CN105979968A - 具有持久性的透明质酸凝胶组合物 - Google Patents
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Abstract
本发明涉及一种具有长期持久性的交联的多糖类凝胶组合物,其用于化妆品以及医药领域的交联的透明质酸凝胶组合物,所述具有长期持久性的交联的多糖类凝胶组合物,使得具有抑制多糖类分解以及抗氧化作用的物质包含于交联的多糖类凝胶,即使不提高交联率,也在生体内维持长期的持久性,所述具有长期持久性的交联的多糖类凝胶组合物的特征在于,其为在未交联的或交联的多糖类中包括熊果酸的水凝胶复合体。
Description
技术领域
本发明涉及一种用于化妆品以及医药领域的交联的多糖类凝胶(gel)组合物,更为详细地,涉及一种具有持久性的透明质酸(hyaluronic acid)凝胶组合物,所述具有持久性的透明质酸凝胶组合物使得具有抑制多糖类分解以及抗氧化作用的物质包含于交联的多糖类凝胶,从而即使不提高交联率,也在生体内维持长期的持久性。
背景技术
多糖类作为糖的复合体,是通过配糖体(glycoside)结合使单糖类结合的形态,尤其是透明质酸钠(Natrium)正广泛用于化妆品以及医药领域。
透明质酸钠是一种生体高分子物质,其作为存在于真皮层的粘多糖(mucopolysaccharide),N-乙酰(acetyl)-D-氨基葡萄糖(glucosamine)与D-葡萄糖醛酸(glucuronic acid)通过beta-1,3糖苷键(glycosidic bond)来连接,并且所述重复单元以线性的形式连接。
此外,作为在体液、牛的眼球、鸡冠、动物的缓冲组织、胎盘等发现的生体构成物质,特别是以高浓度的形式存在于***以及皮肤。
此外,透明质酸钠具有可含有本身重量的1000倍程度的水的能力,因此广泛用作防止皮肤干燥的化妆品的保湿剂,并且在皮肤美容领域,***至特定部位,从而使得软组织扩张,以此,正用作在改善皱纹或校正轮廓等方面使用的皮肤填充剂(dermal filler)等。另外,透明质酸钠具有良好的粘弹性+++、生物相容性、生物降解性,从而使用范围不仅包括皮肤美容,而且正广泛用作退行性骨关节炎治疗药物、伤口治疗药物、眼球手术辅助剂以及用于防止术后组织间粘连的防粘连剂等。
但是,由于天然(native)透明质酸(hyaluronic acid:HA)在生体内通过透明质酸酶(hyaluronidase)与自由基(free radicals)进行快速分解,从而半衰期非常短,为一天的程度,因此尽管所述透明质酸具有优越性,但是在如皱纹治疗药物一样需要长久的半衰期的领域中,无法将天然透明质酸直接适用于产品。
为了克服所述不足,开发了多种交联技术(Cross-linking technology),在欧洲与美国大量开发了利用其的交联的透明质酸填充剂(Cross-linked hyaluronic acidfiller)并在最近几年间也在韩国推出了几种产品。
美国专利第4,582,865号中公开了一种将二乙烯基砜(DVS)用作交联剂并进行交联的透明质酸衍生物,其的水凝胶(hydrogel)形态以Hylaform为商品名正在市场上销售,美国专利第5,827,937号中公开了一种通过将多功能环氧(epoxy)化合物用作交联剂来制造透明质酸衍生物交联物的方法,其中,作为多功能环氧化合物,通过将1,4-丁二醇二缩水甘油醚(BDDE)用作交联剂而制造的作为透明质酸交联物的水凝胶形态的玻尿酸(Restylane)获得美国FDA的批准,从而作为用于增强组织的填充剂正在在世界性的市场销售。
所述产品都是由透明质酸的羟基(hydroxy)与交联剂结合而生成的,相比于未交联透明质酸,虽然其生体内持久性增大,但是仍然需要6-12个月之内的时间进行分解等,因而存在生体持久性低的问题。
由于所述大部分的交联的透明质酸填充剂的持久性为一年之内,因此为了延长持久性,虽然试图提高交联率,但是由于高的储能模量可导致有坚硬的异物感,因此所述方法有限。
由此,为了延长持久性,切实需要开发一种多糖类凝胶组合物,所述多糖类凝胶组合物具有与皮肤的感觉类似的储能模量的同时,可延长持久性,而非提高交联率。
