CN116715726A - 合成肽及其组合物和用途 - Google Patents
合成肽及其组合物和用途 Download PDFInfo
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 210000000427 trigeminal ganglion Anatomy 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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Abstract
本发明提供一种具有式(I)R1‑Arg‑Arg‑Ile‑Arg‑Pro‑Lys‑R2的肽或其美容上可接受的盐、或其药学上可接受的盐、或它们的组合物、以及它们在制备用于抑制TRPV1活性,抗敏舒缓、修复皮肤屏障,治疗或预防疼痛、瘙痒、炎症,治疗、预防或修复皮肤老化或光老化的组合物中的用途。
Description
技术领域
本发明涉及医药和化妆品技术领域,特别是一种能够抑制瞬时受体电位香草酸1(transientreceptor potentialvanilloid 1,TRPVl)活性的肽以及含有这些肽的美容组合物或药用组合物,以及它们用于治疗或护理通过抑制TRPVl活性得以改善或预防的病况、障碍和/或疾病的用途。
背景技术
人体皮肤内含有丰富的感觉神经纤维,这些神经纤维让中枢神经系统可以随时察觉到皮肤的状况,并对各种化学刺激、冷热状况、生理刺激等作出反应。然而,敏感性皮肤由于皮肤的天然屏障遭受破坏、自我防御能力下降,使外界刺激物容易渗入,使皮肤感觉神经信号传入增强、耐受阈值降低,对外界微弱刺激反应过度,激活皮肤的免疫反应,导致血管扩张、炎症细胞浸润,皮肤会出现红肿、毛细血管扩张,感觉有紧绷感、灼热、瘙痒等各类肌肤不适症状。
瞬时受体电位(transientreceptorpotential,TRP)通道是一类广泛分布于外周和中枢神经系统的阳离子通道蛋白。它具有6次跨膜的α螺旋结构域,其中由第五和第六跨膜结构域共同构成通道L区;此外,TRP的N端和C端结构域均位于胞内,在N端含有多个与锚蛋白结合的部位,称为锚蛋白重复区域(ARD)。哺乳动物的TRP离子通道超家族可分为七个亚族,包括TRPA、TRPC、TRPM、TRPML、TRPN、TRPP和TRPV。其中,TRPV亚家族是一类在人体中分布广泛的四聚体通道蛋白,在细胞功能以及信号通路传递中扮演重要角色。TRPV亚家族至少有6个亚型已被发现,即TRPV1-6,其中TRPV1-4为热敏感离子通道,而TRPV5、TRPV6为对Ca2+具有高选择性的离子通道。
TRPV1是TRPV亚家族中第一个被发现及克隆的通道蛋白,广泛分布于神经元、免疫细胞、脏器上皮细胞及角质形成细胞中,参与神经源性炎症的发生及维持过程,主要表达于后根节和三叉神经节的小型神经元中,通过介导轴突内Ca2+浓度升高促进轴突内致密核心囊泡胞吐,释放出降钙素基因相关肽(calcitonin generelatedpeptide,CGRP)、P物质(substanceP,SP)等炎症因子,诱导皮肤角质形成细胞分泌IL-1、IL-8和神经生长因子(nerve growthfactor,NGF)等细胞因子及NO等。
TRPV1在皮肤中广泛表达,也是研究最为广泛、最受关注的一种非选择性配体门控阳离子通道受体,可被多种外源性因素如辣椒素、酸度(pH<5.9)、温度(>43℃)、光照和污染物等所激活,它对热刺激的阈值可以因降低pH值、炎症及致痛物质(缓激肽、ATP和神经生长因子等)的存在而降低;亦可被内源性脂质、内源性炎症介质所激活,炎症介质可以与神经元上各自的受体结合,通过各自胞内信号通路作用于TRPV1,引起中枢或外周神经敏化,最终导致皮肤紧绷、发痒甚至灼烧感。因此,抑制或降低TRPV1的活性可以阻断各种刺激介导的反应,从而提高肌肤的耐受阈值,例如反式4-叔丁基环己醇抑制辣椒素诱导的TRPV1活化,用于舒缓敏感肌。此外,研究发现TRPV1可以调节热和紫外线诱导的人角质形成细胞中的MMP-1表达,在紫外线诱导的光老化过程中起着重要作用。因此通过抑制TRPVl的活性,降低紫外线诱导的MMP和促炎细胞因子的表达,可以减少皮肤褶皱厚度和细胞内Ca2+内流,改善紫外线诱导的皮肤炎症和光老化。
目前,通过对TRPV1的研究,已发现了多种结构的TRPV1抑制剂或拮抗剂,例如不饱和脂肪酸、查尔酮类、萜烯类、呋喃香豆素类、苯并咪唑类、二芳基脲类和多肽等。但是,仍然有必要将TRPV 1作为皮肤舒缓和修护的研究靶点,进行基于受体的TRPVl抑制剂设计和筛选,从而开发可替代现有技术中已知化合物的新型多肽,以用于治疗或护理通过抑制TRPVl活性得以改善或预防的那些病况、障碍和/或疾病。
发明内容
本发明的发明人研究发现,精氨酸残基对于TRPVl活性的抑制或拮抗作用具有重要影响,结合TRPVl序列分析,得到一种能够抑制TRPV1活性的肽。这些肽以及含有这些肽的美容组合物或药用组合物,可用于治疗或护理通过抑制TRPVl活性而得以改善或预防的那些病况、障碍和/或疾病。
鉴于此,本发明提供一种式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐,
R1-Vk-Wm-AA1-Arg-AA2-AA3-AA4-AA5-Xn-Yp-Zq-R2(I)
式(I)中,
AA1选自:-Arg-或-Gln-;
AA2选自:-Pro-、-Ala-或-Ile-;
AA3选自:-Ser-、-Ile-或-Arg-;
AA4选自:-Met-、-Leu-、-Thr-、-Pro-或键;
AA5选自:-Lys-、-Ile-或键;
V、W、X、Y和Z为氨基酸并且它们本身独立地选择;
k、m、n、p和q本身独立地选择并且具有0或1的值;
k+m+n+p+q小于或等于3;
R1选自:H、CH3CH(OH)CO-、或R3-CO-,其中R3选自:取代的或未取代的烷基、取代的或未取代的烯基;
R2选自:-NR4R5或-OR4,其中各个R4和R5彼此独立地选自:H、取代的或未取代的烷基、取代的或未取代的烯基;
所述烷基是指具有1-24个碳原子(可选具有1-16个碳原子;可选具有1-14个碳原子;可选具有1-12个碳原子;可选具有1、2、3、4、5、或6个的碳原子)的饱和脂肪族直链或支链的烷基;可选选自:甲基、乙基、异丙基、异丁基、叔丁基、戊基、己基、庚基、辛基、癸基、十二烷基、十四烷基、十六烷基、十八烷基、2-乙基己基、2-甲基丁基、或5-甲基己基;
所述烯基是指具有2-24个碳原子(可选具有2-16个碳原子;可选具有2-14个碳原子;可选具有2-12个碳原子;可选具有2、3、4、5、或6个碳原子)的直链或支链烯基;所述烯基具有一个或多个碳-碳双键,可选具有1、2或3个共轭或非共轭的碳-碳双键;所述烯基是通过一个单键而结合至分子的其余部分;可选选自:乙烯基、油烯基、或亚油烯基;
可选地,所述“取代的烷基”、“取代的烯基”中的取代基选自C1-C4烷基;羟基;C1-C4烷氧基;氨基;C1-C4氨基烷基;C1-C4羰氧基;C1-C4氧基羰基;卤素(如氟、氯、溴、以及碘);氰基;硝基;叠氮化物;C1-C4烷基磺酰基;硫醇;C1-C4烷硫基;C6-C30芳氧基如苯氧基;-NRb(C=NRb)NRbRc,其中Rb和Rc是独立地选自:H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C10环烷基、C6-C18芳基、C7-C17芳烷基、具有三至十元的杂环基、或氨基的保护基。
可选地,R1选自:H、CH3CH(OH)CO-、咖啡酰基(CA-)、乙酰基、叔-丁酰基、己酰基、2-甲基己酰基、辛酰基、癸酰基、月桂酰基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油酰基或亚油酰基;R4、R5彼此独立地选自:H、甲基、乙基、己基、十二烷基或十六烷基;
可选地,R1选自H、CH3CH(OH)CO-、咖啡酰基(CA-)、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基;R4是H并且R5选自:H、甲基、乙基、己基、十二烷基或十六烷基;
可选地,R1是H、咖啡酰基(CA-)或乙酰基;R2是-OH或-NH2。
可选地,k和m为0,n+p+q小于或等于3。
可选地,n、p和q为0,k+m小于或等于2。
可选地,k、m、n、p和q为0。
可选地,式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐,选自下列肽(1)-(54):
(1)H-Arg-Arg-Pro-Ser-Met-OH;
(2)H-Arg-Arg-Pro-Ser-Met-NH2;
(3)CA-Arg-Arg-Pro-Ser-Met-OH;
(4)CA-Arg-Arg-Pro-Ser-Met-NH2;
(5)Ac-Arg-Arg-Pro-Ser-Met-OH;
(6)Ac-Arg-Arg-Pro-Ser-Met-NH2;
(7)H-Arg-Arg-Ile-Arg-Pro-Lys-OH;
(8)H-Arg-Arg-Ile-Arg-Pro-Lys-NH2;
(9)CA-Arg-Arg-Ile-Arg-Pro-Lys-OH;
(10)CA-Arg-Arg-Ile-Arg-Pro-Lys-NH2;
(11)Ac-Arg-Arg-Ile-Arg-Pro-Lys-OH;
(12)Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2;
(13)H-Arg-Arg-Ala-Ile-Thr-Ile-OH;
(14)H-Arg-Arg-Ala-Ile-Thr-Ile-NH2;
(15)CA-Arg-Arg-Ala-Ile-Thr-Ile-OH;
(16)CA-Arg-Arg-Ala-Ile-Thr-Ile-NH2;
(17)Ac-Arg-Arg-Ala-Ile-Thr-Ile-OH;
(18)Ac-Arg-Arg-Ala-Ile-Thr-Ile-NH2;
(19)H-Phe-Leu-Arg-Arg-Ile-Arg-OH;
(20)H-Phe-Leu-Arg-Arg-Ile-Arg-NH2;
(21)CA-Phe-Leu-Arg-Arg-Ile-Arg-OH;
(22)CA-Phe-Leu-Arg-Arg-Ile-Arg-NH2;
(23)Ac-Phe-Leu-Arg-Arg-Ile-Arg-OH;
(24)Ac-Phe-Leu-Arg-Arg-Ile-Arg-NH2;
(25)H-Pro-Arg-Arg-Ile-Arg-Ile-OH;
(26)H-Pro-Arg-Arg-Ile-Arg-Ile-NH2;
(27)CA-Pro-Arg-Arg-Ile-Arg-Ile-OH;
