CN116262122A - 络丝蛋白和/或vegf-c的生产和/或活性促进剂及利用其的皮肤外用剂 - Google Patents
络丝蛋白和/或vegf-c的生产和/或活性促进剂及利用其的皮肤外用剂 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一种络丝蛋白和/或VEGF-C的生产和/或活性促进剂及利用其皮肤外用剂。
背景技术
水肿(Edema)是指体内组织细胞之间出现组织液积聚的状态,简单来说就是身体水肿的症状。这可能会因心脏病、肾病或身体某一部分的血液循环障碍而发生。就腿部而言,由于距离心脏距离远且受重力影响较大,使得流向心脏的血流减少而导致水肿。而且,就女性而言,在正常怀孕时或妊娠中毒症时会发生水肿,摄取大量水分或盐时或疲劳或睡眠不足时,可能会暂时出现水肿,但会自行消退。当毛细血管通透性增加时,例如,在烧伤、外伤、局部炎症、过敏反应等情况下也会发生局部水肿。尤其,在腿部水肿时,会伴随脚、脚踝水肿,因此很容易察觉到鞋子紧绷的感觉,而且与水肿的感觉一并伴有腿部沉重的感觉,因此也会将全身的疲劳认为是腿部水肿。全身性水肿可分为心源性水肿、肾源性水肿、肝源性水肿、内分泌性水肿、营养不良性水肿,局部性水肿有因血管、***的阻塞而引起的水肿和血管舒缩性水肿等。如果出现水肿,则会让身体浮肿、体重增加、睡醒后眼部浮肿、手指上的戒指发紧、会感觉鞋子变小。如果用手指按压小腿胫骨部位,也会出现凹陷的凹陷性水肿(压凹性水肿)。已知,水肿会促进皮肤内局部水分过多引起的血液循环障碍及皮肤老化。一般来说,皮肤问题会进一步恶化具有淋巴***的功能不全和超负荷的淋巴水肿的人的状态。
皮肤在我们人体内与外部环境的接触最为紧密,是保护人体内部的重要器官。这样的皮肤大致分为表皮(epidermis)、真皮(dermis)、皮下脂肪(hypodermis)。其中,皮下脂肪由形成脂肪组织的脂肪细胞构成,执行在生物体内储存或释放能量的作用,所述脂肪组织用脂肪储存能量。换言之,皮下脂肪在能量供大于求时,在脂肪细胞内储存为中性脂肪,而在能量枯竭时,分解为游离脂肪酸和葡萄糖。
另外,近年来,在现代社会中,随着经济的成长,生活水平的提高,运动不足及以高蛋白为主的饮食文化导致肥胖人口剧增,由肥胖引起的疾病也越来越多。因此,在现代社会,为了治疗肥胖,正在进行着运动疗法、饮食疗法及药物疗法等。
但是,对于生活忙碌的现代人来说,对于肥胖及肥胖相关疾病,以运动疗法和饮食疗法来解决的话,很难期待适宜的效果,更何况,脂肪细胞一旦形成,虽然可以缩小大小,但由于无法自然消失,存在永久留在人体内的问题。因此,认为更适合的方式是开发出能够帮助脂肪分解的安全的皮肤外用剂(例如软膏、化妆品等)并进行并行使用。
因此,本发明人将以特定化学式表示的化合物作为有效成分,促进络丝蛋白(reelin)和/或VEGF-C的生产或活性,进而借助于此能够改善水肿、淋巴水肿、皮肤皱纹及肥胖,对此进行确认之后,完成了本发明。
发明内容
要解决的技术问题
根据一实例,旨在提供一种促进络丝蛋白和VEGF-C的生产或活性的促进剂。
根据另一实例,旨在提供一种利用所述促进剂的皮肤外用剂。
问题的解决手段
根据一实例,提供一种络丝蛋白和/或VEGF-C的生产和/或活性促进剂,其作为有效成分包含以下述化学式1表示的化合物或其盐。
[化学式1]
在所述化学式1中,
R1至R15分别独立地为羟基、羧基、取代或未取代的C1至C20烷氧基、取代或未取代的C1至C20烷基或者取代或未取代的C6至C20芳基。
所述R1至R5分别独立地可以为羟基。
