CN101132693A - 用于控制过度增生性皮肤病的组合物以及方法 - Google Patents
用于控制过度增生性皮肤病的组合物以及方法 Download PDFInfo
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- CN101132693A CN101132693A CNA2004800436759A CN200480043675A CN101132693A CN 101132693 A CN101132693 A CN 101132693A CN A2004800436759 A CNA2004800436759 A CN A2004800436759A CN 200480043675 A CN200480043675 A CN 200480043675A CN 101132693 A CN101132693 A CN 101132693A
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- boswellic acid
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Abstract
本发明描述了治疗过度增生性皮肤病如银屑病的组合物和方法。优选的组合物包含选自乳香树胶脂，其提取物、分离物或衍生物的天然白三烯抑制剂，组合有生物可利用的有机硒营养补充剂。这些组合物以最适宜的剂量通过口服和局部施用于需要治疗的人或动物来获得期望的效果，没有不利的副作用。
Description
技术领域
本发明涉及治疗过度增生性皮肤病如银屑病和它们的相关症状的组合物和方法。本文描述的组合物包含选自乳香树胶脂(Boswellia serrata gum resin)，其提取物、分离物或衍生物的天然白三烯抑制剂，与生物可利用的有机硒营养补充剂相组合。这些组合物以最适宜的剂量和适合的剂型通过口服和局部给药于需要治疗的人或动物来获得期望的效果，没有不利的副作用。
背景技术
银屑病是一种慢性的皮肤病，特点是被银色的薄而易剥落的表皮覆盖的非常明显的红色斑点周期性的发作。在银屑病中，皮肤表皮常遭受由应激和环境因素所引发的免疫系统的遗传变异所引起的破坏性的病变。在表皮中有不成熟的角化细胞的过度增生，形成斑点或者色斑，并有银色的薄而易剥落的死皮从表面脱落。在真皮中，血管对变异的增殖角化细胞提供增加的血液供应，引起银屑病的潜在的炎症和红色的特征。几种类型的银屑病可以独立、同时或相继发生。最普通的银屑病形式是斑块状银屑病。银屑病关节炎是一种使人虚弱无力的病症，包括银屑病和关节炎。
银屑病在临床上使用局部药物治疗、光疗法和系统药物治疗。如甾族类药物、环孢霉素、甲氨蝶呤、口服或局部给药的类维生素A、硫化硒等为治疗该病而用于药物制剂中的药物都有各种各样的副作用。没有已知的治愈银屑病的先例。
橄榄科乳香树(Boswellia serrata(Roxb.))是一种生长在印度干旱和丘陵地区的大树。乳香树的渗出物是一种树胶脂，通常被称作“Dhup”、“印度乳香(Indian Frankincense)”或者“印度乳香(Indian Olibanum)”(无名作者，1948，以及Chopra等，1956)。被称为Salai Guggal的树胶脂已经应用于印度草药治疗的药物，应用于风湿病、呼吸系统疾病和肝病等的治疗(Kirtikar和Basu，1935)。古代的印度草药治疗记载(Shushrutha Samhitha Gulabkunvarba，1949)和Charaka Samhitha(Chowkhamba，1968)都提到了guggals(乳香，Boswelliaserrata中分离得到的非甾体药物)的抗风湿病的活性。乳香树胶脂的非酸性油级分被发现对大鼠表现显著的减轻疼痛的效果(Menon和Kar，1971，和Menon和Kar，1969)。乳香树胶的酸性级分，含有乳香酸，被发现对大鼠和兔子表现退热作用(Singh和Atal，1986，Sigh等，1993)。然而乳香树胶(gumBoswellia serrata)的酸性级分并未发现有任何止痛的特性。实际上，乳香酸存在于来自乳香树(Boswellia serrata Roxb.)的树胶或分泌物中。树胶中含有四种乳香酸的混合物。
乳香酸抑制5-脂氧合酶(Safayhi等，1992)，这种酶催化花生四烯酸转化为引起炎症的白三烯。乳香酸也抑制人类白细胞弹性蛋白酶(HLE)，该酶催化结缔组织的分解(Safayhi等，1997)。