(28)CA-Pro-Arg-Arg-Ile-Arg-Ile-NH2;
(29)Ac-Pro-Arg-Arg-Ile-Arg-Ile-OH;
(30)Ac-Pro-Arg-Arg-Ile-Arg-Ile-NH2;
(31)H-Gln-Arg-Pro-Ser-Met-Lys-Leu-OH;
(32)H-Gln-Arg-Pro-Ser-Met-Lys-Leu-NH2;
(33)CA-Gln-Arg-Pro-Ser-Met-Lys-Leu-OH;
(34)CA-Gln-Arg-Pro-Ser-Met-Lys-Leu-NH2;
(35)Ac-Gln-Arg-Pro-Ser-Met-Lys-Leu-OH;
(36)Ac-Gln-Arg-Pro-Ser-Met-Lys-Leu-NH2;
(37)H-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH;
(38)H-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-NH2;
(39)CA-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH;
(40)CA-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-NH2;
(41)Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH;
(42)Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-NH2;
(43)H-Gln-Arg-Pro-Ser-Leu-Lys-Thr-Leu-OH;
(44)H-Gln-Arg-Pro-Ser-Leu-Lys-Thr-Leu-NH2;
(45)CA-Gln-Arg-Pro-Ser-Leu-Lys-Thr-Leu-OH;
(46)CA-Gln-Arg-Pro-Ser-Leu-Lys-Thr-Leu-NH2;
(47)Ac-Gln-Arg-Pro-Ser-Leu-Lys-Thr-Leu-OH;
(48)Ac-Gln-Arg-Pro-Ser-Leu-Lys-Thr-Leu-NH2;
(49)H-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-OH;
(50)H-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2;
(51)CA-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-OH;
(52)CA-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2;
(53)Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-OH;
(54)Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2。
可选地,式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐,选自下列肽(3)、肽(8)、肽(12)、肽(14)、肽(18)、肽(20)、肽(39)、肽(41)、肽(45)、肽(50)和肽(54),具体地,
(3)CA-Arg-Arg-Pro-Ser-Met-OH;
(8)H-Arg-Arg-Ile-Arg-Pro-Lys-NH2;
(12)Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2;
(14)H-Arg-Arg-Ala-Ile-Thr-Ile-NH2;
(18)Ac-Arg-Arg-Ala-Ile-Thr-Ile-NH2;
(20)H-Phe-Leu-Arg-Arg-Ile-Arg-NH2;
(39)CA-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH;
(41)Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH;
(45)CA-Gln-Arg-Pro-Ser-Leu-Lys-Thr-Leu-OH;
(50)H-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2;
(54)Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2。
可选地,式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐,选自下列肽(12)、肽(18)、肽(41)和肽(54),具体地,
(12)Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2;
(18)Ac-Arg-Arg-Ala-Ile-Thr-Ile-NH2;
(41)Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH;
(54)Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2。
本发明的式(I)所示的肽可以作为立体异构体或立体异构体的混合物存在;例如,其所包含的这些氨基酸可以具有L-、D-的构型、或彼此独立地是外消旋的。因此,有可能获得同分异构混合物以及外消旋混合物或非对映混合物、或纯的非对映异构体或对映异构体,这取决于不对称碳的数量和存在什么同分异构体或同分异构混合物。本发明的式(I)所示的肽的优选的结构是纯的同分异构体,即,对映异构体或非对映异构体。
例如,当本发明所述-Arg-时,应理解-Arg-选自-L-Arg-、-D-Arg-、或两者的混合物,是外消旋的或非外消旋的。在本文件中描述的制备方法使本领域的普通技术人员能够通过选择具有正确构型的氨基酸来获得本发明的肽的每种立体异构体。
本发明还包括式(I)所示的肽的所有合适的同位素变体。本发明的这些肽的同位素变体此处理解为是指这样的化合物:其中在本发明的肽内至少一个原子被替换为相同原子序数的另一个原子,但所述另一原子的原子质量不同于自然界中通常或主要存在的原子质量。可掺入本发明的肽中的同位素的实例是:氢、碳、氮、氧或硫的那些,例如2H(氘)、3H(氚)、13C、14C、15N、17O、18O、33S、34S、35S或36S。本发明的肽的特定的同位素变体(特别是其中已经掺入一种或多种放射性同位素的那些)可能有利于,例如检查在体内的作用机理或活性化合物的分布;由于相对简单的可制备性和可检测性,尤其是用3H或14C同位素标记的化合物适用于该目的。另外,由于化合物的更强的代谢稳定性,同位素(例如氘)的掺入可以产生特定的治疗益处,例如体内半衰期的延长或所需活性剂量的降低;因此,在某些情况下,本发明的肽的这种改性还可构成本发明的优选实施方案。通过本领域技术人员已知的方法,例如通过在下文中进一步描述的方法和在实施例中所述的方法,通过使用各自的试剂和/或起始物质的相应的同位素改性物,可制备本发明的肽的同位素变体。
此外,本发明还包括本发明的肽的前药。术语“前药”在本文中意指这样的化合物:其本身可以是生物学上有活性的或无活性的,但是在它们在身体内的停留时间期间,其反应(例如代谢或水解)生成本发明的肽。
术语“美容上可接受的盐或药学上可接受的盐”指被认可的在动物,并且更确切地说在人类中使用的一种盐,包括式(I)所示的肽的金属盐,所述金属包括,但不局限于:锂、钠、钾、钙、镁、锰、铜、锌或铝等;包括式(I)所示的肽与有机碱形成的盐,所述有机碱包括,但不局限于:乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、精氨酸、赖氨酸、组氨酸或哌嗪等;包括式(I)所示的肽与无机酸或有机酸形成的盐,所述有机酸包括,但不局限于:乙酸、柠檬酸、乳酸、丙二酸、马来酸、酒石酸、延胡索酸、苯甲酸、天冬氨酸、谷氨酸、琥珀酸、油酸、三氟乙酸、草酸、扑酸(pamoate)或葡萄糖酸等;所述无机酸包括,但不局限于:盐酸、硫酸、硼酸或碳酸。
本发明式(I)所示的肽、或其立体异构体或其美容上可接受的盐、或其药学上可接受的盐的合成可以根据现有技术中已知的常规方法来进行,例如固相合成法、液相合成法或固相与液相结合的方法,还可以通过以产生所希望的序列为目标的生物技术方法、或通过具有动物、真菌、或植物来源的蛋白质的控制水解来制备。
例如,一种获得式(I)所示的肽的方法包括以下步骤:
-将具有受保护的N-末端和自由的C-末端的氨基酸与具有自由的N-末端和受保护的或与固体载体结合的C-末端的氨基酸偶联;
-消除保护N-末端的基团;
-重复该偶联顺序和消除保护N-末端的基团,直到获得所希望的肽序列;
-消除保护C-末端的基团或从该固体载体裂解。
优选地,C-末端与一种固体载体结合并且该方法是在固相上进行,包括将具有受保护的N-末端和自由的C-末端的氨基酸与具有自由的N-末端和与一种聚合物载体结合的C-末端的氨基酸偶联;消除保护N-末端的基团;并且重复此顺序所需要的次数以便因此获得具有所希望的长度的肽,接着从最初的聚合物载体裂解所合成的肽。
在整个合成中这些氨基酸的侧链的官能团用临时或永久的保护基团保持充分地保护,并且可以与从该聚合物载体裂解肽的过程同时地或正交地脱保护。
可选地,固相合成可以通过将二肽或三肽偶联到聚合物支持体上或偶联到先前与聚合物支持体结合的二肽或氨基酸上的汇集策略(convergent strategy)来进行。
使用本领域已知的标准条件和方法对N-末端和C-末端脱保护和/或以非确定的次序从聚合物支持体裂解肽,随后可以修饰所述末端的官能团。可以对与聚合物支持体结合的式(I)的肽进行N-末端和C-末端的任选的修饰,或在肽已从聚合物支持体裂解后进行N-末端和C-末端的任选的修饰。
本发明的另一方面,提供一种美容或药用组合物,包括有效量的上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐,以及至少一种赋形剂和任选的美容上或药学上可接受的佐剂。