发明内容
本发明在所述的背景下发明的,本发明的目的在于,提供一种交联的透明质酸凝胶组合物,所述交联的透明质酸凝胶组合物使得具有抑制多糖类分解以及抗氧化作用的物质包含于交联的多糖类凝胶,即使不提高交联率,也能够在生体内具有长期的持久性。
本发明的其他目的在于,提供一种具有长期持久性的交联的透明质酸凝胶组合物,就用于化妆品以及医药领域的交联的多糖类凝胶组合物而言,所述具有长期持久性的交联的透明质酸凝胶组合物构成为,将熊果酸(ursolic acid)包含于交联的多糖类凝胶,所述熊果酸即使不提高交联率,也具有抑制多糖类分解以及抗氧化作用。
用于达到所述目的的本发明,特征在于,其为在未交联的或交联的透明质酸包含熊果酸的水凝胶复合体。
此外,特征在于,根据本发明,所述水凝胶组合物包括透明质酸(hyaluronic acid)、纤维素(cellulose)、壳聚糖(chitosan)、葡聚糖(dextran)、硫酸葡聚糖(dextransulfate)、软骨素(chondroitin)、硫酸软骨素(chondroitin sulfate)、肝素(heparin)、硫酸肝素(heparin sulfate)、藻酸盐(alginate)中至少一个或一个以上的多糖类。
此外,特征在于,根据本发明,所述多糖类的分子量为20,000道尔顿(Da)至5,000,000道尔顿(Da)。
此外,特征在于,根据本发明,所述熊果酸的浓度为0.001mM至1M。
此外,特征在于,根据本发明,还包括利多卡因。
如上所述,本发明优点在于,包含有熊果酸的交联的多糖类凝胶组合物具有良好的生物相容性,并在不提高储能模量的情况下,将组合物注入生体内时,维持与皮肤的感觉最类似的储能模量的同时,在生体内具有良好的长期持久性。
此外,优点在于,根据本发明的添加有作为局部麻醉剂的利多卡因的组合物,在施行手术时使得患者的疼痛得以缓解。
此外,效果在于,根据本发明的组合物,使得皮肤的皱纹消除或改善,并使得组织恢复至鼻、脸颊、嘴唇、胸、臀、深的伤口等部位。
此外,本发明的优点在于,用作防粘连剂,所述防粘连剂在泌尿外科方面,用于使得男性的象征扩大的用途,并用于防止术后内脏器官的粘连,并作为用于退行性关节的改善以及治疗的润滑剂,用作退行性关节炎治疗药物。
附图说明
图1为关于根据本发明的交联的透明质酸与熊果酸的复合体结构的概略图。
图2为表示通过根据本发明的透明质酸酶与自由基的透明质酸-熊果酸复合体的分解率的图表。
图3为表示关于根据本发明的透明质酸-熊果酸复合体的流变特性的图表。
图4为表示关于根据本发明的透明质酸-熊果酸复合体的挤压力的图表。
具体实施方式
参照附图对本发明进行更为具体地说明。
图1为关于根据本发明的一个实施例的交联的透明质酸与熊果酸的复合体结构的概略图。
如图所示,根据本发明的具有长期持久性的交联的多糖类凝胶组合物包括水凝胶组合物,所述水凝胶组合物在未交联的或交联的多糖类中包括熊果酸。
更为具体地,本发明组合物包括水凝胶组合物,所述水凝胶组合物包括透明质酸(hyaluronic acid)、纤维素(cellulose)、壳聚糖(chitosan)、葡聚糖(dextran)、硫酸葡聚糖(dextran sulfate)、软骨素(chondroitin)、硫酸软骨素(chondroitinsulfate)、肝素(heparin)、硫酸肝素(heparin sulfate)、藻酸盐(alginate)中至少一个多糖类与作为在抑制多糖类分解以及抗氧化方面起作用的物质的熊果酸(ursolic acid)。
所述多糖类使用透明质酸(hyaluronic acid)、纤维素(cellulose)、壳聚糖(chitosan)、葡聚糖(dextran)、硫酸葡聚糖(dextran sulfate)、软骨素(chondroitin)、硫酸软骨素(chondroitin sulfate)、肝素(heparin)、硫酸肝素(heparin sulfate)、藻酸盐(alginate)中至少一个或一个以上的多糖类,并优选地使用透明质酸。
