CN107428841A - 非那雄胺和肽的结合物 - Google Patents
非那雄胺和肽的结合物 Download PDFInfo
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- CN107428841A CN107428841A CN201680000881.4A CN201680000881A CN107428841A CN 107428841 A CN107428841 A CN 107428841A CN 201680000881 A CN201680000881 A CN 201680000881A CN 107428841 A CN107428841 A CN 107428841A
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- amino acid
- hair
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- finasteride
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Abstract
本发明涉及一种用于防脱发的组合物。更具体来说,本发明涉及一种用于预防脱发或促进毛发生长的化合物、包含该化合物的药物组合物或化妆品组合物,所述化合物具有通过共价键使非那雄胺与肽结合的结构。本发明的化合物具有通过共价键而使非那雄胺与肽结合的结构,其不仅具有如预防脱发、促进毛发生长、促进细胞生长等优异的生理活性,而且还具有优异的在水中的稳定性以及优异的皮肤渗透性,由此可以用作用于预防脱发和促进毛发生长的组合物。
Description
技术领域
本发明涉及一种化合物及其用于预防脱发或促进毛发生长的应用,所述化合物具有通过共价键而使非那雄胺与肽结合的结构。
背景技术
毛囊是哺乳动物皮肤特有的器官。毛囊由原始表皮向下生长,延伸到皮肤更深的层中。毛囊的基部具有被称为小囊或真皮乳头的细胞塞。真皮乳头对于毛囊的正常循环及毛干的生长而言是必需的。毛干为由填充有角蛋白丝和丝聚合蛋白(filamentaggregating protein)的紧密粘结的上皮细胞构成的螺纹状结构。
人类的毛发周期性地重复毛发生长初期(anagen)、毛发生长中期(categen)和毛发生长终期(telogen)的循环,并经过毛发脱落和再生的过程。毛发生长周期受到激素或很多生长因子的调节。严重的压力或营养不良也会使毛发过早进入毛发生长中期和毛发生长终期,由此引发严重的脱发。
头发从头皮脱落称为脱发。脱发可能由各种因素引起,包括环境因素(例如暴露于天气、光或热等)和内部因素(如疾病、生育、激素分泌和改变、药物摄入、营养条件等)。5α还原酶是介导脱发机制的主要激素(韩国专利公开No.10-2008-0077762)。5α还原酶是通过将睾酮(雄激素的一种类型)转化为双氢睾酮(DHT)从而增加皮脂分泌的一种酶。在脱发市场中,在各种用于预防脱发和促进毛发生长的产品中,有许多产品都旨在抑制5α还原酶的作用。除了酶反应,脱发也可能由营养不良、头皮干燥,压力等引起(Eunju Ryu,et al.,TheJournal of Korean Society of Design Culture,18(2),p.89-100,2012)。在由于这些原因的脱发的情况中,通过补充足够的营养、进行头皮治疗以及摄取或施用抗氧化物质就可以抑制脱发并促进毛发生长。
无论原因如何,脱发最终可能会导致自尊心和自豪感丧失,同时产生显著的精神、社会及两性影响。为了治疗脱发,迄今为止,已经将多种物质用作药品,但它们的缺点在于价格太过昂贵或者它们的效果具有巨大的个体差异。另外,就化妆品而言,虽然已经使用了廉价但效果较小的植物提取物,但效果甚微。
脱发的治疗和解决方案在很长一段时间内发生了显著的变化。可以用假发、局部假发和接发来隐藏秃发的部分,但是这并不能长出新发。此外,已知的最新的两种市售药物(米诺地尔和非那雄胺)可以延缓进一步脱发,但无法将其实际用于诱导毛囊再生的目的。另外,作为毛发化妆品产品,已经研发了很多采用植物提取物等的防脱发产品,但一直难以找到对产生新发生长有效的产品。
各种因素在头发的生长及退化的进展中相关联。例如,已经有许多关于使用一系列生长因子的报道,这些生长因子用于促进角质形成细胞生长因子、提高血管内皮生长因子的活性,以及通过抑制BMP型蛋白活性而促进毛发生长。然而,尽管这些生长因子展示出优异的效果,但是为了获得天然的生长因子,需要额外的再折叠过程和更多的时间,并且在纯化过程中,需要用于去除来自大肠杆菌的污染源的复杂纯化步骤。另外,由于其稳定性和高分子量,所以不易于穿越头发的保护层,因此,这些原因加上昂贵的成本降低了其使用。
此外,还有这样一种方法,其基于非那雄胺对雄激素的作用,通过非那雄胺对5α还原酶的拮抗作用,从而抑制头发变稀并且使变稀的头发再次变多。作为代表性例子,Propecia(Merck U.S.A.)作为第一种可食用的脱发治疗剂在1997年12月被美国食品和药物管理局(FDA)承认了其效果和稳定性,并且在第二年作为脱发治疗剂进入市场。非那雄胺是一种抑制5α还原酶的药物,5α还原酶将睾酮(一种雄激素)转化成引发脱发的DHT。通过服用该药物,DHT的产生受到抑制,所以该药物能够起到使稀少的头发再次变多变长。然而,非那雄胺发挥抑制脱发的作用需要花费几个月的时间。另外,对于女性而言,服药时出现胎儿先天畸形的可能性高,并且对于男性而言,担忧出现的副作用如性欲减退、勃起功能障碍、射精障碍等,并且仅当终生服药时才可以实现防脱发效果的压力。因此,实际临床使用有很多局限性(韩国专利公开No.10-2012-0120912)。
