CN106456702A - 用于治疗雄激素性脱发的四肽和甘油酯的组合 - Google Patents
用于治疗雄激素性脱发的四肽和甘油酯的组合 Download PDFInfo
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- CN106456702A CN106456702A CN201580024999.6A CN201580024999A CN106456702A CN 106456702 A CN106456702 A CN 106456702A CN 201580024999 A CN201580024999 A CN 201580024999A CN 106456702 A CN106456702 A CN 106456702A
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Abstract
本发明涉及一种组合,其包含肽和月桂酸甘油酯或其一种衍生物,所述肽包含序列A–Lys–Gly–His–Lys–NH2,其中A代表对应于C1–C18饱和或不饱和脂肪酸的基团。本发明还涉及其用于刺激头发生长的用途。
Description
技术领域
本发明涉及一种新的包含序列Lys–Gly–His–Lys的肽缀合物和月桂酸甘油酯或其衍生物的组合,以及所述组合在头发科学领域中的用途,以对抗头发微型化和治疗雄激素性脱发。
背景技术
毛囊是皮肤中固定在皮下组织的微小器官,其主要功能是产生毛干。毛囊由结缔组织鞘(CTS)、外根鞘(ORS)和内根鞘(IRS)组成,所述结缔组织鞘由成纤维细胞和细胞外基质蛋白形成,毛囊形成毛干生长时用作引导毛干的壁。毛囊的近端是毛球。毛球由真皮乳头、黑色素细胞和基质细胞组成,其是IRS的毛囊角质细胞的祖细胞和毛干的祖细胞。真皮乳头由与血管系统相连的特定成纤维细胞组成,在头发生长中起重要作用。毛囊还包含位于皮脂腺下和外根鞘内的上皮和黑色素干细胞的储备:隆突。这些细胞的特征在于漫长的细胞周期和分化成数种细胞类型(包括基质细胞)的能力(K.Krause和K.Foitzik,SeminCutan Med Surg,2006;G.Cotsarelis,American Journal of Pathology,1997)。
头发生长周期按时间表示为三个阶段(生长期(anagène)、退化期、静止期),其中最重要的是生长期(毛干成长期(phase de croissance))。
雄激素性脱发是由于头发周期的加速(缩短头发周期的长度),一种现象,其首先导致微型化头发或“毫”毛的出现,然后导致头发替换过程的早衰状况。实际上,生长期(成长期)的长度缩短,由几年(2至5年)减低至几个月,甚至几周(Whiting等人,J InvestigDermatol Symp Proc,1999)。结果是过早脱发。
现在已经知道负责雄激素性脱发的机制尤其涉及,具有雄激素受体(=睾酮和DHT受体)过表达的激素成分和更多5-α-还原酶活性。激素调节异常导致二氢睾酮(睾酮的活性代谢物)的过度生成。在真皮乳头中,该代谢物刺激头发周期抑制剂的生成,导致生长期的缩短,几个周期后必然导致毛囊产生毛干的能力的衰竭。
在脱发的一般性治疗中开发的性质还指向刺激VEGF(一种促血管生长因子)的生成。
实际上,真皮乳头(该结构控制头发生长)特征在于在生长期存在高度发达的血管网。已经显示在这个时期该乳头的细胞以强烈方式表达促血管生长因子VEGF(S.LachgarM.Charveron in“Hair for the next millenium”-Eds.DJJ Van Neste-VA Randall-H.Baden-H.Ogawa和R.Oliver-Elsevier-Amsterdam-1996-p.407–412)。该血管内皮生长因子保持新头发生长必需的血管形成,并且其发育贯穿生长期。
不同头发周期调节剂的表达由不同细胞信号通路调节,无论是在生长期活化细胞生长和分化或者是当转到退化期时建立大量细胞凋亡。这些通路本身由诱导剂和抑制剂调节,诱导剂和抑制剂的水平随周期的阶段变化,因此允许极佳地控制从一个阶段到另一个阶段的转变。
