CN112955116A - 动物细胞的细胞活化剂 - Google Patents
动物细胞的细胞活化剂 Download PDFInfo
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- CN112955116A CN112955116A CN202080005786.XA CN202080005786A CN112955116A CN 112955116 A CN112955116 A CN 112955116A CN 202080005786 A CN202080005786 A CN 202080005786A CN 112955116 A CN112955116 A CN 112955116A
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Abstract
本发明公开了含有3H‑咪唑并[4,5‑d][1,2,3]三嗪‑4,6(5H,7H)‑二酮的动物细胞的细胞活化剂。
Description
技术领域
本发明涉及动物细胞的细胞活化剂。
背景技术
皮肤是由表皮和真皮构成的组织,发挥保护身体免受来自外界的物理和化学压力的屏障功能。表皮和真皮被基底膜分隔,表皮与外界接触。表皮从基底膜一侧开始,由基底层、棘层、颗粒层、角质层四层构成,主要由表皮角化细胞(角质形成细胞,keratinocyte)构成。在基底层分裂的表皮角化细胞经过分化、成熟而迁移到外层,到达最外层的角质层后脱落,反复更新(turnover)。表皮具有最外层的角质层带来的屏障功能以及角质层内侧的颗粒层的紧密连接带来的屏障功能。表皮的更新与皮肤的屏障功能、水分量的保持等有关。因此,当因老化、外部压力造成表皮角化细胞的分化、成熟、迁移、脱落的更新停滞时,会导致皮肤粗糙、皮肤干燥等。
位于表皮内侧的真皮存在有毛细血管、分泌腺(汗腺、皮脂腺)、毛囊、神经,起到为表皮提供营养或者接收来自表皮的信息的作用。真皮分为乳头层和网状层。在占据了真皮大部分的网状层中,胶原纤维形成了密集的网眼,并伴有弹性纤维网。通过胶原纤维和弹性纤维的组合来赋予皮肤强度、易拉伸性、弹力性。在纤维束之间存在产生胶原纤维及弹性纤维的成纤维细胞、巨噬细胞、肥大细胞、浆细胞、真皮树突状细胞等。真皮含有凝胶状基质,其中存在有蛋白聚糖(透明质酸、硫酸软骨素、硫酸皮肤素等)、蛋白质和矿物质。蛋白聚糖具有与水的结合能力。
以往,在皮肤用化妆品及皮肤用药品的领域,进行了许多使皮肤的细胞自身活化从而改善皮肤症状、产生抗炎效果或创伤治疗效果的研究,提供了各种皮肤细胞活化剂(例如,专利文献1~4)。
现有技术文献
专利文献
专利文献1:日本特开2011-148742号公报;
专利文献2:日本特开2013-194008号公报;
专利文献3:国际公开第2015/015816号;
专利文献4:日本特开2016-37470号公报。
发明内容
发明要解决的问题
本发明的目的在于提供一种能够活化动物细胞、特别是活化皮肤细胞的新型细胞活化剂。
用于解决问题的手段
为了解决上述课题,本发明人等进行了专心研究,结果发现:3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮(别名:2-氮杂-8-氧代-次黄嘌呤,以下,有时称为“AOH”)具有活化动物细胞特别是皮肤细胞的作用。
即,本发明如下。
[1]一种动物细胞的细胞活化剂,其含有3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮。
[2]如[1]所述的细胞活化剂,其中,动物细胞是皮肤细胞。
