CN115887475A - 络丝蛋白和/或vegf-c的生产和/或活性促进剂及使用该促进剂的皮肤外用剂 - Google Patents
络丝蛋白和/或vegf-c的生产和/或活性促进剂及使用该促进剂的皮肤外用剂 Download PDFInfo
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- CN115887475A CN115887475A CN202211304782.9A CN202211304782A CN115887475A CN 115887475 A CN115887475 A CN 115887475A CN 202211304782 A CN202211304782 A CN 202211304782A CN 115887475 A CN115887475 A CN 115887475A
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- skin
- vegf
- edema
- lymphatic
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Abstract
本发明提供一种作为有效成分包含由以下化学式1表示的化合物和/或含该化合物的人参提取物的络丝蛋白和/或VEGF‑C的生产和/或活性促进剂及含该促进剂的皮肤外用剂。[化学式1]
在所述化学式1中，各取代基如说明书中所定义。
Description
技术领域
本公开涉及一种络丝蛋白和/或VEGF-C的生产和/或活性促进剂及使用该促进剂的皮肤外用剂。
背景技术
浮肿(Ederma)是指组织液在体内组织细胞之间积聚的一种状态，简单来说就是身体水肿的一种症状。它可能是由心脏疾病、肾脏疾病或身体任何部位的血液循环不良引起的。尤其是腿部，由于距离心脏很远且受重力影响大，流向心脏的血流减少，从而发生浮肿。此外，对于女性来说，浮肿发生在正常怀孕或先兆子痫期间，当大量喝水或摄入盐分、或者疲劳或睡眠不足时，浮肿可能会暂时出现，但它会自行消退。在毛细血管通透性增加的情况下，例如在烧伤、外伤、局部炎症、过敏反应等情况下，也会出现局部浮肿。尤其，对于腿部浮肿，还会伴随足部和脚踝的浮肿，所以通过鞋子过紧的感觉容易察觉到，而且由于浮肿的感觉伴随着腿部的沉重感，通过全身的疲劳也会察觉到腿部浮肿。全身性浮肿可分为心脏性、肾脏性、肝脏性、内分泌性和营养不良性浮肿，局部浮肿包含血管和淋巴管阻塞导致的浮肿和血管舒缩性浮肿等。当出现浮肿时，身体会水肿，体重增加，睡醒后眼睛肿，手指上的戒指紧绷，鞋子会显得小。当用手指按压小腿胫骨部时，也会出现凹陷的凹陷性浮肿(pittingedema)。众所周知，浮肿会促进皮肤内局部水分过多而导致的血液循环障碍和皮肤老化。一般来说，皮肤问题会加剧淋巴系统功能不全和超负荷的淋巴浮肿患者的状况，这是众所周知的。
皮肤在人体中与外部环境接触最密切，是保护人体内部的重要器官。皮肤主要分为表皮(epdirmis)、真皮(dermis)和皮下脂肪(hypodermis)，其中皮下脂肪由将能量储存为脂肪的形成脂肪组织的脂肪细胞组成，用于在生物体内蓄积或释放能量。换言之，皮下脂肪在能量供应大于需求时以中性脂肪形式储存在脂肪细胞中，而当能量耗尽时，皮下脂肪会分解为游离脂肪酸和葡萄糖。
另一方面，在现代社会，随着经济增长，生活水平提高，由于缺乏运动以及高蛋白饮食文化，导致肥胖人数迅速增加，肥胖引起许多疾病。因此，在现代社会，运动疗法、饮食疗法和药物疗法被用于治疗肥胖症。
然而，对于生活忙碌的现代人来说，很难期待通过运动疗法和饮食疗法来解决肥胖和肥胖疾病的适当效果，而且脂肪细胞一旦形成，虽然大小可以缩小，但是不可能自然清除，存在永久留在人体内的问题。因此，开发一种可助脂肪分解的安全的皮肤外用剂(例如，软膏、化妆品等)切实可行。
因此，本发明人确认特定药艾提取物作为有效成分会促进络丝蛋白(reelin)和/或VEGF-C(Vascular Endothelial Growth Factor-C，血管内皮生长因子C)的生产或活性，进而改善水肿、淋巴浮肿、皮肤皱纹和肥胖后，完成了本发明。
发明内容
技术问题
一个实施方案旨在提供一种促进络丝蛋白和VEGF-C的生产或活性的促进剂。
