CN110709075A - 用于预防或治疗瘙痒的组合物 - Google Patents
用于预防或治疗瘙痒的组合物 Download PDFInfo
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- CN110709075A CN110709075A CN201780088472.9A CN201780088472A CN110709075A CN 110709075 A CN110709075 A CN 110709075A CN 201780088472 A CN201780088472 A CN 201780088472A CN 110709075 A CN110709075 A CN 110709075A
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- pruritus
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- skin
- itching
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Abstract
本公开涉及通过使用天然衍生的成分预防、改善或治疗瘙痒的组合物。本公开的组合物可用于安全有效地改善或治疗由各种原因引起的瘙痒，而没有副作用的风险。
Description
技术领域
本公开涉及用于预防或治疗瘙痒的组合物，其含有天然成分。
背景技术
瘙痒症(瘙痒)被定义为引起想要抓挠皮肤的令人不快的感觉(Andersen HH等人，Human surrogate models of histaminergic and non-histaminergic itch，ActaDermato-Venereologica.95(7):7717.(2015))。虽然它是皮肤病和全身性疾病中常见的症状，但尚未充分了解其特征。
据估计，约有2.8亿人(占世界人口的4％)患有瘙痒症。这超过了患有牛皮癣的2％至3％的人口(Vos,T等人,Years lived with disability(YLDs)for 1160sequelae of289diseases and injuries 19902010:a systematic analysis for the Global Burdenof Disease Study 2010,Lancet.380(9859):216396.(2012))。
瘙痒可以由各种刺激引起或加重，各种刺激包括物理因素、机械因素和化学因素。炎症介质也会引起各种炎症性皮肤病中的瘙痒。然而，并不是所有类型的瘙痒都与介质有关，由机械刺激或电刺激和干性皮肤引起的瘙痒可能会在没有介质的情况下发生。
根据国家卫生信息门户网站(http://health.mw.go.kr)，组胺、血清素、前列腺素E、速激肽、细胞因子、蛋白酶、阿片肽、血小板活化因子等被称为引起瘙痒的介质。
组胺由皮肤中的肥大细胞合成，储存在肥大细胞颗粒中并响应各种刺激而分泌。皮肤中存在两种类型的组胺受体H1和H2。组胺与H1受体结合导致瘙痒。组胺与许多炎性皮肤病有关，包括UV引起的皮炎。
血小板中存在血清素。它通过激活真皮肥大细胞，从而释放组胺，或通过作用于中枢神经系统的5-HT3受体，而引起瘙痒。
前列腺素E本身不会引起瘙痒，但会加重其他介质引起的瘙痒。在瘙痒相关的皮肤病例如湿疹和UV引起的炎症中，前列腺素E增加。
P物质是速激肽神经肽家族的成员。它在伤害性感受器C纤维的背根神经节中合成，传递给无髓鞘的感觉神经纤维并充当神经递质。物质P通过充当有效的血管扩张药而引起过敏和瘙痒。物质P由肥大细胞的类胰蛋白酶释放，并直接地或通过NK-1受体从真皮肥大细胞释放组胺引起瘙痒。
细胞因子是在所有真核细胞中产生的小蛋白质。它们充当细胞表面受体，包括白细胞介素(IL)、趋化因子、干扰素等。虽然IL-1和IL-8不诱导瘙痒，但是当给癌症患者注射人重组IL-2用于治疗时，其引起伴有皮肤过敏和嗜酸性粒细胞增多的严重瘙痒。
