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CN1615839A - 富马酸二烷基酯的用途 - Google Patents

富马酸二烷基酯的用途 Download PDF

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CN1615839A
CN1615839A CNA200410011769XA CN200410011769A CN1615839A CN 1615839 A CN1615839 A CN 1615839A CN A200410011769X A CNA200410011769X A CN A200410011769XA CN 200410011769 A CN200410011769 A CN 200410011769A CN 1615839 A CN1615839 A CN 1615839A
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autoimmune disease
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拉金德拉·K·乔希
汉斯-彼得·斯特雷贝尔
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Abstract

本发明涉及某些富马酸二烷基酯在制备用于移植医学或治疗自体免疫疾病的药学制剂中的用途，并涉及微片剂或丸剂形式的所述组合物。为此目的，所述富马酸二烷基酯也可以与在移植医学使用的常规制剂以及免疫抑制剂，尤其是环孢菌素组合使用。

Description

富马酸二烷基酯的用途
本申请是1999年10月29日提交的，发明名称为“富马酸二烷基酯的用途”的中国专利申请99812388.9的分案申请。
技术领域
本发明涉及富马酸二烷基酯在制备用于移植医学或治疗自体免疫疾病的药学制剂中的用途，并涉及微片剂或微丸剂形式的含有富马酸二烷基酯的药学制剂。
因此，一方面它尤其涉及富马酸二烷基酯在制备治疗、减少或抑制受者对移植物的排斥反应，即宿主抗移植物反应，或移植物对受者的排斥反应，即移植物抗宿主反应的药学制剂中的用途。另一方面，它涉及富马酸二烷基酯在制备治疗自体免疫疾病如多关节炎、多发性硬化、幼年发病性糖尿病、桥本甲状腺炎、格雷夫斯病、系统性红斑狼疮(SLE)、斯耶格伦综合征、恶性贫血和慢性活动型(类狼疮)肝炎的药学制剂中的用途。
背景技术
移植物排斥和自体免疫疾病都是以医学不良反应或免疫系统的调节障碍为基础的。细胞素如白细胞介素或肿瘤坏死因子α(TNF-α)为影响免疫系统的基本介质。通常给予免疫抑制剂如环孢菌素对二者进行治疗。
作为总的结果，自体免疫疾病可被定义为内源性物质或抗原的耐受性的衰退。通常这种耐受性仅在抗原与免疫细胞接触时能够被保持。当这种耐受性丧失时，形成自体抗体，即对内源性组织的体液免疫应答。尚不知TNF-α影响的确切性质。
移植为组织或器官移植，即组织如角膜、皮肤、骨(碎骨片)、血管或筋膜，器官如肾、心、肝、肺、胰腺、肠，或个别细胞如胰岛细胞、α-细胞和肝细胞的转移；肾是最重要的移植器官。
我们根据供者和受者之间的关联程度，区分自体移植(转移到同一个体机体的另一部位)、同系移植(转移到另一遗传学相同的个体)和同种异体移植(转移到另一同一物种的个体)。根据原始的和移植的部位，我们进一步区分同位移植(转移到同一部位)和异位移植(转移到不同部位)。上述移植在现代医学中起到重要的作用。
