CN105101984B - 丙氨酸-谷氨酰胺、透明质酸和燕麦提取物的协同组合以及其在用于愈合伤口和修复皮肤损伤的组合物中的用途 - Google Patents
丙氨酸-谷氨酰胺、透明质酸和燕麦提取物的协同组合以及其在用于愈合伤口和修复皮肤损伤的组合物中的用途 Download PDFInfo
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Abstract
本发明涉及包含二肽L‑丙氨酰‑L‑谷氨酰胺、透明质酸或其一种盐和燕麦提取物的组合，有利地用于愈合伤口和修复皮肤损伤。
Description
技术领域
本发明涉及包含二肽L-丙氨酰-L-谷氨酰胺、透明质酸或其一种盐和燕麦提取物的协同组合，有利地用于愈合伤口和修复皮肤损伤。
背景技术
愈合是一系列局部防御现象，在侵袭(外伤、烧伤、皮肤病学的行为、外科手术)之后发生。来自血液和组织的大量活性产物在这些现象中释放：酶、各种蛋白质、组胺等。愈合包括几个步骤，其第一步是血液的凝固，停止出血。血液中的白细胞清除死亡细胞。然后存活的细胞进行增殖并产生新组织，该组织的外观取决于损伤的位置。
愈合取决于多种因素，特别是营养、代谢、内分泌或用药(médicamenteux)；愈合的拖延在营养不良或老年受试者中观察到，或在长期服用肾上腺皮质激素的情况中观察到。随着年龄的增长，改善愈合和恢复皮肤损伤的过程实际上变得不太有效，该过程更慢了。
仍然存在提供新的组合物用于皮肤损伤的快速和美学修复的需求。
在文献中描述的、经口服途径施用的二肽L-丙氨酰-L-谷氨酰胺的药理学性质有很多。
其中，二肽L-丙氨酰-L-谷氨酰胺作为给运动者的补充剂经口使用，以促进训练(l’effort)后和外科手术后的恢复，减少住院时间。
这个二肽也在肠外营养中推荐，在需要谷氨酰胺摄入的恢复患者中，作为氨基酸或肠外营养中使用的其他混合物的标准溶液的补充物。
发明内容
在本发明中，发明人以令人惊讶的方式展示了通过局部途径使用的二肽L-丙氨酰-L-谷氨酰胺具有皮肤上的生物活性，基于它的再生特性：对角质细胞迁移的作用。
此外，发明人还展示了当这个二肽与燕麦提取物和透明质酸组合时，这种活性将大大增强。
特别地，发明人证实了对于角质细胞的迁移，三种组分间协同作用的存在，该三种组分为燕麦提取物(更具体地为燕麦苗提取物)、透明质酸或其一种盐以及L-丙氨酰-L-谷氨酰胺。这种活性在组织再生和皮肤损伤的愈合中特别有趣。
事实上，上皮细胞的迁移是发育和组织修复过程(例如胚胎发育和愈合)的重要步骤。
细胞运动的引发(d’initiation)、协调和停止的机制尚未完全阐明，然而细胞迁移的重要作用是公认的。能够刺激该细胞过程的一些药剂已被表征，例如某些基质(matricielles)或胞质蛋白(SANTORO MM.,GAUDINO G.,Cellular and molecular facetsof keratinocyte reepithelization during wound healing.EXP.CELL.RES.304(1):274-286,2005)(WERNER S.,GROSE R.Regulation of wound healing by growth factorsand cytokines.PHYSIOL.REV.83(3):835-870,2003)(STEFFENSEN B.,AKKINEN L.,LARIAVA H.Proteolytic events of wound healing-coordinated interactions amongmatrix metallopteinases(MMPs),integrins,and extracellular matrixmolecules.CRIT.REV.ORAL BIOL.MED.12(5):373-398,2001)。
