CN109843278A - 抗炎用组合物 - Google Patents
抗炎用组合物 Download PDFInfo
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- CN109843278A CN109843278A CN201780063670.XA CN201780063670A CN109843278A CN 109843278 A CN109843278 A CN 109843278A CN 201780063670 A CN201780063670 A CN 201780063670A CN 109843278 A CN109843278 A CN 109843278A
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Abstract
本发明涉及抗炎用组合物,根据本发明,基于优异的皮肤稳定性,不仅对人体无害,而且调节与炎症性皮肤疾病相关的介质因子的表达,从而显示出优异的抗炎效果,能够有用地用作抗炎用组合物。
Description
技术领域
本发明涉及抗炎用组合物,详细地,涉及通过调节炎症性皮肤疾病相关介质因子的表达而具有抗炎效果的抗炎用药物组合物和化妆品组合物。
背景技术
炎症是具有如下作用的生物体防御反应中的一种,即,由外部的生物学原因(细菌、病毒、寄生虫)、物理学原因(机械刺激、热、放射线、电)、化学性原因等引起细胞损伤,释放组胺和激肽等,从而发生血管扩张、毛细血管渗透性增加以及巨噬细胞向炎症部位聚集,由此,感染部位的血流量增加、浮肿、免疫细胞和抗体移动、疼痛、发热等而阻止生物体组织受到损伤。
炎症性皮肤疾病一般是指湿疹性皮炎。湿疹(eczema)是指在急性期出现伴有瘙痒的水泡(vesicle,小水泡)、红斑(erythema,皮肤的红色变化)、浮肿等,在慢性期浮肿和水泡减少,反而形成苔藓化(lichniscation,由于干燥并***的皮肤,所以皮肤上正常存在的手纹等线更加明显的情况)、鳞屑(scale)、皮肤颜色的变化等的皮肤疾病。这样的湿疹性皮炎的例子有接触性皮炎(contact dermatitis)、特应性皮炎(atopic dermatitis)、脂溢性皮炎(seborrheic dermatitis)等。
如上所述,皮肤中的炎症反应(inflammatory response)是在因物理性刺激或化学物质、细菌等而诱发皮肤损伤时以用于对此进行防御的作用而开始,多种免疫细胞和促炎症细胞因子参与其中。作为上述细胞因子的代表性的例子,可举出白细胞介素、增殖因子、趋化因子、肿瘤坏死因子和干扰素等,作为具体的例子,可举出胰岛素、IGF(***)-I、IGF-II、EGF(表皮生长因子)、TGF(转化生长因子)-α、TGF-β1、TGF-β2、FGF(成纤维细胞生长因子)-1、FGF-2、FGF-3、FGF-4、FGF-5、FGF-6、FGF-7、FGF-8、FGF-9、FGF-10、FGF-11、FGF-12、FGF-13、FGF-14、FGF-15、FGF-16、FGF-17、FGF-18、FGF-19、VEGF(血管内皮细胞生长因子)-A、VEGF-B、VEGF-C、VEGF-D、NGF(神经生长因子)、IL(白细胞介素)-1α、IL-1β、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、GM-CSF(粒细胞巨噬细胞集落刺激因子)、G-CSF(粒细胞集落刺激因子)、M-CSF(巨噬细胞集落刺激因子)、SCF(干细胞因子)、FL(flt-3配体)、血管生成素、EPO(***)、TPO(血小板生成素)、OSM(抑瘤素M)、LIF(白血病抑制因子)、活化素、抑制素、BMP(骨形成蛋白)、PDGF(血小板衍生生长因子)、HGF(肝细胞生长因子)、TNF(肿瘤坏死因子)-α、TNF-β、Fas-L(Fas配体)、CD40配体、MIP(巨噬细胞炎症蛋白)、MCP(单核细胞趋化蛋白)、IFN(干扰素)α、IFNβ、IFNγ、GDNF(胶质细胞源性神经营养因子)以及血管紧张素等。