引起炎症的白三烯已经被发现与银屑病的发病机理和病理生理学有关。在银屑病和湿疹患者的受损皮肤中，白三烯B4被发现增加了大约6.6倍(Reilly等2000)。一种来自花生四烯酸的5-脂氧合酶催化产物，白三烯B4，被认为在银屑病发病机理中起重要作用(Iversen等，1997)。在受损皮肤中发现人类白细胞弹性蛋白酶(HLE)活性大规模增加，银屑病31倍，变应性接触性皮炎55倍，特应性皮炎35倍，但是在得病患者的正常皮肤中没有发现增加(Wiedow，1992)。
WO96/19212描述了乳香酸在治疗脑瘤中的作用。
WO97/07796描述了乳香酸及其衍生物在抑制正常的和增加的白细胞弹性蛋白酶或纤维蛋白溶酶活性中的作用。
US5888514描述了一种用于治疗骨骼或关节炎的包含乳香酸的天然组合物。
US5629351描述了一种乳香酸组合物及其制备方法。
US5494668描述了一种用于治疗肌与骨骼疾病的乳香酸组合物。
US5720975描述了薰香(incense)治疗阿尔茨海默病的用途。
EP0552657描述了纯乳香酸、生理上可接受的盐、衍生物、或衍生物的盐或含有乳香酸的草药制剂预防和/或控制在人和兽医学中由白三烯形成的增加引起的发炎过程的用途。
WO00/57893描述了包含乳香提取物(Boswellia serrata extract)的组合物，其中包含的乳香提取物、乳香酸或其衍生物在制备皮肤护理或头发护理组合物中非常有用，能够为受刺激的皮肤提供润滑效果。
硒是一种重要的微量元素营养，对高等动物和人类活细胞的生长和机能有多种作用。在分子水平上，硒(以硒代半胱氨酸形式)是抗氧化酶谷胱甘肽过氧化物酶和参与甲状腺功能的碘化甲腺氨酸-5′-脱碘酶与哺乳动物硫氧还蛋白还原酶的活性位点的主要成分。硒也存在于几种其它哺乳动物的含硒蛋白质中。低硒情况与疾病免疫能力降低和多种癌症流行的发生有关。
患有中度或重度银屑病的患者已经表明具有低血硒水平和增加水平的丙二醛，一种自由基诱导氧化的产物(Corrocher等1989)。在临床研究中，低硒的饮食摄入已经与银屑病的发展相关联(Serwin等1999)。已经证明在受试的人和实验动物中局部使用硒代甲硫氨酸能够降低由紫外线辐射引起的皮肤损害的程度(Burke等1992)。通过硒代甲硫氨酸在抗氧化酶中的作用(Cronin，2002)，其抗氧化功能也因而能够在银屑病病例中有所帮助。
近期研究表明，银屑病并不是一种皮肤疾病，而是一种皮下免疫失调。皮肤的表现是表面皮肤细胞(朗格汉斯细胞)过度受激的结果，而这种过度受激是由白细胞介素2、6和8增加以及转化生长因子-α白细胞介素-10减少引起的(Christ，1999)。
在7个银屑病患者中，调查硒元素补充(6星期，400微克/天补充硒酵母，含有大约70％的硒代甲硫氨酸)对皮肤和血液硒含量、皮肤谷胱甘肽过氧化物酶活性以及血液和皮肤的各种化学、免疫学参数的影响。这项研究的结果表明，硒代甲硫氨酸也许能够通过增加CD4+T细胞的数目来调控银屑病损伤的免疫机制(Harvima，1993)
肿瘤坏死因子-α(TNF-α)和它的受体在银屑病损伤的诱导和维持中起重要作用。一项近期研究报道了在斑块状银屑病中口服补充硒代甲硫氨酸作为辅助治疗是没有效果的，并且尽管能够减轻皮肤损伤，也可能帮助维持银屑病患者提高的TNF-R1(可溶解的TNF-α受体类型1)浓度(Serwin等，2003)
专利申请CN1233482描述了富硒灵芝在治疗银屑病中的应用。
WO02096429描述了一种用于外部治疗银屑病的药剂，其是甲基黄嘌呤(methylxathine)基团的脂质体乳剂的剂型，硒和一些其它制剂被用作有效成分。
IT1244459描述了可以通过局部施药治疗皮肤病如白斑病、粉刺、银屑病、脱发症、稀发症的药物制剂，其包含一种或多种选自鳕鱼肝油、貂油和龟油等来源于动物的油剂，这些油剂中含有锂、锌、铜，也可能有金、银、硫、硒和硅溶解或分散于其中。
美国专利6630442描述了一种谷胱甘肽和硒的组合物，其在局部载体中有含硒氨基酸或硒酵母提取物和表皮生长因子。也描述了使用这种组合物减轻和修复由针对皮肤的美容(表皮剥落和化学去皮)和外科(激光和其它疗法)程序和其它化学和热灼伤造成的皮肤损伤的方法。
以上所引用的现有技术都没有使用5-脂氧合酶和人类白细胞弹性蛋白酶的天然双重抑制剂与有机硒补充剂相组合治疗银屑病。乳香酸的抗补体活性在文献中有详细描述(Kapil，A等1992)。TNF-α的补体依赖的诱导作用是一种早已确立的方式。因此本发明的组合治疗能够阻止任何非硒元素补充所致的潜在的TNF-α水平的提高。
以下是本申请引用的文献列表，其中每一篇都在此完全地引入作为参考：
Anonymous(1948)，The Wealth of India：Raw Materials，Vol I，CSlR出版社，Delhi，pp 208-210.