在皮肤愈合期间和在慢性皮肤炎症感染中，角质细胞被“激活”以进行迁移过程。然后这些细胞看到它们的表型一方面被与胞外基质的相互作用影响，另一方面被细胞-细胞相互作用影响(MCMILLAN J.R.,AKIYAMA M.,SHIMIZU H.Epidermal basement membranezone component:ultrastructural distribution and molecular interactions.J DERMSC.31:169-177,2003)。伤口边缘的基底层的角质细胞迁移至伤口上并覆盖伤口。事实上，角质细胞是与纤连蛋白、间质真皮胶原蛋白(1型)、胶原IV和基底层的层粘连蛋白5接触而活化的。它们也受某些多肽生长因子的调控，例如TGFβ、TGFα和EGF。此外，在角质细胞活化后，细胞因子(IL1，TGFα)和趋化因子(RANTES和IL8)也有助于加快伤口重新形成上皮(ré-épithélisation)的速度(SZABO I.,WETZEL M.A.,ROGERS TJ.Cell-Density-RegulatedChemotactic Responsiveness of Keratinocytes In Vitro.J INVEST DERMATOL 117:1083-1090,2001)。
附图说明
唯一的附图说明了燕麦苗提取物/透明质酸和L-丙氨酰-L-谷氨酰胺及其组合对角质细胞迁移的作用。
具体实施方式
本发明的主题是包含L-丙氨酰-L-谷氨酰胺、透明质酸或其一种盐和燕麦提取物的组合。
术语“L-丙氨酸”指的是(S)-2-氨基丙酸，也称为α-氨基丙酸。L-丙氨酸是一个有轻微非极性和疏水性特征的中性氨基酸。
术语“L-谷氨酰胺”指的是2-氨基戊酰胺酸(l’acide 2-aminoglutaramique)。L-谷氨酰胺是半必需的、极性不带电荷的和亲水的氨基酸。
在本发明的特定实施方案中，组合包含高分子量的透明质酸或其一种盐。优选地，分子量为50 000至750 000Da，优选250 000至450000Da。
透明质酸盐优选是透明质酸钠。
根据本发明的实施方式，透明质酸盐有50 000至750 000Da，优选250 000至450000Da的分子量。
在本发明的实施方案中，燕麦提取物从燕麦苗中获得，优选地如WO 2010/054879所述。
在本发明的意义之内，“燕麦苗”是指穗头出现之前的燕麦，也就是说在发芽后阶段(发芽后约2周至2个月)的燕麦，而从拔节至穗头出现的阶段不包括在内。“拔节”是指在开花前的生长阶段，其对应于茎的伸长和形成中的穗的长高。次生代谢物在专利申请WO2010/054879中描述，作为燕麦苗提取物的组成成分：黄酮类和燕麦皂苷类型的皂苷。所述提取物的特征在于存在2至15％的黄酮类和0.2至2％的燕麦皂苷A和B。
制备燕麦提取物的方法可以如下：
-干燥和研磨燕麦的部分，优选燕麦苗，
-在有机溶剂中提取，该溶剂选自酮、酯、C1至C4醇以及这些溶剂的任何可混溶比例的混合物，和
-离心或过滤。
有利地，根据本发明的方法的有机溶剂选自丙酮、甲基乙基酮、甲基异丁基酮、乙酸乙酯、C1至C4醇以及这些溶剂的任何可混溶比例的混合物。
然后通过离心或过滤从提取物中分离提取步骤获得的残渣，溶液可以或多或少浓缩直至获得干提取物。
根据本发明的实施方式，在干燥步骤中可以加入载体(support)，该载体相比于提取的干物质的重量比可以在1至75％之间变化。载体可以是糖(例如麦芽糊精、乳糖)、二氧化硅或任何其他美容学上(cosmétologiquement)可接受的载体。
在本发明的另一个实施方案中，将溶液浓缩以获得燕麦汁，其包含60至80％的干物质，优选70％的干物质。
在特定的实施方案中，根据本发明的组合的特征在于透明质酸/燕麦提取物/L-丙氨酰-L-谷氨酰胺重量比分别为2/1/3至2/1/5。
在另一个实施方式中，透明质酸、燕麦苗提取物和L-丙氨酰-L-谷氨酰胺比例分别为重量比2/1/4。
在另一个优选的实施方案中，根据本发明的组合物包含比例分别为2/1/4的透明质酸/燕麦苗提取物/L-丙氨酰-L-谷氨酰胺。
本发明的另一个主题涉及新的皮肤病学或化妆品组合物，其旨在加速皮肤修复以便重新建立皮肤的完整性和质量。
