CN114007578A - 毛发增长及头皮制剂 - Google Patents
毛发增长及头皮制剂 Download PDFInfo
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- CN114007578A CN114007578A CN202080001627.2A CN202080001627A CN114007578A CN 114007578 A CN114007578 A CN 114007578A CN 202080001627 A CN202080001627 A CN 202080001627A CN 114007578 A CN114007578 A CN 114007578A
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Abstract
本文中公开的制剂和方法可用于通过皮肤将包含L‑K‑E‑K‑K序列(SEQ ID NO:1)的肽传递到头皮以刺激毛发生长。在一些实施例中,本文中公开的制剂和方法可用于经皮传递包含SEQ ID NO:1的肽以及细菌和/或微生物活性成分。
Description
相关申请的交叉引用
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背景技术
每根毛发都由两种不同的结构组成:位于真皮中的动态毛囊和毛干,毛干是伸出皮肤表面的坚硬的角质化部分。毛发按由三个不同阶段界定的周期生长:生长期、退化期和休止期。生长期是指新物质通过毛囊细胞的快速分裂沉积在毛干上的生长阶段。生长期头皮毛发生长速度为每月1厘米,持续2-6年。生长期的持续时间决定了毛发的最长长度,并且由基因决定。退化期是一个过渡阶段,它持续大约2-3周,以毛发停止生长为标志。在这个阶段期间,毛囊消退,附着在毛干上,并角质化形成杵状毛发,当真皮乳头脱落时,毛发被向上推至头皮。休止期是静止阶段。毛囊退化,变成完全角质化,并且很容易被拉出。头皮毛发的休止期阶段持续大约3个月。脱落后,随着乳头和毛囊的再次结合,下一根头发可以开始生长。一个健康的成人头皮,通常有70-85%的毛发处于生长期阶段,有10-15%的毛发处于退化期,其余的在休止期。脱发通常与生长期阶段的缩短和过早进入到退化期阶段有关。在正常的毛发生理过程中,毛发在生长期(生长阶段)、退化期(过渡阶段)和休止期(静止和下降阶段)循环,然后重新进入到早期的生长期,以便开始新头发的生长。
脱发和秃发(脱发症)是包括人类在内的哺乳动物中的常见现象,在成年男性中极为常见,在成年女性中也很常见。事实上,从青春期开始,头顶上的某种程度的脱发被认为是一种普遍现象,无论是男性还是女性。
脱发可能是自然发生的(原发性脱发),也可能是由化学或物理因素引起的(继发性脱发)。在青春期前和青春期后患者中也经常因为抗癌化疗的副作用而观察到脱发。脱发也可能是由于特定的疾病状态(如疥癣)或因啃咬形成疤痕组织以及随着年龄增长而造成。
脱发的生理现象可能导致患者出现心理问题,社交活动减少,演化成心理疾病。在癌症患者的情况下,化疗引起脱发的可能性可能导致拒绝接受治疗。由于脱发的普遍存在及其潜在的毁灭性影响,人们对开发有效的临床治疗产生了极大的兴趣,这些治疗既能防止脱发,又能刺激脱落的头发再生。
尽管脱发普遍存在,需要预防和治疗,并为寻找合适的治疗方法进行了广泛的研究,但仍然迫切需要有效的治疗。例如,由于缺乏行之有效的治疗脱发的方法,所以许多饱受折磨的患者开始戴假发或发块。另一种用于对抗脱发的极端措施是植发手术,在许多情况下,例如在化疗后,植发手术并不是一种选择,充其量只能提供部分治疗。
米诺地尔(Upjohn Company,Kalamazoo,Mich.)是一种常见的用于刺激毛发生长的非手术治疗,目前已临床使用。含有米诺地尔作为活性成分的溶液称为如患者信息手册(The Upjohn Company,Kalamazoo,Mich,1992年6月修订)中所声明,米诺地尔是一种血管扩张药,它在口服治疗高血压时有严重的副作用。同时,局部施用米诺地尔来治疗脱发仅部分有效,并且有一些缺点。例如,它只建议治疗头顶(或前额衰退)的男性型脱发症,必须每天两次至少四个月,并且需要正常的头皮并没有局部擦伤、皮炎或晒伤,这些状况可能会增加吸收进入血液和随之而来的副作用的风险。此外,米诺地尔的有效性是有限的,因为对于那些对米诺地尔治疗有反应的患者,新头发可能在停止治疗后的几个月内脱落。
