CN112867479A - 盐皮质激素受体活性阻碍用组合物 - Google Patents
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Abstract
提供一种作为有效成分含有由特定化学式表示的化合物的盐皮质激素受体活性阻碍用组合物。
Description
技术领域
本记载涉及一种盐皮质激素受体活性阻碍用组合物。
背景技术
自古以来压力就被称为是万病之根源,尤其,在现代社会中,由于学业、工作、结婚、育儿等的社会原因、天气、交通等的周围环境原因等多种原因而无论男女老少全部过度承受着压力,因此被认为是非常重要的社会问题。
随着我们社会的急速发展和多变化,需要现代人所起的作用越来越多,由此,因多种压力而诉苦广泛性焦虑症以及精神疾病的人在增加。据保健福祉部发表的“2006年度精神疾病实情流行病学调查”指出,在2006年一年间有过患有一种以上的精神疾病经验的人口比率(“精神疾病一年有病率”)显示17.1%。其相当于18岁以上64岁以下的成人6名中就有1名,到2006年目前为止有过终身患有一种以上的精神疾病经验的人口比率(“精神疾病终身有病率”)为成人3名中就有1名而显示30%。最近因过度的治学热情或者各种压力而青少年精神疾病在增加,如果考虑到这种趋势,则整体人口的有病率可能会变得更高。
目前临床上并行药物治疗和长期性的精神治疗来治疗焦虑症,作为药物治疗,主要使用诸如地西泮(diazepam)、劳拉西泮(lorazepam)、氯硝西泮(clonazepam)、阿普唑仑片(alprazolam)之类的苯二氮(benzodiazepine)类的抗焦虑药物,阿扎哌隆(azapirone)类的丁螺环酮(buspirone)选择性地与血清素(serotonin)受体作用,从而作为可以选择性地缓和焦虑症候群的药物来使用。另外,最近活跃进行着对来自天然物质的压力调节物质的研究,所述天然物质能够完善所述药物的副作用。
本发明人不断研究来自能够预防或者治疗精神压力相关疾病的天然物质的物质,确认到在精神压力状态下表皮内浓度增加的皮质醇与盐皮质激素受体亲和性地结合,从而降低皮肤屏障功能。另外,又确认到所述皮肤屏障功能降低现象与不缘于精神压力的其他原因(例如,物理伤害或者老化等)引起的现象,其作用机制完全不同。进一步地,确认到从松叶提取的特定化合物妨碍表皮内浓度增加的皮质醇与盐皮质激素受体的亲和性地结合程度,由此完成了本发明。
进一步地,目前为止尚未公开有通过阻碍因表皮内浓度增加的皮质醇的结合而被激活的盐皮质激素受体的活性,从而能够预防或者治疗皮肤屏障功能降低的物质,其中,所述表皮内浓度增加的皮质醇并不是因物理伤害或者老化等引起的而是因精神压力引起的。
发明内容
技术问题
根据一实现例,想要提供一种(化妆料)组合物,其通过阻碍因皮质醇的结合而被激活的盐皮质激素受体的活性,从而能够缩短角质层的屏障功能恢复时间,其中,所述皮质醇成为因精神压力引起的皮肤屏障功能下降的原因。
技术方案
根据一实现例,提供一种盐皮质激素受体活性阻碍用组合物,其作为有效成分含有由以下化学式1表示的化合物:
【化学式1】
在所述化学式1中,
R1至R4各自独立为氢原子或者取代或未被取代的C1至C20烷基。
可以是所述R1以及R2各自独立为未被取代的C1至C20烷基,所述R3为取代的C1至C20烷基,所述R4为氢原子。
由所述化学式1表示的化合物可以为松叶提取物。
由所述化学式1表示的化合物可以阻碍皮质醇对盐皮质激素受体的结合。
由所述化学式1表示的化合物可以含有0.01μg/ml至1000μg/ml的浓度范围。
所述组合物可以为化妆料组合物。
发明效果
根据一实现例,通过阻碍因皮质醇的结合而被激活的盐皮质激素受体的活性,从而能够缩短角质层的屏障功能恢复时间,其中,所述皮质醇成为因精神压力引起的皮肤屏障功能下降的原因。即,能够特别预防以及治疗多种皮肤屏障功能下降的原因中精神压力引起的皮肤屏障功能下降现象。
附图说明
图1是示出糖皮质激素受体以及盐皮质激素受体的遗传基因表达水平的照片。
图2是通过荧光素酶启动子实验(Luciferase promoter assay)示出盐皮质激素受体的活性程度的图表。
具体实施方式
以下,详细说明本发明的实现例以供本发明所属技术领域中具有通常知识的人容易实施。然而,本发明可以实现为多种不同的形态,不限于在此说明的实现例。
