CN101370489A - 链烷二羧酸和类视黄醇用于治疗红斑痤疮和其它炎症性皮肤疾病的用途 - Google Patents
链烷二羧酸和类视黄醇用于治疗红斑痤疮和其它炎症性皮肤疾病的用途 Download PDFInfo
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- CN101370489A CN101370489A CNA2007800029173A CN200780002917A CN101370489A CN 101370489 A CN101370489 A CN 101370489A CN A2007800029173 A CNA2007800029173 A CN A2007800029173A CN 200780002917 A CN200780002917 A CN 200780002917A CN 101370489 A CN101370489 A CN 101370489A
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Abstract
为了实现红斑痤疮的另一种治疗可能性,本发明公开了至少一种具有7-13个碳原子的α,ω-正-链烷二羧酸或其酯以及至少一种类视黄醇制备药物制剂的用途。本发明所公开的配制品同样在其他炎症性皮肤疾病(例如牛皮癣、特应性皮炎和寻常痤疮)的治疗中同样有效。
Description
在先申请的权益
本申请要求申请号为DE 10 2006 004 804.0的德国专利申请(申请日为2006年1月23日)和US60/760,952(申请日为2006年1月23日)的在先申请的权益。
技术领域
本发明涉及链烷二羧酸(alkanedicarboxylic acids)和类视黄醇用于制备治疗红斑痤疮和其它炎症性皮肤疾病的药物制剂的用途。
现有技术
DE 28 17 133公开了可以使用能够被皮肤酶分解的具有7-13个碳原子的α,ω-正-链烷二羧酸及其酯来治疗色素沉着性皮肤病(hyperpigmentary dermatoses)或皮肤色素沉着(dermalhyperpigmentations)。此外,EP 0 336 880 A2描述了含有壬二酸并可用于治疗各种年龄诱导的面部皮肤的变化的药物组合物。单独使用壬二酸(作为单独的活性成分)对抗炎症性皮肤病(例如痤疮和红斑痤疮)也同样包括在现有技术中。
EP 0 443 413 B1公开了用于抗光老化和褪色皮肤治疗的药物组合物,其含有作为活性成分的壬二酸和维甲酸。未对这种活性成分的组合用于抗炎症的目的的用途进行描述。
更多的现有技术可见于:
DE 69400428 T2
CN 1185951 A
US 2002/0155180 A1
US 2003/077301 A1
US 2005/0169948 A1
WO 99/581104 A1
WO 2005/115546 A2
US 4661519
发明的详细描述
本发明的目的是为了实现另一种红斑痤疮和其他炎症性皮肤疾病(例如银屑病、特应性皮炎和寻常痤疮)的治疗可能性,或实现相应药物制剂的可能性。
这一目的是通过权利要求的特征得以实现的。
根据本发明,
-至少一种具有7-13个碳原子的α,ω-正-链烷二羧酸或其酯和
-至少一种类视黄醇的用途是用于制备治疗炎症性皮肤疾病的药物制剂。
优选的是选自以下一组的α,ω-正-链烷二羧酸或其酯:庚二酸、辛二酸、壬二酸、癸二酸、1,9-壬二羧酸、1,10-葵二羧酸和1,11-十一烷二羧酸。
更优选壬二酸或其酯,以及最优选壬二酸。
相互独立的具有1-5个碳原子的烷基,可作为酯基用于α-和ω-位。烷基可以是直链或支链形式的甲基、乙基、丙基、丁基或戊基。
优选来自以下一组的类视黄醇:维甲酸、异维甲酸、莫维A胺、阿维A酯、阿达帕林、贝沙罗汀和他扎罗汀。
更优选维甲酸和异维甲酸和阿达帕林,最优选维甲酸。
根据本发明的药物制剂或根据本发明的上述活性成分的用途特别适于具有炎症成分的皮肤疾病,且所述疾病的描述如下:
-红斑痤疮是一种初期为慢性充血(红斑痤疮I),然后演变成为慢性炎症(红斑痤疮II和II)的面部疾病。其可有助于增强血管反应和炎症过程并伴随白细胞渗透和炎症介质的释放。其特征在于具有急性炎症阶段的持续性红斑伴随着水肿、丘疹和脓疱的形成。红斑痤疮的成功治疗是困难的。根据本发明的组合物适于对炎症性成分(丘疹和脓疱)和红斑痤疮的血管成分(红斑和毛细血管扩张)施加有益效果。
