CN115023432A - 具有细胞损伤保护活性的肽和脂质体制剂 - Google Patents
具有细胞损伤保护活性的肽和脂质体制剂 Download PDFInfo
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明涉及通过核苷酸切除修复(NER)修复因暴露于外部试剂(尤其是紫外线)而受损的细胞DNA的所选肽及其在皮肤治疗中的美容品或药物用途。本发明还涉及用于局部施用的组合物,所述组合物含有优选以脂质体形式携带的肽,以防止和治疗因暴露于紫外线而引起的皮肤损伤,尤其是在受着色性干皮病影响的受试者中。
Description
技术领域
本发明涉及含有它们的肽和组合物及其用于限制或纠正由外部因素(例如太阳辐射、环境应力和/或表皮细胞老化)引起的细胞损伤的用途。
还描述了肽及其脂质体制剂用于预防和限制紫外线照射引起的皮肤损伤的用途,尤其是在受着色性干皮病影响的受试者中。所述肽及其制剂也可应用于美容品领域。
背景技术
皮肤是人体最外层的组织,因此,皮肤是最容易受到太阳辐射、大气因素和环境污染等外部因素影响的组织。
这些外部因子的日常作用不仅有助于加速皮肤的生理老化过程,而且有利于皮肤疾病和皮肤癌前病变或癌变形式的发展。最近的研究表明,在大多数情况下,后者可归因于暴露于太阳辐射,特别是紫外线辐射引起的细胞DNA损伤。
光照可损伤细胞DNA,导致嘧啶光产物和环丁烷嘧啶二聚体(CPD)的形成。当皮肤短时间暴露在紫外线辐射下时,也会形成这些光产物。因此,能够清除受损DNA的不同修复机制对细胞的正常功能起着决定性的作用。
在这些突变控制过程缺失或减少的情况下,上皮细胞很容易受到紫外线辐射诱发的肿瘤的影响。
通过观察着色性干皮病(XP)患者,可以获得DNA修复机制重要性的重要证据。
XP是一种罕见的常染色体隐性遗传病,其特征是在修复辐射引起的遗传损伤的途径的早期阶段存在酶缺陷。其结果是对阳光极度敏感,导致晒伤、低色素和/或高色素现象、早期光化性角化病和多发性皮肤肿瘤的高风险。在生命的最初几年,患者对阳光表现出异常和显著的体温反应。到20岁时,大约90%的患有这种疾病的人至少患上了一种皮肤癌。
40多年前,Tanaka及其同事证明,内切酶T4 V是从感染T4噬菌体的大肠杆菌中分离出来的一种16.5KDa多肽,能够通过切除人类细胞中的核苷酸来增加细胞修复,并启动CPD的去除。从那时起,编码这种酶的基因denV被克隆并测序。
研究表明,无论是通过转染denV基因在真核细胞中表达,还是作为从大肠杆菌中分离的异源酶在细胞内施用,单独使用该酶都能够取代用于核苷酸切除修复的多酶复合物。这项研究还记录了在体内和体外对这种酶有效恢复紫外线照射引起的细胞损伤的能力的重要结果。
这些观察结果导致了适合在细胞内携带酶的酶内切酶T4 V(T4N5)局部配方的开发。几项研究表明,局部配方T4N5穿过角质层并穿透表皮最深层,积聚在角质形成细胞和朗格汉斯细胞中。
在临床试验过程中,T4N5配方的局部应用证明有助于消除应用部位的CPD,并证明可有效预防XP患者基底细胞光化性角化病和癌的发展。
蛋白内切酶T4 V是一个单一的紧密结构域,具有两个不同的催化活性位点:
(i)一个位点起着嘧啶二聚体糖基化酶的作用,即识别DNA的受损部分并切割紫外线辐射形成的二聚体,消除突变的碱基;
(ii)第二个位点从同一糖苷中去除糖和磷酸盐。
用于识别酶活性所必需的残基的插入突变表明,序列的羧基末端区域对于识别和结合CPD至关重要。
目前,需要具有活性成分,其作用是修复细胞损伤,尤其是由暴露于外部试剂(通常是紫外线辐射)引起的细胞损伤
因此,本发明的目的之一在于提供具有生物活性的活性成分,用于治疗因暴露于外部制剂,尤其是紫外线辐射而引起的皮肤病。
本发明的另一个目的是提供具有生物活性的活性成分,用于皮肤的美容治疗和延缓生理性皮肤老化过程。
本发明的另一个目的是提供用于局部应用的制剂,以便在皮肤层和细胞内携带具有细胞修复活性的肽。
发明内容
本发明源于已鉴定出可提高哺乳动物细胞中受损DNA修复的生理过程/机制的速度和/或有助于在细胞DNA水平上去除环丁烷嘧啶二聚体和/或嘧啶光产物的所选生物活性肽。
作者还发现,本发明的生物活性肽即使在细胞内供应时也能发挥其活性。
因此,在第一方面中,本发明涉及具有序列SEQ ID NO:1的肽、其类似物、衍生物或盐。
SEQ ID NO:1的肽具有从N末端到C末端的序列,由通式(1)表示:
(1):R.1-Y-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10
其中:
Xaa1是Trp(色氨酸)、Phe(苯丙氨酸)或Tyr(酪氨酸);
Xaa2是Trp(色氨酸)、Phe(苯丙氨酸)或Tyr(酪氨酸);
Xaa3为:Lys(赖氨酸);
Xaa4是Tyr(酪氨酸)、Trp(色氨酸)或Phe(苯丙氨酸);
Xaa5是Tyr(酪氨酸)、Trp(色氨酸)或Phe(苯丙氨酸);
Xaa6为Gly(甘氨酸)或Ala(丙氨酸);
Xaa7为Lys(赖氨酸);
Xaa8为Ala(丙氨酸)或Aib(氨基异丁酸);
Xaa9为Ile(异亮氨酸)、Leu(亮氨酸)或Ala(丙氨酸);
Xaa10为Tyr(酪氨酸);
当Y存在时,Y则为Aib(α-氨基异丁酸),其中
当R1存在时,R1为H、CF(羧基荧光素)、棕榈酰(CH3(CH2)14CO-)、油基(CH3(CH2)7(CH)2(CH2)7CO-)、硬脂酰(CH3(CH2)16CO-)、亚麻油(CH3(CH2)4(CH)2CH2(CH)2(CH2)7CO-)或亚油酸(CH3CH2(CH)2CH2(CH)2CH2(CH)2(CH2)7CO-)。
取代基Y和R1是可选的。
根据本发明的肽具有使其比酶内切酶T4 V具有相当高的生产简单性的结构,使得分子适合用作活性成分。
此外,本发明的肽表现出显著的细胞活性,但不同于T4 V酶的活性。包含非天然氨基酸,例如Aib(氨基异丁酸)或脂链,进一步提高酶降解的稳定性。
这些特性使本发明的肽具有皮肤细胞的高修复活性,使其能够用于医疗和美容品应用。
根据本发明实施例,提供具有序列SEQ ID NO:2的肽、具有以下氨基酸序列的其类似物、衍生物或盐:
H2N-Aib-Trp-Phe-Lys-Tyr-Tyr-Gly-Lys-Ala-Ile-Tyr
所选肽对CPD具有很高的识别和结合能力。
根据本发明的具体实施例,提供以下优选肽(Ptd-1-7),其类似物、衍生物或盐具有以下序列SEQ ID NO.2-8:
在医学领域,肽或其盐可用于治疗和保护细胞免受外部侵蚀剂(尤其是紫外线辐射)诱导的损伤,以及治疗因暴露于紫外线而引起的皮肤病。
在美容品领域,本发明的肽或其盐用于预防和/或治疗因老化和/或紫外线辐射等外部因素的作用而导致的皮肤老化或皮肤缺陷的痕迹。