另一个实施方案旨在提供一种使用所述促进剂的皮肤外用剂。
技术方案
根据一个实施方案，提供一种络丝蛋白和/或VEGF-C的生产和/或活性促进剂，其作为有效成分包含由以下化学式1表示的化合物和/或含该化合物的人参提取物。
[化学式1]
在所述化学式1中，
X1为氧原子或硫原子，
R1至R10各自独立地为羟基或取代或未取代的C1至C20烷基，
n1和n2各自独立地为0至4的整数，1≤n1+n2≤4。
所述人参提取物可以是发酵人参提取物。
在所述化学式1中，R1为被羟基取代的C1至C20烷基，R2和R8各自独立地为羟基，R3至R7和R9各自独立地为未取代的C1至C20烷基，R10为被由以下化学式2表示的官能团取代的C1至C20烷基，n1为1的整数，n3为3的整数，
[化学式2]
在所述化学式2中，
L1为取代或未取代的C1至C20亚烷基，
R11和R12各自独立地可为氢原子或取代或未取代的C1至C20烷基。
所述化学式1可由以下化学式1-1表示。
[化学式1-1]
相对于所述络丝蛋白和/或VEGF-C的生产和/或活性促进剂总量，可以1μg/ml至100mg/ml的浓度范围包含含有所述由化学式1表示的化合物的人参提取物。
相对于所述络丝蛋白和/或VEGF-C的生产和/或活性促进剂总量，可以50nmol至5000nmol的浓度范围包含所述由化学式1表示的化合物。
另一个实施方案提供一种皮肤外用剂，用于通过促进络丝蛋白和/或VEGF-C的生产和/或活性来改善水肿、淋巴浮肿、皮肤皱纹或肥胖，其特征在于，作为有效成分包含所述由化学式1表示的化合物和/或含该化合物的人参提取物。
所述皮肤外用剂是水肿改善剂，所述水肿可能是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
所述皮肤外用剂是淋巴浮肿改善剂，所述淋巴浮肿可能是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
所述皮肤外用剂是肥胖改善剂，所述肥胖可能是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
发明效果
根据一个实施方案，可以提供一种新成分，其通过诱导络丝蛋白和/或VEGF-C的表征来激活淋巴管功能，从而有效预防或控制水肿、淋巴浮肿、形成皱纹或肥胖。
附图说明
图1是示出淋巴细胞中发酵人参提取物的细胞毒性试验结果的图。
图2是示出角质形成细胞中发酵人参提取物的细胞毒性试验结果的图。
图3是示出淋巴细胞中发酵人参提取物的络丝蛋白细胞因子分析结果的图。
图4是示出淋巴细胞中由化学式1-1表示的化合物的络丝蛋白细胞因子分析结果的图。
图5是示出角质形成细胞中发酵人参提取物的VEGF-C细胞因子分析结果的图。
图6是示出角质形成细胞中由化学式1-1表示的化合物的VEGF-C细胞因子分析结果的图。
具体实施方式
在下文中，将详细描述本发明的实施方案，以便本发明所属领域的普通技术人员能够容易地实施本发明。然而，本发明能够以各种不同的方式实施，并不限于本文所述的实施方案。
本说明书中使用的“络丝蛋白(Reelin，RELN)”是指细胞外基质相关分子。
在本说明书中，除非另有说明，否则“取代”或“取代的”是指本发明的官能团中的至少一个氢原子被选自由卤素原子(F、Br、Cl或I)、羟基、硝基、氰基、氨基(NH2、NH(R200)或N(R201)(R202)，其中R200、R201和R202彼此相同或不同且各自独立地为C1至C10烷基)、脒基、肼基、腙基、羧基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的脂环族有机基团、取代或未取代的芳基和取代或未取代的杂环基中的一种以上取代基取代。
在本说明书中，除非另有说明，否则“烷基”是指C1至C20烷基，具体指C1至C15烷基，“环烷基”是指C3至C20环烷基，具体指C3至C18环烷基，“烷氧基”是指C1至C20烷氧基，具体指C1至C18烷氧基，“芳基”是指C6至C20芳基，具体指C6至C18芳基，“烯基”是指C2至C20烯基，具体指C2至C18烯基，“亚烷基”是指C1至C20亚烷基，具体指C1至C18亚烷基，“亚芳基”是指C6至C20亚芳基，具体指C6至C16亚芳基。
