CN106999457A - 使用三碘甲腺乙酸(triac)和脱氢表雄酮(dhea)的组合治疗皮肤萎缩 - Google Patents
使用三碘甲腺乙酸(triac)和脱氢表雄酮(dhea)的组合治疗皮肤萎缩 Download PDFInfo
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- CN106999457A CN106999457A CN201580063734.7A CN201580063734A CN106999457A CN 106999457 A CN106999457 A CN 106999457A CN 201580063734 A CN201580063734 A CN 201580063734A CN 106999457 A CN106999457 A CN 106999457A
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- triac
- dhea
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- atrophoderma
- corticosteroid
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Abstract
本研究的目的是调查在人类中三碘甲腺乙酸(TRIAC)和脱氢表雄酮(DHEA)的组合与单独的TRIAC、DHEA或安慰剂相比对皮质甾类诱导的胶原蛋白合成的效应的影响。6位年龄为40‑65岁的健康男性人类志愿者参与所述研究。将四个腹部皮肤区域用戊酸倍他米松霜剂预处理3周。然后将相同区域用相同霜剂介质中的下列可替选物之一处理2周：TRIAC，DHEA，TRIAC+DHEA，以及安慰剂。然后使用真空泵在这些区域的每一个中产生吸吮水泡。从每个区域收集水泡液并冷冻，直至进行分析。吸吮水泡液中人类I型前胶原蛋白(PINP)的氨基端前肽的分析使用可商购的免疫测定试剂盒(Orion Diagnostics)来进行。这项研究首次显示了TRIAC和DHEA的组合能够在用戊酸倍他米松预处理的皮肤中有效地刺激胶原蛋白合成，这由PINP的增加所证实，并且所述组合比单独的TRIAC或DHEA更加有效。这种组合可用于在皮质甾类诱导的皮肤萎缩中有效地治疗皮肤萎缩。它也可用于治疗由其他情况造成的皮肤萎缩例如晒伤皮肤和由高龄造成的皮肤萎缩。另一个有趣的应用是将TRIAC和DHEA与强效皮质甾类组合以便预防皮质甾类诱导的皮肤萎缩。如果这种组合在湿疹和银屑病的治疗中仍然有效并且没有皮肤萎缩的风险，则这种组合将是强效表面用皮质甾类应用的重要突破。
Description
技术领域
本发明涉及三碘甲腺乙酸(TRIAC)和脱氢表雄酮(DHEA)的组合在皮肤萎缩的治疗中的用途。所述TRIAC和DHEA的组合提供了出人意料的协同效应。
背景技术
众所周知，使用皮质类固醇的表面治疗引起作为副作用的皮肤萎缩。然而，由强效皮质类固醇引起的皮肤萎缩的有效治疗目前尚不可用。
皮肤萎缩涉及表皮和真皮厚度的降低、皮脂腺的退化、皮下脂肪的丧失和肌肉层萎缩。通常，这些变化可以在开始使用中至高效表面用皮质类固醇治疗后2至3周看到。受影响的区域通常是具有高渗透性的皮肤例如面部，但可能出现在进行皮质类固醇施用的任何区域。萎缩症也可能在施用低效皮质类固醇后看到，并且通常在治疗结束后逆转。然而，在许多病例中，萎缩症是不会逆转的永久表象。
已经尝试了开发使用另一种药理学方法的皮质类固醇替代疗法，但到目前为止只有少数比皮质类固醇的抗炎活性更低的替代疗法可用。这些治疗方案由维生素A和D衍生物和钙调磷酸酶抑制剂例如他克莫司构成。
本发明提供了TRIAC和DHEA的组合，其可用于有效治疗皮肤萎缩，例如由使用皮质类固醇或长期暴露于日光所诱导的皮肤萎缩。
发明详述
本发明涉及TRIAC和DHEA的组合在皮肤萎缩、尤其是由使用皮质类固醇或长期暴露于日光而诱导的皮肤萎缩的治疗中的用途。本发明还涉及包含TRIAC和DHEA的组合物。所述组合物被设计用于表面给药到皮肤。TRIAC和DHEA的组合显示出在皮肤萎缩的治疗中具有协同效应。
TRIAC和DHEA的组合，也可用于或提供在与一种或多种皮质类固醇一起的组合物中。
TRIAC和DHEA的组合
正如在本文的实施例中所证实的，本发明人首次显示了TRIAC和DHEA的组合可以在用戊酸倍他米松预处理的皮肤中有效地刺激I型前胶原蛋白(PINP)的完整N-端前肽的合成，并且所述组合比单独的TRIAC或DHEA更加有效。这种组合可用于在皮质类固醇诱导的皮肤萎缩中有效地治疗皮肤萎缩。它也可用于治疗由其他情况造成的皮肤萎缩例如晒伤皮肤和由衰老造成的皮肤萎缩。另一个有趣的应用是将TRIAC和DHEA与强效皮质类固醇组合，以便预防皮质类固醇诱导的皮肤萎缩。设想了这种组合可能在湿疹和银屑病的治疗中有效并且没有皮肤萎缩的风险，这种组合将是强效表面用皮质类固醇应用的重要突破。