发明人还发现脂质体是本发明肽经皮和细胞内传递的合适系统。特别是,磷脂囊泡(如脂质体)中包含的肽允许肽携带穿过皮肤层和细胞内,在细胞内发挥其活性。
脂质体携带或配制的肽穿透表皮最深层,积聚在角质形成细胞和胰岛细胞中。
因此,根据一个方面,本发明涉及一种组合物,其包含序列为SEQ ID NO:1的肽、其类似物、衍生物或盐以及用于通过皮肤层运输肽的载体。
优选地,用于该应用的组合物包含具有SEQ ID NO:2和/或序列SEQ ID NO:3的肽、其类似物、衍生物或盐以及生理上可接受的载体,优选脂质体。
在一个实施例中,该组合物包含具有序列SEQ ID NO:2-8的肽、其类似物、衍生物或盐、脂质体和生理上可接受的载体,优选脂质体。
优选地,该组合物用于局部使用。
发明人还观察到,将本发明的肽(或其盐)包含在脂质体中执行通过皮肤层和通过靶细胞的细胞膜的运输的双重功能,这些靶细胞通常是胰岛细胞和角质形成细胞。
将脂质体用作经皮携带本发明活性肽的系统具有以下优点:高容量运输亲水性和亲脂性分子,由于与生物膜的亲和力和兼容性而在细胞中具有高渗透性,结合皮肤角质层的湿润和再生特性使用的高安全性。
本发明的组合物可以是药物组合物或美容品组合物。
还描述了包含一个或多个彼此相等或不同的上述序列号1-8的肽及其衍生物或盐的组合物作为药物的用途。
所述肽和肽化合物在预防和/或治疗与细胞尤其是皮肤组织的DNA损伤相关的疾病和病理状况方面具有活性,例如通过暴露于紫外线诱导的疾病和病理状况。本发明的另一方面涉及一种组合物,其包含一个或多个SEQ ID NO:1-8的肽(彼此相等或不同)、其衍生物或盐,用于预防和/或治疗皮肤肿瘤。
另一方面涉及一种组合物,其包含一个或多个SEQ ID NO:1-8的肽(彼此相等或不同)、其衍生物或盐,用于预防和/或治疗着色性干皮病(XP)。包含一个或多个彼此相同或不同的SEQ ID NO:1-8的肽及其衍生物或盐的组合物也用于预防和治疗晒伤、红斑、色素沉着不足和/或过度沉着现象、早期光化性角化病和皮肤肿瘤。
根据另一方面,本发明涉及一种美容品组合物的用途,该美容品组合物包含一个或多个SEQ ID NO:1-8的肽(彼此相等或不同)、其衍生物或盐,防止和/或治疗皮肤老化痕迹或皮肤缺陷,尤其是由皮肤老化和/或紫外线辐射等外部因素对皮肤的作用引起的。
根据另一方面,本发明涉及SEQ ID NO:1-8的一个或多个肽(彼此相等或不同)、其衍生物或盐或含有它们的局部施用美容品组合物在皮肤缺陷治疗中的美容品用途。
本发明的美容品组合物主要用于治疗斑点和/或色素沉着和/或皮肤变色。
该美容品组合物还可用于预防和/或治疗因暴露于紫外线而导致的皮肤老化痕迹(例如褶皱和皱纹,尤其是面部皱纹)。
有利地,本文所述组合物通过减轻皮肤的斑点或变色来起作用,如附图3和4以及本发明的以下详细描述中所示。
根据一个方面,本发明提供了一种用于治疗皮肤标记或皮肤变色或斑点皱纹的美容品套件,其包含如本文所述的组合物。
根据一个实施例,用于皮肤美容治疗的套件包括
-一种用于去皮的美容品组合物,优选包含α-羟基酸,优选包括乙醇酸、扁桃酸或曲酸;
-包含一个或多个肽(或其盐)的组合物,每个肽或其盐彼此相等或不同,SEQ IDNO:1-8;
-优选呈凝胶形式的组合物,其包含脂质体、S-熊果苷和脂质体;以及可选
-优选呈溶液形式的去皮后舒缓组合物;
-优选呈乳状形式的用于紫外线保护的组合物。
附图说明
现在将参考以下附图详细描述本发明:
图1报告了用实施例1中定义的脂质体制剂处理72小时的细胞KB-31中荧光信号的流式细胞术分析结果:在所示图像中,灰色(浅色)轮廓表示扩张细胞的信号A.黑色轮廓:用XP-0处理的细胞(根据实施例1,脂质体制剂不含肽);B.黑色轮廓:用XP-1处理的细胞(根据实施例1的脂质体制剂);C.黑色轮廓:经XP-T4V处理的细胞;D.绿色轮廓表示用XP-2处理的细胞(含有根据实施例1用羧基荧光素荧光团官能化的肽的脂质体制剂)。浅绿色:XP-2 10-40μL/mL;深绿色:XP-2 50μL/mL。
图2报告了共聚焦显微镜对活细胞成像的分析。XPC-F用配方XP-2处理,并用SunTest CPS+(ATLAS,Urai,意大利)辐照(300-800nm,360W/m2,7分钟)。辐照结束时,使用Cell Observer(Zeiss)系统,在受控条件下(37℃,5%CO 2)观察样品2小时。在无辐射(A-E)的情况下用该制剂处理的细胞用作对照。用配方XP-2处理并辐照的成纤维细胞如图F-J所示。
图3显示了使用实施例3中所述的全面去角质和去色素美容品套件治疗的个体的皮肤斑点上获得的结果的代表性图像。
图4显示了在使用实施例3中所述的全面去角质和去色素美容品套件治疗的个体的肤色上获得的结果的代表性图像。
具体实施方式
在一个方面,本发明源于发现并合成有利于修复表皮细胞DNA的肽,尤其是因暴露于太阳辐射而受损的DNA。
作者通过核苷酸切除修复(NER)机制观察到本文所述肽如何有利于修复因暴露于阳光或致癌物质而受损的DNA。
在该首字母缩略词T4N5的上下文中,指定酶内切酶T4 V。根据第一方面,本发明因此提供如所附权利要求1中定义的肽。
属于通式的那些肽中的优选肽在所附权利要求2中定义。
另一优选肽在所附权利要求3中定义。
在本发明中,当使用以下定义时:
-“-Aib-”旨在包含非编码天然氨基酸:α-氨基异丁酸;
所有其他氨基酸都用三个字母代码描述,例如Gly=甘氨酸,Leu=亮氨酸,Ala=丙氨酸。如果没有规定,所有手性氨基酸都有L构型。
肽可以单独使用或组合使用,并且可以以组合物的形式制备。它们可以作为水溶液制备,可以与适合延长其在植物表面的持久性或粘附性的物质一起溶解。
还描述了肽,其中至少一个氨基酸残基已被移除且优选仅一个,并且不同的残基已插入其位置。有关蛋白质化学和结构的详细描述,请参见Schulz G.E.等人,1979(7)和Creighton T.E.,1984(8)。可对本发明的肽分子进行的取代是保守的取代,并在本文中定义为以下基团之一内的交换:
1、脂肪族、非极性或微极性残留物:Ala和Gly;
2、带正电的极性残基:Lys。
在属于上述不同基团(或以上未显示的两个其他氨基酸基团)的氨基酸之间,而不是在同一基团的氨基酸之间,通过较少的保守取代,功能性质发生了实质性变化,它们对(a)取代区肽主链结构的维持(b)目标位点分子的电荷或疏水性的维持,或(c)侧链的阻碍的维持的影响更为显著。根据本发明的大多数替代物是不会在肽分子的特性中产生根本变化的替代物。即使在生产前很难预测替代品的确切效果时,本领域技术人员也会理解,可以通过常规筛选分析来评估效果,优选下面描述的生物测试。使用本领域技术人员熟知的方法测试肽性质的修饰,包括氧化还原或热稳定性、疏水性、对蛋白水解降解的敏感性或与载体或多聚体聚集的趋势。