在本说明书中，除非另有定义，否则“组合”是指混合或共聚。此外，“共聚”是指嵌段共聚或无规共聚，“共聚物”是指嵌段共聚物或无规共聚物。
皮肤脉管系统位于真皮内，由血管和淋巴管组成。为了维持体内平衡，必须使已流出血管的组织液回流到静脉。皮肤的静脉有效地将血液输送到中枢。然而，静脉本身缺乏接收组织液的能力。由此可知，接收组织液的组织即淋巴管在皮肤中也是必不可少的结构。
淋巴管回收皮肤中存在的不必要物质或从血管不断外泄的水分和蛋白质，从而在维持细胞周围微环境的恒定状态方面发挥着重要作用。此外，人们认为在通过T淋巴细胞的输送抵抗来自外部的感染因子或外部因素方面淋巴管发挥作用。
作为淋巴管功能障碍的病症，已知有水肿或淋巴浮肿等症状。此外，淋巴管的功能对紫外线引起的皮肤光老化(形成皱纹)也发挥重要作用，不限于水肿。
从目前的研究来看，VEGFR-3已被确定为一种特异性地存在于淋巴管中的跨膜受体，并且已发现VEGF-C和VEGF-D为其配体。VEGF-C作用于淋巴管，促进淋巴管内皮细胞的增殖、迁移和形成管腔，从而激活淋巴管功能。此外，正在摸索根据VEGF-C引入作为水肿病理状态的浮肿进行基因治疗的可能性。
此外，近年来，众所周知，具有导致淋巴管功能异常的基因突变的小鼠在成熟时会出现肥胖。关于淋巴管形成和功能异常表现出肥胖的机制，可以获得流经淋巴管的淋巴液会促进前体肥大细胞分化为脂肪的见识。也就是说，由于淋巴管的功能异常，淋巴液会从淋巴管中渗出，其导致脂肪的分化，进而导致肥胖。因此，VEGF-C促进剂也有望作为预防肥胖的治疗剂，其在功能上诱导淋巴管新生。
VEGF(Vascular Endothelial Growth Factor，血管内皮生长因子)家族基因存在VEGF-A到VEGF-E。其中，VEGF-B和VEGF-E已被确定为仅作用于血管的因子。VEGF-A存在于皮肤中并作用于淋巴管，但已知它是使淋巴管功能恶化的因子。
据报道，在皮肤中，VEGF-D以微量存在于真皮中，但由于VEGF-D敲除小鼠根本不会引起皮肤淋巴管的形成和功能异常，因此VEGF-D被认为不是皮肤中形成淋巴管的必不可少的因子。另一方面，从表皮中VEGF-C高表征的小鼠真皮中存在的淋巴管数量增加可知，皮肤中的VEGF-C在表皮中表征较强。另外，在表皮中使VEGF-C的受体即VEGFR-3的中和抗体高表征，以阻断表皮中VEGF-C的效果，其结果证实了真皮的淋巴管数量极度减少(Makinen,T.,Jussila,L.,Veikkola,T.,Karpanen,T.,Kettunen,M.I.,Pulkkanen,K.J.,Kauppinen,R.,Jackson,D.G.,Kubo,H.,Nishikawa,S.,Yla-Herttuala,S.&Alitalo,K.(2001)Nat Med 7,199-205)。由此可见，存在于皮肤真皮中的淋巴管的功能受表皮中表征的VEGF-C的控制，由于VEGF-C不起作用，从而呈现水肿(浮肿)。
进一步地，近年来已经进行各种尝试，通过激活或加强人体内的淋巴或淋巴管来控制水肿或浮肿、改善皮肤老化(皱纹)以及预防、抑制和治疗肥胖，而对于所述淋巴或淋巴管的激活或强化，除了VEGF-C之外，还可以通过促进络丝蛋白的生产、分化和活性来实现。
因此，本发明人进行了大量的实验和反复试验，以找出一种可以通过促进人体内络丝蛋白和/或VEGF-C的生产或活性来改善水肿、淋巴浮肿、皮肤皱纹或肥胖的有效成分，最终确认作为有效成分包含可由人参提取物(具体为发酵人参提取物)获得的由以下化学式1表示的化合物和/或含该化合物的发酵人参提取物的组合物作为络丝蛋白和/或VEGF-C的生产和/或活性促进剂能够发挥作用，从而完成了本发明。
[化学式1]
在所述化学式1中，
X1为氧原子或硫原子，
R1至R10各自独立地为羟基或取代或未取代的C1至C20烷基，
n1和n2各自独立地为0至4的整数，1≤n1+n2≤4。
所述由化学式1表示的化合物可由发酵人参提取物获得，无法从没有发酵(或发酵前)的人参(如鲜参)提取物获得。本发明人对人参提取物的功能性进行了数年的持续研究后，首次证实发酵人参提取物的络丝蛋白和/或VEGF-C生产性比未发酵人参提取物显著增加，还首次证实通过促进所述络丝蛋白和/或VEGF-C分泌激活淋巴管，最终可以改善皮肤水肿等，从而完成了本发明。