在这方面,本发明人研发的由SEQ ID No.3的氨基酸序列构成的Nokkin肽(韩国专利公开No.10-2010-0085407),由SEQ ID No.2的氨基酸序列构成的Keramin2肽(韩国专利公开No.10-2009-0108323)以及由SEQ ID No.1的氨基酸序列构成的WINT肽(韩国专利公开No.10-2011-0023991)比天然生长因子具有更优异的稳定性,并且可以改进由于天然生长因子的大分子量所带来的问题,同时具有与天然生长因子相同或相似的功能或效果。然而,常规使用的非那雄胺或由氨基酸序列SEQ ID No.1至3构成的多肽在改善防脱发效果和促进毛发生长、降低副作用以及提高水中溶解度等的方面仍然有待提高。
发明内容
技术任务
本发明旨在改进常规生发液的问题。本发明的技术任务在于提供一种用于预防脱发和/或促进毛发生长的物质,该物质具有与常规生发液(如天然生长因子或者由SEQ IDNo.1至3的氨基酸序列构成的肽或者非那雄胺)相同或者更优异的功能,并具有诸如皮肤渗透性以及水中稳定性等优异的生理特性。
完成技术任务的技术手段
为了完成上述技术任务,本发明提供了一种化合物,其具有通过共价键而使非那雄胺和肽结合的结构。
根据本发明的实施方案,所述肽可以由2至30个氨基酸构成,优选由5至20个氨基酸构成,更优选由8至15个氨基酸构成,还更优选由10至12个氨基酸构成,但不限于此。
根据本发明的实施方案,所述肽优选为但不限于水溶性肽。根据本发明优选的实施方案,水溶性肽具有至少50%,优选至少60%,更优选至少70%,更优选至少80%,更优选至少90%,最优选100%的具有亲水性侧链的氨基酸,因此优选该比例是高的。根据本发明的实施方案,具有亲水性侧链的氨基酸可以是带电荷的氨基酸,例如,但不限于精氨酸(Arg)、组氨酸(His)、赖氨酸(Lys)、天冬氨酸(Asp)或谷氨酸(Glu)。根据本发明的实施方案,所述水溶性肽可包含至少3个带电荷的氨基酸,优选至少5个带电荷的氨基酸,更优选至少7个带电荷的氨基酸,但不限于此。
根据本发明优选的实施方案,所述水溶性肽具有5个以下具有疏水性侧链的氨基酸,优选4个以下,更优选3个以下,更优选2个以下,更优选1个以下,最优选不包含具有亲水性侧链的氨基酸。
根据本发明的实施方案,所述肽可以是由SEQ ID No.1的氨基酸序列构成的Nokkin肽、由SEQ ID No.2的氨基酸序列构成的Keramin2肽、或由SEQ ID No.3的氨基酸序列构成的WINT肽,但不限于此。
此外,本发明提供了一种用于预防脱发或促进毛发生长的药物组合物,其包含任意一种上述的化合物。
此外,本发明提供了一种用于预防脱发或促进毛发生长的化妆品组合物,其包含任意一种上述的化合物。
根据本发明的实施方案,所述化妆品组合物可以具有如润肤液、牛奶乳液、滋养霜、按摩乳、精华素、眼霜、清洁霜、清洁泡沫、洁肤水、面膜、喷雾、粉、生发油、发乳、洗发液、洗发香波、染发液、护发素、发胶、头发喷雾、润发油、溶胶凝胶、乳液、油、蜡和气溶胶等剂型,但不限于此。
有益效果
本发明的化合物具有通过共价键使非那雄胺和肽结合的结构,其不仅具有如预防脱发、促进毛发生长、促进细胞生长等优异的生理活性,而且还具有优异的水中稳定性以及优异的皮肤渗透性,由此可以用作用于预防脱发和促进毛发生长的组合物。
附图说明
图1为示出本发明的化合物和非那雄胺在水中的溶解度的照片。
图2a和2b为示出本发明的化合物和非那雄胺对5α还原酶活性的影响的图。图2a和2b分别示出了利用本发明的化合物和非那雄胺处理后,DHT和睾酮的相对浓度。
图3a是免疫染色照片,其示出了利用本发明的化合物和非那雄胺处理后,角质形成细胞的形状和数目,图3b为示出根据化合物处理的浓度,角质形成细胞的相对数目的图。
图4a是免疫染色照片,其示出了利用本发明的化合物和非那雄胺处理后,人毛发真皮乳头细胞(HHDPC)的形状和数目,图4b为示出根据化合物处理的浓度,角质形成细胞的相对数目的图。
图5a是免疫印迹照片,其示出了利用本发明的化合物和非那雄胺处理后,在HHDPC细胞内β-链蛋白向细胞核内的转移,图5b是将该转移转换成相对于阴性对照的相对数值的图。
图6a是免疫印迹照片,其示出了利用本发明的化合物和非那雄胺处理后,在HHDPC细胞内磷酸-Smad1/5/8的表达,图6b是将该表达转换成相对于BMP2的相对数值的图。
图7a是电泳照片,其示出了利用本发明的化合物和非那雄胺处理后,在HHDPC细胞内DKK-1mRNA的表达,图7b是将该表达转换成相对于阴性对照的相对数值的图。
图8a和8b是通过动物试验确认本发明化合物对于毛发生长效果的照片。图8a比较了施用非那雄胺和本发明的化合物的小鼠毛发生长率,并且图8b利用H&E通过毛发的H&E染色确认了毛囊的数目,该毛发是施用非那雄胺和本发明的化合物的小鼠背部皮肤的毛发。
图9a和9b为示出本发明化合物的皮肤渗透性试验结果的图。
本发明的最佳实施方式
为了完成上述技术任务,本发明提供了一种化合物,其具有通过共价键而使非那雄胺和肽结合的结构。
非那雄胺是N-(1,1-二甲基乙基)-3-氧代-(5α,17β)-4-氮杂雄-1-烯-17-羧酰胺,并且具有由以下式1所表示的结构式。