[3]如[2]所述的细胞活化剂,其中,其是从由皮肤新陈代谢促进剂、皮肤创伤治愈促进剂、皮肤抗老化剂、皮肤老化改善剂、皮肤抗皱剂、皮肤屏障功能改善剂、皮肤用保湿剂、皮肤弹性改善剂、皮肤暗沉改善剂、皮肤粗糙改善剂和皮肤用美白剂组成的组中选出的至少一种,优选为皮肤用保湿剂。
[4]如[1]~[3]中任一项所述的细胞活化剂,其为化妆品。
[5]如[1]~[3]中任一项所述的细胞活化剂,其为药品或准药品(quasi drug)。
[6]如[1]~[5]中任一项所述的细胞活化剂,其为外用剂。
[7]如[1]或[2]所述的细胞活化剂,其为试剂。
[8]如[7]所述的细胞活化剂,其为细胞培养用试剂或组织培养用试剂。
[9]一种动物细胞或动物组织的培养方法,包括在培养细胞或培养组织中添加权利要求[8]所述的细胞活化剂的工序。
[10]一种动物细胞的活化方法,包括向对象给药3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮。
[11]如[10]所述的方法,其是皮肤细胞的活化方法。
[12]一种包括向对象给药3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮的皮肤新陈代谢促进方法、皮肤创伤治愈促进方法、皮肤抗老化方法、皮肤老化改善方法、皮肤抗皱方法、皮肤屏障功能改善方法、皮肤保湿方法、皮肤弹性改善方法、皮肤暗沉改善方法、皮肤粗糙改善方法或皮肤美白方法,优选为一种包括向对象给药3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮的皮肤保湿方法。
[13]一种3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮在动物细胞的细胞活化剂的制备中的用途。
[14]如[13]所述的用途,其中,动物细胞是皮肤细胞。
[15]一种3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮在从由皮肤新陈代谢促进剂、皮肤创伤治愈促进剂、皮肤抗老化剂、皮肤老化改善剂、皮肤抗皱剂、皮肤屏障功能改善剂、皮肤用保湿剂、皮肤弹性改善剂、皮肤暗沉改善剂、皮肤粗糙改善剂以及皮肤用美白剂组成的组中选出的至少一种的制备中、优选为在皮肤用保湿剂的制备中的用途。
[16]一种用于动物细胞的活化方法的3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮。
[17]如[16]所述的3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮,动物细胞为皮肤细胞。
[18]一种用于皮肤新陈代谢促进方法、皮肤创伤治愈促进方法、皮肤抗老化方法、皮肤老化改善方法、皮肤抗皱方法、皮肤屏障功能改善方法、皮肤保湿方法、皮肤弹性改善方法、皮肤暗沉改善方法、皮肤粗糙改善方法或皮肤美白方法、优选为皮肤保湿方法的3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮。
发明的效果
根据本发明的细胞活化剂,能够活化动物细胞,特别是皮肤的细胞。
具体实施方式
(AOH)
本发明的动物细胞的细胞增殖促进剂含有AOH,即3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮(别名:2-氮杂-8-氧代-次黄嘌呤)。AOH是下述式(I)所示的化合物。
AOH是已知具有植物生长调节作用的化合物(国际公开第2012/147750号,以下,称为“参考文献1”)。AOH例如能够通过参考文献1记载的方法来制备。具体而言,通过使黄嘌呤氧化酶作用于作为AOH的前体物质的植物激素、7H-咪唑[4,5-d][1,2,3]三嗪-4(3H)-酮(别名:2-氮杂次黄嘌呤,以下,有时称为“AHX”),从而能够得到AOH。另外,通过对植物施用AHX,从植物体分离作为AHX代谢产物产生的AOH,从而也能够得到AOH。