此外,人们认识到,与其它非肠道给药方法相比,通过皮肤(即,经皮)传递这些活性成分是非常困难的。在这方面,为了有效,用于毛发治疗的活性剂必须穿过皮肤或表皮的外层进入到真皮层,然后才能被血液吸收。表皮包括两个主要部分:角质层和生发层。角质层形成表皮的最外层,它由许多层状细胞层组成,这些细胞紧密、扁平、角质化,细胞核消失。该最外层充当微生物和化学试剂的物理屏障。特别地,它相当于药物经皮吸收的主要屏障。由于皮肤的屏障效果,一般只可能传递“低剂量”(即,在15毫克/天或更少的范围内)或低分子量的药物。另外,经皮传递的药物必须有适当的亲脂-亲水平衡,以便允许足够的吸收,脂溶性物质比水溶性物质具有大得多的皮肤渗透性。
最近,一种由Merck and Company of West Point,Penn.生成的以商标销售的口服全身性药物(即,非那雄胺)在临床上证实能有效治疗患男性型脱发(雄激素性脱发)的男性脱发症。是II型5a-还原酶的竞争性的特异性抑制剂,II型5a-还原酶是一种细胞内酶,它将雄激素睾酮转化为双氢睾酮(DHT)。给药可降低头皮和血清DHT浓度,并通过这一机制,似乎中断了因遗传易感患者雄激素性脱发的发展而导致的酶途径。
尽管在临床上能有效治疗男性型脱发,但是已知会产生显著的不良反应。这些不良反应包括性功能障碍以及报道的乳腺增生和增大的发生率。此外,该组合物还具有极强的致畸性,因为疑似会导致男性胎儿性器官发育受损,所以孕妇不得使用该组合物。
因此,与其它脱发治疗方法相比,本领域中迫切需要能够有效刺激毛发生长并能够经皮传递毛发生长促进剂、同时又安全、易于使用且相对便宜的组合物。
发明内容
在美国专利号6,767,891中公开了一种具有与创伤愈合相关的生理活性的基本上纯化的肽,该美国专利以引用的方式全文并入到本文。在'891专利中公开的肽具有包括L-K-E-K-K的序列(SEQ ID NO:1),其中肽为线性或环状形式,并且其中当肽为线性形式时,可选地对氨基端进行乙酰化。
本文中公开的制剂和方法可用于将包含SEQ ID NO:1的肽经皮传递到头皮,以用于毛发生长刺激和再生。
另外,许多患者同时遭受脱发、头皮或毛囊细菌和/或微生物感染。在一些情况下,细菌可能导致脱发,而螨虫(如蠕形螨)可能会传播细菌,从而加剧细菌问题。当细菌或微生物问题在毛囊中根深蒂固时,经皮传递细菌或微生物剂很重要。因此,在一些实施例中,本文中公开的制剂和方法可用于经皮传递包含SEQ ID NO:1的肽以及细菌和/或微生物活性成分。
在一方面中,一种制剂包括:包含L-K-E-K-K序列(SEQ ID NO:1)的肽;以及辛乙二醇。
在一实施例中,所述肽包括至少5个氨基酸。在一实施例中,肽的重量平均分子量为150道尔顿到200道尔顿。
在一实施例中,所述肽的浓度在0.1mg到0.5mg之间,并且辛乙二醇的浓度在1g到5g之间。
在一实施例中,该制剂进一步包括胶体硫,胶体硫的浓度可在1g到3g之间。
在一实施例中,该制剂进一步包括硫化氨基酸,硫化氨基酸的浓度可在1mg到5mg之间。在一实施例中,硫化氨基酸选自由蛋氨酸、半胱氨酸、高半胱氨酸和牛磺酸组成的组。
在一实施例中,该制剂进一步包括硫粘多糖提取物,硫粘多糖提取物的浓度可在0.5g至1g之间。在一实施例中,硫粘多糖选自由硫酸软骨素、硫酸皮肤素、硫酸角质素、肝素、硫酸肝素和透明质酸(玻尿酸)组成的组。
在一实施例中,该制剂进一步包括红三叶花提取物、印楝提取物、墨旱莲提取物或其组合。在一实施例中,月见草(夜来香)提取物包括:
·亚油酸73.88±0.09
·y-亚麻酸9.24±0.05
·油酸6.93±0.02
·棕榈酸6.31±0.14
·硬脂酸1.88±0.02
·十八碳烯酸0.81±0.03
·二十碳烯酸0.55±0.01
·二十酸0.31±0.03
·二十二酸0.10±0.01。
在一实施例中,该制剂进一步包括式(I)的化合物:
在一实施例中,该制剂进一步包括一个或多个载体、赋形剂、防腐剂、芳香剂和/或稀释剂。
在一方面中,一种抗菌洗发水包含制剂,该制剂包括:包含序列L-K-E-K-K(SEQ IDNO:1)的肽;以及辛乙二醇。在一实施例中,该抗菌洗发水是一种毛囊抗菌洗发水,即,含有抗菌活性成分和传递剂的洗发水,其能够增加到达受试者的毛囊的抗菌剂的浓度(相对于到达受试者的头发的量)。例如,传递剂可以是能够经皮运输的成分。在一实施例中,传递剂在化学上或物理上与抗菌剂结合或关联。在一实施例中,传递剂在化学上或物理上不与抗菌剂结合或关联,而是传递剂打开真皮结构,由此允许其它试剂穿透真皮。
在一方面中,一种毛发生长产品包括制剂,该制剂包括:包含序列L-K-E-K-K(SEQID NO:1)的肽;以及辛乙二醇。
在一方面中,一种用于降低有需要的受试者的毛发或头皮上的细菌浓度的方法包括向受试者施用治疗有效量的本文中公开的制剂。
在一方面中,一种用于降低有需要的受试者的毛发或头皮上的微生物浓度的方法包括向受试者施用治疗有效量的本文中公开的制剂。
在一方面中,一种用于诱导有需要的受试者的毛发生长的方法包括向受试者施用治疗有效量的本文中公开的制剂。