可选地,所述佐剂选自:抑制TRPV1活性的其他试剂、镇痛剂、抑制PAR-2活性的剂、胶原合成刺激剂、调节PGC-1α合成的剂、调节PPARγ的活性的剂、增加或减少脂肪细胞的甘油三酸酯含量的剂、刺激或延迟脂肪细胞分化的剂、脂解剂或刺激脂肪分解的剂、溶脂剂、生脂剂、乙酰胆碱受体聚集的抑制剂、抑制肌肉收缩的剂、抗胆碱能试剂、弹性蛋白酶抑制剂、基质金属蛋白酶抑制剂、黑色素合成刺激或抑制剂、增白剂或脱色剂、促色素沉着剂、自晒黑剂、抗老化剂、NO-合酶抑制剂、5α-还原酶抑制剂、赖氨酰羟化酶和/或脯氨酰羟化酶的抑制剂、抗氧化剂、自由基清除剂和/或抗大气污染的剂、活性羰基类物质清除剂、抗糖化剂、抗组胺剂、抗病毒剂、抗寄生虫剂、乳化剂、润肤剂、有机溶剂、液体推进剂、皮肤调理剂、保留水分的物质、α羟基酸、β羟基酸、增湿剂、表皮水解酶、维生素、氨基酸、蛋白质、色素、染料、生物聚合物、胶凝聚合物、增稠剂、表面活性剂、软化剂、粘合剂、防腐剂、抗皱剂、能够减少或治疗下眼袋的剂、角质层分离剂、抗微生物剂、抗真菌剂、抑真菌剂、灭菌剂、抑菌剂、刺激真皮或表皮大分子的合成和/或能够抑制或预防它们的降解的剂、刺激弹性蛋白合成的剂、刺激核心蛋白聚糖合成的剂、刺激层粘连蛋白合成的剂、刺激防御素合成的剂、刺激伴侣蛋白合成的剂、刺激cAMP合成的剂、刺激HSP70合成的剂、刺激热休克蛋白合成的剂、刺激透明质酸合成的剂、刺激纤连蛋白合成的剂、刺激去乙酰化酶合成的剂、刺激脂质和角质层组分的合成的剂、神经酰胺、脂肪酸、抑制胶原降解的剂、抑制弹性蛋白降解的剂、抑制丝氨酸蛋白酶的剂、刺激成纤维细胞增殖的剂、刺激角质形成细胞增殖的剂、刺激脂肪细胞增殖的剂、刺激黑色素细胞增殖的剂、刺激角质形成细胞分化的剂、抑制乙酰胆碱酯酶的剂、皮肤松弛剂、刺激糖胺聚糖合成的剂、抗角化过度剂、粉刺溶解剂、抗银屑病剂、抗湿疹剂、DNA修复剂、DNA防护剂、稳定剂、止痒剂、用于治疗和/或护理敏感性皮肤的剂、固化剂、紧致剂、重构剂、抗拉伸纹剂、调节皮脂产生的剂、止汗剂、刺激愈合的剂、协助愈合的剂、刺激再上皮化的剂、协助再上皮化的剂、细胞因子、镇静剂、抗炎剂、麻醉剂、作用于毛细血管循环和/或微循环的剂、刺激血管生成的剂、抑制血管渗透性的剂、静脉紧张剂、作用于细胞代谢的剂、用于改善真皮-表皮接合的剂、诱导毛发生长的剂、毛发生长抑制或延缓剂、香料、螯合剂、植物提取物、精油、海洋提取物、得自生物发酵过程的剂、无机盐、细胞提取物、防晒剂、以及有效抗A和/或B紫外线的有机或无机光防护剂或其混合物。
可选地,所述美容或药用组合物的制剂选自:霜剂、油、香膏、泡沫、洗剂、凝胶、擦剂、浆液、软膏、摩丝、粉末、杆剂、笔剂、喷雾剂、气溶胶、胶囊剂、片剂、颗粒剂、口香糖、溶液、混悬液、乳剂、酏剂、多糖薄膜、胶冻或明胶;
可选地,所述胶囊剂包括:软胶囊剂、硬胶囊剂,可选为明胶胶囊剂;所述片剂包括:糖衣片剂。
本发明的肽根据它们的序列的性质或N-末端和/或C-末端中的任何可能的修饰,在水中具有可变的溶解度。因此本发明的肽可以通过水溶液掺入组合物中,且不溶于水的那些可溶解于美容上或药学上可接受的常规溶剂中,所述溶剂例如并且不限于乙醇、丙醇、异丙醇、丙二醇、甘油、丁二醇或聚乙二醇或其任何组合。
待施用的美容上或药学上有效量的本发明的肽以及它们的剂量将依赖于许多因素,包括年龄、患者的状态、病症或疾病的严重性、施用的途径和频率以及待使用的肽的具体性质。
“美容上或药学上有效量”意指无毒性的但足以提供希望的效果的本发明的一种或多种肽的量。在本发明的美容组合物或药用组合物中以获得希望的效果的美容上或药学上有效的浓度使用本发明的肽;在一个优选形式中,相对于组合物的总重量,在0.00000001%(按重量计)和20%(按重量计)之间,优选在0.000001%(按重量计)和15%(按重量计)之间、更优选在0.0001%(按重量计)和10%(按重量计)之间,并且甚至更优选在0.0001%(按重量计)和5%(按重量计)之间。
本发明的另一方面,提供一种美容上或药学上可接受的递送系统或缓释系统,以便实现有效成分的更好渗透和/或改进它的药物代谢动力学和药效动力学特性,其包含有效量的上述式(I)所示的肽,或其立体异构体、或立体异构体的混合物,或其美容上可接受的盐、或其药学上可接受的盐,或上述的美容或药用组合物。
术语“递送系统”是指与本发明的肽一起施用的稀释剂、佐剂、赋形剂或载体,它们选自:水、油或表面活性剂、包括石油来源、动物来源、植物来源、或合成来源的那些,例如并且不限于花生油、大豆油、矿物油、芝麻油、蓖麻油、聚山梨醇酯、脱水山梨糖醇酯、醚硫酸酯、硫酸酯、甜菜碱、葡萄糖苷、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、毛地黄皂苷和类似物。本领域的普通技术人员已知在可以给予本发明的肽的不同递送系统中可以使用的稀释剂。
术语“缓释”以常规含义使用,指提供化合物在一段时间内逐渐释放的化合物的递送系统,且优选地但不是必须地,在整个时间段内具有相对恒定的化合物释放水平。
递送系统或缓释系统的实例是脂质体、油质体、非离子型表面活性剂脂质体囊泡、醇质体、毫米胶囊、微米胶囊、纳米胶囊、纳米结构的脂质载体、海绵状物、环糊精、类脂囊泡、胶束、毫米球、微米球、纳米球、脂质球、微米乳液、纳米乳液、毫米粒子、微米粒子或纳米粒子。优选的递送系统或缓释系统是脂质体和微米乳液,更优选具有反胶束的内部结构的油包水型微米乳液。
缓释系统可以通过现有技术中已知的方法来制备,并且可以例如通过以下方式来给予:通过局部或经皮给药,包括粘附贴剂、非粘附贴剂、封闭贴剂、以及微电子贴剂;或通过全身给药例如并且不局限于,口服或胃肠外途径,包括鼻、直肠、皮下植入或注射、或直接植入或注射至特定身体部位中,并且优选地应该释放相对恒定量的本发明的这些肽。在该缓释系统中包含的肽的量将取决于例如该组合物将被给予的部位、本发明的肽的释放动力学和持续时间、以及有待治疗和/或护理的病状、病症和/或疾病的性质。
本发明的另一方面,提供一种上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或上述美容或药用组合物、或上述的美容上或药学上可接受的递送系统或缓释系统在制备用于抑制TRPV1活性的美容组合物或药物组合物中的用途。
本发明的另一方面,提供一种上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或上述美容或药用组合物、或上述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗或预防疼痛的美容组合物或药物组合物中的用途;
可选地,所述疼痛包括,但不限于急性疼痛、慢性疼痛、伤害性疼痛、神经性疼痛、炎性痛、内脏痛、腹痛、消化系统痛、呼吸系统痛、泌尿生殖系统痛、内分泌系统痛、心脏痛、胰痛、肝痛、因胆石引起的疼痛、胆汁淤积、肠痛、胃痛、因十二指肠溃疡引起的疼痛、因食道炎引起的疼痛、因胃食管返流疾病引起的疼痛、脾痛、血管中的疼痛、豆状核后综合征痛、肠易激综合征、与克罗恩病相关的疼痛、与溃疡性结肠炎、憩室炎、胃肠道粘膜炎相关的疼痛、头痛、紧张性头痛、与窦炎相关的头痛、偏头痛、眼痛、干眼综合征、手术后疼痛、由外科切口引起的手术后疼痛,由骨中植入物插入引起的手术后疼痛,由骨置换引起的手术后疼痛、因感染引起的手术后疼痛、由截肢引起的手术后疼痛、由骨折引起的疼痛、由癌症引起的疼痛、由骨癌引起的疼痛、与良性骨肿瘤相关的疼痛、与骨样骨瘤相关的疼痛、与成骨细胞瘤相关的疼痛、由癌症治疗引起的疼痛、由化学疗法引起的疼痛、由呕叶引起的疼痛、由化学治疗导致的呕吐引起的疼痛、肌肉骨骼痛、痉挛肌肉疼痛、纤维肌痛、复杂区域疼痛综合征、精神性疼痛、神经痛、由脱髓鞘疾病引起的疼痛、与颈肌张力障碍相关的颈痛、背痛、腰部疼痛、坐骨神经痛、神经原性感染、神经炎、皮肤灼痛、接触敏感性、寒冷敏感性、热敏感性、皮肤刺激、毛发去除后皮肤刺激、剃毛后皮肤刺激、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、扁平苔癣、烧伤、晒斑、关节炎、类风湿关节炎、骨关节炎、牛皮癣关节炎、葡萄膜炎,由神经损伤引起的疼痛、神经痛、疱疹后神经痛、神经病、周围神经病、幻痛、异常性疼痛、痛觉过敏、冷痛觉过敏、由腕管综合征引起的疼痛、灼痛、Grierson-Gopalan综合征、口灼伤综合征、感觉错乱、Fabry病、面部疼痛、三叉神经痛、由糖尿病引起的神经性疼痛、由AIDS引起的神经性疼痛、口面疼痛、牙痛、由拔牙引起的疼痛、由智齿拔除引起的疼痛、牙齿对冷的敏感性、牙齿对热的敏感性、口腔粘膜炎、颞下颌关节痛、由痛风引起的关节痛、与纹身或纹身去除过程相关的疼痛、拇滑囊肿痛、睾丸痛、肌盘膜痛、膀胱痛、泌尿道痛、膀胱炎、由肾脏结石引起的疼痛、肾绞痛、外阴痛、阴道痛、产后痛、月经疼痛、阴囊痛、会阴痛、骨盆痛或过敏症、皮肤痛或手术后刺激、利用强脉冲光疗法治疗后刺激、利用单色脉冲光治疗进行治疗后的刺激、利用化学剥脱剂治疗后的刺激或对攻击性外部试剂过度暴露后的刺激以及由长期酒精滥用引起的疼痛。
本发明的另一方面,提供一种上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或上述美容或药用组合物、或上述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗或预防瘙痒的美容组合物或药物组合物中的用途;
可选地,瘙痒选自与病况、疾病和/或障碍相关的瘙痒,所述疾病包括,但不限于皮炎、特异性皮炎、接触性皮炎、尿布皮炎、疱疹样皮炎、光照性皮肤病、光敏感性、与怀孕相关的皮肤病、与绝经相关的皮肤病、湿疹、敏感性皮肤、银屑病、水痘、疱疹、带状疱疹、Netherton综合征、脱皮综合征、扁平苔癣、粉刺、头皮屑、皮脂溢、皮脂溢皮炎、脱发、运动员足、念珠菌病、痔疮、阴道瘙痒、肛门瘙痒症、肛生殖道瘙痒症、晒斑、荨麻疹、瘙痒性耳炎、老年皮肤瘙痒症、水源性瘙痒症、结节性痒疹、prurigo planus、玫瑰糠疹、干燥病和干性皮肤、或与透析、HIV感染、恶性肿瘤、何杰金氏病、白血病、骨髓瘤、淋巴瘤、实体瘤、腺癌、肺癌、肝病、黄疸、胆汁淤积、肝功能衰竭、肝硬化、红细胞增多症、高嗜酸细胞增多综合征、原发性血小板增多症、骨髓增生异常综合征、缺铁引起的贫血、系统性红斑狼疮、内分泌疾病、甲状腺疾病、甲状腺功能亢进、甲状腺功能减退、甲状旁腺疾病、糖尿病、肾病、肾功能衰竭、尿毒症、寄生虫病、疥疮、虱、蛔虫、过敏反应、对药物的过敏、食物过敏、对化学制品的过敏、对有毒植物的暴露、对虫咬的暴露、化学疗法、压力和焦虑等相关的瘙痒。
本发明的另一方面,提供一种上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或上述美容或药用组合物、或上述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗或预防炎症的美容组合物或药物组合物中的用途;