-银屑病是一种炎症性、慢性、过度增生性皮肤疾病。其损伤是具有增殖性白色脱皮的边界清晰的、变厚的红斑。通常,肘、膝、面部皮肤、生殖器和臀沟被感染。根据本发明的组合物特别适于对炎症性损伤施加有益效果。
-特应性皮炎/神经性皮炎是一种皮肤疾病,其征状与其他湿疹、炎症性皮肤改变(例如发红、脱皮、小水疱、丘疹和结节)的征状基本相同,伴随着通常的刺激性瘙痒症是最重要的标准。此外,皮肤特别干燥也是其特征。根据本发明的活性成分的应用特别作用于所述疾病的炎症性部分。
-痤疮是具有炎症性丘疹、脓疱和囊肿的皮脂腺异常,还伴有非炎症性黑头。在大多数情况下,其影响青少年和年轻人。根据本发明的组合物适于对痤疮具有全面的有益效果,能记录到丘疹、脓疱和囊肿的明显减少。
如上面对单独临床现象的简述,在炎症性皮肤疾病的治疗中组合使用前述根据本发明的活性成分,显示出足以令本领域技术人员吃惊的治疗效果,该治疗效果明显超出两种单独物质的治疗效果。
表明组合治疗具有加性或协同效应的检测结果迄今为止还未知。
活性成分的组合对于炎症性皮肤疾病的效应利用针对局部或全身性应用的检测物质的抗炎能力的常规药理学评估模型得以证明。为此,通过巴豆油的方式在小鼠耳上诱导炎症性反应(即,刺激性接触性皮炎)并应用检测物质。这一检测可在以下实施例的框架之内进行更加详细的解释。
根据本发明的用途包括预防性和治疗性措施。所制备用于本发明的用途的药物制剂的成分可在一剂中在相同时间和/或空间给药;此外,它们还可物理性地和/或在时间上分开施用。
就治疗效果而言,合适的剂量是不同的且依赖于例如在药物制剂中单个成分的浓度、宿主、给药类型、以及待治疗病症的类型和严重程度。
α,ω-正-链烷二羧酸(特别是壬二酸)的优选浓度为2-40%(重量百分比),更优选5-30%,最优选10-20%。
优选0.005%-0.2%(重量百分比)的类视黄醇(特别是维甲酸)浓度,更优选0.025-0.1%,且最优选0.04-0.06%。
此外,优选除了两种活性成分α,ω-正-链烷二羧酸和类视黄醇之外不再存在有其他的活性成分。特别优选根据本发明的所述制剂不含角鲨烷、烟酰胺、***或其他糖皮质激素或皮质甾类、二甲砜、甲硝唑或其他抗生素。
制备用于根据本发明的用途的药物制剂可根据本领域公知的方法加工成制剂学中常规的具有添加剂和/或载体的常规局部施用形式。优选根据本发明的组合物与至少一种生理学相容的药理学佐剂或载体组合。药理学佐剂和载体在Remington′s Pharmaceutical Science,15th Ed.,Mack Publishing Company,Easton,Pennsylvania(1980)中有记载。
可以通过将具有适当的添加剂的活性成分转化成所希望的施用形式(例如,溶液、洗液、乳剂、软膏、糊剂或凝胶)从而在局部治疗中以任合常规的方式施用所述药物制剂。所述凝胶优选用于痤疮和红斑痤疮。所述洗液、乳剂、软膏和凝胶可使用常规的乳化剂以常规方式进行制备(Kirk Othmer:Encyclopedia of Chemical Technology,3rd Ed.,1979,John Wiley & Sons,New York,Vol.8,pp.900-930)。
此外,可以将角质溶解剂(例如,水杨酸、维生素A酸、间苯二酚、苯酚、甲酚等)加入所述药物制剂中(尽管这并不是优选的实施方式)。
致湿因素(水复合物),例如丙二醇、丙三醇、聚乙二醇或氨基酸混合物、puroba oil(=希蒙得木油)、维生素(优选维生素A和E)、生命复合物(vital complexes)(例如,胎盘提取物)、酶、草药提取物(例如,金缕梅提取物或黄春菊提取物)或蛋白(例如,胶原)可用作亲水性和/或亲脂性添加剂。烃类,例如,凡士林、石蜡或硬脂、或蜡(例如蜂蜡)适合作为油/水乳剂的油相或脂肪相。适当的油/水乳化剂例如有硬脂醇、聚氧乙烯硬脂酸酯(例如,复合乳化剂(例如,和山梨糖醇酐脂肪酸酯(例如,Tween )或羧基乙烯聚合物(例如,)。所述水相还可额外地含有缓冲物质(例如乙二胺-N,N,N′,N′-四乙酸的二钠盐)和防腐剂(例如苯甲酸、氯喹那多、对羟基苯甲酸酯或苯扎氯铵)。
根据用于治疗痤疮和红斑痤疮的一个特别优选的实施方式,所述两种活性成分的生物利用率可通过使用以下的药物载体得以提高:于包含水和盐的水相中的三酰丙三醇酯、丙二醇、聚山梨酯、聚丙烯酸和大豆卵磷脂、构成水凝胶的组合物。