通式(1)SEQ ID NO:1的“化学衍生物”,含有通常不属于肽的其他化学亚单位。肽的共价修饰包括在本发明的范围内。可通过使肽的适当氨基酸残基与能够与所选侧链或末端残基反应的有机衍生剂反应,将此类修饰引入分子中。
肽的化学衍生物的其他示例如下。
赖氨酸的N端残基可以用琥珀酸或其他羧酸酸酐衍生。用环羧基酸酐衍生具有逆转赖氨酸残基电荷的效果。用于衍生含有α-氨基的残基的其他合适试剂包括亚胺酯,例如甲基吡啶咪酸盐;磷酸吡哆醛;吡哆醛;氯硼氢化物;三硝基苯磺酸;O-甲基异脲;2,4戊二酮;和转氨酶催化的乙醛酸反应。
羧基、天冬氨酰或谷氨酰侧基可通过与碳二亚胺(RN=C=N-R’)反应进行选择性修饰,例如1-环己基-3-(2-吗啉基-(4-乙基)碳二亚胺或1-乙基-3-(4-氮杂氮-4,4-二甲基戊基)碳二亚胺。此外,天冬氨酰和谷氨酰残基可通过与氨反应转化为天冬氨酰和谷氨酰残基。
其他修饰包括脯氨酸和赖氨酸的羟基化、丝氨酸或苏氨酸残基羟基的磷酸化、赖氨酸氨基的甲基化(Creighton,上文,第79-86页)、N端胺的乙酰化和C端羧基的酰胺化。
肽也包括其中一个或多个L-氨基酸被一个或多个D-氨基酸取代的肽。
肽也包括其中一个或多个D-氨基酸被一个或多个L-氨基酸取代的肽。此外,可提供经修饰的氨基酸或氨基酸的化学衍生物,使得肽含有通常不属于天然蛋白质一部分的额外化学成分或经修饰的氨基酸。这种衍生函数可以改善溶解度、吸收、生物半衰期等。例如,雷明顿的《药物科学》1980(9)中报道了能够调节这种效应的衍生化。
所述序列的肽包括其中一个或多个酰胺功能被N-甲基化的肽。
本发明的肽可通过基于固相肽合成的一般方法制备,优选使用受保护基团Fmoc(芴甲基氧羰基)保护的氨基酸。
通常,可通过固相肽合成制备肽,并使用通常官能化的固体载体,例如通过使用Cl-Trt或Sasrin型耐酸Wang型树脂或超强耐酸树脂,在C末端获得羧酸。
在使用Cl-Trt树脂的情况下,将第一氨基酸Fmoc-Tyr(tBu)-OH溶解在适当的溶剂中,通常为DMF,并优选在DIPEA存在下结合到树脂上。最好使用DCM:MeOH:DIPEA混合物(例如80:15:5)进行10分钟的加盖程序。
NH保护的Fmoc基团可通过处理消除,通常持续7-9分钟,例如在DMF中使用20%的哌啶,然后使用相同试剂进行第二次处理,例如8-12分钟。
每种氨基酸的偶联是通过使3个当量的Fmoc AA-OH与树脂活性位点的摩尔数反应来实现的。优选地,使用3个过量当量的DIC和3个过量当量的OxymaPure获得羧基功能的活化。优选地,在HOBt/HOAt或尿盐(例如TBTU、HATU、HBTU)存在下,使用碳二亚胺作为活化剂进行偶联反应。有利地,偶联反应在DMF溶液中进行,例如1hr,然后进行洗涤程序,例如用DMF洗涤6次。通过在DMF中使用20%哌啶溶液进行双重处理,然后通过过滤和洗涤程序去除多余试剂,可获得每个Fmoc AA OH的氨基功能的脱保护。对肽链中的每个新残基重复该过程。
可以通过Kaiser测试检查每个耦合是否成功。在整个序列的合成结束时,肽树脂可以用DMF(×3)、DCM(×4)洗涤,然后最好在真空下干燥。
根据一个实施例,为了从树脂中分离并从肽链中消除保护基团,在室温下使用裂解混合物(三氟乙酸/H2O/三异丙基硅烷=95/2.5/2.5v/v,3ml/100mg树脂)处理树脂,例如3小时。裂解反应后,可通过添加冷乙醚沉淀产物,然后在50℃下真空干燥。
原料产物在0.05%~0.1%TFA存在下通过制备性RP-HPLC纯化。收获的洗脱液可以冷冻干燥。在从稀释HCl反复冻干后,可以获得作为三氟乙酸盐和氯化物盐的纯产品。
通过RP-HPLC和质谱(ESI-TOF)对由此获得的肽进行了表征。
*r.t.:色谱柱Phenomentex,Kinetex XB-C184.6x100mm,流量1mL/min;缓冲B在30分钟内梯度20-80%。缓冲液A:H2O中0.1%TFA缓冲液B:CH 3CN中0.1%TFA。
#MW:分子量。
根据另一方面,本发明提供如所附权利要求4-6中所定义的组合物。
本发明的组合物包含如本文所述的肽和生理上可接受的载体。
在本发明的上下文中,术语“载体”是指赋形剂、载体、稀释剂或佐剂,它们可能或全部可能存在于本发明的组合物中。可以使用任何载体和/或赋形剂,尤其是在适合局部施用组合物的情况下。
优选地,载体在生理上是可接受的,它有助于穿过皮肤屏障,并允许到达肽发挥修复作用的表皮最深层。
在本发明范围内,优选载体为脂质体。
通常,所用脂质体基于包含一个或多个脂质双层的囊泡,其包围水环境。脂质体是细胞膜的模拟膜,由磷脂或磷脂和胆固醇的混合物组成,使粒子具有生物相容性、高膜穿透能力和生理屏障的优点。
脂质体的行为类似于包裹肽的系统,因此肽与周围环境物理隔离,因此在到达目标区域之前免受任何化学或酶降解过程的影响。在本文所述的组合物中,脂质体可以发挥肽载体和生物活性物质的双重作用。例如,在红斑或皮肤干燥的情况下,脂质体可以与皮肤的脂质、蛋白质和碳水化合物相互作用,对角质层具有有益的保湿和恢复作用。
该组合物的配方中存在的脂质体携带肽穿过表皮和下面的皮肤层达到细胞水平,克服细胞膜。脂质体保持其湿润和再生能力,有助于增加其他物质的渗透性、溶解度或稳定性,将其与周围环境隔离,并在其药代动力学和药效学上插入控制因素。
优选地,本发明组合物通过将其施用于需要治疗的面部和/或身体的皮肤而用于局部使用。
该组合物可用于美容品或医药(药物)用途。
美容品组合物可以是固体、半固体或液体形式。
固体形式的合适组合物包括面霜、凝胶、发油、糊状物、软膏。
液体形式的合适组合物包括溶液、悬浮液、乳液、血清、水包油乳液和油包水乳液。
在优选实施例中,用于局部施用的配方为基于脂质体的乳液的形式。
本发明组合物可包含常用于局部使用的制剂配方中的赋形剂,例如防腐剂、杀菌剂、稳定剂、抗氧化剂、乳化剂、缓冲剂、保湿剂、染料和其他常用于药物或美容品制备技术中的赋形剂,数量与普通药物或美容品配方的预期数量一致。
对于溶液、悬浮液、乳液形式的配方,水以稀释剂或溶剂的形式存在,可选择与用于美容品组合物配方的其他液体混合,例如醇和二醇,如丙二醇。
有利地,该组合物可含有脂肪物质的载体,例如用于美容品配方中的脂质体或脂肪酸。
根据产品的化学物理特性、所需的活性类型、待处理区域的类型和范围、用户的性别和年龄,本发明的组合物可含有数量在0.0001%到10%(按重量计)之间的肽。
根据某些实施例,本发明的化妆品组合物进一步包含一种或多种活性物质,例如矿物质、微量营养素、维生素和任选的其他生物活性物质。
举例来说,该组合物可包括选自氨基酸(例如精氨酸、脯氨酸、甘氨酸、赖氨酸)、多肽、羟基酸(例如乳酸、乙醇酸、水杨酸、酒石酸、苹果酸等)、天然提取物或植物精油、维生素(例如生育酚、硫辛酸、视黄醇、泛酚、抗坏血酸、类黄酮等)中的一种或多种进一步成分。,聚糖,如透明质酸、硫酸软骨素、类肝素等,蛋白质,如小麦蛋白、胶原蛋白、硅酮,各种分子,如尿囊素、咖啡因、双沙博洛尔、辅酶Q10。