所述R6至R8分别独立地可以为羧基。
所述R9至R15分别独立地可以为取代或未取代的C1至C20烷基。
以所述化学式1表示的化合物可以以下述化学式1-1表示。
[化学式1-1]
在所述化学式1-1中,
R1至R15分别独立地为羟基、羧基、取代或未取代的C1至C20烷氧基,、取代或未取代的C1至C20烷基或者取代或未取代的C6至C20芳基。
以所述化学式1表示的化合物的盐可以为钾盐。
相对于所述络丝蛋白和/或VEGF-C的生产和/或活性促进剂的总量,可以以1ppm至200ppm的浓度范围包含以所述化学式1表示的化合物。
根据另一实例,提供一种皮肤外用剂,其通过促进络丝蛋白和/或VEGF-C的生产和/或活性,改善水肿、淋巴水肿、皮肤皱纹或肥胖,其特征在于,作为有效成分包含以所述化学式1表示的化合物或其盐。
所述皮肤外用剂为水肿改善剂,所述水肿可以由***的形成异常、***的功能异常或所述两种引起。
所述皮肤外用剂为淋巴水肿改善剂,所述淋巴水肿可以由***的形成异常、***的功能异常或所述两种引起。
所述皮肤外用剂为肥胖改善剂,所述肥胖可以由***的形成异常、***的功能异常或所述两种引起。
根据又一实例,提供一种用于络丝蛋白和/或VEGF-C的生产和/或活性促进剂的制备的以下述化学式1表示的化合物或其盐的用途。
发明效果
根据一实例,通过诱导络丝蛋白和/或VEGF-C的表达来活化***功能,从而提供对预防或控制水肿、淋巴水肿、皮肤皱纹或肥胖有效的新成分。
附图说明
图1为示出以化学式E-1表示的化合物的细胞毒性实验结果的图表。
图2为示出以化学式E-1表示的化合物的络丝蛋白细胞因子的分析结果的图表。
图3为示出以化学式E-1表示的化合物的VEGF-C细胞因子的分析结果的图表。
具体实施方式
下面,对本发明的实例进行详细说明,以便本发明的所属技术领域的普通技术人员容易实施。但本发明可以以各种相异的形态体现,并非限定于在此说明的实例。
在本说明书中所使用的术语"络丝蛋白(Reelin,RELN)"是意指细胞外基质相关分子。
在本说明书中,当不另外提供具体定义时,"取代"或"取代的"是意指,本发明的功能基团中的一个以上的氢原子被选自以下的组中的一种以上的取代基所取代:卤原子(F、Br、Cl或I)、羟基、硝基、氰基、氨基(NH2、NH(R200)或N(R201)(R202),其中R200、R201及R202相同或不同,分别独立地为C1至C10烷基)、脒基、肼基、腙基、羧基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的脂环族有机基团、取代或未取代的芳基及取代或未取代的杂环基。
在本说明书中,当不另外提供具体定义时,"烷基"意指,C1至C20烷基,且具体而言是意指C1至C15烷基,"环烷基"是意指,C3至C20环烷基,且具体而言是意指C3至C18环烷基,"烷氧基"是意指,C1至C20烷氧基,且具体而言是意指C1至C18烷氧基,"芳基"是意指,C6至C20芳基,且具体而言是意指C6至C18芳基,"烯基"是意指C2至C20烯基,且具体而言是意指C2至C18烯基,"亚烷基"是意指,C1至C20亚烷基,且具体而言是意指C1至C18亚烷基,"亚芳基"是意指,C6至C20亚芳基,且具体而言是意指C6至C16亚芳基。
在本说明书中,当不另外提供定义时,“组合”是意指混合或共聚。此外,“共聚”是意指嵌段共聚或无规共聚,且“共聚物”是意指嵌段共聚物或无规共聚物。