在本说明书中,皮肤屏障功能改善是指,阻碍因精神压力引起表皮内浓度增加的皮质醇与盐皮质激素受体的亲和性地结合,从而降低所述盐皮质激素受体的活性程度,这与因物理外伤或者老化等导致的抑制氧化应激或者维持皮肤稳态等无关。这是因为因物理外伤或者老化等导致的抑制氧化应激或者维持皮肤稳态等并不是精神压力引起的,因此其机制完全不同。
另外,在本说明书中,精神压力作为与医药学领域上所指的精神病不同的含义,所述精神病是指对心理压力无法完全适应而扭曲的不适应状态,然而本说明书中的精神压力是指,虽然在适应心理压力,然而与当事人的意志无关而表皮内浓度增加的皮质醇与盐皮质激素受体亲和性地结合,从而所述盐皮质激素受体被激活的状态。
在本说明书中,没有特别提及的情况下,“取代”是指至少一个氢原子被卤原子(F、Cl、Br、I)、羟基、C1至C20烷氧基、硝基、氰基、胺基、亚氨基、叠氮基、脒基、肼基、亚肼基、羰基、氨基甲酰基、硫醇基、酯基、醚基、羧基或其盐、磺酸基或其盐、磷酸或其盐、C1至C20烷基、C2至C20烯基、C2至C20炔基、C6至C20芳基、C3至C20环烷基、C3至C20环烯基、C3至C20环炔基、C2至C20杂环烷基、C2至C20杂环烯基、C2至C20杂环炔基、C3至C20杂芳基或者其组合的取代基取代。
在本说明书中,提及到层、膜、区域、板等部分位于其他部分“上方”时,其不仅包括“直接”位于其他部分“上方”的情况,还包括在其中间存在又一其他部分的情况。与此相反地,提及到某一部分“直接”位于其他部分“上方”时,是指在中间不存在其他部分。
在本说明书中,没有另外有定义时,“组合”是指混合或者共聚合。另外,“共聚合”是指嵌段共聚合乃至无规共聚合,“共聚物”是指嵌段共聚物乃至无规共聚物。
以下,说明根据一实现例的盐皮质激素受体活性阻碍用组合物。
根据一实现例的盐皮质激素受体活性阻碍用组合物,作为有效成分含有由以下化学式1表示的化合物:
【化学式1】
在所述化学式1中,
R1至R4各自独立为氢原子或者取代或未被取代的C1至C20烷基。
例如,在所述化学式1中,可以是R1以及R2各自独立为未被取代的C1至C20烷基,R3为取代的C1至C20烷基,R4为氢原子。
由所述化学式1表示的化合物阻碍在精神压力状态下表皮内浓度增加的皮质醇与盐皮质激素受体的结合,从而具有防止所述盐皮质激素受体被激活的效果,因此,根据一实现例的组合物也能在精神压力状态下防止皮肤屏障功能降低或者快速改善因精神压力而弱化的皮肤屏障功能。
具体为,受到精神压力,则伤口治愈变缓慢,皮肤屏障功能降低,导致角质层的牢固性降低或者损伤后屏障功能恢复变缓慢,具体为,在精神压力状态下,下丘脑-垂体-肾上腺轴(hypothalamus pituitary adrenal axi)被激活而增加糖皮质激素(glucocorticoids;GC)的分泌以及增加末梢组织内可的松(cortisone)还原酶(11β-羟化类固醇脱氢酶1;11β-hydroxysteroid dehydrog enase 1)的活性,由此导致末梢组织内皮质醇(被激活的GC形态)浓度的增加。另外,所述皮质醇以类似的亲和力与作为末梢组织内受体的糖皮质激素受体(glucocorticoid receptor;GR)和盐皮质激素受体(mineralocorticoid receptor;MR)进行结合,由此通过应激诱发多种现象,所述多种现象中具有代表性的就是皮肤屏障功能的降低。根据一实现例的组合物能够妨碍表皮内浓度增加的皮质醇与盐皮质激素受体的结合,阻碍所述盐皮质激素受体被激活,从而防止皮肤屏障功能下降。
例如,由所述化学式1表示的化合物可以为松叶提取物。由所述化学式1表示的化合物也可以为其他物质的提取物而不是松叶的提取物,然而不是来自松叶而是来自其他物质的由所述化学式1表示的化合物难以作为化妆料组合物使用,进一步地,不能起到阻碍与精神压力有关的、表皮内浓度增加的皮质醇与盐皮质激素受体的结合的作用。即,由所述化学式1表示的化合物为来自松叶的提取物时,可以最有效地阻碍盐皮质激素受体被激活。另外,由所述化学式1表示的化合物为从其他物质而不是松叶中提取时,与由所述化学式1表示的化合物为从松叶提取的情况进行比较,其作用机制完全不同。