虽然已经知道人参提取物的各种功效，但并不是所有的人参提取物都对预防或控制水肿、淋巴浮肿、形成皱纹或肥胖具有有效作用。迄今为止，仅尝试推出含有少量人参提取物(如鲜参提取物)的保健功能食品，或将人参提取物用于治疗肌肉疾病或呼吸系统疾病。具体地，任何人都还不知道发酵人参提取物可以用作络丝蛋白和/或VEGF-C的生产和/或活性促进剂。
例如，所述发酵人参提取物可以通过发酵人参来获得，将所述人参揉捻后，使其发酵，从而获得所述发酵人参提取物。也就是说，所述发酵人参提取物可以是将揉捻的人参发酵而得到的提取物。与不实施所述揉捻步骤直接发酵人参而得到的提取物相比，所述将揉捻的人参发酵而得到提取物可能更适合用作络丝蛋白和/或VEGF-C的生产和/或活性促进剂。所述揉捻可指利用物理力量反复揉搓人参和人参须根的工艺(破坏细胞组织和细胞壁)。
例如，所述发酵人参可以是厌氧条件下发酵的人参。在此情况下，与好氧条件下发酵的人参相比，可能更适合用作络丝蛋白和/或VEGF-C的生产和/或活性促进剂。
例如，在所述化学式1中，R1为被羟基取代的C1至C20烷基，R2和R8各自独立地为羟基，R3至R7和R9各自独立地为未取代的C1至C20烷基，R10为被由以下化学式2表示的官能团取代的C1至C20烷基，n1为1的整数，n3为3的整数，
[化学式2]
在所述化学式2中，
L1为取代或未取代的C1至C20亚烷基，
R11和R12各自独立地可为氢原子或取代或未取代的C1至C20烷基。
例如，所述化学式1可由以下化学式1-1表示。
[化学式1-1]
例如，相对于所述络丝蛋白和/或VEGF-C的生产和/或活性促进剂总量，可以1μg/ml至100mg/ml、例如1μg/ml至10mg/ml、例如1μg/ml至1mg/ml、例如1μg/ml至500μg/ml、1μg/ml至100μg/ml、例如1μg/ml以上且100μg/ml以下、90μg/ml以下、80μg/ml以下、70μg/ml以下、60μg/ml以下、50μg/ml以下、40μg/ml以下、30μg/ml以下、20μg/ml以下、例如1μg/ml至50μg/ml的浓度范围包含含有所述由化学式1表示的化合物的(发酵)人参提取物。
例如，相对于所述络丝蛋白和/或VEGF-C的生产和/或活性促进剂总量，可以50nmol至5000nmol、例如50nmol以上且5000nmol以下、4500nmol以下、4000nmol以下、3500nmol以下、3000nmol以下、2500nmol以下、2000nmol以下、1500nmol以下、1000nmol以下、例如50nmol至2500nmol的浓度范围包含所述由化学式1表示的化合物。
根据一个实施方案的络丝蛋白和/或VEGF-C的生产和/或活性促进剂作为有效成分包含所述由化学式1表示的化合物和/或含该化合物的(发酵)人参提取物以及满足所述浓度范围，从而可以非常有效地促进淋巴管的形成和功能。作为淋巴管的功能障碍导致的症状，不仅包含水肿或淋巴浮肿等，还可以包含紫外线导致的皮肤光老化(形成皱纹等)和肥胖等。根据本发明的一个实施方案的络丝蛋白和/或VEGF-C的生产和/或活性促进剂可以有效地防止、抑制水肿或淋巴浮肿、紫外线导致的皮肤光老化和肥胖。此外，也可以有效地治疗先天性淋巴浮肿。
皮肤光老化是指一般反复暴露在太阳光下而发生的皮肤外观和功能的变化。太阳光中的紫外线(UV)，特别是中波紫外线(称为UVB，波长为290-320nm)，主要导致光老化。目前尚不清楚引起光老化所需的UVB曝光量。然而，反复暴露于引起红斑或晒伤的UVB通常会导致光老化。在临床上，光老化可以被特定为皮肤粗糙、形成皱纹、色斑沉着、变成土色、松弛、毛细血管扩张病发病、产生痣、紫斑病发病、易结疤、萎缩、产生纤维化病的色素去除区域、前期恶性肿瘤和恶性肿瘤发作等。光老化通常发生在习惯性地暴露于阳光下的皮肤上，例如面部、耳朵、头部、颈部和手部。
根据另一个实施方案，提供一种皮肤外用剂，用于通过促进络丝蛋白和/或VEGF-C的生产和/或活性来改善水肿、淋巴浮肿、皮肤皱纹或肥胖，其特征在于，作为有效成分包含所述由化学式1表示的化合物和/或含该化合物的(发酵)人参提取物。
例如，所述皮肤外用剂是水肿改善剂，所述水肿可能是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