由皮质类固醇引起的皮肤萎缩的有效治疗目前尚不可用。然而，开发这种产品将是有利的。就此而言，本发明提供了一种新的方法。在患有临床确认的萎缩症的患者中的效果，主要可以使用超声波扫描术以评估在使用TRIAC和DHEA霜剂/凝胶的治疗期间的皮肤厚度来评估。效能也可以通过活组织检查、临床评定量表和患者评定量表来评估。不利事件应该被记录。血浆中的甲状腺激素水平被用于监测TRIAC的系统效应，并且可以使用DHEA硫酸酯的测量来监测DHEA的可能的系统效应。
正如上面提到的，本发明涉及TRIAC和DHEA的组合的用途以及含有TRIAC和DHEA的表面用组合物。正如在实施例中证实的，在皮肤萎缩的治疗中，TRIAC和DHEA的组合表现出比单独使用的任何药理活性组分(即TRIAC和DHEA)更高的效能。所述效能优选地用来自于皮肤的吸吮水泡液中PINP的产量来度量。更多的细节出现在本文的实施例中。
本发明提供了三碘甲腺乙酸(TRIAC)和脱氢表雄酮(DHEA)的组合，其用于改善受试者的皮肤。在本发明的情形中，术语“改善受试者的皮肤”打算意味着待改善的皮肤是经受皮肤萎缩的皮肤、晒伤皮肤、固有地衰老的皮肤、湿疹和银屑病、光化性皮肤损伤、固有地衰老的皮肤、光损伤的皮肤、扁平苔癣、鱼鳞癣、痤疮、银屑病、起皱皮肤、毛囊角化病、湿疹、特应性皮炎、脂溢性皮炎硬皮病、胶原蛋白缺乏的皮肤、由系统性、吸入和表面糖皮质激素给药诱导的皮质类固醇萎缩症、氯痤疮、糠疹和皮肤瘢痕。
尤其是，所述TRIAC和DHEA的组合用于皮肤萎缩的治疗或预防。
皮肤萎缩的最常见病因是日光诱导的萎缩以及正如在本发明的背景中提到的，由使用皮质类固醇的治疗造成的萎缩。通常，皮质类固醇被用于皮肤病例如皮炎、特应性皮炎、皮疹和湿疹。皮肤萎缩也可能发生在皮质类固醇的系统性给药或吸入之后。
较弱的表面用甾类被用于皮肤薄且敏感的区域，特别是包藏下的区域，例如在面部、眼睑、尿布区域、肛周皮肤以及腹股沟或体褶的褶烂上。中等的甾类被用于特应性皮炎、钱币状湿疹、干燥性湿疹、外阴萎缩性硬化型苔藓、疥疮(在杀疥疮剂后)和严重皮炎。强的甾类被用于成年人中的银屑病、扁平苔癣、盘状狼疮、足皲裂、慢性单纯性苔藓、严重的毒葛暴露、斑秃、钱币状湿疹和严重特应性皮炎。
为了防止快速抗药反应，表面用甾类通常被要求以用药一周停药一周的例行程序使用。某些人推荐表面用甾类用药连续三天，然后停药连续四天。表面用甾类的长期使用可以引起真菌或细菌的二次感染(参见隐匿藓)、皮肤萎缩、毛细管扩张(血管凸显)、皮肤淤血和脆弱(Burton JL,Lovell CR.“皮肤萎缩症”(Cutaneous atrophy)，第44章：结缔组织的障碍(Disorder of Connective Tissue)，在Rook,Wilkinson,Ebling的《皮肤病学教科书》(Textbook of Dermatology)中，由Champion RH,Burton JL,Burns DA,Breathnach SM主编，Vol 3，第6版，Blackwell Science Ltd.,Oxford,1998,pp.2004-2018)。
表面用皮质类固醇根据效能分类，I类是最弱的，IV类是最强的。分类在不同国家可能不同。
组I
最弱的表面用甾类类别。
·作为2.5％霜剂、洗剂和软膏销售的氢化可的松
·作为1％销售的氢化可的松
组II
·氯倍他松
·氢化可的松17-丁酸酯
·醋酸曲安奈德
组III
·醋酸氟轻松0.05％
·哈西奈德0.05％
·安西奈德0.05％
·去羟米松0.25％
·戊酸倍他米松*
·二丙酸倍他米松
·糠酸莫米他松
组IV
非常强效：比氢化可的松强多达600倍
·丙酸氯倍他索0.05％
·丙酸卤倍他索0.05％
·醋酸双氟拉松0.05％
*氢化可的松效能的50-100倍
可以将任何皮质类固醇、例如上面提到的那些，与TRIAC和DHEA组合，以便预防或治疗本文中所提到的皮肤病症。此外，可以将TRIAC和DHEA添加到任何现有产品、例如上面提到的那些中。
剂量
本发明的组合的剂量和给药频率取决于具体的表面用组合物以及待治疗皮肤障碍的身份和严重性。
通常，本发明的组合物含有约0.005至约2％w/w的TRIAC，尤其是约0.01至约0.5％w/w的TRIAC。
通常，本发明的组合含有约0.5至约5％的DHEA，尤其是约1至约3％w/w的DHEA。
| DHEA(％w/w) | TRIAC(％w/w) | DHEA/TRIAC的比率 |
| 0.5 | 0.005 | 100 |
| 0.5 | 2 | 0.25 |
| 5 | 0.005 | 1000 |