(动物细胞)
作为本发明的细胞活化剂的对象的细胞为动物细胞。优选本发明的细胞活化剂直接应用于活体动物。作为对象的动物,能够举出人及除人以外的哺乳类,但优选为人。作为除人以外的哺乳类,例如,可举出小鼠、大鼠、豚鼠、仓鼠、兔、猫、狗、绵羊、猪、牛、马、山羊、猴。
作为存在有动物细胞的组织或器官,例如,可举出皮肤、肌肉、骨、关节、脂肪、脑、脊髓、消化器官、生殖器官、内分泌器官、呼吸器官、循环系统、免疫系统、骨、关节及脂肪组织等,其中,优选皮肤。本发明的细胞活化剂特别是对皮肤细胞发挥效果。作为皮肤细胞,可举出构成表皮和真皮的细胞,其中,优选为构成表皮的细胞。作为构成表皮的细胞,例如,可举出表皮角化细胞(角质形成细胞)、色素细胞(黑素细胞)、朗格汉斯细胞、麦克尔细胞,其中,优选为表皮角化细胞。构成表皮的细胞优选为存在于表皮的基底层、棘层、颗粒层或角质层的细胞。
作为构成真皮的细胞,例如,可举出成纤维细胞、巨噬细胞、肥大细胞、浆细胞、真皮树突状细胞,其中,优选为成纤维细胞。构成真皮的细胞优选为存在于真皮的乳头层或网状层的细胞。
将本发明的细胞活化剂应用于皮肤时,作为应用的部位,例如,能够应用于包括头皮、脸(额头、脸颊、嘴唇、鼻子、耳朵)、脖子、肩、背、胸部、腹部、性器官、手臂、手、下肢、脚、指甲、毛发的身体的所有体表面。
(细胞活化剂的作用、功能、用途)
本发明的细胞活化剂含有AOH,因而具有细胞活化作用。即,本发明的细胞活化剂的有效成分为AOH。作为本发明的细胞活化剂的细胞活化作用,具体而言,可举出细胞增殖作用和各种基因表达的增强作用。另一方面,本发明的细胞活化剂的细胞毒性低。因此,本发明的细胞活化剂安全性高,也适合应用于生物体。
本发明的细胞活化剂应用于动物皮肤时,作用于构成表皮和/或真皮的细胞,表现出细胞增殖作用和各种基因表达的增强作用。将本发明的细胞活化剂应用于皮肤时,在表达增强的基因群中,包括与细胞间粘附功能、屏障功能、角质层剥离功能、分化功能、保湿功能、美白功能相关的基因。因此,本发明的细胞活化剂能够用于促进皮肤新陈代谢、促进皮肤创伤治愈、防止皮肤老化、改善皮肤老化、防止皮肤皱纹、改善皮肤屏障功能、皮肤保湿、改善皮肤弹性、改善皮肤暗沉、改善皮肤粗糙、皮肤美白等用途。即,本发明的细胞活化剂能够用作从由皮肤新陈代谢促进剂、皮肤创伤治愈促进剂、皮肤抗老化剂、皮肤老化改善剂、皮肤抗皱剂、皮肤屏障功能改善剂、皮肤保湿剂、皮肤弹性改善剂、皮肤暗沉改善剂、皮肤粗糙改善剂以及皮肤用美白剂组成的组中选出的至少一种。
对本发明的细胞活化剂的形状没有特别限定,可以为固体、液体(溶液或悬浮液)、乳液或霜(cream)等乳化状、膏(paste)、凝胶、摩丝(mousse)状等任意形状。本发明的细胞活化剂能够用作化妆品、药品或准药品。
(药品)
对作为药品的细胞活化剂的剂型没有特别限定,例如,可举出气溶胶剂、溶液剂、悬浮剂、乳剂、霜剂、软膏剂、凝胶剂、擦剂、洗剂、巴布剂(cataplasms)、贴剂(tape)、滴眼剂、滴鼻剂、滴耳剂、栓剂、酏剂、胶囊剂、颗粒剂、丸剂、散剂、片剂、糖浆剂、注射剂、锭剂等。在用作皮肤用药品时,优选为外用剂。通过设为外用剂,AOH直接作用于皮肤细胞,从而能够发挥更强的效果。作为外用剂,优选为气溶胶剂、溶液剂、悬浮剂、乳剂、霜剂、软膏剂、凝胶剂、擦剂、洗剂、巴布剂、贴剂等剂型。
(准药品、化妆品)