用于本发明的所述多糖类的分子量为20,000道尔顿(dalton)至5,000,000道尔顿,优选地为500,000道尔顿至3,000,000道尔顿。
用于本发明的熊果酸(ursolic acid)为五环三萜(pentacyclic triterpenoid)类化合物,并广泛分布于药用植物与草药,所述五环三萜类化合物以urson、prunol、micromerol与malol等著称。
所述熊果酸在药物学方面长时间被认为是具有惰性的,熊果酸与熊果酸盐(例如:熊果酸钾或熊果酸钠(potassium or sodium ursolates))在制药、化妆品并食品中全部用作表面活性剂。
但是,通过更为缜密的研究表明,当局部服用熊果酸时,在药学方面两种都具有活性。
熊果酸的效果体现在抗炎症作用、抗癌作用(皮肤癌)、抗菌作用方面。如大部分的三萜(triterpenoids)类化合物一样,熊果酸是在植物界中非常常见的化合物,而且是使得***发生起源与分类位置多元化的多种植物的成分。
熊果酸是从苹果、梨、蔓越橘、李子等水果皮中分离的。此外,熊果酸衍生物也大量存在于海藻类。
用于本发明的熊果酸(ursolic acid)在抑制多糖类分解的同时,具有抗氧化的作用,从而同时具有多糖类分解抑制剂与抗氧化剂的双重作用,从而成为用于增加多糖类凝胶的生体内持久性的最佳物质。
用于本发明的熊果酸的浓度为0.01mM至1M,优选地为0.05mM至100mM,更为优选地为0.1mM至10mM。
此外,根据本发明,为了在施行手术时减轻患者的疼痛,可将作为局部麻醉剂的利多卡因(lidocaine)添加至含有熊果酸的交联的多糖类凝胶组合物。
本发明的组合物在医学方面或美容方面使得皮肤的皱纹消除或改善,或者可用于将组织恢复至鼻、脸颊、嘴唇、胸、臀、深的伤口等部位。
此外,用作防粘连剂,所述防粘连剂在医学方面用于使得男性的象征(symbol)扩大,或者防止术后内脏器官的粘连,并作为用于退行性关节的改善以及治疗的润滑剂,可用作退行性关节炎治疗药物。
以下,根据下述实施例对本发明进行更为详细地说明,但是,下述实施例仅用于对本发明进行举例说明,本发明的范围并未仅限定于此。
对比例1:准备已开发的交联的透明质酸填充剂
将PBS(pH 7.0)溶液100uL添加至HA浓度为24mg/mL,储能模量(G′)为130Pa程度的交联的透明质酸填充剂(REVOLAXTM,ACROSS CO.,LTD.)1g之后,进行搅拌,以便于完全混合。
实施例1:制造本发明的透明质酸-熊果酸(0.1mM)复合体水凝胶
将添加有熊果酸0.1mM的PBS(pH 7.0)溶液100uL添加至HA浓度为24mg/mL,储能模量(G′)为130Pa程度的交联的透明质酸填充剂(REVOLAXTM,ACROSS CO.,LTD.)1g之后,进行搅拌,以便于完全混合。
实施例2:制造本发明的透明质酸-熊果酸(0.5mM)复合体水凝胶
将添加有熊果酸0.5mM的PBS(pH 7.0)溶液100uL添加至HA浓度为24mg/mL,储能模量(G′)为130Pa程度的交联的透明质酸填充剂(REVOLAXTM,ACROSS CO.,LTD.)1g之后,进行搅拌,以便于完全混合。
实施例3:制造本发明的透明质酸-熊果酸(1mM)复合体水凝胶
将添加有熊果酸1mM的PBS(pH 7.0)溶液100uL添加至HA浓度为24mg/mL,储能模量(G′)为130Pa程度的交联的透明质酸填充剂(REVOLAXTM,ACROSS CO.,LTD.)1g之后,进行搅拌,以便于完全混合。
实施例4:制造本发明的透明质酸-熊果酸(5mM)复合体水凝胶
将添加有熊果酸5mM的PBS(pH 7.0)溶液100uL添加至HA浓度为24mg/mL,储能模量(G′)为130Pa程度的交联的透明质酸填充剂(REVOLAXTM,ACROSS CO.,LTD.)1g之后,进行搅拌,以便于完全混合。
实施例5:制造本发明的透明质酸-熊果酸(10mM)复合体水凝胶
将添加有熊果酸10mM的PBS(pH 7.0)溶液100uL添加至HA浓度为24mg/mL,储能模量(G′)为130Pa程度的交联的透明质酸填充剂(REVOLAXTM,ACROSS CO.,LTD.)1g之后,进行搅拌,以便于完全混合。