在一实施例中,局部施用该制剂。在一实施例中,每天至少一次施用该制剂。
附图说明
图1是示出在Boyden室迁移试验中肽TB4和TA1对内皮细胞迁移的影响的图表。
图2是示出在MTT(四唑)试验中,肽T84和TA1在刺激4小时和24小时后对内皮细胞的增殖的影响的图表。
具体实施方式
一般来说,本文中所使用的术语和短语具有它们在本领域公认的意义,这可通过参考标准文本、期刊参考文献和本领域技术人员已知的上下文来找到。提供以下定义是为了澄清它们在本描述的上下文中的特定使用。
“氨基酸”是蛋白质的分子构建块。“氨基酸残基”是蛋白质链或肽的最简单的离散单元或单体。
在本说明书的上下文中,术语“基本上纯化”是指纯度至少为50%、较佳为至少70%、更佳为至少85%并且甚至更佳为至少95%并且其中在实质缺少具有生理活性的其它肽或蛋白质的情况下存在具有生理活性的肽的纯度状态。
“硫粘多糖”又称为糖胺聚糖(GAG)。它们是高度硫酸化的复合多分散线性多糖的系列。
肽TA1
包含SEQ ID NO:1的肽其中之一是命名为TA1的28-氨基酸肽。该肽具有序列SEQID NO:2:Ac-S-D-A-A-V-D-T-S-S-E-1-T-T-K-D-L-K-E-K-K-E-V-V-E-E-A-E-N。在该肽和本文中公开的其它肽中,肽的氨基端处的符号“Ac”表示氨基端被乙酰化。一般来说,这个乙酰基可在不损害肽的功能的情况下裂解。该肽是线性的。该肽具有乙酰化氨基端,其分子量为3071道尔顿。该肽的等电点为4.1,这表明酸性氨基酸占优势。该肽可由胸腺素的裂解而得。
肽TB4
肽TB4是由44个氨基酸组成的肽。该肽具有序列SEQ ID NO:3:Ac-A-N-K-G-Q-A-P-G-E-A-M-K-P-S-F-L-K-E-K-K-E-V-V-E-R-S-K-E-E-E-G-P-A-K-M-N-L-V-1-E-M-P-K-D。该肽是线性的。该肽的氨基端是乙酰化的。该肽包含保守序列L-K-E-K-K(SEQ ID NO:1)。
除了在L-K-E-K-K(SEQ ID NO:1)的高度保守序列中之外具有保守氨基酸取代的肽属于本发明的范围。蛋白质和肽化学的一个既定原则是,通常可在不改变蛋白质或肽的构象或功能的情况下在蛋白质或肽中进行某些氨基酸取代(称为“保守”氨基酸取代)。此类变化包括:用异亮氨酸(I)、缬氨酸(V)和亮氨酸(L)中的任一种取代这些氨基酸中的任何其它氨基酸;用天冬氨酸(D)取代谷氨酸(E),反之亦然;用谷氨酰胺(Q)取代天冬酰胺(N),反之亦然;以及用丝氨酸(S)取代苏氨酸(T),反之亦然。上述取代并不是唯一可视为是“保守的”氨基酸取代。取决于特定氨基酸的环境,其它取代也可视为是保守的。例如,甘氨酸(G)和丙氨酸(A)经常可以互换,丙氨酸(A)和缬氨酸(V)也可经常互换。相对疏水的蛋氨酸(M)经常可以与亮氨酸(L)和异亮氨酸(I)互换,并且有时可以与缬氨酸(V)互换。赖氨酸(K)和精氨酸(R)在在氨基酸残基的显着特征是其电荷,并且二者在这两个氨基酸残基的pK值差异不显著的位置经常可互换。当半胱氨酸形成二硫键的能力不合预期或不需要时,经常可以用丝氨酸(S)来代替半胱氨酸(C)。在特定环境中,还有其它变化也可视为是“保守的”。
如上文所指示,本文中公开的肽可以是环形或线性的。然而,上文描述的特定肽是线性的。一些肽的氨基端被阻断,通常是通过乙酰化进行阻断。然而,这些乙酰基可以通过水解而裂解,而不会干扰肽的功能。
编码肽的核酸
本文中公开的肽可通过分离的核酸进行编码。如本文中所使用,术语“核酸”包括DNA和RNA以及单链和双链形式;如果是双链,那么还包含DNA-RNA混合。叙述单链核酸序列还包括其补充物,所述补充物是根据公认的Watson-Crick规则进行碱基配对的。编码这些肽的核酸可以是DNA或RNA;然而,在许多应用中,DNA是首选。
本文中使用术语“分离”来指示,核酸与本文中公开的不编码肽的核酸分子基本上以分离的形式存在。在本说明书的上下文中,术语“分离”是指至少为50%、较佳为至少70%、更佳为至少85%并且甚至更佳为至少95%的纯度状态。
然而,核酸可并入到更大的核酸分子中,诸如用于转染适当的宿主细胞并制造肽的载体,并且术语“分离”不应解释为排除这些自然界中不存在的合并成的更大的基因工程分子。
根据传统的三联体遗传密码来选择核酸的序列,以便编码特定肽的氨基酸序列。由于通过三联体密码子在核酸序列中指定氨基酸的遗传密码退化,并且许多氨基酸由一个以上的密码子指定,所以可使用所有可能的密码子备选。然而,在一些情况下,转录和/或转译核酸序列的效率可能会受到密码子选择的影响。在此类情况下,最好使用能提供较高核酸序列的转录和/或转译的效率的密码子。
载体和宿主细胞