本发明的组合物可应用于医药和/或美容品领域。
根据另一方面,本发明涉及用作药物的通式(1)的肽或其盐。
根据一个方面,本发明提供权利要求8所述的供使用的肽或其盐。根据一些实施例,本发明的肽或其盐和含有它们的组合物可用于治疗患有着色性干皮病(XP)的受试者,这些受试者具有导致DNA修复缺陷的基因突变,并且具有发生恶性肿瘤的高风险。在临床试验过程中,当局部应用时,本文所述组合物已证明有助于消除应用部位的CPD,并已证明可有效防止XP患者基底细胞中光化性角化病和癌的发展。局部使用的组合物包含一个或多个肽,彼此相等或不同,SEQ ID NO:1或SEQ ID NO:2,SEQ ID NO:3-8,当其衍生物或盐应用于皮肤时,穿过角质层并穿透表皮最深层,积聚在角质形成细胞和朗格汉斯细胞中。当脂质体携带该组合物的肽时,这些特性更加显著。
根据某些方面,本发明提供一种美容品组合物,其包含本文所述的至少一种肽和美容上可接受的赋形剂或载体,用于防止或减少皮肤老化的痕迹,尤其是由于暴露于紫外线辐射而引起的。
根据其他方面,本发明提供一种美容品组合物,其包含至少一种本文所述肽和用于本文所述用途的医药上可接受的赋形剂或载体。
根据另一方面,本发明提供了一种用于皮肤治疗,特别是用于如权利要求10中所定义的皮肤去色素美容品套件。
在一个实施例中,去色素美容品套件包括
-一种用于去皮的组合物,其包含α-羟基酸,例如乙醇酸、扁桃酸和曲酸;
-去皮后舒缓溶液;
-脂质体配方XP-1(Ptd-1(WFKYYGKAIY)0.1%脂质体,如实施例1所示)
-基于S-熊果苷和脂质体的凝胶;
-经过处理后的防晒霜。
脂质体组合物XP-1通过进行修复作用来再生受损的皮肤细胞。
此外,该试剂盒的其他重要活性功能成分包括乙醇酸、扁桃酸和曲酸(在去角质溶液中)以及S-熊果苷(在美白配方中)。
乙醇酸是一种α-羟基酸,通常用作具有去角质作用的皮肤制剂的成分,因为它具有加速角质层细胞更新的能力。
扁桃酸也是一种α-羟基酸,经证明具有抗菌和去角质特性,可有效改善皮肤纹理、痤疮、皮肤过早老化和色素沉着。
曲酸(AC)是真菌产生的一种天然代谢产物,具有抑制黑色素合成中酪氨酸酶活性的能力。AC及其衍生物在化妆品中用作抗氧化剂、抗增殖剂、抗炎剂和皮肤美白剂。
此外,S-熊果苷由于其作为酪氨酸酶抑制剂的作用,是一种抗黑色素生成物质,因此具有美白和去色素作用。
下面通过说明给出了本发明实施例的以下示例。
实施例
实施例1
多肽在着色性干皮病患者中的治疗应用
用7种选定的脂质体制剂进行体外药效试验,
每个都含有不同的肽:
-XP-1:脂质体中的Ptd-1(WFKYYGKAIY)0.1%;
-XP-2:脂质体中的Ptd-2(羧基荧光素WFKYYGKAIY)0.1%;
-XP-3:脂质体中Ptd-3(棕榈酰WFKYYGKAIY)0.1%;
-XP-5:脂质体中的Ptd-5(棕榈酰-WFKYYGK Aib IY)0.1%;
-XP-6:脂质体中的Ptd-6(羧基荧光素WFKYYGK Aib IY)0.1%;
-XP-7:Ptd-7(Aib-WFKYYGKAIY)0.1%脂质体;
-XP-8:脂质体中的Ptd-1(WFKYYGKAIY)0.01%。
脂质体制剂用于对上皮细胞KB-31和通过活检分离的原发性成纤维细胞进行疗效试验,这些原发性成纤维细胞属于着色性干皮病(XPC-F)患者。
进行的试验包括:
a)流式细胞术检测上皮源性细胞系KB-31的细胞摄取。将样品XP-1与不含肽的脂质体制剂(XP-0)、含有酶内切酶T4V(XP-T4V)的脂质体制剂和含有相同的羧基荧光素功能化肽(CF)的脂质体制剂XP-2进行比较。
b)使用含有荧光团羧基荧光素(CF)功能化肽的脂质体制剂XP-2,通过活细胞成像评估XPC-F成纤维细胞对脂质体的细胞摄取。
c)脂质体制剂的生物活性评估:
-XPC-F成纤维细胞,通过转录水平分析,比较扩增细胞、经紫外线辐射和未经处理的细胞、经脂质体制剂XP-T4V处理的细胞和经脂质体制剂XP-1处理的细胞;
-在上皮细胞KB-31上,通过评估基因表达水平,测试脂质体制剂XP-1、XP-3、XP-5、XP-6、XP-7、XP-8的生物活性。
d)通过细胞活力试验和细胞周期研究评估XPC-F上脂质体制剂的生物活性,并比较未经辐照的细胞、未经辐照的细胞、经配方XP-T4V处理的辐照细胞以及经辐照和经脂质体肽处理的细胞。
1.1体外试验结果
a)KB-31角质形成细胞摄取试验。
通过流式细胞术监测配方XP-0、XP-1、XP-T4V和XP-2的细胞摄取。为了进行分析,使用浓度范围为10至50μL/mL的配方对KB-31细胞进行处理。在处理开始72小时后,使用BD-FACSCanto II流式细胞仪对细胞进行分析。对用配方XP-2处理的样品进行的分析显示,大量的荧光细胞(>90%)证实,细胞对荧光团标记的肽有明显的摄取。同样重要的是要强调,在治疗72小时后,荧光信号仍然可以明显检测到。
b)通过XPC-F成纤维细胞活细胞成像评估脂质体的细胞摄取。
为了验证脂质体的细胞摄取,用含有配方XP-2的溶液(20μL/mL)处理XPC-F细胞,并立即使用太阳模拟器以360W/m2的剂量暴露于紫外线照射(300-800nm)下7分钟[SunTestCPS+(ATLAS,Urai,意大利)]。使用相同脂质体配方处理且未经辐照的XPC-F细胞作为对照。照射结束后10分钟,使用配备有恒温箱的细胞观察系统(蔡司),通过共聚焦延时显微镜观察细胞,确保控制大气条件(37℃,5%CO2)。荧光信号发出后,对XP-2脂质体进行2小时的监测。
XPC-F细胞已成功吸收XP-2脂质体,并在2小时的培养时间内保持细胞内荧光。
该研究强调,接受治疗但未经照射的细胞能够内化脂质体;然而,只有在辐射后,由于这种应激引起的细胞环境的变化,脂质体结构才能够在细胞核和细胞质内逐渐释放肽。
c)通过分析转录水平评估脂质体制剂对XPC-F成纤维细胞和KB-31角质形成细胞的生物活性。
XPC-F的亚流细胞培养物用脂质体制剂XP-T4V和XP-1(20μL/mL)处理,并以360W/m2(SunTest CPS+-ATLAS,Urai,意大利)的剂量暴露于紫外线辐射(300-800nm)下7分钟。
作为平行试验,使用脂质体制剂XP-1、XP-3、XP-5、XP-6、XP-7、XP-8(20μL/mL)处理KB-31上皮细胞的亚流培养物,并使用意大利SunTest CPS+-ATLAS,Urai的紫外线(300-800nm,360W/m2剂量,7分钟)照射。
照射结束时,XPC-F和KB-31细胞在含有脂质体的溶液中培养6小时。未经任何制剂处理且未经辐照的细胞以及未经脂质体制剂处理而受到辐照的细胞被用作每种细胞类型的对照。