[式1]
在本发明中,术语“肽”是指通过氨基酸残基的肽键形成的直链分子。肽可以通过本领域公知的生物或化学合成法来制备,特别是通过固相合成技术来制备(文献“Merrifield,J.Amer.Chem.Soc.85:2149-54(1963)”;“Stewart,et al.,Solid PhasePeptide Synthesis,2nd.ed.,Pierce Chem.Co.:Rockford,111(1984)”)。
肽用来提高非那雄胺的水溶性。在这方面,所述肽优选但不限于是水溶性肽。根据本发明的实施方案,所述肽可以由2至30个氨基酸构成,优选由5至20个氨基酸构成,更优选由8至15个氨基酸构成,还更优选由10至12个氨基酸构成。根据本发明优选的实施方案,肽具有至少50%,优选至少60%,更优选至少70%,更优选至少80%,更优选至少90%,最优选100%的具有亲水性侧链的氨基酸,因此优选该比例是高的。在另一方面,所述肽具有50%以下,优选40%以下,更优选30%以下,更优选20%以下,更优选10%以下,且最优选0%的具有疏水性侧链的氨基酸,因此优选该比例是低的。在本发明中,“具有亲水性侧链的氨基酸”是指精氨酸(Arg)、组氨酸(His)、赖氨酸(Lys)、天冬氨酸(Asp)、谷氨酸(Glu)、丝氨酸(Ser)、苏氨酸(Thr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、半胱氨酸(Cys)、硒代半胱氨酸(Sec)、甘氨酸(Gly)和脯氨酸(Pro),“具有疏水性侧链的氨基酸”是指丙氨酸(Ala)、缬氨酸(Val)、异亮氨酸(Ile)、亮氨酸(Leu)、甲硫氨酸(Met)、苯丙氨酸(Phe)、酪氨酸(Tyr)和色氨酸(Trp),但不限于此。除了存在于自然界的氨基酸,也可以使用它们的变体而没有限制。根据本发明的实施方案,具有亲水性侧链的氨基酸优选是带电荷的氨基酸,例如,但不限于精氨酸(Arg)、组氨酸(His)、赖氨酸(Lys)、天冬氨酸(Asp)或谷氨酸(Glu)。根据本发明的实施方案,所述水溶性肽可包含至少3个带电荷的氨基酸,优选至少5个带电荷的氨基酸,更优选至少7个带电荷的氨基酸,但不限于此。
根据本发明优选的实施方案,所述肽包含5个以下,优选4个以下,更优选3个以下,更优选2个以下,更优选1个以下的具有疏水性侧链的氨基酸,最优选不包含具有疏水性侧链的氨基酸。根据本发明的实施方案,所述肽可以是由SEQ ID No.1的氨基酸序列构成的Nokkin肽、由SEQ ID No.2的氨基酸序列构成的Keramin2肽、或者由SEQ ID No.3的氨基酸序列构成的WINT肽,但不限于此。
根据本发明的实施方案,本发明的化合物具有促进角质形成细胞和HHDPC细胞生长的功能。根据本发明的实施方案,本发明的化合物具有激活WNT信号通路的作用。根据本发明的实施方案,本发明的化合物使β-链蛋白(beta-catenin)转运到细胞核中。
本发明的化合物本身具有优异的稳定性,但其稳定性可以通过修饰构成与该化合物结合的肽的任意氨基酸来进一步提高。根据本发明的实施方案,为了进一步提高稳定性,所述肽的N-末端可以与以下保护基团结合,所述保护基团选自由乙酰基、芴基甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基、硬脂酰基和聚乙二醇(PEG)构成的组中。根据本发明的实施方案,为了进一步提高稳定性,所述肽可以与以下保护基团结合,所述保护基团选自由乙酰基、芴基甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基、硬脂酰基和聚乙二醇(PEG)构成的组中。
上述氨基酸的修饰极大地提高了本发明化合物的稳定性。在本发明中,使用的术语“稳定性”不仅包括“体内”稳定性,而且还包括“体外”稳定性,如储存稳定性(例如,在室温下的储存稳定性)。另外,上述保护基团保护本发明的化合物免受蛋白水解酶的体内和体外攻击。
另外,本发明提供了用于治疗或改善脱发的组合物,其包含所述化合物作为活性成分。根据本发明的实施方案,本发明提供了用于改善皮肤状况的包含所述肽作为有效成分的组合物。在本发明中,组合物可以是药物组合物或保健食品的形式,但不限于此。
由于本发明的组合物包含作为活性成分的本发明的化合物,所以省略了它们之间共同的描述,以避免导致本说明书复杂的不必要的冗余。
根据本发明的实施方案,由本发明的化合物治疗或改善脱发是指促进毛发生长或使毛发生长。根据本发明的优选的实施方案,本发明的化合物能够促进角质形成细胞和HHDPC细胞生长,促进β-链蛋白信号传递途径,这是WNT蛋白的代表性信号传递途径。通过基于该结果进行的动物试验,可以发现,本发明的化合物显着地促进毛发生长。因此,本发明的组合物在改善毛发生长和皮肤状况方面非常有效。
此外,根据本发明的实施方案,由本发明的化合物改善皮肤状况包括改善皱纹、改善皮肤弹性、防止皮肤老化、改善皮肤保湿能力、消除疤痕或使皮肤再生。
由于本发明的组合物包含作为活性成分的本发明的化合物,所以省略了它们之间共同的描述,以避免导致本说明书复杂的不必要的冗余。
根据本发明的优选的实施方案,本发明的组合物是包含(a)药学有效量的本发明的化合物;和(b)药学上可接受的载体的药物组合物。
在本说明书中,术语“药学上的有效量”是指足以实现本发明化合物的效力或活性的量。
