CN107567329B - 皮壳正青霉的发酵提取物和其美容用途 - Google Patents
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Abstract
来自皮壳正青霉物种细菌菌株的用于皮肤、粘膜、毛发和/或指甲的美容处理和/或护理的发酵提取物;及其美容用途。
Description
发明领域
公开的技术涉及来自皮壳正青霉(Eupenicillium crustaceum)物种的菌株的发酵提取物,其用于皮肤、粘膜、毛发和/或指甲的美容处理和/或护理。特别地,所述发酵提取物在减轻或预防皮肤老化的迹象以及在皮肤颜色淡化或皮肤去色素或美白上是有活性的。
背景技术
皮肤老化是由时间和环境因素(主要是紫外线辐射)引起的复杂过程。皮肤老化的迹象或症状包括皮肤弹性和紧致度(firmness)的丧失,出现如皱纹和犁沟等特征、暗黑眼圈、眼睛浮肿、眼袋、日光斑(老年斑)和斑驳皮肤。皮肤老化的第一个迹象通常表现在人的脸上,特别是眼睛周围的区域。这些包括暗黑眼圈(眶周色素沉着过度),浮肿眼睛(眶周浮肿),眼袋(眶下睑袋) 和皱纹(例如眶周皱纹)的存在。在人的皮肤、特别是他们的脸上存在老化迹象在美学上是不希望有的。希望有看起来更年轻的皮肤,即老化迹象减轻的皮肤。
皮肤、粘膜、毛发和/或指甲在生物体和其环境之间提供物理障碍。皮肤由两个主要层,表皮和真皮组成。真皮是最厚层(厚度约为皮肤厚度的90%),且含有胶原蛋白,弹性蛋白,几种分化结构如血管,以及许多细胞类型如成纤维细胞(其合成胶原蛋白和弹性蛋白)。表皮包含角质形成细胞,黑素细胞和朗格汉斯细胞,主要细胞群由角质形成细胞组成。
胶原蛋白是皮肤结缔组织中最丰富的蛋白质,且在皮肤中起着重要的结构作用。它在皮肤结缔组织中形成网状结构,有助于在新细胞生长时支持新细胞同时提供所需的柔韧性。皮肤中存在连续的胶原蛋白合成和降解,且两者之间的平衡决定了皮肤的拉伸强度和弹性。弹性蛋白是结缔组织中的蛋白质,具有弹性。弹性蛋白有助于保持皮肤柔韧且紧致,如果拉扯皮肤,则弹性蛋白会提供反弹反应。老化过程伴随着皮肤中胶原纤维和弹性纤维的变性和裂解。皮肤中弹性纤维逐渐消失导致皮肤弹性进行性丧失。胶原纤维的变性和裂解导致皮肤失去抵抗力(紧致度)。真皮中连接纤维裂解的进一步的后果是整体上真皮厚度的逐渐降低,特别是通过胶原纤维减少所致的真皮厚度的逐渐降低。 [Bonta M,DainaL,G.老化过程反映在皮肤组织学变化中(The process of ageing reflected byhistological changes in the skin),Rom J Morphol Embryol.2013;54(3Suppl):797-804]
皮肤老化的另一个因素是高级糖化终产物(AGE)的出现。AGE从称为涉及糖和蛋白质的糖化反应获得。这些产物在皮肤中的存在改变了物理、生物力学(皮肤变硬和失去弹性)和生物学特性(被细胞调节的基质的合成、降解)。 AGE可以调节细胞外基质(ECM)的蛋白质作为胶原蛋白的表达,并且它们还可以修饰负责其降解的酶(弹性蛋白酶和金属蛋白酶)的表达和合成[Pageon H.,糖化反应和人皮肤:对皮肤及其组分的影响,以重建的皮肤为模型(Reaction of glycation and human skin:the effects on the skin and itscomponents, reconstructed skin as a model),Pathol Biol(巴黎),2010年6月;58(3):226-31]。结果是皮肤的弹性和厚度降低。在皮肤中,I型胶原的糖化与皮肤迟钝的发展和皮肤弹性的降低有关。
由于皮肤弹性、紧致度和厚度的降低,皮肤能出现皱纹,例如出现在眼睛周围的皱纹。需要提供可以帮助防止皮肤中胶原蛋白降解和/或刺激皮肤中胶原蛋白生成的活性剂。需要提供一种可以帮助防止皮肤中弹性蛋白降解和/或刺激皮肤中弹性蛋白生成的活性剂。需要提供可以抑制皮肤中AGE形成的活性剂。这类活性剂可用于处理皮肤以预防或缓解老化迹象。
老化过程也影响皮肤的脉管系统。血管变化包括毛细血管壁变薄和微循环减慢。血管壁的改变引起血管通透性的变化,并且可导致纤维间(interfibrillar) 水肿的出现[Bonta M,Daina L,Mutiu G.,通过皮肤中组织学变化反映的老化过程(The process ofageing reflected by histological changes in the skin), Rom J MorpholEmbryol.2013;54(3Suppl):797-804]。因此,老化的一个迹象是眼睛周围和下面的间质液的积累,例如,浮肿的眼睛和眼袋(也称为眼下袋)。这些在美学上是不美观的,并且希望减少皮肤浮肿/眼袋体积。需要能够降低与浮肿的眼睛和眼袋中形成的水肿有关的血管通透性的活性剂。
随着皮肤老化,它变薄。例如,Bonta等人注意到降低的血管功效,特别是在浅表真皮中,通过适应脉管系统的功效,在表皮中产生一系列主要作用,即通过减少细胞层的数量,即,通过减小厚度[Bonta M,Daina L,G.,老化过程反映在皮肤组织学变化中(The process of ageing reflected by histological changes in the skin),Rom JMorphol Embryol.2013;54(3 Suppl):797-804]。这种薄度可以导致潜在的血管和发色团(如胆红素和黑色素) 变得更加可察觉到。这是暗黑眼圈的一个原因,这是一个非常常见的美容问题,影响了大多数人[Ranu H,Thng S,Goh BK,Burger A,Goh CL.,亚洲人眶周色素沉着过度:流行病学研究和提出的分类(Periorbital hyperpigmentation in Asians:anepidemiologic study and a proposed classification),Dermatol Surg.,2011年9月;37(9):1297-303]。认为这个问题进一步加剧,血管随着衰老而泄漏,结果是血液的分解产物胆红素积聚在眼睛周围。具体来说,胆红素是血红素代谢的分解产物。血红素是血红蛋白、肌红蛋白和几种酶中发现的含铁卟啉,所述的几种酶中肝细胞色素是最重要的代表。大约80%的日常胆红素产生来自衰老的红血细胞。它们破碎,且铁从血红素分子中除去,以及剩余的卟啉环在单个位置处被氧化和切割,以形成胆绿素的四吡咯链结构。胆绿素的进一步减少导致胆红素的形成,造成在眶下眼皮中出现的着色为暗黑眼圈[Stillman AE.,黄疸,临床方法:历史、身体和实验室检查(Jaundice.Clinical Methods:The History,Physical,and Laboratory Examinations),第3版,Boston: Butterworths;1990年,第87章]。暗黑眼圈是一个复杂的面部美容问题,有多种原因,并且这些原因包括黑色素沉积,铁血黄素沉积的静脉淤滞和眼眶结构问题。真皮中的黑色素沉积物可能是先天性的或继发于环境因素,如过度暴露于阳光,内源的或使用外源的雌激素,怀孕和母乳喂养。需要提供可以降解胆红素和/或减少皮肤中黑色素量的活性剂,色素中的这两种色素对眼睛周围暗黑眼圈色素沉着负有责任。
老化的迹象,如皱纹、暗黑眼圈、浮肿眼睛、眼袋可以因疲劳,压力,使用药物和酒精等因素而加剧。
皮肤颜色的修饰,包括皮肤变淡,例如暗黑眼圈的减轻以及老年斑的消除或减轻,是许多人所期望的美容效果。通常该目的是实现均匀的皮肤颜色。使用去色素的化妆品来减少色素过多,通常,去色素剂通过抑制黑色素生物合成途径起作用。
黑色素是复杂的色素,为哺乳动物的皮肤、头发和眼睛提供颜色和防止电离辐射的光保护。黑色素生成是由黑色素合成产生的生理过程,且其特征在于,总体上通过黑素细胞的黑色素生产过程和随后的分布。哺乳动物黑素细胞通过被称为黑素体的复杂细胞器中的不同酶产生两种化学上不同类型的黑色素,黑色至棕色的真黑色素和黄色至红褐色的褐黑素。真黑色素和褐黑素都源自被酪氨酸酶(TYR)形成的共有前体多巴醌。酪氨酸酶也称为多酚氧化酶,且是含铜多功能酶。它是黑色素形成级联第一阶段的关键酶,催化L-酪氨酸转化为 L-多巴醌(Ito S.,Wakamatsu K.和Ozeki,H.,黑色素的化学分析及其在研究调节黑色素生成中的应用(Chemical analysis of melanins and its application to thestudy of the regulation of melanogenesis),Pigment Cell Res.2000:13Suppl.8.103-9)。除了酪氨酸酶之外,已经显示两种称为酪氨酸酶相关蛋白 (TRP)的相关蛋白调节真黑色素生成。TRP-1(酪氨酸酶相关蛋白-1)或 DHICA(5,6-二羟吲哚-2-羧酸氧化酶)和TRP-2(酪氨酸酶相关蛋白-2),也称为多巴色素互变异构酶(Hearing.V.J.,黑素体:细胞对环境应答的完美模型(The melanosome:the perfect model for cellularresponse to the environment),Pigment Cell Res.2000;13Suppl.8,23-4)。黑色素形成也源于黑素细胞内被酪氨酸酶将酪氨酸氧化为二羟基苯丙氨酸(DOPA)。
黑素体是溶酶体相关的细胞器,其具有产生黑色素的独特能力,并且当它们成熟时进行四个连续形态学步骤(I,II,III和IV期)。I期黑素体是通常在核周区域发现的圆形的、膜结合的和电子透明囊泡。到II期黑素体的过渡涉及囊泡的伸长以及内部不同纤维结构的出现。这些内部基质纤维的产生和从I 期到II期黑素体的成熟取决于称为Pmel17(也称为gp100或SILV)的结构蛋白的存在。Pmel17在递送至I期黑素体后不久,被切割成几个片段,其形成该细胞器的纤维基质。在色素细胞中,黑色素沉积在这些纤维上,导致逐渐着色的内部基质,此时该细胞器被称为III期黑素体。在高度着色的组织中,黑色素合成和沉积继续进行,直到很少或没有内部结构可见,此时它们被称为 IV期黑素体。已经鉴定出几种蛋白质是黑素体特异的蛋白质(Tyr、Trp1、Trp2、 MART-1、Pmel17、GPNMB等)。MART-1是由T细胞蛋白识别的黑素瘤相关抗原(也称为黑色素-A),为黑素体特异性蛋白,没有可检测的酶活性,在早期黑素体(I期和/或II期黑素体)中高度富集,并与Pmel17形成复合物,且影响其表达、稳定性、运输以及黑素体结构和成熟所需的加工,并因此在调节哺乳动物色素沉着中起重要作用(Hoashi T,Watabe H,Muller J, Yamaguchi Y,Vieira WD,Hearing VJ.,MART-1是黑素体基质蛋白 PMEL17/GP100的功能和黑素体成熟所必需的(MART-1isrequired for the function of the melanosomal matrix protein PMEL17/GP100andthe maturation of melanosomes),J Biol Chem.,2005年4月8日;280(14): 14006-16,Epub 2005年1月28日)。GPNMB(糖蛋白(跨膜)非转移性黑素瘤蛋白b)是高度糖基化的I型跨膜蛋白,显示与Pmel17具有高相似性。 GPNMB包含与其在黑素细胞中的功能相关的几个结构域。已经证实,GPNMB 的精氨酸-甘氨酸-天冬氨酸(RGD)基序可以结合至整联蛋白以调节黑素细胞与角质形成细胞的粘附,表明它参与黑色素的转移。作为黑素体的重要结构蛋白,GPNMB已被证明存在于黑素体的所有阶段(1-IV)中,并且特别富集于成熟阶段。黑素细胞中缺失GPNMB使黑素体形成急剧减弱,表明其在黑素体合成中的关键作用(Zhang P,Liu W,Zhu C,Yuan X,Li D,Gu W,Ma H, Xie X,Gao T,通过siRNA沉默GPNMB抑制了黑素细胞中以不依赖MITF 的方式形成黑素体(Silencing of GPNMB by siRNA inhibits theformation of melanosomes in melanocytes in a MITF-independent fashion),PLoSOne. 2012;7(8):e42955)。
黑素体内的黑色素产生后,通过存在于黑素细胞中的树突转移到邻近的角质形成细胞,在那里它将被转运和降解。这种黑色素转移可能通过三种不同的机制发生:角质形成细胞对黑素细胞树突状尾的细胞吞噬过程;将细胞质的黑素体直接迁移到角质形成细胞;释放黑素体到细胞外空间中并将其掺入角质形成细胞。因此,皮肤色素沉着取决于黑色素的数量、化学性质和含量(酪氨酸酶活性)和产生的黑素体的分布,和由每个黑素细胞转移到围绕它的角质形成细胞簇。
由于直接或间接刺激,增加的黑色素生成是皮肤的防御反应,以防止太阳侵袭。紫外线照射后,黑素体重新分布在细胞核周围,以保护细胞的遗传物质,并因此,除了促进皮肤和毛发着色之外,黑色素还促进光保护,作为太阳滤光物发挥作用,衍射或反射太阳辐射。黑素细胞-角质形成细胞复合物通常以旁分泌和/或自分泌的方式迅速响应宽范围的环境刺激。因此,黑素细胞对UV-R、野灰蛋白信号传递蛋白、促黑素细胞激素(MSH)、内皮素、生长因子、细胞因子等产生反应。在UV-R暴露后,黑素细胞增加其表达阿黑皮素原(POMC, MSH的前体)及其受体黑皮质素1受体(MC1-R)、TYR和TYRP1、蛋白激酶C(PKC)和其他信号因子。另一方面,已知紫外线刺激角质形成细胞产生内皮素-1(ET-1)和POMC,并且这些因子然后可以以旁分泌的方式起作用以刺激黑素细胞功能。除了角质形成细胞外,成纤维细胞和皮肤中可能的其他细胞也产生细胞因子、生长因子和炎性介质,它们可以增加黑色素产生和/或刺激黑素细胞转移黑色素到角质形成细胞。黑素细胞生长因子不仅影响黑素细胞的生长和色素形成,还影响其形状、树突、与基质蛋白的粘附和迁移性。
α-MSH,ACTH,碱性成纤维细胞生长因子(bFGF),神经生长因子(NGF),内皮素,粒细胞-巨噬细胞集落刺激因子(GM-CSF),青灰因子,白血病抑制因子(LIF)和肝细胞生长因子(HGF)是角质形成细胞衍生因子,被认为参与调节黑素细胞的增殖和/或分化,一些因子通过受体介导的信号传导途径起作用。已经表明,在人类表皮中,α-MSH和ACTH在角质形成细胞中产生并释放,并且参与调节黑色素生成和/或黑素细胞树突形成。α-MSH和ACTH与黑素细胞特异性受体MC1-R结合,MC1-R通过G蛋白激活腺苷酸环化酶,其然后从三磷酸腺苷升高cAMP。环AMP通过蛋白激酶A(PKA)部分发挥其作用,所述蛋白激酶A磷酸化并激活cAMP应答元件结合蛋白(CREB),所述CREB与小眼相关转录因子(MITF)基因的M启动子中存在的cAMP应答元件(CRE)结合。MITF-M表达的增加诱导TYR、TYRP1和DCT的上调,这导致黑色素合成。
色素形成过度是由黑色素生成过量引起的疾病。因素诸如过度的太阳暴露、老化、激素变化、炎症、过敏等可能引起黑色素生成和分布过程中的不平衡,导致皮肤变污。日光斑(也称为老年痣、光斑、肝斑或老年斑)是周围有界限的色素斑,其通常为浅褐色,但颜色程度与墨黑色(jet black)不同。通常在身体的紫外线暴露区域(脸部,手背,伸肌前臂,上背部和低领部)发现日光斑。它们无论在哪里其尺寸范围可以从1毫米到几厘米直径,并且在严重受到太阳损伤的皮肤区域可能会合并成甚至更大的损伤。希望提供可以减轻色素沉着过度皮肤例如日光斑(老年斑)的颜色的美容活性物质。
目前提出的出现日光斑的分子机制涉及由ET-1/ETBR(由ET-1与其受体 ETBR结合启动)和SCF/c-kit(由干细胞因子与其受体c-Kit的结合启动)组成的两个表皮级联的刺激,以及紫外线暴露后这两者之间的串扰。暴露于紫外线辐射诱导角质形成细胞增加产生ET-1,并因此其分泌刺激黑素细胞产生黑色素。位于SL损伤表皮中的角质形成细胞产生ET-1的潜力显著高于损伤周围的正常对照,并且ETBR转录物也有加强的表达。ET-1的产生增加和定位与黑素细胞中酪氨酸酶的增加量并行。分别地,SCF(也由角质形成细胞产生) 与黑素细胞上的c-KIT受体结合。与非损伤对照相比,日光斑损伤表皮表达增加的SCF mRNA转录物和蛋白质的水平。[Costin GE,Hearing VJ,人皮肤色素形成:黑素细胞应答于压力时调节肤色(Human skin pigmentation: melanocytes modulate skin color in responseto stress),FASEB J.2007年4月; 21(4):976-94]。
然而,皮肤中的其他级联也可以有助于在日光斑(solar lentigines)中观察到的过度色素形成。触发黑素细胞干细胞分化的Wnt信号通路在日光斑病变中参与黑素细胞干细胞的加速分化,参与SL的形成。Wnt信号通路与黑素细胞生物学密切相关。这种信号途径对于黑素细胞干细胞触发分化成滤泡黑素细胞和表皮黑素细胞也很重要。蛋白质dickkopfWNT信号通路抑制剂1 (DKK1)是Wnt信号通路的抑制剂,防止黑色素生成和降低黑素细胞密度。 DKK1通过调节小眼相关转录因子(MITF)和b-联蛋白来抑制黑素细胞功能和生长。[Yamaguchi Y,Morita A,Maeda A,Hearing VJ,通过爪蟾dkk-1 (DKK1)调节皮肤色素形成和厚度(Regulation of skin pigmentation and thickness by Dickkopf-1(DKK1)),JInvestig Dermatol Symp Proc.2009年8 月;14(1):73-5.][Yamada T,Hasegawa S,InoueY,Date Y,Arima M,Yagami A,Iwata Y,Takahashi M,Yamamoto N,Mizutani H,Nakata S,Matsunaga K,Akamatsu H,黑素细胞干细胞的加速分化对形成过度色素斑的贡献(Accelerated differentiation of melanocyte stem cells contributes to theformation of hyperpigmented maculae),Exp Dermatol.2014年9月;23(9):652-8]。
因此,可以抑制黑色素生物合成途径或直接作用于其的活性剂可以对皮肤具有淡化或去色素作用,例如可抑制酪氨酸酶活性、抑制黑素细胞中黑色素产生或影响参与黑色素生成过程的基因表达的活性剂可以作为去色素剂发挥作用。需要一种对皮肤有淡化颜色、美白或去色素作用的新活性剂。