还考虑了一种包含DNA的载体,所述载体可操作地链接到至少一个能影响DNA表达的控制元素。这些控制元素可以是启动子、操作子、增强子或影响DNA的表达的其它核酸序列。载体可来自原核或真核源。载体可包括染色体序列、非染色体序列或合成的DNA序列。通常,这些载体包括包含限制性核酸内切酶序列的一个或多个克隆位点,这些序列可由特定的限制性核酸内切酶容易地裂解。一般较佳的是,为了更有效地克隆期望的序列,这些限制性核酸内切酶产生内聚或“粘性”末端。一些合适的原核克隆载体包括来自大肠杆菌的质粒,如colE1、pCR1、pBR322、pMB9、pUC、pKSM或RP4。原核载体还包括噬菌体DNA的衍生物,如M13和其它丝状单链DNA噬菌体。可使用其它载体,如杆状病毒载体。
有用的表达受控的序列的示例有:lac系统,trp系统,tac系统,trc系统,噬菌体λ的主要操作子和启动子区域,fd外壳蛋白的控制区域,酵母的糖酵解启动子(例如,3-磷酸甘油酸激酶的启动子),酵母酸性磷酸酶的启动子(例如,Pho5),酵母α-交配因子的启动子,以及来源于多瘤病毒、腺病毒、逆转录酶病毒和猴病毒的启动子(例如,SV40的早期和晚期启动子),以及已知控制原核或真核细胞及其病毒的基因的表达的其它序列,或其组合。在酵母中有用的载体是可用的。一个合适的示例是2μ质粒。在动物细胞中使用的载体也已为人所知。这些载体包括SV40的衍生物、腺病毒、逆转录病毒衍生的DNA序列以及来源于功能性哺乳动物载体(如上述所述的载体)与功能性质粒和噬菌体DNA的组合的穿梭载体。另一种合适的载体是杆状病毒载体。然而,一般来说,最好是使用适合于在大肠杆菌中表达的载体。
将载体插入到宿主细胞中以进行表达。通常,通过本领域中已知的方法将这些载体插入到宿主细胞中,如转染、转变、电穿孔、直接注入DNA、脂转染以及其它众所周知的方法。可根据选择的宿主细胞以及DNA的大小和构象来选择要使用的方法。一些有用表达宿主细胞包括众所周知的原核细胞和真核细胞。一些合适的原核宿主包括例如大肠杆菌,如大肠杆菌SG-936、大肠杆菌HB101、大肠杆菌W3110、大肠杆菌1776、大肠杆菌2282、大肠杆菌DHI和大肠杆菌MRCI。也可使用其它细菌和真菌宿主细胞,如假单胞菌、芽孢杆菌物种(如枯草芽孢杆菌)和链霉菌。可使用的其它宿主细胞有:真核细胞,如酵母和其它真菌;昆虫细胞;动物细胞,如COS细胞和CHO细胞;人类细胞;以及组织培养中的植物细胞。
肽的制备方法
固态肽合成
可通过标准的固态肽合成方法来合成肽,如M.Bodanszky在“Principles ofPeptide Synthesis”(Springer-Verlag,Berlin,2d ed.,1993)中描述的方法。这涉及到在不溶性聚合物(如衍生的苯乙烯-二乙烯基苯共聚物)上合成。所用的反应顺序是标准的。
基因工程
可通过基因工程来制备肽。一般而言,制备具有生理活性的基本上纯化的肽的方法包括以下步骤:(1)培养转染有载体的宿主细胞,其中,该载体包括编码肽的DNA,该载体可操作地链接到至少一个能影响DNA的表达的控制元素;以及(2)分离由宿主细胞产生的肽,以便产生基本上纯化的肽。
在例如D.V.Goeddel,"Gene Expression Technology"(Academic Press,SanDiego,1991)中描述的表达方法。一般来说,此类方法在本领域中众所周知。
一旦进行了表达,便可通过标准的蛋白质分离技术来分离肽,包括诸如二乙氨乙基纤维素或羧甲基纤维素的树脂离子交换层析法、尺寸排除媒介上的层析法(凝胶过滤)、等电点聚焦、层析聚焦和其它标准方法,如R.K.Scopes在“Protein PurificationPrinciples and Practice”(3d Ed.,Springer-Verlag,New York,1994)中描述的方法。
如果为这些肽制备多克隆或单克隆抗体,那么可通过诸如在以上Scopes的书中描述的标准方法,在亲和层析中使用这些抗体。制备多克隆抗体或单克隆抗体的此类方法在本领域中众所周知,并且不需要在此作进一步的详细描述。一般来说,通过向产生抗体的哺乳动物(如鼠、兔、绵羊或山羊)体内注射肽而产生多克隆抗体,其中,肽可有或没有合适的佐剂,如弗氏完全佐剂。肽可偶联到载体蛋白,如钥孔戚血蓝素。一旦产生多克隆抗体,便可通过标准技术将产生此类多克隆抗体的细胞与合适的融合伙伴融合,从而得到产生具有明确特异性的单克隆抗体的杂交瘤。
使用方法
肽可通过多种途径给药。当用于刺激毛发生长时,它们通常作为制剂的一部分局部地施用头皮皮肤,制剂可以是乳霜、油、洗发水、喷雾剂、酊剂、药膏等的形式。