6小时后,使用TRI试剂溶液(Zymo Research,USA),按照制造商指定的程序提取细胞总RNA。使用NanoDrop 2000(Thermo-Fisher Scientific,Inc.,Waltham,MA)对样品进行定量后,使用qPCRBIO SYGREEN试剂盒(Resnova,意大利)、寡核苷酸(InvitrogenTMLifeTechnologies)和Mic Real-time PCR(Bio Molecular Systems)系统进行一步qRT-PCR分析。
这项研究旨在评估辐射应激信号通路中几个基因的转录水平。
分析的基因如下:
-BCL2(B细胞淋巴瘤/白血病-2):是一种抗凋亡基因,可防止或减少由多种刺激物激活的细胞凋亡,包括紫外线辐射。
-CCNB1(细胞周期蛋白B1):它是细胞周期依赖性激酶(CDK)的一个调节亚单位,是细胞周期从G2期进展到M期的正确控制机制所必需的。之所以考虑对其进行研究,是因为在文献中已知紫外线辐射导致细胞周期在G2期受阻。
-p53:它是肿瘤抑制基因家族的一个基因,在紫外线诱导的DNA损伤后刺激有效的核苷酸切除修复(NER)所必需,并参与诱导无法修复紫外线诱导的损伤的细胞凋亡。
-p21:它是一种细胞周期调节因子,在核水平上被p53激活。这种蛋白质诱导细胞周期减慢。该基因的下调导致细胞周期的更大进展。
-p27:这是基因组稳定性的一个指标,在辐射情况下会降低。
-p66Shc:是氧化应激的一个指标,在线粒体水平上是活跃的;激活后,p66Shc保护细胞免受活性氧(ROS)的侵害。
-ErbB3(HER3):编码EGF受体3。这些受体的丧失导致对皮肤及其再生过程产生负面影响。
-TNFR1:是编码肿瘤坏死因子-α(TNF-α)受体1的基因,通过凋亡参与支持炎症反应。
-TNFR2:编码肿瘤坏死因子-α(TNF-α)受体2的基因,作为细胞存活的积极调节因子参与炎症反应。
-FGFR2:是编码成纤维细胞生长因子7(FGF7)受体2的基因。它作为FGF7的作用介质,在许多肿瘤中似乎上调。其下调对肿瘤生长有抑制作用。
下表中报告的结果比较了经所选脂质体制剂处理的细胞中标记物的表达水平与未经处理且受到同等紫外线照射的细胞中标记物的表达水平。
XPC-F | XP-T4V | XP-1 |
BCL2 | NE | NE |
CCNB1 | NE | Down-R |
p53 | Up-R | NE |
p21 | Down-R | Down-R |
p27 | Down-R | Down-R |
p66Shc | Up-R | NE |
ErbB3(HER3) | Up-RNE | NE |
TNFR1 | NE | Down-R |
TNFR2 | NE | Up-R |
FGFR2 | NE | Down-R |
Up-R:上调;:Down-R:下调;NE:无影响
Up-R:上调;:Down-R:下调;NE:无影响;NO-Exp:无表达
总之,收集到的数据表明,紫外线照射触发了一系列细胞机制,这些机制控制细胞凋亡、细胞周期、氧化应激水平的调节和对生长因子的反应。用脂质体肽处理细胞对所分析的一些基因的基因表达水平有明确的影响。
配方XP-T4V和XP-1在两种细胞类型中具有不同的作用,强调了成纤维细胞和上皮细胞如何在皮肤稳态中协同发挥不同的作用。
尤其是,对XPC-F进行的分析强调了负调节细胞周期进展的因子的下调以及增殖(如p21和p27)如何通过上调肿瘤抑制因子来抵消,从而对癌症的发生具有防护作用,强调了所用制剂的安全性。
在KB-31上进行的研究强调了从脂质体制剂中获得的类似效果,在配方XP-3和XP-5中更为显著。
d)通过细胞活力试验评估脂质体制剂对XPC-F的生物活性。
使用脂质体制剂XP-T4V、XP-1、XP-3、XP-5、XP-6、XP-7和XP-8(20μL/mL)对XPC-F的亚流培养物进行处理,并使用SunTest CPS模拟器+(ATLAS,Urai,意大利)以360W/m2的剂量进行紫外线照射(300-800nm)7分钟。
以未经处理/辐射的相同时间维持培养的成纤维细胞和未经脂质体制剂处理但经辐射的细胞作为对照。
照射结束后,将细胞在完整的生长培养基中培养24小时、48小时和72小时,然后进行细胞活力分析。
使用BD细胞活力试剂盒(BD,美国新泽西州)处理用胰蛋白酶EDTA从培养板上分离的成纤维细胞:使用噻唑橙(TO)(42μmol/L)和碘化丙啶(PI)(4.3mmol/L)溶液在室温下进行5分钟培养。在该程序结束时,用BD-FACSCanto II流式细胞仪对样品进行分析。获得的结果如下所示:
24h | -LIPO/-UV | -LIPO/+UV | XP-T4V | XP-1 | XP-3 | XP-5 | XP-6 | XP-7 | XP-8 |
活细胞 | 80.0% | 73.8% | 73.6% | 63.1% | 59.4% | 58.3% | 46.6% | 49.9% | 73.6% |
凋亡细胞 | 18.1% | 26.3% | 23.2% | 33.8% | 38.9% | 41.3% | 50.2% | 48.3% | 26.2% |
48h | -LIPO/-UV | -LIPO/+UV | XP-T4V | XP-1 | XP-3 | XP-5 | XP-6 | XP-7 | XP-8 |
活细胞 | 86.7% | 76.7% | 71.0% | 76.3% | 72.2% | 69.0% | 57.9% | 70.2% | 67.5% |
凋亡细胞 | 10.9% | 14.1% | 15.1% | 10.6% | 15.5% | 16.9% | 20.7% | 15.7% | 17.6% |
72h | -LIPO/-UV | -LIPO/+UV | XP-T4V | XP-1 | XP-3 | XP-5 | XP-6 | XP-7 | XP-8 |
活细胞 | 62.5% | 48.0% | 47.3% | 41.1% | 39.9% | 42.4% | 46.4% | 57.1% | 45.6% |
凋亡细胞 | 33.9% | 47.7% | 47.8% | 41.5% | 56.2% | 52.3% | 47.3% | 47.3% | 44.7% |
-LIPO/-UV:无脂质体制剂/无辐射;-LIPO/+UV::无脂质体制剂/有辐射。
在这项研究中,细胞在紫外线照射24小时后显示出细胞活力降低,无论脂质体制剂的预处理如何,但是使用XP-T4V、XP-1和XP-8制剂获得的凋亡细胞百分比较低。
辐照48小时后,发现与未添加脂质体制剂的辐照样品相比,使用脂质体制剂(尤其是XP-1)处理的培养物中的凋亡细胞数量较低。最后,在辐照72小时后,用受试制剂预处理的成纤维细胞显示出与在没有制剂的情况下在辐照细胞中获得的结果相当的结果。