皮肤脉管***分布在真皮内,由血管和***构成。为了维持体内动态平衡,已移动至血管外的组织液必须再回流至静脉中。皮肤的静脉向中枢有效地输送血流。然而,静脉本身缺乏摄取组织液的能力。由此,可以理解,摄取组织液的组织,即***在皮肤中也是必要结构。
***通过回收存在于皮肤中的废物、持续从血管漏出的水分、蛋白质,从而对于使细胞周围的微环境保持稳定状态而担负重要作用。此外,认为***担负介由T淋巴细胞的输送来抵抗来自外界的感染因子、外部因素的作用。
作为***功能不全的病态,已知水肿或淋巴水肿等症状。此外,已知***功能不仅对水肿、而且对伴随紫外线的皮肤的光老化(皱纹形成)都担负重要的作用。
迄今为止的研究表明,已经鉴定出VEGFR-3作为特异性存在于***中的跨膜型受体,并发现了VEGF-C和VEGF-D作为其配体。VEGF-C作用于***、促进***内皮细胞增殖、迁移进而形成管腔,从而活化***功能。此外,向作为水肿的病态的水肿导入VEGF-C,对于根据于此的基因治疗的可能性正在摸索当中。
而且,最近,已知当导致***功能异常的基因变异小鼠成熟时呈现肥胖。关于***的形成和功能的异常而呈现肥胖的机制,可确认到流过***的淋巴液促进祖肥大细胞向脂肪分化。即,已经报道了由于***的功能异常而使淋巴液向***外漏出,这与脂肪的分化、进而形成肥胖相关。因此,也期待将VEGF-C促进剂作为使***功能性新生的、预防肥胖的治疗药。
VEGF家族基因存在VEGF-A至VEGF-E。其中,鉴定出VEGF-B和VEGF-E作为仅作用于血管的因子。已知VEGF-A是存在于皮肤中的、对***起作用、但反过来会使***的功能恶化的因子。
对于皮肤,虽然已经有报告指出VEGFD在真皮中微量存在,但是由于VEGF-D的敲除小鼠完全没有对皮肤***的形成和功能造成异常,因此认为VEGF-D不是皮肤的***形成所不可缺少的因子。另外,就在表皮高表达了VEGF-C的小鼠而言,存在于真皮中的***数增加,由此可知皮肤中的VEGF-C在表皮中强表达。而且,确认到,在表皮高表达作为VEGF-C的受体的VEGFR-3的中和抗体,从而阻断处于表皮的VEGF-C的效果,其结果,确认到真皮的***数极端减少(Makinen,T.,Jussila,L.,Veikkola,T.,Karpanen,T.,Kettunen,M.I.,Pulkkanen,K.J.,Kauppinen,R.,Jackson,D.G.,Kubo,H.,Nishikawa,S.,Yla-Herttuala,S.&Alitalo,K.(2001)Nat Med 7,199-205)。由此,可知存在于皮肤真皮内的***的功能可通过在表皮表达的VEGF-C来控制,由于VEGF-C丧失功能而呈现水肿(浮肿)。
进而,关于活化或强化人体内淋巴或***,从而控制水肿或浮肿,改善皮肤老化(皱纹),预防、抑制及治疗肥胖,正进行各种尝试,而所述淋巴或***的活化或强化,除了VEGF-C之外,也可通过络丝蛋白的生产、分化及促进活性而实现。
据此,为了找出在人体内能够通过促进络丝蛋白和/或VEGF-C的生产或活性,来改善水肿、淋巴水肿、皮肤皱纹或肥胖的有效成分,本发明人经过无数次的实验和试错,最终确认,作为有效成分包含以下述化学式1表示的化合物的组合物,能够实现作为络丝蛋白和/或VEGF-C的生产和/或活性促进剂的功能,从而完成了本发明。
[化学式1]
在所述化学式1中,
R1至R15分别独立地为羟基、羧基、取代或未取代的C1至C20烷氧基、取代或未取代的C1至C20烷基或者取代或未取代的C6至C20芳基。
例如,在所述化学式1中,R1至R5分别独立地可以为羟基。