本发明旨在解决一些或全部上述问题,并满足一些或全部上述需求。
发明概述
第一方面,本发明涉及一种来自皮壳正青霉物种菌株的发酵提取物。已经发现,来自皮壳正青霉物种菌株的发酵提取物在皮肤、粘膜、毛发和/或指甲的美容处理和/或护理中特别有效。
在本发明的上下文中,美容处理和/或护理包括:皮肤、粘膜、毛发和/或指甲的去色素或美白或颜色淡化;老年斑的去色素或美白或颜色淡化;暗黑眼圈皮肤的去色素或美白或颜色淡化;维持或改善皮肤光泽度;减轻或预防皮肤老化的迹象;处理皮肤皱纹,如眶周皱纹;处理暗黑眼圈;处理浮肿眼;处理眼袋;平滑或减少皮肤皱纹;减少浮肿眼睛或眼袋的体积;维持或改善皮肤弹性;维持或改善皮肤抵抗力、紧致度或拉伸强度。
令人吃惊的是,本发明人已经发现,来自皮壳正青霉物种菌株的发酵提取物能有效地平滑皮肤皱纹并减少浮肿眼睛或眼袋的体积。本发明人还发现,来自皮壳正青霉物种菌株的发酵提取物能够促进胶原蛋白和弹性蛋白的合成,所述胶原蛋白和弹性蛋白分别形成胶原纤维和弹性纤维,能够抑制对胶原蛋白和弹性蛋白的降解负有责任的酶,并能够抑制胶原蛋白的糖化。此外,他们已经发现,来自皮壳正青霉物种菌株的发酵提取物能够降低与浮肿的眼睛和眼袋中形成的水肿有关的血管通透性。在一个实施方案中,美容处理和/或护理包括对皮肤、粘膜、毛发和/或指甲使颜色淡化、美白或去色素。令人吃惊的是,本发明人发现本发明的发酵提取物对过度色素沉着皮肤如老年斑和暗黑眼圈在颜色淡化或去色素方面特别有效。本发明人已经发现,来自皮壳正青霉物种菌株的发酵提取物能够抑制酪氨酸酶活性,抑制黑素细胞中黑色素的产生,并影响黑色素生成过程中涉及的基因表达,并因此可以作为皮肤去色素剂/美白剂/颜色淡化剂。此外,他们已经发现,这种效果在过度色素沉着的皮肤例如老年斑中更显著。他们发现,皮壳正青霉物种菌株的发酵提取物能够降低胆红素和黑色素浓度,这两种色素对眼睛周围暗黑眼圈的皮肤中的暗黑色素化负有责任。
在第二方面,本发明提供了来自皮壳正青霉物种菌株的发酵提取物用于皮肤、粘膜、毛发和/或指甲的美容处理和/或护理的用途。
在第三方面,本发明提供一种美容组合物,其包含美容有效量的来自皮壳正青霉物种菌株的发酵提取物。
在第四方面,本发明提供了所述组合物在皮肤、粘膜、毛发和/或指甲的美容处理和/或护理中的用途。
在第五方面,本发明提供了用于处理皮肤的美容方法,包括局部施用来自皮壳正青霉物种菌株的发酵提取物或包含其的组合物。
发明描述
下面列出的优选实施方案可应用于本发明的所有上述方面。
定义
在本发明的上下文中,“皮肤”理解为构成皮肤的各个层,从最顶层或角质层至最底层或下皮,这两者均包括在内。这些层包含不同类型的细胞如角质形成细胞、成纤维细胞、黑素细胞和/或脂肪细胞等细胞。在本发明的上下文中,术语“皮肤”包括头皮。术语“皮肤”包括人皮肤。
本说明书上下文中使用的术语“处理”,当它未附带性质用语“美容的”或“非治疗的”时,意指施用本发明化合物以缓和或消除疾病或病症、或者减少或消除一种或多种与这种疾病或病症相关的症状、或者缓和或消除疾病或病症的生理后果。
当术语“处理(treatment)”或者“护理(care)”附带限定用语“美容的”时,其指处理或者护理是非治疗的并且旨在改善皮肤的美学外观。这可以通过改善皮肤的性质,例如但不限于水合水平、弹性、紧致度、光泽、色调或质地,这些性质影响皮肤的美容外观。在本说明书的上下文中,术语“护理”是指维持皮肤的性质。通过在健康受试者以及存在皮肤和/或粘膜的疾病和/或病症的受试者的美容处理和/或护理来改善和维持皮肤的性质,所述皮肤和/或粘膜的疾病和/ 或病症例如但不限于皮肤上的溃疡和损伤、牛皮癣、皮炎、痤疮或酒渣鼻等。
本发明中使用的术语“预防”是指本发明的活性物质在其疾病或病症或皮肤特性/特征出现之前预防、延缓或阻碍其出现或发展的能力。
在本发明的上下文中,术语“老化”指皮肤随年龄(时间老化)或因暴露于阳光(光老化)或暴露于环境物质如烟草烟雾、冷、热或风的极端气候条件、化学致污物或污染物而遭遇的变化,并且包括全部外部可见变化和/或触摸可察觉的变化,如且不限于皮肤上形成不连续面如皱纹、细线、犁沟、不规则性或粗糙,毛孔大小增加、丧失弹性、丧失紧致度、丧失光滑度、丧失变形恢复能力、皮肤下垂如脸颊下垂、出现眼袋或出现双下巴等,皮肤颜色改变如记号、发红、眼袋或出现过度色素沉着区域如老年斑或雀斑等、异常分化、过度角质化、弹性组织变性,角化症、毛发丧失、橘皮状皮肤、丧失胶原蛋白结构和角质层、真皮、表皮、血管系统(例如出现蜘蛛状血管病或毛细血管扩张症)或那些接近于皮肤的组织的其他组织学变化等。术语“光老化”将一组因皮肤长期暴露于紫外辐射所致的过程归并在一起,所述过程导致皮肤过早老化并且展现与老化相同的物理特征,如且不限于松弛、下垂、颜色改变或色素沉着不规则、异常和 /或过度角质化。由于老化引起的皮肤变化(例如随时间老化、光老化和/或环境老化)在本文中也称为皮肤老化的迹象或体征。
在第一方面,本发明涉及来自皮壳正青霉物种菌株的发酵提取物,其用于皮肤、粘膜、毛发和/或指甲的美容处理和/或护理。本发明人发现了新的美容成分;衍生自皮壳正青霉物种菌株的发酵提取物。有利地,这种新的美容活性物质来源于天然资源,并且在皮肤、粘膜、毛发和/或指甲的美容处理和/或护理中令人惊奇地有效。特别地,在减轻或预防皮肤老化的迹象中是有效的。此外,在皮肤、粘膜、毛发和/或指甲的颜色淡化、美白或去色素方面是有效的。
本发明中使用的来自皮壳正青霉物种菌株的发酵提取物是皮壳正青霉物种菌株的发酵产物。发酵提取物是来自已经进行了发酵过程的皮壳正青霉物种菌株的提取物,并且可以是从发酵肉汤中分离出来的皮壳正青霉物种细胞的提取物,或者可以是来自发酵肉汤本身的提取物,其仍然含有皮壳正青霉物种的细胞。本文称为发酵提取物或简称提取物。
可以通过在合适的水性培养基中发酵皮壳正青霉物种菌株获得发酵提取物。将发酵肉汤常规搅拌并通气,以使所需产物合成和分泌到培养基中,且然后分离和纯化发酵提取物。可以在15℃至40℃之间的温度,通常在25℃于搅拌和通气的培养基中进行发酵,培养基的pH在5至9之间,一般地约7.5,如果需要,在发酵期间进行调节。发酵的持续时间为2至10天,在一个实施方案中为3至8天,在另一个实施方案中为4至7天。
可以通过本领域技术人员已知的方法实施从发酵肉汤中分离和纯化发酵提取物的方法,例如离心、破碎和提取。例如,在第一步中,可以使用离心自培养肉汤分离出皮壳正青霉物种菌株的细胞;在第二步中,可以使用破碎来释放细胞内化合物;并且在第三步中,可以进行细胞内化合物的提取以获得发酵提取物。提取物将包括可溶于提取溶剂中的那些细胞内化合物。可以简单地通过提取发酵肉汤,即没有离心和破碎步骤,来获得发酵提取物。然而,优选使用破碎步骤使所需产物的产率最大化。
在皮壳正青霉物种菌株的发酵中,可以使用含有外源性糖(例如但不限于半乳糖,葡萄糖,甘露糖,甘露糖醇,苦杏仁苷,纤维二糖,麦芽糖,淀粉,糖原,乳糖,其混合物)的培养基和/或含有这些糖的混合物的提取物用作碳源。在一个实施方案中,可以提供2至40g/L或3至10g/L的外源性甘露糖醇供应。
培养基可以包含额外的氮源或碳源,例如酵母提取物、麦芽提取物或蛋白胨,其中这些组分中每种组分的浓度为0.1至20g/L或0.5至10g/L。
培养基可以包含海盐。海盐是浓度为5至40g/L或25至35g/L之间的矿盐。在一个实施方案中,除了海盐以外或作为海盐的备选,也向发酵培养基提供矿盐。这些盐选自提供离子Na+,K+,NH4 +,Ca2+,Mg2+,PO4 3-,SO4 2-, Cl-,F-,I-,CO3 2-,NO3 -、柠檬酸盐或痕量元素如Cu,Mn,Mo,Fe,Sr,B, Br,Si,Al,Li和Zn的盐。
使用溶剂如异丙醇实施提取步骤。可以使用其它溶剂如乙醇、丙酮和乙酸乙酯。
来自皮壳正青霉物种菌株的发酵提取物通常含有肽、游离氨基酸、糖和脂质。在一个实施方案中,所述发酵提取物包含以下相对物质百分比:31至79%的肽,1至8%的游离氨基酸,10至27%的糖和15至40%的脂质,条件是百分比的总和不超过100%。在另一个实施方案中,发酵提取物显示以下相对物质百分比:35至73%的肽,2至7%的游离氨基酸,12至25%的糖和17至37%的脂质,条件是百分比的总和不超过100%。在另一个实施方案中,发酵提取物显示以下相对物质百分比:39.4至65.6%的肽,2.2至6.4%的游离氨基酸, 13.3至22%的糖和18.8至32.8%的脂质,条件是百分比的总和不超过100%。在另一个实施方案中,发酵提取物显示以下相对物质百分比:39至46%的肽, 3至7%的游离氨基酸,21至22%的糖和29至33%的脂质,条件是百分比的总和不超过100%。这些百分比是重量百分比。
通常,发酵提取物的分子量小于3400Da。这是在实施例2中详述的条件下,通过具有尺寸排阻柱TSK gel G2000SWXL的色谱(HPLC)分析测量。尺寸排阻柱的内径为7.8mm,长度为30.0cm,粒径为5mm,孔径为洗脱液为0.1M磷酸缓冲液pH 6.7+0.1M Na2SO4,且洗脱保持为等度洗脱,流速为1mL/分钟。来自皮壳正青霉物种的发酵提取物在11.5和13.5分钟之间显示出峰,高斯分布具有10至20分钟的保留时间。
在一个示例性和优选的实施方案中,皮壳正青霉物种菌株是具有保藏号为 CECT20901的皮壳正青霉物种菌株。该菌株于2014年3月20日保藏在西班牙典型培养物保藏中心(de Cultivos Tipo(CECT))(西班牙,瓦伦西亚,46980帕特纳,卡替德拉蒂可阿古斯丁埃斯卡迪诺9,巴伦西亚公民大学(Parc Científic Universitat deValencia),3楼CUE),该机构是根据 1977年4月28日颁布的关于国际承认的微生物保藏的布达佩斯条约合法认可的为了所述目的的机构。
在第二方面,本发明提供了发酵提取物用于皮肤、粘膜、毛发和/或指甲的美容处理和/或护理的用途。特别地,已经发现,发酵提取物在皮肤的美容处理和/或护理中特别有效,包括:皮肤、粘膜、毛发和/或指甲的去色素或美白或颜色淡化;老年斑的去色素或美白或颜色淡化;暗黑眼圈皮肤的去色素或美白或颜色淡化;维持或改善皮肤光泽度;减轻或预防皮肤老化的迹象;处理皮肤皱纹,如眶周皱纹;处理暗黑眼圈;处理浮肿眼;处理眼袋;平滑或减少皮肤皱纹;减少浮肿眼睛或眼袋的体积;维持或改善皮肤弹性;维持或改善皮肤抵抗力、紧致度或拉伸强度。已经发现,发酵提取物可以促进胶原蛋白和弹性蛋白的合成,抑制由于胶原酶的作用而导致的胶原蛋白降解,并抑制由于弹性蛋白酶的作用而导致的弹性蛋白的降解。认为所述发酵提取物用于补充和维持老龄化皮肤中的胶原蛋白和弹性蛋白水平,从而保持和改善皮肤弹性、皮肤抵抗力和/或皮肤拉伸强度。这导致更多的色调和更坚固的皮肤,其具有较少的下垂和/或皱纹的倾向。还发现所述发酵提取物可抑制高级糖化终产物(Advance Glycation End product;AGE)的形成。认为这进一步增加了发酵提取物帮助维持老化皮肤中胶原蛋白(I型胶原蛋白)水平的能力,并因此保持皮肤弹性。此外,该抑制AGE形成的能力导致据信使皮肤迟钝的化合物的形成减少,其中所述化合物的形成伴随着弹性蛋白的减少,因此使用这种美容活性物质可以改善皮肤光泽度。因此,在本发明的第二方面的一个实施方案中,提供了所述发酵提取物的用于维持或改善皮肤弹性、皮肤抵抗力、皮肤紧致度、皮肤拉伸强度和/或皮肤光泽度的美容用途。本发明提供了所述发酵提取物用于维持或改善皮肤弹性、皮肤抵抗力、皮肤拉伸强度和/或皮肤光泽度的美容用途,以及所述发酵提取物作为皮肤紧致和调色剂和/或皮肤增亮剂的美容用途。
此外,已经发现本发明的发酵提取物有效地平滑皮肤皱纹或减小皮肤皱纹的尺寸,特别是眶周皱纹,例如鱼尾纹(crow’s feet)。因此,在本发明的第二方面的一个实施方案中,提供了所述发酵提取物用于处理皱纹的美容用途。本发明提供了用于处理皱纹的美容用途的所述发酵提取物,以及所述发酵提取物作为皮肤抗皱剂的美容用途。
还发现本发明的发酵提取物有效减少眼袋的体积。认为这至少部分是由于发酵提取物降低血管通透性的有效性(血管通透性的增加与老化的皮肤相关),因此减少了保留在眼睛下的皮肤中的流体的量。因此,在本发明的第二方面的一个实施方案中,提供了所述发酵提取物用于处理眼袋和/或浮肿眼睛的美容用途。本发明提供了用于处理眼袋和/或浮肿眼睛的美容用途的所述发酵提取物,以及所述发酵提取物作为眼袋和/或浮肿眼睛处理剂的美容用途。
还已经发现,本发明的发酵提取物有效淡化皮肤颜色或去色素或美白皮肤。认为这部分是由于发酵提取物有效抑制黑素细胞中黑色素形成、抑制酪氨酸酶活性和/或影响黑色素生成过程中参与的基因表达。因此,在本发明第二方面的一个实施方案中,提供了所述发酵提取物的美容用途,用于淡化皮肤、粘膜、毛发和/或指甲的颜色或对皮肤、粘膜、毛发和/或指甲美白或去色素。本发明提供了用于美白皮肤或淡化皮肤颜色或对皮肤去色素的美容用途的发酵提取物,以及所述发酵提取物的美容用途,其中所述发酵提取物作为皮肤美白剂或皮肤颜色淡化剂或皮肤去色素剂。特别地,所述发酵提取物有效淡化过度色素沉着的皮肤颜色或对过度色素沉着的皮肤去色素或美白,例如老年斑。认为这种影响老年斑的能力部分是由于发酵提取物有效下调EDNRB基因表达以及对黑素细胞Wnt信号传导途径的抑制作用(基因DKK1的上调和参与此途径的基因的下调)。因此,在本发明第二方面的一个实施方案中,提供了所述发酵提取物用于处理老年斑的美容用途。本发明提供用于处理老年斑的美容用途的所述发酵提取物,以及所述发酵提取物作为老年斑处理剂的美容用途。本发明的发酵提取物在暗黑眼圈中减轻皮肤的暗色也特别有效。认为这部分是由于发酵提取物有效促进胆红素分解以及其影响黑色素形成的能力。因此,在本发明第二方面的一个实施方案中,提供了所述发酵提取物用于处理暗黑眼圈的美容用途。本发明提供了用于处理暗黑眼圈的美容用途的所述发酵提取物,以及所述发酵提取物作为暗黑眼圈处理剂的美容用途。这种淡化皮肤颜色的能力也对发酵提取物维持和/或改善皮肤光泽度的能力作出贡献。
在本发明第二方面的一个实施方案中,提供了本发明的发酵提取物用于缓解和/或预防皮肤老化的症状或迹象的用途。因此,本发明提供了用于美容用途的所述发酵提取物,用于缓解和/或预防皮肤老化的迹象,以及所述发酵提取物作为皮肤抗老化剂的美容用途。皮肤老化的症状或迹象包括:出现皮肤皱纹,暗黑眼圈,老年斑,浮肿眼睛和/或眼袋,皮肤黯淡,皮肤弹性、皮肤抵抗力、皮肤紧致度和/或皮肤拉伸强度丧失。因此,在这个实施方案中,美容处理和/ 或护理包括:处理皮肤皱纹,暗黑眼圈,老年斑,浮肿眼睛和/或眼袋;平滑或减少皮肤皱纹的尺寸;减少浮肿眼睛和/或眼袋的体积;暗黑眼圈的皮肤颜色变淡;老年斑的颜色变淡;维持或改善皮肤弹性、皮肤光泽度、皮肤抵抗力、皮肤紧致度和/或皮肤拉伸强度。在一个实施方案中,美容处理和/或护理是皮肤变淡、美白或去色素,并且包括暗黑眼圈和/或老年斑的皮肤颜色的淡化和/ 或维持或改善皮肤光泽度。在一个实施方案中,美容处理和/或护理是处理眼睛区域周围的皮肤,并且包括处理皮肤皱纹,暗黑眼圈,浮肿眼睛和/或眼袋。
在本发明的一个实施方案中,皮肤、粘膜、毛发和/或指甲的美容处理和/ 或护理是用于最暴露于环境的皮肤,例如面部皮肤,手和前臂的皮肤,低领部皮肤(décolletage)和腿。在本发明的一个实施方案中,皮肤、粘膜、毛发和/ 或指甲的美容处理和/或护理是用于颜色淡化、美白或去色素,所述处理和/或护理用于皮肤,对皮肤而言,较浅的颜色是个体在美容上期望的,所述个体具有例如过度色素沉着的皮肤,如老年斑或由于高黑色素含量(如乳头的皮肤) 而自然较暗的皮肤。
在一个实施方案中,美容处理和/或护理是用于白种人或亚洲人。在一个实施方案中,美容处理和/或护理是用于20岁以上的个体。
根据本发明第三方面,提供了一种美容组合物,其包含美容有效量的来自皮壳正青霉物种菌株的发酵提取物和至少一种美容上可接受的赋形剂、辅助剂和/或成分。所述发酵提取物如本发明第一方面所述。所述组合物可以通过本领域技术人员已知的常规方法制备[“Harry’s Cosmeticology”,第七版,(1982), Wilkinson J.B.,Moore R.J.编著,Longman House,Essex,GB]。
本发明组合物中发酵提取物的美容有效量及其用量取决于许多因素,其可以包括年龄,患者状况,皮肤老化的迹象的性质或严重性,待处理和/或护理的皮肤的暗度,提取物的施用途径和频率。
“美容有效量”理解为无毒但足够量的发酵提取物以提供期望的效果。本发明的发酵提取物以达到所需美容效果的浓度使用,并且这些包括基于组合物总重量的提取物干重为0.0000000001重量%至20重量%或0.00000001重量%至 10重量%或0.000001重量%至5重量%,或0.000001重量%或0.00005重量%至1重量%。
本发明的发酵提取物可以并入美容递送系统和/或持续释放系统中。
术语“递送系统”涉及与本发明的提取物一起施用的稀释剂、辅助剂、运载体(vehicle)或添加物。这些美容用载体可以是液体,如水、油或表面活性剂,包括石油源、动物源、植物源或合成源的那些液体,如且不限于花生油、大豆油、矿物油、芝麻油、蓖麻油、聚山梨醇酯、山梨糖醇酐酯、醚硫酸酯、硫酸酯、甜菜碱、糖苷、麦芽糖苷、脂肪醇、壬苯醇醚、泊洛沙姆、聚氧乙烯、聚乙二醇、右旋糖、甘油、毛地黄皂苷等。本领域技术人员知道可以用于不同递送系统中的稀释剂、辅助剂或添加物,在所述递送系统中可以施用本发明的发酵提取物。
术语“持续释放”按照描述递送系统的常规含义使用,所述递送系统在一段时间期间提供化合物的逐步释放。在一个实施方案中,递送系统提供在一段时间期间相对恒定的化合物释放水平。
递送或持续释放系统的例子包括脂质体、混合型脂质体、油质体 (oleosomes)、乙氧基化脂肪醇类构成的脂质体(niosome)、醇质体(ethosomes)、毫米级粒子(milliparticle)、微粒子、纳米粒子和固态脂质纳米粒子、纳米结构化脂质支持体、海绵、环糊精、囊泡、胶束、表面活性剂的混合胶束、表面活性剂-磷脂混合胶束、毫米球(millisphere)、微球和纳米球、脂质球(liposphere)、毫米胶囊(millicapsule)、微胶囊和纳米囊,以及微乳液和纳米乳液,可以添加它们以实现本发明有效成分的更大穿透作用。在一个实施方案中,递送或持续释放系统选自脂质体、表面活性剂-磷脂混合胶束和微乳液,和具有内部反向胶束结构的油包水微乳液和含有纳米囊的微乳液。