通常用于制剂的本发明的药物组合物的药物学上可接受的载体可以包括,但不限于,乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶橡胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、甲基羟基苯甲酸酯、丙基羟基苯甲酸酯、滑石、硬脂酸镁和矿物油。除了上述成分之外,本发明的药物组合物可以进一步包含润滑剂、湿润剂、甜味剂、调味剂、乳化剂、悬浮剂和防腐剂等。合适的药物学上可接受的载体和制剂的详细内容描述于Remington's Pharmaceutical Sciences(第19版,1995)中。
本发明的药物组合物可以根据本领域普通技术人员容易实施的方法,利用药物学上可接受的载体和/或赋形剂制备成单位剂量或多剂量形式。在这种情况下,剂型可以是油质溶液或水性介质溶液、悬浮液或者乳液的形式,或者也可以是提取物、粉末、颗粒、片剂、胶囊或者凝胶(例如,水凝胶)的形式,并且可以进一步包含分散剂或者稳定剂。
根据本发明的药物组合物在临床施用中可以口服施用或者胃肠外施用,并且可以以药物制剂的一般形式使用。即,在实际临床施用中,本发明的药物组合物可以以各种口服和胃肠外剂型施用。配制时,通常可以使用常用的稀释剂或赋形剂,如填料、增稠剂、粘合剂、润湿剂、崩解剂、表面活性剂等。用于口服施用的固体制剂包括片剂、丸剂、粉末、颗粒、胶囊等,这些固体制剂通过将如淀粉、碳酸钙、蔗糖或乳糖、明胶等的至少一种赋形剂与草药提取物或草药发酵产物混合来制备。此外,除了简单的赋形剂之外,可以使用如硬脂酸镁或滑石之类的润滑剂。用于口服施用的液体制剂包括悬浮液、溶液、乳液、糖浆等,并且除了水和液体石蜡(经常使用的简单稀释剂)之外,可以包括各种赋形剂,例如湿润剂、调味剂、芳香剂、防腐剂等。用于肠胃外施用的制剂包括无菌水溶液、非水溶液、悬浮液、乳液、冻干制剂和栓剂。作为非水性溶剂或悬浮液,可以使用丙二醇、聚乙二醇、植物油(如橄榄油),可注射酯(如油酸乙酯)等。作为栓剂的基质,可以使用witepsol、聚乙二醇(Macrogol)、吐温61、可可脂、月桂脂(laurin fat)、甘油、明胶等。
单位剂型可含有(例如)1、2、3或4个单剂量或单剂量的1/2、1/3或1/4。单剂量包含在一次应用中施用的活性药物的量,这通常对应于每日剂量的全部、1/2、1/3或1/4。
本发明的药物组合物可以根据本领域的普通技术人员可以容易地实施的方法,利用药物学上可接受的载体和/或赋形剂以单位剂量或多剂量形式制备。在这种情况下,制剂可以是油质溶液或水性介质溶液、悬浮液或乳液的形式,或者可以是提取物、粉末、颗粒、片剂、胶囊或凝胶(例如,水凝胶)的形式,并且还可包含分散剂或稳定剂。
根据本发明的优选的实施方案,本发明的组合物是化妆品组合物,其包含(a)化妆品学上有效量的本发明的化合物;和(b)化妆品学上可接受的载体。
在本说明书中,术语“化妆品学上有效量”是指足以实现本发明组合物的改善皮肤的效果的量。
本发明的化妆品组合物还可以制备成在本领域中通常制备的任意剂型。例如,可以制成以下剂型:溶液、悬浮液、乳液、糊剂、凝胶、乳膏、洗剂、粉末、肥皂、含表面活性剂的清洗剂、油、粉末粉底、乳液粉底、蜡粉底及喷雾剂等,但不限于此。更详细而言,可以制备成各种形式,如润肤液、牛奶乳液、滋养霜、按摩乳、精华素、眼霜、清洁霜、清洁泡沫、洁肤水、面膜、喷雾、粉、生发油、发乳、洗发液、洗发香波、染发液、护发素、发胶、头发喷雾、润发油、如凝胶等溶液、溶胶凝胶、乳液、油、蜡、气溶胶等,但不限于此。
当本发明的制剂是糊剂、乳膏或者凝胶时,作为载体成分可以利用动物油、植物油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅、膨润土、二氧化硅、滑石或者氧化锌等。
当本发明的制剂是粉末或者喷剂时,作为载体成分可以利用乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙或者聚酰胺粉末,特别地,喷剂可以进一步包含如氯氟烃、丙烷/丁烷或者二甲醚的推进剂,但不限于此。
当本发明的制剂是溶液或者乳液时,作为载体成分可以利用溶剂、增溶剂或者乳化剂。例如,可以使用水、乙醇、异丙醇、碳酸乙酯、醋酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇油、丙三醇脂肪族酯、聚乙二醇或者山梨糖醇酐脂肪酸酯,但不限于此。
当本发明的制剂是悬浮液时,作为载体成分可以利用如水、乙醇或者丙二醇的液体稀释剂、如乙氧基异硬脂醇、聚氧乙烯山梨醇酯及聚氧乙烯山梨聚糖酯的悬浮剂、微晶性纤维素、偏氢氧化铝、膨润土、琼脂或者黄蓍胶等,但不限于此。
当本发明的制剂是含表面活性剂的清洗剂时,作为载体成分可以利用脂肪醇硫酸盐、脂肪醇醚硫酸盐、磺基琥珀酸单酯、羟乙基磺酸盐、咪唑啉盐(imidazolinium)衍生物、甲基牛磺酸、肌氨酸盐、脂肪酸酰胺醚硫酸盐、烷基酰胺甜菜碱、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂衍生物或者羟乙基化甘油脂肪酸酯等,但不限于此。