目前,为了炎症性皮肤疾病的预防和治疗,使用布洛芬之类的合成药物制剂、抗组胺剂、类固醇、可的松、免疫抑制剂、免疫激动剂等,但是治疗效果是暂时性的,或者单纯地缓和症状,过敏反应、免疫***恶化等副作用多,在炎症的根本性的治疗上存在局限。另外,韩国授权专利第0563548号、韩国授权专利第0697319号、韩国授权专利第1309172号和韩国专利授权第1141802号中公开了用于开发利用了天然提取物的具有抗炎功能的化妆品组合物的各种尝试,但因为由其引起的其他皮肤刺激或变色等原因,其使用量受限,或者在水中的溶解度不好,因此在适用于实际制品时,由于用途的限制,难以获得实质性的效果。
对此,本申请的申请人对作为炎症性皮肤疾病相关介质因子的促炎症细胞因子的活性抑制程度深入地进行了研究,结果发现了由特定的醇或氨基酸衍生的化合物没有细胞毒性、诱发过敏的可能性等,因此不仅对皮肤安全,而且对促炎症细胞因子(特别是IL-8和IL-17)的生成抑制有效地发挥作用,为了提供包含它的抗炎组合物而完成了本发明。
发明内容
技术课题
本发明的目的是提供一种抗炎用组合物,该抗炎用组合物不诱发皮肤的副作用,有效地抑制皮肤炎症,同时具有优异的皮肤细胞再生效果。
用于解决课题的手段
本发明提供包含由下述化学式1表示的化合物作为有效成分的抗炎用组合物。
[化学式1]
[化学式1中,
R1各自独立地为氢、直链的(C1~C30)烷基、(C2-C30)烯基、(C2-C30)炔基、(C1~C30)烷氧基或羟基(C1~C30)烷基;
R2为或被取代或未被取代的氨基酸基,上述R11为羟基(C1~C30)烷基。]
根据本发明的一实施方式的抗炎用组合物包含作为有效成分的上述化合物,通过细胞因子的调节和炎症介质分子的表达抑制,能够调节刺激和炎症。详细地,根据本发明的抗炎用组合物尤其对IL-8(interleukin-8,白介素-8)、IL-17(interleukin-17,白介素-17)等促炎症细胞因子的抑制能力优异。
即,根据本发明的一方式的抗炎用组合物通过使巨噬细胞或中性粒细胞之类的抑制炎症细胞的活性的调解T细胞(Treg)的分布增加,有效地抑制炎症表达,从而能够显示出优异的抗炎效果。
本发明包含由上述化学式1表示的化合物作为有效成分而能够制成药物组合物或化妆品组合物,上述组合物对于炎症性皮肤疾病、特别是特应性皮炎和/或过敏性皮炎的改善效果优异。
发明效果
根据本发明,通过抑制细胞因子的调节,从而有效地防止炎症反应,能够显示出对于炎症性皮肤疾病,特别是特应性皮炎或过敏性皮炎等的优异的抗炎效果。
另外,包含根据本发明的有效成分的抗炎用组合物没有细胞毒性和皮肤副作用,从而能够安全地用作多种剂型的化妆品和药物组合物。
附图说明
图1是与一般皮肤模型(control,对照组)相比而确认了在诱发了特应性皮炎的皮肤模型(AD)中IL-8和IL-17A增加,且用根据本发明的抗炎用组合物对诱发了特应性皮炎的皮肤模型进行处理时通过免疫组织化学确认了与一般皮肤模型类似地IL-8、IL-17A表达减少的结果。
图2图示了将图1中得到的免疫组织化学结果定量化的图表。
具体实施方式
下面,对根据本发明的抗炎用组合物进行详述,但是此时使用的技术用语和科学用语如果没有其他定义,则具有该发明所属技术领域中的具有常规知识的技术人员通常理解的意思,在下述的说明中,对于可能会不必要地混淆本发明的主旨的公知功能和构成的说明将省略。