Chopra，R.N.Nayar，S.L.，Chopra，I.C.(1956)，Glossary of India MedicinalPlants，SCIR，Delhi.Chowkhamba(1968)，Charaka Samhita(第二版)，SanskritSeries Office，Varanasi.
Kirtikar，K.R.和Basu，B.D.(1935)，Indian Medicinal Plants，Vol.I，pp.521-529.
Menon，M.K.和Kar.A.(1971)，Analgesic and psycho-pharmacologicaleffects of the gum resin of Boswellia serrata.Planta Med.19：338-341.
Menon，M.K.和Kar，A.(1969).Analgesic effects of the gum resin ofBoswellia serrata.Life Sciences 8(1)：1023-28.
Singh，G.B.和Atal，C.K.(1986)，Pharmacology of an extract of salai guggalex-Boswellia serrata，a new non-steroidal anti-inflammatory agent，Agents andActions 18(3/4)：407-411.
Singh，G.B.等(1993)，Boswellic Acids，Drugs of the Future 18(4)：307-309.
Sushruta Samhita(1949)，Shree Gulabkunvarba，Vol 16，Ayurvedic Soc.，Jamnagar.
Reilly DM.等(2000)Inflammatory mediators in normal，sensitive anddiseased skin types.Acta Derm Venereol 80(3)：171-4
Iversen L，等(1997)Significance of leukotriene-A4 hydrolase in thepathogenesis of psoriasis.Skin Pharmacol.10(4)：169-77
Wiedow O，等(1992)Lesional elastase activity in psoriasis，contactdermatitis，and atopic dermatitis.Invest Dermatol.99(3)：306-9
Safayhi，H.等(1992)Boswellic acids：novel，specific，non-redox inhibitorsof 5-lipoxygenase.J.Pharmacol.Exp.Ther.261：1143-6.
Safayhi，H.等(1997)Inhibition by boswellic acids of human leukocyteelastase.J.Pharmacol.Exp.Ther.281：460-463
Corrocher，R.等(1989)Effect of fish oil supplementation on erythrocytelipid pattern，malondialdehyde production and glutathione-peroxidase activity inpsoriasis.Clin Chim Acta 179(2)：121-31
Serwin AB，等(1999)Selenium nutritional status and the course of psoriasis.Pol Merkuriusz Lek.6(35)：263-5
Burke，K.E.等(1992)The effect of topical L-selenomethionine on minimalerythema dose of ultraviolet irradiation in humans.Photodermatol PhotoimmunolPhotomed 9(2)：52-7
Cronin，J.R.(2000)Dietary selenium：Elemental Nutrition for Muscles，Immunity，Well-Being and Cancer Prevention.Alt.Complement.Therap.6(6)：342-346.