对作为准药品或化妆品的细胞活化剂的形态没有特别的限定,例如,可举出化妆水、乳液、霜、凝胶、美容液、防晒用化妆品、面膜、护手霜、护脚霜、润肤乳、润肤霜等基础化妆品;洗面奶、卸妆品,皂、沐浴液、洗发剂、漂洗剂(rinse)、护发素(conditioner)、洗甲水等洗涤用化妆品;粉底、妆前霜、唇膏、口红、腮红、眼影、眉笔、指甲油、染发剂等化妆品;止汗剂;洗浴剂;香水;营养功能食品、功能性食品、特定保健用食品、特殊用途食品等食品与饮料等。在用作皮肤用准药品或化妆品时,也与药品一样,优选外用剂。通过设为外用剂,AOH直接作用于皮肤细胞,从而能够发挥更强的效果。作为外用剂的准药品或化妆品优选为上述列举中除食品与饮料以外的形态的准药品和化妆品。
(基剂、载体、添加剂)
在本发明的细胞活化剂中可以包含化妆品、药品或准药品中常用的基剂或载体以及根据需要的各种添加剂。作为添加剂,例如,能够举出赋形剂、油剂类、粉体类、缓冲剂、增溶剂、抗氧化剂、表面活性剂、增稠剂、保存剂、pH调节剂、螯合剂、稳定剂、刺激缓和剂、防腐剂、颜料、着色剂、香料、光亮剂、胶凝剂、醇类、水溶性高分子、成膜剂、树脂、角质软化剂等。根据需要能够组合使用一种或多种基剂、载体以及各种添加剂。
(其他有效成分)
在不损害作为细胞活化剂的效果的范围内,本发明的细胞活化剂能够含有除AOH以外的有效成分。作为除AOH以外的有效成分的具体例,例如,可举出保湿成分、抗炎成分、抗菌成分、细胞活化成分、抗老化成分、血液循环促进成分、防紫外线成分、美白成分、维生素类、蛋白质、肽、氨基酸、醇类等。根据需要,这些有效成分能够组合使用一种或多种。
本发明的细胞活化剂能够通过配合AOH和根据需要的上述其他成分,用本领域技术人员熟知的方法来制备。另外,本领域技术人员能够根据细胞活化剂的给药对象、剂型、用途、目标效果等适当设定本发明的细胞活化剂中所含的AOH的浓度和含量。例如,在本发明的细胞活化剂中可以含有0.0001~5质量%的AOH,优选含有0.001~1质量%的AOH,更优选含有0.01~0.5质量%的AOH。另外,本领域技术人员也能够根据细胞活化剂的给药对象、剂型、用途、目标效果等,适当设定本发明的细胞活化剂的给药次数、给药量、给药方法。但是,在本发明的细胞活化剂的对象为皮肤细胞的情况下,给药方法优选为涂布、贴附于皮肤等的皮肤给药。
如上所述,本发明的细胞活化剂本身可以用作具有细胞活化作用的化妆品、药品或准药品,但也可以以对化妆品、药品或准药品附加本发明的细胞活化剂所具有的功能为目的来添加。即,本发明的细胞活化剂也能够用作化妆品、药品或准药品原料。例如,也可以在直接应用于皮肤的外用剂、例如驱虫剂等中配合本发明的细胞活化剂。
另外,本发明的细胞活化剂也可以是试剂。本发明的细胞活化剂能够有效地活化动物细胞,因此能够用作用于使用动物细胞的实验或研究的试剂。这种实验或研究可以是体外的,也可以是体内的。
作为用于这种实验或研究的试剂,例如,能够举出细胞培养用试剂或组织培养用试剂。作为该细胞培养试剂的对象的细胞,同样地能够举出上述说明的动物细胞。另外,作为该组织培养用试剂的对象的组织或器官,同样地能够举出上述说明的存在有动物细胞的组织或器官。
例如,本发明的细胞活化剂除了如上所述地直接应用于活体动物以外,还能够在体外应用于从动物分离出的细胞或来自动物的培养细胞。这样的细胞也可以是正常细胞、癌细胞、干细胞、杂交瘤等融合细胞。通过本发明的细胞活化剂所具有的细胞增殖作用及基因表达增强作用,能够使这些细胞活化。
本发明还提供包括在培养细胞或培养组织中添加上述细胞活化剂的工序的动物细胞或动物组织的培养方法。培养时,通过在细胞或组织中添加本发明的细胞活化剂,能够通过细胞增殖作用和基因表达增强作用,有效地活化培养细胞或培养组织。作为培养细胞或培养组织,同样地能够举出上述细胞、组织、器官。本领域技术人员能够适当确定培养条件、细胞活化剂的添加时机和添加量等。
实施例
(实施例1.皮肤刺激性试验)
