CN105916511A - 用于治疗和/或预防特应性皮炎的阿维菌素家族或美贝霉素家族的化合物 - Google Patents
用于治疗和/或预防特应性皮炎的阿维菌素家族或美贝霉素家族的化合物 Download PDFInfo
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Abstract
本发明涉及一种药物组合物,其包含在可药用载体中的阿维菌素家族的化合物或美贝霉素家族的化合物,用于特应性皮炎的治疗和/或预防,所述阿维菌素家族的化合物优选是伊维菌素。
Description
技术领域
本发明涉及一种适用于治疗和/或预防特应性皮炎的药物组合物。
背景技术
皮炎源自希腊语的“真皮(derma)”和“炎(itis)”,“真皮”意味着皮肤,“炎”意味着炎症。因此,皮炎对应于皮肤的炎症,根据其位置、病因和症状,归类到几个特定和不同类型皮炎。皮炎的非穷尽性实例是接触性皮炎、疱疹样皮炎、肢端皮炎、剥脱性皮炎、口周皮炎、脂溢性皮炎和特应性皮炎。
特应性皮炎是影响大量的遗传性易患有特应症个体的表皮病症,所述个体包括婴儿,儿童和孕妇。通常情况下,特应性皮炎开始于婴儿期和幼儿早期,特别是2个月左右的年龄。大约50%的特应性皮炎开始于两岁之前。特应性皮炎在成年期首发症状是非常罕见的。
由于在遗传倾向和环境因素之间复杂的相互作用,特应性皮炎成为越来越普遍的瘙痒的炎性皮肤病症。特应性皮炎具有复杂的病因,涉及异常免疫和炎症通路,其包括有缺陷的皮肤屏障,暴露于环境因素和神经精神因素。特应性皮炎的诊断是根据皮肤红色斑块,出疹,和/或苔藓样硬化的临床表现,通常为伴有强烈的瘙痒和皮肤超敏的肿胀区域。病理检查显示在急性病变中的皮肤海绵层水肿、角化过度症和角化不全,标志着在慢性病灶周围的表皮增生,棘层肥厚,淋巴细胞和肥胖细胞(肥大细胞)的血管周围积聚。
虽然特应性皮炎的确切病理生理学尚未被清楚地理解,已经报道,特应性皮炎具有至少两个主要成因,对应于受损的皮肤屏障和失调的免疫应答。
事实上,已经报道了体外的特应性皮炎是由与IgE相关的免疫机理而发生的,并且已经证实在特应性皮炎患者中IgE的增加是与细胞介导的免疫功能障碍相关的。
还已经注意到,皮肤干燥是特应性皮炎产生的主要因素之一,特别是由于在受特应性皮炎影响的个体皮肤上中间丝相关蛋白的减少表达,如由Seguchi等人(Arch.Dermatol.Res.,1996,288,442-446)和Jensen等人(J.Invest.Dermatol.,2004,122,1423-1431)所证明的。Bieber等人.(N.Eng.J.Med.2008,358,1483-1494)甚至已经证明,特应性皮炎70%患者是仅与受损的皮肤屏障相关,并且30%患者涉及了中间丝相关蛋白的突变。
考虑到特应性皮炎最新的已知原因、机制和症状,已经开发了用于特应性皮炎治疗和预防的治疗剂。
几个作者已经提出了药物或皮肤病学组合物以治疗特应性皮炎的症状,如皮肤干燥、红色斑块、出疹、苔藓样硬化,强烈瘙痒或皮肤超敏,并且在更大程度上,以补偿表皮屏障的缺陷。例如,吡咯烷酮羧酸(Takaoka,JP2004168763)和瓜氨酸或某些氨基酸如甘氨酸、甲硫氨酸和丙氨酸(Harano等人,WO2005077349)已经被用作用于治疗特应性皮炎的润肤组合物中的保湿剂。Tezuka(JP08020525)已经提出了含有钠蒙脱石和保湿剂的络合物的香波,所述保湿剂其本身可以是尿素、氨基酸、蛋白质、蛋白质、吡咯烷酮羧酸或水解丝蛋白。
为了通过减少IgE的产生,目的是减少免疫反应,天然或合成的免疫抑制剂,抗组胺剂和类固醇也已经在药物组合物中使用以治疗特应性皮炎。例如,环孢素A是令人瞩目的免疫抑制剂或钙调神经磷酸酶抑制剂,并且由诺华公司以商品名销售。然而,使用类固醇和抗组胺剂的特应性皮炎的常规处理剂仅仅可以暂时缓解症状。此外,当局部或口服类固醇作为长期给药时,患者的皮肤变薄和诱导骨质疏松症。他克莫司,其以商品名和销售,还可以被提到作为钙调神经磷酸酶抑制剂的佼佼者用于治疗特应性皮炎。然而,这种药物被怀疑携带有致癌的危险和FDA(食品药品管理局)甚至已经在2005年3月发出了健康警告。
根据特应性皮炎病理生理学的复杂性和这种炎性皮肤疾病当前疗法的副作用,存在着开发新的药物组合物及其用于治疗和/或预防特应性皮炎的需求。
发明内容