首选剂量为0.5ml、100μg/ml溶液的肽或剂量为50μg的肽。给药的剂量可由本领域技术人员取决于以下状况确定:问题的临床严重性、患者的年龄和体重、患者暴露于可能影响毛发生长过程的环境状况、存在或不存在潜在的系统性问题(如糖尿病、血液循环受损和免疫功能低下的状态)以及本领域中一般了解的其它药物动力学因素(如肝脏和肾脏代谢)。E.J.Freireich等人在“Quantitative Comparison of Toxicity of AnticancerAgents in Mouse,Rat,Hamster,Dog,Monkey and Man,”(Cancer Chemother.Rep.50:219-244(1966))中描述了基于mg/m3表面积的各种大小和物种的动物与人类的剂量的相互关系。可以对剂量方案进行调整,以便优化治疗反应。剂量可以按日进行分配和施用,也可根据治疗情况按比例减少剂量。
通常将活性成分与生理上耐受且与活性成分相容的稀释剂或赋形剂混合。合适的稀释液和赋形剂有例如水、盐水、葡萄糖、甘油等及其组合。另外,如果需要,组合物还可包含少量的辅助物质,如润湿剂或乳化剂、稳定剂或pH缓冲剂等。有关上述内容的更详细描述,请参阅标准药物文本,如Remington's Pharmaceutical Sciences,Mack PublishingCo.Easton,Pa.(1970)。
根据本发明的方法可用于治疗人类或社会或经济上重要的动物物种,如狗、猫、马、绵阳、牛、山羊或猪。根据本发明的方法不限于在人类中使用。
药物组合物
一般而言,本文中公开的药物组合物包括:(1)包含生理有效量的SEQ ID NO:1的肽;(2)另一种活性剂;以及(3)药学上可接受的载体。
本领域技术人员可参考上文描述的剂量确定生理学上有效的量。
本领域中已知的常规的药学上可接受的载体包括:醇类,如乙醇;血清蛋白;胆固醇;人血清白蛋白;脂质体;缓冲液,如磷酸盐、水、无菌生理盐水或其它盐等;电解质;甘油;羟甲基纤维素;丙二醇;聚乙二醇;聚氧乙烯山梨醇酐;其它表面活性剂;植物油;以及传统的抗菌或抗真菌剂,如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等。药学上可接受的载体符合无菌、等渗性、稳定性和非致热性的行业标准。
以下示例说明本发明。这些示例只是为了说明的目的,而不是要限制本发明。
示例1:TB4和TA1对内皮细胞迁移的影响
确定TB4和TA1对内皮细胞迁移的影响。为了研究这些肽影响正常人血管内皮细胞(NHVEC)体外迁移的可能性,进行了Boyden室迁移试验。
结果见表1和图1。在表1和图1的实验中,使用正常的人微血管内皮细胞,每孔5×104个细胞。孔涂以100μg/ml IV型牛血清白蛋白。
这些结果表明,TB4和TA1均充当内皮细胞的趋化剂,从而刺激NHVEC在Boyden室内的迁移。相比于只有媒介时的迁移,在100μg/ml的浓度,TB4和TA1均显著增强了细胞迁移。值得注意的是,与血管内皮生长因子(VEGF)、血小板源性生长因子(PDGF)和成纤维细胞生长因子(FGF)这三个阳性对照相比,TB4和TA1在此浓度下显示出增强的反应。另外,内皮细胞迁移对这两种肽都有剂量响应,TB4和TA1在100ng/ml浓度对迁移达到最大效应。
表1
示例2:TB4和TA1对内皮细胞增殖的影响
采用MTT(四唑)试验确定TB4和TA1对内皮细胞增殖的影响。图2中示出了三种浓度10ng/ml、100ng/ml和1000ng/ml的肽在刺激4小时和24小时后的结果。这些结果显示,这些肽能刺激内皮细胞增殖。在浓度为10ng/ml时,TB4和TA1最大限度地刺激细胞增殖,分别是对照组的2倍和3倍。
示例3:毛发和头皮制剂
这个示例描述毛发和头皮制剂的主要成分。通常,去离子水是这些成分的主要载体。
表2.毛发和头皮制剂成分
成分 | 浓度(g) |
肽(SEQ ID NO:1) | 0.00005-0.0005 |
辛乙二醇(1,2-辛二醇) | 1-5 |
胶体硫 | 0-3 |
印楝(印楝种子)提取物 | 0-2 |
墨旱莲(醴肠)提取物 | 0-2 |
示例4:毛发生长刺激/再生霜
这个示例描述一种包含如表3所示的成分的毛发生长刺激/再生霜,以及,使用该霜和使用安慰剂以增加毛发密度的结果。
表3.毛发生长刺激/再生霜成分
动物模型研究
材料和方法:
·预先选择毛发生长处于休止期I阶段的染色C57/BL6老鼠。局部施用具有血清的提取物,以便评定休止期到生长期的过渡。
·进行免疫组织化学研究,以便特别识别抗原。
·处于毛发生长的生长期阶段的动物对FGF-7呈阳性。
·处于休止期阶段的动物只对于BMP4抗原呈阳性。
结果:
·表3中的剂型增强了老鼠的背侧皮肤的生长期增长的诱导,其特征是,沿着毛干出现内根鞘。
·在C57和BL6老鼠中,表3中的剂型增加了FGF-7,而减少了FGF-5。
结论
·结果表明,表3中的剂型具有增强毛囊生长的潜力,通过调节FGF-7和FGF-5来促进毛发生长。