最近,某些工作已经提示Wnt/β-连环蛋白通路在确保正常头发周期中的主要作用(Lien等人,Nature Cell Biology,2014)。该信号通路,特别是在胚胎形成和头发周期的成长阶段期间,确实经常涉及高度细胞增殖现象。该通路的缺陷将导致破坏毛囊在生长期的发育。
发明内容
本发明旨在提供新的化妆品或皮肤病学组合物,其能够使Wnt/β-连环蛋白通路(经典Wnt通路)正常化,其在毛囊细胞再生中起主要作用,并且将用于治疗雄激素性脱发。
本申请人在从脱发受试者(雄激素性脱发)拔下的毛囊样品上进行研究。该研究确立AAG中头发密度下降和Wnt/β-连环蛋白信号通路破坏之间密切关系的存在。该研究显示编码Wnt/β-连环蛋白通路的抑制剂的基因的扩增导致脱发受试者的毛囊样品中相应蛋白质的增加,这看起来提示雄激素性脱发的出现涉及Wnt/β-连环蛋白通路的调节异常。
本申请人已经证明包含序列Lys–Gly–His–Lys的肽和月桂酸甘油酯或其衍生物之间抑制SFRP1基因表达水平和刺激FZD1基因表达水平的协同作用的存在,所述SFRP1基因编码Wnt/β-连环蛋白通路抑制剂,所述FZD1基因编码Wnt配体受体,所述Wnt配体受体负责真皮乳头细胞和基质细胞中Wnt/β-连环蛋白通路的活化(Reddy等人,J Invest Dermatol.,2004)。
另外,还已经证明活性剂的这种组合活化特定角蛋白(包括KRT17、KRT25、KRT27和KRT81)的基因表达水平的协同作用,所述角蛋白的表达由Wnt/β-连环蛋白通路调节,这些角蛋白是毛球上皮干细胞分化为毛囊角质细胞的标记物。
更具体地说,活性剂的这种组合通过恢复Wnt/β-连环蛋白通路功能使头发周期的更新正常化。
因此,活性剂的这种组合使其能够对抗头发周期的缩短(充当真实的头发生长“增量剂”)和头发的微型化。
因此,本发明的目的是一种组合,其包含肽和月桂酸甘油酯或其衍生物,所述肽包含序列A–Lys–Gly–His–Lys–NH2,其中A代表对应于C1–C18饱和或不饱和脂肪酸的基团。
在包含序列A–Lys–Gly–His–Lys–NH2的肽中,“A”优选代表乙酰基、棕榈酰基或硬脂酰基。
例如,这种肽描述于文献EP 1 663 285中。
在一个特定实施方案中,肽缀合物为乙酰基四肽–3,其序列为:A–Lys–Gly–His–Lys–NH2,其中A为乙酰基;相应的CAS号码为827306–88–7。
所述四肽将刺激头皮微循环并且将促进细胞代谢必需的元素的供应。
采用月桂酸甘油酯(作为5-α-还原酶抑制剂)观察到协同作用,但是该作用扩展到以下式I的月桂酸甘油酯衍生物/前体
其中
-如果X=NH,那么R1、R2、R3、R4中每一个代表氢原子;
-如果X=N,那么该环是芳香性的,并且R1、R2、R3和R4代表氢原子,或者R1、R2、R3和R4之一为甲基;并且当R2=R3=R4=H时,R1还可以代表卤素原子或芳基、杂芳基、烯基、乙炔基基团。
例如,这些衍生物描述于申请WO2013/083825中。
根据本发明的一个特定实施方案,月桂酸甘油酯和肽之间的质量比在0.5至300之间,优选1至200之间,更优选约100。
本发明进一步涉及一种包含肽和月桂酸甘油酯或其衍生物的组合,其用于治疗雄激素性脱发的局部用途,和该组合促进头发生长的用途,所述肽包含序列A–Lys–Gly–His–Lys–NH2,其中A代表对应于C1–C18饱和或不饱和脂肪酸的基团。
本发明还涉及一种化妆品或皮肤病学组合物,其包含作为抗脱发活性剂的组合,并且进一步包含至少一种化妆品学或皮肤病学上可接受的赋形剂,所述组合包含肽和月桂酸甘油酯或其衍生物,所述肽包含序列A–Lys–Gly–His–Lys,其中A代表对应于C1–C18饱和或不饱和脂肪酸的基团。
优选地,可接受的赋形剂适合于局部施用。
特别地,可接受的赋形剂提供良好的稳定性和令人愉快的质地和触感。例如,他们也可以为化妆品中已知和常用的配制剂或添加剂:可以提及表面活性剂、着色剂、防腐剂、芳香剂、成膜剂等。
根据本发明的组合物可以用于局部施用在头发和头皮上的常规已知的形式出现,即特别是,洗发精、护发素、发乳、头发洗剂或免洗喷雾。
