CN1251989A - 防护和处理人皮肤经时性衰老的方法和组合物 - Google Patents
防护和处理人皮肤经时性衰老的方法和组合物 Download PDFInfo
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- CN1251989A CN1251989A CN98803970A CN98803970A CN1251989A CN 1251989 A CN1251989 A CN 1251989A CN 98803970 A CN98803970 A CN 98803970A CN 98803970 A CN98803970 A CN 98803970A CN 1251989 A CN1251989 A CN 1251989A
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- Medicines Containing Plant Substances (AREA)
Abstract
时间的流逝对人皮肤的有害作用(即人皮肤的经时性衰老)可通过局部施用视黄酸类化合物(较佳为视黄醇)加以防护和处理。我们发现,人皮肤光致衰老(即日光引起的未成熟皮肤的衰老)中同一激活的途径中的某些(即应激结合的途径、SAP途径)在老年人皮肤中有类似的提高。我们还发现,在同一皮肤中其它途径(即促细胞***原活化的ERK途径)受到抑制。用视黄酸类化合物处理经时性衰老皮肤既抑制真皮胶原的降解又促进前胶原的合成。老年人(80岁以上)皮肤活检切片显示。单剂处理可增加表皮厚度,改善真皮胶原密度和促进表皮突和真皮***的形成(见图13),并可减少c-Jun的数目和增加Ⅰ型和Ⅲ性前胶原的量(见图18)。这些益处也有助于防护老年人皮肤的挫伤、撕裂和溃疡。
Description
相关的申请
本申请部分基于1997年2月25日提交的待批临时申请60/040,594和1997年4月7日提交的待批临时申请60/042,976,其内容纳入本文作为参考。
发明的背景
1.发明的领域
本发明涉及用于改善中老年皮肤中角朊细胞和成纤维细胞增殖、减少基质金属蛋白酶(MMP)表达和改善胶原合成、从而提供起使老年皮肤回春作用的相应方法和组合物,特别是包含视黄酸类的组合物,且以局部施用为佳。
2.本领域现状
就哺乳动物而论,人基本上是无毛的,即可不受毛发的干扰而见到人体的大部分皮肤。因此,皮肤暴露于环境所包含的任何损害(天然和人为的)。人们第一次认识到太阳引起红斑,因此采取措施避免它的“有害射线”。一个世纪以前,在伊丽沙白女王的英国流行不惜代价避免太阳光。但那些伊丽沙白们的皮肤仍然起皱和显示其它经时性衰老的症状。
人的皮肤是一个复杂的器官,它延伸复盖全身。身体的不同部位有不同类型的皮肤;例如,脸的皮肤不同于头皮,甚至手前部(掌)的皮肤不同于手背的皮肤。虽然人体表面皮肤的类型可以不同,但皮肤通常都是由主要的两层组织组成的。表皮(epidermis或cuticle),即最外层,由浅表层(从外向内:角质层、透明层和粒层)和深层(棘层和基底层)组成。真皮(dermis或cutis vera或the true skin)由上面的***层和下面的网状层组成。
自古以来,各种各样物质被施用于皮肤,一般通过影响皮肤的最外层改善其外观,或通过影响真皮来治疗皮肤疾病。最近所作的努力是使皮肤回春和恢复因暴露于阳光(紫外线辐射)和气候而失去的弹性和柔软性。
经时性衰老或内在衰老的皮肤(intrinsically-aged skin)(老皮)与光致衰老皮肤(photo aged skin)(即由于太阳紫外光辐射显得衰老的皮肤)的生理学之间有差异。老皮典型地保持光滑和无瑕疵的外观,与之相比,光致衰老皮肤则坚韧粗糙、有斑、常有深深的皱纹。老皮的表皮典型地比正常皮肤薄,而光致衰老皮肤的表皮典型地比正常皮肤厚(棘皮症的),并经时性萎缩。光致衰老皮肤典型地有大片境界带(Grenz zone)(紧靠表皮下嗜酸性物质宽带,胶原形成和指示伤口愈合的结构),这在经时性衰老皮肤上是没有的。见N.A.Fenske & C.W.Lober,“正常衰老皮肤的结构和功能变化”,J.Am.Acad.Dermatol.,15:571-185(1986)。
Kligman等在EP-A2-0 379,367中描述了一种用视黄酸类治疗或预防内在衰老皮肤的方法。Kligman等在无毛小白鼠和5名中年以上白种妇女身上试验了全反式视黄酸(维生素A乳剂(Retin A cream)],只在研究前和研究后对妇女作了临床观察,只报告做了一例活组织检查,是在治疗6个月后(即该出版物没有公开治疗前或治疗早期从接受活组织检查的受试者上得到的对比活组织检查)。
美国专利No.3,932,665和4,934,114分别公开了使用视黄醛(维生素A醛)治疗痤疮和治疗皮肤角化病。还见美国专利No.3,060,229。视黄醛及其衍生物还被建议用于治疗如皱纹、疣、牛皮癣、湿症、头皮屑等(见EP-A2-0 391 033)。还有证据表明,维A酸(全反式视黄酸)改善光致衰老皮肤的外观。Albert M.Kligman,“光致衰老皮肤治疗中维A酸局部给药的现状”,Drugs & Aging,2(1):7-13(1992);Chas.N.Ellis等,“维A酸:在光损伤修复中的应用”,及A.S.Zelickson等,“光致衰老中维A酸的局部给药:超微结构研究”,Journal ofCutaneous Aging & Cosmetic Dermatology,vol.1,No.1,p.33-40和41-47(1988)。
Burger等在美国专利5,665,367中描述了局部施用于皮肤的组合物,它们包含柑桔素和/或槲皮黄素和一种视黄酸;描述了这些组合物能有效治疗很多互不相关的皮肤疾病,如皱纹、痤疮、皮肤白化和老年斑;所论这些组合物对人皮肤的作用是以酶(转谷氨酰胺酶)对细胞膜形成和表皮形成的重要性来描述的。相反,本发明针对真皮的变化和有益真皮细胞的增生及结构。