使用XPC-F的亚流培养物进行细胞周期分析,用脂质体制剂XP-T4V和XP-1(20μL/mL)处理。随后,如上所述对细胞进行辐照。以未经脂质体/未经辐照配方处理的成纤维细胞和未经脂质体配方处理/接受辐照的细胞作为对照。
照射后,细胞在生长培养基中培养24小时、48小时和72小时。每次使用BDFACSCanto II流式细胞仪进行样本评估。
对辐照后24小时的受照成纤维细胞细胞周期的研究强调,这两种配方(XP-T4V和XP-1)都能够减缓细胞周期,可能是为了有利于DNA修复过程的发展。特别是,配方XP-1诱导G2期细胞百分比增加。照射48小时后,用两种脂质体制剂处理的样品中出现了较高比例的S期和G2期细胞,表明细胞周期未被阻断。照射后48小时也出现同样的效应。因此可以假设,细胞水平上的肽功能与凋亡前阶段的延长特别相关,使细胞有更长的损伤修复时间间隔,最终达到预防凋亡的效果。
实施例2
1临床研究设计
对实施例4中所述的化妆品盒进行临床研究,以根据光学比色法测试、皮肤电视镜检查和对所涉及受试者的自我评估问卷,评估其疗效和耐受性。
这项临床研究是在皮肤科监督下,在一个单独的中心进行的,为期4周。设想在去色素产品XP-1和脂质体熊果苷凝胶添加或不添加去色素产品XP-1和脂质体熊果苷凝胶的情况下,对去皮程序(去皮液+去皮后舒缓液+SPF 50+防晒霜)的功效进行受试者内比较(半脸法)。
这项研究共有20名女性受试者,年龄39-60岁(平均50岁),面部有色素沉着的皮肤斑点。
用去皮液和合适的刷子对受试者的整个面部(不包括眼睑)进行双侧表面化学去皮。在治疗皮肤出现红斑和轻微美白效果后,使用去皮后舒缓液中和反应。
受试者在家中独立地继续治疗,每天两次(上午和晚上,最好同时)在面部一侧涂抹以下产品:
●脂质体配方XP-1(直接在皮肤科医生在基本检查期间选择的色素沉着点上),
●脂质体熊果苷凝胶(在同一面的整个表面上)。
最后,在整个研究过程中,在上午和晚上将治疗后的美白防晒霜(SPF 50+)涂抹在整个面部。为了确定所研究治疗的去色素活性,在以下时间,通过光学比色法和图像分析,双侧测量皮肤亮度以及所选色素沉着点的颜色和大小(面积和周长):
□基线(去皮程序前的初始检查-T0)
□去皮后2周(中间检查-T2)
□去皮后4周(中间检查-T4)。
研究期间出现两名辍学者;由于个人原因,10号和15号志愿者提前中断了这一过程。对18名按照方案完成研究的受试者进行统计分析。在研究期间,没有发生可能干扰测试结果的其他重大事件。
去色素试剂盒在每个时间间隔内的活性以相对于基线(T0)和仅接受去皮程序的对照面的绝对值表示。数据处理如下:
●关于基线条件的评估(T0)
非参数检验(Friedman检验),在正态性假设被Shapiro-Wilk正态性检验拒绝的情况下(阈值为5%);或参数检验(重复测量的方差分析检验),如果正态性假设得到证实;如果Holm-Sidak调整试验的结果具有统计学意义,则遵循这两项试验。
●T0、T2和T4时两种治疗方法(去皮+去色素治疗与去皮)的比较
非参数检验(Wilcoxon检验),在正态性假设被Shapiro-Wilk正态性检验拒绝的情况下(阈值为5%);或参数检验(配对t检验),在正态性假设得到证实的情况下。
2临床研究结果:产品疗效
2.1肤色评估(光学比色法)
下表总结了参数L*、a*和b*的变化百分比,这些参数分别代表皮肤亮度(L*)、发红泛红(a*)和色素沉着(b*),在非色素沉着皮肤(正常皮肤)和色素沉着皮肤(直接在斑点上)上测得。
(*)p<0.05Holm-Sidak调整试验vs T0。
(#)p<0.01Wilcoxon符号秩检验vs T0。
在接受去皮+去色素处理的非色素沉着皮肤(正常皮肤)上,从T2处的对照开始,突出显示如下:
●皮肤亮度(L*)的临床/统计显著改善,在统计上大于仅面部去皮的结果;
●皮肤泛红、发红减少(a*),单纯去皮的面部没有检测到,
●皮肤色素沉着的显著减少(b*)在临床上比单纯去皮更显著。
这些结果表明,综合处理加速和提升了提亮美白去皮性能。
在整个研究结束时,面部两侧的皮肤通常看起来更明亮、更均匀。
在关于色素沉着的皮肤(有斑点)上,虽然面部两侧之间没有发现统计上的显著差异,但与仅用去皮处理的一侧相比,用XP-1和脂质体熊果苷凝胶处理的一侧的去色素活性更明显,皮肤斑点/色素沉着的颜色和可见性显著降低(b*)。
2.2皮肤斑点图像分析(视频皮肤镜)
下表总结了通过图像分析测量的光斑面积和周长减少的百分比值:
(*)p<0.05Holm-Sidak调整试验vs T0。
从对照T2开始,综合去色素处理(去皮溶液+配方XP-1和脂质体熊果苷凝胶)的结果突出:
●与T0相比,黑斑面积在统计学上显著减少,与单独去皮获得的面积相当。
●与T0相比,黑斑周长的减少更明显,且在统计学上更显著,表明黑斑色素沉着的减少更均匀。
2.3向相关受试者提出的自我评估问卷
疗效评估
66%的受试者在接受全面去角质和美白提亮处理的一侧,斑点不太明显(平均33%,显著22%,非常显著11%的效果)和55.5%的缩小(平均38.8%,显著16.7%的效果),44%的受试者,整体去色素效果比面部去皮更明显。研究发现,两种治疗方法对皮肤亮度和干燥度的改善具有可比性。
美容品可接受性评估
产品(XP-1、脂质体熊果苷凝胶、治疗后美白防晒霜)的化妆品可接受性总体良好。特别是,100%的志愿者都认为效果非常好:
-脂质体熊果苷凝胶-在以下方面:颜色(94%的受试者)、涂抹前后的香味(72%的受试者)、质地(78%的受试者)、延展性(94%的受试者)、吸收(61%的志愿者)、对皮肤的影响(72%的受试者)和涂抹后的无残留物(83%的志愿者)。
-配方XP-1-在以下方面:颜色(94.5%的受试者)、涂抹前后的香味(分别占77.8%和72.2%)、质地(89%的受试者)、延展性(83%的受试者)、吸收(78%的受试者)、对皮肤的影响(83%的受试者)和涂抹后的无残留物(94.5%的受试者)。
-处理后的提亮美白防晒霜-在以下方面:颜色(94%的受试者)、涂抹前后的香味(77.8%的受试者)、质地(100%的受试者)、延展性(83%的受试者)、吸收(72%的志愿者)、对皮肤的影响(77.8%的受试者)和涂抹后的无残留物(83%的志愿者)。
3耐受性评估
研究人员和志愿者对受试产品耐受性的判断在所有治疗病例中均为良好/优秀;研究3期间未发生与研究治疗相关的不良事件。
4研究结论
这项研究的结果证实了由XP-1产品和脂质体熊果苷凝胶组成的综合去色素美容品套件的优越功效,如果与仅去皮处理相比,突出了更高的亮度和“抗斑点”性能。
研究期间未发生不良事件或反应;实验者判断受试治疗的耐受性良好/极好。
实施例3