按照作为OECD试验指南(No.439)和欧洲替代方法验证中心(European Centrefor the Validation of Alternative Methods,ECVAM)公开的实验方案的皮肤刺激性试验(SKINETHIC SKIN IRRITATION TEST)、化学品急性皮肤刺激预测的试验方法(TESTMETHOD FOR THE PREDICTION OF ACUTE SKIN IRRITATION OF CHEMICALS)来实施皮肤刺激性试验。该皮肤刺激性试验是使用设计成与人的表皮的生物化学特性、生理学特性极其类似的再生人表皮(RhE)模型(使用来源于人的非转化表皮角化细胞作为细胞源,由组织化的基底层、棘层、颗粒层、角质层构成),将局部涂布受检物质的RhE模型的细胞存活率作为受检物质的皮肤刺激性的指标。通过MTT法测定RhE模型的细胞存活率。在MTT法中,利用作为生物染色色素的MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐,噻唑蓝)通过活细胞的酶促反应还原为蓝色甲臜的性质,通过对蓝色甲臜进行定量测定细胞存活率。如果RhE模型的细胞存活率高于规定值,则能够判断涂布的受检物质为非刺激性。
在增殖培养基中培养SkinEthicTM-RHE24小时,转移到维持培养基中。从表皮侧滴加10μL的灭菌纯化水,使其均匀后,从其上添加16mg的试验试样。
另外,作为阴性(非刺激性)对照,使用PBS(-);作为阳性(刺激性)对照,使用5%SDS水溶液,分别从表皮侧暴露16μL,从上方应用尼龙膜。
将试验样品暴露42分钟后,迅速通过洗涤操作从表皮模型中去除试验样品,在新鲜的增殖培养基中再培养42小时。培养后,将表皮模型转移到含有1.0mg/ml的MTT的维持培养基中,培养3小时。然后,通过将表皮模型在异丙醇中浸渍2小时,提取表皮模型中的蓝色甲臜,用酶标仪(MicroPlate Reader)测定提取液在570nm处的吸光度。对暴露于阴性对照和阳性对照的表皮模型也进行了同样的处理,测定吸光度。
(结果)
细胞存活率用暴露了试验试样的皮肤模型的吸光度相对于暴露了阴性对照的皮肤模型的吸光度的百分率表示。结果表明:将作为阴性对照的经PBS(-)处理后的皮肤模型的细胞存活率设为100%时,作为阳性对照的经5%SDS处理后的皮肤模型的细胞存活率为1.2%,经AOH处理后的皮肤模型的细胞存活率为100%。因此,AOH被判定为非刺激性。
(实施例2.表皮细胞活化作用)
使用HuMedia KG2培养基(KG2)以5.0×103个细胞/孔的密度将正常人表皮角化细胞播种在96孔板中。播种24小时后,更换为含有试验试样的HuMedia KB2培养基(KB2)。作为试验试样,使用AOH和AHX(2-氮杂次黄嘌呤);作为细胞活化作用的阳性对照(P.C.),对KG2进行处理代替试验试样;作为阴性对照,使用未经试样处理的细胞。培养48小时后,更换为含有0.2mg/ml的MTT的KB2,培养1小时。除去培养基后,添加2-丙醇,测定使细胞溶解后的细胞溶解液在550nm和650nm处的吸光度。从550nm处的吸光度中减去源自细胞浊度的650nm处的吸光度,求出MTT被还原为蓝色甲臜的量。以MTT还原量为指标,以经试验试样处理后的细胞的吸光度相对于未经试验试样处理的细胞(阴性对照)的吸光度的百分率即指标(Index)(%)的形式表示表皮角化细胞活化作用。
(结果)
将试验结果示于表1。表1中,经AOH处理的细胞在7.8~31.3μg/ml的浓度条件下表现出指标(Index)的显著增加,暗示了活细胞增殖。另一方面,经AHX处理的细胞不具有经AOH处理的细胞那样的增殖效果,在31.3μg/mL以上的浓度条件下显著减少,指标的减少比例也比经AOH处理的细胞大。这些结果表明,AOH的细胞毒性比AHX低,具有细胞活化作用。
表1
(实施例3.微阵列试验)
根据实施例1和2,观察到AOH与AHX不同,对细胞的毒性低,反而有促进细胞增殖的效果,因此,在实施例3中利用微阵列验证了促进细胞增殖的要因。