发明的概述
主要的发明是发现使人皮肤回春的方法。本发明的说明书和权利要求书中所用的术语“回春”包括在老年人的皮肤中同时预防胶原降解和刺激新胶原的形成的步骤。本发明对比了受处理和不受处理的老年(80岁以上)志愿者的防日晒人皮肤的活组织检查与青年志愿者防日晒皮肤的活组织检查。与青年人的皮肤相比,老年人的皮肤较薄,表皮(角朊细胞)和真皮(成纤维细胞)中细胞较少,密度较低,结构破坏的***较多,cJun激酶活性和基质金属蛋白酶(MMP)的水平较高,ERK活性、细胞周期蛋白D2和I型、III型前胶原的水平降低。
简言之,我们的一个发明是发现局部施用其量能有效抑制胶原降解和促进前胶原合成的一种或一种以上化合物能使老年人皮肤回春,以有规律地施用为宜。起这两种作用的一类较佳的化合物为视黄酸类,特别是视黄醇和全反式视黄酸。
促进前胶原合成可使老年人皮肤受益。我们的另一个发明是发现有规律地对皮肤施用有效量的视黄酸可增加老年人皮肤的前胶原水平。在优选实施方案中,处理还包括用MMP抑制剂抑制胶原降解。
除了处理和/或预防皮肤的经时性衰老外,我们的发现,即有效量视黄酸施用于皮肤可增加前胶原合成,提供了预防皮肤溃疡的另一个发明。提高皮肤的胶原含量,则皮肤的形态结构、强度和功能均提高。前胶原合成增加,则皮肤胶原含量增加、缓和了由于胶原减少、降解所致的强度和支撑作用的减弱,这样改善的前胶原合成可望减轻皮肤溃疡的发生和/或严重程度。
与上述有关,我们的另一个发明是发现局部施用视黄酸(较佳也是有规律地反复施用)使有益于皮肤完整性的角朊细胞和成纤维细胞数目增加。成纤维细胞营养表皮,在正常情况下,它们分泌一些生长因子(如FGF、IGF和KGF等)和产生前胶原,后者进入真皮基质,成为结构胶原。
还有一个发明是对衰老皮肤局部施用有效量的视黄酸,使衰老皮肤中cJun活性和/或皮肤中c-Jun蛋白的量降低,并且ERK活性提高两者并存。
在另外的实施方案中,与选自如下附加化合物的至少一种活性成分合用,增强对皮肤的经时性衰老的预防和治疗作用,这些化合物为:用于长波紫外线1(UVA1)、长波紫外线2(UVA2)和长波紫外线3(UVB)中至少一种的遮光剂;抗氧化剂;MMP(基质金属蛋白酶)抑制剂,及其混合物。
附图的简要说明
图1描绘在理想的皮肤细胞中某些ERK和ASP途径。
图2描绘在所研究的各年龄群体中由活组织检查得到的成纤维细胞密度(2A)、真皮***特征(2B)、表皮厚度(2C)和角朊细胞密度(2D)。
图3描绘在所研究的各年龄群体中人角质细胞(3A)和成纤维细胞(3B)的相对生长潜力(以每一活检的细胞集落数计)。
图4描绘在所研究的每个年龄群体中发现的三种MMP(4A.MMP-1;4B.MMP-9;4C.MMP-2)的相对活性。
图5描绘在体内试验中青年和老年皮肤间质胶原酶表达的差异。
图6描绘在体内试验中青年和老年皮肤I型前胶原表达的差异。
图7描绘在体内试验中青年和老年皮肤ERK活性的差异。
图8描绘在体内试验中青年和老年皮肤磷酸化(活化)ERK表达的差异。
图9描绘在体内试验中青年和老年皮肤细胞周期蛋白D2表达的差异。
图10描绘在体内试验中青年和老年皮肤cJUN激酶活性的差异。
图11描绘使用一种视黄酸(1%视黄醇,使用一次,封闭,7天后检查)在老年人(80岁以上)皮肤中成纤维细胞密度(11A)、真皮***特征(11B)、表皮厚度(11C)和角朊细胞密度(11D)。
图12描绘视黄酸(视黄醇)处理对取自活检样本的体外培养人角朊细胞和成纤维细胞生长的影响。
图13表示青年个体(13A和13B)、老年个体(13C和13D)和单次使用1%视黄醇(封闭,保留7天,然后作活检)后同一老年个体(13E和13F)的皮肤染色后的横切面及特写镜头。
图14描绘老年人皮肤单次使用视黄醇后活检测得的对三种MMP酶(MMP1、2和9,与图4类似)活性的效应。
图15描绘在培养的人皮肤成纤维细胞中视黄酸介导的I型胶原合成的诱导。
图16描绘对老年人皮肤使用视黄醇引起的III型前胶原α1(III)mRNA的体内诱导。
图17描绘对老年人皮肤使用视黄醇引起的ERK活性的体内诱导。
图18是一张,单次使用1%视黄醇7天后老年人皮肤活检切片染色的显微照片显示cJUN蛋白减少,皮肤中I型和III型前胶原的量增加。
本发明优选实施方案的描述
图1描绘了基于我们的发现,实现理想的皮肤细胞的功能的某些降解途径。在老年人群中人皮肤经时性衰老的特别重要的原因似乎是不同的,包括如饮食、遗传和环境等因素。但一般说来,我们相信,皮肤经时性衰老是由于应激激活途径(SAP)的活化和促细胞***剂激活的途径(ERK)的阻遏。与常识相反,将我们的有关与人皮肤的光致衰老的发明相比,我们发现,人皮肤的经时性衰老和光致衰老有相似的分子病理生理。ERK介导健康皮肤所需要的生长因子的作用。干扰ERK可导致经时性衰老皮肤的变薄,因为表皮和真皮中细胞的数目减少。几乎相反,SAP激活促进前胶原合成抑制和成熟胶原降解的因子(如cJun),从而导致皮肤形态结构、强度和功能的减弱。皮肤经时性衰老可认为包括对ERK的某种干扰和/或对SAP的某种激活:我们发现这两种情况均出现于经时性衰老的人皮肤。如图1所示,理想皮肤细胞101具有细胞膜103,各种化合物通过该膜或在膜上经细胞表面受体与细胞相互作用。以105表示的一组输入信号激活ERK途径,通过磷酸化作用启动ERK。活化的ERK在细胞核中诱导细胞周期蛋白D2生成(107),其结果是促进细胞生长。以109表示另一组输入信号,它激活应激激活的途径,导致cJUN激酶活性的提高。一旦激活(也通过磷酸化),cJUN变成激活蛋白(AP-1)组份,导致MMP生成(111),MMP输出细胞,其结果是真皮基质中的胶原降解。基质金属蛋白酶(MMP)包括胶原酶、明胶酶和其它天然存在于人皮肤的酶,它们降解细胞外基质分子,如胶原。虽然不想束缚于特定的理论,我们还是相信,cJUN激酶活性的提高干扰前胶原(可溶性胶原前体)的合成,后者输出细胞(113,参见图1),进入基质,变成结构胶原(不溶性胶原)。我们相信,活化的cJUN抑制前胶原合成中的一个或多个步骤,如图中所示。