即,为了在精神压力状态下加强皮肤屏障,需要降低表皮内皮质醇浓度,或者阻碍表皮内浓度增加的皮质醇与盐皮质激素受体的亲和性地结合,由所述化学式1表示的化合物能够通过阻碍皮质醇对盐皮质激素受体的结合,从而防止精神压力状态下皮肤屏障功能的降低。
由此,一实现例提供一种作为有效成分含有从所述松叶提取的由所述化学式1表示的化合物的盐皮质激素受体活性阻碍用组合物,所述组合物可以单独含有药学上有效的量的所述香豆雌酚或者含有一个以上的药学上可接受的载体、赋形剂或者稀释剂。
所述松叶是指属于红松、油松、马尾松、海松等的松树科的松叶,从属于其他松树科的松叶中提取的提取物也可以包含在本发明的范围中。所述松叶提取物可以包括干燥所述松叶之后,添加水或者低级醇进行提取的松叶的粗提物。另外,也可以包括在松叶的乙醇提取物中使用己烷、氯仿等的有机溶剂和水,依次级分提取的级分物。
所述组合物内由所述化学式1表示的化合物可以含有0.01μg/ml至1000μg/ml的浓度范围,例如0.01μg/ml至100μg/ml的浓度范围。由所述化学式1表示的化合物使用不足0.01μg/ml的浓度时,阻碍皮质醇对盐皮质激素受体的结合力的效果微弱,可能不具有皮肤屏障功能改善效果,由所述化学式1表示的化合物使用超过1000μg/ml的浓度时,显示细胞毒性而有可能对人体产生有害影响,因此不优选。
以上“药学上有效的量”是指向动物或者人给予所述生理活性成分而显示想要的生理学或者药力学活性的充分的量。然而,所述药学上有效的量可以根据症状的程度、患者的年龄、体重、健康状态、性别、给药路径以及治疗时间等而适当变化。
另外,以上“药学上可接受”是指生理学上允许且向人类给药时,一般不引起诸如胃肠障碍、晕眩感的过敏反应或者与其类似的反应。作为所述载体、赋形剂以及稀释剂的示例,可以举出乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、聚乙烯吡咯烷酮、水、甲基羟苯酸酯、丙基羟苯酸酯、滑石、硬脂酸镁以及矿物油。另外,还可以含有填充剂、抗凝剂、润滑剂、润湿剂、香料、乳化剂以及防腐剂等。
例如,所述组合物可以为化妆料组合物。
在本说明书中,“化妆料”可以是指,不仅具有美容功能,还可以具有除美容功能之外进一步具有医学功能的所有物质。
所述化妆料组合物的剂型不受特别限制,根据目的可以适当选择。
例如,所述化妆料组合物可以剂型化为溶液、悬浮液、乳浊液、糊剂、凝胶、霜、乳液、粉、皂剂、含表面活性剂的清洁剂、油、粉状粉底、乳状粉底、蜡状粉底以及喷雾等,然而不限于此。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、焗油剂、润发乳、洗发水、乳液、养发剂或者染发剂等的化妆料组合物;水包油(O/W)型、油包水(O/W)型等的基础化妆料。另外,所述组合物在各个剂型中,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并进行调配。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。其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、在水相分散油相得到的乳剂、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态,或者霜、化妆水、乳液、粉、软膏、喷雾或者遮瑕棒形态。所述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,可以使用诸如水、乙醇或者丙二醇的液态稀释剂;诸如乙氧基化异硬脂醇、聚氧乙烯山梨醇酯以及聚氧乙烯山梨糖醇酐酯的悬浮剂;微晶纤维素;偏氢氧化铝;膨润土、琼脂或者黄蓍胶等。
当本发明的剂型为糊剂、霜剂或者凝胶剂时,作为载体成分,可以使用动物性油、植物性油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、氧化硅、滑石或者氧化锌等。
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,尤其为喷雾剂时,还可以含有诸如氯氟烃、丙烷/丁烷或二甲醚的推进剂。
在本发明的一实施形态中,所述化妆料组合物还可以含有增粘剂。本发明的化妆料组合物中包含的增粘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、羟基乙纤维素、羧乙烯聚合物、聚季铵盐、鲸蜡硬脂醇、硬脂酸、卡拉胶等,可以优选使用羧甲基纤维素、羧乙烯聚合物、聚季铵盐中的一种以上,可以最优选为羧乙烯聚合物。