持续释放系统可以通过现有技术中已知的方法制备,并且含有这些持续释放系统的组合物可以例如通过局部或经皮施用法施用,包括黏性贴剂、非黏性贴剂、闭塞性贴剂和微电贴剂。在一个实施方案中,持续释放系统应当释放相对恒定量的本发明提取物。持续释放系统中所含的提取物的量例如取决于组合物在何处待施用、释放本发明提取物的动力学和持续时间,以及待处理和/或防止的病状、病症和/或疾病的性质。
含有本发明发酵提取物的组合物也可以吸附在固态有机聚合物或固态无机支持物上,如且不限于滑石、膨润土、二氧化硅、淀粉或麦芽糖糊精等。
含有所述发酵提取物的组合物也可以并入与皮肤直接接触的织物、非织造织物或医药用装置中,因此通过生物降解织物、非织造织物或医药用装置的结合系统或因它们与身体之间摩擦、因身体潮气、皮肤pH或体温而释放本发明的提取物。另外,本发明的提取物可以并入用于生产与身体直接接触的服装中的织物和非织造织物内。
可以在以下文献中找到将化合物固定到织物、非织造织物、服装、医药用装置以及手段的例子,其中有上述递送系统和/或持续释放系统,并且它们是现有技术已知的[Schaab C.K.(1986)HAPPI May 1986;Nelson G.,“Application of microencapsulationin textiles”,(2002),Int.J.Pharm.,242(1-2),55-62;“Biofunctional Textiles andthe skin”(2006)Curr.Probl.Dermatol.v.33, Hipler U.C.和Elsner P.编著,S.KargerAG,Basel,Switzerland;Malcolm R.K. 等人,“Controlled release of a modelantibacterial drug from a novel self-lubricating silicone biomaterial”,(2004),J.Cont.Release,97(2),313-320]。优选的织物、非织造织物、服装和医药用装置是绷带、纱布、T恤衫、袜子、紧身衣、内衣、腰带、手套、尿布、卫生巾、修整用物(dressings)、床罩、抹布、黏性贴剂、非黏性贴剂、闭塞性贴剂、微电贴剂和/或面罩。
含有本发明发酵提取物的美容组合物可以不同类型的局部或经皮施加组合物来使用,任选地,所述组合物包含美容可接受的配制所需施用形式必需的赋形剂。
本发明的美容组合物可以用于局部或经皮施用,且可以任何固态、液态或半固态制剂产生,所述制剂如且不限于乳膏剂、多种乳剂,如且不限于水包油和/或水包聚硅氧烷乳剂、油包水和/或聚硅氧烷包水乳剂、水/油/水或水/聚硅氧烷/水型乳剂、以及油/水/油或聚硅氧烷/水/聚硅氧烷型乳剂、无水组合物、含水分散体、油、乳、香脂、泡沫、美容水、凝胶剂、凝胶膏霜(cream gel)、水醇溶液、水二醇溶液、水凝胶、搽剂、精华液(sera)、皂、洗发剂、调理剂、浆液(serum)、多糖薄膜、软膏、摩丝、润发油、脂粉、棒、笔和喷雾剂或气溶胶(喷雾剂),包括原位保留和淋洗制剂。可以使用本领域技术人员已知的技术,将这些局部或经皮施加制剂并入不同类型的固态配件中,如且不限于绷带、纱布、T恤衫、袜子、紧身衣、内衣、腰带、手套、尿布、卫生巾、修整用物、床罩、抹布、黏性贴剂、非黏性贴剂、闭塞性贴剂、微电贴剂和/或面罩,或可以将它们并入不同的美容产品如美容粉底,如液体粉底和压缩粉底、卸妆洗液、卸妆乳、暗黑眼圈遮暇膏、眼影、唇膏、护唇用品、唇彩和香粉等。
本发明的美容组合物可以包含增加本发明化合物经皮吸收的物质,例如且不限于二甲基亚砜、二甲基乙酰胺、二甲基甲酰胺、表面活性剂、氮酮(1-十二烷基氮杂环庚烷-2-酮)、醇、脲、乙氧基二甘醇、丙酮、丙二醇或聚乙二醇等。另外,本发明的美容组合物或皮肤药用组合物可以借助离子导入、超声导入 (sonophoresis)、电穿孔、微电贴剂、机械压力、渗透压梯度、闭锁性治疗、借助压力的微量注射或无针注射,如通过氧压力注射,或其任意组合,施加至待处理的局部区域以实现本发明发酵提取物的更大穿透。施加区域将由待处理和 /或防止的病状、病症和/或疾病的性质决定。
在本发明所述的美容组合物中所含的美容可接受的赋形剂、辅助剂和/或成分当中,存在美容组合物中常用的额外成分,例如并且不限于减少皮脂产生的物质、抗脂溢剂、哑光剂(mattifying agents)、抗痤疮剂、刺激真皮大分子或表皮大分子合成和/或能够抑制或防止它们降解的物质、其他胶原蛋白合成刺激剂、其他弹性蛋白合成刺激剂、核心蛋白聚糖合成刺激剂、层粘连蛋白合成刺激剂、防卫素合成刺激剂、伴侣蛋白合成刺激剂、cAMP合成刺激剂、调节AQP-3的物质、调节水通道蛋白合成的物质、来自水通道蛋白家族的蛋白质、透明质酸合成刺激剂、糖胺聚糖合成刺激剂、纤连蛋白合成刺激剂、去乙酰化酶(sirtuin)合成刺激剂、热休克蛋白、热休克蛋白合成刺激剂、抑制神经元胞吐的物质、其他抗胆碱能剂、抑制肌肉收缩的物质、其他抗老化剂、其他抗皱剂、止汗剂、抗炎剂和/或镇痛药、止痒剂、镇静剂、乙酰胆碱受体聚集抑制剂、抑制乙酰胆碱酯酶的物质、皮肤舒缓剂、其他黑色素合成抑制剂、净白或去色素剂、NO-合酶抑制剂、5α-还原酶抑制剂、赖氨酰和/或脯氨酰羟化酶抑制剂、抗氧化剂、自由基清除剂和/或抗大气污染物质、反应性羰基种类清除剂、抗糖化剂、抗组胺剂、抗病毒剂、抗寄生虫剂、乳化剂、润滑剂、有机溶剂、液体推进剂、皮肤调理剂、湿润剂、保留水分的物质、α羟酸,β羟酸、保湿剂、表皮水解酶、维生素、氨基酸、蛋白质、颜料或色料、染料、生物聚合物、胶凝聚合物、增稠剂、表面活性剂、柔化剂、乳化剂、粘合剂、防腐剂、能够减少或处理眼袋的物质、剥离剂、角质溶解剂、剥落剂、抗微生物剂、抗真菌剂、抑真菌剂、杀细菌剂、抑细菌剂、刺激脂质和角质层组分合成的物质、神经酰胺、脂肪酸、抑制胶原蛋白降解的其他物质、抑制基质金属蛋白酶的物质、抑制弹性蛋白降解的其他物质、抑制丝氨酸蛋白酶如血管舒缓素、白细胞弹性蛋白酶或组织蛋白酶G的物质、刺激成纤维细胞增殖的物质、刺激角质形成细胞增殖的物质、刺激脂肪细胞增殖的物质、刺激黑素细胞增殖的物质、刺激角质形成细胞分化的物质、刺激或延缓脂肪细胞分化的物质、抗角化过度剂、粉刺溶解剂、抗银屑病剂、DNA修复剂、DNA保护剂、干细胞保护剂、稳定剂、处理和/或护理敏感皮肤的物质、紧合剂、抗伸展纹剂、接合剂、脂肪分解剂或刺激脂解的物质、成脂剂、调节PGC-1α表达的物质、调节PPARγ活性的物质、增加或降低脂肪细胞甘油三酯含量的物质、抗脂肪团(cellulite) 剂、抑制PAR-2活性的物质、刺激愈合的物质、协助性愈合剂、刺激再表皮化的物质、协助性再表皮化剂、细胞因子生长因子、作用于毛细血管循环和/ 或微循环的物质、刺激血管生成的物质、抑制血管通透性的物质、静脉强壮剂(venotonicagents)、作用于细胞代谢的物质、改善真皮-表皮结合部的物质、诱导毛发生长的物质、毛发生长抑制或阻滞剂、落发阻滞剂、防腐剂、香精、吸味剂和/或体味掩蔽性除臭剂、螯合剂、植物提取物、精油、海洋提取物、从生物技术过程获得的物质、无机盐、细胞提取物、有效对抗紫外A 和/或B射线和/或红外A射线的防晒剂和有机或无机光防护剂、或它们的混合物,条件是它们在物理和化学上与组合物中的其余组分和特别地与由皮壳正青霉物种菌株产生的发酵提取物相容。同样地,这些额外成分的性质不应当不可接受地改变本发明提取物的益处。这些额外成分的性质可以是合成的或天然的,如植物提取物,或来自生物技术过程,或来自合成过程和生物技术过程的组合。额外的例子可以在CTFA国际美容品成分字典和手册第12版(2008)中找到。在本发明的上下文中,将生物技术过程理解为在生物中或在其部分中产生活性成分或其部分的任何过程。
在一个实施方案中,本发明的美容组合物含有:
-0.0000000001%(以重量计)和20%(以重量计)之间来自皮壳正青霉物种菌株的发酵提取物;
-0.1%(按重量计)和20%(按重量计)之间的湿润剂,选自(INCI名称)丙三醇、丙二醇、丁二醇、戊二醇、辛酰二醇、乳酸、脲、透明质酸钠;
-0.1%(按重量计)和20%(按重量计)之间的柔润剂或皮肤调理剂,选自 (INCI名称)聚二甲基硅氧烷、硬脂酸甘油酯、辛酸/癸酸甘油三酯、鲸蜡硬脂醇、卵磷脂、C12-15烷基苯甲酸酯、角鲨烷、羊毛脂、山嵛醇、醋酸生育酚、泛醇、牛油果脂、视黄醇棕榈酸酯、视黄醇;
-0.1%(按重量计)和20%(按重量计)之间的表面活性剂,选自(INCI名称) 黄原胶、月桂醇聚醚硫酸钠、硬脂酸、聚山梨醇酯20、聚山梨醇酯80、硬脂醇、鲸蜡醇、硬脂醇聚醚-2、鲸蜡硬脂醇醚-20、椰油酰胺丙基甜菜碱。
该组合物可以进一步包含减少皮脂产生的物质、抗脂溢剂、哑光剂和/或抗痤疮剂,例如但不限于选自BASF销售的Mat-XS Clinical[INCI:肌氨酸,黄原胶]、Mat-XSBright[INCI:肾茶(Orthosiphon Stamineus)叶提取物、麦芽糖糊精、黄原胶]、Betapur[INCI:Reumus Boldus叶提取物、黄原胶]或 Neurobiox[INCI:欧蓍草(AchilleaMillefolium)提取物、黄原胶]; Sederma/Croda销售的Evermat[INCI:依南木(EnantiaChlorantha)树皮提取物、石竹素]、Ac.net[INCI:丁二醇、Peg-60杏仁甘油脂、辛酰二醇、甘油、卡波姆、去甲二氢愈创木酸、石竹素]或Sebuless[INCI:麦芽糖糊精、欧洲丁香(SyringaVulgaris)(Lilac)提取物]、Crodarom销售的Phytessence Purple Ginseng[INCI:甘油或拳参(Polygonum Bistorta)根提取物]、Silab销售的 P-Refinyl[INCI:兵豆(LensEsculenta)(小扁豆)种子提取物]、Codif销售的 EPS Seamat[INCI:浮游生物的表多糖-5、苯氧基乙醇]或Epidermist 4.0 [INCI:浮游生物提取物],Alban Muller销售的Seborami[INCI:篱芥子 (Sisymbrium Ofiicinale)提取物、牛蒡(Arctium Lappa)根提取物、柠檬酸、乙醇酸、锌PCA、菌核胶],Mibelle销售的Poreaway[INCI:Pistacia Lentiscus Gum/Pistacia Lentiscus(Mastic)Gum、卵磷脂],Provital销售的Citrustem [INCI:黄原胶、苯甲酸钠、葡萄糖酸内酯、葡萄糖酸钙]或Affipore[INCI: 南非香叶木(Barosma Betulina)叶提取物、柠檬酸],Laboratories Expanscience销售的Sweetone[INCI:糖水解物、麦芽糖糊精],Solabia销售的Seboxyl[INCI:黑茶镳子(Ribes Nigrum)(黑加仑(Black Currant))叶提取物、悬钩子(Rubus Idaeus)(山莓(Raspberry))叶提取物]或Saniskin[INCI: 虎杖(Polygonum Cuspidatum)根提取物、十四烷基醇],DSM销售的Alpaflor Alp-Sebum[INCI:弗来歇氏柳叶菜(Epilobium Fleischeri)提取物、柠檬酸、山梨酸钾]或Regu-Seb[INCI:刺阿干树(Argania Spinosa)核提取物、锯叶棕(Serenoa Serrulata)果实提取物、芝麻(Sesamum Indicum)(Sesam)种子提取物],Lipotec/Lubrizol销售的[INCI:乙酰基二肽-3氨基己酸酯]、MatmarineTM[INCI:假交替单胞菌属(Pseudoalteromonas)发酵提取物],Aqua Bio Technology销售的Dermaclarine[INCI:水解的卵蛋白(和) 蛋白酶],Lucas Meyer销售的Linumine[INCI:亚麻(LinumUsitatissimum) (Linseed)种子提取物],Evonik销售的Granactive Acne[INCI:稻(OryzaSativa)(Rice)麸提取物、齿叶乳香树(Boswellia Serrata)提取物、蜂蜜提取物、寡肽-10],Seppic销售的Sepicontrol A5[INCI:辛酰甘氨酸、肌氨酸、肉桂(CinnamoniumZeylanicum)树皮提取物],Symrise销售的Sympeptide 380 [INCI:十四酰六肽-23],或Laboratoires Serobiologiques/Cognis/BASF销售的Sebaryl[INCI:烟酰胺、酵母提取物、欧洲七叶树(Aesculus Hippocastanum)(Horse Chestnunt)种子提取物、甘草酸铵、泛醇、丙二醇、葡萄糖酸锌、咖啡因、生物素]等。
组合物可以还包含额外的抗皱纹和/或抗老化剂,选自例如但不限于以下:葡萄(Vitis vinifera)、犬蔷薇(Rosa canina)、姜黄(Curcuma longa)、可可 (Theobromacacao)、银杏(Ginkgo biloba)、高山火绒草(Leontopodium alpinum) 或盐生杜氏藻(Dunaliella salina)的提取物或水解提取物等、Sederma/Croda销售的[INCI:棕榈酰五肽-4]、[INCI:棕榈酰四肽-7、棕榈酰寡肽]、Synthe’6TM[INCI:丙三醇、水、羟丙基环糊精、棕榈酰三肽-38]、EssenskinTM[INCI:羟蛋氨酸钙]、Renovage[INCI:替普瑞酮]、 ResistemTM[INCI:心叶球花(Globularia Cordifolia)发酵物]、Beautifeye[INCI:合欢(Albizia Julibrissin)树皮提取物、吡喃葡糖苷]、Meiritage[INCI:膜荚黄芪(Astragalus Membranaceus)根提取物、白术(AtractyloidesMacrocephala)根提取物、阿尔泰柴胡(Bupleurum Falcatum)根提取物]、Senestem[INCI:长叶车前(Planta Lanceolata)叶提取物]、BeautifeyeTM[INCI:ALbizia Julibrissin树皮提取物]、Venuceane[INCI:嗜热栖热菌(Thermus Thermophillus)发酵物] 或[INCI:棕榈酰寡肽]、Pentapharm/DSM销售的[INCI:五肽-3]、[INCI:二肽二氨基丁酰苄基酰胺二乙酸盐]、 [INCI:棕榈酰三肽-5]、Phytaluronate[INCI:刺槐角豆(长角豆(Ceratonia siliqua)胶]、Regu-Scence[INCI:石刁柏(AsparagusOfficinalis)茎提取物、苯甲酸钠、山梨酸钾、葡糖酸内酯、葡糖酸钙]、Syn-TC[INCI:十四烷基氨基丁酰缬氨酰氨基丁酸脲三氟乙酸盐、棕榈酰三肽-5、棕榈酰二肽-5二氨基丁酰羟基苏氨酸]或[INCI:野大豆(Glycine soja)(大豆)蛋白、氧化还原酶]、Laboratoires Sérobiologiques/Cognis/BASF销售的MyoxinolTM[INCI:水解的咖啡黄葵(Hibiscus esculentus)提取物]、SyniorageTM[INCI:乙酰基四肽 -11]、DermicanTM[INCI:乙酰基四肽-9]、Shadownyl[INCI:藻提取物、己二醇、辛酰二醇、黄原胶]或DN AGETM LS[INCI:翅荚决明(Cassia alata)叶提取物]、Exsymol销售的[INCI:甲基硅烷醇甘露糖醛酸酯]、Exage [INCI:咪唑基乙基二氨基丙酰胺]或羟基脯氨酯硅烷醇[INCI:甲基硅烷醇羟脯氨酸酯天冬氨酸酯]、Lipotec/Lubrizol销售的[INCI:乙酰基六肽-8]、SNAP-7[INCI:乙酰基七肽-4]、SNAP-8[INCI:乙酰基八肽-3]、[INCI:六肽-10]、[INCI:五肽-18]、[INCI:乙酰基六肽-30]、[INCI:水解小麦蛋白、水解大豆蛋白、三肽-1]、[INCI:二氨基丙酰三肽-33]、[INCI:三肽-10瓜氨酸]、[INCI:三肽-9瓜氨酸]、[INCI:假交替单胞菌发酵产物提取物、水解小麦蛋白、水解大豆蛋白、三肽-10瓜氨酸、三肽-1]、[INCI:乙酰基四肽-5]、肽AC29[INCI:乙酰基三肽-30瓜氨酸]、[INCI:乙酰基精氨酰三色氨酰联苯基甘氨酸]、[INCI:乙酰基四肽-22]、LipochromanTM[INCI:二甲基甲氧基苯并二氢吡喃醇]、[INCI:棕榈酸二甲基甲氧基色满酯]、[INCI:假交替单胞菌发酵产物提取物]、dGlyageTM[INCI:赖氨酸HCl、卵磷脂、三肽-9瓜氨酸]、VilasteneTM[INCI:赖氨酸HCl、卵磷脂、三肽-10瓜氨酸]、 HyadisineTM[INCI:假交替单胞菌发酵产物提取物]、HyanifyTM[INCI:糖类同分异构体]、DiffuporineTM[INCI:乙酰基六肽-37]、SilusyneTM[INCI:大豆 (野大豆)油、失水山梨糖醇倍半油酸酯、异十六烷、透明质酸钠、月桂基二甲基铵羟丙基水解大豆蛋白、乙酰基六肽-39]、AdifylineTM[INCI:乙酰基六肽 -38]、UplevityTM[INCI:乙酰基四肽-2]、JuvelevenTM[INCI:乙酰基六肽-51 酰胺]或TelangynTM[INCI:乙酰基四肽-40]、Institut Europeen de Biologie Cellulaire销售的[INCI:三肽-1、葡聚糖]、Vincience/ISP/Ashland 销售的IS[INCI:六肽-9]、Laminixyl ISTM[INCI:七肽]、OrsirtineTM GL[INCI:稻(Oryza sativa提取物]、D’OrientineTM IS[INCI:海枣(Phoenix dactylifera)(椰枣)籽提取物]、PhytoquintescineTM[INCI:单粒小麦(Triticum monococcum)提取物]、肽Q10[INCI:五肽-34三氟乙酸盐]、Telosense[INCI:水解酵母蛋白、水解大豆蛋白]或QuintescineTM IS[INCI:二肽-4]、Infinitec Activos销售的BONT-L-肽[INCI:棕榈酰六肽-19]、Seppic销售的DeepalineTM PVB[INCI:棕榈酰基水解小麦蛋白]或DPHP[INCI:二棕榈酰羟脯氨酸]、Gattefossé销售的Expression[INCI:千日菊(Acmella oleracea) 