·向上调节FGF-7。
·向下调节FGF-5。
人类临床研究
开展了关于表3中成分的效果的研究。随机招募30名发际线后退的志愿者,将他们分为两组。
初步研究
1.第I组接收安慰剂(15名受试者)
2.第II组接收本产品(15名受试者)
选择30名发际线后退的志愿者
·10名男性
·20名女性
持续时间:研究为期4个月,每天局部施用本产品。
在每天施用本产品后,使用数字分析装置对头皮进行评定,其中,数字分析装置用于测量毛发密度以及生长期和休止期阶段的毛发比例。
观察:
在施用安慰剂和本产品4个月后,第II组显示,相比于在研究开始时采取的对照措施,生长期阶段毛发密度(毛发生长增加)平均增加13%,并且休止期阶段毛发脱落减少29%。
第I组显示,相比于研究开始时采取的对照措施,生长期阶段毛发密度(毛发生长增加)平均增加2%,并且休止期阶段毛发脱落增加28%。
在第二组中,在发际线处,处于生长期的毛发与处于休止期的毛发的比例A/T增加了42%。结果与第I组大不相同,在第I组中,在实验过程中,处于生长期的毛发与处于休止期的毛发的比例减少。结论:
第II组经历了测试产品对毛发生长的积极作用。
示例5:抗菌洗发水
这个示例描述包含如表4所示的成分的抗菌洗发水以及使用该洗发水的研究结果。
表4.抗菌洗发水成分
动物模型研究资料
材料和方法:
·预先选择毛发生长处于休止期I阶段的染色C57/BL6老鼠。局部施用具有血清的提取物,以便评定休止期到生长期的过渡。
·进行免疫组织化学研究,以便特别识别抗原。
·处于毛发生长的生长期阶段的动物对于FGF-7呈阳性。
·处于休止期阶段的动物只对于BMP4抗原呈阳性。
结果:
·表4中的剂型增强了老鼠的背侧皮肤的生长期增长的诱导,其特征是,沿着毛干出现内根鞘。
·在C57和BL6老鼠中,表4中的剂型增加了FGF-7,而减少了FGF-5。
结论
·结果表明,表4中的剂型具有增强毛囊生长的潜力,以便通过调节FGF-7和FGF-5来促进毛发生长。
·向上调节FGF-7。
·向下调节FGF-5。
关于通过引用并入和变型的说明
在本申请中引用的所有参考文献(例如,专利文件,包括已发布或授权的专利或同等物)、专利申请公布和非专利文献或其它来源的资料由此以引用的方式全文并入到本文,就像单独以引用的方式并入一样。
本文中采用的术语和表述用作描述项而不是限制项,并且在使用此类术语和表述时,没有意图排除任何显示和描述的特征或其部分的等效物,但应该意识到,在本发明权利要求的保护范围内,可以进行各种修改。因此,应了解,尽管通过较佳实施例、示例性实施例和可选特征特别公开了本发明,但是本领域技术人员可对本文中公开的概念进行修改和改变,并且此类修改和改变视为在由随附权利要求限定的本发明的范围内。本文中提供的特定实施例是本发明的有用实施例的示例,并且本领域技术人员将明白,可使用本描述中阐述的装置、装置组件和方法步骤的大量变型来进行本发明。本领域技术人员将明白,对于本发明方法和装置有用的方法和装置可包括大量可选的组合物以及处理要素和步骤。
当本文中公开取代物的群组时,应了解,单独公开该群组的所有个别成员以及所有子组。当本文中使用Markush群组或其它分组时,该组中的所有单个成员以及该组中所有可能的组合和子组合都应单独包含在本公开中。
必须注意,除非上下文另外明确规定,否则如本文中和随附权利要求书中所使用,单数形式“一”、“一个”和“该”包括复数引用。因此,例如,对“肽”的引用包括本领域技术人员已知的多个此类肽及其等效物等。同样地,术语“一”(或“一个”)、“一个或多个”和“至少一个”在本文中可互换使用。还应注意,术语“包括”、“包含”和“具有”可互换使用。表述“如权利要求XX-YY中任一权利要求所述的”(其中XX和YY是指权利要求号)意欲以备选形式提供多个从属权利要求,并且在一些实施例中,可以与表述“如同在权利要求XX-YY中任一权利要求”互换。
除非另外定义,否则本文中所使用的所有技术和科学术语具有与本发明所属领域的技术人员普遍理解的含义相同的含义。尽管描述了较佳的方法和材料,但是在实践或测试本发明时可使用与本文中描述的方法和材料相似或等效的任何方法和材料。本文中的任何内容均不应解释为承认本发明无权因先前的发明而提前公开。
每当本说明书中给出范围(例如,整数范围、温度范围、时间范围、组成范围或浓度范围)时,本公开中意指包含所有中间范围和子范围以及在给定的范围中包含的所有个别值。如本文中所使用,范围特别包括作为范围的端点值提供的值。如本文中所使用,范围特别包括范围的所有整数值。例如,1到100的范围特别包括端点值1和100。将了解,包含在本文中的描述中的任何子范围或范围或子范围中的个别值均可排除在本文中的权利要求书之外。