在本发明的一实施形态中,所述化妆料组合物根据需要,可以适当含有各种基质和添加剂,这些成分的种类和量可由发明人容易选定。可以根据需要含有可接受的添加剂,例如,还可以含有本领域常规的防腐剂、色素、添加剂等的成分。
作为防腐剂,具体可以为苯氧乙醇(Phenoxyethanol)或者1,2-己二醇(1,2-Hexanediol)等,香料可以为人工香料等。
此外,在本文发明的一实施形态中,化妆料组合物可以含有水溶性维生素、油溶性维生素、高分子肽、高分子多醣、神经鞘脂类以及海藻汁而成的组中的组合物。作为除此之外可以添加的调配成分,可以举出油脂成分、保湿剂、润滑剂(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,所述任意成分也可以在不破坏本发明的目的以及效果的范围内进行调配。
进一步地,根据一实现例的化妆料组合物,如上所述,不仅可以作为药学组合物使用,还可以作为保健食品使用。例如,可以容易作为食品的主原料、副原料、食品添加剂、功能性食品或者饮料使用。
所述“食品”是指含有一种或者其以上的营养素的天然物质或者加工品,优选为,是指经过某种程度的加工工序,成为可以直接食用的状态,作为通常的含义,是指包含食品、食品添加剂、功能性食品以及饮料全部。
作为可以添加所述食品用组合物的食品,例如具有各种食品类、饮料、口香糖、茶、维生素复合物、功能性食品。进一步地,包括特殊营养食品(例如,配方奶粉、婴、幼儿食品等)、肉制品、鱼肉制品、豆腐类、凉粉类、面类(例如,拉面类、面条类等)、面包类、健康辅助食品、调味食品(例如,酱油、大酱、辣椒酱、混合酱等)、酱汁类、饼干类(例如,快餐类)、糖果类、巧克力类、口香糖类、雪糕类、乳制品(例如,发酵乳、奶酪等)、其他加工食品、辣白菜、腌制食品(各种泡菜类、酱菜类)、饮料(例如,水果饮料、蔬菜饮料、豆乳类、发酵饮料类等)、天然调味料(例如,拉面调料包等),然而不限于此。所述食品、饮料或者食品添加剂可以通过常规的制备方法制备。
另外,所述“功能性食品”或者“保健食品”是指在食品利用物理学、生物化学、生物工学上的方法等赋予附加价值以使该食品的功能在特定目的中起作用、表现的食品群,或者设计为使食品组分所具有的与调节生物防御节律、防止疾病和疾病恢复等有关的体内调节功能对生物充分进行表达,并进行加工的食品,具体可以为保健食品。所述功能性食品可以包括食品学上可接受的食品辅助添加剂,可以进一步包括功能性食品的制备中通常使用的合适的载体、赋形剂以及稀释剂。
所述保健食品的种类不限于此,可以为粉末、颗粒、锭剂、胶囊或者饮料形态。
用于实施发明的形态
针对本文发明的优点、特征以及达成其的方法,参考详细后述的实施例会变明确。以下,通过实施例详细说明本文发明。然而,所述实施例是用于具体说明本发明,本发明的范围不由所述实施例进行限定。
(实施例)
试验例1:盐皮质激素受体的遗传基因表达的确认
从CV-1细胞分离RNA,利用逆转录酶(reverse transcriptase)进行PC R(聚合酶链反应),确认作为皮质醇受体的糖皮质激素受体(GR)和盐皮质激素受体(MR)的遗传基因表达,将该结果显示在图1中。参考图1,可以确认到,在CV-1细胞(cell)中仅是盐皮质激素受体(MR)的遗传基因发生表达,由此可以确认到,CV-1细胞为适合确认盐皮质激素受体活性阻碍效果的细胞。
试验例2:盐皮质激素受体活性阻碍效果
在24-well(孔)平板培养器中培养CV-1细胞。24小时之后,将培养基替换成10%的活性炭/葡聚糖处理胎牛血清-DMEM(charcoal dextran-treated FBS-DMEM),4小时之后,利用转染试剂盒(TransFast reagent(Promega)),转染(transfection)MMTV-荧光素酶报告基因质粒(MMTV-luciferase report er plasmid)和作为内部对照组的pRL-SV-40质粒(plasmid)的混合DNA。24小时之后,处理10μg/ml的由以下化学式1-1表示的化合物(Ramidus A B),2小时之后,处理地塞米松(dexamethasone;1nM)之后,培养24小时。