当本发明的制剂是洗发香波时,将用于构成香波的基础成分(例如增稠剂、表面活性剂、粘度调节剂、保湿剂、pH调节剂、防腐剂、精油等)与本发明的化合物混合。作为增稠剂,可以使用CDE。作为表面活性剂,可以使用阴离子表面活性剂(如LES)和两性表面活性剂(如椰油甜菜碱)。作为粘度调节剂,可以使用聚季铵盐(polyquater)。作为保湿剂,可以使用甘油。作为pH调节剂,可以使用柠檬酸和氢氧化钠。作为防腐剂,可以使用葡萄柚提取物。除此之外,还可以添加精油(如杉木、薄荷、迷迭香等)和蚕丝氨基酸、pentaol、维生素E等。根据本发明的实施方案,相对于100重量份的本发明的化合物,可以将5至10重量份的CDE、30至40重量份的LES、10至20重量份的椰油甜菜碱、0.1至0.2重量份的聚季铵盐、5至10重量份的甘油、0.1至1.01重量份的葡萄柚提取物、0.5至1重量份的蚕丝氨基酸、0.5至1重量份的pintail、0.5至2重量份的维生素E、以及0.01至0.1重量份的作为精油的杉木、薄荷、迷迭香中任意一者混合,但不限于此。
除了作为活性成分的本发明的化合物和载体成分之外,包含在本发明的化妆品组合物中的成分包括在化妆品组合物中通常使用的成分。例如,可以进一步包含常规的佐剂,如稳定剂、增溶剂、维生素、色素和香料,但不限于此。
以下,将参照实施例对本发明进行详细地说明。
然而,仅提供以下实施例用于解释本发明,而本发明的范围不限于以下实施例。
实施例1.本发明的化合物的合成
<1-1>肽的合成
<1-1-1>SEQ ID No.3的肽的合成
添加10ml的二氯甲烷(MC),之后将700mg的氯三苯甲基氯树脂(CTL树脂;Novabiochem[0064]分类No.01-64-0021)投入反应器中并搅拌3分钟。除去溶液后,添加10ml的二甲基甲酰胺(DMF)。然后,搅拌3分钟后,再次除去溶剂。向反应器中添加10ml的二氯甲烷(DCM)之后,添加200mmol的Fmoc-Cys(trt)-OH(Bachem,Swiss)和400mmol的二异丙基乙胺(DIEA),并通过搅拌充分溶解。在搅拌下反应1小时后,将混合物洗涤并用甲醇和DIEA(2:1)的DCM溶解。反应10分钟后,将混合物用过量的DCM/DMF(1:1)洗涤。除去溶液之后,随后添加10ml的DMF,并搅拌3分钟,再次除去溶剂。向反应器中添加10ml的脱保护溶液(20%哌啶/DMF),之后将混合物在室温下搅拌10分钟,然后除去该溶液。再次添加相同量的脱保护溶液,进行反应10分钟,之后除去溶液,分别用DMF洗涤两次、用MC洗涤一次并用DMF洗涤一次,分别3分钟,从而制备Cys(trt)-CTL树脂。
向另一个反应容器添加10ml的DMF后,添加200mmol的Fmoc-His(trt)-OH(Bachem,Swiss)和200mmol的Bop,并通过搅拌充分溶解。向反应容器中添加两个级分的400mmolDIEA,将混合物至少搅拌5分钟直到所有的固体溶解。将所得氨基酸混合物溶液添加到含有脱保护树脂的反应器中,并在室温下通过搅拌反应1小时。除去反应溶液后,随后用DMF溶液搅拌3次,各5分钟,将溶液去除。取出少量已反应的树脂并进行Kaiser试验(Nihydrine试验),以确定反应的程度。以如上所述相同的方式,利用脱保护溶液进行脱保护两次,制备了His(trt)-Cys(trt)-CTL树脂。用DMF和MC充分洗涤并再次进行Kaiser试验后,以上述相同的方式如下所述进行氨基酸连接。
根据所选择的氨基酸序列,以Fmoc-Cys(trt)、Fmoc-Arg、Fmoc-Gln(trt)、Fmoc-Val、Fmoc-Arg、Fmoc-Thr、Fmoc-Gln(trt)和Fmoc-Arg(pbf)的顺序进行链反应。在使Fmoc-保护基团与脱保护溶液分别反应2次,各10分钟后,充分洗涤除去溶液。添加乙酸酐、DIEA和HoBt进行乙酰化一小时后,将制备的肽基树脂洗涤3次,每次用DMF、MC和甲醇,通过缓慢流动的氮气干燥,在减压条件下,P2O5的存在下,完全干燥,间歇搅拌的条件下,在室温下与30ml的离去溶液(含有95%的三氟乙酸,2.5%的蒸馏水和2.5%的苯硫基甲烷)反应2小时。过滤该树脂并用少量TFA溶液洗涤,此后将滤液与母液合并。在减压下蒸馏以使总体积减少至约一半后,通过添加50ml的冷乙醚产生沉淀,通过离心收集形成的沉淀物,然后用冷乙醚洗涤两次。除去母液后,将所得物在氮气氛下充分干燥,从而得到0.65g的未纯化的NH2-Arg-Gln-Thr-Arg-Val-Gln-Arg-Cys-His-Cys-OH肽(SEQ ID No.3)(产率:92.6%)。使用分子量分析仪测定分子量为1287.1(理论值:1286.5)。
<1-1-2>SEQ ID No.1和SEQ ID No.2的肽的合成
使用与实施例<1-1-1>中相同的方法合成SEQ ID No.1(Glu-Leu-Ile-Glu-His-Gly-Gly-Gly-Arg-Pro-Ala-Asp:ELIEHGGGRPAD)的肽和SEQ ID No.2(Ac-Tyr-Lys-Ser-Lys-Lys-Gly-Gly-Trp-Thr-His:Ac-YKSKKGGWTH)的肽。
[表1]
<1-2>本发明的化合物的合成
添加270mg(2.0当量)的1-羟基苯并三唑(HOBt)和759mg(2.0当量)N,N,N’,N'-四甲基-O-(1H-苯并三唑-1-基)脲六氟磷酸酯、O-(苯并三唑-1-yl)-N,N,N’,N'-四甲基脲六氟磷酸酯,之后将1mmol的肽基树脂和10ml的1-甲基-2-吡咯烷酮(NMP)投入到肽反应器中并反应30分钟。添加388mg(3当量)的N,N-二异丙基乙胺(DIEA)和624mg(2.0当量)的非那雄胺类似物后,使混合物在室温下反应24至72小时,通过过滤获得反应的肽基树脂。利用裂解溶液在室温下使得到的树脂反应2小时,之后除去树脂和保护基团。用10ml(10mmol)二乙醚重结晶后,得到杂合肽。以下详细地描述了化合物的反应图解,该化合物具有通过共价键而使非那雄胺和肽结合的结构。