在本文的上下文中,本发明人令人惊讶地证实,包含阿维菌素家族的或美贝霉素家族的化合物、特别是依维菌素,甚至在低剂量下的药物组合物,可以有效地用于治疗和/或预防特应性皮炎并且具有较少的或无副作用。
本发明涉及一种药物组合物,其包含在可药用载体中的阿维菌素家族的或美贝霉素家族的化合物,用于特应性皮炎的治疗和/或预防。
在一个具体的实施方案中,阿维菌素家族的化合物选自伊维菌素、阿维菌素,阿巴汀,多拉菌素,依普菌素和西拉菌素,除虫菌素B、AB或C,埃玛菌素B1a,埃玛菌素B1b和它们的衍生物。更优选地,所述阿维菌素家族的化合物是伊维菌素。
在另一个具体的实施方案中,美贝霉素家族的化合物选自雷皮菌素、弥拜菌素、美贝霉素肟和莫西菌素、6′-乙基雷皮菌素、6′-甲基雷皮菌素及其衍生物或尼莫克汀α、β、γ或δ。
有利的是,根据本发明的药物组合物是用于在孕妇、儿童和婴儿中、更有利地在婴儿中特应性皮炎的治疗和/或预防。
在本发明上下文中使用的组合物通过局部应用给药,优选为乳液、霜剂、洗剂、凝胶或溶液的形式。
根据本发明,该组合物包含以组合物总重量计的0.001至5重量%的阿维菌素家族的或美贝霉素家族的化合物,优选为伊维菌素,优选从0.001至1%,更优选从0.001至0.3%,并且甚至更优选从0.001至0.05%。
在一个优选的实施方案中,该组合物在水中含有以组合物总重量计的重量%的如下物质:
本发明人已经令人惊讶地确定了伊维菌素呈现用于治疗和/或预防特应性皮炎的治疗特性。特别的是,发明人已经显示在特应性皮炎的被许可的小鼠模型中局部施用伊维菌素的治疗效率。
因此,本发明涉及一种药物组合物,其包含在可药用载体中的阿维菌素家族的或美贝霉素家族的化合物,用于特应性皮炎的治疗和/或预防。
本发明还涉及一种用于治疗和/或预防特应性皮炎的方法,其包括向患有特应性皮炎的患者施用有效量的组合物,所述组合物包含在可药用载体中的阿维菌素家族的或美贝霉素家族的化合物。
本发明进一步涉及一种用于治疗和/或预防特应性皮炎的方法,其包括向患有特应性皮炎的患者施用组合物,所述组合物包含在可药用载体中的阿维菌素家族的或美贝霉素家族的化合物,从而降低总IgE的产生、细胞因子的产生、和/或嗜酸性粒细胞和肥大细胞的数目。
本发明还涉及包含在可药用载体中的阿维菌素家族的或美贝霉素家族的化合物的药物组合物在用于治疗和/或预防特应性皮炎的药物制备中的应用。
在一个具体的实施方案中,阿维菌素家族的化合物选自伊维菌素、阿维菌素,阿巴汀,多拉菌素,依普菌素和西拉菌素,除虫菌素B,AB或C,埃玛菌素B1a,埃玛菌素B1b和它们的衍生物。
更优选地,所述阿维菌素家族的化合物是伊维菌素。
在另一个具体的实施方案中,美贝霉素家族的化合物选自雷皮菌素、米尔螨素、美贝霉素肟和莫西菌素、6′-乙基雷皮菌素、6′-甲基雷皮菌素及其衍生物或尼莫克汀α、β、γ或δ。
通过治疗和/或预防特应性皮炎的这些方法相关的优选受试者是孕妇、儿童和婴儿,优选婴儿。
伊维菌素是属于阿维菌素类的两种化合物5-O-去甲基-22,23-双氢阿维菌素A1a和5-O-去甲基-22,23-双氢阿维菌素A1b的混合物。它们也被称为22,23-双氢阿维菌素B1a和22,23-双氢阿维菌素B1b。伊维菌素包含至少80%的22,23-双氢阿维菌素B1a和低于20%的22,23-双氢阿维菌素B1b。这种活性物质是阿维菌素类的一部分,一组由细菌链霉菌(Streptomyces avermitilis)产生的大环内酯。
在20世纪80年代中期,伊维菌素是作为用于兽医用途的广谱抗寄生虫药物产品(Campbell等人:科学(Science),1983,221,823-828)。伊维菌素可有效对抗除绦虫外的最常见的肠道寄生虫、大多数螨和一些虱子。尤其是,它显示出对存在于无脊椎动物神经细胞和肌肉细胞中的谷氨酸盐依赖性氯化物通道相当的亲和力。其对这些通道的结合促进了膜对氯离子通透性的增加,导致神经或肌肉细胞的超极化。由此产生可导致某些寄生虫死亡的神经肌肉麻痹。伊维菌素还与其他配体依赖性氯离子通道相互作用,如那些涉及神经介质GABA(γ-氨基丁酸)的通道。
伊维菌素更具体地公开为用于人类的驱虫药,用于治疗由旋盘尾丝虫(Onchocercavolvulus)造成的河盲症,胃肠道类圆线虫病(鳗形线虫病(anguillulosis))(产品),和人的疥疮(Meinking等人,N.Engl.J.Med.,1995,333,26-30)),并且也用于由于班氏丝虫(Wuchereria bancrofti)在患有象皮病个体中确诊的或疑似的微丝蚴血病的治疗。