本发明总的涉及将一定量的视黄酸类化合物(较佳为视黄醇或视黄酸)局部施用(较佳为有规律地)于老年人的皮肤,其量足以诱导老年人皮肤中角朊细胞和成纤维细胞中的至少一种细胞增殖,降低MMP的表达,刺激老年人皮肤中前胶原的合成,使之回复到正常水平,及/或提高老年人皮肤中活化ERK的水平,降低cJUN激酶的活性和降低cJUN蛋白的水平。
老年人皮肤的分析
将得自18-80岁以上40个人的避光皮肤的同样4mm钻取活检样本进行比较,我们发现,存在与年龄相关的角朊细胞和成纤维细胞数目的减少。角朊细胞是组成表皮的主要细胞。表皮的细胞通过基础角朊细胞的分化而形成,基础角朊细胞中有一些穿过逐层的被覆盖的各层分化成角质层(皮肤的最外层)。图2A、2B、2C和2D表示根据我们进行的整个人口调查得到的形态结构(morphometic)资料。如图2A和2D所示,从我们的志愿者的活检证明,最年轻的年龄组(18-29岁)与最老的年龄组(80岁以上)相比,角质细胞平均减少27%,成纤维细胞平均减少39%(两种细胞均是p<0.1);我们还注意到皮肤上与年龄相关的变化见于30岁以上成纤维细胞有一次减少和80岁以上成纤维细胞有另一次减少(图2A)。我们的人口调查还证明,60岁以上不合需要的真皮***特征数目增加(图2B)及60岁以上表皮厚度减少(图2C)。这些数据表明,存在如图2B所示的与年龄相关的***结构破坏和/或降解(最年老组比最年轻组增加2.25倍,p<0.05)。通过从老年受试者得到的活检皮肤组织的显微镜组织学检查测定***的结构破坏和降解,并与青年人皮肤活检的组织学检查进行比较。
这些发现被我们的以下发现进一步证实,从活检组织培养物中的细胞集落数测得与年龄相关的角朊细胞(减少54%)和成纤维细胞(减少50%)生长减少,还是上述相同的两年龄组间比较(对此两型细胞,P<0.1),如图3所示。
如图4所示,我们还发现,青年和老年组相比,MMP-1、MMP-2和MMP-9的相对活性有与年龄相关的增加(分别增加40%、82%和53%,p值分别为p<0.01、p<0.001和p<0.01)。这些结果是用得自我们的40个志愿受试者的同样4mm钻取活检样本测得的。
如图5所示,我们测定了两组(青年组和老年组)各16人的活检皮肤的间质胶原酶,揭示在老年组皮肤中存在胶原酶蛋白的相对表达,其量约双倍于在青年受试者中所发现的。
图6描绘了我们从两组受试者(青年和老年)得到的未暴露皮肤的体内样本中确定I型前胶原存在的分析。我们发现,未暴露(遮避阳光)的青年皮肤中I型前胶原的表达约两倍于未暴露的老年人皮肤。
图7提供了我们按本发明所述方法关于老年(80岁以上)和青年(19-29岁)志愿者皮肤活检中ERK的稳态活性的发现。图7直方图显示老年志愿者皮肤中ERK的相对活性几乎是年轻人皮肤中该活性水平的一半。
ERK活性的降低可以起因于衰老皮肤中ERK水平的降低或ERK激活的减低,或两者兼有之。一次,我们测试了15名志愿者以确定皮肤中存在的ERK的相对量,总量和活化(磷酸化)形式,及活化形式刺激细胞生长。如图8所示,老年受试者他们的皮肤中ERK的总量基本上与年轻半个世纪的受试者相同,但活性磷酸化形式的ERK明显降低。据此,我们发现老年人皮肤中ERK活性的降低并不是由于ERK总量的降低,而是由于活化形式的低浓度。
在图1所示ERK途径中,ERK诱导细胞周期蛋白D2,后者是细胞生长所需要的。干扰此ERK效应器会预料到导致细胞生长和修复的延缓由此可促进皮肤的衰老。图9描绘了我们关于12名青年受试者和11名老年受试者正常被覆的(避光)皮肤中细胞周期蛋白D2的表达的分析结果。图9直方图显示经时性衰老的皮肤中表达的细胞周期蛋白D2量比青年人皮肤中的表达明显地减少。
我们测试了两个年龄组的15名受试者(19-29岁青年受试者和80岁以上老年受试者),测定各组中应激激活的蛋白激酶(“SAPK”)的活化程度,SAPK活性用cJUN蛋白的磷酸化来测定。图10显示,青年受试者未暴露皮肤的体内样本中cJUN激酶活性为老年受试者未暴露皮肤的25%。从这些结果,我们可预言老年人皮肤中活化cJUN水平的升高将导致MMP活性提高。
视黄酸类化合物对老年皮肤的处理
再回到图1,SAP的激活(应激激活的途径109)通过产生包括胶原酶和92kDa明胶酶的MMP来促进皮肤胶原的降解。SAP可被紫外光辐照(我们的待批申请08/588,771(1996年1月16日提交)和临时申请60/048,520(1997年6月4日提交)、60/057,976(1997年9月5日提交)有描述,它们均涉及人皮肤的光致衰老,其公开内容纳入本文作为参考)、肿瘤坏死因子(如TNF-α)、白介素(如IL-1α)和其它应激状况所激活或上调。如前面注为′771的申请和′520、′976的临时申请中所述,激活蛋白-1(AP-1)包括降解胶原的酶MMP。在上述列为参考的光致衰老专利申请中,我们指出可干扰紫外光诱导的胶原酶的产生,但是经时性衰老所涉及的有其它途径,当处理患者皮肤的光致衰老时并不必然预期到产生皮肤经时性衰老的这些途径(如ERK途径)会受到影响(例如,用只抑制MMP形成的化合物并不必然影响ERK途径)。