例如,在所述化学式1中,R6至R8分别独立地可以为羧基。
例如,在所述化学式1中,R9至R15分别独立地可以为取代或未取代的C1至C20烷基。
例如,以所述化学式1表示的化合物可以以下述化学式1-1表示,但并非限定于此。
[化学式1-1]
在所述化学式1-1中,R1至R15分别独立地为羟基、羧基、取代或未取代的C1至C20烷氧基、取代或未取代的C1至C20烷基或者取代或未取代的C6至C20芳基。
在所述化学式1-1中,R1至R15的定义可与所述化学式1中的定义相同。
例如,以所述化学式1表示的化合物的盐可以为钾盐,例如可以为二钾盐。
例如,相对于所述络丝蛋白和/或VEGF-C的生产和/或活性促进剂的总量,可以以1ppm至200ppm,例如1ppm以上且200ppm以下、190ppm以下、180ppm以下、170ppm以下、160ppm以下、150ppm以下、140ppm以下、130ppm以下、120ppm以下、110ppm以下、100ppm以下、90ppm以下、80ppm以下、70ppm以下、60ppm以下、50ppm以下、40ppm以下、30ppm以下、20ppm以下,例如,以1ppm至10ppm的浓度范围包含以所述化学式1表示的化合物。
根据一实例的一种络丝蛋白和/或VEGF-C的生产和/或活性促进剂作为有效成分包含以所述化学式1表示的化合物,且满足所述浓度范围,因此能够在促进***的形成及功能上非常有效。***的功能不全的症状,不仅包括水肿或淋巴水肿等,而且还可包括伴随紫外线的皮肤的光老化(皱纹形成等)及肥胖等。根据一实例的本发明的络丝蛋白和/或VEGF-C的生产和/或活性促进剂,能够在水肿及淋巴水肿和伴随紫外线的皮肤的光老化及肥胖的预防、抑制方面非常有效。而且在先天性淋巴水肿的治疗方面也非常有效。
通常,皮肤的光老化意指,作为反复被日光照射的结果,可确认的皮肤的外观及机能变化。作为日光构成要素的紫外线(UV)、特别是中波UV(称为UVB、波长290~320nm)主要引起光老化。引起光老化所需的UVB的照射量目前尚不清楚。但是,引起红斑、晒黑的水平下的UVB的反复照射通常与光老化相关。在临床上,光老化可特定为皮肤粗糙、皱纹的形成、斑的着色、土色化、松弛的形成、毛细管扩张症的发病、黑痣的发生、紫癜的发病、容易受伤、萎缩、纤维化的色素除去区域的产生、初癌和恶性肿瘤的发病等。光老化一般发生在像脸、耳、头、颈和手等习惯暴露在日光下的皮肤。
根据另一实例,提供一种皮肤外用剂,其通过促进络丝蛋白和/或VEGF-C的生产和/或活性,改善水肿、淋巴水肿、皮肤皱纹及肥胖,其特征在于,作为有效成分包含以所述化学式1表示的化合物。
例如,所述皮肤外用剂为水肿改善剂,所述水肿可以由***的形成异常、***的功能异常或所述两种引起。
例如,所述皮肤外用剂为淋巴水肿改善剂,所述淋巴水肿可以由***的形成异常、***的功能异常或所述两种引起。
例如,所述皮肤外用剂为肥胖改善剂,所述肥胖可以由***的形成异常、***的功能异常或所述两种引起。
根据一实例的皮肤外用剂,根据其使用目的,可适当确定用量、适用形态、剂型。例如,以所述化学式1表示的化合物作为有效成分,相对于皮肤外用剂的总浓度,可以以1ppm至10ppm,例如1ppm至5ppm、例如5ppm至10ppm、例如2ppm至9ppm、例如3ppm至8ppm的浓度进行调配,但并非限定于此。对于所述皮肤外用剂的适用形态不进行特别限定,均可适用于吸入和经皮。作为剂型,下述任意形态均可,例如香水、香波/护发素类、护肤用品、洗澡液、身体冲洗液、爽身粉类、芳香剂、除臭剂、浴用制剂、乳液(lotion)、霜、香皂、牙膏剂、气雾剂制品等化妆料、其它香料的一般所使用的任意形态。也可以用于吸入药等药品。