根据本发明的组合物包含作为皮肤病学或化妆品活性成分的透明质酸、燕麦提取物和L-丙氨酰-L-谷氨酰胺的前述组合，并进一步包含至少一种皮肤病学或化妆品学上可接受的赋形剂。
在本发明优选的实施方案中，组合物用于局部施用。
皮肤病学上(药学上)或化妆品学上相容的赋形剂可以是在本领域技术人员公知的那些中的任何赋形剂，目的在于获得以乳剂、霜剂、香膏、油剂、洗液、凝胶、发泡凝胶、软膏、喷雾剂等的形式用于局部施用的组合物。
在优选的实施方案中，组合物是霜剂、软膏的形式。
在实施方案中，根据本发明的组合物包含至少一种其他活性成分。
根据本发明的“活性成分”是指具有皮肤病学或化妆品特性的任何物质。
这种其他活性成分可以特别地选自愈合、舒缓、止痒、抗衰老、抗皱、抗自由基、抗紫外线剂、刺激皮肤大分子的合成或能量代谢的药剂、保湿、抗细菌、抗真菌、消炎、麻醉剂。
优选地，使用愈合和/或舒缓剂。
最后，本发明的另一主题涉及基于透明质酸，燕麦提取物和L-丙氨酰-L-谷氨酰胺的组合的组合物用于治疗和愈合皮肤损伤的用途。
此外，本发明涉及根据本发明的透明质酸，燕麦苗提取物和L-丙氨酰-L-谷氨酰胺的组合用于制备旨在帮助角质细胞迁移的组合物。
根据本发明的组合物用于受损皮肤的护理：
·在侵入行为/治疗之后：有或无缝合的手术行为(撕除手术(exérésis)、削除手术(shavings))、冷冻疗法、激光消融、中度或深度去皮(peelings)、美塑疗法(mésothérapie)、刮除术(curettage)。
·浅表割伤或烧伤的创伤后阶段(post traumatique)。
·在需要愈合产品的浅表(非侵入型)行为之后，该愈合产品加快皮肤恢复，可在长期使用(直到皮肤的完全修复)。
·在轻微的外观改变之后：浅表擦伤，晒伤。
根据本发明的皮肤和粘膜损伤的治疗可以特别地包括割伤、缝合、擦伤、划伤、刮伤、手术后疤痕或美学后皮肤病学干预(post-acte de dermatologie esthétique)、浅表烧伤、晒伤的治疗。
此外，本发明涉及根据本发明的化妆品组合物旨在改善皮肤愈合和修复的用途。
阅读以下的结果将更好地理解本发明，该结果对本发明作出说明但并不限制本发明的范围。
对角质细胞迁移的药理评价
这项测试的目的是评价透明质酸、燕麦苗提取物、L-丙氨酰-L-谷氨酰胺及其组合对角质细胞迁移的作用，该测试使用Oris细胞迁移测定试剂盒(Platypus Technologies)。
生物材料
使用了自发性无限增殖的HaCaT人类角质细胞系，该细胞系在文献中经常作为参考模型引用。
细胞迁移方案
用于研究细胞迁移的方案以96孔试剂盒，Oris细胞迁移测定试剂盒(PlatypusTechnologies-TEBU)的使用为基础，实现了这种细胞过程的微型化和量化。
这项测试的原理在于研究向着96孔板的孔的中心的细胞迁移。其包括在孔中放置挡块，以形成2mm直径的检测区。然后当细胞已正确粘附在挡块周围的表面时将挡块移除，从而使细胞能够向着检测区迁移。移除挡块的有活性成分的板在DMEM(Dulbecco'sModified Eagle Medium)0％SVF(胎牛血清)中于37℃孵育24小时。分析位于区域中细胞的数量，所述区域为挡块所在的区域，以评价细胞的迁移。蒙片(cache)使得独特地显示和计数位于这个区域中的细胞成为可能。对于每种条件，以6至8个孔确定平均值。
在不含SVF的培养基中孵育细胞。
测试的产品
-EGF：33ng/ml，
-燕麦苗提取物：10或30μg/ml，
提取物的制备：
用100ml丙酮/水(80/20)(v/v)提取溶剂提取10g磨碎的幼苗。
过滤并用提取溶剂冲洗残渣。
蒸发丙酮并获得水相。
过滤。通过干燥浓缩直至获得干燥提取物。
-透明质酸钠(分子量250-450kDa)：20或60μg/ml，
-L-丙氨酰-L-谷氨酰胺：40或90μg/ml。
结果的分析
结果表示为：
-与已迁移细胞的数量成正比的荧光强度(IF)。
-相比于对照0％SVF的百分比活性。
统计分析