Christ HW.(1999)Immunomodulating therapy of psoriasis vulgaris.MedKlin 94 Suppl 3：90-2
Serwin，A.B.等Soluble tumor necrosis factor-alpha receptor type 1 duringselenium supplementation in psoriasis patients.Nutrition.2003 Oct；19(10)：847-850.
Hawima，R.J.(1993)Screening of effects of selenomethionine-enrichedyeast supplementation on various immunological and chemical parameters ofskin and blood in psoriatic patients.Acta Derm.Venerol.73(2)：88-91.
Kapil，A和Moza，N Anticomplementary activity of boswellic acids-aninhibitor of C3-convertase of the classical complement pathway.Int JImmunopharmacol.1992 Oct；14(7)：1139-43.
发明内容：
过度增生性皮肤疾病以银屑病为例。银屑病是一种慢性的皮肤病，特点是以出现在皮肤上的被银色的薄而易剥落的表皮覆盖的红色斑点的形式周期性的发作。银屑病归因于由环境因素引发的免疫系统的遗传变异，因此被归为一种自身免疫疾病。银屑病有几种不同形式，其中斑块状银屑病是最普通的，发生在肘、膝盖和下背等部位。在银屑病关节炎中，银屑病斑伴随着关节炎的症状。银屑病关节炎的特点是关节僵硬、敏感和发炎。
本发明用一种新的治疗方案治疗过度增生性皮肤病，其中包括口服摄取以及局部给药天然的5-脂氧合酶和人类白细胞弹性蛋白酶的双重抑制剂，并与口服摄入生物可利用的有机硒补充剂组合。
导致所有自身免疫疾病的进程包括由遗传控制的人类白细胞抗原(HLA)系统。这个系统的功能紊乱是大多数免疫疾病包括银屑病关节炎的根源。本发明专注于提供通过抑制炎症性酶前体的表达和调节角质形成细胞生长因子的表达从而抑制发炎过程的营养素。成功的治疗必须配置能够有利地影响相关地潜在的遗传过程的正确的给药方案。
附图的简要说明
图1展示了患者1、2、3初始的、以及在治疗过程中8周末(检查1)和12周末(检查2)的银屑病斑的外观。
图2展示了患者4、5、6初始的、以及在治疗过程中8周末(检查1)和12周末(检查2)的银屑病斑的外观。
图3展示了患者7、8、9初始的、以及在治疗过程中8周末(检查1)和12周末(检查2)的银屑病斑的外观。
图4展示了患者10、11、12初始的、以及在治疗过程中8周末(检查1)和12周末(检查2)的银屑病斑的外观。
实施发明的方式
本发明典型的实施方案介绍了银屑病成功治疗的组合物和给药方案。
实施例1本发明的组合物
本发明有效成分组合物的口服制剂的具体实例列于表1中。
表1：口服剂型的有效成分组合物
| 有效成分 | 含量 |
| β-乳香酸 | 64mg |
| 乙酰基-β-乳香酸 | 48mg |
| 11-酮-β-乳香酸 | 24mg |
| 乙酰基-11-酮-β-乳香酸 | 32mg |
| L(+)-硒代甲硫氨酸(研磨于磷酸氢钙中) | 20mg |
制剂可被制成胶囊、片剂、粉剂、缓释胶囊剂(spansule)或者其它剂型，同时使用为制成以上剂型的常用的赋型剂和添加剂。
局部使用的制剂实例列于表2中。
表2：局部使用的乳膏组合物
成分 ％(w/w)
纯净水 60.00
Carbomer 940 0.250
甘油 4.000
尼泊金甲酯 0.200
乙二胺四乙酸钠盐 0.010
十六烷醇 3.500
十八烷醇 3.500
硬脂酸 6.500
甘油硬脂酸酯 2.500
PEG-100硬脂酸酯 2.500
棕榈酸异丙酯 6.000
醋酸维生素E 1.000
二甲硅油 0.100
尼泊金丙酯 0.100
棕榈酸维生素A 0.100
抗坏血酸棕榈酸酯 0.200
Boswellin 5.000
纯净水 2.000
三乙醇胺 0.400
Imiduria 0.300
Boswellin(Sabinsa Corporation，NJ，USA的产品商标)是一种标准的乳香树胶脂提取物，含有β-乳香酸、乙酰基-β-乳香酸、11-酮-β-乳香酸和乙酰基-11-酮-β-乳香酸。
有效成分可以被制成乳膏、洗液、贴剂、凝胶或者任何其它局部用剂型。
实施例2使用本发明的组合物和方法治疗人银屑病患者。
12位18～65岁的患者(6名男性和1名女性)参与这项研究，他们的症状表现为初级的斑块状和第二等级的环状、多环状、麻疹状损伤，伴有搔痒、皮肤剥落和因擦伤出血等症状。
患者口服含有400mg乳香酸和100mcg L(+)硒代甲硫氨酸形式的硒的药片，并且也用含有400mg乳香酸的局部用乳膏进行治疗。
所遵循的日给药方案为如上所述的每次1片药，并施以如上所述的局部用乳膏，每天三次共150天。PASI值(银屑病区域严重指数)将体表面积和红斑(红色)、硬化(厚度)和多鳞屑考虑在内，每间隔四星期评估一次。血清生化参数也同样进行评估。
对身体上的银屑病患处在研究开始时以及每间隔四周进行拍照。
对患者进行另外30天的追踪，表明银屑病症状有所改善，并且没有不利的副作用。