提取物]、In-Tense[INCI:金钮扣(Spilanthes acmella)花提取物]或Age Defense 2[INCI:胡桃(Juglans regia)籽提取物]、Biotechmarine 销售的ThalassineTM[INCI:藻提取物]、Atrium/Unipex Innovations销售的 ChroNOlineTM[INCI:Caprooyl四肽-3]或Thymulen-4[INCI:乙酰基四肽-2]、 Coletica/Engelhard/BASF销售的EquiStat[INCI:苹果(Pyrus malus)果实提取物、野大豆籽提取物]或Juvenesce[INCI:乙氧基二甘醇和辛酸甘油三酯、视黄醇、熊果酸、植物甲萘醌、伊洛马司他]、EpigenistTM[INCI:班马纳花生 (Voandzeia Subterranea)种子提取物],LOX-AGETM[INCI:菊苣(Cichorium Intybus)(Chicory)叶提取物]、Mibelle Biochemistry销售的Ameliox[INCI:肌肽、生育酚、水飞蓟(Silybum marianum)果提取物]、Phytocelltec Symphytum [INCI:异麦芽、聚合草(Symphytum Officinale)根细胞培养物、卵磷脂、苯甲酸钠]、雪藻粉[INCI:)Chlamydocapsa提取物、麦芽糖糊精、卵磷脂]、Dermcom [INCI:阿拉伯胶树(AcaciaSenegal)胶、Crocus Chyrsanthus鳞茎提取物]、 Anagain[INCI:豌豆(Pisum sativum)(豌豆)、幼苗提取物]或PhytoCellTec栽培苹果(Malus domestica)[INCI:栽培苹果(Malusdomestica)果实细胞培养物]、 Silab销售的Bioxilift[INCI:茴芹(Pimpinella anisum)提取物]、Vitagenyl [INCI:桃(Prunus Persica)叶提取物]或SMS[INCI:番荔枝 (Annona squamosa)籽提取物]、Symrise销售的Symvital Agerepair[INCI:姜(Zingiber Officinale)根提取物]、Provital销售的柑橘[INCI:黄原胶、苯甲酸钠、葡糖酸内酯、葡糖酸钙]、Melavoid[INCI:黄细心(Boerhavia Diffusa)根提取物]、Darkout[INCI:非洲马铃薯(Hypoxis Rooperi)根茎提取物、刺云实 (Caesalpinia Spinosa)胶]或Linefill[INCI:异山梨醇酐二甲醚、芝麻(Sesamum Indicum)籽提取物]、Lucas Meyer销售的Adipofill’in[INCI:鸟氨酸、磷脂、糖脂/糖脂类]、Elix-IR[INCI:扁蓄(PolygonumAviculare)提取物]或Progeline [INCI:三氟乙酰三肽-2]、Alban Muller销售的Amiperfect[INCI:平铺白珠树(Gaultheria Procumbens)叶提取物]或Repulpami ER[INCI:猴面包树 (Adansonia Digitata)果肉提取物、玫瑰茄(Hibiscus Sabdariffa)花提取物]、 Solabia销售的Celloxyl[INCI:Uapaca Bojeri叶提取物]或Resistress[INCI:槐(Sophora Japonica)花提取物]、Codif销售的Actiporine8G[INCI:叉珊藻 (JaniaRubens)提取物]或EPS Seafill[INCI:浮游生物提取物]、Lakesis[INCI: 乳香黄连木(Pistacia Lentiscus)(Mastic)树胶]、Induchem销售的Novhyal Biotech G[INCI:乙酰壳糖胺磷酸二钠]或Rubixyl[INCI:六肽-47]、Ca2+通道拮抗剂例如且不限制于阿尔维林、锰盐或镁盐、某些仲胺或叔胺、视黄醇及其衍生物、艾地苯醌及其衍生物、辅酶Q10及其衍生物、乳香酸及其衍生物、 GHK及其衍生物和/或盐、肌肽及其衍生物、DNA修复酶例如且不限制于光裂合酶或T4核酸内切酶V、或氯离子通道激动剂等和/或其混合物。
组合物可以还包含抗炎剂和/或镇痛剂,例如但不限于羟基积雪草苷(madecassoside)提取物、海胆(echinacea)提取物、苋属植物(amaranth) 种子油、檀香木油、桃树叶提取物、芦荟(Aloe vera)、山金车(Arnica montana)、普通蒿(Artemisiavulgaris)、细辛(Asarum maximum)、金盏花(Calendula officinalis)、辣椒属(Capsicum)、石胡荽(Centipeda cunninghamii)、母菊(Chamomilla recutita)、文珠兰(Crinum asiaticum)、金缕梅(Hamamelis virginiana)、爪钩草(Harpagophytumprocumbens)、金丝桃(Hypericum perforatum)、白百合(Lilium candidum)、锦葵(Malvasylvestris)、互叶白千层(Melaleuca alternifolia)、墨角兰(Origanum majorana)、野牛至 (Origanum vulgare)、桂樱(Prunus laurocerasus)、迷迭香(Rosmarinusofficialis)、白柳(Salix alba)、水飞蓟(Silybum marianum)、野甘菊(Tanacetumparthenium)、百里香(Thymus vulgaris)、钩藤(Uncaria guianensis)或欧洲越桔(Vaccinum myrtillus)的提取物、ω3和ω6脂肪酸、Atrium Innovations/Unipex Group销售的NeutrazenTM[INCI:水,丁二醇,葡聚糖,棕榈酰三肽-8]、Lipotec/Lubrizol销售的DelisensTM[建议的INCI:乙酰基六肽-46]、Institut Européen de Biologie Cellulaire/Unipex Group销售的[INCI:葡聚糖,乙酰基七肽-1]、LaboratoiresSerobiologiques/Cognis/BASF销售的SkinasensylTM[INCI:乙酰基四肽-15]或AnasensylTM[INCI:甘露糖醇,甘草酸铵,咖啡因,马栗(Hippocastanum) 提取物],Shawdonyl[INCI:藻类提取物,己二醇,辛酰二醇,黄原胶]、 Mibelle销售的MAXnolia[INCI:厚朴(Magnolia Officinalis)树皮提取物,葡萄/葡萄种子提取物,维生素E]、CM-Naringenin-查耳酮[INCI:四钠四羧甲基柚皮苷查尔酮]、Induchem销售的Unisooth[INCI:没食子酸丙酯、没食子基葡糖苷(Gallyl Glucoside)、表儿茶素Galletyl葡糖苷]、Sederma/Croda 销售的CalmosensineTM[INCI:乙酰基二肽-1]、辅酶Q10或烷基甘油基醚。
组合物可以还包含额外的紧实和/或再密实和/或重建物质,例如选自以下并且不限于这些:红叶金虎(Malpighia punicitolia)、洋蓟(Cynara scolymus)、草棉(Gossypiumherbaceum)、库拉索芦荟(Aloe Barbadensis)、稷(Panicum miliaceum)、黑桑(Morusnigra)、芝麻(Sesamum indicum)、野大豆、小麦(Triticum vulgare)的提取物、Provital销售的Refirming HSC[INCI:小麦、水飞蓟(Silybum Marianum)、大豆、问荆(Equisetum Arvense)、羽衣草(Alchemilla Vulgaris)、紫花苜蓿(Medicago sativa)、萝卜(Raphanus sativus)]、 Lipout[INCI:浮游生物提取物]或Refirming[INCI:紫锥花、积雪草(Asiatic Centella)、墨角藻(Fucus)、葫芦巴(Fenugreek)]、AtriumBiotechnologies/Unipex Innovations销售的[INCI:山梨醇、藻提取物]、Pentapharm/DSM销售的[INCI:天然营养因子]、含有异黄酮的植物提取物、Sederma/Croda销售的Biopeptide ELTM[INCI:棕榈酰寡肽]、Biopeptide CLTM[INCI:棕榈酰寡肽]、[INCI:水(Aqua)、丙二醇、卵磷脂、咖啡因、棕榈酰肉碱]、[INCI:棕榈酰五肽-3]、 3000[INCI:棕榈酰四肽-3、棕榈酰寡肽]或Bio-BustylTM[INCI:甘油聚甲基丙烯酸酯、拉恩氏菌(Rahnella)大豆蛋白发酵物、水(Aqua)、丙二醇、丙三醇、 PEG-8、棕榈酰寡肽]、Laboratoires Serobiologiques/Cognis/BASF销售的HC[INCI:丙三醇、水(Aqua)、葡糖氨基葡聚糖、糖原]、[INCI:甘露醇、环糊精、糖原、熊果(Aratostaphylos Uva Ursi)叶提取物]、LS[INCI:水解酪蛋白、水解酵母蛋白、赖氨酸HCl]或LS9120[INCI:榄仁树(Terminalia catappa)叶提取物、西洋接骨木 (Sambucus Negra)花提取物、PVP、鞣酸]、Silab销售的[INCI:水解小麦蛋白]、[INCI:水解大豆细粉]或[水解大豆蛋白]、 Lipotec/Lubrizol销售的[INCI:六肽-10]、DecorinylTM[INCI:三肽-10瓜氨酸]、[INCI:假交替单胞菌发酵产物提取物、水解小麦蛋白、水解大豆蛋白、三肽-10瓜氨酸、三肽-1]、SilusyneTM[INCI:大豆(野大豆(Glycine soja))油、失水山梨糖醇倍半油酸酯、异十六烷、透明质酸钠、月桂基二甲基铵羟丙基水解大豆蛋白、乙酰基六肽-39]或AdifylineTM[INCI:乙酰基六肽-38]、Coletica/Engelhard/BASF销售的[INCI:卵磷脂、熊果酸、缺端胶原、黄原胶、软骨素硫酸钠]、Eperuline[INCI:麦芽糖糊精、镰形木荚苏木(Eperua Falcata)树皮提取物]或[INCI:水解麦芽提取物]、Pentapharm/DSM销售的[INCI:棕榈酰三肽-5]、Atrium Biotechnologies/Unipex Innovations销售的[INCI:水(Aqua)、葡糖氨基葡聚糖、小核菌胶]、Evonik销售的Sphingokine NP[INCI:己酰基(Caprooyl)植物鞘氨醇]、Lucas Meyer销售的Body3Complex[INCI:膨润土、牛油果(Butyrospermum Parkii)(乳木果)果仁提取物、鳄梨(Persea Gratissima) 果提取物]、Lonza销售的Prosynergen DF[INCI:乳杆菌 (Lactobacillus)/Ulkenia Amoeboidea发酵物提取滤液]或Institut Europeen de Biologie Cellulaire/Unipex Innovations销售的IP2000[INCI:葡聚糖、三氟乙酰三肽-2]、连同其他。
组合物可以还包含减少脂肪细胞的甘油三脂含量的物质、延缓脂肪细胞分化的物质、抗脂肪团剂、分解脂肪剂、静脉强壮剂、抑制PGC-1α表达剂或抑制PPARγ活性的物质。此类物质可以选自例如但不限于以下植物的提取物或水解提取物:羽衣草(Alchemillavulgaris),当归(Angelica sinensis),杏仁属中的种(Armeniacea sp.),山金车(Arnicamontana L),Atractylodis platicodon,竹子,桦木(Betula alba),中国柴胡(Bupleurumchinensis),金盏花(Calendula officinalis),苍术(cangzhu),聚蚁树(Cecropiaobtusifolia),鸡冠花(Celosia cristata),积雪草(Centella asiatica),藜麦(Chenopodium quinoa),金黄洋甘菊(Chrysanthellum indicum),黑类叶升麻(Cimifugaracemosa),阿玛拉橙黄柑橘(Citrus aurantium amara),藏掖花(Cnicus benedictus),小果咖啡(Coffea arabica),Cola nipida,髯毛鞘蕊花(Coleus barbatus),彩叶草(Coleusblumei),Coleus esquirolii,Coleus forskohlii, Coleus scutellaroides,Coleussp.,Coleus xanthantus,没药(Commiphora myrrha),海茴香(Crithmum maritimum),枯茗(Cuminum cyminum),薯蓣(Dioscorea colettii),Dioscorea villosa,丁香(Eugeniacaryophyllus), Filipendula ulmaria L,茴香(Foeniculum vulgare),茴香(Fucusvesiculosus),石花菜(Gelidium Cartilagineum),银杏(Ginkgo biloba)、ginkgobiloba,大豆,甘草(Glycyrrhiza glabra),常春藤(Hedera helix)(常春藤提取物),木槿(Hibiscus sabdariffa),普通大麦(Hordeum vulgare),蛇麻(Humulus lupulus),Hyperycum perforatum,巴拉圭冬青(Ilex paraguariensis),非洲吊灯树(Kigeliaafricana),掌状海带(Laminaria digitata),羽扇豆(Lupinus perennis),红莲(Nelumbium speciosum),直管草(Orthosiphon stamincus benth),人参(Panaxginseng),巴西香可可(Paullinia cupana),波耳多树(Peumus boldus),褐藻(Phyllacantha fibrosa),卡瓦胡椒(Piper methysticum),黑胡椒(Piper nigrum),夏枯草(Prunella vulgaris),甜扁桃(Prunus amygdalus dulcis),迷迭香(Rosmarinusofficinalis),悬钩子 (Rubus idaeus),假叶树(Ruscus aculeatus)(假叶树的提取物),药用鼠尾草(Salvia officinalis L),黑接骨木(Sambucus nigra),锯叶棕(Serenoarepens),灰菝葜(Smilax aristolochiaefolia),螺旋藻(Spirulina platensis) 藻类,红果蒲公英(Taraxacum erythrospermum),西洋蒲公英(Taraxacum officinale),绿茶、榆木(Ulmus rubra),绒毛钩藤(Uncaria tomentosa),马鞭草(Verbena officinalis),西洋牡荆果(Vitex agnus-castus), Dysmorphococcus globosus等,alverin,alverin柠檬酸盐,二氢杨梅酮,辅酶 A,脂肪酶,浅蓝菌素(cerulenin),芸香苷,海罂粟碱,马栗树皮甙,维司那定,咖啡因,茶碱,可可碱,氨茶碱,黄嘌呤,肉毒碱,福斯高林,七叶树溶血皂角素,鲁斯可皂甙元,常春藤素,三乙醇胺碘化物,AMPc合成诱导剂, Atrium/Unipex销售的[INCI:金黄洋甘菊(Chrysanthellum Indicum)提取物],BASF销售的Slim-ExcessTM[INCI:水,丁二醇,氯化钠,水解的角叉菜胶,黄原胶],SveltineTM[INCI:水,丁二醇,肉毒碱,卵磷脂,咖啡因,卡波姆,水杨酸,端胶原,积雪草(Centella Asiatica)提取物,马栗树皮甙,硫酸软骨素钠],Peru Liana[INCI:绒毛钩藤(Uncaria tomentosa) 提取物]或FlavengerTM[INCI:辛酸/癸酸甘油三脂,二甲基甲硅烷基化硅石,油酸甘油酯,槲皮素辛酸酯],Codif销售的Scopariane[INCI:细枝黑顶藻 (Sphacelaria Scoparia)],Phyco R75[INCI:掌状海带(Laminaria Digitata)], Pheoslim[INCI:褐藻(Phyllacantha fibrosa)提取物],Buckwheat Wax[INCI: 荞麦(Polygonum fagopyrum)]或茴香(AreaumatSamphira)[INCI:海茴香 (Crithmum Maritimum)提取物],Actiporine 8.G[甘油,水,叉珊藻(Jania Rubens)提取物],Cosmetochem销售的苗条因子KarkadeTM[INCI:木槿 (HibiscusSabdariffa)],Infinitec Activos销售的Liposuctionine[建议的INCI: 乙酰基六肽];Exsymol销售的[INCI:茶碱甲基硅烷醇甘露糖醛酸酯],Theophyllisilane[INCI:甲基硅烷醇羧甲基茶碱藻酸盐],[INCI:焦谷氨酰胺乙基吲哚]或Cafeisilane C[INCI:硅氧基三醇藻酸盐,咖啡因,丁二醇],Greentech销售的[INCI:聚葡萄糖醛酸],Indena销售的维司那定[INCI:维司那定]或银杏二聚类黄酮磷脂复合物[INCI:磷脂,银杏叶提取物],LaboratoiresSerobiologiques/Cognis/BASF 销售的LS 9509[INCI:聚蚁树(Cecropiaobtusifolia)树皮提取物], Lipotec/Lubrizol销售的SilusyneTM[INCI:大豆油,失水山梨醇倍半油酸酯,异十六烷,透明质酸钠,月桂基二甲基銨羥丙基水解的大豆蛋白,乙酰基六肽 -39]或[INCI:水,甘油,卵磷脂,咖啡因,假叶树(Ruscus