本发明中使用的用语“炎症”是指细胞或组织由于某种原因而受到损伤时,出于使该反应最小化并使损伤的部位恢复成原样的一系列的防御目的而出现的现象,引起神经、血管、***、体液反应、细胞反应,最终引起疼痛、浮肿、发红、发热等,诱发功能障碍。由上述炎症引起的炎症性皮肤疾病可以是选自特应性皮炎、牛皮癣、接触性皮炎、湿疹性皮炎、光敏性皮炎、脂溢性皮炎、疱疹性皮炎、扁平苔藓、硬化性苔藓、坏疽性脓皮病、天疱疮、大疱性表皮松懈症、***性硬化症、皮肌炎、多发性肌炎、炎症性肌病、麻风病、塞扎里氏综合征中的1种以上,荨麻疹(urticaria)、昆虫过敏、食品过敏和药物过敏等过敏性皮炎也属于同一范畴。
在本发明中使用的用语“IL-8”和“IL-17”是促炎症细胞因子的一个例子中的一种,通过炎症反应而表达持续地增加,对其进行抑制对于缓和炎症是非常重要的。此时,在本发明中,上述IL-17可以选自IL-17A、IL-17B、IL-17C、IL-17D、IL-17E和IL-17F等,特别是,其中,根据本发明的抗炎用组合物不仅能够增加T细胞的分布,而且对于IL-17A的抑制能力优异,因此本发明中使用的用语“IL-17”优选IL-17A。
在本发明中使用的用语“涂布”是表示用任意的适当的方法使本发明涉及的组合物与个体的皮肤接触,其目的是通过该涂布使该组合物吸收到皮肤内部。
本发明中使用的用语“改善”是指由于本发明涉及的组合物的涂布而炎症状态好转或变得有利的所有行为。
本申请人对作为炎症性皮肤疾病相关介质因子的促炎症细胞因子的活性抑制程度进行深入研究的结果,确认了由下述化学式1表示的化合物能够有效地抑制作为促炎症细胞因子的白细胞介素-8和白细胞介素-17A的产生。
即,根据本发明,通过抑制炎症性皮肤疾病相关介质因子的产生,从而能够实现优异的抗炎效果。
[化学式1]
[化学式1中,
R1各自独立地为氢、直链的(C1~C30)烷基、(C2-C30)烯基、(C2-C30)炔基、(C1~C30)烷氧基或羟基(C1~C30)烷基;
R2为或被取代或未被取代的氨基酸基,上述R11为羟基(C1~C30)烷基。]
本发明中记载的“烷基”、“烷氧基”以及除此以外的包含“烷基”部分的取代基优选为直链形态。另外,根据本发明的烷基、烷氧基和羟基烷基优选直链形态的具有1至7个碳原子数的基团或在上述碳原子数的基础上具有直链形态的基团,但具有8至30个碳原子数的基团当然也是本发明的一个方式。
另外,本发明中记载的“烯基”优选为包含一个以上的双键的直链形态的烃基,作为例子,可举出乙烯基、丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基、丙-2-烯-2-基、丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基等,但不限定于此。本发明中记载的“炔基”优选为包含一个以上的三键的直链形态的烃基,作为例子,可举出乙炔基、丙-1-炔-1-基、丙-2-炔-1-基、丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等,但不限定于此。
另外,根据本发明的一个方式的组合物含有上述化合物作为有效成分,从而能够促进皮肤脂质生物合成。详细而言,根据本发明,在促进皮肤角质形成细胞的分化、恢复皮肤屏障功能、消除皮肤的紧绷、粗糙方面显示出效果。
即,根据本发明的一个方式的组合物优选用作抗炎用组合物,但也可以作为皮肤保湿用、皮肤角质形成细胞分化促进用和/或皮肤屏障功能恢复用组合物而有用地应用。
根据本发明的一个方式的上述化合物是非常稳定的物质,从剂型开发容易,特别是对特应性皮炎或过敏性皮炎等显示出有效的抗炎效果的方面出发,优选地,R1可以为具有直链形态的(C1~C20)烷基、(C1~C20)烷氧基或羟基(C1~C20)烷基。