Manetta和Watkins(WO 2004/093886)已经建议使用伊维菌素用于生产用于红斑痤疮和其它皮肤病治疗的局部用药物组合物。
然而,伊维菌素从未被公开或建议在用于治疗特应性皮炎的组合物中。
因此,本发明涉及一种药物组合物,其包含在可药用载体中的阿维菌素家族的或美贝霉素家族的化合物,用于特应性皮炎的治疗和/或预防。
根据本发明,该药物组合物被配制在可药用载体中意味着药物组合物包含伊维菌素与可药用载体相结合。从与制剂的其他成分相容而不是对其接受者有害的意义上而言,所述载体必须是“可接受的”。尤其是,在本发明的上下文中,载体是与人体皮肤相容的。
该药物组合物是通过局部应用而有益的施用的并且,因此,是以适合于局部施用到皮肤的形式。例如,它可能是以任选的凝胶、油性溶液、任选的两相分散体的洗剂型、脂肪相分散在水相(O/W)或反之(W/O)所获得的乳液、或三乳剂(W/O/W或O/W/O)或离子和/或非离子型的囊泡分散体的形式。这种局部用组合物可以是无水形式,水性形式或乳剂的形式。这些组合物可以按照常规方法而制备。根据本发明,通过在水相中分散脂肪相而获得的乳剂形式的组合物(O/W)是优选使用的。
该组合物可以是更多或更少的流体并且可能是油膏、乳剂、霜剂、乳液、软膏、浸渗垫、合成洗涤剂(syndets)、溶液、凝胶剂、喷雾剂或气溶胶、泡沫、悬浮液、洗剂或贴剂的形式。优选地,本发明中使用的组合物是乳剂、软膏、洗剂型、凝胶,或溶液的形式,并且更优选的是乳剂的形式。
本发明的组合物优选根据在专利申请WO 2004/093886所公开的配方而配制。一些配方列于实施例1中。
在本发明的上下文中,包括阿维菌素家族的或美贝霉素家族的化合物的药物组合物用于治疗和/或预防特应性皮炎,优选用在孕妇、新生婴儿、婴儿和儿童中,并且更优选在婴儿中。
的确,如在本申请实施例中所示,伊维菌素显示为特应性皮炎的有效显效药,即使在非常低的剂量下并且具有较少或无副作用。
如本文所使用的,新生婴儿是从0到28天的婴儿,婴儿是从1个月至2岁的婴儿,并且儿童年龄是从2岁到14岁或从2岁到***的年龄。
本发明的组合物包含以组合物总重量计的0.001至5重量%的阿维菌素家族的或美贝霉素家族的化合物。优选地,该组合物包含以组合物总重量计的0.001至1重量%的阿维菌素家族的或美贝霉素家族的化合物。有利的是,该组合物包含以组合物总重量计的0.001至0.3重量%、有利地从0.001至0.05重量%的阿维菌素家族的或美贝霉素家族的化合物。再更有利的是,该组合物包含适用于其施用到特定个体的阿维菌素家族的或美贝霉素家族的化合物的总量,所述个体如孕妇、新生婴儿、婴儿和儿童。阿维菌素家族的化合物优选伊维菌素。
以下的实施例说明本发明进一步的方面和优点,其在本质上是没有限制性的。
附图说明
图1:在粉尘螨(Der f)-诱导的皮肤炎症和0.003%、0.01%、0.03%和0.1%伊维菌素,和0.05%曲安奈德的局部应用后,小鼠耳平均厚度的测量。
图2:在粉尘螨-诱导的皮肤炎症和0.003%、0.01%、0.03%、和0.1%伊维菌素,0.05%曲安奈德的局部应用后,小鼠表皮厚度中位数的测量。
图3:在粉尘螨-诱导的皮肤炎症和0.003%、0.01%、和0.03%伊维菌素,和0.05%曲安奈德的局部应用后,嗜酸性粒细胞过氧化物酶(EPO)的定量。
图4:在粉尘螨-诱导的皮肤炎症和0.003%、0.01%、0.03%、和0.1%伊维菌素,和0.05%曲安奈德的局部应用后,IgE的定量。
图5:在粉尘螨-诱导的皮肤炎症和0.1%伊维菌素、0.05%曲安奈德、和0.1%他克莫司的局部应用后,白细胞介素的定量(IL-10,IL-13,IL-17,IL-4,IL-5和IFNg)。
图6:在粉尘螨-诱导的皮肤炎症和0.003%、0.01%、0.03%、和0.1%伊维菌素,和0.05%曲安奈德的局部应用后,肥大细胞计数。
具体实施方式
实施例
实施例1:本发明的组合物
实施例1a:组合物1
实施例1b:组合物2
成分 | 以组合物总重量计的重量% |
伊维菌素 | 1.00 |
甘油 | 4.0 |
硬脂醇聚醚-2 | 1.0 |
硬脂醇聚醚-21 | 2.0 |
硅酸铝镁/二氧化钛/二氧化硅 | 1.0 |
对羟基苯甲酸甲酯 | 0.2 |
对羟基苯甲酸丙酯 | 0.1 |