在蛋白酶中，激肽释放酶在注入皮肤时引起瘙痒。除激肽释放酶外，其他蛋白酶如胰凝乳蛋白酶、胰蛋白酶、木瓜蛋白酶等也会引起瘙痒。
阿片样肽通过作用于中枢或外周神经系统而引起瘙痒。阿片样肽有三种亚型，μ、δ和κ。然而，其药理作用是通过μ-受体发挥的，因为其主要由纳洛酮抑制。当将吗啡注射到脊髓中时，在大多数患者中引起瘙痒，而当注射到真皮中时，不考虑前列腺素或组胺的释放，导致瘙痒和过敏。
血小板活化因子是由多种炎性细胞分泌的有效的炎症诱导物质。据报道，血小板活化因子在动物试验中直接引起瘙痒。在人体中，其通过诱导肥大细胞分泌组胺而间接引起瘙痒。
根据不同原因，瘙痒可分为：1)阵发性发作的阵发性瘙痒；2)皮肤瘙痒，包括冬季瘙痒、肛门瘙痒、外阴瘙痒、阴囊瘙痒、水因性瘙痒和头皮瘙痒；3)内科疾病伴随的瘙痒，内科疾病包括淤胆型瘙痒、慢性肾功能衰竭、恶性肿瘤、缺铁性贫血、真性红细胞增多症、甲状旁腺功能亢进、甲状旁腺功能减退、糖尿病和获得性免疫缺陷综合征；4)精神皮肤疾病伴随的瘙痒，精神皮肤疾病如慢性单纯性苔藓、痒疹、拔毛症、神经性瘙痒、皮肤行为病、妄想性寄生虫病等；和5)伴随感冒等的鼻瘙痒、颈痒、伴随眼部疾病如结膜炎等的眼部瘙痒、伴随牙病的口腔瘙痒等。
目前有多种治疗方法，包括抗组胺药、类固醇、抗生素、抗病毒药、抗真菌药、麻醉药、益生菌、免疫抑制剂、光疗法如UV等。但是，根据瘙痒的类型，治疗效果是暂时的或有限的。由于副作用和长期使用是不可取的，肾上腺皮质激素或皮质类固醇的使用仅限于急性或严重病例。因此，需要开发对各种原因引起的瘙痒的安全有效疗法。
以上描述仅用于帮助理解本公开的背景，不应被认为是相关领域的普通技术人员所公知的。
发明内容
技术问题
本公开的发明人已经努力寻找天然衍生的物质，其可以安全地用于由各种原因引起的瘙痒而没有副作用的风险。结果，他们已经确定一些基于异黄酮的化合物对由各种原因引起的瘙痒非常有效并且已经完成了本公开。
本公开涉及提供用于预防或治疗瘙痒的药物组合物。
本公开还涉及提供用于预防或改善瘙痒的食品组合物。
本公开还涉及提供用于预防或改善瘙痒的化妆品组合物。
根据以下详细描述、附图和权利要求，其他特征和方面将是显而易见的。
技术方案
在一方面，本公开提供一种用于预防或治疗瘙痒的药物组合物，其含有化学式1的化合物作为活性成分：
其中R为H或OH。
作为努力寻找可以安全地处置由各种原因引起的瘙痒的天然衍生物质的结果，本公开的发明人已经确定化学式1的化合物对由各种原因引起的瘙痒非常有效。
根据本公开的发明人进行的实验，本公开的化合物对由各种原因引起的瘙痒显示出显著的治疗效果，各种原因引起的瘙痒包括组胺诱导的瘙痒、氯喹诱导的瘙痒、DNCB(2,4-二硝基氯苯)诱导的瘙痒、SLIGRL(H-Ser-Leu-Ile-Gly-Arg-Leu-NH2)诱导的瘙痒、TSLP(胸腺基质淋巴细胞生成素)诱导的瘙痒症等。此外，仅在染料木黄酮和黄豆苷元中观察到对瘙痒的改善和治疗效果，而不是在所有基于异黄酮的化合物(染料木黄酮、黄豆苷元、黄豆黄素和雌马酚)中观察到(实施例6)。
染料木黄酮是本公开的活性成分之一，具有化学式2的结构。具有优异的抗氧化效果(Han，Rui-Min等人，Comparison of Flavonoids and Isoflavonoids asAntioxidants,Journal of Agricultural and Food Chemistry.57(9):37805.(2009))，其通常用作化妆品添加剂。然而，对其改善瘙痒的效果却一无所知。
黄豆苷元，本公开的另一种活性成分，具有化学式3的结构。已知其激活PPAR(DangZ.C.等人,The Balance between Concurrent Activation of ERs and PPARsDetermines Daidzein-Induced Osteogenesis and Adipogenesis,Journal of Bone andMineral Research.19(5):853861.(2004))和在高浓度给药时降低患乳腺癌的风险(deLemos,M.L.,Effects of soy phytoestrogens genistein and daidzein on breastcancer growth,Annals of Pharmacotherapy.35(9):11118-11121(2001))。然而，关于黄豆苷元改善瘙痒症的效果一无所知。