含有实施例1脂质体的制剂。
实施例1中报告的配方从水中磷脂的基本组成开始制备,使用防腐剂稳定,包含嵌入脂质体系统内的肽SEQ ID NO:1-8。
配方的脂质浓度为100mM,胶囊化肽浓度为1mM。
配方的INCI如下:水、卵磷脂、Polysorbate 20、乙基己基甘油、1,2-己二醇、辛基乙二醇、酒精变性剂、肽SEQ ID NO:1-7、生育酚、原酮。
实施例4
去色素美容品套件,包括5种具有特定活性的产品(成分)。
去皮液是一种用于皮肤去角质的制剂,由于含有两种α-羟基酸和曲酸,因此能够发挥作用。配方的INCI如下:水、乙醇酸、扁桃酸、曲酸、聚山梨酯20、乙基己基甘油、1,2-己二醇、辛基乙二醇、肌醇酮。
去皮后舒缓溶液由缓冲液组成,旨在在处理完成后中和去皮液。其INCI为:水、戊二醇、磷酸二钠、磷酸钠。
去色素美容品套件还包含一种高防晒产品,SPF 50+防晒霜。其在保护皮肤免受UVA和UVB射线伤害方面的效率是通过组合使用3种不同的防晒霜来实现的。其INCI如下:
水、辛酸/癸酸甘油三酯、戊二醇、硬脂酸乙基己酯、甲氧基肉桂酸乙基己酯、二氧化钛、亚甲基双苯并三唑基四甲基丁基苯酚、丙二醇、花生四烯醇、异壬酸异壬酯、甲氧基二苯甲酰甲烷丁酯、苯乙醇、透明质酸钠、花生四烯苷、聚丙烯酰胺、尿素、二氧化硅、C13-14异石蜡、二甲基硅酮,氯化钠,劳雷斯-7。
最后,该去色素美容品套件包含两种具有靶向去色素作用的产品。第一种被称为去色素素配方XP-1,在实施例3中报告,有助于受损细胞修复辐射造成的损伤。
第二种产品是脂质体熊果苷凝胶,其对皮肤的提亮美白作用是由于熊果苷,一种已知的黑色素抑制剂。
该产品的INCI为:水、卵磷脂、熊果苷、甘油、聚山梨酯20、乙基己基甘油、1,2-己二醇、辛基乙二醇、酒精变性剂、生育酚、肌钙酮。
实施例5
美容品用乳液配方
含有配方为SEQ ID NO:1的肽的脂质体配方包含在晒后舒缓乳液中,该乳液对皮肤具有三重舒缓、再生和抗衰老作用。本产品的INCI包括:水、甘油、十六醇、英仙花油、杏仁核油、十六醇酯-25、聚山梨酯20、薄荷醇、金盏花提取物、透明质酸钠、尿素、肽SEQ ID NO:1。
SEQUENCE LISTING
<110> IRA应用研究所
<120> 具有细胞损伤保护活性的肽和脂质体制剂
<130> P021264WO-01
<150> IT102019000019667
<151> 2019-10-23
<160> 8
<170> BiSSAP 1.3.6
<210> 1
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<221> NON_STD
<222> 1
<223> if present is, CF (carboxyfluoroscein), palmitoyl
(CH3(CH2)14CO-), oleyl (CH3(CH2)7(CH)2(CH2)7 CO-), stearyl
(CH3(CH2)16CO-), lynoleil (CH3(CH2)4(CH)2CH2(CH)2(CH2)7CO-), or
lynolenil (CH3CH2(CH)2CH2(CH)2CH2(CH)2(CH2)7CO-)
<220>
<223> SEQ ID NO:1
<220>
<221> NON_STD
<222> 2
<223> if present, is Aib
<220>
<221> NON_STD
<222> 3
<223> Trp, Phe or Tyr
<220>
<221> NON_STD
<222> 4
<223> Trp, Phe or Tyr
<220>
<221> NON_STD
<222> 5
<223> Lys
<220>
<221> NON_STD
<222> 6
<223> Tyr, Trp, or Phe
<220>
<221> NON_STD
<222> 7
<223> Tyr, Trp, or Phe
<220>
<221> NON_STD
<222> 8
<223> Gly or Ala
<220>
<221> NON_STD
<222> 9
<223> Lys
<220>
<221> NON_STD
<222> 10
<223> Ala, or Aib
<220>
<221> NON_STD
<222> 11
<223> Ile, Leu or Ala
<220>
<221> NON_STD
<222> 12
<223> Tyr
<400> 1
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 2
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<221> NON_STD
<222> 1
<223> Aib
<220>
<223> SEQ ID NO:2
<400> 2
Xaa Trp Phe Lys Tyr Tyr Gly Lys Ala Ile Tyr
1 5 10
<210> 3
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> SEQ ID NO:3
<400> 3
Trp Phe Lys Tyr Tyr Gly Lys Ala Ile Tyr
1 5 10
<210> 4
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<221> NON_STD
<222> 1
<223> CF (Carboxyfluorescein)
<220>
<223> SEQ ID NO:4
<400> 4
Xaa Trp Phe Lys Tyr Tyr Gly Lys Ala Ile Tyr
1 5 10
<210> 5
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<221> NON_STD
<222> 1
<223> palmitoyl (CH3(CH2)14CO-)
<220>
<223> SEQ ID NO:5
<400> 5
Xaa Trp Phe Lys Tyr Tyr Gly Lys Ala Ile Tyr
1 5 10
<210> 6
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> SEQ ID NO:6
<220>
<221> NON_STD
<222> 8
<223> Aib
<400> 6
Trp Phe Lys Tyr Tyr Gly Lys Xaa Ile Tyr
1 5 10
<210> 7
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<221> NON_STD