另外,根据本发明的一个方式的抗炎用组合物中,上述化合物从溶解度和与溶剂的相溶性优异的方面出发,更优选地,R1为乙基、正丙基、正丁基或正戊基,R2选自下述结构,但并不限定于此。
[上述结构中,
R21和R22各自独立地为氢或(C1~C7)烷基。]
在根据本发明的一个方式的抗炎用组合物中,优选上述化合物的R21和R22各自独立地选自甲基、乙基和丙基,但并不限定于此。
另外,本申请中,可以将包含由上述化学式1表示的化合物作为有效成分的抗炎用组合物制成化妆品组合物、药物组合物等,可以根据细胞因子的活性抑制、皮肤安全性、剂型化时的容易性等条件而适当地调节含量范围。上述化妆品组合物和/或药物组合物中,上述有效成分的含量范围没有限制,相对于组合物总重量,可以包含0.001至50重量%,优选地,可以包含0.01至30.0重量%,更优先地,可以包含0.01至20.0重量%。
下面,对根据本发明一个方式的抗炎用化妆品组合物具体地进行说明。
根据本发明的化妆品组合物可以包含通常使用的适当的添加剂而制造。此时,作为上述添加剂的例子,可以是选自水性添加剂和油性添加剂中的一种以上,上述水性添加剂是选自纯化水、稳定剂、乳化剂、增稠剂、保湿剂、液晶膜强化剂、pH调节剂、抗菌剂、水溶性高分子、被膜剂、多价螯合剂、氨基酸、有机胺、高分子乳液、pH调整剂、皮肤营养剂、抗氧化剂、抗氧化助剂、防腐剂、香料等中的一种以上,上述油性添加剂是选自油脂类、蜡类、烃油、高级脂肪酸油、高级醇、合成酯油和硅油等中的一种以上。
根据本发明的一个方式的上述水性添加剂只要是本领域中通常使用的原料就没有限制,作为具体的例子,可以是选自甘油、二丙二醇、丁二醇、戊二醇、甲基丙二醇、山梨糖醇、双甘油、赤藓糖醇、季戊四醇、聚丁二醇-10、聚甘油-3、聚甘油-4、聚甘油-6、聚甘油-10、聚甘油-20、聚甘油-40、山梨醇聚醚(Sorbeth)-5、山梨醇聚醚-6、山梨醇聚醚-20、山梨醇聚醚-30、山梨醇聚醚-40、肌醇、麦芽糖醇、麦芽糖、甘露聚糖、甘露糖醇、甘露糖、乳糖醇、乳糖、二羟基丙基PG-葡糖苷、二硫杂辛二醇、果糖、葡糖胺、甲基葡糖胺、葡萄糖、1,2,6-己三醇、甲基葡糖醇聚醚-10、甲基葡糖醇聚醚-20、臭氧化甘油、植三醇、硫甘油、苏糖醇、三羟甲基丙烷、木糖醇、乙二胺四乙酸(EDTA)、瓜尔胶、榅桲籽(quince seeds)、卡拉胶、半乳聚糖、***树胶、果胶、甘露聚糖、淀粉、黄原胶、可得然胶、甲基纤维素、羟乙基纤维素、羧甲基纤维素、甲基羟丙基纤维素、硫酸软骨素、硫酸皮肤素、糖原、硫酸乙酰肝素、透明质酸、透明质酸钠、黄蓍胶、硫酸角质素、软骨素、硫酸粘多糖、羟基乙基瓜尔胶、羧基甲基瓜尔胶、葡聚糖、硫酸角质、槐豆胶、琥珀酰聚糖、卡洛宁酸几丁质、脱乙酰几丁质、羧甲基几丁质、琼脂、聚乙烯醇、聚乙烯吡咯烷酮、羧基乙烯基聚合物、聚丙烯酸钠、聚乙二醇、膨润土、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯氧基乙醇、1,2-己二醇、乙基己基甘油等中的1种以上。另外,上述油性添加剂只要是本领域中通常使用的原料就没有限制,可以例示选自橄榄油、山茶油、霍霍巴油、甘油三酯、三辛酸甘油酯、三异棕榈酸甘油酯等液态油脂和椰子油、氢化椰子油、棕榈油、氢化油、氢化蓖麻油等固体油脂、蜜蜡、小烛树蜡、巴西棕榈蜡、羊毛脂、霍霍巴蜡等。作为烃油,可以例示液体石蜡、角鲨烯、凡士林、微晶蜡等。作为高级脂肪酸,可以例示月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、山萮酸等蜡类、鲸蜡醇、硬脂醇、山萮醇、肉豆蔻醇、鲸蜡硬脂醇等,作为合成酯油,可以选自肉豆蔻酸异丙酯、辛酸十六烷基酯、肉豆蔻酸辛基十二烷基酯、棕榈酸异丙酯、月桂酸己酯、肉豆蔻酸肉豆蔻酯、乳酸十六烷基酯、异硬脂酸异十六烷基酯、新戊二醇二癸酸酯、乙基己基甘油、己酸十六烷基乙酯、棕榈酸乙基己酯、鲸蜡硬脂醇等高级醇、二甲基聚硅氧烷、甲基苯基聚硅氧烷、甲基氢聚硅氧烷等链状硅油、十二甲基环六硅氧烷、八甲基环四硅氧烷、十甲基环戊硅氧烷等环状硅油等中的1种以上,但不限定于此。