在本公开中，术语“瘙痒症”或“瘙痒”没有特别限制，但被解释为包括阵发性瘙痒、冬季瘙痒、肛门瘙痒、外阴瘙痒、阴囊瘙痒、水因性瘙痒、头皮瘙痒、鼻瘙痒、颈痒、口腔瘙痒、眼部瘙痒、内科疾病伴随的瘙痒，内科疾病例如淤胆型瘙痒、慢性肾功能衰竭、恶性肿瘤、缺铁性贫血、真性红细胞增多症、甲状旁腺功能亢进、甲状旁腺功能减退、糖尿病和获得性免疫缺陷综合征等，和精神皮肤疾病伴随的瘙痒，精神皮肤疾病例如慢性单纯性苔藓、痒疹、拔毛症、神经性瘙痒、皮肤行为病、妄想性寄生虫病等。
阵发性瘙痒是阵发性发作的瘙痒，常见于慢性单纯性苔藓、皮炎等。
冬季瘙痒发生在约50％的70岁或70岁以上人群中，应与如疥疮、扁平苔藓等的瘙痒性皮肤病或全身性疾病引起的瘙痒有所区别。在女性人群中，它可能作为绝经后综合征的症状出现。水分含量下降和老化皮肤皮脂分泌逐渐下降是皮肤干燥的主要原因，并且上肢和胫骨常见细小裂纹和鳞屑。
肛门瘙痒是肛门周围的令人不快的刺激，导致抓挠的欲望，经常涉及心理因素。无论年龄大小，都可能发生，但在老年人群中更常发生。然而，并非所有的瘙痒症都是心因性的，肛门周围的污染和刺激可能是原因。结肠直肠疾病如裂隙、痔疮、瘘管和慢性腹泻、辛辣食物、药物等可能加重刺激。各种传染病如葡萄球菌、链球菌、真菌、念珠菌、单纯疱疹病毒等可引起这种瘙痒症。其中，念珠菌感染是最常见的原因，并且观察到皮肤的裂纹和肿胀。肛门周围的皮肤病如牛皮癣、脂溢性皮炎、扁平苔藓等也可能引起严重的瘙痒，在其他区域也可发现病变。以剧烈瘙痒导致反复揉搓直至出血为特征的肛门神经性皮炎，可能表现出与其他部位的慢性单纯性苔藓相似的症状。
外阴瘙痒最常见的原因是念珠菌感染。其他原因包括滴虫性阴道炎和由护垫、避孕药、阴道清洗液、避孕套等引起的接触性皮炎。在老年人中，硬化性苔藓是常见的原因。严重的瘙痒也可能发生在大汗腺性痒疹(Fox-Fordyce)疾病中。然而，临时外阴瘙痒也可能由怀孕期间的摩擦、出汗或外阴充血引起。
关于阴囊瘙痒，成人的阴囊对真菌感染具有免疫力，就像成人头皮一样，但是是慢性单纯性苔藓经常发生的部位。它主要是由心理因素引起的。尽管进行了强化治疗，但苔藓样变仍严重发生，症状通常持续数年。
水因性瘙痒的特征是严重的、令人不愉快的、针刺样的瘙痒，在与水接触后几分钟内发生，持续约1小时。其与水的温度无关，并且在皮肤中没有观察到明显的变化。对于一些患者，可能是由环境温度的变化引起的。约1/3的患者有家族史。症状通常是慢性的，对治疗无反应。尽管在皮肤和血液中观察到组胺水平增加，但由于抗组胺药没有缓解症状，因此并不认为组胺是唯一的介质。由于症状相似，因此需要与真性红细胞增多症区分。
头皮瘙痒可能作为一种独立症状出现，头皮上没有明显的病变。它在中年人或老年人中发现，但其原因尚不清楚。瘙痒非常严重，并且是阵发性发作。疲劳或压力使情况进一步恶化。它需要区别于疱疹样皮炎、慢性单纯性苔癣、脂溢性皮炎、牛皮癣等。
胆汁性肝硬化伴有严重的全身性瘙痒。瘙痒与血浆中胆汁酸水平升高有关。严重的瘙痒可能是通过直接应用一定浓度的胆汁酸诱导的，该浓度临床上可导致起泡的皮肤病变瘙痒。
在接受血液透析治疗的慢性肾功能衰竭患者中约有20％至50％发生瘙痒。瘙痒发生在局部或全身。在大多数情况下，血液透析期间症状加重。但是，症状可能会暂时缓解。据报道，组胺、尿素和肌酐的血液水平与瘙痒程度之间没有直接关系。一些患者患有干皮病，但大多数患者的皮肤正常，使用保湿剂不能缓解或减轻症状。
关于恶性肿瘤，如果在没有明确原因的中年或老年人中发生全身性瘙痒，则需要对恶性肿瘤进行广泛诊断。在15％至25％的患有霍奇金病患者(一种导致淋巴结肿大的代表性疾病)中，瘙痒持续发生。其通常伴有灼痛和潮红，其原因尚不清楚。全身性瘙痒也可能发生在白血病中。
缺铁也可能是瘙痒的原因。据报道，当口服补铁剂后，真性红细胞增多症患者和缺铁患者的瘙痒减少。