| 5 | 2 | 2.5 |
| 1 | 0.005 | 200 |
| 1 | 2 | 0.5 |
| 3 | 0.005 | 600 |
| 3 | 2 | 1.5 |
| 0.5 | 0.01 | 50 |
| 0.5 | 0.5 | 1 |
| 5 | 0.01 | 500 |
| 5 | 0.5 | 10 |
| 1 | 0.01 | 100 |
| 1 | 0.5 | 2 |
| 3 | 0.01 | 300 |
| 3 | 0.5 | 6 |
正如从上表看到的，在本发明的组合或组合物中DHEA与TRIAC之间的重量比为约0.25至约1,000，例如约0.5至约600。此外，所述比率可以为约1至约500或约1.5至约300。所述重量比也可以为约2至约200或约2.5至约100。DHEA与TRIC之间的大量适合的重量比可以从上表中提到的任何数字构建，即任何组合都在本申请的范围之内。
特别有趣的比率是约10至约200，例如约30至约150或约50至约100。正如从本文的实施例看到的，使用了含有重量比为2/0.03＝66.7的DHEA和TRIAC的组合物，并证实了它具有协同效应。因此，感兴趣的甚至更窄的重量比范围为约60至约75或约60至70。
通常，TRIAC以约0.1至约50微克/cm2皮肤表面的量施用，DHEA以约10至约1000微克/cm2皮肤表面的量施用。正如上面提到的，调整DHEA和TRIAC的量，使得DHEA与TRIC之间的重量比在上面提到的或从上面提到的数字计算的范围之内。
在本文的实施例中，TRIAC以1.5微克/cm2皮肤表面的量施用，并且DHEA以100微克/cm2皮肤表面的量施用，这对应于DHEA与TRIAC之间的重量比为约66至约67。
组合物
本发明的组合在组合物中被递送到皮肤的患病区域，所述组合物在可表面用介质中含有TRIAC和DHEA的组合。当在本文中使用时，可表面用介质是可接受以施用到皮肤表面，用于TRIAC和DHEA的组合的表面或真皮递送的介质。
本发明的组合可以被包含在适合于施用到皮肤的任何组合物中。因此，本发明的组合物不限于特定剂型或特定配方类型。所选的特定剂型或特定配方类型当施用到皮肤时，对所述组合的效能没有负面影响。适合于施用到皮肤的剂型和配方的实例以及如何制备这些组合物的实例可以在《Remington制药学》(Remington’s PharmaceuticalSciences)第18版，Mack Publishing Company，1990和更晚的版本中找到，将其引为参考。
本发明提供了表面用组合物，其采取软膏、霜剂、洗剂、擦剂或其他可涂抹液体或半固体制剂、溶液、分散系、乳液例如微乳液、水包油乳液或油包水乳液、混悬剂、凝胶、脂质体、可喷洒组合物、气溶胶、薄膜、粉剂、洗涤剂、香波等的形式。
正如上面提到的，所述组合物可以采取乳液的形式。霜剂和洗剂通常是采取乳液形式的组合物的实例。乳液是包含至少两种不混溶的液体相(油相和水性相)的分散体系，一相分散在另一相中。通常包含乳化剂以提高物理稳定性。乳化剂的选择取决于所需的是水包油还是油包水乳液。一般来说，为了获得水包油乳液，选择具有低于约10的HLB数(亲水亲脂平衡值)的乳化剂，而为了获得油包水乳液，选择HLB数为8和更大的乳化剂。正如在下表中指明的，存在一定交叠。
| HLB范围 | 用途 |
| 0-3 | 消泡剂 |
| 4-6 | w/o乳化剂 |
| 7-9 | 润湿剂 |
| 8-18 | o/w乳化剂 |
| 13-15 | 去污剂 |
| 10-18 | 增溶剂 |
所述乳化剂可以是阴离子型、阳离子型或非离子型的。阴离子型乳化剂的实例是例如硫酸酯化的醇类，例如脂肪醇如月桂醇或鲸蜡醇的硫酸酯。阳离子型乳化剂是例如季铵化合物如鲸蜡基三甲基溴化铵。非离子型乳化剂的实例是例如甘油酯如单硬脂酸甘油酯、聚氧乙烯二醇酯或醚、失水山梨糖醇脂肪酸酯例如失水山梨糖醇单棕榈酸酯、失水山梨糖醇脂肪酸酯的聚氧乙烯衍生物等。
上面提到的乳化剂也可用于不采取乳液形式的组合物中，因为这些乳化剂具有表面活性性质，其例如作为稳定剂或作为溶解增强剂可能是有用的。
本发明的组合物也可以采取混悬剂的形式。混悬剂的实例是例如分散系、软膏、擦剂、喷剂和气溶胶。混悬剂是一种两相系统，一相是细分固体，其分散在可以是固体、液体或气体的另一相中。通常，在制药或化妆品领域中，混悬剂是固体在液体或气体中的分散系。
混悬剂含有分散介质，其通常是溶剂或溶剂混合物例如水、醇类(乙醇、丙醇、异丙醇等)、丙二醇、天然或合成的油、气体等。它可能含有表面活性剂(正如上面作为乳化剂提到的)、润湿剂(例如醇类、甘油)、絮凝剂(例如电解质)、增粘剂(例如甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、果胶、藻酸盐等)以及下面提到的添加剂。