对粗迁移值进行了Dunnett检验统计分析。然后这项检验给出“p值”的值，表征了不同条件下获得的结果的显著性。显著性的程度定为
p<0.05(*显著)
p<0.01(**非常显著)
p<0.001(***极显著)
p>0.05(不显著)。
结果
燕麦苗提取物、透明质酸和L-丙氨酰-L-谷氨酰胺，单独或组合，在不同浓度下对角质细胞迁移的作用的结果被编入表1和2中，然后显示于唯一附图中。显示于这条曲线上的荧光强度值对应于6至8次测量的平均值，所述测量在3次独立操作代表的实验中进行。
在DMEM和0％SVF存在下，EGF实验的阳性对照确实诱导了角质细胞的迁移。在这些实验条件下，单独的燕麦苗提取物(10或30μg/ml)和单独的透明质酸(20或60μg/ml)对角质细胞迁移没有任何显著作用。另一方面，它们的组合看起来显示了增加迁移的趋势：相比于对照+45％或+27％，随测定的浓度而变化(表1和2)。
单独的L-丙氨酰-L-谷氨酰胺以浓度依赖的方式诱导角质细胞迁移。这些诱导甚至比EGF阳性对照更为重要。3种活性成分——燕麦苗提取物，透明质酸和L-丙氨酰-L-谷氨酰胺——的组合以非常重要和统计学显著的方式诱导角质细胞迁移。表1和2以及唯一附图显示相比于对照这些诱导是统计学显著的，而相比于单独的燕麦苗提取物和单独的透明质酸或相比于其组合这些诱导也是统计学显著的。
唯一附图显示了燕麦苗干燥提取物(ES)、透明质酸(AH)、L-丙氨酰-L-谷氨酰胺(Ala-Glu)及其组合对角质细胞迁移的作用。百分比对应于相对于对照的额外活性百分比。
表1：燕麦苗干燥提取物(ES)、透明质酸(AH)、L-丙氨酰-L-谷氨酰胺(A-G)及其组合对角质细胞迁移的作用。
DS：标准差，**p<0.01相比于对照。
表2：燕麦苗干燥提取物(ES)、透明质酸(AH)、L-丙氨酰-L-谷氨酰胺(A-G)及其组合对角质细胞迁移的作用。
DS：标准差，*p<0.05，**p<0.01相比于对照。
| 组别 | 浓度 | 平均值±DS | ％迁移 |
| 对照 | 1729±384 | 100 | |
| EGF | 33ng/ml | 3553±1556 | 301* |
| ES | 30μg/ml | 1386±226 | 62 |
| AH | 60μg/ml | 1735±488 | 101 |
| A-G | 90μg/ml | 2586±1092 | 194 |
| ES+AH | 30+60μg/ml | 1152±541 | 127 |
| ES+AH+A-G | 30+60+90μg/ml | 2877±1024 | 317** |
因此，燕麦苗提取物、透明质酸或其一种盐和L-丙氨酰-L-谷氨酰胺的组合以协同的方式增加角质细胞的迁移。这些结果证实在皮肤病学或化妆品的愈合组合物中使用这样的组合的好处。
组合物的示例：水包油乳剂
Claims (7)
1.由L-丙氨酰-L-谷氨酰胺、透明质酸和燕麦提取物组成的组合物，其中所述透明质酸是分子量为50000至750000Da的透明质酸钠片段的形式，其中所述燕麦提取物从燕麦苗中获得，其特征在于存在2至15％的黄酮类和0.2至2％的燕麦皂苷A和B，并且其中透明质酸/燕麦苗提取物/L-丙氨酰-L-谷氨酰胺重量比分别为2/1/3至2/1/5。
2.根据权利要求1所述的组合物，其特征在于透明质酸/燕麦苗提取物/L-丙氨酰-L-谷氨酰胺比例分别为重量比2/1/4。
3.根据权利要求1或2所述的组合物在制备用于局部使用旨在帮助角质细胞迁移的药物中的用途。
4.根据权利要求1或2所述的组合物在制备用于局部使用旨在治疗皮肤损伤的药物中的用途。
5.根据权利要求1或2所述的组合物在制备用于局部使用旨在改善皮肤愈合和恢复的药物中的用途。
6.皮肤病学或化妆品组合物，其包含作为活性成分的根据权利要求1或2所述的组合物，与至少一种皮肤病学或化妆品学上可接受的赋形剂。
7.根据权利要求6所述的组合物在制备用于治疗割伤、缝合、擦伤、划伤、刮伤、手术后疤痕或美学后皮肤病学干预、浅表烧伤、晒伤的药物中的用途。