可选地,所述炎症包括,但不限于神经原性炎症、关节炎症、腱炎症、肌肉炎症、败血病、血管炎症、呼吸系统炎症、慢性阻塞性肺疾病、鼻炎、变应性鼻炎、哮喘、耳炎、肠炎、克罗恩病、胰腺炎、肝炎、与慢性炎症相关的病况、急性炎症、肾炎、系统性红斑狼疮、关节炎、类风湿关节炎、成人和青少年类风湿关节炎、斯蒂尔病、牛皮癣关节炎、骨关节炎、由痛风引起的关节炎、类风湿性脊柱炎、肾小球肾炎、神经炎、神经组织炎症、多发性硬化、免疫系统障碍、动脉粥样硬化、心肌炎、心包炎、脉管炎、炎症性皮肤病况、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、过度增生性皮肤病、烧伤、晒斑、阴道黏液的炎症、外阴痛、阴道炎、口腔粘膜炎症、牙龈炎、牙周炎、炎症性眼病、葡萄膜炎、眼和春季结膜炎、肉瘤样病、溃疡病、荨麻疹、大疱性类天疱疮、纤硬皮病化、纤维化、血管性水肿、过敏反应、脱发、肝硬化、再狭窄、风湿性多肌痛、血清阴性脊柱关节病,包括强直性脊柱炎和Reiter’s综合征、皮肌炎、包涵体肌炎、多肌炎和淋巴管平滑肌增多。
本发明的另一方面,提供一种上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或上述美容或药用组合物、或上述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗、预防或修复红肿的美容组合物或药物组合物中的用途。
本发明的另一方面,提供一种上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或上述美容或药用组合物、或上述的美容上或药学上可接受的递送系统或缓释系统在制备用于皮肤抗敏舒缓的美容组合物或药物组合物中的用途,其中,所述皮肤抗敏舒缓包括修复皮肤屏障、降低皮肤对刺激物的神经性反应、增强皮肤耐受能力。
本发明的另一方面,提供一种上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或上述美容或药用组合物、或上述的美容上或药学上可接受的递送系统或缓释系统在制备抗敏剂中的用途。
本发明的另一方面,提供一种上述式(I)所示的肽、或其立体异构体、或其立体异构体的混合物、或其美容上可接受的盐、或其药学上可接受的盐、或上述美容或药用组合物、或上述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗、预防或修复皮肤老化或光老化的美容组合物或药物组合物中的用途。
为了便于理解本发明,对在本发明所使用的一些术语和表述的含义说明如下:
在本发明中,术语“皮肤”应理解为是构成它的多个层,从最上层或角质层至最下层或皮下组织,两个端点都包括在内。这些层由不同类型的细胞组成,如角质形成细胞、成纤维细胞、黑色素细胞、和/或脂肪细胞等。在本发明中,术语“皮肤”包括头皮。
术语“治疗”,指的是给予根据本发明的肽以减轻或消除一种疾病或病症、或减少或消除与这种疾病或病症相关的一种或多种症状。术语“治疗”还涵盖了减轻或消除该疾病或病症的生理后果的能力。
术语“护理”包括疾病和/或病症的预防。
术语“预防”,指的是本发明的肽在一种疾病或病症出现前防止、延迟、或阻碍其出现或发展的能力。
术语“修复”,指的是本发明的肽在一种疾病或病症出现后改善、缓解或恢复其原状的能力。
术语“老化”指的是皮肤随着年龄的增长经历的变化(自然老化),或通过暴露于阳光(光老化)或暴露于环境污染物,如化学污垢或污染物、烟草烟雾等而经历的变化,并且包括所有外在可见的和/或通过触摸可感知的变化,例如并且不局限于:皮肤上的不连续性的发展(如皱纹、细纹、表情纹、拉伸纹、条纹、沟纹、不平整或粗糙、毛孔尺寸增大、水分损失、弹性损失、紧致性损失、平滑性损失、变形恢复能力损失、回弹性损失)、皮肤下垂(如脸颊下垂、眼睛下方出现眼袋、或出现双下巴等)、皮肤颜色的变化(如瘢痕、变红、眼袋、或出现色素过度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、脱发、橘皮样皮肤、胶原结构损失,以及角质层、真皮、表皮、血管系统(例如出现蜘蛛静脉或毛细血管扩张症)或靠近皮肤的那些组织的其他组织学变化。
术语“光老化”指的是由于皮肤长期暴露于紫外线辐射而导致的皮肤过早老化,它呈现出与自然老化相同的生理特征,例如并且不局限于: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。
在本说明书中,用于氨基酸的缩写遵循IUPAC-IUB生化命名委员会(IUPAC-IUBCommission of Biochemical Nomenclature)在欧洲生物化学杂志(Eur.J.Biochem.1984,138:9-37)中所指定的规则。
因此,例如,Lys表示NH2-CH(CH2CH2CH2CH2NH2)-COOH,Lys-表示NH2-CH(CH2CH2CH2CH2NH2)-CO-,-Lys表示-NH-CH(CH2CH2CH2CH2NH2)-COOH,并且-Lys-表示-NH-CH(CH2CH2CH2CH2NH2)-CO-。因此,表示肽键的连字符消除了当位于该符号的右侧时的氨基酸(在此用常规非离子化形式来表示)1-羧基中的OH,并且消除了当位于该符号的左侧时的氨基酸2-氨基中的H;两种修饰可以应用于同一个符号(见表1)。
表1氨基酸残基的结构以及它们的单字母和三字母缩写符号
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缩写“Ac-”在本发明中用来表示乙酰基(CH3-CO-);缩写“CA-”在本发明中用来表示咖啡酰基;Ser:丝氨酸;Arg:精氨酸;Ala:丙氨酸;Lys:赖氨酸;Leu:亮氨酸;Gln:谷氨酰胺;Met:甲硫氨酸;Pro:脯氨酸;Ile:异亮氨酸;Thr:苏氨酸;Asp:天冬氨酸;Phe:苯丙氨酸。
本发明具有以下优点和效果:
1、本发明的肽通过人工设计得到,合成方便,且对人体安全无刺激。
2、本发明的肽能够抑制TRPV1的活性,可以在化妆品或医药领域用于治疗或预防疼痛、瘙痒、炎症,改善红肿症状,或用于治疗、预防或修复皮肤老化或光老化。
3、本发明的肽能够降低皮肤对刺激物的神经性反应,增强皮肤耐受能力,修复皮肤屏障,发挥抗敏舒缓作用,亦可用于制备抗敏剂。
附图说明
为了更清楚地说明本发明的技术方案,下面将对本发明的描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1是肽(12)Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2(分子式C37H71N17O7)质谱图,[M+2H]2+双电荷离子峰的质荷比(m/z)为433.8087,质谱测得的分子量为865.62。
图2是肽(18)Ac-Arg-Arg-Ala-Ile-Thr-Ile-NH2(分子式C33H63N13O8)质谱图,[M+2H]2+双电荷离子峰的质荷比(m/z)为385.7671,质谱测得的分子量为769.53。
图3是肽(41)Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH(分子式C41H73N13O13S)质谱图,[M+2H]2+双电荷离子峰的质荷比(m/z)为494.7824,质谱测得的分子量为987.56。
图4是肽(54)Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2(分子式C47H86N16O14)质谱图,[M+2H]2+双电荷离子峰的质荷比(m/z)为550.3511,质谱测得的分子量为1098.70。
图5是测试样品对辣椒素引起的小鼠舔足和抬脚行为影响结果图。
图6是测试样品对温度引起的小鼠甩尾潜伏时间影响结果图。
图7是测试样品对辣椒素引起的小鼠抓挠行为影响结果图。
图8是测试样品对TEWL值的影响结果图。
图9是测试样品对经皮水分流失率的影响结果图。
具体实施方式
为使本发明的所述目的、特征和优点能够更加明显易懂,下面结合附图和实施例对本发明作进一步详细的说明。显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
需要说明的是,在本发明中,用于氨基酸的缩写遵循IUPAC-IUB的生物化学命名委员会在Eur.J.Biochem.(1984)138:9-37和J.Chem.(1989)264:633-673中指定的规则。
Amide Resin:一种多肽合成用的起始树脂(交联度1%,替代度1.72mmol/g,粒度100-200目);Wang Resin:一种多肽合成用的起始树脂;Fmoc-Linker:4-[(2,4-二甲氧基苯基)(Fmoc-氨基)甲基]苯氧乙酸;Ac2O:醋酸酐;DMF:N,N-二甲基甲酰胺;DIPEA:二异丙基乙胺;DIC:二异丙基碳二亚胺;piperidine:哌啶;HOBt:1-羟基苯并三氮唑;TFA:三氟乙酸;TIS:三异丙基硅烷;EDT:1,2-乙二硫醇;Ser:丝氨酸;Ala:丙氨酸;Lys:赖氨酸;Leu:亮氨酸;Gln:谷氨酰胺;Met:甲硫氨酸;Arg:精氨酸;Pro:脯氨酸;Ile:异亮氨酸;Asp:天冬氨酸;Thr:苏氨酸;Fmoc:9-芴基甲氧羰基;Boc:叔丁氧基羰基;tBu:叔丁基;OtBu:叔丁氧基;Trt:三苯甲基;Pbf:2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基。
实施例1计算机模拟
TRPV1拮抗剂主要通过阻断受体活性位点的R557和E570形成盐桥,导致TRPV1通道关闭,从而发挥抑制作用。基于此,利用计算机模拟方法,将多肽与TRPV1进行对接并分析它们与受体的结合模式,筛选出候选肽。
多肽与TRPV1蛋白的对接打分结果见下表2。
表2多肽与TRPV1蛋白的对接打分结果
结果显示,本发明的肽可以与TRPV1蛋白较好地结合,从而抑制TRPV1受体活性,可用于治疗或护理通过抑制TRPVl活性得以改善或预防的病况、障碍和/或疾病。
实施例2Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2的制备
2.1Fmoc-Linker-Amide Resin的制备
称取5g的Amide Resin树脂于固相合成反应柱中,用DMF溶胀,洗涤树脂,抽走溶剂。
称取7.4g的Fmoc-Linker、2.10g的HOBt于干燥三角瓶中。用DMF溶剂溶解后置于冰水浴中冷却10min,加DIC活化10min,避免水汽。
将活化后的Fmoc-Linker加入溶胀后的树脂中反应2.5h,抽走反应液,洗涤树脂,抽走溶剂。
继续加入Ac2O与DIPEA封端处理1.5h。洗涤树脂,抽走溶剂。
2.2脱Fmoc
Fmoc-Linker-Amide Resin用20%piperidine/DMF脱Fmoc二次,每次10min,取样K检,显色深蓝。用DMF洗涤树脂7次,抽走溶剂。
2.3投料反应
称取5.7g的Fmoc-Lys(Boc)-OH,3.71g的HOBt加入干燥三角瓶中,加入DMF使其溶解,密封置于-18℃冰箱30min。加2.892g DIC活化3min,避免水汽。将活化后的氨基酸加入脱保护后树脂中反应2h,抽走反应液。K检树脂无色透明说明反应完全。