在一个优选的实施方案中,所述组合物将为免洗喷雾的形式。
本发明的目的在于根据本发明的组合或根据本发明的化妆品组合物促进头发生长的化妆品用途。根据本发明的组合或根据本发明的化妆品组合物的化妆品用途更特别地旨在调节头发周期或促进毛囊再生。
本发明还涉及一种通过促进头发生长改善头发美观的化妆品头发护理方法,其特征在于其在于向头发和头皮应用有效量的根据本发明的组合或根据本发明的化妆品组合物,使其与头发接触,和任选地冲洗头发。
本发明的另一个目的涉及一种包含作为活性剂的根据本发明的组合的皮肤病学组合物,其用于治疗雄性激素脱发的用途。
在本发明一个优选的实施方案中,所述组合物旨在局部应用。
在一个特定的实施方案中,根据本发明的皮肤病学和化妆品组合物包含至少一种其他活性剂。
该其他活性剂可以特别地选自其他5-α-还原酶抑制剂。
根据一个特定的实施方案,根据本发明的组合物进一步包含烟碱衍生物,所述烟碱衍生物为维生素PP(烟酰胺)或选自乙基、甲基、2–乙基己基、肉豆蔻基和苄基烟酸酯的酯以及α-生育酚烟酸酯或δ-生育酚烟酸酯。
优选地,该额外抗脱发活性剂为α-生育酚烟酸酯。其充当其他活性剂的渗透促进剂,其刺激细胞代谢并且其促进皮肤微循环(刺激VEGF的生成)。
在该实施方案中,根据本发明的组合物包含一种组合,其包含肽、月桂酸甘油酯或其衍生物和α-生育酚烟酸酯,所述肽包含序列A–Lys–Gly–His–Lys,其中A代表对应于C1–C18饱和或不饱和脂肪酸的基团。
根据本发明的另一个实施方案,所述组合物将进一步包含四磷酸二鸟苷(GP4G)。
GP4G是从浮游动物盐水卤虫(Artemia Salina)中提取的海洋生物技术活性剂,并且具有以下化学结构:
根据本发明的组合物则包含一种组合,其包含肽、月桂酸甘油酯或其衍生物和GP4G,所述肽包含序列A–Lys–Gly–His–Lys。
在一个优选的实施方案中,所述组合进一步包含生育酚烟酸酯和GP4G,其中这两种额外活性剂充当亲血管复合物(complexe vasculotrope)(见EP1336402)。
在一个优选的实施方案中,所述生育酚烟酸酯和GP4G复合物以如下量存在
-相对于组合物总重量以重量计0.05%至5%之间,优选0.1%至2.5%之间的生育酚烟酸酯
-相对于组合物总重量以重量计0.01%至5%之间,优选0.05%至2.5%之间的GP4G。
在一个优选的实施方案中,最终的组合物将是透明的,优选是透明洗剂的形式。
表述“透明的组合物”是指均质(仅一相)和澄清的组合物,其允许光线透过,例如允许粘附于含有所述组合物的透明玻璃或塑料瓶的标签的背面通过所述瓶被读出。
为了那个目的,已经显示除了乙醇(10%至40%),待用的溶剂(其用于促进抗脱发产品的渗透)为异丙醇,其量为相对于组合物总重量以重量计1%至5%之间,优选2.5%。观察到异丙醇(2.5%)起到使亲脂性蜡状活性剂增溶的作用,其中活性材料小于己二醇(10%)四倍,己二醇通常用于改善进入毛囊的渗透性,所述亲脂性蜡状活性剂即生育酚烟酸酯和月桂酸甘油酯,溶剂作用不仅对产品的视觉质量是必需的,而且对增加这两种活性剂的生物利用度是必需的,这两种活性剂分别用作增加血流和调节5-α-还原酶活性。
所述组合物的轻薄质地进一步允许最佳渗透,而不引起头发油腻。从首次应用开始,头发恢复力量和活力。
根据本发明的组合物能够阻止脱发并且延长头发周期。现存的头发在数量和质量上得到保持。
具体实施方式
下面的实施例旨在阐明本发明某些特定的实施方案,并且特别地代表可用于实施本发明的某些组合物。示例性组合物中提及的赋形剂仅用于说明的目的,本领域技术人员有能力替换成其他。
材料和方法
毛囊球来自两名捐赠者的整形外科废弃物(整容),通过显微解剖分离到,用活性剂(乙酰基四肽–3、月桂酸甘油酯及其组合)培养和处理6小时。提取RNA(ARN),分析,逆转录,通过定量实时PCR分析皮脂腺毛囊中表达的一组基因的表达。
该研究产生的结果的分析导致对每个应用条件和每个研究目的基因的相对数量(QR)的计算。QR对应于相对于其基础表达水平(针对对照条件获得的表达,对照条件的QR被设定为1)的基因表达水平。因此,基因表达水平的调节当以下情况被认为是显著:
-QR大于或等于2:基因表达比对照条件高2倍;
-QR小于或等于0.5:基因表达比对照条件低2倍。
由于QR不能被加合,当活性剂组合获得的QR显著高于或低于每个活性剂单独测试时获得的QR时被认为是协同作用。
下面呈现的一组结果对应于该研究两名捐赠者获得的平均结果。
结果
在所研究的一种基因中,11种目的基因以协同方式有利地被乙酰基四肽–3(ATP–3)和月桂酸甘油酯(GL)的组合调节。
乙酰基四肽–3和月桂酸甘油酯的组合刺激COL3A1和COL7A1基因(参与毛囊固定)的表达水平和IGF1R基因(参与毛囊生长期的发育)的表达。该组合看起来还诱导SHH基因的表达且抑制BMP4基因的表达,这两种基因均参与音猬因子(Sonic Hedgehog)信号,其有助于毛囊干细胞自我更新、增殖和分化。
通过乙酰基四肽–3和月桂酸甘油酯的组合的基因表达水平的协同调节参与Wnt/β-连环蛋白信号通路。
该信号通路据称经常参与头发周期的调节(静止期→生长期转变),在生长期维持毛囊和产生新毛干方面起不可或缺的作用。实际上,其刺激毛球上皮干细胞和祖细胞向毛囊角质细胞的的增殖和分化。Wnt/β-连环蛋白通路据称被雄激素作用抑制,在治疗雄激素性脱发中恢复该信号代表了优势的来源。
受体“卷曲家族受体1”(由FZD1基因编码)是经典(Wnt/β-连环蛋白)和非经典Wnt通路的跨膜受体。在毛囊中,其由ORS细胞、基质细胞和真皮乳头细胞表达。其表达水平在静止期很低,在生长期开始时(生长期启动)增加。在ORS中,最多表达的Wnt配体是配体Wnt5a和Wnt11,据称其活化非经典Wnt通路,这使其能够调节祖干细胞由毛球向基质迁移。在基质和真皮乳头中,最多表达的Wnt配体是配体Wnt10a和Wnt10b,据称其活化Wnt/β-连环蛋白通路。
处理6小时之后,乙酰基四肽–3(ATP–3)和月桂酸甘油酯(GL)的组合协同刺激FZD1基因的表达水平。
人毛囊中FZD1基因的表达水平的监测在下表I中给出:
表I
蛋白质“分泌型卷曲相关蛋白1”(由SFRP1基因编码)是Wnt/β-连环蛋白通路的抑制剂。其具有与卷曲受体上的Wnt结合位点同源的结构域;因此其能够与Wnt蛋白结合并阻止他们与卷曲受体结合,其还能够与卷曲受体形成抑制剂复合物,由此阻止Wnt信号的活化。
Karnik等人的文章(Microarray analysis of androgenetic and senescentalopecia:Comparison of gene expression shows two distinct profiles,Journal ofDermatological Science 72(2013)183–183)描述了雄激素性脱发(AAG)的各种特异性标记物,其中之一是编码SFRP1抑制剂的基因,该基因被发现在AAG患者中相比于对照组过度表达3.73倍。
处理6小时之后,乙酰基四肽–3(ATP–3)和月桂酸甘油酯(GL)的组合协同抑制SFRP1基因的表达水平。
人毛囊中SFRP1基因的表达水平的监测在下表II中给出:
表II
在静止期-生长期转变期间和在生长期开始时,毛球上皮干细胞分化为毛囊角质细胞从而产生同心层,形成毛囊再生所必需的ORS、IRS和毛干。构成毛囊的每一层特征在于一种类型的角质细胞产生一组不同于自身的蛋白质,主要是角蛋白。因此,角蛋白是该分化的标记物,他们的表达在极大程度上由Wnt/β-连环蛋白信号通路调节。
由KRT17基因编码的角蛋白17由ORS的毛囊角质细胞表达。由KRT25和KRT27基因分别编码的角蛋白25和27由IRS的毛囊角质细胞表达。由KRT81基因编码的角蛋白81由皮质的毛囊角质细胞表达。
Karnik等人的文章(Microarray analysis of androgenetic and senescentalopecia:Comparison of gene expression shows two distinct profiles,Journal ofDermatological Science 72(2013)183–183)还显示角蛋白27为AAG的特异性标记物,KRT27基因被发现在AAG患者中相比于对照组过度表达4.92倍。