实施例
通过使用下文中的图表/实施例对本发明进行更详细的解释。在本申请中:
图1所示为表示在小鼠耳上水肿形成的条形图,
图2所示为表示嗜中性粒细胞浸润的条形图,以及
图3所示为粒细胞浸润的条形图。
就局部或全身性施用的检测物质的抗炎症潜力的药理学评估而言,炎症反应(刺激性接触性皮炎)的诱导是已被证实的模型(Trancik and Lowe(1985)Evaluation of Topical Nonsteroidal Anti-Inflammatory Agents,Models in Dermatology,H.Maibach and N.J.Lowe.Basel,Karger:35-42)。
可将巴豆油施用于小鼠耳部进行所述研究,这导致了伴随在24小时内到达峰值的水肿和初级多形核粒细胞浸润的急性、炎症性反应。检测物质可预防性地(即在施加炎症性刺激物之前)施加,或与巴豆油同时施加。
在这一检测中,可将于作为载体的乙醇/异丙基豆蔻酸酯中的1%的巴豆油在t=0h时施加。将单独的载体用作对照。可将物质壬二酸(10-20%)和维甲酸(0.05%)单独或组合施用于小鼠耳部,并同时施用同样溶解于乙醇/异丙基豆蔻酸酯中的刺激性巴豆油。在触发湿疹24小时后处死动物,并将耳重确定为对炎症和水肿形成的度量。此外,可从耳匀浆中确定弹性蛋白酶和过氧化物酶参数。动物的数量基本为n=10只/组。
弹性蛋白酶是一种很大程度上嗜中性粒细胞-特异性酶,并由此成为对浸润的嗜中性粒细胞的数量的度量。嗜中性粒细胞在皮肤的炎症过程中发挥着重要作用,并且在红斑痤疮、痤疮、牛皮癣和特应性湿疹中数量大量增加从而能够在皮肤中得以检测。过氧化物酶通过所有粒细胞表达,除此之外还通过单核细胞表达。其可用于测定浸润的粒细胞和单核细胞。与嗜中性粒细胞相似,粒细胞和单核细胞/巨噬细胞同样参与皮肤的炎症性过程,并可在前述疾病的浸润物中被重复地检测。
所述检测包括将以下物质施用于小鼠耳部:
载体(乙醇/异丙基豆蔻酸酯) 索引号:1
巴豆油 索引号:2
壬二酸(10%) 索引号:3
壬二酸(15%) 索引号:4
壬二酸(20%) 索引号:5
维甲酸(0.05%) 索引号:6
壬二酸(10%)和维甲酸(0.05%) 索引号:7
壬二酸(15%)和维甲酸(0.05%) 索引号:8
壬二酸(20%)和维甲酸(0.05%) 索引号:9
图1的条形图表示在施用各种物质后在小鼠耳上水肿的形成。在施用(1)载体之后,鼠耳的平均重量是0.06g。由于作为炎症指征的水肿和细胞浸润,巴豆油(2)的施用引起了耳的重量的增加,据此给出了在施用检测物质之后确定偏离百分数的基础。
壬二酸的施用可以以10%(3),15%(4)和20%(5)的浓度进行。在本申请中,不能观察到水肿的明显减轻;相反,在15%的浓度时,还能观察到增加。以0.05%(6)的浓度施用维甲酸未导致以耳重度量的耳的水肿或炎症的任何明显减轻。然而,壬二酸和维甲酸的组合施用,却意外地显示出水肿的明显减轻。因此,壬二酸(10%)和维甲酸(0.05%)(7)、壬二酸(15%)和维甲酸(0.05%)(8)和壬二酸(20%)和维甲酸(0.05%)(9)的施用分别导致水肿增加34%、48%和39%。因此,在两种治疗性剂的施用中清楚地证实了协同机制。
作为对嗜中性粒细胞的皮肤浸润的抑制的度量,根据对弹性蛋白酶活性的测定也得到相对应的发现。由于在炎症框架内由嗜中性粒细胞引起的细胞浸润,巴豆油引起了嗜中性粒细胞弹性蛋白酶的浓度的升高。弹性蛋白酶活性的对应值在图2中以条形图进行表示。这些值反映了对应于图1的结果,即,所述值不会受到单独施用浓度范围为10-15%(3,4)的壬二酸的明显影响。仅20%的壬二酸(5)使得嗜中性粒细胞弹性蛋白酶降低。采用与10-15%(3,4)的壬二酸的相同方式单独施用的0.05%(6)的维甲酸未导致耳匀浆中弹性蛋白酶浓度的降低。然而,足以让人惊讶的是,10-15%的壬二酸与0.05%(7,8)的维甲酸的组合导致在耳匀浆中对弹性蛋白酶浓度的测定基础上的耳部炎症的明显减轻。这反过来确证了两种治疗剂的组合的协同机制。这不能在20%的壬二酸(9)的条件下检测到,因为在该物质的这一浓度下,已经检测到非常显著的弹性蛋白酶的抑制,其随后不会再因为额外施用维甲酸而进一步增加。