根据本发明的一个方式的化妆品组合物除了本发明中特别公开的制造方法以外,当然也可以利用通常已知的制造方法,制造成普通的乳化剂型和增溶制剂等形态。此时,上述化妆品组合物可以根据需要适当选择,作为具体的例子,可以制成选自柔肤化妆水、收敛化妆水、营养化妆水、眼霜、营养霜、按摩膏、洁肤霜、洁肤泡沫、洁肤水、粉、精华、面膜等中的剂型,但不限于此。
下面,对根据本发明的一个方式的抗炎用药物组合物具体地进行说明。
根据本发明的一个方式的上述抗炎用药物组合物可以通过本发明所属技术领域中具有通常的知识的技术人员能够容易地实施的方法而包含可药用的载体。上述抗炎用药物组合物中包含的可药用的载体是制剂时通常被利用的载体,可以是乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、***树胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油,但并不限定于此。本发明的抗老化用药物组合物除了上述成分以外,还可以进一步包含润滑剂、湿润剂、甜味剂、香味剂、乳化剂、悬浮剂或保存剂等。
根据本发明的一个方式的药物组合物除了本发明中特别公开的制造方法以外,当然还可以利用通常已知的制造方法来制造,根据需要,可以制成适当的形态。作为其具体例子,可举出乳液、软膏、凝胶、霜剂、贴剂、喷雾剂等形态,但并不限定于此。
根据本发明的一个方式的抗炎用组合物具有改善炎症性皮肤疾病的效果。特别是,特应性皮炎和/或过敏性皮炎改善效果优异。
下面,为了有助于本发明的理解,提示优选实施例。但是下述实施例仅是为了更容易地理解本发明而提供的,下述实施例仅是例示性的,不以任何方式限制本发明的范围。
(评价方法)
1.确认细胞毒性
利用在下述实施例中制造的抗炎用组合物,测定了针对人的成纤维细胞(ATCC2076)的细胞存活率。
使人的成纤维细胞(ATCC 2076)的浓度为5x104细胞/ml,并接种于含有10%的牛血清的IMDM(Iscove′s Modified Dulbecco′s Medium(伊思柯夫改良培养液),GIBCO)24孔培养板,接种后,24小时后替换成没有血清的培养基,然后以0.5、1、5或10ug/ml的浓度添加试验试料,在37℃、5%CO2培养箱中培养一天后,除去上清液,再次每次加入5%的PBS(phosphate buffered saline(磷酸盐缓冲溶液))200ul进行清洗,然后,将MTT溶液每孔添加1.0ml后,4小时后除去MTT,然后,将DMSO每孔添加1.0ml,在37℃孵育一夜后,在570nm测定吸光度,利用下述式1求出细胞存活率,示于下述表1。此时,阴性对照组采用了没有使用有效成分的实验组。
[式1]
细胞存活率(%)=(A570λ值/B570λ值)×100
A:实施例的在570nm的吸光度值
B:阴性对照组的在570nm的吸光度值
2.确认对人体皮肤的安全性
为了诱导皮肤刺激,使用0.1重量%的SLS(sodium lauryl sulfate(十二烷基硫酸钠))用作阳性对照组,制造将下述实施例中制造的各有效成分添加1、50、以及100ppm的剂型,以30名健康的成人为对象,使用它在上前臂部位进行按隔日共9次的24小时累积贴布,从而测定了根据本发明的抗炎用组合物是否对皮肤带来刺激。贴布方法利用了试斑器(Finn chanber,Epitest Ltd,芬兰),将上述制造的皮肤外用剂在试斑器中分别滴加15μl后,进行贴布。将每次皮肤上出现的反应程度利用下述式2进行评分来确认皮肤反应度,示于下述表2。此时,平均皮肤反应度小于3时,判定为安全的组合物。