气溶胶通常含有加压气体例如碳氟化合物。气溶胶是一种活性药剂的递送依赖于液化或压缩的气体的产品。所述活性药剂以细小分散的雾、泡沫或半固体形式递送。如果在皮肤上得到的组合物是含有活性物质的薄膜，则气溶胶也可能含有例如成膜剂。典型的成膜剂是纤维素和纤维素衍生物，包括甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素。
本发明的组合物可以采取凝胶或水凝胶的形式。凝胶通常含有可溶胀的聚合物如纤维素或纤维素衍生物(正如前文中提到的那样)、果胶、藻酸盐、黄芪胶、卡波姆、聚乙烯醇、明胶、基于丙烯酸酯的聚合物等。
所述组合物也可以采取软膏的形式，其是含油的半固体，并且含有即使有也是很少的水。通常，软膏基于烃类例如蜡、矿物脂或胶凝矿物油。
本发明的组合物也可以含有一种或多种添加剂例如pH调节剂、缓冲剂、粘度调节剂、芳香剂、抗氧化剂、保湿剂、防腐剂、稳定剂等。
下面给出作为本发明的目的的两种药物物质的概述。
三碘甲腺乙酸(TRIAC)
三碘甲腺乙酸(TRIAC)是一种甲状腺激素代谢物(1)。在人体中，TRIAC如下形成：甲状腺素(T4)氧化脱胺成四碘甲腺乙酸(Tetrac)，然后5’-脱碘以最终形成TRIAC(1)。三碘甲状腺氨酸(T3)也可以通过氧化脱胺转变成TRIAC(2)。为了获得相近的代谢效果，比T3高15倍(3)和比T4高10倍(4)的剂量是必需的。已显示，TRIAC不像T4或T3那样有效地激起心动过速(4-5)。因此，用于TRIAC的治疗窗口大于用于T4和T3的治疗窗口。
自从1957年起，TRIAC已在临床调查之下(3)。给药形式主要是口服或注射(4，6)。在法国市场上，TRIAC可以以口服和皮肤制剂获得(7)。0.2％霜剂适用于蜂窝组织炎的治疗。口服配方的适应症是促甲状腺激素(TSH)抑制，推荐剂量是每日0.7至1.75mg。长达3周的使用口服给药的临床研究显示，3.4mg的每日剂量被良好地耐受(4)。
已在大鼠中的两个单剂实验中研究了TRIAC的总体毒性。在使用悬浮在0.8％羟丙基甲基纤维素凝胶中的TRIAC的腹膜内给药的研究中，发现无明显效应的水平(NOEL)是46.4mg/kg，最低致死剂量为100mg/kg。可以计算在这项研究中的LD50值，并发现它们对于雄性和雌性大鼠来说分别为143和295mg/kg。在使用2000mg/kg的与腹膜内研究中相同地悬浮的TRIAC在大鼠背部皮肤施用24小时的研究中，既没有观察到总体毒性的任何临床征兆，也没有在施用位点处观察到任何局部刺激(3-6)。
在每日两次共4周重复表面给药的喜马拉雅兔中进行了TRIAC霜剂的局部耐受研究。将具有三种强度即0.03％、0.1％和0.3％并且体积为0.5ml的TRIAC霜剂施用到兔子背部上的完整皮肤(左侧)和磨损皮肤(右侧)上。总共使用了24只兔子(每种剂量组中3只雄性和3只雌性)。对照组接受介质霜剂。在宏观和微观上都没有观察到与物质相关的病理变化。
在培养的人类外周淋巴细胞中，在埃姆斯试验和体外染色体畸变测定法中调查了TRIAC的基因毒性潜力。从这些试验的结果可以得出结论，TRIAC没有基因毒性潜力。
维生素A和D衍生物已被用于治疗晒伤皮肤和皮肤萎缩(11-13)。然而，它们两者都具有副作用，例如皮肤刺激并伴有发红和鳞状剥落。使用维生素A和D衍生物获得的皮肤厚度的增加事实上可能是由表皮和真皮两者中的水肿而不是蛋白质合成代谢作用造成的。使用TRIAC时没有观察到副作用(8-10)。
来自于小鼠中临床前研究的结果显示，TRIAC的表面给药阻止由强效表面用糖皮质激素的使用而诱导的皮肤萎缩(8-10)。它在小鼠中也可以增加正常皮肤的皮肤厚度(9)。
本发明人中的一些人已进行了三项使用表面施用的TRIAC的临床研究(14-16)。第一项研究的目的是在初步研究中调查0.1％TRIAC软膏对银屑病的效果(14)。所述研究的结论是使用TRIAC的表面治疗是安全的，但与安慰剂相比没有发现对银屑病的令人满意的显著效果。第二项研究旨在调查0.03％和0.1％TRIAC霜剂对用表面倍他米松17-戊酸酯预处理后恢复正常皮肤胶原蛋白合成的效果(15)。在治疗开始后7天，与安慰剂相比，在两个组中都存在前胶原蛋白I和III两者的统计上显著的增加。在第三项研究中，用0.1％TRIAC霜剂处理由强效皮质类固醇的表面治疗造成的在手背上具有皮肤萎缩的患者(16)。在治疗8周后，在TRIAC组中，表皮和真皮两者中的皮肤厚度明显更高。
由于活性物质是甲状腺激素代谢物，它可以引起甲状腺机能亢进的症状例如心动过速、神经质、出汗和腹泻。从调查性霜剂配方的经皮穿透预计是低的或可忽略的。在所有3项临床研究中，在治疗8周后没有注意到对甲状腺激素水平的显著影响(14-16)。甚至其他血液分析显示出正常水平(15-16).