例如，所述皮肤外用剂是淋巴浮肿改善剂，所述淋巴浮肿可能是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
例如，所述皮肤外用剂是肥胖改善剂，所述肥胖可能是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
根据一个实施方案的皮肤外用剂，可以按照使用目的适当地确定使用量、施用形式、剂型。所述皮肤外用剂的施用形式没有特别限制，吸入和经皮两者都可以采用。剂型包含例如香水、香波和调理剂、护肤品、沐浴露、身体调理剂、沐浴粉、空气清新剂、除臭剂、沐浴剂、洗剂、面霜、香皂、牙膏、化妆料如气溶胶产品和其他用于一般香料的任何形式。此外，也可用于吸入药物等药品。
此外，除了所述必要成分之外，所述皮肤外用剂中还可以根据需要适当混合通常用于化妆料或药品等皮肤外用剂的成分，例如美白剂、保湿剂、抗氧化剂、油性成分、紫外线吸收剂、表面活性剂、增稠剂、醇类、粉末成分、着色剂、水性成分、水、各种皮肤营养剂等。
此外，还可以适当地包含依地酸二钠、依地酸三钠、柠檬酸钠、聚磷酸钠、偏磷酸钠、葡萄糖酸等金属封锁剂、咖啡因、丹宁、维拉帕米、凝血酸及其衍生物、甘草提取物、光甘草定、木瓜果实的热水提取物、各种生药、生育酚乙酸酯、甘草酸及其衍生物或其盐等药剂、维生素C、抗坏血酸磷酸镁、抗坏血酸葡糖苷、熊果苷、曲酸等美白剂、葡萄糖、果糖、甘露糖、蔗糖、海藻糖等糖类、视黄酸、视黄醇、乙酸视黄醇酯、棕榈酸视黄醇酯等维生素A类等。
例如，所述皮肤外用剂可以是化妆料组合物。
在本说明书中，“化妆料”可指不仅具有美容功能，还可以具有美容功能之外的医疗功能的所有物质。
所述化妆料组合物的剂型不受特别限制，可以根据目的适当地选择。
例如，所述化妆料组合物可以配制成溶液、悬浮液、乳液、糊剂、凝胶、乳霜、洗剂、粉末、肥皂、含表面活性剂的卸妆剂、油、粉状粉底、乳状粉底、蜡状粉底和喷雾剂等剂型，但不限于此。更加详细地，可以剂型化为清洗剂、营养液(tonic)、头发定型剂、营养化妆水、精华液、精华乳、油剂、润发乳、洗发水、乳液、养发剂或者染发剂等化妆料组合物；水包油(O/W)型、油包水(O/W)型等基础化妆料。例如，所述组合物可以具有选自润肤乳、润肤液、收敛剂、乳液、牛奶乳液、保湿乳液、滋养乳液、按摩霜、营养霜、保湿霜、护手霜、软膏、粉底、精华液、滋养精华液、面膜、皂剂、洁面泡沫、洁面乳、清洁霜、身体乳、沐浴乳、乳液、软膏、凝胶、霜剂、贴片以及喷雾剂中的一种剂型。另外，所述组合物在各自剂型中，除了所述必要成分之外，其他成分可根据其他外用剂的种类或者使用目的等，本领域技术人员容易适当选择及调配。例如，还可以包含紫外线阻隔剂、护发调理剂、香料等。
所述化妆料组合物可以含有化妆品学上可接受的介质或者基质。作为适合局部使用的所有剂型，可以提供为例如溶液、凝胶、固体或者糊状无水生成物、水相中分散油相所得到的乳剂、悬浮液、微乳剂、微胶囊、微颗粒球或者离子型(脂质体)以及/或者非离子型的囊素分散剂形式，或者乳霜、护肤水、乳液、粉末、软膏、喷雾剂或者遮瑕棒形式。这些组合物可以按照本领域中的常规方法制备。
当本发明的剂型为溶液或者乳浊液时，作为载体成分，使用溶剂、增溶剂或者破乳剂，例如有水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇油、甘油脂肪酯、聚乙二醇或者山梨糖醇的脂肪酸脂。
当本发明的剂型为悬浮液时，作为载体成分，可以使用液态稀释剂(如水、乙醇或者丙二醇)、悬浮剂(如乙氧基化异硬脂醇、聚氧乙烯山梨醇酯和聚氧乙烯山梨糖醇酐酯)、微晶纤维素、偏氢氧化铝、膨润土、琼脂或者黄蓍胶等。
当本发明的制剂为糊剂、霜剂或凝胶剂时，作为载体成分，可以使用动物油、植物油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、氧化硅、滑石或氧化锌等。
当本发明的剂型为粉剂或者喷雾剂时，作为载体成分，可以使用乳糖、滑石、氧化硅、氢氧化铝、硅酸钙或聚酰胺粉剂，特别是在剂型为喷雾剂时，还可以含有推进剂如氯氟烃、丙烷/丁烷或二甲醚等。