[式2]
平均皮肤反应度=[{∑(反应指数(a)×出现反应的受试者数(b))}/(总受试者数×最高分数(4分))×100]÷检测次数
反应指数:没有肉眼可见的反应(0),略有红斑(1),严重的红斑(2),严重的红斑和浮肿(3),严重的红斑和浮肿及水泡(4)
3.测定抗炎效果
为了测定抗炎功效,对于作为促炎症细胞因子的IL-8、IL-17A,诱发特应性皮炎而测定了其表达量。
为了在由MatTek销售的3D培养组织(3D culture tissue,EpiDerm FullThickness 400)诱发特应性皮炎,使用含有Poly(I:C)、TNF-α、IL-4、IL-13的介质(media),将N-(2-羟基乙基)辛酰胺(N-(2-hydroxyethyl)octanamide)以最终浓度成为100μM的方式处理72小时。接着,将3D培养组织(3D culture tissue)固定在***(formalin)中,制成石腊块(paraffin block),评价了促炎症细胞因子子的表达程度,将其结果示于下述图1和2。
4.测定特应性皮炎改善效果
为了测定特应性皮炎改善效果,制造了下述实施例中制造的抗炎用组合物。此时,特应性皮炎改善效果是利用EASI(Eczema Area Severity Index(湿疹面积严重度指数))评分进行测定的。以30名小儿特应性皮炎患者为对象,按1天2次,处理4周后,测定了对特应性皮炎症状的效果。此时,阴性对照组采用了没有使用上述有效成分的实验组。
(实施例1)
步骤1.
将辛酸(1.9mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(2.8mmol)、1-羟基苯并***水合物(2.1mmol)在二氯甲烷中充分地搅拌。添加单乙醇胺(2.1mmol)后,缓慢地添加三乙胺(5.7mmol),搅拌5小时以上。在反应混合物中添加水,用二氯甲烷进行萃取。利用MgSO4干燥有机相,进行减压蒸馏。将未纯化产物用硅胶柱色谱(二氯甲烷:甲醇=45:1)进行纯化,得到了最终目标化合物N-(2-羟基乙基)辛酰胺(收率:84.0%)。
MS(ESI pos,ion)m/z 188.2(MH+),C10H21NO2,正确的质量计算值:187.16
1H-NMR(600MHz,CDCl3):5.92(s,1H),3.74-3.72(m,2H),3.44-3.42(m,2H),2.67(t,1H),2.21(t,2H),1.66-1.61(m,2H),1.32-1.27(m,8H),0.88(t,3H)
步骤2.
制造了包含上述步骤1中制造的N-(2-羟基乙基)辛酰胺1.0wt%(在H2O中)的抗炎用组合物。
用上述方法制造的抗炎用组合物在上述评价方法的浓度范围未显示细胞毒性(参照表1)。另外,确认了对人体皮肤的安全性的结果,平均皮肤反应度为0.74(使用0.1重量%时),可以确认对皮肤的安全性非常优异(参照表2)。
在下述图1中,AD是诱发了特应性皮炎的皮肤模型,以IL-8和IL-17A的表达量为基准评价了抗炎效果。
其结果,确认了随着对诱发了特应性皮炎的皮肤模型处理根据本发明的抗炎用组合物,能够实现与作为对照组(control)的一般皮肤模型类的数值的IL-8、IL-17A表达量,从而确认了对特应性皮炎显示出优异的效果。
另外,基于下述图1中获得的通过免疫组织化学而进行确认的结果,将各细胞因子抑制效果数值化,并示于下述图2。
其结果,确认了根据本发明的抗炎用组合物相对于诱发了特应性皮炎的模型,显示出48.6%以上的IL-8抑制能力,而且显示出57.5%以上的IL-17A抑制能力。
另外,测定特应性皮炎改善效果的结果,确认了显示出显著的数值减少。
(实施例2)
步骤1.