其他甲状腺激素类似物以及天然存在的甲状腺激素与DHEA组合时也可能具有同样的有益效果。
脱氢表雄酮(DEAH)
脱氢表雄酮(DHEA)是由肾上腺皮质产生并分泌的一种甾类激素。它在儿童期中期以高浓度存在于血流中，在成年期早期达到峰值，随后随着年龄增加而降低。DHEA被认为是一种弱的雄激素，因为它在外周组织中被代谢成睾酮和雌二醇。据认为，它的作用是通过睾酮和雌激素受体，但对于DHEA是否可能通过其自身的或其他受体而具有自身效应，仍存在持续不断的争论。当通过口服途径给药时，它在老年人中对皮肤病症具有正面效果(19)。在开放式研究中，在20位绝经后女性的两个组中，将1％DHEA配方或介质表面施用到面部和手部皮肤4个月。这项初步研究的结果是，表面DHEA提高了皮肤亮度并抵消了作为皮肤衰老的特征性特点的皮肤的纸状外观和表皮萎缩，但介质没有做到这一点。
替代DEAH或除了DEAH之外，可以使用合成代谢甾类例如雄烯二酮、二氢睾酮、apotone、氧雄龙、羟勃龙、诺龙或睾酮。特别是，TRIAC、DEAH和睾酮的组合是感兴趣的。
在绝经后女性中已进行了其他研究(20，21)，并且(21)中给出的结果表明DHEA可能对皮肤具有抗衰老效果。
在下面的非限制性实施例中对本发明进行说明。
实施例1
TRIAC和DHEA的组合的协同效果
本研究的目的是证实是否存在表面用TRIAC和DHEA对皮肤中前胶原蛋白I合成的累加或协同效果。
材料和方法
受试者。6位健康男性志愿者年龄在40-65岁之间。排除标准是：使用系统或表面糖皮质激素治疗，持续严重感染，免疫抑制。
研究配方。TRIAC和DHEA获自Sigma。将它们与Essex霜剂(Merck)混合以获得4种不同的研究配方：
A.0.03％TRIAC在Essex霜剂中
B.0.03％TRIAC和2％DHEA在Essex霜剂中
C.单独的Essex霜剂
D.2％DHEA在Essex霜剂中
Essex霜剂是含有白色软石蜡(150mg/g)和石蜡油(也被称为液体石蜡)(60mg/g)的霜剂。其他成分是浓磷酸、纯水、鲸蜡硬脂醇、聚乙二醇鲸蜡硬酯醚、二水磷酸二氢钠和氯甲酚。它由Merck,Sharp&Dome在北欧国家销售。
研究设计。概念验证性单盲开放式前瞻性研究，比较了TRIAC、DHEA和两者的组合与无活性治疗相比对短期糖皮质激素诱导的皮肤萎缩的效果。
试验区域是6位男性志愿者中的正常外观腹部皮肤。用永久性记号笔标记出4个不同的10x 10cm的皮肤区域。
所有区域每日两次用0.5gr戊酸倍他米松(Betnovate,GSK)预处理，每日两次共21日。然后将每个试验区域每日两次用0.5gr试验配方之一进行处理，共14日。
吸吮诱导的皮肤水泡。吸吮水泡使用置于试验区域上并连接到具有约60mm Hg真空的真空泵的一次性装置(Dermovac,Ventipress,Lappeeranta,Finland)来诱导。每个装置在约1小时内产生5个吸吮水泡。使用注射器收集得到的液体，然后合并并在-70℃下冷冻。
吸吮水泡液中人类I型前胶原蛋白(PINP)的氨基端前肽的分析。使用可商购的RIA试剂盒，从在用试验配方处理14天后获得的吸吮水泡液进行PINP的分析。(UniQ PINP RIA,Orion Diagnostics,Espoo,Finland；检测极限2μg/L；批内变异系数，5.4％；批间变异系数，9.5％)。
统计学。使用Kruskal-Wallis检验，在4种不同处理之间做出成对比较。
结果
在所有志愿者中成功地产生吸吮水泡，并将来自于所有志愿者的吸吮水泡液储存以备人类I型前胶原蛋白(PINP)的分析。
在表1中呈现了所有四种不同可替选物(TRIAC、TRIAC+DHEA、DHEA和安慰剂)的平均值。统计分析证实了显著的治疗效果。在安慰剂处理的区域中PINP浓度最低。PINP被DHEA、TRIAC的处理增加，并且TRIAC和DHEA的组合证实了最高浓度。结果显示，使用DHEA的处理仅仅略微好于使用安慰剂的处理。然而，TRIAC和DHEA的组合显著改善了效果，并证实了两种药物物质之间的协同效应。
表1.在用戊酸倍他米松预处理3周的4个皮肤区域中，前胶原蛋白I(PINP)的分析的平均值(μg/l)。然后将所述皮肤区域用下列可替选物之一处理2周：A：TRIAC，B：TRIAC+DHEA，C：安慰剂，D：DHEA。
| A.TRIAC | 555 |
| B.TRIAC+DHEA | 729 |
| C.安慰剂 | 257 |
| D.DHEA | 279 |
讨论
在较早在小鼠中的研究中，已显示浓度为0.03％的单独的TRIAC可以在用戊酸倍他米松预处理的小鼠中恢复皮肤厚度(8-9)。在人类健康志愿者中，在用戊酸倍他米松预处理的皮肤中，与安慰剂相比，使用0.03％TRIAC霜剂的治疗在刺激PINP合成方面明显更加有效(15)。在另一项研究中，在用强效表面用皮质类固醇治疗手部湿疹的患者中，用TRIAC的处理似乎逆转了糖皮质激素诱导的皮肤萎缩(16)。