使用HuMedia-KG2培养基以1.5×105个细胞/孔的细胞密度将正常人表皮角化细胞播种到6孔板中。培养24小时后,更换为含有0、30、100、300μg/mL浓度的AOH的HuMedia-KB2培养基3mL。更换后培养24小时,将细胞浸渍在QIAzol试剂中,进行溶解。从溶解液中回收用microRNA提取试剂盒(miRNeasy Mini Kit(德国凯杰公司(QIAGEN)))纯化的RNA,使用mRNA表达分析芯片(DNA芯片Genopearl(注册商标)实施DNA微阵列。对得到的结果进行分析,各种基因表达以对照校正值为1的比值表示,采用t检验进行显著性差异检验(显著性水平5%)。
(结果)
在微阵列的分析结果中,将表示基因表达变化的代表性结果示于表2。表2中,如果值大于1,则基因表达提高,如果p值小于0.05,则能够判定相对于对照有显著性变化(表中用*表示))。通过AOH处理,一些基因表达发生了浓度依赖性的变化。表明了与细胞间粘附、屏障功能相关的封闭蛋白1(CLDN1)、桥粒芯胶粘蛋白1(DSC1)、桥粒芯糖蛋白1(DSG1)和E钙粘蛋白(CDH1)的基因表达显著提高。
另外,表明了与角质层剥离有关的蛋白酶激肽释放酶5(KLK5)和激肽释放酶7(KLK7)以及作为其控制剂的丝氨酸蛋白酶抑制剂(SPIMK5)的基因表达显著提高。
另外,作为一般分化指标的角蛋白1(KRT1)、角蛋白10(KRT10)、转谷氨酰胺酶1(TGM1)、内披蛋白(IVL)和角质化包膜(角质细胞膜)构成蛋白SPRR1B的基因表达显著提高。
另外,确认了透明质酸合成酶(HAS3)的基因表达显著提高。
在细胞外基质相关的基因群中,观察到纤维连接蛋白(FN1)基因表达有轻微提高。
根据这些结果,暗示了对细胞的AOH处理有可能促进表皮更新、促进分化成熟、促进旧角质新陈代谢、提高保湿作用等广泛作用于表皮功能。
作为引起黑色素产生的基因群的前列腺素E合成酶(PTGES)、环氧合酶(PTGS2)的基因表达显著减少,另一方面,内皮素1(EDN1)基因表现出显著提高。由此暗示了对美白作用也可能有效果。
(实施例4.化妆水的制备)
按照表3的组成如下地制备化妆水。
表3
将表3的A成分的原料混合后溶解。将B成分的原料混合,加热使其分散,添加到C成分中。将添加有B成分的C成分和A成分混合,制备化妆水。
将该化妆水应用于脸部和头皮后,没有刺激感,皮肤湿润。
(实施例5.长期连续使用试验)
使用实施例4的含有0.1重量%的AOH的化妆水(化妆水B)、以及除了不含有AOH以外与实施例4的化妆水相同组成的安慰剂(placebo)化妆水(化妆水A)进行长期连续使用试验(双盲试验),进行角质水分量和经表皮水分蒸发量(TEWL)的评价。要求22名受试者(女性,平均年龄48.4±4.68岁)在早晚两次洗脸后,在半张脸上涂化妆水A,在半张脸上涂化妆水B,连续进行8周。在试验开始时、4周后及8周后测定角质水分量和TEWL。受试者的左右脸颊部的角质层水分量和TEWL分别使用SKICON-200EX(弥生株式会社(Yayoi Co.,Ltd.))和旋风水分蒸发器AS-CT1(日本阿什株式会社(ASCH JAPAN Co.,Ltd.))测定。除试验开始时的角质水分量的左右差异为150μS以上的2名受试者以外,将20名作为有效受试者进行试验结果的分析。
将开始使用前的角质水分量和TEWL设为100,将4周后和8周后的相对值的平均值示于表4。
表4
安慰剂化妆水 | 含AOH化妆水 | |
4周后的角质水分量 | 138.8 | 154.9 |
8周后的角质水分量 | 114.4 | 134.3 |
4周后的TEWL | 121.5 | 110.8 |
8周后的TEWL | 93.2 | 85.6 |