如本文中所使用,“包括”与“包含”、“含有”或“其特征在于”同义且可互换使用,具有包容性或开放性,并且不排除额外的、未记载的要素或方法步骤。如本文中所使用,“由...组成”排除权利要求要素中没有指定的任何要素、步骤或成分。如本文中所使用,“基本上由...组成”不排除不会实质影响权利要求的基本和新颖特性的材料或步骤。在本文中的每个实例中,任何术语“包括”、“基本上由...组成”和“由...组成”可以用其它两个术语中的任何一个术语替换。在此适当地说明性地描述,可在缺少本文中没有特别公开的任何一个或多个要素、限制的情况下实践本公开。
本公开中包含本领域已知的材料和方法的功能等效物。采用的术语和表述用作描述项而非限制项,并且在使用此类术语和表述时不希望排除示出和描述的特征或其部分的任何等效物,而是意识到,各种修改可能在要求权利要求的本发明的范围内。因此,应了解,尽管通过较佳实施例和可选特征特别公开了本发明,但是本领域技术人员可对本文中公开的概念进行修改和改变,并且此类修改和改变视为在由随附权利要求限定的本发明的范围内。
序列表
<110> C.扎维拉(ZAVERI, Chanda) 林明盛( LIM, Meng Teng)
<120> 毛发增长及头皮制剂
<130> 1-20 WO
<160> 3
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> 具有生理活性的合成肽(Synthetic peptide with physiological activity)
<400> 1
Leu Lys Glu Lys Lys
1 5
<210> 2
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 具有生理活性的合成肽
<400> 2
Ser Asp Ala Ala Val Asp Thr Ser Ser Glu Ile Thr Thr Lys Asp Leu
1 5 10 15
Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn
20 25
<210> 3
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 具有生理活性的合成肽
<400> 3
Ala Asn Lys Gly Gln Ala Pro Gly Glu Ala Met Lys Pro Ser Phe Leu
1 5 10 15
Lys Glu Lys Lys Glu Val Val Glu Arg Ser Lys Glu Glu Glu Gly Pro
20 25 30
Ala Lys Met Asn Leu Val Ile Glu Met Pro Lys Asp
35 40
Claims (20)
1.一种制剂,包括:
包含L-K-E-K-K序列(SEQ ID NO:1)的肽;以及
辛乙二醇。
2.如权利要求1所述的制剂,其中所述肽的浓度在0.1mg到0.5mg之间,并且所述辛乙二醇的浓度在1g到5g之间。
3.如权利要求1所述的制剂,进一步包括胶体硫。
4.如权利要求3所述的制剂,其中所述胶体硫的浓度在1g到3g之间。
5.如权利要求1所述的制剂,进一步包括硫化氨基酸。
6.如权利要求5所述的制剂,其中所述硫化氨基酸选自由蛋氨酸、半胱氨酸、高半胱氨酸和牛磺酸组成的组。
7.权利要求5所述的制剂,其中所述硫化氨基酸的浓度在1mg到5mg之间。
8.如权利要求1所述的制剂,进一步包括硫粘多糖提取物。
9.如权利要求8所述的制剂,其中所述硫粘多糖选自由硫酸软骨素、硫酸皮肤素、硫酸角质素、肝素、硫酸肝素和透明质酸(玻尿酸)组成的组。
10.如权利要求8所述的制剂,其中所述硫粘多糖提取物的浓度在0.5g至1g之间。
11.如权利要求1所述的制剂,进一步包括红三叶花提取物。
12.如权利要求1所述的制剂,进一步包括印楝提取物。
13.如权利要求1所述的制剂,进一步包括墨旱莲提取物。
15.如权利要求1所述的制剂,进一步包括一个或多个载体、赋形剂、防腐剂和/或稀释剂。
16.一种抗菌洗发水,包括如权利要求1所述的制剂。
17.一种毛发生长产品,包括如权利要求1所述的制剂。
18.一种用于减少有需要的受试者的毛发或头皮上的细菌浓度的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1所述的制剂。
19.一种用于诱导有需要的受试者毛发生长的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1所述的制剂。
20.如权利要求书18或权利要求19所述的方法,其中局部施用所述制剂。