DHEA是涉及生理性衰老的一种甾类激素。当通过口服途径给药时，它对老年人的皮肤病症具有正面效果(19)。
在涉及绝经后女性的另一项研究中，结果指示了表面施用的DHEA可以通过刺激胶原蛋白生物合成、改进真皮的结构组织和调节角化细胞代谢来发挥抗衰老效果的可能性(20)。
在我们的研究中，我们首次显示了TRIAC和DHEA的组合能够在用戊酸倍他米松预处理的皮肤中有效地刺激PINP合成，并且所述组合比单独的TRIAC或DHEA更加有效。这种组合可用于在皮质类固醇诱导的皮肤萎缩中有效地治疗皮肤萎缩。它也可用于治疗由其他情况造成的皮肤萎缩例如晒伤皮肤和由高龄造成的皮肤萎缩。另一个有趣的应用是将TRIAC和DHEA与强效皮质类固醇组合以便预防皮质类固醇诱导的皮肤萎缩。如果这种组合在湿疹和银屑病的治疗中仍然有效并且没有皮肤萎缩的风险，则这种组合将是强效表面用皮质类固醇应用的重要突破。
下面给出了本发明的组合物的实施例。它们不打算以任何方式限制本发明。
配方实施例
下面是给出的配方实施例，即利用适用于本发明的介质的实施例。TRIAC和DHEA以及任选地皮质类固醇，通常被添加到介质，或者可以任选地利用加热至最高80℃，将它们溶解在一种或多种成分中。与制备方法和适合的介质的其他实例相关的细节，存在于《Remington制药学》(Remington’s Pharmaceutical Sciences)第18版，Mack PublishingCompany,1990中。
配方实施例1
在制备本发明的组合物中使用的洗剂基料
配方实施例2
o/w乳液
液体凡士林 (HLB 10.5) 50g
乳化剂 5g
失水山梨糖醇单油酸酯 (HLB 4.3)
聚氧乙烯20失水山梨糖醇单油酸酯 (HLB 15)
水 添加至100ml
配方实施例3
软膏
1g软膏含：
液体石蜡 30mg
α-生育酚 20μg
白色软石蜡 补充至1g
配方实施例4
可喷雾组合物
1g含
羟甲基纤维素 150mg
乙醇 补充至1g
配方实施例5
洗剂
1g含
参考文献
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18.EP 0831769和相关专利和专利申请的专利和专利保护报告。和Gulliksson 2007和2008。
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Claims (13)
1.一种组合物，其包含三碘甲腺乙酸(TRIAC)和脱氢表雄酮(DHEA)。
2.权利要求1的组合物，其用于表面使用。
3.权利要求1或2的组合物，其含有0.01％至2％w/w的TRIAC。
4.前述权利要求任一项的组合物，其含有0.01％至0.5％w/w的TRIAC。
5.前述权利要求任一项的组合物，其含有0.5％至5％的DHEA。
6.前述权利要求任一项的组合物，其含有1％至3％w/w的DHEA。
7.前述权利要求任一项的组合物，其还包含皮质类固醇。
8.三碘甲腺乙酸(TRIAC)和脱氢表雄酮(DHEA)的组合应用，用于改善或治疗受试者的皮肤。
9.权利要求8的组合应用，其中所述待改善或治疗的皮肤选自：皮肤萎缩、晒伤皮肤、固有地衰老的皮肤、湿疹和银屑病、光化性皮肤损伤、固有地衰老的皮肤、光损伤的皮肤、扁平苔癣、鱼鳞癣、痤疮、银屑病、起皱皮肤、毛囊角化病、湿疹、特应性皮炎、脂溢性皮炎硬皮病、胶原蛋白缺乏的皮肤、皮质类固醇萎缩症、氯痤疮、糠疹和皮肤瘢痕。
10.权利要求8或9的组合应用，其用于皮肤萎缩的治疗或预防。
11.权利要求8-10任一项的组合应用，其用于由皮质类固醇诱导的皮肤萎缩的治疗或预防。
12.权利要求8-11任一项的组合应用，其中所述组合还包含皮质类固醇。
13.一种治疗受试者的受损皮肤的方法，所述方法包括向所述受试者的皮肤施用TRIAC和DHEA的组合。
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| PL (1) | PL3223808T3 (zh) |
| PT (1) | PT3223808T (zh) |
| RU (1) | RU2017121884A (zh) |
| WO (1) | WO2016083325A1 (zh) |
| ZA (1) | ZA201702989B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706479A (zh) * | 2004-06-08 | 2005-12-14 | 美国酶医公司 | 加速乙醇代谢的方法和组合物 |