约50％的真性红细胞增多症患者在接触水后几分钟内出现严重瘙痒，且症状持续约15分钟至60分钟。由于其通常在洗澡后发生，其被称为浴痒。皮肤没有明显的变化，并且无论水温如何，症状都会出现。然而，发现血清和尿液中组胺水平升高。认为血小板聚集导致包括组胺在内的几种瘙痒介质的释放。
甲状旁腺功能亢进可能发生严重的全身性瘙痒。血流量增加引起的皮肤温度升高和由此导致的瘙痒阈值降低是全身性瘙痒的原因。甲状旁腺功能减退相关的和黏液水肿相关的全身性瘙痒可能与皮肤的严重干燥有关。在这两种疾病中，由于皮肤黏膜念珠菌病，瘙痒可能发生在生殖器周围。
在一些糖尿病患者中，由于皮肤黏膜念珠菌病，肛门和生殖器周围可能发生瘙痒。然而，在一些患者中也可能发生全身性瘙痒。
获得性免疫缺陷综合征的重要症状之一是瘙痒。获得性免疫缺陷综合征患者瘙痒的原因包括疥疮、虱病、念珠菌病、脂溢性皮炎、肾功能衰竭、胆汁淤积等。通常，发生全身性丘疹或色素性皮疹，引起典型地严重的瘙痒。
慢性单纯性苔癣是一种以反复摩擦或抓挠皮肤为特征的疾病，导致皮肤变厚、坚韧。由于反复瘙痒，慢性单纯性苔癣可能在正常皮肤中继发。其在30岁至50岁更常见，女性与男性相比更常见。
痒疹是一种以多发性结节和严重瘙痒为特征的疾病。其不能很好地被治愈，并且往往会持续很长时间。其原因尚不清楚，贫血、肝病、艾滋病、妊娠、肾功能衰竭、精神紧张等可能是原因。
拔毛症是一种冲动控制障碍，其特征在于导致拔出毛发的异常冲动。精神压力和社会压力是原因。家庭或学校的压力、兄弟姐妹的竞争、搬家、父母住院、母女关系等可能是原因。其几乎发生在从儿童到成人的所有年龄组。
神经性瘙痒是一种疾病，其特征在于反复挖扣自己的皮肤的冲动，经常导致皮肤病变。患者承认他们的行为是造成病变的原因，但无法抗拒。它可以发生在任何年龄，但在中年妇女中更常发生。它经常由于精神压力而发生。其经常发生在皮肤病变区域，如瘙痒、昆虫叮咬等。神经性瘙痒也与抑郁、强迫症和焦虑有关。这种症状在具有强迫性、顽固性、监督性和完美主义倾向以及对失败恐惧的人中更频繁发生。
人为皮炎是一种由为了引起同情或逃避责任而故意造成自身皮肤损伤引起的皮炎。皮肤损伤是通过机械或化学、腐蚀等方式产生的。另外，也使用钉子、锋利器具、热金属等。患者为了满足心理需求而伤害自己。这在女性中更常发生，并且可以发生在所有年龄组中。大多数患者是幼稚和具有依赖性的，具有冲动控制障碍。
皮肤行为病是一种长期重复的强迫性自我伤害行为。自我伤害行为往往是一种自杀行为，在青春期，可能进行这种尝试来炫耀勇敢。
妄想性寄生虫病是一种妄想症，患者错误地认为他们感染了寄生虫。它是一种慢性、单一症状的疑病症，不会损害人格或思维能力。患者提供皮肤、棉绒、薄纸、胶带等，并要求进行寄生虫检查。据报道，2％至3％的患者之前曾经历过寄生虫感染。
其他可能包括伴有鼻部疾病例如鼻炎的鼻瘙痒、伴有眼部疾病例如结膜炎的眼部瘙痒和伴有牙齿疾病的口腔瘙痒。
用于本公开的组合物中的活性成分不仅包括化学式1的化合物本身，还包括其药学上可接受的盐、水合物、溶剂合物或前药。
术语“药学上可接受的盐”是指发挥所需的药理学作用即改善瘙痒的活性的化学式1的化合物的盐。该盐可以通过使用无机酸(例如盐酸盐、氢溴酸盐和氢碘酸盐)或有机酸(例如乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、硫酸氢盐、氨基磺酸盐、硫酸盐、氨基磺酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、双葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚酸盐(glucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、2-羟基乙烷硫酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、甲苯磺酸盐和十一酸盐)。
术语“药学上可接受的水合物”是指发挥所需的药理学作用的化学式1的化合物的水合物。术语“药学上可接受的溶剂合物”是指发挥所需的药理学作用的化学式1的化合物的溶剂合物。水合物和溶剂合物也可以通过使用上述酸来制备。