乙二胺四乙酸二钠 | 0.05 |
柠檬酸一水化物 | 0.05 |
棕榈酸异丙酯 | 4.0 |
甘油/聚乙二醇100硬脂酸酯 | 2.0 |
自乳化蜡 | 1.0 |
棕榈硬脂酸 | 2.00 |
二甲基硅酮20-350cS | 0.5 |
丙二醇 | 4.0 |
三乙酸甘油酯 | 1.00 |
苯氧基乙醇 | 0.5 |
10%氢氧化钠 | 适量pH |
水 | 适量100 |
实施例1c:组合物3
成分 | 以组合物总重量计的重量% |
伊维菌素 | 1.00 |
甘油 | 4.0 |
丙烯酸C10-30烷基丙烯酸交联聚合物 | 0.15 |
对羟基苯甲酸甲酯 | 0.2 |
乙二胺四乙酸二钠 | 0.05 |
柠檬酸一水化物 | 0.05 |
肉豆蔻酸异丙酯 | 4.0 |
十六烷醇 | 3.0 |
硬脂醇 | 2.0 |
自乳化蜡 | 0.8 |
棕榈硬脂酸 | 0.5 |
硬脂醇聚醚-20 | 2.0 |
山梨坦棕榈酸酯 | 1.0 |
二甲基硅酮20 | 0.5 |
对羟基苯甲酸丙酯 | 0.1 |
丙二醇 | 4.0 |
三乙酸甘油酯 | 1.0 |
苯氧基乙醇 | 0.5 |
10%氢氧化钠 | 适量pH |
水 | 适量100 |
实施例1d:组合物4
实施例1e:组合物5
实施例1f:组合物6
成分 | 以组合物总重量计的重量% |
伊维菌素 | 1.4 |
甘油 | 4.0 |
丙烯酸C10-30烷基丙烯酸交联聚合物 | 0.2 |
对羟基苯甲酸甲酯 | 0.2 |
乙二胺四乙酸二钠 | 0.05 |
柠檬酸一水化物 | 0.05 |
山梨坦棕榈酸酯 | 4.0 |
十六烷醇 | 3.5 |
硬脂醇 | 2.5 |
油醇 | 2.0 |
鲸蜡硬脂醇醚-20 | 3.0 |
山梨糖醇酐一硬脂酸酯 | 2.0 |
二甲基硅酮200 20cs | 0.5 |
对羟基苯甲酸丙酯 | 0.1 |
丙二醇 | 2.0 |
苯氧基乙醇 | 1.0 |
10%氢氧化钠 | 适量pH |
水 | 适量100 |
实施例2:通过局部途径评价伊维菌素在尘螨诱导的特应性皮炎(AD)样小鼠模型中的免疫调节潜力。
1.材料与方法
1.1粉尘螨-诱导的特应性皮炎小鼠模型
粉尘螨(Der f)-诱导的特应性皮炎小鼠模型已经被证明是适合于特应性皮炎的病理生理学研究和新疗法的评价(J.Invest.Dermatol.,2009,129,31-40)。
粉尘螨购自Greer Laboratories,并且在70%DMSO的MilliQ水中制备以12.5毫克/毫升的粉尘螨溶液。
1.2.化合物
1.2.1.伊维菌素
伊维菌素已经由Galderma公司交付,0.003%、0.01%、0.03%、和0.1%伊维菌素的丙酮溶液已经被配制。
1.2.2.曲安奈德和他克莫司
曲安奈德和他克莫司已经被选择作为粉尘螨模型的阳性对照。0.05%曲安奈德和0.1%他克莫司的丙酮溶液已经被配制。
1.3.小鼠
Balb/c小鼠品系已经被用于该研究。这些动物已经获得自控制饲养并且是无特定病原体的。这些动物由Janvier SAS,法国提供。
1.4.方案
由20μl的粉尘螨溶液在第1天、第8天、第22天、第29天和第36天在右耳局部应用5周,每周一次,AD样病变已经被诱导。在从第19天至第36天用由局部途径施用不同的溶液而每天处理小鼠。
在每个变应原应用之前和24小时后,监测耳厚度的测量值。19天之后,在化合物应用之前,每天测量耳朵。
在异氟烷麻醉下收集血液样本到适当的小瓶中以用于进一步分析(IgE)。然后小鼠被立即安乐死。
在小鼠安乐死后,收集右耳和用70%的乙醇洗涤,并且在PBS中清洗。收集三份皮肤活检用于细胞因子概况、嗜酸性粒细胞过氧化物酶(EPO)的量化和组织切片,以便定量肥大细胞和以便测量表皮厚度。
2.结果
-粉尘螨/丙酮组
粉尘螨的每周一次应用诱导了在耳厚度(图1),在表示增强的嗜酸性粒细胞浸润的EPO(图3),在总IgE分泌(图4),和在细胞因子浓度(图5)中的显著增强。它也诱导了具有明显的肥大细胞浸润的表皮增生(图6)。这些观察是Th2反应的代表。
-粉尘螨/阳性对照
正如预期的,曲安奈德和他克莫司完全抑制了炎症反应。事实上,曲安奈德完全降低了耳水肿(图1),EPO(图3),IgE的分泌(图4)和细胞因子的浓度(图5)。它也强烈地减少了表皮厚度(图2)和肥大细胞的数量(图6)。此外,他克莫司完全降低了耳水肿(图1)和细胞因子的浓度,特别的是,白细胞介素IL-17的生产(图5)。