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EP1776084A1 (de) * | 2004-08-13 | 2007-04-25 | Henkel Kommanditgesellschaft Auf Aktien | Kosmetische zusammensetzungen zur behandlung gestresster haut enthaltend taurin und langkettige fettalkohole |
JP2008163006A (ja) * | 2006-12-04 | 2008-07-17 | Mandom Corp | 皮膚化粧料 |
BR112012026875B1 (pt) * | 2010-06-11 | 2018-12-04 | Avon Products, Inc. | método cosmético para melhorar a aprência da pele afetada pela celulilte e para reduzir recorrência de celulite em uma área previamente afetada e kit |
EP3045161A1 (en) * | 2015-01-18 | 2016-07-20 | Symrise AG | Active compositions comprising 1,2-hexanediol and 1,2-octanediol |
US10507177B1 (en) * | 2016-04-11 | 2019-12-17 | Ino Beauty, Inc. | Anti-aging hair treatment |
-
2020
- 2020-02-28 KR KR1020207031224A patent/KR20210110774A/ko not_active Application Discontinuation
- 2020-02-28 CN CN202080001627.2A patent/CN114007578A/zh active Pending
- 2020-02-28 EP EP20921281.0A patent/EP3930677A4/en not_active Withdrawn
- 2020-02-28 WO PCT/US2020/020527 patent/WO2021173160A1/en unknown
- 2020-02-28 US US17/802,038 patent/US20230301893A1/en active Pending
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US20050250685A1 (en) * | 2000-06-14 | 2005-11-10 | Chanda Zaveri | Peptides with wound healing activity |
US20160271109A1 (en) * | 2013-03-13 | 2016-09-22 | Neocutis Sa | Peptides For Skin Rejuvenation And Methods Of Using The Same |
CN105106028A (zh) * | 2015-08-28 | 2015-12-02 | 深圳市维琪医药研发有限公司 | 一种用于毛发生长的多肽组合物 |
Non-Patent Citations (1)
Title |
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NATALIAMEIER等: "Thymic Peptides Differentially Modulate Human Hair Follicle Growth", JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol. 132, no. 5, pages 1516 - 1519, XP055443689, DOI: 10.1038/jid.2012.2 * |
Also Published As
Publication number | Publication date |
---|---|
EP3930677A4 (en) | 2022-11-23 |
WO2021173160A1 (en) | 2021-09-02 |
EP3930677A1 (en) | 2022-01-05 |
KR20210110774A (ko) | 2021-09-09 |
US20230301893A1 (en) | 2023-09-28 |
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