对N-末端Fmoc基团进行脱保护,并且在存在3.71g HOBt和2.892g DIC的情况下,使用DMF作为溶剂,将活化后的4.1g的Fmoc-Pro-OH偶联至肽基树脂上,持续反应2h。然后洗涤这些树脂并且重复Fmoc基团的脱保护处理以便偶联下一个氨基酸。在每次偶联中,在存在3.71gHOBt和2.892gDIC的情况下,使用DMF作为溶剂,顺序地偶联12.6g的Fmoc-Arg(Pbf)-OH;7.0g的Fmoc-Ile-OH;12.6g的Fmoc-Arg(Pbf)-OH以及随后12.6g的Fmoc-Arg(Pbf)-OH;反应完全之后,洗涤树脂,抽走溶剂。
对肽基树脂的N-末端Fmoc基团脱保护,用20%piperidine/DMF脱Fmoc二次,每次10min,取样K检,显色深蓝。用DMF洗涤树脂6次,抽走溶剂。
在存在DIPEA的情况下,使用DMF作为溶剂,将2.5g的Ac2O偶联至肽基树脂上,持续反应1.5h,洗涤树脂,抽走溶剂,收缩干燥后得到23.9g的Ac-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Linker-Amide Resin。
2.4裂解
量取134mL的TFA、4mL的TIS、4mL的EDT、4mL的苯甲硫醚和4mL的水混合搅拌均匀后得到裂解液,封口放置-18℃冰箱备用;异丙醚放置于-18℃冰箱冷冻备用。
称取23.9g的Ac-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Linker-Amide Resin,加入圆底烧瓶中,加入上述冷冻好的裂解液,搅拌反应2h。抽滤,收集滤液浓缩到15mL后加入异丙醚搅拌离心洗涤6次,直至pH值为3-4,真空干燥,得到10.5g的Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2粗肽。
2.5纯化
称取10.5g粗肽溶于280mL甲醇中,用孔径为0.22μm微孔滤膜过滤得到澄清透明溶液,通过反相HPLC纯化处理,纯化梯度如下表:
时间(min) | 流速(mL/min) | A%(0.1%醋酸+乙腈) | B%(0.1%醋酸+纯水) |
0 | 40 | 5 | 95 |
10 | 40 | 10 | 90 |
30 | 40 | 28 | 72 |
40 | 40 | 35 | 65 |
将过滤后的样品进样纯化,收集馏分,浓缩冻干,得到纯度98.2%的肽(12)Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2。
实施例3Ac-Arg-Arg-Ala-Ile-Thr-Ile-NH2的制备
3.1Fmoc-Linker-Amide Resin的制备
称取5.5g的Amide Resin树脂于固相合成反应柱中,用DMF溶胀,洗涤树脂,抽走溶剂。
称取7.1g的Fmoc-Linker、2.10g的HOBt于干燥三角瓶中。用DMF溶剂溶解后置于冰水浴中冷却10min,加DIC活化10min,避免水汽。
将活化后的Fmoc-Linker加入溶胀后的树脂中反应2.5h,抽走反应液,洗涤树脂,抽走溶剂。
继续加入Ac2O与DIPEA封端处理1.5h。洗涤树脂,抽走溶剂。
3.2脱Fmoc
Fmoc-Linker-Amide Resin用20%piperidine/DMF脱Fmoc二次,每次10min,取样K检,显色深蓝。用DMF洗涤树脂7次,抽走溶剂。
3.3投料反应
称取4.3g的Fmoc-Ile-OH,3.71g的HOBt加入干燥三角瓶中,加入DMF使其溶解,密封置于-18℃冰箱30min。加2.892g DIC活化3min,避免水汽。将活化后的氨基酸加入脱保护后树脂中反应2h,抽走反应液。K检树脂无色透明说明反应完全。
对N-末端Fmoc基团进行脱保护,并且在存在3.71g HOBt和2.892g DIC的情况下,使用DMF作为溶剂,将活化后的4.8g Fmoc-Thr(tBu)-OH偶联至肽基树脂上,持续反应2h。然后洗涤这些树脂并且重复Fmoc基团的脱保护处理以便偶联下一个氨基酸。在每次偶联中,在存在3.71gHOBt和2.892gDIC的情况下,使用DMF作为溶剂,顺序地偶联6.9g的Fmoc-Ile-OH;6.0g的Fmoc-Ala-OH;12.6g的Fmoc-Arg(Pbf)-OH以及随后12.6g的Fmoc-Arg(Pbf)-OH;反应完全之后,洗涤树脂,抽走溶剂。
对肽基树脂的N-末端Fmoc基团脱保护,用20%piperidine/DMF脱Fmoc二次,每次10min,取样K检,显色深蓝。用DMF洗涤树脂6次,抽走溶剂。
在存在DIPEA的情况下,使用DMF作为溶剂,将2.3g的Ac2O偶联至肽基树脂上,持续反应1.5h,洗涤树脂,抽走溶剂,收缩干燥后得到17.8g的Ac-Arg(Pbf)-Arg(Pbf)-Ala-Ile-Thr(tBu)-Ile-Linker-Amide Resin。
3.4裂解
量取108mL的TFA、3mL的TIS、3mL的EDT、3mL的苯甲硫醚和3mL的水混合搅拌均匀后得到裂解液,封口放置-18℃冰箱备用;异丙醚放置于-18℃冰箱冷冻备用。
称取17.8g的Ac-Arg(Pbf)-Arg(Pbf)-Ala-Ile-Thr(tBu)-Ile-Linker-AmideResin,加入圆底烧瓶中,加入上述冷冻好的裂解液,搅拌反应2h。抽滤,收集滤液浓缩到15mL后加入异丙醚搅拌离心洗涤6次,直至pH值为3-4,真空干燥,得到6.7g的Ac-Arg-Arg-Ala-Ile-Thr-Ile-NH2粗肽。
3.5纯化
称取6.7g粗肽溶于260mL的甲醇:醋酸:纯水(V:V:V=1:2:10)中,用孔径为0.22μm微孔滤膜过滤得到澄清透明溶液,通过反相HPLC纯化处理,纯化梯度如下表:
时间(min) | 流速(mL/min) | A%(0.1%醋酸+乙腈) | B%(0.1%醋酸+纯水) |
0 | 40 | 2 | 98 |
10 | 40 | 5 | 95 |
30 | 40 | 15 | 85 |
35 | 40 | 15 | 85 |
50 | 40 | 18 | 82 |
70 | 40 | 28 | 72 |
将过滤后的样品进样纯化,收集馏分,浓缩冻干,得到纯度98.45%的肽(18)Ac-Arg-Arg-Ala-Ile-Thr-Ile-NH2。
实施例4Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH的制备
4.1树脂的溶胀
称取5.5g的Wang树脂于固相合成反应柱中,用DMF溶胀,洗涤树脂,抽走溶剂。
4.2投料反应
称取7.2g的Fmoc-Leu-OH,3.71g的HOBt加入干燥三角瓶中,加入DMF使其溶解,密封置于-18℃冰箱30min。加2.892g DIC活化3min,避免水汽。将活化后的氨基酸加入溶胀后的树脂中反应2h,抽走反应液。K检树脂无色透明说明反应完全。
对N-末端Fmoc基团进行脱保护,并且在存在3.71g HOBt和2.892g DIC的情况下,使用DMF作为溶剂,将活化后的5.0g Fmoc-Ser(tBu)-OH偶联至肽基树脂上,持续反应2h。然后洗涤这些树脂并且重复Fmoc基团的脱保护处理以便偶联下一个氨基酸。在每次偶联中,在存在3.71gHOBt和2.892gDIC的情况下,使用DMF作为溶剂,顺序地偶联10.0g的Fmoc-Lys(Boc)-OH;7.5g的Fmoc-Met-OH;7.8g的Fmoc-Ser(tBu)-OH;6.9g的Fmoc-Pro-OH;14.9g的Fmoc-Arg(Pbf)-OH以及随后14.1g的Fmoc-Gln(Trt)-OH;反应完全之后,洗涤树脂,抽走溶剂。
对肽基树脂的N-末端Fmoc基团脱保护,用20%piperidine/DMF脱Fmoc二次,每次10min,取样K检,显色深蓝。用DMF洗涤树脂6次,抽走溶剂。
在存在DIPEA的情况下,使用DMF作为溶剂,将2.9g的Ac2O偶联至肽基树脂上,持续反应1.5h,洗涤树脂,抽走溶剂,收缩干燥后得到24.4g的Ac-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Met-Lys(Boc)-Ser(tBu)-Leu-Wang Resin。
4.3裂解
量取132.2mL的TFA、3.7mL的TIS、3.7mL的EDT、3.7mL的苯甲硫醚和3.7mL的水混合搅拌均匀后得到裂解液,封口放置-18℃冰箱备用;异丙醚放置于-18℃冰箱冷冻备用。
称取24.4g的Ac-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Met-Lys(Boc)-Ser(tBu)-Leu-Wang Resin,加入圆底烧瓶中,加入上述冷冻好的裂解液,搅拌反应2h。抽滤,收集滤液浓缩到15mL后加入异丙醚搅拌离心洗涤6次,直至pH值为3-4,真空干燥,得到10.7g的Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH粗肽。
4.4纯化
称取10.7g粗肽溶于700mL纯水中,用孔径为0.45μm微孔滤膜过滤得到澄清透明溶液,通过反相HPLC纯化处理,纯化梯度如下表:
时间(min) | 流速(mL/min) | A%(乙腈) | B%(0.1%醋酸+纯水) |
0 | 40 | 2 | 98 |
10 | 40 | 5 | 95 |
30 | 40 | 15 | 85 |
35 | 40 | 15 | 85 |
50 | 40 | 18 | 82 |
70 | 40 | 28 | 72 |
将过滤后的样品进样纯化,收集馏分,浓缩冻干,得到纯度99.2%的肽(41)Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH。
实施例5Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2的制备
5.1Fmoc-Linker-Amide Resin的制备
称取8g的Amide Resin树脂于固相合成反应柱中,用DMF溶胀,洗涤树脂,抽走溶剂。
称取7.1g的Fmoc-Linker、2.10g的HOBt于干燥三角瓶中。用DMF溶剂溶解后置于冰水浴中冷却10min,加DIC活化10min,避免水汽。
将活化后的Fmoc-Linker加入溶胀后的树脂中反应2.5h,抽走反应液,洗涤树脂,抽走溶剂。
继续加入Ac2O与DIPEA封端处理1.5h。洗涤树脂,抽走溶剂。
5.2脱Fmoc
Fmoc-Linker-Amide Resin用20%piperidine/DMF脱Fmoc二次,每次10min,取样K检,显色深蓝。用DMF洗涤树脂7次,抽走溶剂。
5.3投料反应