Aculeatus)根提取物,麦芽糖糊精,二氧化硅,Tea-氢碘化物,丙二醇,常春藤(Hedera Helix)提取物,肉毒碱,七叶树溶血皂角素,三肽-1,黄原胶,角叉菜胶(Chondrus Crispus),EDTA二钠],Mibelle Biochemistry销售的Iso-Slim Complex[INCI:大豆异黄酮,咖啡因,肉毒碱,螺旋藻(Spirulina platensis) 提取物,聚山梨酸酯80,醇,苯氧基乙醇,水(Aqua)],Happybelle-PE[INCI: 卵磷脂,西洋牡荆果(Vitex Agnus Castus)提取物,甘油,抗坏血酸四异棕榈酸酯,维生素E,辛酸/癸酸甘油三脂,环糊精,醇,水]或AmaraShape[INCI: 卵磷脂,咖啡因,阿玛拉橙黄柑橘提取物,戊二醇,醇,水],Pentapharm/DSM 销售的[INCI:麦芽糖糊精,咖啡因,巴西香可可(Paullinia Cupana)种子提取物,肉毒碱,微晶纤维素,半胱氨酸,磺酸泛酰巯基乙胺] 或[INCI:异构化的亚油酸,卵磷脂,甘油,聚山梨酸酯80], Provital销售的ProvislimTM[INCI:丙二醇,水(Aqua),非瑟酮,山莓酮],Myriceline[INCI:二氢杨梅酮],Drenalip[INCI:假叶树根提取物,香橼(Citrus Medica Limonum)果皮提取物,一枝黄花(Solidago Virgaurea)提取物,膜荚黄芪(Astragalus Membranaceus)根提取物]或LipoutTM[INCI:浮游生物提取物],Givaudan销售的Actisculpt[INCI:没药(Commiphora Myrrha)提取物,毛喉鞘蕊花(Coleus Forskohlii)根提取物],Rahn销售的[INCI:水,肉毒碱,咖啡因,假叶树提取物]或Shape [INCI:寻常小球藻(Chlorella Vulgaris)/羽扇豆(Lupinus Albus)蛋白发酵物,毛喉鞘蕊花(Coleus Forskohlii),咖啡因],Rovi Cosmetics销售的ProContourTM[INCI:水,醇,卵磷脂,咖啡因,肉毒碱,积雪草(Centella Asiatica)叶提取物,磷酸钾,毛喉鞘蕊花(Coleus Forskohlii)根提取物], Sederma/Croda销售的UnislimTM[INCI:巴拉圭冬青(Ilex Paraguariensis)(叶) 提取物,水,丁二醇,小果咖啡(CoffeaArabica)(咖啡)种子提取物(豆), PEG-60杏仁甘油脂,甘油,十六烷基羟乙基纤维素],ReduliteTM[INCI:甘油,水,乙氧基二甘醇,黑接骨木(Sambucus nigra),聚丙烯酸钠],PleurimincylTM [INCI:咖啡因,中国柴胡(Bupleurum Chinensis)提取物],PhytotalTM SL[INCI:甘油,马鞭草(Verbena officinalis)提取物,丁二醇,黑接骨木 (Sambucus nigra)花提取物,丁香(Eugenia caryophyllus)花提取物,卵磷脂],PhytosonicTM[INCI:水,细小裸藻(Euglena Gracilis)提取物,咖啡因,黄海罂粟(Glaucium Flavum)叶提取物],OvalissTM[INCI:甘油,水,椰油基-葡糖苷,辛酰二醇,醇,海罂粟碱],LipocareTM[INCI:咖啡因,辅酶A,中国柴胡(Bupleurum Chinensis)提取物],环脂肪酶TM[INCI:甘油基聚甲基丙烯酸酯,水,咖啡因,脂肪酶,磷酸腺苷],CoaxelTM[INCI:咖啡因,辅酶 A,肉毒碱,水,甘油],BodyfitTM[INCI:甘油,Aqua(水),椰油基-葡糖苷,辛酰二醇,醇,海罂粟碱],IntenslimTM[INCI:心叶球花(Globularia Cordifolia) 愈伤组织培养物提取物,红球姜(ZingiberZerumbet)提取物,咖啡因]或Vexel [INCI:水,丙二醇,卵磷脂,咖啡因,棕榈酰肉毒碱],Seppic销售的Voluform [INCI:棕榈酰异亮氨酸],Adipoless[INCI:丁二醇,藜麦(Chenopodium quinoa)种子提取物],Silab销售的[INCI:波耳多树(Peumusboldus)叶提取物],[INCI:阿玛拉橙黄柑橘花提取物], Pro-Sveltyl[INCI:红莲(Nelumbium speciosum)提取物],[INCI: 水解的鸡冠花(Celosia cristata)花/种子提取物,水解的夏枯草(Prunella vulgaris)提取物],[INCI:水解的芫荽(Coriandrum Sativum)果实提取物,甜橙(CitrusAurantium Dulcis)(橙)果实提取物]或Stemsvelt[INCI: 水,丁二醇,水飞蓟(Silybummarinum)提取物],Solabia销售的Delipidol[INCI: 酪氨酰石榴油酸酯],[INCI:丁二醇,水,咖啡因,巴西香可可种子提取物,巴西榥榥木(PtychopetalumOlacoides)树皮提取物]或 [INCI:可可(Theobroma Cocoa)壳提取物],Soliance销售的Abdoliance[INCI: 蔗糖棕榈酸酯,聚山梨酸酯20,甘油基亚麻酸酯,巴西香可可种子提取物,麦芽糖糊精,甜扁桃(Prunus amygdalus dulcis)(甜杏仁)油,卵磷脂,水,阿玛拉橙黄柑橘(苦橙)果皮提取物,苯氧基乙醇,维生素E],Betaphroline[INCI: 灰毛豆(Tephrosia Purpurea)种子提取物]或PRO-DG[INCI:水,浮游生物提取物],Vincience/ISP销售的UCPeptideTM V[INCI:水,丁二醇,五肽]或 ATPeptideTM IS[INCI:三肽-3]等或它们的混合物。
组合物可以包含至少一种进一步的具有抗水肿特性和改善血管通透性/微循环的提取物,例如,选自Provital销售的Legactif[INCI:假叶树的根提取物,柠檬(CitrusLimon)果皮提取物,一枝黄花(Solidago Virgaurea)(秋麒麟草属植物(Goldenrod))提取物,Sederma/Croda销售的LeganceTM[INCI: 红球姜(Zingiber Zerumbet)提取物]和Eyeliss[INCI:橘皮苷甲基查耳酮,二肽-2,棕榈酰四肽-7],Greentech销售的[INCI:紫球藻 (Prophyridium Cruentum)提取物],L.Sérobiologiques/BASF销售的Biophytex[INCI:七叶树溶血皂角素,假叶树的根提取物,甘草酸铵,积雪草(CentellaAsiatica)提取物,水解的酵母蛋白,金盏花(Calendula officinalis)花提取物],Gattefossé销售的Cytobiol Lumin-Eye[INCI:烟酰胺,Franxius Excelsior树皮提取物,硅烷三醇柠檬酸钾],DSM销售的[INCI:水解的稻蛋白,氧化还原酶,大豆蛋白]。
组合物可以包含至少一种额外的具有去色素活性的提取物,例如且不限于欧蓍草(Achillea Millefolium),芦荟(Aloe vera),印度苦楝树(Azadirachta indica),紫萁(Osmunda japonica),面包树(Artocarpus incisus),鬼针草(Bidens pilosa),光叶楮(Broussonetia papyrifera),寻常小球藻(Chlorella Vulgaris),黑升麻(Cimicifugaracemosa),余甘果(Emblica officinalis),甘草(Glycyrrhiza glabra),Glycyrrhizauralensis,冬青(Ilex purpurea),当归(Ligusticum lucidum),Ligusticum wallichii,粗糙帽果(Mitracarpus scaber),海巴戟(Morinda citrifolia),白桑(Morus alba),山桑(Morus bombycis),Naringi crenulata,家李(Prunus domesticus),Pseudostellariaeradix,酸模(Rumex crispus),Rumex occidentalis,无患子(Sapindus mukurossi),虎耳草(Saxifraga sarmentosa),黄芩(Scutellaria galericulata),景天(Sedumsarmentosum Bunge),繁缕(Stellaria medica),普通小麦(Triticum Vulgare),熊果(Uvaursi)或睡茄(Withania somnifera) 的提取物等,和/或至少一种合成的化合物、提取物或衍生自生物发酵工艺的具有去色素活性的产物,例如且不限于LaboratoiresSerobiologiques/BASF销售的ActiwhiteTM LS9808[INCI:水,甘油,蔗糖二月桂酸酯,聚山梨酸酯20,豌豆(Pisum sativum)(豌豆)提取物],NF LS9410[INCI:甘露糖醇,精氨酸盐酸盐,苯丙氨酸,EDTA二钠,柠檬酸钠,曲酸,柠檬酸,酵母提取物]或RadianskinTM[INCI:羟苯氧基丙酸],Sederma销售的 LumiskinTM[INCI:辛酸/癸酸甘油三脂,二乙酰-波尔定碱],MelaclearTM [INCI:甘油,水,二噻辛二醇,葡糖酸,Sutilains,β-胡萝卜素]或EtiolineTM [INCI:甘油,丁二醇,熊果(Arctostaphylos uva ursi)叶提取物,粗糙帽果 (Mitracarpus scaber)提取物],O.D.A.WhiteTM[INCI:十八碳烯二酸],WonderlightTM[INCI:蛇麻(Humulus Lupulus)球果],Seppic销售的 SepiwhiteTM MSH[INCI:十一烯酰基苯丙氨酸]或Seashine[INCI:藻类提取物,裙带菜(UndariaPinnatifida)提取物],Vincience销售的Achromaxyl [INCI:水,欧洲油菜(Brassicanapus)提取物],Pentapharm/DSM销售的 GigawhiteTM[INCI:水,甘油,锦葵(Malvasylvestris)(锦葵)提取物,薄荷 (Mentha piperita)叶提取物,樱草(Primula veris)提取物,羽衣草 (Alchemilla Vulgaris)提取物,药用婆婆纳(Veronica officinalis)提取物,香蜂花(Melissa officinalis)叶提取物,欧蓍草(Achillea Millefolium)提取物],[INCI:白细胞提取物,AHA](白细胞提取物,α羟酸),[INCI:水,熊果(Arctostaphylos uva-ursi)叶提取物,甘油,抗坏血酸磷酸酯镁]或[INCI:白藜芦醇],Exsymol销售的 [INCI:氨基乙基磷酸,丁二醇,水],Atrium/Lucas Meyer销售的 TyrostatTM-11[INCI:水,甘油,Rumex occidentalis提取物]或[INCI:葡聚糖,九肽-1],Unipex销售的β-White[INCI:寡肽-68],Provital销售的DarkoutTM[INCI:非洲马铃薯(Hypoxis Rooperi)根状茎提取物,塔拉胶(Caesalpina Spinosa Gum)],Lonza销售的VivillumeTM [INCI:白花鹤望兰(StrelitziaNicolai)种子假种皮提取物],Lucas Meyer销售的Superox-CTM[INCI:榄仁树(TerminaliaFerdinandiana)果实提取物],熊果苷和其异构体,曲酸和其衍生物,维生素C和衍生物,例如且不限于6-O- 棕榈酰抗坏血酸,二棕榈酰抗坏血酸,抗坏血酸-2-磷酸镁盐(MAP),抗坏血酸-2-磷酸钠盐(NAP),抗坏血酸葡萄糖苷或抗坏血酸四异棕榈酸酯(VCIP) 等,视黄醇及其衍生物,包括维甲酸和异烟肼,艾地苯醌,羟基苯甲酸及其衍生物,类黄酮,大豆提取物,柠檬提取物,橙提取物,银杏提取物,黄瓜提取物,天竺葵提取物,熊果提取物,角豆提取物,肉桂提取物,马郁兰提取物,迷迭香提取物,丁香提取物,可溶性甘草提取物,黑莓叶提取物,烟酰胺,甘草苷,间苯二酚和其衍生物,氢醌,α-生育酚,γ-生育酚,壬二酸,白藜芦醇,汞盐,亚油酸,α-硫辛酸,二氢硫辛酸,α-羟基酸,β-羟基酸,鞣花酸,阿魏酸,肉桂酸,石竹素,芦荟蛋白及其衍生物和/或丝氨酸蛋白酶抑制剂,例如且不限于类胰蛋白酶、胰蛋白酶或PAR-2抑制剂等。
组合物可以包含刺激真皮大分子或表皮大分子合成的额外物质,例如选自以下并且不限于这些:胶原蛋白合成刺激剂、弹性蛋白合成刺激剂、核心蛋白聚糖合成刺激剂、层粘连蛋白合成刺激剂、伴侣蛋白合成刺激剂、去乙酰化酶 (sirtuin)合成刺激剂、去乙酰化酶活化剂、水通道蛋白合成调节物质、纤连蛋白合成刺激剂、抑制胶原蛋白降解的物质、抑制抑制弹性蛋白降解的物质、抑制丝氨酸蛋白酶如激肽释放酶、白细胞弹性蛋白酶或组织蛋白酶G的物质、刺激成纤维细胞增殖的物质、刺激脂肪细胞增殖的物质、加快或延迟脂肪细胞分化的物质、和DNA修复物质和/或DNA保护剂,如且不限制于积雪草(CentellaAsiatica)、酿酒酵母(Saccharomyces cerivisiae)、马铃薯(Solanum tuberosum)、迷迭香(Rosmarinus officinalis)、狭叶越桔(Vaccinium angustifolium)、巨藻 (Macrocystispyrifera)、粉团扇藻(Padina pavonica)的提取物、大豆、麦芽、亚麻、鼠尾草、红色车轴草、kakkon、白色羽扇豆植株的提取物、榛提取物、玉米提取物、酵母提取物、榉树苗提取物、豆科植物籽实提取物、植物激素提取物如赤霉素、植物生长激素或细胞分裂素等,或盐生浮游动物的提取物、乳的保加利亚乳杆菌(Lactobacillus bulgaricus)发酵产物、积雪草苷及其衍生物、维生素C及其衍生物、肉桂酸及其衍生物、Sederma/Croda销售的[INCI:棕榈酰五肽-3]、3000[INCI:棕榈酰四肽-3、棕榈酰寡肽] 或Biopeptide CLTM[INCI:甘油聚甲基丙烯酸酯、丙二醇、棕榈酰寡肽]、 Lipotec/Lubrizol销售的[INCI:假交替单胞菌发酵产物提取物]、[INCI:三肽-10瓜氨酸]、[INCI:六肽-10]、Lipeptide [INCI:水解植物蛋白]、[INCI:水解小麦蛋白、水解大豆蛋白、三肽-1]、RelistaseTM[INCI:乙酰基精氨酰三色氨酰联苯基甘氨酸]、 ThermostressineTM[INCI:乙酰基四肽-22]、肽AC29[INCI:乙酰基三肽-30瓜氨酸]、DiffuporineTM[INCI:乙酰基六肽-37]、SilusyneTM[INCI:大豆(野大豆)油、失水山梨糖醇倍半油酸酯、异十六烷、透明质酸钠、月桂基二甲基铵羟丙基水解大豆蛋白、乙酰基六肽-39]或AdifylineTM[INCI:乙酰基六肽-38]、 Alban Muller销售的PF[INCI:酵母β-葡聚糖]、comercializado por Solabia销售的Phytovityl[INCI:水、玉蜀黍(Zea mays)提取物]、 Coletica/Engelhard/BASF销售的[INCI:水解麦芽提取物]、 Vincience/ISP/Ashland销售的Phytocohesine PSPTM[INCI:β-谷甾醇硫酸钠]、[INCI:甲基葡糖苷磷酸盐脯氨酸赖氨酸铜复合物]、矿物质如钙等,类视黄醇及其衍生物、异黄酮类化合物、类胡萝卜素类,特别地,番茄红素、伪二肽类、类视黄醇及其衍生物如视黄醇或视黄醇棕榈酸酯等、或类肝素等。
在另一方面,本发明提供本文所述的发酵提取物在制备用于皮肤、粘膜、毛发和/或指甲的美容处理和/或护理的美容组合物中的用途。美容处理和/或护理如本文所述。
在本发明第四方面,提供了本发明的发酵提取物用于皮肤、粘膜、毛发和 /或指甲的美容处理和/或护理的用途,其中所述发酵提取物存在于如本文所述的组合物中。因此,本发明第四方面涉及一种美容组合物,其包含美容有效量的来自皮壳正青霉物种菌株的发酵提取物,用于皮肤、粘膜、毛发和/或指甲的美容处理和/或护理。美容组合物可以如本文所述。美容处理和/或护理如本文所述。
在本发明第五方面,提供了一种处理和/或护理皮肤的美容方法,其包括向皮肤施用美容有效量的发酵提取物。美容处理和/或护理如本文所述。在一个实施方案中,施用是局部的。在一个实施方案中,施用是透皮的。在一个实施方案中,通过离子导入、超声导入、电穿孔、机械压力、渗透压梯度、闭锁性治疗、微量注射,借助压力无针注射、通过微电贴剂、面罩或其任意组合实施局部或透皮施用。在本发明的这个方面,所述发酵提取物可以存在于美容组合物中,例如本文所述的美容组合物。因此,本发明提供了一种处理和/或护理皮肤的美容方法,其包括向皮肤施用包含美容有效量的发酵提取物的美容组合物。
美容有效量的发酵提取物的施加或施用的频率可以根据每位受试者的需要广泛变动,建议了一系列的从每月一次至每日10次、从每周一次至每日4 次、从每周3次至每日3次、每日1次或2次的施加或施用。
另一方面,本发明涉及一种刺激胶原蛋白或弹性蛋白合成的方法,其包括向人真皮成纤维细胞(皮肤)施用美容有效量的发酵提取物。
生物材料的保藏
根据布达佩斯条约,皮壳正青霉物种的菌株保藏于西班牙典型培养物保藏中心(Colecciónde Cultivos Tipo(CECT))(西班牙,瓦伦西亚,46980 帕特纳,卡替德拉蒂可阿古斯丁埃斯卡迪诺9,巴伦西亚公民大学(Parc Científic Universitat deValencia),3楼CUE)。在2014年3月20日进行了保藏并且保藏号是CECT-20901。
上文提到的每份文献均通过引用方式并入本文,包括所述文献要求了优先权的任何在先申请,无论上文是否具体列出。提到任何文献不是承认在任何司法管辖区这份文献视作现有技术或构成技术人员的常识。除非在实施例中或另外明确指出的情况下,本说明书中指示的材料数量、反应条件、分子量、碳原子数目等的全部数值量均理解为近似,即,所示数值的±5%、±3%、±1%、±0.1%、或±0.01%变动。应当理解可以独立地组合本文所述的量、范围和比率上限和下限。类似地,本文所述的每种技术要素的范围和量可以与任何其他要素的范围或量一起使用。