<222> 1
<223> palmitoyl (CH3(CH2)14CO-)
<220>
<223> SEQ ID NO:7
<220>
<221> NON_STD
<222> 9
<223> Aib
<400> 7
Xaa Trp Phe Lys Tyr Tyr Gly Lys Xaa Ile Tyr
1 5 10
<210> 8
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<221> NON_STD
<222> 1
<223> CF (Carboxyfluorescein)
<220>
<223> SEQ ID NO:8
<220>
<221> NON_STD
<222> 9
<223> Aib
<400> 8
Xaa Trp Phe Lys Tyr Tyr Gly Lys Xaa Ile Tyr
1 5 10
Claims (10)
1.一种肽或其盐,其氨基酸序列由SEQ ID NO:1表示:
R.1-Y-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10
其中:
Xaa1是Trp(色氨酸)、Phe(苯丙氨酸)或Tyr(酪氨酸);
Xaa2是Trp(色氨酸)、Phe(苯丙氨酸)或Tyr(酪氨酸);
Xaa3为:Lys(赖氨酸);
Xaa4是Tyr(酪氨酸)、Trp(色氨酸)或Phe(苯丙氨酸);
Xaa5是Tyr(酪氨酸)、Trp(色氨酸)或Phe(苯丙氨酸);
Xaa6为Gly(甘氨酸)或Ala(丙氨酸);
Xaa7为Lys(赖氨酸);
Xaa8为Ala(丙氨酸)或Aib(α-氨基异丁酸);
Xaa9为Ile(异亮氨酸)、Leu(亮氨酸)或Ala(丙氨酸);
Xaa10为Tyr(酪氨酸);
Y当存在时,则为Aib(氨基异丁酸),其中
R1当存在时,为H、CF(羧基荧光素)、棕榈酰(CH3(CH2)14CO-)、油基(CH3(CH2)7(CH)2(CH2)7CO-)、硬脂酰(CH3(CH2)16CO-)、亚麻油(CH3(CH2)4(CH)2CH2(CH)2(CH2)7CO-)或亚油酸(CH3CH2(CH)2CH2(CH)2CH2(CH)2(CH2)7CO-)。
2.如权利要求1所述的肽或其盐,其中肽选自以下组:
SEQ ID NO:3:WFKYYGKAIY
SEQ ID NO:4:CF-WFKYYGKAIY
SEQ ID NO:5:Pal-WFKYYGKAIY
SEQ ID NO:6:WFKYYGK-Aib-IY
SEQ ID NO:7:Pal-WFKYYGK-Aib-IY
SEQ ID NO:8:CF-WFKYYGK-Aib-IY
SEQ ID NO:2:Aib-WFKYYGKAIY
或其混合物。
3.如权利要求1或2所述的肽或其盐,其特征在于,具有由SEQ ID NO:3表示的从N末端到C末端的氨基酸序列。
4.一种组合物,其特征在于,包含根据权利要求1至3中任一权利要求所述的一种或多种彼此等同或不同的肽或其盐以及生理上可接受的载体。
5.如权利要求4所述的组合物,其特征在于,所述载体包含脂质体作为局部施用的载体。
6.如权利要求4或5所述的组合物,其中肽被脂质体包埋和/或携带。
7.如权利要求1-3中任一权利要求所述的的肽或其盐,或根据权利要求4-6中任一权利要求所述的组合物,其特征在于,所述肽或其盐或所述组合物用于药物。
8.根据权利要求1-3中任一权利要求所述的肽或其盐,或根据权利要求4-6中任一权利要求所述的组合物,其特征在于,所述肽或其盐或所述组合物用于治疗由紫外线照射引起的DNA损伤引起的疾病,特别是用于治疗色素性干皮病或癌症或癌前皮肤病。
9.根据权利要求1-3中任一权利要求所述的肽或其盐,或根据权利要求4-6中任一权利要求所述的组合物,其特征在于,在的美容方面的用途,用于治疗皮肤的美容缺陷,尤其是皮肤斑点或变色或面部皱纹。
10.一种用于皮肤美容治疗的套件,包括去色素美容品套件,其特征在于,所述去色素美容品套件包括
-一种用于去皮的美容品组合物,包含α-羟基酸,乙醇酸、扁桃酸或曲酸;
-根据权利要求4-6中任一权利要求所述的组合物;
-呈凝胶形式的组合物,包含脂质体、S-熊果苷和脂质体;以及可选
-呈溶液形式的去皮后舒缓组合物;
-呈乳状形式的用于紫外线保护的组合物。
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PCT/IB2020/059968 WO2021079328A1 (en) | 2019-10-23 | 2020-10-23 | Peptides with cell damage protection activity and liposomial formulations |
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2020
- 2020-10-23 BR BR112022007823A patent/BR112022007823A2/pt unknown
- 2020-10-23 WO PCT/IB2020/059968 patent/WO2021079328A1/en active Application Filing
- 2020-10-23 IL IL292322A patent/IL292322A/en unknown
- 2020-10-23 EP EP20811090.8A patent/EP4048680B1/en active Active
- 2020-10-23 AU AU2020370221A patent/AU2020370221A1/en active Pending
- 2020-10-23 CN CN202080089355.6A patent/CN115023432A/zh active Pending
- 2020-10-23 US US17/770,122 patent/US20220396600A1/en active Pending
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IL292322A (en) | 2022-06-01 |
WO2021079328A1 (en) | 2021-04-29 |
BR112022007823A2 (pt) | 2022-07-05 |
AU2020370221A1 (en) | 2022-05-19 |
EP4048680A1 (en) | 2022-08-31 |
US20220396600A1 (en) | 2022-12-15 |
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