在本发明的一个实施方式中，所述化妆料组合物还可以含有增稠剂。本发明的化妆料组合物中包含的增稠剂可以使用甲基纤维素、羧甲基纤维素、羧甲基羟基鸟嘌呤、羟甲基纤维素、羟乙基纤维素、羧乙烯聚合物、聚季铵盐、鲸蜡硬脂醇、硬脂酸、卡拉胶等，优选可以使用羧甲基纤维素、羧乙烯聚合物和聚季铵盐中的一种以上，最优选可以使用羧乙烯聚合物。
在本发明的一个实施方式中，根据需要，所述化妆料组合物可以含有各种适当的基质和添加剂，这些成分的种类和量可由发明人容易选择。可以根据需要含有可接受的添加剂，例如，还可以包含本领域的常规成分如防腐剂、色素、添加剂等。
防腐剂具体可为苯氧乙醇(Phenoxyethanol)或1,2-己二醇(1,2-Hexanediol)等，香料可以是人造香料等。
此外，在本申请发明的一个实施方式中，化妆料组合物可以包含选自水溶性维生素、油溶性维生素、高分子肽、高分子多醣、神经鞘脂和海藻汁中的组合物。除此之外，作为可以添加的调配成分，可以举出油脂成分、保湿剂、润肤剂(emollients)、表面活性剂、有机和无机颜料、有机粉体、紫外线吸收剂、防腐剂、杀菌剂、抗氧化剂、植物提取物、pH调节剂、乙醇、色素、香料、血液循环促进剂、凉感剂、止汗剂、净化水等。
另外，除此之外，可添加的调配成分不限于此，所述任意成分都可以在不损害本发明的目的及效果的范围内进行调配。
进一步地，根据一个实施方案的皮肤外用剂可以用作药学组合物。
参照下面详细描述的实施例就可以清楚地理解本发明的优点和特征以及实现它们的方法。在下文中，将通过实施例详细描述本发明。然而，下述实施例仅用于详细描述本发明，本发明的范围不限于下述实施例。
(实施例)
制备例：制备发酵人参提取物以及确认由化学式1-1表示的化合物
鲜参用水清洗2～3次后，揉捻30分钟，切割/破碎成大小为1～2cm后密封(50℃)，在厌氧条件下发酵3周。然后，用60℃的热风干燥1天，从而得到发酵人参。
将所述发酵人参置于50～80％的EtOH中，并在50～80℃下反复提取1～3次，时间为1～5小时。对提取的试样用沃特曼(Whatman)1号滤纸进行减压过滤，将过滤后的提取液用真空旋转浓缩器进行浓缩除去溶剂成分，然后进行纯化，以制备发酵人参提取物。
还进行了HPLC分析，通过采用色谱柱(Mightysil RP-18GP C18)、UV吸光度检测器(203nm)、注入量(10uL)、流量(1.0mL/min)、流动相(D.I WATER，乙腈)的条件，确认了所述发酵人参提取物中存在由以下化学式1-1表示的化合物(Sigma-aldrich)。
[化学式1-1]
试验例1：分析细胞毒性
(1)将人源淋巴细胞(Human Dermal Lymphatic Endothelial Cells；HDLEC，PromoCell，Germany)在96孔培养皿中重新培养1天后，分别以0ppm(μg/ml)至200ppm(μg/ml)的浓度处理所述制备例的发酵人参提取物。在培养24小时和72小时后，使用QuantiMaxWST-8细胞活力检测试剂盒(Cell viability assay kit)检测450nm下的吸光度并确认细胞存活率，其结果示于图1中。
从图1可以确认，所述药艾提取物在200ppm的浓度范围内没有细胞毒性。
(2)将人源角质形成细胞(Normal Human Epidermal Keratinocytes；NHEK，PromoCell，Germany)在96孔培养皿中重新培养1天后，分别以0ppm(μg/ml)至200ppm(μg/ml)的浓度处理所述制备例的发酵人参提取物。在24小时和72小时后，使用QuantiMax WST-8细胞活力检测试剂盒检测450nm下的吸光度并确认细胞存活率，其结果示于图2中。
从图2可以确认，所述药艾提取物在50ppm的浓度范围内没有细胞毒性。
试验例2：分析络丝蛋白细胞因子
将人源淋巴细胞在6孔板中培养24小时后进行DMSO处理的作为对照组(reference；(100％))，分别以1、10、20、50和100μg/ml的浓度以及100、250、500、1000和2000nmol的浓度处理所述制备例的发酵人参提取物和所述由化学式1-1表示的化合物(Sigma-aldrich)并培养48小时，然后使用Human reelin ELISA试剂盒(Mybiosource，美国)根据使用说明书分析络丝蛋白细胞因子，从而检测出络丝蛋白的生产和活性度，其结果示于图3和图4中。