-粉尘螨/伊维菌素
如所观察到的,伊维菌素令人惊讶地能够减少由粉尘螨应用所诱导的炎症反应。事实上,它显著降低了耳水肿(图1),EPO(图3),IgE的分泌(图4)和细胞因子的产生(图5)。它也减少了表皮厚度(图2)和真皮内肥大细胞的数量(图6)。重要的是要注意,0.003%伊维菌素能够将炎症反应减少到与0.05%曲安奈德和0.1%他克莫司相同的程度。更高浓度的伊维菌素(0.01、0.03、和0.1%)虽然显示出显著的抗炎症反应,但与最弱浓度(0.003%)相比仅保持了较低的有效。
3.结论
这些数据清楚地表明,用伊维菌素的局部治疗可以减少皮肤发炎和确认伊维菌素用于治疗和/或预防特应性皮炎的极大利益。另外,发明人已经令人惊讶地证实与炎性活性的逆剂量反应。伊维菌素的应用因此是非常适合于治疗和/或预防特应性皮炎的,尤其是在如孕妇,儿童和婴幼儿的个体中。
Claims (12)
1.一种药物组合物,其包含在可药用载体中的阿维菌素家族的化合物或美贝霉素家族的化合物,用于特应性皮炎的治疗和/或预防。
2.根据权利要求1应用的药物组合物,其中阿维菌素家族的化合物选自伊维菌素,阿维菌素,阿巴汀,多拉菌素,依普菌素和西拉菌素,除虫菌素B,AB或C,埃玛菌素B1a,埃玛菌素B1b和它们的衍生物。
3.根据权利要求2应用的药物组合物,其中阿维菌素家族的化合物是伊维菌素。
4.根据权利要求1应用的药物组合物,其中美贝霉素家族的化合物选自雷皮菌素、弥拜菌素、美贝霉素肟和莫西菌素、6′-乙基雷皮菌素、6′-甲基雷皮菌素及其衍生物或尼莫克汀α、β、γ或δ。
5.根据权利要求1至4中任一项应用的药物组合物,用于在孕妇、儿童和婴儿中特应性皮炎的治疗和/或预防。
6.根据权利要求5应用的药物组合物,用于在婴儿中特应性皮炎的治疗和/或预防。
7.根据权利要求1至6中任一项应用的药物组合物,其中组合物通过局部施用给药。
8.根据权利要求1至7中任一项应用的药物组合物,其中所述组合物为乳剂、霜剂、洗剂、凝胶或溶液的形式。
9.根据权利要求1至8中任一项应用的药物组合物,其中所述组合物包含以组合物总重量计的0.001重量%至5重量%、更优选0.001重量%至1重量%的阿维菌素家族的或美贝霉素家族的化合物。
10.根据权利要求9应用的药物组合物,其中所述组合物在水中包括以组合物总重量计的重量%的如下物质:
11.根据权利要求9应用的药物组合物,其中所述组合物包含以组合物总重量计的0.001重量%至0.3重量%的阿维菌素家族的化合物或美贝霉素家族的化合物。
12.根据权利要求10应用的药物组合物,其中所述组合物包含以组合物总重量计的0.001重量%至0.05重量%的阿维菌素家族的化合物或美贝霉素家族的化合物。
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EP13306633.2 | 2013-11-29 | ||
EP13306633 | 2013-11-29 | ||
PCT/EP2014/075927 WO2015079016A1 (en) | 2013-11-29 | 2014-11-28 | Compound of the avermectin family or of the milbemycin family for the treatment and/or prevention of atopic dermatitis |
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CN105916511A true CN105916511A (zh) | 2016-08-31 |
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CN201480065423.XA Pending CN105916511A (zh) | 2013-11-29 | 2014-11-28 | 用于治疗和/或预防特应性皮炎的阿维菌素家族或美贝霉素家族的化合物 |
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US (2) | US20170000812A1 (zh) |
EP (1) | EP3074021B1 (zh) |