银屑病外部表观的治疗效果在图1-4中用照片展示。
Claims (12)
1.用于治疗过度增生性皮肤疾病的组合物和方法。
2.权利要求1所述的组合物和方法，其中过度增生性皮肤病是银屑病。
3.权利要求1所述的组合物，其含有5-脂氧合酶和人类白细胞弹性蛋白酶的双重抑制剂，该抑制剂选自乳香树胶脂、包含乳香酸的乳香树胶脂提取物、分离的乳香酸、合成的乳香酸、或衍生物中的一种或它们的组合；和选自硒代甲硫氨酸、甲基硒代半胱氨酸、富硒植物物质的生物可利用的有机硒营养补充剂。
4.权利要求1的组合物是通过口服和局部给药于需要治疗的人类或动物对象。
5.权利要求1的组合物和方法，由口服给药的乳香提取物和硒代甲硫氨酸制剂，和局部给药的乳香提取物制剂组成。
6.权利要求5的口服制剂，其含有50-500mg由下列组中的一种或多种表示的乳香酸：a)β-乳香酸、乙酰基β-乳香酸、11-酮β-乳香酸、乙酰基-11-酮-β-乳香酸，单独或混合物，b)β-乳香酸、乙酰基-β-乳香酸、11-酮β-乳香酸、乙酰基-11-酮-β-乳香酸的同类物或衍生物；单独或组合；和100mcg硒代甲硫氨酸形式的硒。
7.权利要求5的局部使用制剂，其含有50-400mg由下列组中的一种或多种表示的乳香酸：a)β-乳香酸、乙酰基β-乳香酸、11-酮β-乳香酸、乙酰基-11-酮-β-乳香酸，单独或混合物，b)β-乳香酸、乙酰基β-乳香酸、11-酮β-乳香酸和乙酰基-11-酮-β-乳香酸的同类物或衍生物；单独或组合。
8.权利要求5的口服制剂，其含有10-400mg的乙酰基-11-酮-β-乳香酸和10-100mcg的L(+)-硒代甲硫氨酸。
9.权利要求5的局部使用制剂，其含有10-400mg的乙酰基-11-酮-β-乳香酸。
10.权利要求5的口服制剂，其为片剂、胶囊、缓释胶囊剂、粉末或其他剂型。
11.权利要求5的局部使用制剂，其为乳膏、洗液、凝胶、贴剂、药用油或其他剂型。
12.权利要求9的局部使用制剂，其适于皮肤、头皮或指甲应用。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/710,778 | 2004-08-02 | ||
| US10/710,778 US7582314B2 (en) | 2003-12-03 | 2004-08-02 | Compositions and methods for the management of hyperproliferative dermatological conditions |
| PCT/US2004/033846 WO2006022762A1 (en) | 2004-08-02 | 2004-10-14 | Compositions and methods for the management of hyperproliferative dermatological conditions |
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| Publication Number | Publication Date |
|---|---|
| CN101132693A true CN101132693A (zh) | 2008-02-27 |
| CN101132693B CN101132693B (zh) | 2012-11-07 |
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| CN2004800436759A Expired - Fee Related CN101132693B (zh) | 2004-08-02 | 2004-10-14 | 用于控制过度增生性皮肤病的组合物以及方法 |
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| Country | Link |
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| EP (1) | EP1791423B1 (zh) |
| JP (1) | JP4820819B2 (zh) |
| CN (1) | CN101132693B (zh) |
| AU (1) | AU2004322710B2 (zh) |
| DK (1) | DK1791423T3 (zh) |
| ES (1) | ES2422893T3 (zh) |
| NZ (1) | NZ552027A (zh) |
| PL (1) | PL1791423T3 (zh) |
| PT (1) | PT1791423E (zh) |
| RU (1) | RU2366412C2 (zh) |
| WO (1) | WO2006022762A1 (zh) |
| ZA (1) | ZA200700694B (zh) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670690A (zh) * | 2011-03-14 | 2012-09-19 | 苏州博创园生物医药科技有限公司 | 一种抗牛皮癣纯天然药物乳膏及其制备方法 |
| CN102670565A (zh) * | 2011-03-14 | 2012-09-19 | 苏州博创园生物医药科技有限公司 | 一种含天然药物的透皮吸收贴片 |