[反应图解1]CG-肽-非那雄胺杂合肽的反应图解
[反应图解2]CG-Nokkin-非那雄胺杂合肽的反应图解
[反应图解3]CG-Keramin2-非那雄胺杂合肽的反应图解
[反应图解4]CG-WINT-非那雄胺杂合肽的反应图解
实验例1.本发明的化合物的溶解度测试
将实施例<1-2>中制备的非那雄胺-CG-Nokkin化合物(化合物1)、非那雄胺-CG-Keramin2化合物(化合物2)、非那雄胺-CG-WINT化合物(化合物3)、以及非那雄胺各以10mg/ml的浓度分别溶解于蒸馏水中。
作为结果,可以确认非那雄胺本身几乎不溶于水,而本发明的化合物1至3均完全溶解于水中(图1)。
实验例2.本发明的化合物对5α还原酶活性影响的分析。
为了确认本发明的化合物对5α还原酶活性的影响,首先,通过蛋白提取法收集已知具有大量5α还原酶的肝细胞提取物。睾酮与非那雄胺或本发明的化合物1至3反应之后,将肝细胞提取物投入到相应的溶液中,并在37℃下反应1小时。将肝细胞提取物投入到睾酮,并使其在37℃下反应1小时的反应物是受到控制的。反应完成后,通过HPLC确认睾酮和DHT的量。在以下条件下进行HPLC分析。
-C18柱
-UV 240nm
-流速:1ml/分钟
-流动相:A:0.1%甲酸的水溶液
B:0.1%甲酸乙腈溶液
-梯度:0分钟B 5%~30分钟B 80%
结果,与对照相比,当利用非那雄胺和本发明的化合物处理时睾酮的浓度增加,并且其中DHT的浓度成比例的下降。此外,与非那雄胺处理的情况相比,可以确认,当用本发明的化合物处理时,睾酮浓度的增加与DHT浓度的降低均更加显著(参见图2a和2b)。
实验例3.本发明的化合物对角质形成细胞生长的影响
为了分析生长因子相对于实施例<1-2>中合成的化合物的相似的效果和抑制效果,根据Rizzino等人的方法,使用HaCaT角质形成细胞(韩国细胞系库)进行磺酰罗丹明B(SRB)量热测定(Rizzino,et al.Cancer Res.48:4266(1988))。
在96孔板的各孔用3,000个细胞接种之后,在5%CO2、37℃下,在Dulbecco改良Eagle培养基(DMEM,Gibco,U.S.A.)中培养HaCaT角质形成细胞24小时,所述培养基含有10%胎牛血清(FBS;Sigma)。用1%胰蛋白酶溶液处理培养的细胞系,以从培养瓶底部分离培养的细胞系,并离心以收集细胞团。将它们重悬于不含FBS的DMEM培养基中并在5%CO2、37℃下培养24小时。24小时后,用相同的不含血清培养基更换该培养基,并且在上述相同的条件下培养细胞72小时,同时在无菌条件下将空白样品溶解于10%的DMSO中作为参考,并将本发明的式1至3的化合物(50μM)、非那雄胺(50μM)和EGF(100nM)用作阳性参考。除去上清液并用乙醇固定细胞后,将细胞用磷酸盐缓冲盐溶液(PBS)洗涤三次。除去洗涤溶液后,用量热SRB溶液处理,随后用1%乙酸进行充分洗涤,在显微镜下观察细胞以评估细胞活力。另外,在560nm的紫外线下测定吸光度,从而对细胞增殖进行分析。
在用本发明的化合物处理角质形成细胞之后,72小时后观察细胞的形态变化,可以确认本发明的化合物改变了角质形成细胞的生长和形态学形状(图3a)。另外,可以确认,与非那雄胺处理的情况相比,当用本发明的化合物进行处理时,角质形成细胞的生长大大增加(图3b)。
实验例4.本发明的化合物对HHDPC细胞生长的影响
按照实验例3相同的方式确认本发明的化合物对HHDPC细胞(ATCC/U.S.A.)生长的影响。在该情况下,将MNX(10uM)和IGF-1(1uM)用作阳性对照。
结果,可以确认本发明的化合物改变了HHDPC细胞的生长和形态学形状(图4a)。另外,可以确认,与非那雄胺处理的情况相比,当用本发明的化合物进行处理时,HHDPC的生长大大增加(图4b)。
实验例5.本发明的化合物对β-链蛋白向细胞核内转移的影响的分析
在利用实施例<1-2>合成的本发明的化合物处理经培养48小时的HHDPC细胞5小时之后,测定本发明的化合物通过WNT蛋白代表性信号传递途径对β-链蛋白向细胞核内转移的影响,β-链蛋白是促进毛发生长所必须的信号物质。通过免疫印迹,使用抗β-链蛋白抗体(SantaCruz,U.S.A.),观察β-链蛋白的表达,并通过免疫组织化学使用相同的抗体确认β-链蛋白是否转移进入细胞核。具体来说,在6孔板的各孔用100,000个细胞接种后,将HHDPC细胞在37℃下在CO2培养箱中培养24小时。将培养基更换成不含血清的DMEM培养基,然后用非那雄胺、非那雄胺-WINT化合物、WINT以5μM和50μM的浓度分别处理细胞,之后将细胞培养24小时。使用蛋白提取试剂盒提取核蛋白和细胞质蛋白,之后在以下条件下进行免疫印迹。
-制备12%SDS-PAGE
-向SDS-PAGE中加载15μg的蛋白
-转移到PVDF膜
-室温下用5%脱脂奶粉溶液封闭1小时
-在室温下,与1/3000浓度的第一抗体(抗β-链蛋白抗体,抗-HDAC,抗α微管蛋白抗体)反应2小时
-用PBST洗涤三次,每次10分钟
-在室温下与1/5000浓度的第二抗体反应1小时
-用PBST洗涤三次,每次15分钟
-检测