现在通过以下非限制性实施例来说明本发明。
实施例
实施例1:通过具有保藏号CECT-20901的皮壳正青霉菌株产生的发酵提取物的制备。
A)具有保藏号CECT-20901的皮壳正青霉菌株的培养方法。
具有保藏号CECT-20901的皮壳正青霉菌株在25℃和pH7.5的发酵罐中,在含有水、5g/L甘露糖醇作为碳源,5g/L酵母提取物,5g/L大豆蛋白胨作为碳和氮的来源、以及30g/L海盐的培养基中培养。用5%体积的生长的预培养物接种培养基。发酵进行约1周,在此期间向培养物供给足够的空气供应物并以150和350转/分钟之间的搅拌速度搅拌。
B)分离由具有保藏号CECT-20901的皮壳正青霉菌株产生的发酵提取物。
通过在约10000g连续离心将皮壳正青霉细胞与步骤A)产生的发酵肉汤分离。弃去上清液,用林格1/4缓冲液(氯化钠2.25g/L,氯化钾0.105g/L,氯化钙六水合物0.12g/L和碳酸氢钠0.05g/L)重新悬浮皮壳正青霉细胞。之后,使用法式压力机破碎细胞,在40KPsi操作2个循环。接下来,在搅拌的容器中用异丙醇(异丙醇:破碎的肉汤的体积比为4.7:1.0)提取破碎的肉汤3小时以上。然后,通过在40-50℃的温度旋转蒸发提取物来进行提取物的纯化。然后通过在110℃干燥(液体)提取物直到获得恒定的重量来获得样品提取物的干燥重量。具体地说,将2mL提取物在110℃干燥直到达到恒重。然后将恒重的干燥提取物用于计算提取物的干重浓度(样品的干重除以样品的重量)。这给出了10%(W/W)的值。在实施例中,除非另有说明,否则发酵提取物以液体(即,非干燥)的形式使用,并且在谈及提取物重量时,这是提取物的等效干重。将液体提取物保持在-20℃的温度直到进一步使用。
实施例2:具有保藏号CECT-20901的皮壳正青霉菌株产生的发酵提取物的物理化学特征。
对于发酵提取物的物理化学特征,对三个不同批次的具有保藏号 CECT-20901的皮壳正青霉菌株的提取物进行游离氨基酸和肽分析、糖分析(苯酚-硫酸法)和脂质含量分析。根据实施例1获得批次1。根据实施例1中所述的方案获得批次2和3,唯一的区别是使用与实施例1中所述的连续离心条件相当的不连续离心。
游离氨基酸和肽分析
使用相同的方法分析游离氨基酸和肽,区别在于游离氨基酸不进行(第i 部分)水解,而对于肽则进行(第i部分)水解。
i.水解
来自具有保藏号CECT-20901的皮壳正青霉菌株的三批发酵提取物具有以下干重:批次1具有10%(W/W)的干重浓度;批次2具有18.4%(W/W) 的干重浓度;批次3具有19.9%(W/W)的干重浓度。
对于每一批次,将25mg提取物置于10mL干净的水解管中。加入1mL 6N HCl+0.5%苯酚,并将混合物加热至110℃,持续24小时。之后,将水解的样品冷冻干燥并溶解在3mL20mM HCl中。
ii.氨基酸衍生化。
使用基于AccQ-Fluor试剂(由WATERS Cromatografia,SA)的 ACCQ-TAG化学包分析氨基酸。将加热区块预热至55℃。打开前轻拍小瓶2A 以确保所有AccQ Fluor试剂粉末在小瓶的底部。通过从小瓶2B中抽出1mL AccQ·Fluor试剂稀释液漂洗干净的微量移液管并丢弃该1mL AccQ·Fluor试剂稀释液。将1mL AccQ·Fluor试剂稀释液从小瓶2B转移到小瓶2A中的 AccQ·Fluor试剂粉末。轻轻盖上小瓶2A,并涡旋10秒钟。可以在室温于干燥器中储存该重构的AccQ·Fluor试剂长达一周。之后,必须衍生化校准标准品(含有2-100pmol/μL的每种氨基酸,除了半胱氨酸为1-50pmol/μL以外)。在洁净的样品管底部加入10μL校准标准品,然后加入70μL AccQ.Fluor硼酸盐缓冲液到样品管并短暂涡旋。之后,再添加20μL重构的AccQ.Fluor试剂到样品管并旋涡数秒钟。在室温下孵育混合物1分钟,并且然后在55℃加热小瓶 10分钟。
对样品遵循相同的方法(用水解样品替代校准标准品)。用于分析的柱是 AccQ·Fluor柱(来自WATERS),并且洗脱液是A)AccQ·Fluor洗脱液A,和B)水/乙腈(40:60)。洗脱梯度从0% B开始,0.2分钟内增加到2% B。然后,在第15分钟,B浓度升高到7%,且在19分钟时升高到10% B。B的浓度继续升高并且在第32分钟时,B的浓度为33%。然后,浓度保持稳定1 分钟,并且之后B的浓度在一分钟内增加至100%。将100% B保持恒定3分钟,以洗涤柱,并且最后将浓度回到0%,以重新开始。在所有分析期间,流速是恒定的(1mL/分钟),并且在荧光检测器(λex=250nm;λem=395nm)中进行检测。注射体积为10μI,且炉温为37℃。
基于校准标准品,计算游离氨基酸(非水解样品)和肽(总浓度,可以从其减去游离氨基酸浓度)的浓度。
糖分析(苯酚-硫酸法)
将葡萄糖的不同标准品以不同浓度溶解在水中(20至500μg/mL)。另外,将500mg苯酚溶解在10mL水中以制备5%苯酚溶液。在水中以10mg/mL制备来自具有保藏号CECT-20901的皮壳正青霉菌株的每一批发酵提取物。然后向100μL该溶液(或标准品之一)中加入100μL5%苯酚溶液。将所得溶液混合,并然后加入500μl硫酸。混合后,将反应液在40℃温育30分钟。之后,将反应在室温下保持15-20分钟,并读出490nm处的吸光度。在用葡萄糖标准品进行校准的基础上,计算样品的糖浓度。
脂质含量分析(己烷提取试验)
将批次1、2和3的各5g溶于10ml己烷中。将该溶液超声处理10分钟,并在涡旋中混合5分钟。之后,将溶液以4000转/分钟离心10分钟以分离固体。回收液相,然后将固体用5mL己烷洗涤两次,以提取所有脂质,然后弃去固体。将有机相混合并通过氮气流蒸发。之后,将从提取得到的固体在冷冻干燥器中干燥过夜并称重。将样品中脂质的浓度计算为:经提取的称重固体占被称重的总样品的百分数。
脂质含量分析(重铬酸盐试验)
该方法是上述己烷提取试验的替代方法,并且当有少量样品时该方法是有用的。将批次1、2和3的各30mg溶于2.5mL己烷中。将该溶液超声处理10 分钟,并涡旋混合5分钟。之后,将溶液以4000转/分钟离心10分钟以分离固体。回收液相,然后将固体用5mL己烷洗涤两次,以提取所有脂质,然后弃去固体。将有机相混合并通过氮气流蒸发。之后,加入3mL反应液(2.5g K2Cr2O7溶于1L H2SO4 36N),加热至100℃,持续45分钟,在不同的时间混合3次。将样品冷却至室温,并将0.2mL的等分试样稀释于2.5mL水中。之后,读取350nm处的吸光度并从空白(除了没有样品外的相同处理)中减去。差值与脂质的量成比例。使用标准样品以通过比较吸光度差异来计算脂质含量未知的样品中的脂质。
对来自具有保藏号CECT-20901的皮壳正青霉菌株的三个不同批次进行游离氨基酸和肽分析、糖分析和脂质含量分析的结果示于表1中。使用己烷提取试验获得了批次1的脂质分析结果,和使用重铬酸盐试验获得了批次2和3的脂质分析结果。
表1-游离氨基酸、肽、糖和脂质的相对重量百分比。
HPLC特征
将根据实施例1获得的来自具有保藏号CECT-20901的皮壳正青霉菌株的发酵提取物用水/异丙醇(1:4,v/v)稀释为1mg/mL,并用具有尺寸排阻柱 TSKgel G2000SWXL通过HPLC使用以下条件进行分析:柱是TSKgel G2000SWXL(7.8mm ID×30.0cm长,粒径5mm,孔径)。洗脱液为0.1M 磷酸缓冲液pH 6.7+0.1M Na2SO4,且洗脱液使用1mL/分钟的流动保持等度。检测器为紫外线(λ=220nm),注射量为25μL,且炉温度为37℃。
发酵提取物在12和12.3分钟时显示峰,高斯分布具有10至20分钟之间的保留时间。总面积的73.5%位于11至16分钟之间,且总面积的65%位于11 至14分钟之间。使用具有不同分子量的不同标准品(甲状腺球蛋白,670,000Da;白蛋白,66000Da;核糖核酸酶,13700Da;和氨基苯甲酸,122Da),从保留时间计算分子量。发酵提取物的峰(12分钟和12.3分钟)的分子量在325.9Da 和229.2Da之间,当使用标准品计算时高斯分布具有在3400Da和122Da(这是标准品的最小重量)之间的间隔。当使用标准品计算时,高斯分布下的73.5%的面积具有1053.9和122Da之间的分子量。
实施例3:通过酶联免疫吸附测定(ELISA)体外研究人皮肤成纤维细胞上的I型胶原蛋白合成。
I型胶原蛋白是皮肤中存在的胶原蛋白的主要类型,并且负责皮肤的强度和弹性。胶原蛋白随年龄退化和裂解。成纤维细胞是胶原蛋白的主要细胞生产者。因此,作为通过用候选美容活性物质处理人类皮肤成纤维细胞(HDFa)的结果,对胶原蛋白合成诱导的体外定量提供了该候选物是否作为皮肤抗老化剂有效的指示。如果候选物诱导胶原蛋白合成,这是候选物作为皮肤抗老化剂有效的指标。
通过酶联免疫吸附测定(ELISA)评估化妆品诱导的胶原蛋白。
用胰蛋白酶处理人皮肤成纤维细胞,并将5x104个细胞/孔接种在48孔板中。在37℃,5%CO2湿润空气中孵育24h(小时)后,加入新鲜培养基,将根据实施例1获得的具有保藏号CECT20901的皮壳正青霉物种菌株的提取物规模 (scalar)稀释为20-0.1μg/mL。一式三份测试每个浓度。将未处理的细胞作为对照接种在48孔板中的6孔中。将细胞在37℃,5%CO2湿润空气中培养额外的48小时。然后,收集孔的培养基,以便可以通过ELISA分析它。从1mg/ml 的储备溶液开始,用来自小牛皮肤(Sigma)的I型胶原蛋白制备标准曲线。将标准曲线稀释液和从细胞培养处理收集的上清液转移至96孔板。用样品中的和标准曲线稀释液中的胶原蛋白包被96孔板的壁,其在加湿气氛中保持在 4℃过夜。然后,将孔板用PBS-0.05%吐温-20(v:v)(Sigma)洗涤三次,并用3%牛血清白蛋白(BSA)(w:v)(Sigma)封闭1小时。封闭后,将孔板与抗胶原蛋白I型抗体(Sigma)孵育2小时。在这个孵育后,加入二级抗体 IgG-HRP(Molecular Probes)。此时,将孔板与磷酸酶底物(OPD,Sigma) 一起在搅拌下孵育30分钟。通过加入3M H2SO4停止反应,并在微量滴定板读数器TECAN GENios中读取490nm处的吸光度。使用I型胶原蛋白标准曲线的线性回归确定胶原蛋白浓度。与未处理细胞(对照)比较,胶原蛋白合成增加的结果示于表2。
表2-相对于对照,3次测定的I型胶原蛋白百分数的平均值。
结果显示,本发明的提取物促进人成纤维细胞中的I型胶原蛋白合成。
实施例4:胶原酶活性的体外测定法
胶原蛋白是皮肤结缔组织中最丰富的蛋白质。它形成网状结构,有助于在新细胞生长时支持新细胞,同时提供所需的柔性。皮肤中有持续的胶原蛋白合成和胶原蛋白降解,并且这些过程之间的平衡决定了皮肤的拉伸强度和弹性。随年龄的增长,胶原蛋白降解增加。胶原酶是一种将胶原蛋白切割成片段的金属蛋白酶。因此,认为可以抑制胶原酶活性的美容活性物质可以有效地改善皮肤抵抗力和作为皮肤抗老化剂。
用EnzChek Gelatinase/Collagenase Assay Kit(Molecular Probes)测定胶原酶活性。根据实施例1得到具有保藏号CECT20901的皮壳正青霉物种菌株的提取物,并制成浓度为10和0(对照)mg/ml提取物在反应缓冲液中的溶液。将这些溶液加入到黑色的96孔微孔板中。每个浓度一式二份测试。接下来,向每个孔加入20μL 1mg/ml DQ Gelatin和100μl胶原酶。将板在室温下避光温育2小时期间,并在多个时间点测量荧光。在微量滴定板读数器Tecan GENios中,在λexc=495nm和λem=515nm处读取荧光。
表3显示了结果,其中结果表示为对最少2次测定而言相对于对照的荧光百分数的平均值。
表3
结果显示,本发明的提取物可以抑制胶原酶活性。
实施例5:对人皮肤成纤维细胞评价弹性蛋白诱导
弹性蛋白是结缔组织中的蛋白质,其是弹性的和有助于保持皮肤柔韧但紧密,如果皮肤被拉动,则提供反弹反应。成纤维细胞是弹性蛋白的主要生产细胞。因此,通过美容活性物质对人皮肤成纤维细胞的弹性蛋白诱导的体外定量提供关于美容活性物质对皮肤潜在具有抗衰老作用的信息。如果美容活性物质诱导胶原蛋白合成,这是美容活性物质作为皮肤抗老化剂有效的指标。
通过Fastin Elastin Assay(Tebu-Bio)评估美容活性物质的弹性蛋白诱导。
用胰蛋白酶处理人皮肤成纤维细胞,并将3x105个细胞/孔接种在培养瓶中。在37℃,5% CO2潮湿空气中培养72小时后,加入新鲜培养基,其中具有根据实施例1获得的保藏号为CECT20901的皮壳正青霉物种菌株提取物浓度为 1、0.1和0.01μg/mL。将未处理的细胞作为弹性蛋白合成的阴性对照接种。每个浓度重复测试。将细胞在37℃,5% CO2潮湿空气中再培养48小时。然后,从细胞中提取弹性蛋白。为此,取出细胞培养基,用PBS(Sigma)将细胞洗涤两次,然后加入细胞解离溶液(Sigma)。将细胞悬浮液转移到微量离心管中,并且加入1M草酸,并在100℃孵育1小时。一旦弹性蛋白溶解后,使用测定试剂盒中提供的α-弹性蛋白制备标准品。从那个点起,样品和标准品一起按照弹性蛋白分离和染色的试剂盒说明进行操作。最后,用试剂盒提供的染料分离试剂提取染料,并在微量滴定板读数器TECANGENios中在540nm测量吸光度。
在表4中,对于最少3次测定显示了相对于阴性对照而言的弹性蛋白诱导百分数的平均值。
表4
结果显示,本发明的提取物促进人皮肤成纤维细胞中的弹性蛋白合成。
实施例6:弹性蛋白酶活性的体外测定
皮肤弹性是受弹性蛋白(真皮中的蛋白质)影响的机械性质,弹性蛋白与胶原蛋白和糖胺聚糖一起构成结缔组织。老化过程中结缔组织蛋白质的代谢减少,酶的存在越来越多,主要是弹性蛋白酶和胶原酶,这些酶对分解弹性蛋白和胶原蛋白负有责任。因此,防止所致的皮肤弹性丧失的一种可能的方法是使用能够抑制弹性蛋白酶活性的有效成分。
使用EnzChek Elastase Assay试剂盒(Molecular Probes)测定弹性蛋白酶活性。
根据实施例1得到具有保藏号CECT20901的皮壳正青霉物种菌株的提取物,并制成浓度为10、5、2、1和0(对照)mg/ml提取物在反应缓冲液中的溶液。将溶液加入到黑色96孔微孔板中。每个浓度重复测试。将50μl弹性蛋白工作溶液(1mg/ml)与100μl稀释的酶一起加入每个孔中。将微孔板在室温避光温育4小时,并在多个时间点测量荧光。在微量滴定板读数器TECAN GENios中,在λexc=490nm和λem=535nm处读取荧光。
在表5中,显示了对最少2次测定相对于对照而言的荧光百分数的平均值。
表5
结果表明,本发明的提取物可以抑制弹性蛋白酶活性。
实施例7:体外评估高级糖化终产物的形成
糖化是蛋白质和还原糖如葡萄糖之间的非酶反应。反应形成所谓的高级糖化终产物(AGE)。糖化改变了蛋白质的结构和功能,导致蛋白质的功能障碍。在皮肤中,认为I型胶原蛋白的糖化与皮肤迟钝的发展和皮肤弹性的降低有关。随年龄增加,糖化增加。因此,能够抑制AGEs形成的美容活性物质对改善皮肤的弹性和光泽度有影响。这类美容活性物质将是有效的皮肤抗老化剂。
在按照实施例1获得的具有保藏号CECT20901的皮壳正青霉物种菌株的提取物的存在下,温育0.2M葡萄糖和0.6%的胶原蛋白(v:v),胶原蛋白浓度为100、1和0(基础对照)μg/ml。每个浓度重复测试。所有溶液在60℃温育,在0和3天取样,并测量AGE形成。
用OxiSelectTM高级糖化终产物竞争ELISA试剂盒(Cell Biolabs)评估葡萄糖和I型胶原蛋白之间的AGE形成。然后将样品或AGE-BSA标准品加入到 AGE缀合物预吸附的ELISA板中。短暂温育后,加入抗AGE多克隆抗体,随后加入HRP(辣根过氧化物酶)缀合的第二抗体。与第二抗体孵育后,将培养板与底物溶液温育,并通过加入终止液终止反应。在微量滴定板读数器 TECAN GENios中在450nm测量吸光度。
表6显示在3次测定中相对于对照而言的AGE百分数的平均值。
表6
结果表明,当浓度为1μg/ml时,本发明的提取物抑制AGE的产生(产生的AGE的量为当没有提取物存在时产生的量的80.6%)。将提取物的量增加到100μg/ml导致对AGE产生的抑制增加,其中AGE的产生量下降到没有提取物存在时产生的AGE的70.3%。
实施例8:血管通透性的体外测定
虽然浮肿的眼睛和眼袋是由几个有贡献的因素造成的,但认为眼睛下面的过多的体液潴留或水肿被认为是主要原因之一。可能有几个原因引起体液积聚,包括淋巴循环不良和毛细血管通透性增加。因此,降低血管通透性的美容活性物质,从而减少在间质区室中积聚的体液的量,可以是用于美容处理眼睛浮肿和眼袋的良好候选物。
用胰蛋白酶处理人脐静脉内皮细胞,并将5×104个细胞/孔接种在96孔组织培养板中含有1.0μm对称孔的插入物中。在37℃,5% CO2潮湿空气中温育 72小时后,形成内皮单层并且它封闭膜孔。在这个时间点,加入新鲜培养基,其具有浓度为5、1和0.2μg/mL的根据实施例1获得的保藏号CECT20901的皮壳正青霉物种菌株的提取物。未处理的细胞用作血管通透性的对照。每个浓度一式三份进行测试。所有细胞在37℃和5% CO2温育24小时。
处理后,将FITC-葡聚糖添加到细胞的顶部,使其透过细胞单层。在20分钟后在微量滴定板读数器TECAN GENios中于λexc=485nm和λem=535nm处测量板孔溶液的荧光来确定通透性的程度。
表7显示了对于最少3次测定,相对于对照而言的血管通透性的抑制百分数的平均值。
表7
结果表明,本发明的提取物发挥抑制血管通透性,因为与当没有提取物存在比较,当提取物存在时,透过细胞单层的FITC-葡聚糖的量降低了达20.8%。
实施例9:体外测定在胆红素降解中的影响
最近,认为胆红素是眼睛周围存在暗黑眼圈的一个因素。众所周知,眼睛周围的微循环是暗黑眼圈形成中最重要的因素之一。眼睛周围的水肿中血管渗漏导致胆红素的积累,并产生颜色可以从黄色到蓝色的不同暗黑眼圈。因此,可以促进眼睛周围胆红素降解的美容活性物质可以是帮助减少暗黑眼圈的良好的美容剂。