| WO2008154294A1 (en) * | 2007-06-07 | 2008-12-18 | Unicity International, Inc. | Method and composition for providing controlled delivery of biologically active substances |
| US20100009970A1 (en) * | 2008-03-19 | 2010-01-14 | Combinatorx (Singapore) Pte. Ltd. | Compositions and methods for treatment of viral diseases |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH642851A5 (en) | 1980-02-13 | 1984-05-15 | Berema Sa | Medicinal compositions for the treatment of cellulite |
| GB9214202D0 (en) | 1992-07-03 | 1992-08-12 | Leo Pharm Prod Ltd | Chemical compounds |
| PT831769E (pt) | 1995-06-07 | 2004-02-27 | Karobio Ab | Novas utilizacoes para as hormonas da tiroide ou compostos semelhantes as hormonas da tiroide |
| DK1021204T3 (da) * | 1997-09-26 | 2006-05-08 | Noven Pharma | Bioadhæsive præparater og fremgangsmåder til topisk administration af aktive midler |
| FR2808683B1 (fr) | 2000-05-15 | 2003-05-23 | Oreal | Utilisation de la dhea et/ou ses precurseurs et derives chimiques et/ou biologiques, dans une composition notamment cosmetique, pour prevenir ou traiter l'atrophie de l'epiderme |
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2015
- 2015-11-24 CN CN201580063734.7A patent/CN106999457B/zh not_active Expired - Fee Related
- 2015-11-24 BR BR112017010778A patent/BR112017010778A2/pt not_active Application Discontinuation
- 2015-11-24 WO PCT/EP2015/077401 patent/WO2016083325A1/en active Application Filing
- 2015-11-24 MX MX2017006516A patent/MX363010B/es unknown
- 2015-11-24 PT PT15798133T patent/PT3223808T/pt unknown
- 2015-11-24 HU HUE15798133A patent/HUE042970T2/hu unknown
- 2015-11-24 PL PL15798133T patent/PL3223808T3/pl unknown
- 2015-11-24 KR KR1020177016732A patent/KR20170086597A/ko not_active Application Discontinuation
- 2015-11-24 AU AU2015352677A patent/AU2015352677B2/en not_active Ceased
- 2015-11-24 RU RU2017121884A patent/RU2017121884A/ru not_active Application Discontinuation
- 2015-11-24 ES ES15798133T patent/ES2714078T3/es active Active