处理6小时之后,乙酰基四肽–3(ATP–3)和月桂酸甘油酯(GL)的组合协同刺激角蛋白17、25、27和81的基因表达水平。
人毛囊中KRT17基因的表达水平的监测在下表III中给出:
表III
人毛囊中KRT25基因的表达水平的监测在下表IV中给出:
表IV
人毛囊中KRT27基因的表达水平的监测在下表V中给出:
表V
人毛囊中KRT81基因的表达水平的监测在下表VI中给出:
表VI
下面给出两种透明洗剂的实施例以简单阐明本发明的目的:
实施例1:透明洗剂
0.001至0.01%的乙酰基四肽–3PP
0.05至0.3%的月桂酸甘油酯
0.01至5%的GP4G
0.05至5%的生育酚烟酸酯
0.3至1%的右泛醇
1至5%的异丙醇
2至10%的PPG–26–BUT.–26/PEG–40
10至40%的乙醇
适量芳香剂
适量水
实施例2:透明洗剂
0.001至0.01%的乙酰基四肽–3PP
0.05至0.3%的月桂酸甘油酯
0.01至5%的GP4G
0.05至5%的生育酚烟酸酯
0.3至1%的右泛醇
0.5至3%的甜菜碱水合物
1至5%的异丙醇
2至10%的PPG–26–BUT.–26/PEG–40
10至40%的乙醇
适量芳香剂
适量水
Claims (13)
1.一种组合,其包含肽和月桂酸甘油酯或其衍生物,所述肽包含序列A–Lys–Gly–His–Lys–NH2,其中A代表对应于C1–C18饱和或不饱和脂肪酸的基团。
2.根据权利要求1所述的组合,其特征在于A代表乙酰基、棕榈酰基或硬脂酰基基团。
3.根据权利要求1或2所述的组合,其特征在于月桂酸甘油酯和肽之间的质量比在0.5至300之间,优选1至200之间,更优选约100。
4.根据权利要求1至3中任一项所述的组合,其用于治疗雄激素性脱发的局部用途。
5.一种皮肤病学或化妆品组合物,其包含作为活性剂的根据权利要求1至4中任一项所述的组合,以及至少一种皮肤病学或化妆品学上可接受的赋形剂。
6.根据权利要求5所述的组合物,其特征在于肽或肽缀合物以总组合物的重量计0.001%至0.01%的量存在。
7.根据权利要求5和6任一项所述的组合物,其特征在于月桂酸甘油酯或其衍生物以总组合物的重量计0.05%至0.3%的量存在。
8.根据权利要求5至7中任一项所述的组合物,其特征在于赋形剂之一为异丙醇,所述异丙醇作为溶剂以相对于组合物总重量以重量计1%至5%,优选2.5%的量存在。
9.根据权利要求5至8中任一项所述的组合物,其特征在于其进一步包含一种其他的活性剂。
10.根据权利要求9所述的组合物,其特征在于所述其他的活性剂选自其他5-α-还原酶抑制剂及其混合物。
11.根据权利要求9所述的组合物,其特征在于所述其他的活性剂为四磷酸二鸟苷。
12.根据权利要求9所述的组合物,其特征在于所述其他的活性剂为生育酚烟酸酯。
13.根据权利要求5至12中任一项所述的皮肤病学组合物,其用于治疗脱发的用途。
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FR1454401A FR3020951B1 (fr) | 2014-05-16 | 2014-05-16 | Association d'un tetrapeptide et d'un glyceryl ester pour le traitement de l'alopecie androgenique. |
FR1454401 | 2014-05-16 | ||
PCT/EP2015/060644 WO2015173326A1 (fr) | 2014-05-16 | 2015-05-13 | Association d'un tétrapeptide et d'un glycéryl ester pour le traitement de l'alopécie androgénique. |
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