图3同样以条形图的形式显示了作为对单核细胞和粒细胞的皮肤浸润的抑制的度量的过氧化物酶活性。由于在炎症框架内粒细胞和单核细胞的细胞浸润,巴豆油引起了过氧化物酶浓度的升高。后者已经在3种所施用的壬二酸浓度中的2种浓度(3,5)中受到影响。然而,0.05%(6)的维甲酸的单独施用未导致过氧化物酶浓度的显著降低。然而,在两种治疗剂(7,8,9)(特别是以15-20%(8,9)的浓度)的组合施用中,依次诱导了对这一参数的显著抑制,这指示了协同作用。
这一研究的结果概述于下表1中。
表1
综上,可以认为,令本领域技术人员出乎意料的是:与载体相比,于乙醇/异丙基豆蔻酸酯中的维甲酸(0.05%)和壬二酸(10-20%)的组合明显在治疗上是有效的,尽管与载体相比,这两种单独物质维甲酸(0.05%)和壬二酸(10-20%)并未表现出任何同样强烈的治疗效果。
与用载体进行治疗相比,渗透入由巴豆油引起的炎症小鼠皮肤的白细胞可通过维甲酸和壬二酸的组合治疗而受到显著抑制,尽管单独的制剂并不同样有效。
所述效应包括,以皮肤中的过氧化物酶活性度量的白细胞的浸润,以及以皮肤中的弹性蛋白酶活性度量的嗜中性粒细胞的浸润(表1)。
这种细胞群对皮肤的浸润以及促炎症反应物质的释放都参与一系列炎症性疾病的发病。这些疾病包括红斑痤疮、痤疮、过敏性和刺激性接触性皮炎、特应性皮炎和银屑病(Braum-Falco et al.(1995)Dermatologie und Venerologie[Dermatology and Venerology].Heidelberg,Springer)。
进一步的研究
基于这些有希望的结果,进一步的研究证实了根据本发明的配制品在治疗红斑痤疮、过敏性和刺激性接触性皮炎、特应性皮炎、银屑病和痤疮中的有效性。
Claims (24)
1.至少一种具有7-13个碳原子的α,ω-正-链烷二羧酸或其酯以及至少一种类视黄醇用于制备用于治疗红斑痤疮的药物制剂的用途。
2.权利要求1的用途,其中至少一种α,ω-正-链烷二羧酸选自庚二酸、辛二酸、壬二酸、癸二酸、1,9-壬二羧酸、1,10-葵二羧酸、1,11-十一烷二羧酸。
3.权利要求2的用途,其中至少一种α,ω-正-链烷二羧酸是壬二酸。
4.前述权利要求中任一项的用途,其中相互独立的具有1-5个碳原子的烷基作为酯基存在于α-和ω-位。
5.权利要求4的用途,其中所述烷基是直链或支链形式的甲基、乙基、丙基、丁基或戊基。
6.前述权利要求中任一项的用途,其中至少一种类视黄醇选自维甲酸、异维甲酸、莫维A胺、阿维A酯、阿达帕林、贝沙罗汀、和他扎罗汀。
7.权利要求6的用途,其中至少一种类视黄醇是维甲酸。
8.前述权利要求中任一项的用途,其中至少一种α,ω-正-链烷二羧酸或其酯以2-40%的浓度存在。
9.权利要求8的用途,其中至少一种α,ω-正-链烷二羧酸或其酯以5-30%的浓度存在。
10.权利要求8的用途,其中至少一种α,ω-正-链烷二羧酸或其酯以10-20%的浓度存在。
11.前述权利要求中任一项的用途,其中至少一种类视黄醇以0.005%-0.2%的浓度存在。
12.权利要求11的用途,其中至少一种类视黄醇以0.025%-0.1%的浓度存在。
13.权利要求11的用途,其中至少一种类视黄醇以0.04%-0.06%的浓度存在。
14.前述权利要求中任一项的用途,其中与药物添加剂和/或载体一起实现所述用途。
15.权利要求14的用途,其中所述用途包含以下药物载体:于包含水和盐的水相中的三酰丙三醇酯、丙二醇、聚山梨酯、聚丙烯酸和大豆卵磷脂。
16.前述权利要求中任一项的用途,其中所述用途不包括使用任何其他药物活性化合物。
17.至少一种具有7-13个碳原子的α,ω-正-链烷二羧酸或其酯以及至少一种类视黄醇用于制备用于治疗炎症性皮肤疾病的药物制剂的用途。
18.至少一种具有7-13个碳原子的α,ω-正-链烷二羧酸或其酯以及至少一种类视黄醇用于制备用于治疗银屑病、特应性皮炎、或寻常痤疮的药物制剂的用途。
19.权利要求17或18的用途,其中至少一种α,ω-正-链烷二羧酸选自庚二酸、辛二酸、壬二酸、癸二酸、1,9-壬二羧酸、1,10-葵二羧酸和1,11-十一烷二羧酸。
20.权利要求17或18的用途,其中至少一种α,ω-正-链烷二羧酸是壬二酸。
21.权利要求17或18的用途,其中相互独立的1-5个碳原子的烷基作为酯基存在于α-和-ω位。
22.权利要求17或18的用途,其中所述烷基是直链或支链形式的甲基、乙基、丙基、丁基或戊基。