实验例1:透明质酸酶(hyaluronidase)分解实验
为了预测根据本发明的透明质酸-熊果酸复合体的生体内持久性,对于所述对比例1与实施例1-5的透明质酸-熊果酸复合体,执行了通过透明质酸分解酶的分解实验。
对所述对比例1与实施例1-5的透明质酸水凝胶进行冷冻干燥,并将冷冻干燥的试样以相同的质量装入50mL管(tube)。添加了含有透明质酸分解酶(hyaluronidase fromStreptomyces hyalurolyticus,Sigma-Aldrich)200单位(Units)的PBS溶液(pH 7.0)6mL。将所述混合物在37℃下进行24小时的反应后,为了使得透明质酸分解酶钝化,在90℃下加热10分钟。在添加精制水18mL并进行涡旋(vortexing)之后,进行离心分离(4,000rpm,15分钟)。取出上清液1mL后放入epp.管中并进行离心分离(12,000rpm,5分钟)。为了对作为离心分离的上清液所分解出的N-乙酰葡糖胺(NAG)的量进行测定,根据咔唑(Carbozle)的方法进行分析。下述表1表示交联物的分解程度。
表1
[表1]
熊果酸含量(mM) | 分解率(%) | 相对的分解率(%) | |
实施例1 | 0.1mM | 40.2 | 42.3 |
实施例2 | 0.5mM | 25.3 | 26.6 |
实施例3 | 1mM | 10.4 | 10.9 |
实施例4 | 5mM | 7.2 | 7.6 |
实施例5 | 10mM | 2.1 | 2.2 |
对比例1 | 0mM | 95.0 | 100.0 |
如〈表1〉所示,可得知根据熊果酸的浓度对于交联的透明质酸的分解所产生的影响。观察到随着熊果酸浓度的增加,通过透明质酸分解酶(透明质酸酶(hyaluronidase))的交联的透明质酸的分解显著地减少。
此外,当熊果酸的浓度为10mM时,几乎不发生通过透明质酸分解酶(透明质酸酶(hyaluronidase))的交联的透明质酸的分解。在此基础上,若调整熊果酸的浓度,则可制造具有所期望的持久性的透明质酸水凝胶填充剂。
实验例2:自由基(free radicals)分解实验
为了预测根据本发明的透明质酸-熊果酸复合体的生体内持久性,对于所述对比例1与实施例1-5的透明质酸-熊果酸复合体,执行了通过自由基的分解实验。
对所述对比例1与实施例1-5的透明质酸水凝胶进行冷冻干燥,并将冷冻干燥的试样以相同的质量装入50mL管。
添加了含有自由基(0.2mM ascorbic acid与0.2mM hydrogen peroxide的混合物)的PBS溶液(pH 7.0)6mL。在添加精制水18mL并进行涡旋(vortexing)之后,进行离心分离(4,000rpm,15分钟)。取出上清液1mL后放入epp.管中并进行离心分离(12,000rpm,5分钟)。
为了对作为离心分离的上清液所分解出的N-乙酰葡糖胺(NAG)的量进行测定,根据咔唑(Carbozle)的方法进行分析。下述〈表2〉表示交联物的分解程度。
表2
[表2]
熊果酸含量(mM) | 分解率(%) | 相对的分解率(%) | |
实施例1 | 0.1mM | 75.8 | 80.0 |
实施例2 | 0.5mM | 54.5 | 57.6 |
实施例3 | 1mM | 38.0 | 40.1 |
实施例4 | 5mM | 5.9 | 6.2 |
实施例5 | 10mM | 3.1 | 3.3 |
对比例1 | 0mM | 94.7 | 100.0 |
如〈表2〉以及图2所示,可得知根据熊果酸的浓度对于交联的透明质酸的分解所产生的影响。观察到随着熊果酸浓度的增加,通过自由基(free radicals)的交联的透明质酸的分解显著地减少。
此外,当熊果酸的浓度为10mM时,几乎不发生通过自由基(free radicals)的交联的透明质酸的分解。在此基础上,若调整熊果酸的浓度,则可制造具有所期望的持久性的透明质酸水凝胶填充剂。
实验例3:流变特性实验