称取7.1g的Fmoc-Thr(tBu)-OH,3.71g的HOBt加入干燥三角瓶中。加入DMF使其溶解,密封置于-18℃冰箱30min。加2.892g DIC活化3min,避免水汽。将活化后的氨基酸加入脱保护后树脂中反应2h,抽走反应液。K检树脂无色透明说明反应完全。
对N-末端Fmoc基团进行脱保护,并且在存在3.71g HOBt和2.892g DIC的情况下,使用DMF作为溶剂,将活化后的7.3g Fmoc-Asp(OtBu)-OH偶联至肽基树脂上,持续反应2h。然后洗涤这些树脂并且重复Fmoc基团的脱保护处理以便偶联下一个氨基酸。在每次偶联中,在存在3.71g HOBt和2.892g DIC的情况下,使用DMF作为溶剂,顺序地偶联6.3g的Fmoc-Leu-OH;5.8g的Fmoc-Ile-OH;7.7g的Fmoc-Thr(tBu)-OH;5.8g的Fmoc-Ile-OH;6.5g的Fmoc-Ala-OH;14.9g的Fmoc-Arg(Pbf)-OH以及随后14.9g的Fmoc-Arg(Pbf)-OH;反应完全之后,洗涤树脂,抽走溶剂。
对肽基树脂的N-末端Fmoc基团脱保护,用20%piperidine/DMF脱Fmoc二次,每次10min,取样K检,显色深蓝。用DMF洗涤树脂6次,抽走溶剂。
在存在DIPEA的情况下,使用DMF作为溶剂,将3.0g的Ac2O偶联至肽基树脂上,持续反应1.5h,洗涤树脂,抽走溶剂,收缩干燥后得到28g的Ac-Arg(Pbf)-Arg(Pbf)-Ala-Ile-Thr(tBu)-Ile-Leu-Asp(OtBu)-Thr(tBu)-Linker-Amide Resin。
5.4裂解
量取151.8mL的TFA、4.3mL的TIS、4.3mL的EDT、4.3mL的苯甲硫醚和4.3mL的水混合搅拌均匀后得到裂解液,封口放置-18℃冰箱备用;异丙醚放置于-18℃冰箱冷冻备用。
称取28g的Ac-Arg(Pbf)-Arg(Pbf)-Ala-Ile-Thr(tBu)-Ile-Leu-Asp(OtBu)-Thr(tBu)-Linker-Amide Resi n,加入圆底烧瓶中,加入上述冷冻好的裂解液,搅拌反应2h。抽滤,收集滤液浓缩到15mL后加入异丙醚搅拌离心洗涤6次,直至pH值为3-4,真空干燥,得到5.9g的Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2粗肽。
5.5纯化
称取5.9g粗肽溶于400mL的甲醇:醋酸:纯水(V:V:V=1:1:)中,用孔径为0.22μm微孔滤膜过滤得到澄清透明溶液,通过反相HPLC纯化处理,纯化梯度如下表:
时间(min) | 流速(mL/min) | A%(乙腈) | B%(0.1%醋酸+纯水) |
0 | 40 | 2 | 98 |
10 | 40 | 8 | 92 |
30 | 40 | 18 | 82 |
35 | 40 | 18 | 82 |
50 | 40 | 20 | 80 |
70 | 40 | 30 | 70 |
将过滤后的样品进样纯化,收集馏分,浓缩冻干,得到纯度98.7%的肽(54)Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2。
实施例6
本发明式(I)中的其他肽可以通过类似的方法制备。
所获得的这些肽通过ESI-MS测定其分子量,部分肽的测试结果见下表3及图1-4:
表3质谱法测定分子量结果
编号 | 序列 | 分子量质谱分析结果 |
(12) | Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2 | 865.62 |
(18) | Ac-Arg-Arg-Ala-Ile-Thr-Ile-NH2 | 769.53 |
(41) | Ac-Gln-Arg-Pro-Ser-Met-Lys-Ser-Leu-OH | 987.56 |
(54) | Ac-Arg-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr-NH2 | 1098.70 |
实施例7对辣椒素刺激的镇痛实验
7.1实验动物
8周龄雄性BALB/C小鼠,体重20-22g。
7.2实验试剂
PBS辣椒素
7.3待测样品
对照组:生理盐水;
实验组:参比肽(Ac-Tyr-Pro-Phe-Phe-NH2)、肽(12)、肽(18)、肽(41)和肽(54);
给药剂量:使用浓度为100ppm,依据欧盟推荐日用量标准,一日用量为1.54mL*100μg/mL=154μg,根据面部面积占体表面积约5%换算,则体表面积用量为154μg/5%=3080μg=3.08mg,再根据小鼠换算系数,换算成小鼠用量为3.08mg/60kg*9.1=0.46mg/kg。按照小鼠一只20g算,约一次注射用量为0.0092mg,约0.01mg,按照每次注射0.1mL,需配制0.01mg/0.1mL=0.1mg/mL的药物(浓度为100ppm)。
7.4实验方法
将36只小鼠随机分为对照组和实验组,每组6只。对照组小鼠给予生理盐水;实验组小鼠给予待测样品处理,在笼子里适应30min,腹腔注射1h后在小鼠右脚掌皮下注射辣椒素500μM/10μL/只。注射完立即记录30min内小鼠抬脚和舔足的行为反应,并统计抬脚和舔足次数。
实验数据以均数标准差(Mean±SD)表示。
7.5实验结果
本实验以现有技术乙酰基四肽-15(Ac-Tyr-Pro-Phe-Phe-NH2)作为参比肽,其能够减少人体产生的促炎介质降钙素基因相关肽(CGRP)的数量,降低神经元的刺激/兴奋,从而提高皮肤的耐受阈值,使皮肤对各种刺激、疼痛等不适感觉减弱。各测试样品对辣椒素引起的小鼠舔足和抬脚行为影响结果见下表4及图5。
表4测试样品对辣椒素引起的小鼠舔足和抬脚行为影响结果(单位:次)
结果表明,与对照组相比,给予本发明肽(12)、肽(18)、肽(41)和肽(54)处理的小鼠经辣椒素刺激后舔足和抬脚行为次数明显降低,给予肽(12)处理的平均次数为10.3次,给予肽(18)处理的平均次数为15.2次,给予肽(41)处理的平均次数为17.5次,给予肽(54)处理的平均次数为20.8次,舔足和抬脚行为次数明显低于给予生理盐水处理的24.3次和给予参比肽处理的23.0次;其中,肽(12)的技术效果最优。
由此可知,本发明的肽具有明显的镇痛作用,可以用于治疗或预防疼痛,亦可用于制备抗敏剂。
实施例8对热刺激的镇痛实验
8.1实验动物
8周龄雄性BALB/C小鼠,体重20-22g。
8.2实验仪器
恒温水浴锅,其他仪器为常规实验仪器。
8.3待测样品
对照组:生理盐水;
实验组:参比肽、肽(12)、肽(18)、肽(41)和肽(54);
给药剂量:使用浓度为100ppm,依据欧盟推荐日用量标准,一日用量为1.54mL*100μg/mL=154μg,根据面部面积占体表面积约5%换算,则体表面积用量为154μg/5%=3080μg=3.08mg,再根据小鼠换算系数,换算成小鼠用量为3.08mg/60kg*9.1=0.46mg/kg。按照小鼠一只20g算,约一次注射用量为0.0092mg,约0.01mg,按照每次注射0.1mL,需配制0.01mg/0.1mL=0.1mg/mL的药物(浓度为100ppm)。
8.4实验方法
将36只小鼠随机分为对照组和实验组,每组6只。对照组小鼠给予生理盐水;实验组小鼠给予待测样品处理,待恒温水浴锅温度达到48℃并稳定后,用小鼠固定器固定适应10min,将小鼠1/3的尾巴浸入48℃水浴锅内,并记录腹腔注射待测样品后1h的48℃水浴浸尾实验第一次甩尾潜伏时间。
实验数据以均数标准差(Mean±SD)表示。
8.5实验结果
测试样品对温度引起的小鼠甩尾潜伏时间影响结果见下表5及图6。
表5测试样品对温度引起的小鼠甩尾潜伏时间影响结果(单位:秒)
结果表明,与对照组相比,给予本发明肽(12)和肽(18)处理的小鼠经48℃水浴刺激后甩尾潜伏时间明显延长,给予肽(12)处理的平均时长为3.58秒,给予肽(18)处理的平均时长为4.17秒,甩尾潜伏时长明显大于给予生理盐水处理的2.78秒和给予参比肽处理的2.06秒;其中,肽(18)的技术效果最优。
由此可知,本发明的肽能够减弱热痛反应,具有明显的镇痛作用,可以用于治疗或预防疼痛,亦可用于制备抗敏剂。
实施例9辣椒素诱导的小鼠耳肿胀实验
9.1实验动物
8周龄雄性BALB/C小鼠,体重20-22g。
9.2实验试剂
PBS辣椒素
9.3待测样品
对照组:生理盐水;
实验组:参比肽、肽(12)、肽(18)、肽(41)和肽(54);
给药剂量:使用浓度为100ppm,依据欧盟推荐日用量标准,一日用量为1.54mL*100μg/mL=154μg,根据面部面积占体表面积约5%换算,则体表面积用量为154μg/5%=3080μg=3.08mg,再根据小鼠换算系数,换算成小鼠用量为3.08mg/60kg*9.1=0.46mg/kg。按照小鼠一只20g算,约一次注射用量为0.0092mg,约0.01mg,按照每次注射0.1mL,需配制0.01mg/0.1mL=0.1mg/mL的药物(浓度为100ppm)。
9.4实验方法
将36只小鼠随机分为对照组和实验组,每组6只。对照组小鼠给予超纯水灌胃;实验组小鼠给予待测样品处理,在笼子里适应30min,腹腔/皮下给药1h后在小鼠左耳皮下涂抹辣椒素10mg/mL/10μL/只。立即记录30min抓挠次数。
实验数据以均数标准差(Mean±SD)表示。
9.5实验结果
小鼠耳肿胀模型是非特异性炎症模型的一种,主要是以化学物质作为致炎剂来诱导小鼠耳肿胀。近年来,小鼠耳肿胀模型已发展成为一类比较成熟的动物炎症模型。本实验以辣椒素诱导建立小鼠耳肿胀模型,经辣椒素刺激后出现炎症,随着炎症的加重,小鼠开始出现瘙痒反应(抓挠动作),通过统计小鼠抓挠行为,评价测试样品抑制瘙痒,改善红肿的作用及其抗炎活性。
测试样品对辣椒素引起的小鼠抓挠行为影响结果见下表6及图7。
表6测试样品对辣椒素引起的小鼠抓挠行为影响结果(单位:次)
结果表明,与对照组相比,给予本发明肽(12)、肽(18)、肽(41)和肽(54)处理的小鼠经辣椒素刺激后抓挠行为次数明显降低,给予肽(12)处理的平均次数为10.0次,给予肽(18)处理的平均次数为11.0次,给予肽(41)处理的平均次数为16.2次,给予肽(54)处理的平均次数为13.2次,抓挠行为次数明显低于给予生理盐水处理的17.8次;与参比肽相比,肽(12)和肽(18)具有比参比肽更优的技术效果,而且肽(54)的效果与参比肽相当。
由此可知,本发明的肽具有明显的抑制瘙痒,改善红肿的作用,可以用于治疗或预防瘙痒、炎症;同时能够降低小鼠耳部皮肤对辣椒素的神经性反应,增强皮肤的耐受能力,发挥抗敏舒缓的作用,亦可用于制备抗敏剂。
实施例10辣椒素诱导的舒缓修复实验
10.1实验目的
按照随机、双盲和平行试验原则,通过受试者连续使用测试样品,结合仪器检测结果对测试样品的安全性和舒缓修复功效进行综合评估。