术语“药学上可接受的前药”是指化学式1的化合物的衍生物，其必须进行生物转化才能显示化学式1的化合物的药理学作用。制备前药以改善化学稳定性、患者顺应性、生物利用度或器官选择性、改善制备的便利性、延长作用持续时间或减少副作用。根据本领域常用的方法(例如，Burger's Medicinal Chemistry and Drug Chemistry,第5版,1:172-178和949-982(1995))，可以从化学式1的化合物容易地制备本公开的前药。
包含在本公开的药物组合物中的药学上可接受的载剂可以是本领域常用的载剂，可以包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯树胶、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、矿物油等，但不限于此。除了这些成分之外，本公开的药物组合物还可以含有润滑剂、润湿剂、甜味剂、香料、乳化剂、悬浮剂、防腐剂等。合适的药学上可接受的载剂和制剂在《雷氏药学大全》(Remington's Pharmaceutical Sciences)(第19版，1995)中有详细描述。
本公开的药物组合物可以经口或胃肠外给药。可以通过经鼻、经眼、静脉、皮下、肌内、腹膜内、透皮等方式进行肠胃外给药。
本公开的药物组合物的适当给药剂量可以根据诸如制剂方法、给药方法、患者年龄、体重和性别、病理状况、饮食、给药时间、给药途径、排泄率和反应性等因素而变化。普通熟练的医生可以容易地确定和开出对所需治疗或预防有效的给药剂量。在本公开的具体示例性实施方案中，本公开的药物组合物的每日施用剂量为0.001mg/kg至100mg/kg。
根据本公开所属的本领域普通技术人员可以容易实施的方法，通过使用药学上可接受的载剂和/或赋形剂，可以将本公开的药物组合物配制成单位剂型形式或多剂量容器。制剂可以是油性或水性介质的溶液、悬浮剂、乳剂、提取物、散剂、颗粒剂、片剂或胶囊剂形式，还可以含有分散剂或稳定剂。
本公开的药物组合物还可以制备成用于皮肤外用的制剂、气雾剂、喷雾剂、滴眼剂、口服药物或注射剂。
另一方面，本公开提供用于预防或改善瘙痒的食品组合物，其含有化学式1的化合物作为活性成分：
其中R为H或OH。
当将本公开的组合物制备成食品组合物时，除了作为活性成分的化学式1的化合物之外，其还可以包含在食品制备期间通常添加的成分，例如蛋白质、碳水化合物、脂肪、营养素、调味剂或芳香剂。碳水化合物的实例是常见的糖，例如单糖如葡萄糖、果糖等，二糖如麦芽糖、蔗糖、低聚糖等，多糖如糊精、环糊精等，和糖醇如木糖醇、山梨糖醇、赤藓糖醇等。作为芳香剂，可以使用天然香料(奇异果甜蛋白、甜叶菊提取物(例如莱鲍迪苷A、甘草皂苷等)等)或合成香料(糖精，阿斯巴甜等)。
例如，当本公开的组合物制备成饮品时，除化学式1的化合物外，还可以含有柠檬酸、果糖糖浆、蔗糖、葡萄糖、乙酸、苹果酸、果汁、杜仲提取物、枣提取物、甘草提取物等。
本公开的组合物在改善瘙痒方面发挥非常优越的作用。此外，本公开的组合物对人体非常安全，因为它使用具有已证实的生物安全性的基于异黄酮的化合物作为活性成分。
另一方面，本公开提供用于预防或改善瘙痒的化妆品组合物，其含有化学式1的化合物作为活性成分：
其中R为H或OH。
当将本公开的组合物制备成化妆品组合物时，除了化学式1的化合物之外，本公开的组合物还可以包含通常用于化妆品组合物的成分，例如常用的佐剂，如抗氧化剂、稳定剂、增溶剂、维生素、色素和香料和载剂。此外，除了化学式1的化合物之外，本公开的组合物还可以包含迄今为止在不对活性成分的(瘙痒改善)效果产生负面影响的范围内使用的瘙痒改善剂。
作为载剂，可以使用纯净水、一元醇(乙醇或丙醇)、多元醇(甘油、1,3-丁二醇或丙二醇)、高级脂肪酸(棕榈酸或亚油酸)、油或脂(小麦胚芽油、山茶油、霍霍巴油、橄榄油、角鲨烯、葵花籽油、澳洲坚果油、鳄梨油、氢化大豆卵磷脂或脂肪酸甘油酯)等，但不限于此。如果需要，还可以添加表面活性剂、灭菌剂、抗氧化剂、UV吸收剂、抗炎剂或冷却剂。