利用双荧光素酶报告基因检测系统(Dual-Luciferase Reporter Assay System(Promega))测定细胞溶解产物(Cell lysate)内荧光素酶(luciferase)活性,通过校正海肾荧光素酶(renilla luciferase)活性,使转染(transfection)有效性标准化(normalize),从而测定相对的荧光素酶(luciferase)活性之后,将该结果显示在以下图2中。参考图2,可以确认到,由以下化学式1-1表示的化合物阻碍基于地塞米松(dexamethasone)的盐皮质激素受体的活性。
【化学式1-1】
以上详细说明了本发明的优选实施例,然而本发明的权利范围不限于此,利用权利要求书中所定义的本发明的基本概念的本领域技术人员的各种变形以及改良形态也属于本发明的权利范围。
Claims (6)
2.根据权利要求1所述的组合物,其中,
所述R1以及R2各自独立为未被取代的C1至C20烷基,
所述R3为取代的C1至C20烷基,
所述R4为氢原子。
3.根据权利要求1所述的组合物,其中,由所述化学式1表示的化合物为松叶提取物。
4.根据权利要求1所述的组合物,其中,由所述化学式1表示的化合物阻碍皮质醇对盐皮质激素受体的结合。
5.根据权利要求1所述的组合物,其中,由所述化学式1表示的化合物含有0.01μg/ml至1000μg/ml的浓度范围。
6.根据权利要求1所述的组合物,其中,所述组合物为化妆料组合物。
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- 2018-10-15 KR KR1020180122680A patent/KR102673271B1/ko active IP Right Grant
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2019
- 2019-10-15 CN CN201980068134.8A patent/CN112867479A/zh active Pending
- 2019-10-15 US US17/285,750 patent/US20220000816A1/en active Pending
- 2019-10-15 WO PCT/KR2019/013509 patent/WO2020080795A1/ko active Application Filing
Patent Citations (3)
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KR20060104161A (ko) * | 2005-03-29 | 2006-10-09 | 주식회사 한생화장품 | 항균 및 항진균 활성을 갖는 솔방울 추출물, 및 이를유효성분으로 하는 피부질환 개선용 화장료 조성물 |
US20140363530A1 (en) * | 2012-05-31 | 2014-12-11 | Gueulri | Composition comprising the extract of pine tree leaf or the compounds isolated therefrom for the prevention and treatment of cancer disease by inhibiting hpv virus and the uses thereby |
KR20150057390A (ko) * | 2013-11-19 | 2015-05-28 | (주)아모레퍼시픽 | 탈수소 아비에틱산과 트랜스 쿠미닉산의 혼합물을 함유하는 항노화용 조성물 |
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US20220000816A1 (en) | 2022-01-06 |
WO2020080795A1 (ko) | 2020-04-23 |
KR20200042283A (ko) | 2020-04-23 |
KR102673271B1 (ko) | 2024-06-07 |
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