JP (2) | JP6448641B2 (zh) |
KR (1) | KR102341441B1 (zh) |
CN (1) | CN105916511A (zh) |
AU (1) | AU2014356444B2 (zh) |
CA (1) | CA2930909A1 (zh) |
MX (1) | MX370957B (zh) |
RU (1) | RU2669942C1 (zh) |
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CN113382769A (zh) * | 2019-02-04 | 2021-09-10 | 玛路弘株式会社 | 皮肤用组合物 |
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WO2018083196A1 (en) * | 2016-11-03 | 2018-05-11 | Nestlé Skin Health Sa | Compositions comprising a compound of the avermectin family for the treatment and/or prevention of hand eczema |
WO2020021670A1 (ja) * | 2018-07-26 | 2020-01-30 | マルホ株式会社 | 液状外用剤 |
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US20120035123A1 (en) * | 2009-02-16 | 2012-02-09 | Galderma Research & Development | Combination of compounds for treating or preventing skin diseases |
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JPH0820525B2 (ja) | 1986-12-01 | 1996-03-04 | 防衛庁技術研究本部長 | 磁気補償装置 |
US6399651B1 (en) * | 2000-06-29 | 2002-06-04 | L. Dean Parks | Method of treating dermatoses using avermectin compound |
JP2004168763A (ja) | 2002-10-30 | 2004-06-17 | Dsr Corp | 皮膚化粧料 |
FR2854074B1 (fr) | 2003-04-24 | 2007-11-23 | Galderma Res & Dev | Utilisation de l'ivermectine pour le traitement de desordres dermatologiques |
JPWO2005077349A1 (ja) | 2004-02-17 | 2007-10-18 | 大塚製薬株式会社 | ヒトβディフェンシン産生促進剤 |
DE602005020912D1 (de) | 2004-03-18 | 2010-06-10 | Galderma Sa | Ivermectin enthaltende creme |
FR2867684B1 (fr) * | 2004-03-18 | 2006-05-05 | Galderma Sa | Gel creme contenant de l'ivermectine |
FR2883181B1 (fr) | 2005-03-17 | 2007-05-18 | Galderma Sa | Composition a base d'une avermectine et d'acide azelaique notamment pour le traitement de la rosacee |
FR2891460B1 (fr) | 2005-09-30 | 2010-07-30 | Galderma Sa | Utilisation d'au moins un compose de la famille des avermectines pour le traitement des pathologies ophtalmiques dues au demodex folliculorum. |