为了研究经时性衰老皮肤的处理,用1%视黄醇或只用赋形剂对至少80岁的17名受试者进行局部处理,将试验区封闭7天,然后作活检。赋形剂为乙醇和聚乙二醇按70∶30体积比组成的混合物。将来自同一老龄范围的个体的赋形剂处理和未处理皮肤作比较,图2所描述的任何参数,即成纤维细胞和角朊细胞数、表皮厚度和不合需要的真皮***特征,均无统计学意义的显著差异。如图11所示,比较来自相同个体的视黄醇处理皮肤和赋形剂处理皮肤如图11所示,则在视黄醇处理的皮肤中,每个切片的角质细胞数(11A)和成纤维细胞数(11D)增加(分别平均增加273%(p<0.001)和30%(p<0.05))。此外,视黄醇处理实质上增加表皮厚度(11C)。由于视黄酸类化合物(视黄醇)处理时间短,因此有害真皮***特征数(11B)显然变化极少。
图12A和12B证明视黄醇体内处理7天对取自我们80岁以上分别志愿者避光皮肤活检样本中的角朊细胞和成纤维细胞体外生长的效应。即用视黄醇处理(施用一次1%视黄醇,封闭7天)老年志愿者皮肤,处理部位作活检,活检得到的角质细胞和成纤维细胞进行体外培养。细胞的体内视黄醇处理导致这两类细胞体外生长的实质性提高。特别是,角朊细胞生长提高约30%(12A),而成纤维细胞生长提高约200%(12B),两者均为p<0.05。一次,将视黄酸类化合物局部施用于老年皮肤可望增加皮肤中角朊细胞和/或成纤维细胞数目。
我们的新型处理的结果图示于图13。图13A和13B是显示22岁个体避光皮肤组织学外观的显微照相,图13B是图13A中方框区的放大视图。如该图所示,皮肤的组成是表皮E覆盖于真皮D。表皮和真皮之间大的界面区加强了表皮和真皮的粘着部分。该界面由从表皮延伸到真皮中的表皮突(rete pegs)即嵴R和从真皮延伸到表皮中的真皮***P来界定。这些突和***构成了图13A横截面上见到的褶,增加了皮肤两层之间界面的表面积。下面的截面(图13B)显示了真皮的更为详尽的视图,它含有很少细胞C,大部分是胶原L。如从此年轻个体的截面所见,真皮中胶原相对致密,结构均匀。
图13C和13D显示赋形剂处理的86岁老年个体避光皮肤的组织结构。如图13C所示,老年皮肤的表皮较薄,基本上无表皮突和真皮***。图13D详细视图显示老年皮肤真皮与年轻人相比细胞一般较少,胶原密度较低,分布不太均匀。表皮较薄和表皮真皮间界面表面积减少使老年人有挫伤和溃疡病症(如Bateman′s紫癜)高发倾向。
图13E和13F描绘如前所述用视黄醇处理(施用一次视黄醇)7天后从与图13C和13D所示活检同一个体得到的避光皮肤。所显示的皮肤的变化相当显著和意想不到。表皮增厚,界面表面积增加,其证据是存在新的表皮突和真皮***,及如详细视图所示,真皮胶原变得致密,外观更均匀规则。因此,局部使用有效量的视黄酸类化合物有增加表皮厚度(如对应于年轻皮肤的正常化)、促进表皮突和真皮***形成及提高真皮中胶原的量、密度和均匀规则性的作用。这些改变逆转了老年皮肤上所见的明显组织学变化,有助于预防老年皮肤的挫伤、撕伤、溃疡和类似的创伤,这些在年轻人的皮肤上是不出现的。
我们还采用从前述志愿者的活检来测定同样的视黄酸类处理对胶原酶相对活性的影响,这些胶原酶与为得到图4所示结果所研究的相同。图14A、14B和14C描绘用视黄醇处理老年人后的平均MMP活性水平(分别为胶原酶MMP-1和明胶酶MMP-9、MMP-2)。如图14所示,单剂视黄醇处理后7天,MMP-1和MMP-9活性均降低(分别降低48%和39%,两种酶均为p<0.01);MMP-2活性未见明显变化。与只用赋形剂的对照处理相比,MMP-1和9的酶活性水明显降低。(图14A-14C中,每个图的受试者数目均为10;“*”表示相对18-29岁的值,p<0.5,“**”表示p<0.1,“**”表示p<0.001。)
用前面的和类似的技术,采用80岁以上7名志愿者的试样和从其未暴露(避光)皮肤的活检样本培养的成纤维细胞,我们发现,视黄酸浓度0.25μg/ml提高胶原的相对表达三倍于未处理细胞,0.5和1.0μg/ml一般增高这些培养细胞中胶原的生物合成5倍于未处理细胞,如图15所示。
用1%视黄醇乳剂对7名80岁以上老人进行临床治疗,对避光皮肤施用一次,盖上敷料,使其7天不受干扰。敷料下的这些处理区的活检揭示,这些个体的皮肤中,III型前胶原mRNA比用同样方法处理(单剂施用和覆盖7天)的对照(赋形剂处理)区域增加约2.5倍。这些结果见图16。
用前面关于视黄酸处理(1%视黄醇施用于避光皮肤,封闭,7天后测定),同样的技术,我们处理并测试了3名80岁以上志愿者以测定视黄酸处理对ERK活性的影响。从这些个体的活检结果表明,处理后体内ERK活性与相同志原者的用赋形剂处理和活检区域相比,是两倍以上。这些结果见图17(其中将对照的赋形剂处理的皮肤标准化为数值1)。
图18描绘了用视黄酸处理后志愿者中老年组(80岁以上)另外的横截、染色活检。如上所述AP-1诱导MMP形成,本身由c-Jun和c-Fos蛋白的异源二聚合而形成。图18A显示视黄酸(视黄醇,“ROL”)处理1周后老年皮肤中的c-Jun水平(c-Jun被染成红色)与赋形剂处理皮肤的活检切面相比明显降低(几乎没有)。因此,我们的发明看来抑制c-Jun形成,从而抑制AP-1和该结果的MMP的形成。图18B和18C显示在视黄酸类处理的皮肤中I型和III型前胶原(染成红色)水平提高。(18C中真皮中的前胶原密度明显降低是切片制作的假象;视黄醇处理的切片中染色水平明显地高于赋形剂处理的切片)。因此,本发明的一个实施方案包括施用有效、无毒量的视黄酸类有效的一段时间使衰老皮肤回春的方法。有效的一段时间一般是每天,较佳为每天仅施用/给于一次组合物。较佳的处理和维持方案是用有效量的约0.4%视黄酸类,尽管获准可用较高的剂量。视黄醇是较佳的视黄酸类化合物。
在另一个实施方案中,本发明提供局部给予有效、无毒量的视黄酸类(较佳为视黄醇或全反式视黄酸)一段有效的时间来诱导体内角朊细胞和/或成纤维细胞的增生。处理较佳为每天进行一次或两次,视黄酸类化合物的量较佳为约0.1%至约1.0%。