| CN103193853A (zh) * | 2012-01-06 | 2013-07-10 | 苏州博创园生物医药科技有限公司 | 用于治疗银屑病的化合物、组合物及其制备方法 |
| CN109328061A (zh) * | 2016-04-19 | 2019-02-12 | 阿祖拉眼科有限公司 | 用于治疗角化过度症的组合物 |
| US11517586B2 (en) | 2020-01-10 | 2022-12-06 | Azura Ophthalmics Ltd. | Instructions for composition and sensitivity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9101599B2 (en) * | 2008-09-15 | 2015-08-11 | Laila Nutraceuticals | Synergistic anti-inflammatory compositions comprising Boswellia serrata extracts |
| ITVR20080125A1 (it) * | 2008-11-13 | 2010-05-14 | Phytonature Sas Di Masini Dr Antoni O E C | Nuova forma di preparazione ed utilizzo della boswellia serrata |
| EP2536288B1 (en) * | 2010-02-15 | 2022-06-22 | Laila Nutraceuticals | A novel boswellia low polar gum resin extract and its synergistic compositions |
| US20110218172A1 (en) * | 2010-03-02 | 2011-09-08 | Muhammed Majeed | Composition for down-regulating pro-inflammatory markers |
| US9498423B2 (en) * | 2012-05-07 | 2016-11-22 | Sami Labs Limited | Synergistic selenopeptide formulations for the protection of dermal papilla cells |
| US9975917B1 (en) | 2017-09-20 | 2018-05-22 | King Saud University | Pentacyclic triterpenoidal derivatives |
| EP4295842A1 (en) | 2022-06-24 | 2023-12-27 | Faaborg Pharma - IP ApS | A skin care composition |
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| US3670084A (en) * | 1969-06-20 | 1972-06-13 | Leopoldo F Montes | Method of treating psoriasis with cycloheximide |
| DE4201903B4 (de) * | 1992-01-24 | 2004-04-15 | Hermann P.T. Prof. Dr.Med. Ammon | Pharmazeutische Verwendung von Boswelliasäuren |
| DE4445728A1 (de) * | 1994-12-21 | 1996-06-27 | Simmet Th Prof Dr | Verwendung von Boswelliasäure zur Behandlung von Hirntumoren |
| US5536506A (en) * | 1995-02-24 | 1996-07-16 | Sabinsa Corporation | Use of piperine to increase the bioavailability of nutritional compounds |
| CN1064264C (zh) * | 1998-04-28 | 2001-04-11 | 山东省滨州卫生学校 | 富硒灵芝在制备治疗银屑病的药物中的应用 |
| US6399105B1 (en) * | 1999-01-20 | 2002-06-04 | Peter Donald Collin | Sea cucumber carotenoid lipid fraction products and methods of use |
| CA2372772A1 (en) * | 1999-04-30 | 2000-11-09 | Sabinsa Corporation | Compositions of boswellic acids derived from boswellia serrata gum resin, for treating lymphoproliferative and autoimmune conditions |