从图3和图4可以确认，在所述由化学式1-1表示的化合物和含该化合物的发酵人参提取物的情况下，与对照组相比，可以进一步提高络丝蛋白的生产和活性度。
试验例3：分析VEGF-C细胞因子
将人源角质形成细胞在6孔板中培养24小时后进行DMSO处理的作为对照组(reference；(100％))，分别以1、10、20、50和100μg/ml的浓度以及100、250、500、1000和2000nmol的浓度处理所述制备例的发酵人参提取物和所述由化学式1-1表示的化合物(Sigma-aldrich)并培养48小时，然后使用VEGFC Human ELISA试剂盒(ThermoFisher，美国)根据使用说明书分别分析VEGF-C细胞因子，从而检测出VEGF-C的生产和活性度，其结果示于图5和图6中。
从图5和图6可以确认，在所述由化学式1-1表示的化合物和含该化合物的发酵人参提取物的情况下，与对照组相比，可以进一步提高VEGF-C的生产和活性度。
试验例4：皮肤外用剂的制备
按照如下表1所示的组分和含量制备了根据实施例1和比较例1(鲜参提取物；韩国新罗大学)的可用作皮肤外用剂的化妆料组合物。对于净化水，与其他组分混合时，使其总量为100重量％，由此制备化妆料组合物。
【表1】
(单位：ppm)
选出30名50岁以上有下肢小腿浮肿的女性，让她们将根据实施例1和比较例1的组合物每天2次涂抹在有水肿的下肢小腿部位上，连续涂抹7天后，要求每个人检测i)体重变化(使用体重秤)、ii)浮肿最严重的小腿部位的围长变化(使用塑料卷尺)、iii)浮肿状态(目测)，其结果示于下表2中。
【表2】
| 实施例1 | 比较例1 | |
| 体重(0天)(kg) | 61 | 60 |
| 体重(7天)(kg) | 59 | 61 |
| 小腿围长(0天)(cm) | 40 | 40 |
| 小腿围长(7天)(cm) | 39 | 40 |
| 浮肿状态 | 缓解 | 没有变化 |
从上表2可以确认，在施用根据一个实施方案的皮肤外用剂的情况下，与没有施用该皮肤外用剂的情况相比，浮肿状态在一周内得到缓解。
厌氧自然发酵的人参提取物与鲜人参提取物之间主要人参皂苷化合物含量的比
较
使用根据制备例的厌氧自然发酵的人参提取物和未发酵的鲜人参提取物，在相同条件下进行HPLC分析以确定提取物中主要人参皂苷化合物的含量，结果如下表3所示。
【表3】
(单位：％)
从表3可以看出，厌氧自然发酵的人参含有比其它人参皂苷化合物更多的由式1-1表示的化合物。
尽管已经在上面详细描述了本发明的优选实施例，但是本发明的权利范围不限于此，本领域技术人员利用本公开的技术方案中定义的本发明基本概念所做的各种修改和改进也落入本发明的范围内。
Claims (6)
1.一种络丝蛋白和/或VEGF-C的生产和活性促进剂，其中，
作为有效成分包含厌氧发酵人参提取物。
2.根据权利要求1所述的络丝蛋白和/或VEGF-C的生产和活性促进剂，其中，
相对于所述络丝蛋白和/或VEGF-C的生产和活性促进剂总量，以1μg/ml至100mg/ml的浓度范围包含所述厌氧发酵人参提取物。
3.一种皮肤外用剂，用于通过促进络丝蛋白和/或VEGF-C的生产和活性来改善水肿、淋巴浮肿、皮肤皱纹或肥胖，其特征在于，
作为有效成分包含厌氧发酵人参提取物。
4.根据权利要求3所述的皮肤外用剂，其中，
所述皮肤外用剂是水肿改善剂，
所述水肿是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
5.根据权利要求3所述的皮肤外用剂，其中，
所述皮肤外用剂是淋巴浮肿改善剂，
所述淋巴浮肿是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
6.根据权利要求3所述的皮肤外用剂，其中，
所述皮肤外用剂是肥胖改善剂，
所述肥胖是淋巴管形成异常、淋巴管功能异常或所述两者引起的。
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| CN (1) | CN115887475A (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008189609A (ja) * | 2007-02-06 | 2008-08-21 | Shiseido Co Ltd | Ｖｅｇｆｃ産生促進剤 |