根据配对t检验进行统计分析,其结果是,与使用开始前的角质水分量相比,含AOH化妆水的涂布组在4周后的角质水分量显著增加(p<0.05),与使用开始前的TEWL相比,含AOH化妆水的涂布组在8周后的TEWL显著减少(p<0.05)。根据这些结果,确认了AOH具有皮肤保湿的效果。
(实施例6.安全性试验)
对AOH进行了以下的安全性试验,均未发现毒性。
致突变性试验(mutagenicity test)(Ames试验)(OECD TG471)
体外皮肤致敏试验(DPRA法)(OECD TG442C)
体外光毒性试验(OECD TG432)
人斑贴试验。
Claims (10)
1.一种动物细胞的细胞活化剂,其中,含有3H-咪唑并[4,5-d][1,2,3]三嗪-4,6(5H,7H)-二酮。
2.如权利要求1所述的细胞活化剂,其中,动物细胞是皮肤的细胞。
3.如权利要求2所述的细胞活化剂,其中,其是从由皮肤新陈代谢促进剂、皮肤创伤治愈促进剂、皮肤抗老化剂、皮肤老化改善剂、皮肤抗皱剂、皮肤屏障功能改善剂、皮肤用保湿剂、皮肤弹性改善剂、皮肤暗沉改善剂、皮肤粗糙改善剂以及皮肤用美白剂组成的组中选出的至少一种。
4.如权利要求2所述的细胞活化剂,其中,其是皮肤用保湿剂。
5.如权利要求1~4中任一项所述的细胞活化剂,其中,其是化妆品。
6.如权利要求1~4中任一项所述的细胞活化剂,其中,其是药品或准药品。
7.如权利要求1~6中任一项所述的细胞活化剂,其中,其是外用剂。
8.如权利要求1或2所述的细胞活化剂,其中,其是试剂。
9.如权利要求8所述的细胞活化剂,其中,其是细胞培养用试剂或组织培养用试剂。
10.一种动物细胞或动物组织的培养方法,其中,包括在培养细胞或培养组织中添加权利要求9所述的细胞活化剂的工序。
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- 2020-06-02 WO PCT/JP2020/021787 patent/WO2020246468A1/ja unknown
- 2020-06-02 KR KR1020217038943A patent/KR20220003051A/ko not_active Application Discontinuation
- 2020-06-02 US US17/615,122 patent/US20220233547A1/en active Pending
- 2020-06-02 EP EP20818974.6A patent/EP3960244A4/en active Pending
- 2020-06-02 CN CN202080005786.XA patent/CN112955116B/zh active Active
- 2020-06-02 JP JP2021524859A patent/JP7341438B2/ja active Active
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CN112955116B (zh) | 2023-10-27 |
EP3960244A4 (en) | 2023-01-25 |
KR20220003051A (ko) | 2022-01-07 |
JP7341438B2 (ja) | 2023-09-11 |
US20220233547A1 (en) | 2022-07-28 |
WO2020246468A1 (ja) | 2020-12-10 |
JPWO2020246468A1 (zh) | 2020-12-10 |
EP3960244A1 (en) | 2022-03-02 |
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