结果,可以确认当用本发明的化合物处理时,β-链蛋白的表达增加。另外,即使使用免疫组织化学在HHDPC细胞中测定β-链蛋白是否转移到细胞核内时,也可以确认,通过本发明的化合物,β-链蛋白从细胞质转移到细胞核内,并且本发明的化合物仍然存在于细胞质内并具有活性(图5a和5b)。
实验例6.本发明的化合物对BMP信号传输抑制的影响的分析
在利用实施例<1-2>合成的本发明的化合物处理经培养48小时的HHDPC细胞5小时之后,测定本发明的化合物通过BMP蛋白代表性信号传递途径对磷酸-Smad1/5/8活性的影响,磷酸-Smad1/5/8是抑制脱发所必须的信号物质。通过免疫印迹,使用抗磷酸-Smad1/5/8抗体,确认磷酸-Smad1/5/8的表达。具体来说,在6孔板的各孔用100,000个细胞接种后,将HHDPC细胞在37℃下在CO2培养箱中培养24小时。将培养基更换成不含血清的DMEM培养基,然后用非那雄胺和非那雄胺-Nokkin化合物以0.5μM、5μM和50μM的浓度分别处理细胞,之后将细胞培养24小时。使用蛋白提取试剂盒提取核蛋白和细胞质蛋白,之后在以下条件下进行免疫印迹。
-制备12%SDS-PAGE
-向SDS-PAGE中加载15μg的蛋白
-转移到PVDF膜
-室温下用5%脱脂奶粉溶液封闭1小时
-在室温下,与1/3000浓度的第一抗体(抗-磷酸-Smad1/5/8抗体,抗-HDAC,抗α微管蛋白抗体)反应2小时
-用PBST洗涤三次,每次10分钟
-在室温下与1/5000浓度的第二抗体反应1小时
-用PBST洗涤三次,每次15分钟
-检测
结果,可以确认当用本发明的化合物进行处理时,在细胞核内磷酸-Smad1/5/8的表达下降(图6a和6b)。
实验例7.本发明的化合物对DKK-1表达影响的分析
确认了本发明化合物对DKK-1的mRNA表达的影响,DKK-1是由DHT表达的典型的脱发蛋白。具体来说,在6孔板的各孔用100,000个细胞接种后,将HHDPC细胞在37℃下在CO2培养箱中培养24小时。使睾酮与非那雄胺或本发明的化合物1至3的非那雄胺-Nokkin化合物、非那雄胺-Keramin2化合物和非那雄胺-WINT化合物反应,之后将肝细胞提取物置于相应的溶液中并在37℃下反应1小时。将肝细胞提取物投入睾酮,并使其在37℃反应1小时的反应物用作阳性对照。将培养基更换成不含血清的DMEM培养基,然后用非那雄胺、非那雄胺-Nokkin化合物、非那雄胺-Keramine2化合物和非那雄胺-WINT化合物以50μM的浓度分别处理细胞,之后将细胞培养24小时。使用RNA提取试剂盒提取细胞的RNA之后,使用下列引物进行RT-PCR。
1.DKK-1
-正向引物:(5')TGATGAGTACTGCGCTAGTC(3’)(SEQ ID No.4)
-反向引物:(5')CTCCTATGCTTGGTACACAC(3')(SEQ ID No.5)
2.GAPDH
-正向引物:(5')GGAGCCAAAAGGGTCATCAT(3')(SEQ ID No.6)
-反向引物:(5')GTGATGGCATGGACTGTGGT(3')(SEQ ID No.7)
结果,可以确认与利用非那雄胺处理的情况相比,在阳性对照中本发明的化合物更加进一步抑制增加的DKK-1的表达,特别地,其能够将DKK-1的表达抑制到甚至低于未利用任何物质进行处理的阴性对照的水平(图7a和7b)。
实验例8.毛发生长试验
通过动物试验确认本发明的化合物对于毛发生长的影响。具体而言,使用脱毛膏除去7周龄雄性C57BL/6小鼠背部的毛发。制备PBS,浓度为100μg/ml的非那雄胺和本发明的非那雄胺-WINT化合物,然后将其均匀地施加于小鼠背部皮肤,每天一次,从颜色开始变黑的时间点开始,通过拍照观察小鼠背部皮肤的颜色。
然后,处死小鼠,并通过H&E染色,观察背部皮肤的毛发。为此,收集小鼠的背部皮肤,并在4%多聚甲醛(PFA)中固定,之后进行石蜡包埋。切割4μm厚的包埋小鼠的背部皮肤,之后通过H&E染色确认毛囊的数量。
结果,可以确认与施加PBS或非那雄胺的小鼠相比,施加本发明的非那雄胺-WINT化合物的小鼠明显显示出更快的毛发生长速度(图8a),并且与对照组和施用非那雄胺的组相比,毛囊数显著增多(图8b)。
实验例9.皮肤渗透性试验
由于非那雄胺是一种药物控制的类固醇型激素,当口服施用时,可能会有副作用,例如通过血液传播引起全身毒性。因此,如果其渗透皮肤(即使施加在皮肤上),则可能渗入到整个身体并引起毒性,如果它不渗透皮肤,由于它残留在头皮并且不扩散到整个身体中,那么就可以抑制非那雄胺的副作用。在这方面,在三维人造皮肤上施加非那雄胺和本发明的非那雄胺-WINT化合物,之后发明人对其是否渗入皮肤进行了验证。
为此,将非那雄胺和本发明的非那雄胺-WINT化合物分别混入10%乙醇、40%丙二醇和50%纯水的混合溶剂中。使用三维人造皮肤进行Franz膨胀细胞试验。分别将1ml的非那雄胺和非那雄胺-WINT化合物溶液施加在三维人造皮肤上,并静置24小时。对接收室溶液进行采样后,用HPLC检测渗入皮肤的非那雄胺和非那雄胺-WINT化合物。非那雄胺的HPLC检测条件为C18柱,UV 210nm,流速1.6ml/分钟,乙腈:水=45:55,并且检测R.T.为9至10分钟。为了检测本发明的非那雄胺-WINT化合物,使用LC-MS/MS(3200QTRAP)设备进行多反应监测(MRM)分析,这是用于检测相应分子量的一种方法。