23.权利要求17或18的用途,其中至少一种类视黄醇选自维甲酸、异维甲酸、莫维A胺、阿维A酯、阿达帕林、贝沙罗汀和他扎罗汀。
24.权利要求17或18的用途,其中至少一种类视黄醇是维甲酸。
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CN103732218A (zh) * | 2011-06-03 | 2014-04-16 | 阿勒根公司 | 类维生素a化合物至皮脂腺的靶向递送 |
WO2022105894A1 (zh) * | 2020-11-20 | 2022-05-27 | 上海交通大学医学院附属瑞金医院 | 一种判断银屑病对il-17a抗体应答反应及其复发的标志物 |
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EP2201930A1 (en) | 2008-12-23 | 2010-06-30 | Intendis GmbH | Hydrogel composition for the treatment of dermatological disorders |
US20100273756A1 (en) * | 2009-04-27 | 2010-10-28 | Reza Babapour | Adjunctive formulation and methods for palliation of fine wrinkles, mottled hyperpigmentation, tactile roughness of facial skin and related disorders |
DE102010021671A1 (de) | 2010-05-27 | 2011-12-01 | Intendis Gmbh | Azelainsäurehaltige Formulierung mit Pigmentzusatz |
RU2500395C1 (ru) * | 2012-12-07 | 2013-12-10 | Закрытое акционерное общество Фармацевтическое научно-производственное предприятие "Ретиноиды" | Мазевая композиция для местного применения с противоугревой фармакологической активностью |
WO2017019951A2 (en) * | 2015-07-30 | 2017-02-02 | Curology, Inc. | Compositions amd methods of treating acne and photoaging |
WO2017192928A1 (en) | 2016-05-06 | 2017-11-09 | Albany Medical College | Treatment of rosacea with p38 and erk kinase pathway inhibitors |
WO2021029659A1 (ko) * | 2019-08-12 | 2021-02-18 | 연세대학교 산학협력단 | 에틸바닐린, 수베르산, 티아졸 또는 이의 염을 유효성분으로 포함하는 알러지성 질환 또는 아토피 피부염 예방 또는 치료용 조성물 |
KR102081029B1 (ko) * | 2019-08-12 | 2020-02-25 | 연세대학교 산학협력단 | 수베르산 또는 이의 염을 유효성분으로 포함하는 알러지성 질환 또는 아토피 피부염 예방 또는 치료용 조성물 |
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CN103732218A (zh) * | 2011-06-03 | 2014-04-16 | 阿勒根公司 | 类维生素a化合物至皮脂腺的靶向递送 |
WO2022105894A1 (zh) * | 2020-11-20 | 2022-05-27 | 上海交通大学医学院附属瑞金医院 | 一种判断银屑病对il-17a抗体应答反应及其复发的标志物 |
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