表面活性剂可选自聚氧乙烯、氢化蓖麻油、聚氧乙烯油基醚、聚氧乙烯单油酸酯、聚氧乙烯单硬脂酸甘油酯、脱水山梨糖醇单硬脂酸酯、脱水山梨糖醇、蔗糖脂肪酸酯、单月桂酸六甘油酯、聚氧乙烯还原羊毛脂、POE、焦谷氨酸甘油酯、异硬脂酸、二酯、N-乙酰谷氨酰胺和异硬脂基酯。
灭菌剂可选自桧木醇、三氯生、葡萄糖酸氯己定、苯氧乙醇、间苯二酚、异丙基甲基苯酚、薁、水杨酸和吡啶硫酮锌。
作为抗氧化剂，可以使用任何叔丁基-4-羟基茴香醚、没食子酸、没食子酸丙酯和异抗坏血酸。
作为UV吸收剂，可以使用任何二苯甲酮如二羟基二苯甲酮等、黑色素、对氨基苯甲酸乙酯、对二甲氨基苯甲酸2-乙基己酯、西诺沙酯、对甲氧基肉桂酸2-乙基己酯、2-(2-羟基-5-甲基苯基)苯并三唑、尿刊酸和细金属氧化物颗粒。
作为抗炎剂，可以使用甘草次酸二钾或尿囊素。并且，作为冷却剂，可以使用辣椒酊或1-薄荷醇。
该组合物可以制备成任何制剂，其中化学式1的化合物可以作为活性成分混合。用于改善瘙痒的化妆品制剂的实例包括护肤液、洗发水、护发素、润发精、发胶、粉末、凝胶、霜剂、精华液、化妆水、溶胶-凝胶、乳液、油、蜡、喷雾、雾等，但不限于此。另外，它可以制备成含有化学式1的化合物的面膜。
有益效果
本公开的特征和优点可以总结如下：
(i)本公开提供了通过使用天然衍生的成分来预防、改善或治疗瘙痒的组合物。
(ii)本公开的组合物可用于安全有效地改善或治疗由各种原因引起的瘙痒，而没有副作用的风险。
附图说明
图1比较了通过用组胺处理诱导瘙痒后，在1μM和10μM浓度下染料木黄酮、黄豆苷元、黄豆黄素和雌马酚的瘙痒减轻效果(与组胺处理组相比p<0.01)。
图2比较了通过用氯喹处理诱导瘙痒后，在1μM和10μM浓度下染料木黄酮、黄豆苷元、黄豆黄素和雌马酚的瘙痒减轻效果(与氯喹处理组相比p<0.01)。
图3比较了通过用DNCB处理诱导瘙痒后，在1μM和10μM浓度下染料木黄酮、黄豆苷元、黄豆黄素和雌马酚的瘙痒减轻效果(与DNCB处理组相比p<0.01)。
图4比较了通过用SLIGRL处理诱导瘙痒后，在1μM和10μM浓度下染料木黄酮、黄豆苷元、黄豆黄素和雌马酚的瘙痒减轻效果(与SLIGRL处理组相比p<0.05)。
图5比较了通过用TSLP处理诱导瘙痒后，在1μM和10μM浓度下染料木黄酮、黄豆苷元、黄豆黄素和雌马酚的瘙痒减轻效果(与TSLP处理组相比p<0.05)。
本发明最佳实施方式
在下文中，将通过实施例详细描述本公开。然而，以下实施例仅用于说明目的，并且对于本领域普通技术人员显而易见的是，本公开的范围不受实施例的限制。
实施例
<实施例1>试验动物
6周龄的无特定病原体的雄性BALB/c小鼠购自Orient Bio Korea Inc.(Gapyeong，京畿道，韩国)，并饲养在层流柜中。自由采食标准固体食物。在测试开始时，小鼠为7-8周龄。所有动物护理和使用均按照韩国全北国立大学医学院(Chonbuk NationalUniversity Medical School)的机构动物护理和使用委员会(Institutional AnimalCare and Use Committee)的方案进行。
<实施例2>试剂的制备
基于异黄酮的化合物染料木黄酮、黄豆苷元、黄豆黄素和雌马酚购自Sigma。将它们溶解在DMSO中并用蒸馏水稀释。注意使DMSO的含量不超过0.1％。组胺、氯喹和DNCB也购自Sigma。
<实施例3>瘙痒的诱导
1.组胺诱导的瘙痒和氯喹诱导的瘙痒
通过向小鼠皮下注射组胺和氯喹诱导瘙痒。具体而言，分别注射0.1mL的2mg/mL组胺和4mg/mL氯喹。
2.DNCB(2,4-二硝基氯苯)诱导的瘙痒
用DNCB诱导瘙痒。具体地，在从小鼠右耳移除毛发后，将20μL的溶解在橄榄油和乙醇(1:4)的混合物中的1％DNCB用于致敏。7天后，在同一只耳朵上施加10μL的0.5％DNCB(Exp.Dermatol.,2002,11:285-291)。
3.SLIGRL(H-Ser-Leu-Ile-Gly-Arg-Leu-NH2)诱导的瘙痒
用SLIGRL诱导瘙痒。具体地，将20μg的SLIGRL溶解在0.1mL生理盐水中并皮下注射以诱导瘙痒。
4.TSLP(胸腺基质淋巴细胞生成素)诱导瘙痒
用TSLP诱导瘙痒。将0.67μg TSLP溶解在0.1mL生理盐水中并皮下注射以诱导瘙痒。