结果,可以确认仅用非那雄胺处理的药物渗入皮肤,从而被检测到,而对于利用本发明的非那雄胺-WINT化合物处理的药物,没有检测到有物质渗入皮肤并残留在皮肤内(图9a和9b)。
对实验例1至9的实验结果进行总结,可以发现本发明的化合物非常优异地展示出促进毛发生长并抑制脱发的功能,并且展示出抗衰老的功能。
制剂实施例1:柔肤水
根据制备乳液的常规方法制备包含实施例<1-2>中制备的本发明化合物并由以下成分构成的柔肤水。
[表2]
成分 | 含量(重量%) |
本发明的化合物 | 2.5 |
1,3-丁二醇 | 6 |
丙三醇 | 4 |
PEG 1500 | 1 |
透明质酸钠 | 1 |
聚山梨醇酯20 | 0.5 |
乙醇 | 8 |
防腐剂,色素 | 适量 |
二苯甲酮-9 | 0.05 |
香料 | 痕量 |
纯净水 | 余量 |
总计 | 100 |
制剂实施例2.滋养霜
根据滋养霜的常规制备方法制备包含实施例<1-2>中制备的本发明化合物并由以下成分构成的滋养霜。
[表3]
成分 | 含量(重量%) |
本发明的化合物 | 2.5 |
白芒花籽油 | 3 |
鲸蜡硬脂醇 | 1.5 |
硬脂酸 | 1.5 |
硬脂酸甘油酯 | 1.5 |
液体石蜡 | 10 |
蜂蜡 | 2 |
聚山梨醇酯60 | 0.6 |
失水山梨糖醇倍半油酸酯 | 2.5 |
角鲨烷 | 3 |
1,3-丁二醇 | 3 |
丙三醇 | 5 |
三乙醇胺 | 0.5 |
生育酚乙酸酯 | 0.5 |
防腐剂,色素 | 适量 |
香料 | 适量 |
纯净水 | 余量 |
总计 | 100 |
制剂实施例3.牛奶乳液
根据乳液的常规制备方法制备包含实施例<1-2>中制备的本发明化合物并由以下成分构成的牛奶乳液。
[表4]
制剂实施例4.精油
根据精油的常规制备方法制备包含实施例<1-2>中制备的本发明化合物并由以下成分构成的精油。
[表5]
制剂实施例5.头发精华
根据头发精华的常规制备方法制备包含实施例<1-2>中制备的本发明化合物并由以下成分构成的头发精华。
[表6]
制剂实施例6.染发剂
根据染发剂的常规制备方法制备包含实施例<1-2>中制备的本发明化合物并由以下成分构成的染发剂。
[表7]
成分 | 含量(重量%) |
本发明的化合物 | 1 |
丙三醇 | 2 |
1,3-丁二醇 | 2 |
PEG 1500 | 2 |
尿囊素 | 0.1 |
DL-泛醇 | 0.3 |
EDTA-2Na | 0.02 |
透明质酸钠 | 8 |
羧基乙烯基聚合物 | 0.2 |
三乙醇胺 | 0.18 |
乙醇 | 10 |
香料、防腐剂、色素 | 适量 |
纯净水 | 余量 |
总计 | 100 |
Claims (15)
1.一种化合物,具有通过共价键使非那雄胺与肽结合的结构。
2.根据权利要求1所述的化合物,其中所述肽由2至30个氨基酸构成。
3.根据权利要求2所述的化合物,其中所述肽由8至15个氨基酸构成。
4.根据权利要求1所述的化合物,其中所述肽是水溶性肽。
5.根据权利要求4所述的化合物,其中所述水溶性肽具有至少70%的具有亲水性侧链的氨基酸。
6.根据权利要求5所述的化合物,其中所述具有亲水性侧链的氨基酸选自由精氨酸(Arg)、组氨酸(His)、赖氨酸(Lys)、天冬氨酸(Asp)、谷氨酸(Glu)、丝氨酸(Ser)、苏氨酸(Thr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、半胱氨酸(Cys)、硒代半胱氨酸(Sec)、甘氨酸(Gly)和脯氨酸(Pro)构成的组中。
7.根据权利要求5所述的化合物,其中所述具有亲水性侧链的氨基酸是选自由精氨酸(Arg)、组氨酸(His)、赖氨酸(Lys)、天冬氨酸(Asp)和谷氨酸(Glu)构成的组中的带电荷的氨基酸。
8.根据权利要求4所述的化合物,其中所述水溶性肽具有至少三个带电荷氨基酸,所述带电荷氨基酸选自由精氨酸(Arg)、组氨酸(His)、赖氨酸(Lys)、天冬氨酸(Asp)和谷氨酸(Glu)构成的组中。
9.根据权利要求4所述的化合物,其中所述水溶性肽具有5个以下具有疏水性侧链的氨基酸。
10.根据权利要求9所述的化合物,其中所述水溶性肽具有3个以下具有疏水性侧链的氨基酸。
11.根据权利要求9所述的化合物,其中所述具有疏水性侧链的氨基酸选自由丙氨酸(Ala)、缬氨酸(Val)、异亮氨酸(Ile)、亮氨酸(Leu)、甲硫氨酸(Met)、苯丙氨酸(Phe)、酪氨酸(Tyr)和色氨酸(Trp)构成的组中。
12.根据权利要求1所述的化合物,其中所述肽选自由SEQ ID No.1的氨基酸序列构成的Nokkin肽、由SEQ ID No.2的氨基酸序列构成的Keramin2肽以及由SEQ ID No.3的氨基酸序列构成的WINT肽组成的组中。
13.一种用于预防脱发或促进毛发生长的药物组合物,其包含根据权利要求1至12中任一项所述的化合物。
14.一种用于预防脱发或促进毛发生长的化妆品组合物,其包含根据权利要求1至12中任一项所述的化合物。
15.根据权利要求14所述的化妆品组合物,其具有选自由润肤液、牛奶乳液、滋养霜、按摩乳、精华素、眼霜、清洁霜、清洁泡沫、洁肤水、面膜、喷雾、粉、生发油、发乳、洗发液、洗发香波、染发液、护发素、发胶、头发喷雾、润发油、溶胶凝胶、乳液、油、蜡和气溶胶构成的组中的剂型。
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