EP1776877A1 (en) * | 2005-10-21 | 2007-04-25 | N.V. Nutricia | Method for stimulating the intestinal flora |
FR2906467B1 (fr) * | 2006-09-28 | 2012-11-09 | Galderma Sa | Utilisation de composes de la famille des milbemycines pour le traitement de desordres dermatologiques chez l'homme |
FR2907012B1 (fr) | 2006-10-12 | 2012-09-21 | Galderma Sa | Composition dermatologique comprenant des nanocapsules d'avermectine, son procede de preparation et son utilisation |
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WO2010072958A2 (fr) * | 2008-12-23 | 2010-07-01 | Galderma S.A. | Composition pharmaceutique topique comprenant un principe actif sensible a l'eau |
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WO2004093886A1 (en) * | 2003-04-24 | 2004-11-04 | Galderma S.A. | Topical formulation of ivermectin for the treatment of dermatological conditions |
US20120035123A1 (en) * | 2009-02-16 | 2012-02-09 | Galderma Research & Development | Combination of compounds for treating or preventing skin diseases |
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US20170000812A1 (en) | 2017-01-05 |
MX2016006927A (es) | 2016-10-28 |
WO2015079016A1 (en) | 2015-06-04 |
RU2016125752A (ru) | 2018-01-09 |
RU2018135676A (ru) | 2018-11-19 |
RU2669942C1 (ru) | 2018-10-17 |
RU2018135676A3 (zh) | 2022-02-09 |
JP6667602B2 (ja) | 2020-03-18 |
US20170304340A1 (en) | 2017-10-26 |
KR20160082254A (ko) | 2016-07-08 |
EP3074021B1 (en) | 2021-05-12 |
JP2016538311A (ja) | 2016-12-08 |
EP3074021A1 (en) | 2016-10-05 |
AU2014356444A1 (en) | 2016-06-09 |
KR102341441B1 (ko) | 2021-12-24 |
AU2014356444B2 (en) | 2019-11-21 |
MX370957B (es) | 2020-01-09 |
JP2019031572A (ja) | 2019-02-28 |
US10398720B2 (en) | 2019-09-03 |
JP6448641B2 (ja) | 2019-01-09 |
CA2930909A1 (en) | 2015-06-04 |
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