<实施例4>瘙痒的测量
根据Neuroscience，Inc.公司建立的方法，使用MicroAct(Neuroscience，Inc.，东京，日本)评估瘙痒。将小鼠麻醉并将磁片插入左后腿的足部皮肤中。将小鼠放入由线圈包围的腔室中，并且通过计算机基于抓挠产生的电场记录抓挠动作的次数。MicroAct的实验条件设定如下。阈值p-p限值，0.125V；阈值最小持续时间，0.2s；最大振幅范围，0.5V；最小振幅范围，0.05V；最大频率，20Hz；最小频率，5Hz。仅对连续3次或更多次抓挠动作进行记录。
<实施例5>统计分析
所有实验进行至少3次，每组使用2只至3只小鼠。统计数据用平均值和标准差表示。通过单向ANOVA和Fisher检验进行统计学比较。两组之间的显著差异由未配对的t检验确定。p值的显著水平小于0.05。
<实施例6>抑制瘙痒的效果
1.抑制组胺诱导的瘙痒的效果
为了测量染料木黄酮、黄豆苷元、黄豆黄素和雌马酚抑制组胺诱导的瘙痒的效果，将100μg组胺溶解在0.1mL生理盐水中并皮下注射以诱导瘙痒。与组胺一起，分别注射1μM和10μM的染料木黄酮、黄豆苷元、黄豆黄素和雌马酚后，统计1小时抓挠动作的次数。染料木黄酮和黄豆苷元在1μM和10μM的浓度下显著抑制组胺诱导的瘙痒(p<0.01)(图1)。然而，在该浓度下黄豆黄素和雌马酚不抑制组胺诱导的瘙痒(图1)。
2.抑制氯喹诱导的瘙痒的效果
为了测量染料木黄酮、黄豆苷元、黄豆黄素和雌马酚抑制氯喹诱导的瘙痒的效果，将200μg氯喹溶解在0.1mL生理盐水中并皮下注射以诱导瘙痒。与氯喹一起，分别注射1μM和10μM的染料木黄酮、黄豆苷元、黄豆黄素和雌马酚后，统计1小时抓挠动作的次数。染料木黄酮和黄豆苷元在1μM和10μM的浓度下显著抑制氯喹诱导的瘙痒(p<0.01)(图2)。然而，在该浓度下黄豆黄素和雌马酚不抑制氯喹诱导的瘙痒(图2)。
3.抑制DNCB诱导的瘙痒的效果
为了测量染料木黄酮、黄豆苷元、黄豆黄素和雌马酚抑制DNCB诱导的瘙痒的效果，将20μL的1％DNCB溶液施用于小鼠的右耳7天以致敏。7天后，在同一只耳朵上施加10μL的0.5％DNCB，将溶于生理盐水中的1％DNCB和1μM或10μM的染料木黄酮、黄豆苷元、黄豆黄素或雌马酚施用于右耳(生理盐水用于阴性对照组)，并统计1小时抓挠次数。染料木黄酮和黄豆苷元在1μM和10μM的浓度下显著抑制DNCB诱导的瘙痒(p<0.01)(图3)。然而，在该浓度下黄豆黄素和雌马酚不抑制DNCB诱导的瘙痒(图3)。
4.抑制SLIGRL诱导的瘙痒的效果
为了测量染料木黄酮、黄豆苷元、黄豆黄素和雌马酚抑制SLIGRL诱导的瘙痒的效果，其中SLIGRL为蛋白酶激活受体2的激动剂，将20μg SLIGRL溶解在0.1mL生理盐水中并皮下注射以诱导瘙痒。与SLIGRL一起，分别注射1μM和10μM的染料木黄酮、黄豆苷元、黄豆黄素和雌马酚后，统计1小时抓挠动作的次数。染料木黄酮和黄豆苷元在1μM和10μM的浓度下显著抑制SLIGRL诱导的瘙痒(p<0.05)(图4)。然而，在该浓度下黄豆黄素和雌马酚不抑制SLIGRL诱导的瘙痒(图4)。
5.抑制TSLP诱导的瘙痒的效果
为了测量染料木黄酮、黄豆苷元、黄豆黄素和雌马酚抑制胸腺基质淋巴细胞生成素(TSLP)诱导的瘙痒的效果，将0.67μg TSLP溶液溶解在0.1mL生理盐水中并皮下注射以诱导瘙痒。与TSLP一起，分别注射1μM和10μM的染料木黄酮、黄豆苷元、黄豆黄素和雌马酚后，统计1小时抓挠动作的次数。染料木黄酮和黄豆苷元在1μM和10μM的浓度下显著抑制TSLP诱导的瘙痒(p<0.05)(图5)。然而，在该浓度下黄豆黄素和雌马酚不抑制TSLP诱导的瘙痒(图5)。
虽然已经就具体实施方案描述了本公开，但是对于本领域技术人员显而易见的是，在不脱离所附权利要求及其等同物所限定的本公开的精神和范围的情况下，可以进行各种改变和修改。
Claims (9)
1.一种用于预防或治疗瘙痒的药物组合物，其包含化学式1的化合物作为活性成分：
其中R为H或OH。
2.根据权利要求1所述的组合物，其中所述瘙痒选自阵发性瘙痒、冬季瘙痒、肛门瘙痒、外阴瘙痒、阴囊瘙痒、水因性瘙痒、头皮瘙痒、鼻瘙痒、颈痒、口腔瘙痒和眼部瘙痒。