在避光小瓶中进行试验,以避免胆红素氧化。将在水/异丙醇(1:1,v/v) 中的1mL0.1%胆红素溶液加入10ml容量瓶中。之后,加入25mg/ml的在水/ 异丙醇(1:1,v/v)中的按照实施例1获得的具有保藏号CECT20901的皮壳正青霉物种菌株的提取物4ml,然后用水/异丙醇(1:1,v/v)填充烧瓶以达到 10ml。在这些条件下,皮壳正青霉菌株提取物的终浓度为1%。同时,制备不含25mg/mL皮壳正青霉提取物的阴性对照,加入1mL 0.1%的胆红素溶液,并加入所需体积的水/异丙醇(1:1,v/v)至达到10ml容量瓶。一旦制备了两种溶液,就将它们转移到避光的玻璃小瓶中,并在室温下保持恒定搅拌。随后在不同时间通过HPLC获得胆红素浓度。
将缀合的胆红素的面积在时间零点处归一化为100%,以比较三个重复。24 小时后,1%的皮壳正青霉提取物溶液能够降低胆红素浓度19.36%。在表8中显示了不同时间处的胆红素归一化面积。
表8
结果显示,24小时后,在含有本发明提取物的样品中,存在的胆红素量为对照样品的80.64%。因此,相对于正常降解而言,实现了19.36%的胆红素降低。
实施例10:制备包含具有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的美容组合物
制备了美容组合物,其成分列于下表9。在适当的容器中,将A相的成分溶解,并一点一点加入A1相成分,同时搅拌直到达到完全分散。然后加入A2 相成分,并将所得的成分混合物不断搅拌直至它们溶解,并加热至70-75℃。
在另一个容器中,将B相成分在70-75℃熔化,并在涡旋搅拌下将其一点一点加入A、A1和A2相的各成分混合物中。
然后,在40℃,一点一点加入C相的成分,并搅拌。
随后,一点一点加入D相的组分,搅拌直到完全分散,并在搅拌下一点一点加入E相的组分直到完全分散。在搅拌下,通过加入(F相)氢氧化钠将 pH调节至6.0-6.5(适量地加入足够量的氢氧化钠调节至该pH),得到具有表 9所示比例的美容组合物。该组合物是适于局部施用的膏霜。
表9
实施例11:用实施例10的组合物进行体内研究,测试具有保藏号 CECT20901的皮壳正青霉物种菌株的发酵提取物用于处理女性志愿者的鱼尾纹的功效。
本研究进行了超过14天期间,最初在时间=0,然后14天后进行测量。包括20名志愿者,她们是40岁至54岁之间的白人女性。受试者将含有保藏号 CECT20901的皮壳正青霉物种菌株的发酵提取物的实施例10的膏霜应用于一只眼轮廓上(左侧或右侧)和将安慰膏霜应用于另一只眼轮廓上。将膏霜每天应用两次(早和晚)。受试者作为自己的参照,并且在不同时间获得的结果与在初始时间零获得的结果进行比较。此外,用活性膏霜获得的结果与用安慰膏霜获得的结果进行比较。
通过条纹投射系统(fringe projection system)对鱼尾纹(眶周)皱纹的粗糙度参数(Ra,Rz,Rt)的值来评估产品的功效:
Ra(平均粗糙度):绝对高度值的算术平均值
Rz(平均浮出):最高点和最低点之间的距离(5个峰和5个谷)
Rt(总粗糙度):(沿评估长度发现的)最高峰与最低谷之间的距离
表10-相对于初始时间的粗糙度参数而言在14天的变化百分数。
表10所示的结果表明,含有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的膏霜进行14天的处理期间,有效减少由于眶周皱纹引起的皮肤粗糙度。也就是说,皱纹的尺寸减小,起皱的皮肤变得更平滑。
实施例12:美容组合物的制备,该美容组合物包含保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物
制备美容组合物,其成分列于下表11中。在合适的容器中,将A相的成分溶解,并一点一点加入A1相成分,同时搅拌直至达到完全分散。然后加入A2 相成分,并将各成分的该混合物不断搅拌直至溶解,并加热至70-75℃。
在另一个容器中,将B相成分在70-75℃熔化,并将所得混合物在涡旋搅拌下一点一点地添加到A、A1和A2相的各成分混合物中。
然后,在40℃,一点一点加入C相的成分,并搅拌。
然后,一点一点添加D相的组分,搅拌直至全部分散,并一点一点加入E 相的成分,并搅拌直到全部分散。在搅拌下,通过加入(F相)氢氧化钠将pH 调节至6.0-6.5(适量地加入足够量的氢氧化钠调节至该pH),得到具有表11 所示比例的美容组合物。美容组合物是适用于局部使用的膏霜。
表11
实施例13:用实施例12的组合物进行体内研究,测试具有保藏号 CECT20901的皮壳正青霉物种菌株的发酵提取物处理白种皮肤型女性志愿者眼睛下暗黑眼圈的功效。
该研究进行了超过28天,在初始时间零天和然后在28天后测量。包括21 名志愿者,且她们是22岁至65岁之间的白人女性。受试者将含有保藏号 CECT20901的皮壳正青霉物种菌株的发酵提取物的实施例12的膏霜应用于一只眼轮廓上(左侧或右侧)和将安慰膏霜应用于另一只眼轮廓上。将膏霜每天应用两次(早和晚)。受试者作为自己的参照,并且在不同时间获得的结果与在初始时间零获得的结果进行比较。此外,用活性膏霜获得的结果与用安慰膏霜获得的结果进行比较。
通过用于分析血管成分的暗黑眼圈的交叉偏振光下的数码照片来评估产品的功效,结果见表12。
*按平均值计算
表12在28天时暗黑眼圈血管组分强度相对于初始时间的变化百分数
表12所示的结果表明,含有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的膏霜进行超过28天的处理期间有效减少了眼下暗黑眼圈中皮肤的暗度(即,淡化颜色)。
实施例14:制备美容组合物,其包含具有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物
制备美容组合物,其成分列于下表xx中。在适当的容器中,将A相的成分溶解,并一点一点加入A1相成分,同时搅拌直至达到完全分散。然后加入A2 相组分,并且将各成分的这种混合物不断搅拌直至它们溶解,并加热至 70-75℃。
在另一个容器中,将B相成分在70-75℃熔化,并将混合物在涡旋搅拌下一点一点加入A、A1和A2相的各组分的混合物中。然后,在40℃,在搅拌下一点一点加入C相的成分。随后,一点一点加入D相的成分,同时搅拌直到完全分散,并一点一点加入E相的组分并搅拌直到完全分散。在搅拌下,通过加入(F相)氢氧化钠将pH调节至6.0-6.5(适量地加入足够量的氢氧化钠调节至该pH),获得具有表13所示比例的美容组合物。该组合物是适用于局部应用的膏霜。
表13
实施例15:用实施例14的组合物进行体内研究,测试在女性志愿者中处理眼袋的功效。
该研究进行了超过28天,在初始时间零天,然后在14天后和然后在28天后测量。包括20名志愿者,且她们是41岁至66岁之间的白人女性。受试者将含有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的实施例14 的膏霜应用于一只眼轮廓上(左侧或右侧)和将安慰膏霜应用于另一只眼轮廓上。将膏霜每天应用两次(早和晚)。受试者作为自己的参照,并且在不同时间获得的结果与在初始时间获得的结果进行比较。此外,用活性膏霜获得的结果与用安慰膏霜获得的结果进行比较。
通过条纹投射系统评估眼袋的体积来评估产品的功效;结果示于表14中。
表14–在14天和28天眼袋体积相对于初始时间零天的变化百分数。
表14所示的结果表明,含有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的膏霜在14和28天的处理期间后有效减少眼袋的体积。
实施例16:用于人表皮黑素细胞的黑色素生成的体外测定法
黑色素生成是一种在皮肤黑素细胞内发生的过程,且其导致黑色素的合成,该黑色素是皮肤颜色的决定色素。由美容活性物质诱导的体外黑色素定量提供有关它们潜在的美白效果的信息。
用胰蛋白酶处理人黑素细胞,并在6孔板上以2x105个细胞/孔的密度铺板。在37℃,5% CO2孵育过夜后,用10、5、1和0.2μg/mL根据实施例1获得的具有保藏号CECT20901的皮壳正青霉物种菌株的提取物进行第一次处理。未处理的细胞用作对照。每个浓度重复测试。在第3、6、8和10天重复处理。最后,在最后一次处理后将细胞在37℃,5% CO2再温育额外的72小时。
在最终温育后,使细胞不贴壁,用于细胞计数和黑色素测量。将细胞悬浮液以3000转/分钟离心15分钟,将沉淀溶解于1ml具有10% DMSO的1N NaOH中(v:v)。将细胞在80℃裂解2小时,并以12000转/分钟离心10分钟。通过在平板阅读器TECAN GENios中测定450nm处的吸光度来确定黑色素浓度,并且相对于每孔的细胞数对值进行归一化。从已知浓度的合成黑色素绘制的标准曲线确定黑色素浓度,以皮克每细胞(pg/细胞)表示。
在表15中,对3次测定显示了相对于对照的黑色素百分数的平均值。
表15
表15所示的结果表明,本发明的提取物有效抑制人表皮黑素细胞中的黑色素生成(黑色素合成)。
实施例17:酪氨酸酶活性的体外测定
黑色素生成是一种在黑素细胞内发生的过程,且其导致黑色素的合成,该黑色素是皮肤颜色的决定色素。黑色素生成的关键酶是酪氨酸酶。酪氨酸酶引发将酪氨酸转化为黑色素的级联反应。因此,能够抑制酪氨酸酶活性的美容活性剂具有作为皮肤美白剂的潜力。
用HumanLike酪氨酸酶测定试剂盒(Feldan)测量酪氨酸酶活性。将200μl/ 孔的反应混合物加入到微量板的孔中,并将10μl按照实施例1获得的保藏号 CECT20901的皮壳正青霉物种菌株的提取物以100、10和1μg/ml添加。每个浓度重复测试。最后加载2μl酶。没有酶的孔用作空白。在微量滴定板读数器 TECAN GENios(Genios,Tecan)中,在λ=490nm处读取吸光度。
在表16中,对3次测定显示了相对于对照的吸光度百分数的平均值。
表16
表16所示的结果表明,本发明的提取物有效抑制酪氨酸酶活性。
实施例18:人表皮黑素细胞基因表达谱的研究
用胰蛋白酶处理人黑素细胞,并在6孔板上以2x105个细胞/孔的密度铺板。在37℃,5% CO2温育过夜后,用根据实施例1获得的具有保藏号CECT20901 的皮壳正青霉物种菌株的提取物以10μg/mL进行第一次处理。未处理的细胞用作对照。在10个孔中测试每个浓度。在第3、6、8和10天重复处理。最后,在最后一次处理后将细胞在37℃,5% CO2再温育额外的72小时。
在最后的温育后,将细胞直接在孔中裂解,并通过RNeasyPlus Mini试剂盒(Qiagen)按照制造商的方案,从每个复孔和每个条件提取和纯化RNA。简言之,将裂解的细胞进行匀浆并将核糖核酸酶灭活。通过使用gDNA Eliminator旋转柱从样品中除去基因组DNA。然后,将样品通过特殊的RNA 结合柱,并经过几次微量离心洗涤以除去污染物和杂质,用50μl超纯水洗脱纯化的RNA。
通过分光光度法(Nanodrop)和生物分析仪(Agilent Bioanalyzer)评估获得的RNA的纯度、完整性和浓度。根据纯度和完整性的结果选择四个对照样品和四个经处理的样品。
之后,进行标记并将样品在人基因表达微阵列(ASurePrint G3,Agilent) 中杂交。
将用处理样品获得的归一化值与用阴性对照获得的归一化值进行比较,以获得具有差异表达的基因。接下来,通过Bioconductor软件进行数据的参数分析。然后通过GSEA(基因集分析富集(Gene Set Analysis Enrichment))评估获得的值,根据基因本体论和生物学途径将具有差异表达的基因分组在一起。
下表中显示了对参与黑色素生成的所选基因获得的LogFc的结果。LogFC 是倍数变化(FC)的对数(基数2)。FC用于分析微阵列中的基因表达数据,以测量基因表达水平的变化。将倍数变化定义为描述比较的两个实验条件之间的量变化多少的量度,或者作为比较的两个实验条件之间的强度比。在这个意义上,具有LogFC的负值的基因相对于对照而言是下调的,而具有LogFC的正值的基因相对于对照是上调的。
表17-所选的编码参与黑色素合成的不同反应的酶的基因的LogFC值
表18-所选的编码与参与黑色素合成的酶的调节性控制有关的受体、配体和其他蛋白质的基因的LogFC值
表19-所选的参与黑素体组织或生物发生的基因的LogFC值
表18所示的结果表明,本发明的提取物能够上调或下调导致黑色素生成抑制的基因。表19和表17所示的结果表明,本发明的提取物能够下调直接参与黑素体生物发生的基因和编码参与黑色素合成的酶的基因。对于基因调控中的所有这些效应,本发明的提取物发挥抑制黑色素生成过程的作用,这导致了获得的美白效果。
实施例19:制备具有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的美容组合物
在适当的容器中,将A相的成分溶解,并一点一点加入A1相成分,并且搅拌直至达到完全分散。然后加入A2相组分,并且将各成分的这种混合物不断搅拌直至它们溶解,并加热至70-75℃。
在另一个容器中,将B相成分在70-75℃熔化,并将其在涡旋搅拌下一点一点加入到A、A1和A2相的各组分的混合物中。
然后,在40℃,在搅拌下一点一点加入C相的成分。
随后,一点一点加入D相的成分,搅拌直到完全分散,并一点一点加入E 相的组分并搅拌直到完全分散。在搅拌下,通过加入(F相)氢氧化钠将pH 调节至6.0-6.5(适量地加入足够量的氢氧化钠调节至该pH),获得具有表20 所示比例的美容组合物。
表20
实施例20:用实施例19的组合物进行体内研究,测试具有保藏号 CECT20901的皮壳正青霉物种菌株的发酵提取物用于处理亚洲皮肤型志愿者的老年斑的功效和皮肤颜色淡化效果。
该研究在56天期间进行,在初始时间和处理8周后进行测量。38岁至53 岁之间的22名亚洲女性志愿者小组将实施例19的膏霜应用于半边脸,将安慰膏霜应用于另一半边脸,每天两次(早和晚)。将受试者作为自己的参照,并将在不同时间获得的结果与初始时间获得的结果进行比较。此外,将用活性膏霜获得的结果与用安慰膏霜获得的结果进行比较。
如下评价产物的功效:
-通过光的光谱反射测量皮肤颜色,参数L*、b*和ITA°(n=22),结果示于表21。
L*:亮度参数(从暗到亮,皮肤亮度或或光泽度)
b*:色度参数(从蓝色到黄色;皮肤黄度)
ITA°(个人类型角度):[反正切函数(Arc Tangent)((L*-50)/b*)]x 180/3.14159
表21–相对于初始时间,处理8周后过多色素的区域和非过多色素的区域的变化百分数和这两个区域之间的对比度。
在不同时间(基线和8周)测量每个志愿者的每个参数(L*,b*和ITA)。然后计算每个参数的平均值,且表21中包括的%为[(8周平均值–0周平均值)/0周平均值](%)。皮肤对比度是非过多色素的区域参数的值减去过多色素的区域参数的值,即对比度是与皮肤颜色均匀性相关的参数,如果在处理结束时,皮肤颜色更均匀或不均匀。因此,对比度的负值表示皮肤颜色均匀性的改善。使用L*作为例子,对于每个志愿者计算对比度,且参数如下:L*对比度=L*非过多色素–L*过多色素。计算平均对比度值并用于计算处理期间对比度的演变:%对比度=[(在8周时的平均值–在0周时的平均值)/在 0周时的平均值]。该%包括在表21的标题对比度下。
表21所示的结果表明,含有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的膏霜进行8周的处理期间后,有效增加皮肤亮度(L*和ITA°)和在过多色素的皮肤区域(老年斑)减少皮肤黄度(b*)。此外,过多色素的区域和非过多色素的区域之间的对比度降低,显示了对老年斑的美白效果。
通过反射共焦显微镜分析过多色素的区域的黑色素强度(n=2),结果示于表22。
过多色素区域的黑色素强度 | |
安慰膏霜 | -7.19% |
活性膏霜 | -61.12% |
表22-处理8周后黑色素强度相对于初始时间的变化百分数
表22所示的结果表明,含有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的膏霜8周的处理期间后,有效降低皮肤过多色素区域(老年斑) 的黑色素强度。
实施例21:制备包含保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物的微乳液
在合适的容器中,将多库酯钠(Docusate Sodium)USP[INCI:琥珀酸二乙基己酯磺酸钠]和异硬脂酸[INCI:异硬脂酸]混合(A相)。
在另一个容器中,将根据实施例1获得的具有保藏号CECT20901的皮壳正青霉物种菌株的发酵提取物和水[INCI:水(AQUA)]以及BUTILENGLICOL 1.3[INCI:丁二醇]的混合物溶于乙醇[INCI:醇](B相)。慢慢地,在搅拌下将B相加入A相中。见表23
表23
实施例22:制备包含实施例21的微乳液的脂质纳米粒组合物
将水[INCI:水(AQUA)]、[INCI:菌核胶]、ZemeaTM[INCI:丙二醇]、透明质酸[INCI:透明质酸钠]和苯氧乙醇[INCI:苯氧基乙醇](A相成分)依次加入合适的容器中并搅拌直到达到均匀。
将包含实施例XX的微乳液、精制大豆油IP Ph.Eur.[INCI:大豆油]、Arlacel 83[INCI:失水山梨醇倍半油酸酯]和Massocare HD[INCI:异十六烷] (B相成分)的混合物加到另一个容器中。
然后,在涡旋搅拌下将B相成分的混合物加入到A相成分的混合物中直到形成乳液。
最后,在搅拌下缓慢加入SENSOMER CT-400[INCI:肉桂羟丙基三甲基氯化铵](C相)。见表24。
表24
实施例23:体外测定对重新构建的人色素沉着表皮上的黑色素生成抑制
过度色素形成是由夸张的黑色素产生引起的疾病。诸如过度的太阳暴露、老龄、激素变化、炎症、过敏等因素可能引起黑色素生成和分布过程中的不平衡,导致皮肤污渍。太阳痣(SL)(也已知为老年痣、太阳斑、肝斑或老年斑) 是划定了斑周围界限的色素斑,并且通常发现在身体的紫外线暴露区域。对出现太阳痣,目前提出的分子机制涉及刺激表皮信号通路,包括Wnt通路。 WNT-1是参与太阳痣的Wnt信号通路的激活剂。
重新构建的人色素沉着表皮(RHPE),年龄为第10天,摄影原版(phototype) IV(SkinEthic实验室)在抵达后立即从多孔板中的琼脂糖营养液中取出并放置在6孔板中,其中每孔已经事先填充有SkinEthic生长培养基(SkinEthic 实验室)。在37℃,5% CO2温育过夜后,用200ng/ml的重组人WNT-1 (Peprotech)或用200或100μg/ml根据实施例1获得的提取物与WNT-1进行第一次处理。吸出每个孔的培养基并加入新鲜培养基(含有重组人WNT-1 或者含有提取物和重组人WNT-1)。每次测定都具有对照(基础条件)孔,其中RHPE仅用生长培养基处理。每天重复处理直到第6天,即重复处理五天,组织模型包埋入Cryo-M-Bed(Bright).