- 2015-11-24 EP EP15798133.3A patent/EP3223808B1/en not_active Not-in-force
- 2015-11-24 JP JP2017528849A patent/JP6666911B2/ja not_active Expired - Fee Related
- 2015-11-24 US US15/528,882 patent/US10413555B2/en not_active Expired - Fee Related
- 2015-11-24 CA CA2968611A patent/CA2968611A1/en not_active Abandoned
- 2015-11-24 DK DK15798133.3T patent/DK3223808T3/en active
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2017
- 2017-04-28 ZA ZA201702989A patent/ZA201702989B/en unknown
- 2017-05-10 IL IL252203A patent/IL252203A0/en unknown
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2019
- 2019-03-22 US US16/362,576 patent/US20190216822A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706479A (zh) * | 2004-06-08 | 2005-12-14 | 美国酶医公司 | 加速乙醇代谢的方法和组合物 |
| WO2008154294A1 (en) * | 2007-06-07 | 2008-12-18 | Unicity International, Inc. | Method and composition for providing controlled delivery of biologically active substances |
| US20100009970A1 (en) * | 2008-03-19 | 2010-01-14 | Combinatorx (Singapore) Pte. Ltd. | Compositions and methods for treatment of viral diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2015352677B2 (en) | 2019-10-24 |
| US20170319598A1 (en) | 2017-11-09 |
| HUE042970T2 (hu) | 2019-07-29 |
| RU2017121884A (ru) | 2018-12-26 |
| EP3223808B1 (en) | 2019-01-09 |
| BR112017010778A2 (pt) | 2018-01-09 |
| RU2017121884A3 (zh) | 2019-04-05 |
| US20190216822A1 (en) | 2019-07-18 |
| MX363010B (es) | 2019-03-04 |
| EP3223808A1 (en) | 2017-10-04 |
| US10413555B2 (en) | 2019-09-17 |
| KR20170086597A (ko) | 2017-07-26 |
| PT3223808T (pt) | 2019-02-04 |
| CA2968611A1 (en) | 2016-06-02 |
| PL3223808T3 (pl) | 2019-07-31 |
| JP6666911B2 (ja) | 2020-03-18 |
| ZA201702989B (en) | 2019-10-30 |
| ES2714078T3 (es) | 2019-05-27 |
| WO2016083325A1 (en) | 2016-06-02 |
| DK3223808T3 (en) | 2019-03-25 |
| IL252203A0 (en) | 2017-07-31 |
| CN106999457B (zh) | 2020-02-11 |
| MX2017006516A (es) | 2018-01-25 |
| JP2017535590A (ja) | 2017-11-30 |
| AU2015352677A1 (en) | 2017-05-11 |
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