而且,在所述皮肤外用剂中,除了所述必要成分之外,通常可以根据需要适当调配化妆品或药品等的皮肤外用剂中使用的成分,例如美白剂、保湿剂、抗氧化剂、油性成分、紫外线吸收剂、表面活性剂、增稠剂、醇类、粉末成分、着色剂、水性成分、水、各种皮肤营养剂等。
此外,也可以适当还包含乙二胺四乙酸二钠、乙二胺四乙酸三钠、柠檬酸钠、多磷酸钠、偏磷酸钠、葡糖酸等金属螯合剂、咖啡因、丹宁、维拉帕米、凝血酸及其衍生物、甘草提取物、光甘草定、木瓜树的果实的热水提取物、各种生药、生育酚乙酸酯、甘草酸及其衍生物或其盐等药剂、维生素C、抗坏血酸磷酸镁、抗坏血酸葡糖苷、熊果苷、曲酸等美白剂、葡萄糖、果糖、甘露糖、蔗糖、海藻糖等糖类、视黄酸、视黄醇、乙酸视黄酯、棕榈酸视黄酯等维生素A类等。
例如,所述皮肤外用剂可以为化妆料组合物。
在本说明书中"化妆料"可意指,不仅具有美容功能,而且具有除了美容功能之外的追加的医疗功能的所有物质。
对于所述化妆料组合物的剂型不进行特别限定,可根据目的适当进行选择。
例如,所述化妆料组合物可剂型化为溶液、悬浮液、乳状液、糊剂、凝胶、霜、乳液、粉饼、香皂、含表面活性剂的清洗剂、油、粉状粉底、乳状液粉底、蜡状粉底及喷雾剂等,但并不局限于此。更具体地,可剂型化为清洁剂、滋养液、毛发整理剂、营养化妆水、精华液(essence)、精华素(serum)、护理剂、护发素、洗发剂、护发露、生发剂或染发剂等化妆料组合物、水包油(O/W)型、油包水(W/O)型等基础化妆料。例如,所述组合物可以具有选自由下述组中的一种剂型,下述组由护肤水、爽肤水、收敛剂、乳液、牛奶护肤乳液、保湿乳液、营养乳、按摩霜、营养霜、保湿霜、护手霜、软膏、粉底、精华液、营养精华液、面膜、香皂、洗面奶、洗面乳、洁面霜、身体乳、沐浴露、凝胶、霜、贴剂及喷雾剂。另外,本领域的普通技术人员根据其他外用剂的种类或使用目的等,可适当地选择各剂型成分中除所述必要成分之外的其他成分来调配成所述组合物。例如,可进一步包含紫外线阻隔剂、头发调理剂、香料等。
所述化妆料组合物可以含有化妆品可接受的介质或基质。这些作为适合局部应用的全部剂型可以以如下形式提供,即,例如可以是将油相分散在溶液、凝胶、固体或糊状无水产物、水相中所获得的乳剂、悬浮液、微乳剂、微胶囊、微粒或离子型(脂质体)和/或非离子型囊泡分散剂形式,或者以乳霜、护肤水、乳液、粉末、软膏、喷雾剂或遮瑕棒形式提供。这些组合物可以根据相应领域的常规方法来制备。
当本发明的剂型为溶液或乳状液时,使用溶剂、增溶剂或乳化剂作为载体成分,例如有水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁基乙二醇油、甘油脂族酯、聚乙二醇或脱水山梨醇的脂肪酸酯。
当本发明的剂型为悬浮液时,作为载体成分可以利用稀释剂,如水、乙醇或丙二醇;悬浮剂,如乙氧基化异硬脂醇、聚氧乙烯山梨醇酯和聚氧乙烯山梨糖醇酯;微晶性纤维素;偏氢氧化铝;膨润土;琼脂或黄芪胶等。
当本发明的剂型为糊剂、霜或凝胶剂时,作为载体成分可以利用动物油、植物油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅胶、膨润土、二氧化硅、滑石或氧化锌等。
当本发明的剂型为粉末或喷雾剂时,作为载体成分可以利用乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙或聚酰胺粉末,特别是在喷雾剂的情况下,可进一步包含诸如氯氟化烃、丙烷/丁烷或二甲醚的推进剂。