处理5天后,将组织模型在4℃在4%多聚甲醛(Sigma)中固定3小时,并用磷酸盐缓冲盐水(PBS)(Sigma)洗涤4次。然后,将样品从0.6摩尔至 2.3摩尔的蔗糖梯度,在室温温育3小时。最后的温育后,将组织模型包埋入 Cryo-M-Bed。用低温恒温器(Leica)切割成10μm切片,并使用 Fontana-Masson染色试剂盒(Abcam)染色切片中的黑色素。
将组织切片与58-60℃预温的氨银溶液(Ammonical Silver Solution)温育 0-60分钟。一旦组织切片变成黄色/棕色的颜色,就将它们在几次换液的蒸馏水中漂洗。然后,将组织切片在氯化金溶液(Gold Chloride Solution)中温育30 秒,并再次漂洗。将组织切片在硫代硫酸钠溶液中温育1-2分钟,并用水龙头流下的自来水漂洗2分钟,随后进行两次换液的蒸馏水漂洗。将切片在核快红溶液(Nuclear Fast Red Solution)中温育5分钟,并用水龙头流下的自来水漂洗2分钟,随后进行两次换液的蒸馏水漂洗。最后,将这些切片在3次换液的无水酒精中脱水,清洁并安装在(Merck)中。
使用Zeiss光学显微镜观察切片,并使用Zen软件捕获图像。从每个图像中,量化染色面积的量。
表25显示了对于最少3次测定,相对于基础条件而言,黑色素含量的诱导倍数。
表25
结果表明,本发明的提取物在测试浓度下诱导了显著降低过度色素沉着的人皮肤模型中的黑色素含量。
实施例24:用于基因表达分析的体外测定法
本研究的目的是通过使用RT-qPCR阵列系统评估暗黑色素化的黑素细胞中黑色素生成途径的基因表达来研究根据实施例1获得的提取物的去色素效果。
用胰蛋白酶消化来自新生的暗黑色素供体的人表皮黑素细胞(HEMn-DP) (LifeTechnologies),并在6孔培养板上以3x105个细胞/孔的密度铺板在补充有人黑素细胞生长补充物-2(HMGS-2-(无PMA))的培养基254(Life Technologies)中。在37℃,5% CO2温育过夜后,用1μg/ml的实施例1获得的提取物或单独的培养基(基础条件)进行第一次处理。抽吸每个孔的培养基,并然后加入新鲜培养基(含有提取物或仅培养基)。在第3、6、8和10天重复该处理。最后,在最后一次处理后将细胞在37℃,5% CO2再培养额外的72 小时。
在最终温育后,按照Aurum Total RNa Mini试剂盒(BioRad)上所述的方案,根据制造商的方案,将细胞直接裂解在孔中。将裂解的细胞匀浆并灭活核糖核酸酶。然后,将样品通过特殊的RNA结合柱,并经过几次微量离心洗涤以除去污染物和杂质,用80μl洗脱液洗脱纯化的RNA。RNA洗脱后,使用生物光度计(Eppendorf)对RNA样品进行定量和纯度分析。
使用iScript advanced(BioRad)将最终体积为20μl的高质量RNA 0.4μg 逆转录。将完全反应混合物在热循环仪(Eppendorf)中在42℃温育30分钟,在85℃停止反应5分钟。在人黑色素生成96孔板中使用SsoAdvanced Universal Inhibitor-Tolerant SYBRgreen超级混合物(BioRad)和Green(BioRad) 在实时PCR热循环仪(BioRad)中通过qPCR扩增互补DNA。SYBR Green 与双链DNA分子结合并发射荧光,对荧光定量并且荧光与PCR反应中产物的量成比例。BioRad CFX96仪器中的循环条件为95℃3分钟,随后在95℃变性5秒,60℃退火和延伸30秒的40个循环。使用GAPDH(甘油醛3-磷酸脱氢酶)、TBP(TATA盒结合蛋白)和HRPT1(次黄嘌呤磷酸核糖转移酶1) 作为内源对照。使用CFX Manager软件(BioRad),使用具有默认阈值的归一化表达(ΔΔ(Ct))方法计算相对于样品基因和参照基因表达的倍数变化。
表26显示了对最少3次测定,相对于基础条件而言,所示的多个基因的相对表达水平。
表26
结果表明,本发明的提取物在试验浓度下诱导了人黑素细胞中黑色素生成基因表达的显著降低,和DKK1基因的显著增加。DKK1基因编码吞噬抑制物,其也是黑素细胞通过WNT途径增殖的抑制物。
实施例25:通过ELISA定量酪氨酸酶的体外测定法
黑色素生成中的关键酶是酪氨酸酶,其引发了将酪氨酸转化为生物聚合物黑色素的级联反应。该酶催化两个不同的反应:单酚化合物羟基化成邻二酚;以及将邻二酚氧化成邻醌。酶将酪氨酸转化为3,4-二羟基苯丙氨酸(L-多巴),并氧化L-多巴以形成多巴醌。L-多巴在黑色素生物合成中起着重要作用。
胰蛋白酶消化来自新生的暗黑色素供体的人表皮黑素细胞(HEMn-DP) (LifeTechnologies),并在96孔培养板上以5x103个细胞/孔的密度铺板在补充有人黑素细胞生长补充物-2(HMGS-2-(无PMA))的培养基254(Life Technologies)中。在37℃,5% CO2温育过夜后,用50或10μg/ml实施例1 获得的提取物或单独的培养基(基础条件)进行第一次处理。吸出每个孔的培养基,并然后加入新鲜培养基(含有50或10μg/ml提取物或仅培养基)。在第3、6、8和10天重复该处理。培养13天后,对培养的细胞使用酪氨酸酶细胞基ELISA试剂盒(Abnova)进行酶定量。首先,用磷酸盐缓冲盐水(PBS) 漂洗细胞两次,用4%甲醛固定20分钟。然后,用洗涤缓冲液洗涤细胞3次,并加入淬灭缓冲液和温育20分钟。将板再次洗涤并用封闭缓冲液封闭1小时。封闭后,将孔板与抗酪氨酸酶抗体或抗GAPDH抗体一起温育16小时。每个条件共使用6个孔,其中3个孔与抗酪氨酸酶抗体温育,且其余3个孔与抗 GAPDH抗体温育。在这个温育后,将第二抗体(对与抗酪氨酸酶抗体温育的孔,第二抗体是HRP缀合的抗兔IgG,或者对与抗GAPDH抗体温育的孔,第二抗体是HRP缀合的抗小鼠IgG)加入到相应的孔中并温育1.5小时。然后将孔板与TMB一步溶液在黑暗中温和摇动地温育30分钟。通过向每个孔中加入停止溶液来停止反应。在微量滴定板读数器(Clariostar,BMG Labtech)中读取450nm处的吸光度。GAPDH信号用于酪氨酸酶值的归一化。
表27显示了对最少3次测定,相对于基础条件而言,酪氨酸酶水平表达抑制的平均百分数。
表27
结果显示本发明的提取物在所测试的浓度下诱导了黑素细胞培养物中酪氨酸酶蛋白水平的显著降低。
实施例26:基于微球的吞噬作用的体外测定法
皮肤色素形成是由黑色素从黑素细胞转移到邻近的角质形成细胞和由它们在基底上(suprabasal)表皮层中的分布模式以及由黑素细胞中合成的黑色素的量和类型来决定的。黑色素被合成并储存在称为黑素体的特化膜结合的细胞器中。黑素体从细胞体转运到黑素细胞的周围(periphery),并从黑素细胞的树突转移到相邻的角质形成细胞中。转移后,黑素体向细胞核运送,以形成黑色素帽,其作为角质形成细胞中的内部防晒物(sunscreen)。
黑素细胞培养物的上清液获自新生的暗黑色素供体的人表皮黑素细胞 (HEMn-DP)(Life Technologies),将其在6孔培养板上以3x105个细胞/孔的密度铺板在补充有人黑素细胞生长补充物-2(HMGS-2-(无PMA),Life Technologies)的培养基254(LifeTechnologies)中。24小时后,除去培养基,并将细胞与1μg/ml实施例1获得的提取物或单独培养基(上清液对照)一起在37℃CO2培养箱中温育13天。在第3、6、8和10天重复处理。在第13 天,收集上清液并用于人表皮角质形成细胞的处理。
用胰蛋白酶处理人表皮角质形成细胞(HEKa)(Life Technologies),并将3 x105个细胞/孔接种在有盖玻片的用Coating Matrix预包被的12孔培养板中的补充有EpilifeDefined Growth Supplement(EDGS)的Epilife培养基(Life Technologies)中。在37℃,5% CO2潮湿空气中温育24小时后,加入含有100 ng/ml DKK1(R&D Systems)或经处理的黑素细胞上清液的新鲜培养基。每个板具有仅用培养基(基础条件)处理的对照孔。将板在37℃,5% CO2温育30 分钟。处理后,除去培养基,并将细胞与3x108个/ml的羧酸酯修饰的红色荧光微球(0.5μm直径,Life Technologies)温育4小时。根据制造商的说明书,预先用牛血清白蛋白(BSA)(Sigma)包被微球。温育后,用磷酸盐缓冲盐水(PBS)(Sigma)深入洗涤细胞以除去未内化的微球,并在3.7%(V/V)多聚甲醛(Sigma)中固定10分钟。细胞用PBS洗涤并在冷丙酮中温育3分钟。将样品用PBS中的1%(W/V)BSA封闭30分钟。为了可视化细胞轮廓,将细胞在黑暗中用Alexa488鬼笔环肽(Life Technologies)标记20分钟。染色细胞的细胞核,并用具有DAPI的ProLong Gold Antifade试剂(LifeTechnologies)盖上盖玻片。使用Zeiss荧光显微镜观察细胞,并使用Zen软件捕获图像用于定量。
对于微球摄取的定量分析,对于每个条件计数在三个不同实验中随机采取的六个显微镜视野中存在的微球和核的数量。每个图像的微球的数量用每个图像中的核的数量归一化。
表28显示了对于最少3次测定,相对于基础条件而言,吞噬作用的平均诱导倍数。
表28
结果显示,本发明的提取物在测试浓度下诱导了显著抑制角质形成细胞的微球摄入或吞噬作用。
Claims (48)
1.来自皮壳正青霉(Eupenicillium crustaceum)物种菌株的发酵提取物的用途,用于皮肤、粘膜、毛发和/或指甲的美容的非治疗性处理和/或护理,其中所述发酵提取物是通过在水性培养基中发酵皮壳正青霉物种菌株而获得的,且包含31至79%重量的肽、1至8%重量的游离氨基酸、10至27%重量的糖和15至40%重量的脂质,条件是百分比的总和不超过100%,所述美容的非治疗性处理和/或护理是皮肤、粘膜、毛发和/或指甲的美白;维持或改善皮肤光泽度;减轻或预防皮肤老化的迹象;处理浮肿眼;处理眼袋;维持或改善皮肤抵抗力或拉伸强度。
2.根据权利要求1所述的发酵提取物的用途,其中所述发酵提取物是通过在水性培养基中发酵皮壳正青霉物种菌株和将培养肉汤或自培养肉汤分离出的皮壳正青霉物种菌株的细胞进行溶剂提取而获得的。
3.根据权利要求1所述的发酵提取物的用途,其中所述发酵提取物具有小于3400Da的分子量。
4.根据权利要求1所述的发酵提取物的用途,其中所述皮壳正青霉物种菌株是具有保藏号CECT 20901的菌株。
5.根据权利要求1所述的发酵提取物的用途,其中所述皮肤老化的迹象是皮肤皱纹。
6.根据权利要求5所述的用途,其中所述美容的非治疗性处理和/或护理是皮肤、粘膜、毛发和/或指甲的颜色淡化。
7.根据权利要求6所述的用途,其中所述美容的非治疗性处理和/或护理是皮肤、粘膜、毛发和/或指甲的去色素。
8.根据权利要求1所述的用途,其中所述美容的非治疗性处理和/或护理是皮肤的美容的非治疗性处理和/或护理。
9.根据权利要求1所述的用途,其中皮肤的美容的非治疗性处理和/或护理是减轻或预防皮肤老化的迹象。
10.根据权利要求1所述的用途,其中皮肤的美容的非治疗性处理和/或护理是对老年斑、皮肤皱纹、暗黑眼圈、浮肿眼、眼袋中至少一种的处理。
11.根据权利要求10所述的用途,其中所述美容的非治疗性处理和/或护理是平滑或减少皮肤皱纹。
12.根据权利要求11所述的用途,其中所述皮肤皱纹是眶周皱纹。
13.根据权利要求10所述的用途,其中所述美容的非治疗性处理和/或护理是减少浮肿眼或眼袋的体积。
14.根据权利要求10所述的用途,其中所述美容的非治疗性处理和/或护理是暗黑眼圈皮肤美白。
15.根据权利要求10所述的用途,其中所述美容的非治疗性处理和/或护理是老年斑颜色淡化。
16.根据权利要求1所述的用途,其中所述美容的非治疗性处理和/或护理是皮肤光泽度的维持或改善。
17.根据权利要求1所述的用途,其中所述美容的非治疗性处理和/或护理是皮肤弹性的维持或改善。
18.根据权利要求1所述的用途,其中所述美容的非治疗性处理和/或护理是皮肤抵抗力或拉伸强度的维持或改善。
19.根据权利要求1所述的用途,其中所述发酵提取物促进胶原蛋白产生、促进弹性蛋白产生、抑制胶原酶活性、抑制弹性蛋白酶活性、抑制AGE产生、抑制血管通透性、抑制黑色素形成、抑制酪氨酸酶活性和/或促进皮肤中胆红素的破坏。
20.美容组合物,其包含美容有效量的来自皮壳正青霉物种菌株的发酵提取物和至少一种美容可接受的辅助剂和/或成分,其中所述发酵提取物是通过在水性培养基中发酵皮壳正青霉物种菌株和将培养肉汤或自培养肉汤分离出的皮壳正青霉物种菌株的细胞进行溶剂提取而获得的,其中所述发酵提取物具有小于3400Da的分子量且包含31至79%重量的肽、1至8%重量的游离氨基酸、10至27%重量的糖和15至40%重量的脂质,条件是百分比的总和不超过100%。
21.根据权利要求20所述的美容组合物,其中所述皮壳正青霉物种菌株是具有保藏号CECT 20901的菌株。
22.美容组合物,其包含美容有效量的来自皮壳正青霉物种菌株的发酵提取物和至少一种美容可接受的赋形剂,其中所述发酵提取物是通过在水性培养基中发酵皮壳正青霉物种菌株和将培养肉汤或自培养肉汤分离出的皮壳正青霉物种菌株的细胞进行溶剂提取而获得的,其中所述发酵提取物具有小于3400Da的分子量且包含31至79%重量的肽、1至8%重量的游离氨基酸、10至27%重量的糖和15至40%重量的脂质,条件是百分比的总和不超过100%。
23.根据权利要求22所述的美容组合物,其中所述皮壳正青霉物种菌株是具有保藏号CECT 20901的菌株。
24.根据权利要求20所述的美容组合物,其中将发酵提取物掺入美容可接受的递送系统或持续释放系统,所述美容可接受的递送系统或持续释放系统选自脂质体、油质体、醇质体、微粒子、纳米结构化脂质支持体、海绵、环糊精、囊泡、胶束、毫米球、微球和纳米球、脂质球、毫米胶囊、微胶囊和纳米囊、微乳液和纳米乳液;或者吸附在固态有机聚合物或固态无机支持物上,所述固态有机聚合物或固态无机支持物选自滑石、膨润土、二氧化硅、淀粉或麦芽糖糊精。
25.根据权利要求24所述的美容组合物,其中所述脂质体是混合型脂质体。
26.根据权利要求25所述的美容组合物,其中所述脂质体是乙氧基化脂肪醇类构成的脂质体。
27.根据权利要求24所述的美容组合物,其中所述纳米粒子是固态脂质纳米粒子。
28.根据权利要求20所述的美容组合物,其中这种组合物存在于制剂中,所述制剂选自溶液、液晶、含水分散体、油、乳、香脂、泡沫、水性或油性洗液、水性或油性凝胶、膏霜、搽剂、精华液、皂、洗发剂、调理剂、面罩、浆液、多糖膜、摩丝、糊剂、脂粉、棒、笔、喷雾剂或气溶胶。
29.根据权利要求20所述的美容组合物,其中这种组合物存在于制剂中,所述制剂是多重乳液。
30.根据权利要求20所述的美容组合物,其中这种组合物存在于制剂中,所述制剂是水醇溶液。
31.根据权利要求20所述的美容组合物,其中这种组合物存在于制剂中,所述制剂是水二醇溶液。
32.根据权利要求20所述的美容组合物,其中这种组合物存在于制剂中,所述制剂是软膏。
33.根据权利要求20所述的美容组合物,其中这种组合物存在于制剂中,所述制剂是喷发剂。
34.根据权利要求20至33中任一项所述的美容组合物,其中将所述组合物并入织物、非织造织物或医药用装置中。
35.根据权利要求20至33中任一项所述的组合物,其中所述辅助剂和/或成分选自减少皮脂产生的物质、哑光剂、抗痤疮剂、刺激真皮大分子或表皮大分子合成和/或能够抑制或防止它们降解的物质、防卫素合成刺激剂、伴侣蛋白合成刺激剂、cAMP合成刺激剂、调节AQP-3的物质、调节水通道蛋白合成的物质、来自水通道蛋白家族的蛋白质、透明质酸合成刺激剂、糖胺聚糖合成刺激剂、纤连蛋白合成刺激剂、去乙酰化酶合成刺激剂、热休克蛋白、热休克蛋白合成刺激剂、抑制神经元胞吐的物质、其他抑制肌肉收缩的物质、抗皱剂、止汗剂、抗炎剂和/或镇痛药、止痒剂、镇静剂、乙酰胆碱受体聚集抑制剂、皮肤舒缓剂、黑色素合成刺激或抑制剂、NO-合酶抑制剂、5α-还原酶抑制剂、赖氨酰和/或脯氨酰羟化酶抑制剂、抗氧化剂和/或抗大气污染物质、抗糖化剂、抗组胺剂、抗病毒剂、抗寄生虫剂、润滑剂、有机溶剂、液体推进剂、湿润剂、α羟酸,β羟酸、保湿剂、表皮水解酶、维生素、氨基酸、蛋白质、染料、生物聚合物、增稠剂、表面活性剂、柔化剂、能够减少或处理眼袋的物质、剥离剂、角质溶解剂、抗微生物剂、刺激脂质和角质层组分合成的物质、神经酰胺、脂肪酸、抑制胶原蛋白降解的物质、抑制基质金属蛋白酶的物质、抑制弹性蛋白降解的物质、抑制丝氨酸蛋白酶的物质、刺激成纤维细胞增殖的物质、刺激角质形成细胞增殖的物质、刺激黑素细胞增殖的物质、刺激角质形成细胞分化的物质、刺激或延缓脂肪细胞分化的物质、抗角化过度剂、抗银屑病剂、DNA修复剂、DNA保护剂、干细胞保护剂、稳定剂、处理和/或护理敏感皮肤的物质、接合剂、脂肪分解剂、调节PGC-1α表达的物质、调节PPARγ活性的物质、增加或降低脂肪细胞甘油三酯含量的物质、抑制PAR-2活性的物质、刺激再表皮化的物质、作用于毛细血管循环和/或微循环的物质、刺激血管生成的物质、抑制血管通透性的物质、静脉强壮剂、作用于细胞代谢的物质、改善真皮-表皮结合部的物质、毛发生长抑制或阻滞剂、落发阻滞剂、防腐剂、香精和/或体味掩蔽性除臭剂、螯合剂、植物提取物、精油、海洋提取物、从生物技术过程获得的物质、无机盐、有效对抗紫外A和/或B射线和/或红外A射线的有机或无机光防护剂、或它们的混合物。
36.根据权利要求20至33中任一项所述的组合物,其中所述辅助剂和/或成分选自抗胆碱能剂、抗老化剂、抑制乙酰胆碱酯酶的物质、净白剂、皮肤自褐色剂、自由基清除剂、保留水分的物质、颜料或色料、细胞提取物、或它们的混合物。
37.根据权利要求20至33中任一项所述的组合物,其中相对于所述组合物的总重量,所述组合物中所述发酵提取物的有效量基于该提取物干重为基于该组合物总重量的0.0000000001%至20%重量。
38.用于美容的非治疗性处理和/或护理皮肤的美容方法,其包括向个体局部施用有效量的来自皮壳正青霉物种菌株的发酵提取物或权利要求20至33中任一项所述的组合物,其中所述发酵提取物是通过在水性培养基中发酵皮壳正青霉物种菌株和将培养肉汤或自培养肉汤分离出的皮壳正青霉物种菌株的细胞进行溶剂提取而获得的,其中所述发酵提取物具有小于3400Da的分子量且包含31至79%重量的肽、1至8%重量的游离氨基酸、10至27%重量的糖和15至40%重量的脂质,条件是百分比的总和不超过100%,其中所述美容的非治疗性处理和/或护理是皮肤、粘膜、毛发和/或指甲的美白;维持或改善皮肤光泽度;减轻或预防皮肤老化的迹象;处理浮肿眼;处理眼袋;维持或改善皮肤抵抗力或拉伸强度。
39.根据权利要求38所述的美容方法,其中所述皮壳正青霉物种菌株是具有保藏号CECT 20901的菌株。
40.根据权利要求38所述的美容方法,其中所述皮肤美容的非治疗性处理和/或护理缓解或预防皮肤老化的迹象。
41.根据权利要求38所述的美容方法,其中所述皮肤美容的非治疗性处理和/或护理是对皮肤皱纹、暗黑眼圈、浮肿眼和/或眼袋中的至少一种的美容的非治疗性处理。
42.根据权利要求38所述的美容方法,其中所述皮肤美容的非治疗性处理和/或护理用于改善皮肤弹性、皮肤光泽度、皮肤抵抗力、皮肤紧致度和/或皮肤拉伸强度。
43.根据权利要求38所述的美容方法,其中所述皮肤美容的非治疗性处理和/或护理用于淡化皮肤的颜色。
44.根据权利要求43所述的美容方法,其中所述皮肤美容的非治疗性处理和/或护理用于淡化老年斑的颜色。
45.根据权利要求38所述的美容方法,其中所述皮肤美容的非治疗性处理和/或护理用于对皮肤增白。
46.根据权利要求38所述的美容方法,其中所述皮肤美容的非治疗性处理和/或护理用于对皮肤去色素。
47.根据权利要求38所述的美容方法,其中个体为白种人或亚洲人。
48.根据权利要求38所述的美容方法,其中所述个体的年龄在20岁以上。
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KR20170125093A (ko) | 2017-11-13 |
AU2016227434B2 (en) | 2021-05-20 |
EP3265184B1 (en) | 2020-02-19 |
WO2016139602A1 (en) | 2016-09-09 |
US10512603B2 (en) | 2019-12-24 |
ES2784350T3 (es) | 2020-09-24 |
JP6770968B2 (ja) | 2020-10-21 |
KR102611829B1 (ko) | 2023-12-07 |
CN107567329A (zh) | 2018-01-09 |
US20180042840A1 (en) | 2018-02-15 |
EP3265184A1 (en) | 2018-01-10 |
AU2016227434A1 (en) | 2017-09-21 |
BR112017018744A2 (pt) | 2018-04-17 |
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