| CA2451267A1 (en) * | 2002-12-13 | 2004-06-13 | Warner-Lambert Company Llc | Pharmaceutical uses for alpha2delta ligands |
| GB0230203D0 (en) * | 2002-12-27 | 2003-02-05 | Domantis Ltd | Fc fusion |
| CA2511843C (en) * | 2002-12-30 | 2012-04-24 | Celgene Corporation | Fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds and their pharmaceutical uses |
-
2004
- 2004-10-14 JP JP2007524780A patent/JP4820819B2/ja not_active Expired - Fee Related
- 2004-10-14 WO PCT/US2004/033846 patent/WO2006022762A1/en active Application Filing
- 2004-10-14 AU AU2004322710A patent/AU2004322710B2/en not_active Ceased
- 2004-10-14 EP EP04795060.5A patent/EP1791423B1/en not_active Expired - Lifetime
- 2004-10-14 CN CN2004800436759A patent/CN101132693B/zh not_active Expired - Fee Related
- 2004-10-14 RU RU2007102720/14A patent/RU2366412C2/ru active
- 2004-10-14 PL PL04795060T patent/PL1791423T3/pl unknown
- 2004-10-14 ES ES04795060T patent/ES2422893T3/es not_active Expired - Lifetime
- 2004-10-14 NZ NZ552027A patent/NZ552027A/en not_active IP Right Cessation
- 2004-10-14 DK DK04795060.5T patent/DK1791423T3/da active
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670690A (zh) * | 2011-03-14 | 2012-09-19 | 苏州博创园生物医药科技有限公司 | 一种抗牛皮癣纯天然药物乳膏及其制备方法 |
| CN102670565A (zh) * | 2011-03-14 | 2012-09-19 | 苏州博创园生物医药科技有限公司 | 一种含天然药物的透皮吸收贴片 |
| CN103193853A (zh) * | 2012-01-06 | 2013-07-10 | 苏州博创园生物医药科技有限公司 | 用于治疗银屑病的化合物、组合物及其制备方法 |
| CN109328061A (zh) * | 2016-04-19 | 2019-02-12 | 阿祖拉眼科有限公司 | 用于治疗角化过度症的组合物 |
| US11517586B2 (en) | 2020-01-10 | 2022-12-06 | Azura Ophthalmics Ltd. | Instructions for composition and sensitivity |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006022762B1 (en) | 2006-05-04 |
| EP1791423A1 (en) | 2007-06-06 |
| JP4820819B2 (ja) | 2011-11-24 |
| WO2006022762A1 (en) | 2006-03-02 |
| RU2366412C2 (ru) | 2009-09-10 |
| ES2422893T3 (es) | 2013-09-16 |
| JP2008508354A (ja) | 2008-03-21 |
| PT1791423E (pt) | 2013-08-02 |
| AU2004322710A1 (en) | 2006-03-02 |
| ZA200700694B (en) | 2007-11-28 |
| EP1791423B1 (en) | 2013-05-01 |
| CN101132693B (zh) | 2012-11-07 |
| DK1791423T3 (da) | 2013-08-05 |
| AU2004322710B2 (en) | 2011-03-31 |
| NZ552027A (en) | 2009-10-30 |
| PL1791423T3 (pl) | 2013-09-30 |
| EP1791423A4 (en) | 2009-06-17 |
| RU2007102720A (ru) | 2008-09-10 |
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