在本发明的一实施方式中,所述化妆料组合物可进一步包含增稠剂。本发明的化妆料组合物中包含的增稠剂可使用甲基纤维素、羧甲基纤维素、羧甲基羟基鸟嘌呤、羟甲基纤维素、羟乙基纤维素、羧乙烯基聚合物、聚季铵盐、鲸蜡硬脂醇、硬脂酸、卡拉胶等,优选可以使用羧甲基纤维素、羧乙烯基聚合物、聚季铵盐中的一种以上,最优选可使用羧乙烯基聚合物。
在本发明的一实施方式中,所述化妆料组合物可根据需要包含各种适当的基质和添加剂,并且本发明人容易选择这些成分的种类和量。根据需要,可以包含可接受的添加剂,例如,可进一步包含本领域常规的成分,如防腐剂、色素、添加剂等。
防腐剂具体可为苯氧乙醇(Phenoxyethanol)或1,2-己二醇(1,2-Hexanediol)等,香料可以是人造香料等。
而且,在本发明的一个实施方式中,化妆料组合物可以包含选自由水溶性维生素、油溶性维生素、聚合物肽、聚合物多糖、鞘脂及海藻提取物组成的组中的组合物。除此之外,作为可添加的调配成分,例如有油脂成分、保湿剂、润肤剂、表面活性剂、有机和无机颜料、有机粉末、紫外线吸收剂、防腐剂、杀菌剂、抗氧化剂、植物提取物、pH调节剂、酒精、色素、香料、血液循环促进剂、冷却剂、限制剂、纯化水等。
另外,除此之外,可添加的调配成分不限于此,也可以在不损害本发明的目的和效果的范围内调配所述任意成分。
进而,根据一实例的皮肤外用剂可以作为药学组合物来使用。
参照详细后述的实施例可明确本发明的优点及特征、达成它们的方法。以下,将通过实施例详细说明本发明。但是这些实施例用于具体说明本发明,本发明的范围并非限定于这些实施例。
(实施例)
实验例1:细胞毒性分析
将人源淋巴细胞(Human Dermal Lymphatic Endothelial Cells(人真皮淋巴内皮细胞);HDLEC,PromoCell,德国)重新在96孔培养皿培养一天之后,分别以0ppm(μg/ml)至200ppm(μg/ml)浓度处理以下述化学式E-1表示的化合物(BIOGENICS)。在培养24小时及72小时之后,利用QuantiMax WST-8细胞活性检测试剂盒(Cell viability assay kit)测量在450nm中的吸光度来确认细胞的存活率,将其结果表示于图1。
[化学式E-1]
从图1可确认,以所述化学式E-1表示的化合物在200ppm的浓度范围内无细胞毒性。
实验例2:络丝蛋白细胞因子分析
将人源淋巴细胞在6孔板中培养24小时之后,用DMSO处理,以此作为对照组(reference;(100%)),以10ppm的浓度处理以所述化学式E-1表示的化合物并培养48小时之后,利用人络丝蛋白(Human reelin)ELISA试剂盒(Mybiosource,美国)按照制造商说明书分析络丝蛋白细胞因子,从而测量络丝蛋白的生产及活性度,将其结果表示于图2。
从图2可确认,相比于对照组,以所述化学式E-1表示的化合物能更加提高络丝蛋白的生产及活性度。
实验例3:VEGF-C细胞因子分析
将人源淋巴细胞在6孔板中培养24小时之后,用DMSO处理,以此作为对照组(reference;(100%)),分别以1ppm及0ppm的浓度处理以所述化学式E-1表示的化合物并培养48小时之后,利用人VEGFC ELISA试剂盒(ThermoFisher,美国)按照制造商说明书分别分析VEGF-C细胞因子,从而测量VEGF-C的生产及活性度,将其结果表示于图3。
从图3可确认,相比于对照组,以所述化学式E-1表示的化合物能更加提高VEGF-C的生产及活性度。
