,可以得到本发明的阳离子化透明质酸。
阳离子化透明质酸具有聚阳离子的性质,而普通的透明质酸具有聚阴离子的性质。因此,两者在水中共存时通过两者的静电相互作用而形成聚离子络合物,水不溶性凝胶沉淀。该凝胶根据目的可以成形为粒状、薄膜状、块状等各种形状,可以直接使用水凝胶或者将其干燥后使用。
对阳离子化透明质酸与透明质酸的混合比没有特别限定,只要是形成聚离子络合物的范围即可,可以根据目的来适当确定。
另外,当两者在水中共存时,通过将药剂事先溶解或分散在水中,可以将药剂包在凝胶内。或者按照专利文献1记载的方法,采用向阳离子化透明质酸水溶液中滴加溶解有水溶性药剂的透明质酸水溶液的方法、以及将包含油溶性药剂的油相乳化分散在透明质酸水溶液中,将所得乳剂滴加到阳离子化透明质酸水溶液中的方法,也可以将药剂包在凝胶内。
本发明的聚离子络合物,其主体为透明质酸,故生物安全性或生物适应性高,例如可以用作制剂载体等。还可以用作其他医疗用、卫生用、食品用、化妆品用材料等。
另外,根据目的或用途,还可以将本发明的阳离子化透明质酸用于与其他阴离子性物质形成聚离子络合物。对其他阴离子性物质没有限定,只要是分子内具有多个阴离子性基团(例如羧基、硫酸基等)、在水存在下与阳离子化透明质酸形成聚离子络合物的物质即可。
其他阴离子性物质例如有:海藻酸、硫酸软骨素、葡聚糖硫酸、果胶等阴离子性天然多糖类;羧甲基纤维素、羧甲基葡聚糖、羧甲基淀粉、羧甲基脱乙酰壳多糖、硫酸化纤维素、硫酸化葡聚糖等阴离子性合成多糖类;聚谷氨酸、聚天冬氨酸、谷氨酸天冬氨酸共聚物等酸性氨基酸聚合物;多核苷酸;血清白蛋白、胃蛋白酶、尿素酶、胎球蛋白等酸性蛋白质;聚丙烯酸、聚羧乙烯等阴离子性高分子;上述物质的衍生物或盐等。还可以列举其他含有磷酸胆碱基团的阴离子性生物适应性高分子。
以下列举实施例来具体说明本发明,但本发明并不受限于此。
实施例
制备例1阳离子化透明质酸的制备
将10.4mL(0.078mol)缩水甘油基三甲基氯化铵和11.25mL水混合,加入5g透明质酸(商品名:バイオヒアロ9,(株)资生堂制)(以二糖单元计为0.013mol)和1.25mL 2M的氢氧化钠水溶液,溶解。
使该混合液在室温下反应3天。反应后,加入甲醇使反应物沉淀,用丙酮充分洗涤,得到4.2g白色粉末。
通过GPC确认所得粉末中低分子化合物(未反应试剂)已被除去。
另外,利用1H-NMR(参照图1)进行结构确认时,检测到来自三甲基铵的质子的信号,确认导入了2-羟基-3-三甲基铵丙基。
另外,平均取代度由1H-NMR的积分值算出,每1单元透明质酸为约1.4。
试验例1聚离子络合物的形成
制备由制备例1得到的阳离子化透明质酸的1%(w/w)水溶液。另外制备透明质酸(商品名:バイオヒアロ12,(株)资生堂制)的1%(w/w)水溶液。
上述两种水溶液均为透明液体,但将它们等量混合时产生凝胶状沉淀。认为该凝胶是阳离子化透明质酸的阳离子基团与透明质酸的阴离子基团形成离子对的聚离子络合物。
试验例2聚离子络合物的形成
制备由制备例1得到的阳离子化透明质酸的1%(w/w)水溶液。另外制备聚羧乙烯的0.1%(w/w)水溶液。
上述两种水溶液均为透明液体,但将它们等量混合时产生凝胶状沉淀。认为该凝胶是阳离子化透明质酸的阳离子基团与聚羧乙烯的阴离子基团形成离子对的聚离子络合物。
Claims (4)
2.权利要求1的阳离子化透明质酸,其特征在于:是使透明质酸和下述通式(3)所示的阳离子化剂反应而得到的,
式中,R2、R3和R4分别表示碳原子数为1~3的烷基,X表示卤原子。
3.聚离子络合物,其特征在于:是由权利要求1或2的阳离子化透明质酸和阴离子性生物适应性材料形成的。
4.权利要求3的聚离子络合物,其特征在于:其中阴离子性生物适应性材料为透明质酸。
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- 2006-11-17 WO PCT/JP2006/322995 patent/WO2007063725A1/ja active Application Filing
- 2006-11-17 US US12/095,195 patent/US20090281056A1/en not_active Abandoned
- 2006-11-17 ES ES06832873T patent/ES2409065T3/es active Active
Patent Citations (2)
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CN1045394A (zh) * | 1989-02-24 | 1990-09-19 | 格德昂·理查德化学工厂股份公司 | 含透明质酸缔合物的新组合物及其制法 |
US5532305A (en) * | 1993-07-26 | 1996-07-02 | Shiseido Company Ltd. | Controlled release preparation for bioactive substances |
Non-Patent Citations (2)
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JP特开平6-254381A 1994.09.13 |
JP特开平6-48918A 1994.02.22 |
Also Published As
Publication number | Publication date |
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EP1961772A4 (en) | 2011-08-03 |
ES2409065T3 (es) | 2013-06-24 |
JP4220513B2 (ja) | 2009-02-04 |
KR20080071166A (ko) | 2008-08-01 |
EP1961772B1 (en) | 2013-04-10 |
KR101347961B1 (ko) | 2014-01-07 |
WO2007063725A1 (ja) | 2007-06-07 |
EP1961772A1 (en) | 2008-08-27 |
CN101316864A (zh) | 2008-12-03 |
JP2007153944A (ja) | 2007-06-21 |
US20090281056A1 (en) | 2009-11-12 |
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