在还有一个实施方案中,本发明通过局部给予有效量视黄酸类化合物一段有效的时间来降低和/或抑制MMP-1和/或MMP-9在老年皮肤中的表达,较佳的视黄酸类化合物为视黄醇或全反式视黄酸。处理较佳为每天进行一次或两次,视黄酸类化合物的量较佳为约0.1%至约1.0%。
如上所述,角朊细胞和成纤维细胞的减少和MMP表达的增加可视为与年龄有关的状况,并不凭借于诸如日光损伤之类损伤。因此,本发明对任何这些与年龄有关参数的有害变化提供预防,以及提供处理方法以改善衰老引起的这些有害病原学变化。
另一方面,本发明涉及改善或刺激老年人皮肤中I性和III型前胶原的合成。我们发现,在很多(至少50%)衰老个体的避光皮肤中I型和III型前胶原合成明显减少,这种情况可局部使用视黄酸类而加以处理。前胶原是由皮肤成纤维细胞合成、然后分泌到细胞外介质中的一种蛋白质,它在细胞外介质中被天然存在的酶转变为胶原。老年人皮肤中前胶原合成的减少表明在真皮上部(细胞外)和整个真皮的成纤维细胞两者中存在前胶原蛋白的减少,可用例如免疫组织化学方法加以测定。
总之,我们对图1所示控制途径的研究表明,ERK的失活和/或SAP的激活可引起皮肤的经时性衰老。事实上,我们发现这两种情况均存在于老年人皮肤。图7-9描绘的结果显示,老年人的避日光皮肤(该皮肤一般不慢性暴露于日光)中活性ERK的量和细胞周期蛋白D2的量均减少,导致细胞生长的减缓。我们还证明,老年人皮肤中I型和III型前胶原的合成量减少(见图6)。如果真皮中细胞生长少,那么表皮覆盖似乎也受损。我们对人皮肤孕育生长的重要ERK途径的各种信号组分试验的结果表明,人皮肤的经时性衰老特征在于促进细胞生长的途径中至少2个组分的激活减少。皮肤老化时,ERK激活的减少和细胞周期蛋白D2生成的减少导致细胞生长减缓,最终导致皮肤衰老。图15-17所示结果证明视黄酸类化合物的处理在提高ERK活性水平和I型、III性前胶原的生成上的体内有效性。
在另一方面(与建立新的真皮相反的真皮的降解),图4、5和10描绘的结果表明,不暴露的老年人的皮肤中cJUN激酶和MMP活性提高。降解性MMP酶的上调和前胶原合成的下调导致胶原缺乏,引起皮肤衰老和衰老皮肤的修复受损。引起皮肤损坏速度增加的途径活性的增加(如通过MMP介导的真皮基质的降解和前胶原合成的抑制)伴随着促进细胞生长的途径活性的降低(如ERK活性的降低),两者与人皮肤的经时性衰老有关。我们用于防护和使经时性衰老皮肤回春的方法虽然是在不暴露的、避日光皮肤上进行试验的,还常将受处理皮肤封闭,但适用于处理全身经时性衰老的皮肤,包括面部和手。将涉及光致衰老的前述专利和临时申请的教导归结起来,对皮肤每天施用视黄酸类化合物,可改善皮肤的天然衰老作用及日光加剧皮肤天然衰老的作用。
因此,我们虽然并不想束缚于特定的功能理论,但我们相信,如图13E和13F所示结果至少部分由于改善ERK激活、c-Jun量减少和I型和/或III型前胶原量增加的某种结合作用。用关于视黄酸类处理(1%视黄醇施用于避日光皮肤,封闭,7天后测试)同样的技术,我们测试了3名80岁以上的志愿者。如图13所示,这些人的活检结果表明,处理后ERK体内活性为2倍以上(图中,对照的赋形剂处理皮肤标准化为数值1)。
视黄酸类化合物是一类MMP抑制剂。MMP抑制剂可直接作用于MMPs和/或天然产生MMP的转录因子AP-1和k基因结合核因子(NF-κB)。阿斯匹林和E5510(Fujimori,T.等,日本药理学杂志(1991)55(1):81-91)抑制NF-κB激活。视黄酸类化合物(如美国专利No.4,877,805所述)和对AP-1特异拮抗的解离视黄酸类(如Fanjul,et al.,Nature(1994)372:104-110所述),糖皮质激素和维生素D3靶向AP-1。增强维生素D3治疗效应的化合物在待批申请No.08/832,865(J.Voorhees等,“评估1,25(OH)2D3在皮肤中的活性和提高1,25(OH)2D3治疗价值的方法”,1997年4月4日提出申请)中有描述,其公开内容纳入本文作为参考。除了视黄醇外,其它的视黄酸类化合物包括维生素A(视黄醇)、维A醛(视黄醛)、维A酸(视黄酸(RA,包括全反式、9-顺式和13-顺式视黄酸)的天然和合成类似物,依曲替酯(芳香维甲酸etretinate)和EP-A-0 379367、US4,887,805和US 4,888,342中所描述的其它化合物(其内容全部纳入本文作为参考)。各种合成的视黄酸类和具有视黄酸活性的化合物可望在本发明中使用,其程度为显示视黄酸体内活性,及在当面转让给Allergan Inc.的各专利中所描述的作用,如编号如下的美国专利:5,514,825;5,698,700;5,696,162;5,688,957;5,677,451;5,677,323;5,677,320;5,675,033;5,675,024;5,672,710;5,688,175;5,663,367;5,663,357;5,663,347;5,648,514;5,648,503;5,618,943;5,618,931;5,618,836;5,605,915;5,602,130。还有其它描述为具有视黄酸活性的化合物在如下编号的其它美国专利中有描述:5,648,563;5,648,385;5,618,839;5,559,248;5,616,712;5,616,597;5,602,135;5,599,819;5,556,996;5,534,516;5,516,904;5,498,755;5,470,999;5,468,879;5,455,265;5,451,605;5,343,173;5,426,118;5,414,007;5,407,937;5,399,586;5,399,561;5,391,753;等等,上面和下面的所有专利和文献的内容均纳入本文作为参考。