10.2实验对象
受试者:一共招募18岁~50岁的室内工作志愿者30人,最终筛选入组29人,脱组1人。
已签订知情同意书,自愿参加本测试;
符合下列任一项者将被排除:有严重系统疾病、免疫缺陷或自身的免疫性疾病;活动性过敏性的疾病者;体质高度敏感者;近期一个月使用过激素类的药物或者免疫抑制剂者;计划怀孕或妊娠或哺乳期以及产后六个月内的妇女;
剔除及脱落标准:志愿者因自己原因要求中止试验;志愿者产生不良反应导致无法继续试验;志愿者依从性差,比如测试中还使用其它对本试验有影响的护肤品等。
10.3试剂、材料和仪器
辣椒素:用10%乙醇稀释,配制成0.001%辣椒素溶液(w/v);乙醇:用蒸馏水稀释至10%溶液(v/v),常温保存。
空白药敏纸片:直径8mm,厚度0.7mm。
经表皮水分流失测试仪:TM Hex。
10.4待测样品
样品组:乙酰基四肽-15(Ac-Tyr-Pro-Phe-Phe-NH2)、肽(12)、肽(18)。
安慰剂组:空白基质。
空白组:不做任何处理。
10.5实验方法
测试前使用经表皮水分流失测试仪检测受试者右侧鼻唇沟TEWL值评估皮肤屏障情况,然后在同一部位(右侧鼻唇沟外1cm)进行辣椒素实验。在0-2min内用沾取10%酒精的棉签擦洗鼻唇沟外1cm处5次,如有不适反应将被淘汰。在2-4min内,将蘸有10%的酒精溶液的棉棒来回擦洗鼻唇沟lcm处5次,使其适应潮湿,清凉的感觉,如有不适感将淘汰。在4-6min内将真径为0.8cm的两层滤纸放置于受试者鼻唇沟外1cm部位,将50μL浓度为0.001%辣椒素滴在滤纸上,询问受试者的感觉,用5分法(0分几乎不可察觉,1分略易察觉,2分为中等感知,3分为强感知,4分为疼痛)对感知到的每一种性质的感觉的强度进行评估,如果受试者对辣椒素侧的灼热感觉程度≥2分,持续时间>30s,则为辣椒素试验阳性,反之为阴性,筛选辣椒素试验阳性受试者纳入标准,最终筛选入组29人,脱组1人。
对最终筛选入组的29人进行分组测试,其中,测试样品组乙酰基四肽-15和肽(12)样品的受试者10名,测试样品组肽(18)样品的受试者10名,安慰剂组和空白组的受试者9名。测试样品组乙酰基四肽-15和肽(12)样品的受试者连续7天在两侧鼻唇沟分别使用不同的测试样品,测试样品组肽(18)样品的受试者连续7天在一侧鼻唇沟使用测试样品。安慰剂组和空白组的受试者连续7天在一侧使用空白基质,另一侧鼻唇沟不做任何处理。受试部位禁止使用影响测试的制剂。受试部位使用的清洁产品和使用状况与日常一致,受试者以室内活动为主,避免长期暴露在光照下。
在第7天使用样品后,用经表皮水分流失测试仪测定其TEWL值并计算经皮水分流失率,测试完后对同一部位再次进行辣椒素刺激评分,统计辣椒素试验阳性人数和阴性人数,评估皮肤屏障情况。
经皮水分流失率=(使用样品后第7天TEWL值—测试前TEWL值)/测试前TEWL值*100%
10.6实验结果
经皮水分散失(TEWL)又称透皮失水,是反映角质层屏障功能的常用指标。TEWL值不能直接表示角质层的水分含量,但能表明角质层水分散失的情况,可反映皮肤角质层的保水能力。TEWL值是基于菲克扩散定律,在规定的温湿度条件下,通过测量单位时间、单位横截面积,近表皮(近1cm以内)上不同点的水蒸气分压梯度,得到该值。TEWL值越高,代表单位时间、单位横截面积的经表皮水分流失量越多,皮肤屏障越差;TEWL值越低,代表单位时间、单位横截面积的经表皮水分流失量越少,皮肤屏障越好。乙酰基四肽-15,是一种能提高皮肤天然耐受阈值的多肽,通过提高皮肤对环境因子的耐受力,缓解化妆品和皮肤治疗手段带来的不适,达到缓解皮肤敏感的目的。本实验以乙酰基四肽-15作为阳性对照。
连续7天使用不同测试样品后,使用经表皮水分流失测试仪检测TEWL值并计算经皮水分流失率。然后再次使用辣椒素刺激后,对辣椒素刺激部位用5分法对受试者感知到的每一种性质的感觉强度进行评估。实验结果见下表7及图8-9。
表7使用7天测试样品后辣椒素刺激实验结果
由表7结果可知,再次使用辣椒素刺激空白组,阳性比例为100%,安慰剂组阳性比例为88.9%,说明安慰剂组和空白组没有抗敏舒缓效果。与空白组和安慰剂组结果相比,乙酰基四肽-15组的阳性结果为20%,肽(12)组的阳性结果为20%,肽(18)组的阳性结果为30%,阳性比例均显著下降,阴性比例增加,说明本发明的肽能够减轻辣椒素引起的灼热感和疼痛,具有抗敏舒缓的效果。
测试样品对TEWL值的影响结果见图8,结果发现,与测试前TEWL值相比,连续7天使用不同测试样品后,空白组的结果反而升高,安慰剂组和乙酰基四肽-15组的结果虽有一定程度的下降,但没有明显变化,肽(12)组和肽(18)组的TEWL值明显降低,说明本发明的肽(12)和肽(18)样品具有优异的修复皮肤屏障的作用。
测试样品对经皮水分流失率的影响结果见图9,结果发现,与安慰剂组的经皮水分流失率相比,样品组的经皮水分流失率均有所降低,皮肤水分流失量减少,说明受损的皮肤屏障得到较好的修复。与乙酰基四肽-15组的经皮水分流失率相比,肽(12)组和肽(18)组的经皮水分流失率明显降低,说明本发明的肽(12)和肽(18)样品具有比乙酰基四肽-15更优的作用效果,能够减少皮肤水分流失,修复皮肤屏障,具有抗敏舒缓的效果,其中,肽(12)的技术效果最优。
由此可知,本发明的肽不仅能够降低皮肤对刺激物的神经性反应,增强皮肤耐受能力,安全性高,而且还具有修复皮肤屏障的作用,达到抗敏舒缓的效果。可用于制备抗敏舒缓的美容组合物或药物组合物,亦可用于制备抗敏剂。
综上所述,本发明的肽可用于治疗或护理通过抑制TRPVl活性而得以改善或预防的那些病况、障碍和/或疾病;同时还可以在化妆品或医药领域用于皮肤抗敏舒缓,修复皮肤屏障。
实施例11
含肽(12)的脂质体的制备
将二棕榈酰基磷脂酰胆碱称重且溶于氯仿。于真空下蒸发溶剂,直至得到磷脂薄层,将此层于55℃以所需浓度的肽水溶液处理而水化,得到多室脂质体。将多室脂质体通过高压均质处理,得到尺寸更加小而均一的单室脂质体。
实施例12
含肽(18)的精华液的制备
纯化水搅拌加热至85℃,保温30min;将透明质酸钠、黄原胶预溶于丁二醇,加入水中,搅拌溶解完全;搅拌降温至35℃,加入剩余成分,搅拌均匀即得。
实施例13
含肽(41)的乳液的制备
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制备方法:将肽(41)配制为0.02mg/mL的水溶液;将鲸蜡硬脂醇(和)鲸蜡硬脂基葡糖苷、霍霍巴油、矿物油、棕榈酸异丙酯加热至85℃,搅拌均匀;得A相;将甘油、尿囊素、聚丙烯酰胺(和)C13-14异链烷烃(和)月桂醇聚醚-7用水溶解,加热至85℃,得B相;将A相快速加入B相,恒温均质3-5min,冷却;冷却至60℃以下加入防腐剂,搅拌均匀,冷却至45℃以下加入多肽溶液、香精,即得。
实施例14
含肽(54)的爽肤水的制备
制备方法:将尿囊素、甘油用水溶解,加热至85℃,保温30分钟;将PEG-7甘油椰油酸酯、肽(54)用水溶解;上述溶液冷却后混合,搅拌均匀,得混合溶液;将丙二醇、防腐剂、香精依次加入上述混合溶液,加水搅拌均匀,即得。
尽管已描述了本发明实施例的优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例做出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明实施例范围的所有变更和修改。
最后,还需要说明的是,在本文中,诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来,而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者终端设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者终端设备所固有的要素。在没有更多限制的情况下,由语句“包括一个……”限定的要素,并不排除在包括所述要素的过程、方法、物品或者终端设备中还存在另外的相同要素。
以上对本发明所提供的合成肽及其组合物和用途,进行了详细介绍,本文中应用了具体个例对本发明的原理及实施方式进行了阐述,以上实施例的说明只是用于帮助理解本发明的方法及其核心思想;同时,对于本领域的一般技术人员,依据本发明的思想,在具体实施方式及应用范围上均会有改变之处,综上所述,本说明书内容不应理解为对本发明的限制。
Claims (14)
1.式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐,其特征在于,
R1-Arg-Arg-Ile-Arg-Pro-Lys-R2(I)
式(I)中,
R1是乙酰基;R2是-OH或-NH2。
2.根据权利要求1所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐,其特征在于,为Ac-Arg-Arg-Ile-Arg-Pro-Lys-NH2。
3.根据权利要求1或2任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐,其特征在于,
所述美容上可接受的盐或药学上可接受的盐包括式(I)所示的肽的金属盐,其中,所述金属包括:锂、钠、钾、钙、镁、锰、铜、锌或铝;
可选地,所述美容上可接受的盐或药学上可接受的盐包括式(I)所示的肽与有机碱形成的盐,所述有机碱包括:乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、精氨酸、赖氨酸、组氨酸或哌嗪;
可选地,所述美容上可接受的盐或药学上可接受的盐包括式(I)所示的肽与无机酸或有机酸形成的盐,其中,所述有机酸包括:乙酸、柠檬酸、乳酸、丙二酸、马来酸、酒石酸、延胡索酸、苯甲酸、天冬氨酸、谷氨酸、琥珀酸、油酸、三氟乙酸、草酸、扑酸或葡萄糖酸;所述无机酸包括:盐酸、硫酸、硼酸或碳酸。
4.一种美容或药用组合物,其特征在于,包括有效量的如权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐,以及至少一种赋形剂和任选的美容上或药学上可接受的佐剂;