3.根据权利要求1所述的组合物，其中所述瘙痒是内科疾病伴随的瘙痒，所述内科疾病选自淤胆型瘙痒、慢性肾功能衰竭、恶性肿瘤、缺铁性贫血、真性红细胞增多症、甲状旁腺功能亢进、甲状旁腺功能减退、糖尿病和获得性免疫缺陷综合征。
4.根据权利要求1所述的组合物，其中所述瘙痒是精神皮肤疾病伴随的瘙痒，所述精神皮肤疾病选自慢性单纯性苔藓、痒疹、拔毛症、神经性瘙痒、皮肤行为病和妄想性寄生虫病。
5.根据权利要求1所述的组合物，其中所述组合物的形式选自用于皮肤外用的制剂、气雾剂、喷雾剂、滴眼剂、口服药物或注射剂。
6.一种用于预防或改善瘙痒的食品组合物，其包含化学式1的化合物作为活性成分：
其中R为H或OH。
7.一种用于预防或改善瘙痒的化妆品组合物，其包含化学式1的化合物作为活性成分：
其中R为H或OH。
8.根据权利要求7所述的组合物，其中所述化妆品组合物的形式为护肤液、洗发水、护发素、润发精、发胶、粉末、凝胶、霜剂、精华液、化妆水、溶胶-凝胶、乳液、油、蜡、喷雾或雾。
9.一种面膜，其包含权利要求7所述的化妆品组合物。
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| KR10-2017-0031831 | 2017-03-14 | ||
| KR1020170031831A KR101782966B1 (ko) | 2017-03-14 | 2017-03-14 | 가려움증의 예방 또는 치료용 조성물 |
| PCT/KR2017/014565 WO2018169169A1 (en) | 2017-03-14 | 2017-12-12 | A composition for preventing or treating pruritus |
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| US (2) | US20200030283A1 (zh) |
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| KR101782966B1 (ko) * | 2017-03-14 | 2017-09-28 | 전북대학교산학협력단 | 가려움증의 예방 또는 치료용 조성물 |
| KR101900408B1 (ko) * | 2017-09-22 | 2018-09-20 | 주식회사 스템디알 | 가려움증의 예방 또는 치료용 조성물 |
| WO2020080957A1 (en) * | 2018-10-19 | 2020-04-23 | Malcorp Biodiscoveries Limited | Methods of treating or preventing skin conditions |
| JP7478894B1 (ja) | 2022-11-30 | 2024-05-07 | 花王株式会社 | 痒みの予防又は改善剤 |
| JP7478895B1 (ja) | 2022-11-30 | 2024-05-07 | 花王株式会社 | 痒みの予防又は改善剤 |
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- 2017-03-14 KR KR1020170031831A patent/KR101782966B1/ko active IP Right Grant
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| KR101782966B1 (ko) | 2017-09-28 |
| US20210308096A1 (en) | 2021-10-07 |
| WO2018169169A1 (en) | 2018-09-20 |
| US20200030283A1 (en) | 2020-01-30 |
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