MMP还被BB2284(Gearing,A.J.H.et al.,Nature(1994)370:555-557)、GI129471(McGeehan G.M等,Nature(1994),370:588-561)和TIMP(金属蛋白酶的组织抑制剂,抑制脊椎动物胶原酶和其它金属蛋白酶,包括明胶酶和溶基质素)抑制。还有其它化合物可用于本发明,包括异羟肟酸盐和羟基脲衍生物,如Galardin、Batimastat和Marimastat,以及EP-A1-0 558635和EP-A1-0 558648中公开的化合物(其中公开的在治疗其它病因如治疗皮肤溃疡、皮肤癌和大疱性表皮松解中用于抑制MMP)。Goldsmith,L.A.(皮肤的生理学、生物化学和分子生物学,第2版(纽约:牛津大学出版社,1991),第17章)报告视黄酸类引起TIMP mRNA稳态水平提高,这提示转录控制;但是,根据我们的研究,我们发现在人活体皮肤内并不是如此。还有其它可局部使用在实施本发明中有用的MMP抑制剂,包括四环素类及其衍生物,如米诺环素、罗利环素、金霉素、美他环素、土霉素、多西环素、地美环素以及它们的各种盐。由于可能的***反应或过敏反应,局部使用四环素类需小心监测这些不良反应。其它MMP抑制剂包括染料木黄酮和槲皮素(在US 5637703、US 5665367和FR-A-2,671,724中有描述,其内容纳入本文作为参考)及相关的化合物,以及其它抗氧化剂,如NAC(N-乙酰半胱氨酸)、绿茶提取物等。
施用于皮肤的活性成分的有效量较佳为组合物总重量的约0.001-5wt%,更佳为约0.01-2wt%,还要更佳为月0.1-1wt%。组合物配制成在施用时约提供5μg/cm2皮肤的制剂。例如,用于本发明的较佳组合物是Retin-A视黄酸凝胶和乳剂(购自Ortho Pharmaceuticals,用于治疗寻常痤疮),其浓度为0.01%-0.1%;根据特定的制剂,赋形剂较佳包括丁基化羟基甲苯、醇(用叔丁醇和硫酸番木鳖碱变性的酒精)、硬脂酸、肉豆蔻酸异丙酯、硬脂酸-40-聚烃氧基酯、十八烷醇等中的至少一种,及其可相容的混合物。
我们测试了两个年龄组15名受试者,青年受试者(19-29岁)和老年受试者(80岁以上),测定每组SAP激酶激活的程度。用c-Jun的磷酸化来测定SAP激酶的活性。图10显示青年受试者不暴露皮肤的体内样本约为老年不暴露皮肤的相对cJUN激酶活性的25%。从这些结果,可以相应地预言老年人的皮肤中AP-1和MMP的水平升高。
出乎意料地发现,用视黄酸局部处理老年人经时性衰老的皮肤,引起细胞内前胶原蛋白水平的恢复类似于在青年人(如40岁和更年轻的人)中所见。特别是,对经时性衰老皮肤单次施用1%视黄醇,盖上透气粘合带,7天后测试,发现前胶原蛋白水平可以与明显年轻的人(如40岁以下)的避光皮肤相比。老年人施用视黄酸类每天一至二次以维持治疗制度则更好,尽管该物质可以较低的频度但规则地施用(如隔天一次或一周一次)。较适宜的还可使皮肤隔离环境损害,特别是紫外光源、去污剂和其它苛性化学品等。因此,较佳为给视黄酸类组合物加上UV遮光剂、抗氧化剂等。
刺激前胶原的生成是维持经时性衰老皮肤的完整性的重要因素。衰老的皮肤部分由于胶原含量降低和胶原纤维结构松散而变簿、易碎。用视黄酸类刺激前胶原合成、继而转变为胶原,可望减轻易碎性,增加厚度和改善老年皮肤的外观。因此,本发明提供提高经时性衰老皮肤中细胞内和细胞外胶原含量、从而也改善胶原含量的方法。此外,如本文所示,老年人皮肤中MMP水平比青年人皮肤中的提高。如果皮肤中产生的胶原发生降解,则前胶原生成的改善就无效了,因此,用视黄酸类和MMP抑制剂处理老年人皮肤对于获得改善前胶原生物合成的满意效果是重要的。事实上,我们发现在胶原水平不降低的皮肤中用视黄酸类处理并不使胶原水平升高到正常以上;我们的发明从而显示,施用视黄酸类混合物可使胶原水平恢复到所需要的基线水平。因此,我们发明的用视黄酸类化合物的处理方法既增加(前)胶原的成纤维细胞的产生,又干扰引起表皮变簿的MMP的活性。虽然视黄醇是局部使用的较佳化合物,然而有望对实施本发明有用的视黄醇的有效衍生物包括视黄醛、视黄酸(包括全反式、9-顺式和13-顺式异构体)和衍生物(诸如7,8-双脱氢视黄酸)和其它如Kligman等(参见上文,其内容纳入本文作为参考)描述的化合物,包括化妆品上可接受的盐、酯、逆酯(reverse ester),及其醚、其轭合物和其混合物。
本文所述的制成商品的组合物可包括各种常规的着色剂、香料、增稠剂(如黄原胶)、防腐剂、湿润剂、润滑剂、缓和剂、表面活性剂、分散剂、促进渗透剂等,加上它们后可提供额外的益处和改善局部用制剂的感觉和/或外观。组合物还可配制成乳剂、洗剂、软膏、肥皂或沐浴剂、洗发剂或面膜。
前面的描述和下面的方法是对本发明的参数而不是限制。细阅本说明书后,各种变化、修改和添加对于熟练技术人员来说都会变得明了的,意味着这些变化、修改和添加均在本权利要求书限定的范围和精神实质中。
实施例中所用的方法
本部分所注的文献均纳入本文作为参考。
组织学和形态测定法
从每人的臀部皮肤得到复制的4mm钻取活检样本。随机和盲法地用***固定,组织切片,以苏木精和曙红染色。用Olympus BX40显微镜结合SonyDCX-151高分辨照相机对切片进行检测。用NIH Imager Software隔离每边200μm的封闭区,在两块这样的区域上的每块的4个位点(隔开25μm)评估表皮深度。用这两块封闭区域作表皮细胞计数。测定整个组织切片上***核(即不与毛细管联合的真皮-表皮结合部位下的核)的数目,作为真皮细胞构成的度量。将同样的盲法制成的切片作组织纤维间隙、厚度、结构破坏程度和结构破坏深度的计分,每个参数用1-9分计。
用于生化分析的皮肤上清液的制备