将己酰氯(1.5mmol)、L-丝氨酸甲酯盐酸盐(1.3mmol)在水1ml、乙醇5ml中充分搅拌。将温度降至0℃后,缓慢地添加三乙胺(1.5mmol),将温度缓慢地升至常温,搅拌10小时以上。使丙酮通过减压蒸馏而挥发后,用二氯甲烷进行萃取。利用MgSO4干燥有机相,进行减压蒸馏。将未纯化产物用硅胶柱色谱(二氯甲烷:甲醇=20:1)进行纯化,得到了最终目标化合物甲基己酰基L-丝氨酸酯(收率:72.5%).
MS(ESI pos,ion)m/z 218.1(MH+),C10H19NO4,正确的质量计算值:217.13
1H-NMR(600MHz,CDCl3):6.55-6.54(d,1H),4.69-4.67(m,1H),3.99-3.96(m,1H),3.91-3.89(m,1H),3.79(s,3H),3.11(br s,1H),2.27(t,2H),1.64(Quint,2H),1.34-1.30(m,4H),0.90(t,3H)
步骤2.
制造了包含上述步骤1中制造的甲基己酰基L-丝氨酸酯1.0wt%(在H2O中)的抗炎用组合物。
[表1]
根据上述表1所示,即使处理至250uM浓度,与没有使用有效成分的实验组(阴性对照组)相比时,没有显示出具有显著性的细胞毒性效果。
[表2]
如上述表2所示,即使处理至0.1重量%浓度,也没有观察到具有显著性的皮肤刺激,相比于经SLS处理的阳性对照组,可以判定为稳定性非常优异的组合物。
由此,根据本发明的抗炎用组合物对炎症性皮肤疾病相关介质因子的表达抑制活性优异,期待用于多种形式的炎症性皮肤疾病。
以上,详细说明了本发明的特定部分,对于本领域技术人员而言,这样的具体的技术只是具体实施方式,本发明的范围不限于此是显而易见的。因此,本发明的实质性的范围通过权利要求书及其等价物来定义。
Claims (9)
1.一种抗炎用组合物,其中,包含由下述化学式1表示的化合物作为有效成分,
化学式1
在化学式1中,
R1各自独立地为氢、直链的(C1~C30)烷基、(C2-C30)烯基、(C2-C30)炔基、(C1~C30)烷氧基或羟基(C1~C30)烷基;
R2为或被取代或未被取代的氨基酸基,所述R11为羟基(C1~C30)烷基。
2.根据权利要求1所述的抗炎用组合物,其中,所述化合物的R1为甲基、乙基、正丙基、正丁基或正戊基。
3.根据权利要求2所述的抗炎用组合物,其中,所述R2选自下述结构,
在上述结构中,
R21和R22各自独立地为氢或(C1~C7)烷基。
4.根据权利要求1所述的抗炎用组合物,其中,相对于组合物总重量,包含0.001至50重量%的所述化合物。
5.根据权利要求1所述的抗炎用组合物,其中,所述抗炎用组合物为药物组合物或化妆品组合物。
6.根据权利要求5所述的抗炎用组合物,其中,所述化妆品组合物被制成柔肤化妆水、收敛化妆水、营养化妆水、眼霜、营养霜、按摩膏、洁肤霜、洁肤泡沫、洁肤水、粉、精华或面膜。
7.根据权利要求5所述的抗炎用组合物,其中,所述药物组合物被制成乳液、软膏、凝胶、霜剂、贴剂或喷雾剂。
8.根据权利要求5所述的抗炎用组合物,其中,所述药物组合物具有炎症性皮肤疾病改善效果。
9.根据权利要求8所述的抗炎用组合物,其中,所述炎症性皮肤疾病为特应性皮炎、牛皮癣、接触性皮炎、湿疹性皮炎、光敏性皮炎、脂溢性皮炎、疱疹性皮炎、扁平苔藓、硬化性苔藓、坏疽性脓皮病、天疱疮、大疱性表皮松懈症、***性硬化症、皮肌炎、多发性肌炎、炎症性肌病、麻风病或塞扎里氏综合征。
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US20190247344A1 (en) | 2019-08-15 |
US11351131B2 (en) | 2022-06-07 |
WO2018074728A1 (ko) | 2018-04-26 |
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