可选地,所述佐剂选自:抑制TRPV1活性的其他试剂、镇痛剂、抑制PAR-2活性的剂、胶原合成刺激剂、调节PGC-1α合成的剂、调节PPARγ的活性的剂、增加或减少脂肪细胞的甘油三酸酯含量的剂、刺激或延迟脂肪细胞分化的剂、脂解剂或刺激脂肪分解的剂、溶脂剂、生脂剂、乙酰胆碱受体聚集的抑制剂、抑制肌肉收缩的剂、抗胆碱能试剂、弹性蛋白酶抑制剂、基质金属蛋白酶抑制剂、黑色素合成刺激或抑制剂、增白剂或脱色剂、促色素沉着剂、自晒黑剂、抗老化剂、NO-合酶抑制剂、5α-还原酶抑制剂、赖氨酰羟化酶和/或脯氨酰羟化酶的抑制剂、抗氧化剂、自由基清除剂和/或抗大气污染的剂、活性羰基类物质清除剂、抗糖化剂、抗组胺剂、抗病毒剂、抗寄生虫剂、乳化剂、润肤剂、有机溶剂、液体推进剂、皮肤调理剂、保留水分的物质、α羟基酸、β羟基酸、增湿剂、表皮水解酶、维生素、氨基酸、蛋白质、色素、染料、生物聚合物、胶凝聚合物、增稠剂、表面活性剂、软化剂、粘合剂、防腐剂、抗皱剂、能够减少或治疗下眼袋的剂、角质层分离剂、抗微生物剂、抗真菌剂、抑真菌剂、灭菌剂、抑菌剂、刺激真皮或表皮大分子的合成和/或能够抑制或预防它们的降解的剂、刺激弹性蛋白合成的剂、刺激核心蛋白聚糖合成的剂、刺激层粘连蛋白合成的剂、刺激防御素合成的剂、刺激伴侣蛋白合成的剂、刺激cAMP合成的剂、刺激HSP70合成的剂、刺激热休克蛋白合成的剂、刺激透明质酸合成的剂、刺激纤连蛋白合成的剂、刺激去乙酰化酶合成的剂、刺激脂质和角质层组分的合成的剂、神经酰胺、脂肪酸、抑制胶原降解的剂、抑制弹性蛋白降解的剂、抑制丝氨酸蛋白酶的剂、刺激成纤维细胞增殖的剂、刺激角质形成细胞增殖的剂、刺激脂肪细胞增殖的剂、刺激黑色素细胞增殖的剂、刺激角质形成细胞分化的剂、抑制乙酰胆碱酯酶的剂、皮肤松弛剂、刺激糖胺聚糖合成的剂、抗角化过度剂、粉刺溶解剂、抗银屑病剂、抗湿疹剂、DNA修复剂、DNA防护剂、稳定剂、止痒剂、用于治疗和/或护理敏感性皮肤的剂、固化剂、紧致剂、重构剂、抗拉伸纹剂、调节皮脂产生的剂、止汗剂、刺激愈合的剂、协助愈合的剂、刺激再上皮化的剂、协助再上皮化的剂、细胞因子、镇静剂、抗炎剂、麻醉剂、作用于毛细血管循环和/或微循环的剂、刺激血管生成的剂、抑制血管渗透性的剂、静脉紧张剂、作用于细胞代谢的剂、用于改善真皮-表皮接合的剂、诱导毛发生长的剂、毛发生长抑制或延缓剂、香料、螯合剂、植物提取物、精油、海洋提取物、得自生物发酵过程的剂、无机盐、细胞提取物、防晒剂、以及有效抗A和/或B紫外线的有机或无机光防护剂或其混合物。
5.根据权利要求4所述的美容或药用组合物,其特征在于,所述美容或药用组合物的制剂选自:霜剂、油、香膏、泡沫、洗剂、凝胶、擦剂、浆液、软膏、摩丝、粉末、杆剂、笔剂、喷雾剂、气溶胶、胶囊剂、片剂、颗粒剂、口香糖、溶液、混悬液、乳剂、酏剂、多糖薄膜、胶冻或明胶;
可选地,所述胶囊剂包括:软胶囊剂、硬胶囊剂,可选为明胶胶囊剂;所述片剂包括:糖衣片剂。
6.一种美容上或药学上可接受的递送系统或缓释系统,其特征在于,包含有效量的如权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物;
所述美容上或药学上可接受的递送系统或缓释系统选自:脂质体、油质体、非离子型表面活性剂脂质体囊泡、醇质体、毫米胶囊、微米胶囊、纳米胶囊、纳米结构的脂质载体、海绵状物、环糊精、类脂囊泡、胶束、毫米球、微米球、纳米球、脂质球、微米乳液、纳米乳液、毫米粒子、微米粒子或纳米粒子;可选为脂质体或微米乳液,可选具有反胶束的内部结构的油包水型微米乳液。
7.权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物、或权利要求6所述的美容上或药学上可接受的递送系统或缓释系统在制备用于抑制TRPV1活性的美容组合物或药物组合物中的用途。
8.权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物、或权利要求6所述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗或预防疼痛的美容组合物或药物组合物中的用途;
可选地,所述疼痛选自:急性疼痛、慢性疼痛、伤害性疼痛、神经性疼痛、炎性痛、内脏痛、腹痛、消化系统痛、呼吸系统痛、泌尿生殖系统痛、内分泌系统痛、心脏痛、胰痛、肝痛、因胆石引起的疼痛、胆汁淤积、肠痛、胃痛、因十二指肠溃疡引起的疼痛、因食道炎引起的疼痛、因胃食管返流疾病引起的疼痛、脾痛、血管中的疼痛、豆状核后综合征痛、肠易激综合征、与克罗恩病相关的疼痛、与溃疡性结肠炎、憩室炎、胃肠道粘膜炎相关的疼痛、头痛、紧张性头痛、与窦炎相关的头痛、偏头痛、眼痛、干眼综合征、手术后疼痛、由外科切口引起的手术后疼痛,由骨中植入物插入引起的手术后疼痛、由骨置换引起的手术后疼痛、因感染引起的手术后疼痛、由截肢引起的手术后疼痛、由骨折引起的疼痛、由癌症引起的疼痛、由骨癌引起的疼痛、与良性骨肿瘤相关的疼痛、与骨样骨瘤相关的疼痛、与成骨细胞瘤相关的疼痛、由癌症治疗引起的疼痛、由化学疗法引起的疼痛、由呕叶引起的疼痛、由化学治疗导致的呕吐引起的疼痛、肌肉骨骼痛、痉挛肌肉疼痛、纤维肌痛、复杂区域疼痛综合征、精神性疼痛、神经痛、由脱髓鞘疾病引起的疼痛、与颈肌张力障碍相关的颈痛、背痛、腰部疼痛、坐骨神经痛、神经原性感染、神经炎、皮肤灼痛、接触敏感性、寒冷敏感性、热敏感性、皮肤刺激、毛发去除后皮肤刺激、剃毛后皮肤刺激、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、扁平苔癣、烧伤、晒斑、关节炎、类风湿关节炎、骨关节炎、牛皮癣关节炎、葡萄膜炎、由神经损伤引起的疼痛、神经痛、疱疹后神经痛、神经病、周围神经病、幻痛、异常性疼痛、痛觉过敏、冷痛觉过敏、由腕管综合征引起的疼痛、灼痛、Grierson-Gopalan综合征、口灼伤综合征、感觉错乱、Fabry病、面部疼痛、三叉神经痛、由糖尿病引起的神经性疼痛、由AIDS引起的神经性疼痛、口面疼痛、牙痛、由拔牙引起的疼痛、由智齿拔除引起的疼痛、牙齿对冷的敏感性、牙齿对热的敏感性、口腔粘膜炎、颞下颌关节痛、由痛风引起的关节痛、与纹身或纹身去除过程相关的疼痛、拇滑囊肿痛、睾丸痛、肌盘膜痛、膀胱痛、泌尿道痛、膀胱炎、由肾脏结石引起的疼痛、肾绞痛、外阴痛、阴道痛、产后痛、月经疼痛、阴囊痛、会阴痛、骨盆痛或过敏症、皮肤痛或手术后刺激、利用强脉冲光疗法治疗后刺激、利用单色脉冲光治疗进行治疗后的刺激、利用化学剥脱剂治疗后的刺激或对攻击性外部试剂过度暴露后的刺激以及由长期酒精滥用引起的疼痛。
9.权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物、或权利要求6所述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗或预防瘙痒的美容组合物或药物组合物中的用途;
可选地,所述瘙痒选自与选自下述的病况、疾病和/或障碍相关的瘙痒:皮炎、特异性皮炎、接触性皮炎、尿布皮炎、疱疹样皮炎、光照性皮肤病、光敏感性、与怀孕相关的皮肤病、与绝经相关的皮肤病、湿疹、敏感性皮肤、银屑病、水痘、疱疹、带状疱疹、Netherton综合征、脱皮综合征、扁平苔癣、粉刺、头皮屑、皮脂溢、皮脂溢皮炎、脱发、运动员足、念珠菌病、痔疮、阴道瘙痒、肛门瘙痒症、肛生殖道瘙痒症、晒斑、荨麻疹、瘙痒性耳炎、老年皮肤瘙痒症、水源性瘙痒症、结节性痒疹、prurigoplanus、玫瑰糠疹、干燥病和干性皮肤、或与透析、HIV感染、恶性肿瘤、何杰金氏病、白血病、骨髓瘤、淋巴瘤、实体瘤、腺癌、肺癌、肝病、黄疸、胆汁淤积、肝功能衰竭、肝硬化、红细胞增多症、高嗜酸细胞增多综合征、原发性血小板增多症、骨髓增生异常综合征、缺铁引起的贫血、系统性红斑狼疮、内分泌疾病、甲状腺疾病、甲状腺功能亢进、甲状腺功能减退、甲状旁腺疾病、糖尿病、肾病、肾功能衰竭、尿毒症、寄生虫病、疥疮、虱、蛔虫、过敏反应、对药物的过敏、食物过敏、对化学制品的过敏、对有毒植物的暴露、对虫咬的暴露、化学疗法、压力和焦虑相关的瘙痒。
10.权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物、或权利要求6所述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗或预防炎症的美容组合物或药物组合物中的用途;
可选地,所述炎症选自:神经原性炎症、关节炎症、腱炎症、肌肉炎症、败血病、血管炎症、呼吸系统炎症、慢性阻塞性肺疾病、鼻炎、变应性鼻炎、哮喘、耳炎、肠炎、克罗恩病、胰腺炎、肝炎、与慢性炎症相关的病况、急性炎症、肾炎、系统性红斑狼疮、关节炎、类风湿关节炎、成人和青少年类风湿关节炎、斯蒂尔病、牛皮癣关节炎、骨关节炎、由痛风引起的关节炎、类风湿性脊柱炎、肾小球肾炎、神经炎、神经组织炎症、多发性硬化、免疫系统障碍、动脉粥样硬化、心肌炎、心包炎、脉管炎、炎症性皮肤病况、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、过度增生性皮肤病、烧伤、晒斑、阴道黏液的炎症、外阴痛、阴道炎、口腔粘膜炎症、牙龈炎、牙周炎、炎症性眼病、葡萄膜炎、眼和春季结膜炎、肉瘤样病、溃疡病、荨麻疹、大疱性类天疱疮、纤硬皮病化、纤维化、血管性水肿、过敏反应、脱发、肝硬化、再狭窄、风湿性多肌痛、血清阴性脊柱关节病,包括强直性脊柱炎和Reiter’s综合征、皮肌炎、包涵体肌炎、多肌炎和淋巴管平滑肌增多。
11.权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物、或权利要求6所述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗、预防或修复红肿的美容组合物或药物组合物中的用途。
12.权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物、或权利要求6所述的美容上或药学上可接受的递送系统或缓释系统在制备用于皮肤抗敏舒缓的美容组合物或药物组合物中的用途,其中,所述皮肤抗敏舒缓包括修复皮肤屏障、降低皮肤对刺激物的神经性反应、增强皮肤耐受能力。
13.权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物、或权利要求6所述的美容上或药学上可接受的递送系统或缓释系统在制备抗敏剂中的用途。
14.权利要求1-3任一项所述的式(I)所示的肽、或其美容上可接受的盐、或其药学上可接受的盐、或权利要求4或5所述的美容或药用组合物、或权利要求6所述的美容上或药学上可接受的递送系统或缓释系统在制备用于治疗、预防或修复皮肤老化或光老化的美容组合物或药物组合物中的用途。
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CN117247427A (zh) * | 2023-05-16 | 2023-12-19 | 杭州禾泰健宇生物科技有限公司 | 一种肽类化合物、组合物及其应用 |
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CN117304266B (zh) * | 2023-11-29 | 2024-01-30 | 深圳市维琪科技股份有限公司 | 一种皮肤处理多肽、组合物及其应用 |
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