在液氮下用研钵和杵磨碎皮肤样本,在Dounce组织研磨机中在缓冲液中制匀浆,缓冲液含有10mM N-2-羟乙基哌嗪-N′-2-乙烷磺酸(Hepes),1mM乙二胺四乙酸(EDTA),5mM乙二醇双乙胺醚-N-N′四乙酸(EGTA),10mM MgCl2,50mM甘油磷酸盐,5mM NaVO4,2mM二硫芳糖醇(DTT),5mM苯甲基磺酰氟(PMSF),10μg/ml抑蛋白酶肽,10μg/ml亮抑蛋白酶肽,10μg/ml抑胃酶肽和0.5%乙基苯基聚乙二醇(NP-40)。匀浆于14,000g离心15分钟,收集上清液,用于本文所描述的生化测定。
体外细胞生长
将活检样本剪切成小块(每片组织片约15块),将组织碎块转到塑料细胞培养瓶中。培养基组成为:Dulbecco的改良Eagle极限必需培养基,含Earle′s盐、非必需氨基酸和10%胎牛血清。组织碎块于37℃、5%CO2/95%空气中培养达1个月。按照Varani,J.等,J.Clin.Invest.,96,1747-1756(1994)的方法,对每个碎块是否有角朊细胞和/或成纤维细胞长到组织外进行计分,并据此确定分离出角朊细胞和成纤维细胞的碎块的百分率。
基质金属蛋白酶测定
活检后立即将组织片冷冻在液氮中,在20mM Tris HCl(pH7.6)+5mM CaCl2中制成匀浆,于3000×g离心10分钟,除去颗粒。用从3H-标记的纤维I型胶原中释放可溶性放射活性碎片的能力(Fisher,G.J.等,Nature,379,335-339(1996)和Hu,C-L等,Analytic.Biochem.,88,638-643(1978))作为胶原分解活性的评定。组织提取物用1mM氨基苯基乙酸汞(aminophenyl mercuric acetate,APMA)培养3小时,将失活型基质金属蛋白酶转变成活性型。接着将0.2μCi胶原底物(NEN-DuPont,Boston,MA)与50μl组织提取物一起培养24小时。24小时培养期末,将样本于12,000×g离心10分钟,使完整的蛋白质成团。然后测定保留在上清液中的放射活性,由此测得水解的底物的百分率。
用明胶酶谱法(Varani等,op.cit.)评估MMP-2(72-kD明胶酶;明胶酶A)和MMP9(92-kD明胶酶;明胶酶B)活性。将组织提取物在含1mg/ml明胶的8.5%SDS-聚丙烯酰胺凝胶中进行电泳。电泳后,以1%Triton X-100相继洗涤3次除去SDS。前两次洗涤各20分钟,最后一次洗涤过夜。用激光密度测定法对水解区带的宽度进行定量。
ERK磷酸化和活性测定
用购自Santa Cruz Biotechnology Inc.的抗体将皮肤上清液中的ERK1和ERK2作免疫沉淀,并按J.D.Weber等的方法(“细胞外信号调节的激酶I(ERK1)的持续激活是G1期细胞周期蛋白D1连续表达所需要的”,Biochem.J.,326:61-68(1997)),用髓鞘碱性蛋白作底物测定酶活性。用购自New England Biolabs Inc.(Beverly,MA)的抗体作Western分析来测定上清液中总的和磷酸化的ERK1和ERK2。
C-JUN激酶活性测定
用固相激酶测定法测定皮肤上清液中c-Jun的活性(如M.Hibi等,“结合和增强c-Jun活化功能区的癌基因蛋白和UV反应性蛋白激酶的鉴定”,GenesDev.,7:2135-2148(1993))。
RNA的Northern分析
通过盐酸胍裂解和超速离心从皮肤样本分离总RNA(如c-Jun、前胶原α1(III))(G.J.fisher等,“局部视黄酸处理的人皮肤的细胞、免疫和生化特征”,J.Investig.Dermatol.,96:699-707(1991))。如G.J.Fisher等(“全反式视黄酸体内诱导人皮肤中细胞视黄醇结合蛋白”,J.Investig.Dermatol.,105:80-86(1995))所描述的方法,用针对待测的特异mRNA的随机引物32P标记的cDNA探针进行总mRNA的Northern分析(40μg/泳道)。用逆转录多聚酶链反应测定III型前胶原mRNA。
蛋白质的Western分析
用G.J.Fisher等(“人皮肤中视黄酸和视黄酸类X受体蛋白的免疫学鉴定和功能定量”,J.Biol.Chem.,269:20629-20635(1994))所描述的Western分析法检测人皮肤核提取物中的Jun蛋白、细胞周期蛋白D2(二者抗体均购自Santa CruzBiotechnology Inc.)和磷酸化c-Iun(抗体购自New England Biolabs Inc.)。
免疫反应性蛋白用强化化学发光检测法显现,用激光密度测定法定量,或用强化化学荧光检测法显现,用Storm图象仪(Molecular Dynamics,Palo Alto,CA)定量。
Claims (25)
1.使经时性衰老的皮肤回春的方法,其特征在于包括:施用有效、无毒量的至少一种抑制MMP和促进前胶原合成的活性成分。
2.如权利要求1所述的方法,其中活性成分是既抑制MMP又促进前胶原合成的视黄酸类化合物。
3.如权利要求2所述的方法,其中视黄酸类化合物选自视黄醇、视黄醛、视黄酸、视黄酸盐、其衍生物或类似物,或其混合物。
4.如权利要求3所述的方法,其中视黄酸类化合物为视黄醇或视黄酸。
5.如权利要求3所述的方法,其中皮肤是避光皮肤。
6.如权利要求1所述的方法,其中MMP抑制剂选自阿斯匹林、E5510、糖皮质激素、维生素D3、GI12947、TIMPs、异羟肟酸和羟基脲衍生物和四环素类及其衍生物,以及它们的盐。
7.改善经时性衰老皮肤中角朊细胞和/或成纤维细胞增殖的方法,其特征在于包括:对皮肤施用有效、无毒量的视黄酸类化合物。
8.如权利要求7所述的方法,其中皮肤是避日光皮肤。