实验例4:皮肤外用剂的制备
以如同下述表1中的组合和含量,根据实施例1、比较例1(桑叶桑根提取物;SKBIOLAND)及比较例2(柿叶提取物;BIO-FD&C)制备可用作为皮肤外用剂的化妆料组合物。就纯化水而言,与其他组成成分的重量混合时,使总量达到100重量%,而制备出化妆料组合物。
【表1】
(单位:ppm)
选定年龄在50岁以上,且有下肢小腿水肿的30名女性,并按照一天两次为她们的下肢小腿部位涂抹根据实施例1、比较例1及比较例2的组合物,在连续涂抹7天之后,测量每个人的i)体重变化(使用体重计)、ii)水肿最为严重的小腿部位的腿围变化(使用塑料卷尺)、iii)水肿状态(肉眼观察),将其结果表示于表2。
【表2】
实施例1 | 比较例1 | 比较例2 | |
体重(0天)(kg) | 57 | 56 | 56 |
体重(7天)(kg) | 55 | 57 | 56 |
小腿围(0天)(cm) | 37 | 37 | 37 |
小腿围(7天)(cm) | 36 | 37 | 37 |
水肿状态 | 缓解 | 无变化 | 无变化 |
从所述表2可确认,以根据一实例的皮肤外用剂作为处方时,与未进行处方时相比,水肿状态仅一周就得到了缓解。
以上,对本发明的优选实施例进行了详细说明,但本发明的权利范围并非限定于此,所属技术领域的普通技术人员利用权利要求书中定义的本发明的基本概念所做出的若干变形及改良形态均属于本发明的权利范围内。
Claims (18)
2.根据权利要求1所述的络丝蛋白和/或VEGF-C的生产和/或活性促进剂,其中,所述R1至R5分别独立地为羟基。
3.根据权利要求1所述的络丝蛋白和/或VEGF-C的生产和/或活性促进剂,其中,所述R6至R8分别独立地为羧基。
4.根据权利要求1所述的络丝蛋白和/或VEGF-C的生产和/或活性促进剂,其中,所述R9至R15分别独立地为取代或未取代的C1至C20烷基。
6.根据权利要求1所述的络丝蛋白和/或VEGF-C的生产和/或活性促进剂,其中,以所述化学式1表示的化合物的盐为钾盐。
7.根据权利要求1所述的络丝蛋白和/或VEGF-C的生产和/或活性促进剂,其中,相对于所述络丝蛋白和/或VEGF-C的生产和/或活性促进剂的总量,以1ppm至200ppm的浓度范围包含以所述化学式1表示的化合物或其盐。
9.根据权利要求8所述的皮肤外用剂,其中,所述R1至R5分别独立地为羟基。
10.根据权利要求8所述的皮肤外用剂,其中,所述R6至R8分别独立地为羧基。
11.根据权利要求8所述的皮肤外用剂,其中,所述R9至R15分别独立地为取代或未取代的C1至C20烷基。
12.根据权利要求8所述的皮肤外用剂,其中,
所述皮肤外用剂为水肿改善剂,
所述水肿由***的形成异常、***的功能异常或所述两种引起。
13.根据权利要求8所述的皮肤外用剂,其中,
所述皮肤外用剂为淋巴水肿改善剂,
所述淋巴水肿由***的形成异常、***的功能异常或所述两种引起。
14.根据权利要求8所述的皮肤外用剂,其中,
所述皮肤外用剂为肥胖改善剂,
所述肥胖由***的形成异常、***的功能异常或所述两种引起。
16.根据权利要求15所述的用途,其中,所述R1至R5分别独立地为羟基。
17.根据权利要求15所述的用途,其中,所述R6至R8分别独立地为羧基。
18.根据权利要求15所述的用途,其中,所述R9至R15分别独立地为取代或未取代的C1至C20烷基。
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