为了评估本发明的流变特性,对于所述对比例1与实施例1-5的透明质酸-熊果酸复合体,利用流变仪(rheometer)(T.A.Instruments Ltd.,USA)对储能模量(G′)、耗能模量(G″)与%弹性度进行测定。在25℃下,使用40mm 2°锥-板几何(cone-plategeometer)在0.01-10Hz范围中实施实验,在1.0Hz下测定储能模量(G′)与耗能模量(G″)。使用如下式子对%弹性度进行计算。下述〈表3〉表示结果值。
Percentage elasticity(%)=(G′/G′+G″)×100
表3
[表3]
储能模量(G′) | 耗能模量(G″) | 弹性度(%) | |
实施例1 | 132.46 | 31.31 | 80.88 |
实施例2 | 122.53 | 29.48 | 80.61 |
实施例3 | 135.80 | 30.07 | 81.87 |
实施例4 | 134.75 | 31.24 | 81.18 |
实施例5 | 126.89 | 30.29 | 80.73 |
对比例1 | 129.26 | 30.29 | 81.02 |
如〈表3〉以及图3所示,熊果酸的添加未对流变特性带来变化。未添加有熊果酸的交联的透明质酸填充剂与以0.1-10mM浓度添加熊果酸的交联的透明质酸填充剂几乎未对储能模量(G′)、耗能模量(G″)与%弹性度产生影响。在此基础上,若调节熊果酸的浓度,则储能模量(G′)不增加,并可制造可使得持久性增加的透明质酸水凝胶填充剂。
实验例4:挤压力实验
为了评估本发明的挤压力,对于所述对比例1与实施例1-5的透明质酸-熊果酸复合体,用挤压力实验机实施挤压力实验。
将装有想要测定的实验液体的玻璃注射器***夹具(jig)之后,以玻璃注射器的柱塞在挤压板位于中央的形式进行调整。设置托架(培养皿(petri dish)),以便于防止实验液体沾染至夹具,之后,以12mm/min的速度实施挤压力测定。
在测定的结果中,在施加力之后,将5mm地点指定为底部标记位置(bottom markerposition),并在测定结束的地点将5mm之前的地点指定为顶部标记位置(top markerposition),而后取其之间的平均值。下述〈表4〉表示挤压力值。
表4
[表4]
如〈表4〉以及图4所示,熊果酸的添加未对挤压力带来变化。未添加有熊果酸的交联的透明质酸填充剂与以0.1-10mM浓度添加熊果酸的交联的透明质酸填充剂几乎未对挤压力产生影响。在此基础上,若调节熊果酸的浓度,则可制造透明质酸水凝胶填充剂,所述透明质酸水凝胶填充剂在维持适当的挤压力的同时,可使得持久性增加。
Claims (4)
1.一种具有持久性的透明质酸凝胶组合物,其特征在于,将熊果酸包含于未交联或交联的透明质酸。
2.根据权利要求1所述的具有持久性的透明质酸凝胶组合物,其特征在于,所述透明质酸的分子量为20,000道尔顿至5,000,000道尔顿。
3.根据权利要求1所述的具有持久性的透明质酸凝胶组合物,其特征在于,所述熊果酸的浓度为0.001mM至1M。
4.根据权利要求1所述的具有持久性的透明质酸凝胶组合物,其特征在于,还包括利多卡因。
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CA2933153C (en) | 2018-07-03 |
JP2016540025A (ja) | 2016-12-22 |
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MX2016007534A (es) | 2016-12-14 |
US20170000816A1 (en) | 2017-01-05 |
BR112016013219A8 (pt) | 2018-01-30 |
RU2631888C1 (ru) | 2017-09-28 |
EP3081232A4 (en) | 2017-06-14 |
KR101459070B1 (ko) | 2014-11-17 |
WO2015088198A1 (ko) | 2015-06-18 |
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