| KR20150057664A (ko) * | 2013-11-20 | 2015-05-28 | 경희대학교 산학협력단 | 신종균 크리세오박테리움 ｔｈｇ-ｃ4-1 및 이를 이용한 지페노사이드 17 생산 방법 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5926895B2 (ja) * | 2011-05-11 | 2016-05-25 | 株式会社 資生堂 | Ｔｉｅ２活性化剤及びリンパ管安定化剤 |
| KR101345735B1 (ko) * | 2013-10-11 | 2013-12-30 | 주식회사 아미코스메틱 | 인삼열매 아위버섯 발효액을 함유하는 화장료 조성물 |
| WO2016035182A1 (ja) * | 2014-09-04 | 2016-03-10 | 金氏高麗人参株式会社 | ジンセノサイド組成物 |
| KR102441009B1 (ko) * | 2022-05-31 | 2022-09-06 | (주)아모레퍼시픽 | 인삼으로부터 화합물을 추출하는 방법, 상기 화합물을 포함하는 인삼 추출물 및 이를 포함하는 피부장벽 강화용 조성물 |
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2022
- 2022-05-31 KR KR1020220067018A patent/KR102430512B1/ko active IP Right Grant
- 2022-08-03 KR KR1020220096846A patent/KR20230167280A/ko unknown
- 2022-10-24 CN CN202211304782.9A patent/CN115887475A/zh active Pending
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2023
- 2023-04-13 EP EP23167804.6A patent/EP4299065A1/en active Pending
- 2023-05-31 US US18/326,505 patent/US20230383330A1/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008189609A (ja) * | 2007-02-06 | 2008-08-21 | Shiseido Co Ltd | Ｖｅｇｆｃ産生促進剤 |
| KR20150057664A (ko) * | 2013-11-20 | 2015-05-28 | 경희대학교 산학협력단 | 신종균 크리세오박테리움 ｔｈｇ-ｃ4-1 및 이를 이용한 지페노사이드 17 생산 방법 |
Non-Patent Citations (2)
| Title |
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| "Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation.", vol. 197, no. 6, pages 837 - 849 * |
| TATIANA V, PETROVA;ALEJANDRA, GONZÁLEZ-LOYOLA: "Development and aging of the lymphatic vascular system.", pages 63 - 78 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR102430512B1 (ko) | 2022-08-08 |
| US20230383330A1 (en) | 2023-11-30 |
| KR20230167280A (ko) | 2023-12-08 |
| EP4299065A1 (en) | 2024-01-03 |
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