9.防护经时性衰老的皮肤的方法,其特征在于包括:提供可局部施用的无毒量的视黄酸类化合物在适用于化妆品的载体中,对皮肤施用所述视黄酸类化合物至少每周一次,其量能有效地使前胶原合成正常化和抑制胶原降解。
10.如权利要求9所述的方法,其中皮肤是避光皮肤。
11.如权利要求9所述的方法,其中视黄酸类化合物选自视黄醇、视黄醛、视黄酸、视黄酸盐、其衍生物或类似物,或其混合物。
12.如权利要求11所述的方法,其中视黄酸类化合物为视黄醇。
13.如权利要求9所述的方法,其中视黄醇每天施用。
14.使经时性衰老的皮肤中前胶原的产生正常化的方法,其特征在于包括:提供可局部施用的无毒的视黄酸类化合物和对皮肤施用所述视黄酸类化合物,其量能有效地使前胶原产生正常化。
15.如权利要求14所述的方法,其中视黄酸类化合物是视黄醇。
16.如权利要求14所述的方法,其中视黄酸类化合物规则地施用。
17.如权利要求16所述的方法,其中视黄酸类化合物每天施用。
18.如权利要求14所述的方法,进一步包括同时抑制胶原降解的步骤,所述方法进一步包括提供可局部施用的无毒量的MMP抑制剂和对经时性衰老的皮肤规则地施用有效量的所述MMP抑制剂的步骤。
19.如权利要求18所述的方法,其中MMP抑制剂选自阿斯匹林、E5510、糖皮质激素、维生素D3、GI12947、TIMPs、异羟肟酸和羟基脲衍生物和四环素类及其衍生物,以及它们的盐和可配伍的混合物。
20.如权利要求18所述的方法,其中所述视黄酸类化合物和所述MMP抑制剂存在于单剂局部施用的制剂中。
21.如权利要求18所述的方法,其中经时性衰老的皮肤是避日光的皮肤。
22.改善老年人皮肤中ERK活性水平的方法,其特征在于包括对所述皮肤局部施用有效、无毒量的视黄酸类化合物。
23.如权利要求22所述的方法,其中视黄酸类化合物为视黄酸类或视黄酸。
24.降低老年人皮肤中c-Jun蛋白水平和/或cJUN激酶活性的方法,其特征在于包括对所述皮肤局部施用有效、无毒量的视黄酸类化合物。
25.如权利要求22所述的方法,其中视黄酸类化合物为视黄酸类或视黄酸。
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- 1998-02-24 US US09/028,435 patent/US6630516B2/en not_active Expired - Fee Related
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- 2003-06-10 US US10/458,355 patent/US6919072B2/en not_active Expired - Lifetime
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- 2010-05-10 JP JP2010107925A patent/JP2010195817A/ja active Pending
Cited By (4)
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CN1303988C (zh) * | 2000-05-26 | 2007-03-14 | 株式会社资生堂 | 抑制皮脂分泌用皮肤外用剂 |
CN105377228A (zh) * | 2013-06-03 | 2016-03-02 | 皮埃尔·法布尔皮肤化妆品公司 | 组合视黄醛和双甘氨肽油酰胺的化妆品或皮肤病学组合物及其化妆品或皮肤病学用途 |
CN105377228B (zh) * | 2013-06-03 | 2018-09-28 | 皮埃尔·法布尔皮肤化妆品公司 | 组合视黄醛和双甘氨肽油酰胺的化妆品或皮肤病学组合物及其化妆品或皮肤病学用途 |
WO2021147740A1 (zh) * | 2020-01-22 | 2021-07-29 | 中国科学院上海营养与健康研究所 | Mapk/erk通路抑制剂在拮抗皮肤老化与辐射性皮肤早衰中的应用 |
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WO1998036742A1 (en) | 1998-08-27 |
JP2002515898A (ja) | 2002-05-28 |
AU737376B2 (en) | 2001-08-16 |
US20010053347A1 (en) | 2001-12-20 |
CA2281944A1 (en) | 1998-08-27 |
US20040034098A1 (en) | 2004-02-19 |
DE69828620T2 (de) | 2005-12-01 |
BR9807854A (pt) | 2000-02-22 |
AU6537498A (en) | 1998-09-09 |
JP2010195817A (ja) | 2010-09-09 |
IL131543A0 (en) | 2001-01-28 |
IL131543A (en) | 2005-08-31 |
CA2281944C (en) | 2007-05-15 |
EP1005333A4 (en) | 2001-03-14 |
EP1005333B1 (en) | 2005-01-12 |
DE69828620D1 (de) | 2005-02-17 |
US6919072B2 (en) | 2005-07-19 |
US6630516B2 (en) | 2003-10-07 |
EP1005333A1 (en) | 2000-06-07 |
CN100360121C (zh) | 2008-01-09 |
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