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| FR1353231A FR3004353B1 (fr) | 2013-04-10 | 2013-04-10 | Association synergique de l'alanine-glutamine, l'acide hyaluronique et un extrait d'avoine, et son utilisation dans une composition destinee a la cicatrisation et la reparation des lesions cutanees |
| PCT/EP2014/057224 WO2014167039A1 (fr) | 2013-04-10 | 2014-04-10 | Association synergique de l'alanine-glutamine, l'acide hyaluronique et un extrait d'avoine et son utilisation dans une composition destinee a la cicatrisation et la reparation des lesions cutanees |
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| CN103002903A (zh) * | 2010-06-28 | 2013-03-27 | Ade治疗公司 | 瘢痕疙瘩治疗法 |
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| DE102009029813A1 (de) * | 2009-06-18 | 2010-12-23 | Henkel Ag & Co. Kgaa | Antifalten-Kosmetikum |
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| FR2926461A1 (fr) * | 2008-01-23 | 2009-07-24 | Jean Noel Thorel | Nouveau facteur de croissance cellulaire d'origine non animale et applications |
| CN103002903A (zh) * | 2010-06-28 | 2013-03-27 | Ade治疗公司 | 瘢痕疙瘩治疗法 |
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| AU2014253131B2 (en) | 2018-11-15 |
| RU2015142443A (ru) | 2017-05-19 |
| US20160303181A1 (en) | 2016-10-20 |
| EP2983691B1 (fr) | 2017-12-13 |
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| KR20150140319A (ko) | 2015-12-15 |
| MX358845B (es) | 2018-09-05 |
| WO2014167039A1 (fr) | 2014-10-16 |
| CN105101984A (zh) | 2015-11-25 |
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| NO2983691T3 (zh) | 2018-05-12 |
| JP2016515642A (ja) | 2016-05-30 |
| ES2661908T3 (es) | 2018-04-04 |
| DK2983691T3 (en) | 2018-03-19 |
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