移植医学中的主要问题是在组织、器官或细胞移植之后由于受者的免疫防御反应引起的移植物排斥。这种移植物排斥也称为宿主抗移植物反应。机体对异体蛋白的免疫防御反应经常导致移植物的排斥或溶解。在宿主抗移植物反应中，可以区分为不同的阶段。根据受者和供者之间的差异程度，这种反应以不同的速度发生，因此我们称之为急性、亚急性或慢性反应。作为动脉炎或小动脉炎的结果，急性排斥过程在48小时内伴随着移植物的不可逆丧失(坏死)，并且不能通过给予药物影响之。作为移植物的血管病变的结果，亚急性排斥反应作为从12天到4个月的排斥危象表现显著，并伴随不可逆的功能紊乱。最后，将作为血管变化如持续数周或数年并且几乎不受药物影响的堵塞性血管病变的结果的移植物功能丧失称为慢性排斥反应。
反之亦然，移植物对受者的排斥反应，所谓的移植物抗宿主反应可以在免疫活性组织被移植时发生，即主要在骨髓移植中发生。再者，将反应的严重性分级，则有与宿主抗移植物反应基本类似的并发症结果，即动脉病和坏死。
为了避免这种排斥反应，即宿主抗移植物反应和移植物抗宿主反应，移植医学主要利用免疫抑制，即减弱正常免疫应答。为此目的，通常将抗淋巴细胞血清与皮质甾类和所谓的抗代谢物例如嘌呤类似物如作用于核酸和蛋白质合成并因此阻止细胞分裂和增殖的6-巯基嘌呤和硫鸟嘌呤合用。它导致对抗体产生和细胞免疫应答的抑制。用于治疗的免疫抑制剂是特异性或非特异性地抑制或减弱机体的免疫反应的物质。非特异性免疫抑制剂为细胞生长抑制剂如烷化剂或抗代谢物。
此外，已知导致至少部分特异性免疫抑制的活性成分，如皮质甾类、抗血清、抗体FK-506、藤霉素、mycophenolatemofetil和基本环孢菌素如环孢菌素A。使用现代免疫抑制剂，其最为重要的代表物为环孢菌素，尤其是环孢菌素A，结果是可能在最后数年显著地改善移植的结果。目前，一年后的存活率是，肝移植约为60％、心移植约为80％，肾移植约为90％。
内源性免疫系统攻击内源性器官、组织和细胞的自体免疫疾病与移植物抗宿主反应类似。这些也是免疫系统的医学不良反应，可采用免疫抑制剂对其进行治疗。
发明内容
使用免疫抑制剂的危险在于减弱机体对感染性疾病的防御和增加恶性疾病的风险。因此，本发明的目的是提供在移植医学中采用的，可以用于治疗，尤其是抑制、减弱和/或缓解宿主抗移植物反应和移植物抗宿主反应，但没有上述缺陷的药学制剂。
本发明的另一目的是提供可被用于治疗自体免疫疾病，尤其是多关节炎、多发性硬化、幼年发病性糖尿病、桥本甲状腺炎、格雷夫斯病、系统性红斑狼疮(SLE)、斯耶格伦综合征、恶性贫血和慢性活动型(类狼疮)肝炎，但不具有免疫抑制缺陷的药学制剂。
本发明的目的通过使用某些富马酸二烷基酯制备用于移植医学和治疗自体免疫疾病的药学制剂，以及微片剂和微丸剂形式的含有这些富马酸二烷基酯的药学制剂来实现。在权利要求中详细表征了本发明的各主题。本发明的制剂本身不含有任何游离富马酸。
已知在给予后经生物降解进入柠檬酸循环或是其部分的药学制剂，获得增加的治疗意义—尤其是在高剂量给予时，因为它们可以缓解或治愈隐源性疾病。
例如，富马酸抑制小鼠埃利希腹水肿瘤的生长，降低丝裂霉素C和黄曲霉素的毒性作用，并表现出治牛皮癣和抗菌活性。在过去，当非肠道给予、经皮给予和尤其是经口服给予时，高剂量的目前已知的富马酸或其衍生物如二羟基富马酸、富马酰胺和富马腈(fumaronitrile)具有不能接受的严重的副作用和高毒性以致于在大多数情况下，不得不放弃这种治疗。
令人惊奇的是，本申请人所进行的研究已表明富马酸氢甲酯、富马酸二甲酯的代谢物最初增加外周血液的人体单核细胞(外周血液单核细胞＝PBMC细胞)和分离的单核细胞中内毒素促进的TNF-α的分泌。此外，本申请人能够表明富马酸对体内和体外的血凝集作用有影响，该影响可以与环孢菌素比较。
令人惊奇的是，现已发现富马酸二烷基酯在制备用于移植医学和治疗自体免疫疾病的药学组合物中是有利的。这是因为含有这种富马酸二烷基酯的组合物在宿主抗移植物反应、移植物抗宿主反应和其它自体免疫疾病中令人惊奇地允许免疫系统的正调节。
欧洲专利申请0188749已描述了治疗牛皮癣的富马酸衍生物和含有其的药学组合物。治疗牛皮癣的含有富马酸和其它富马酸衍生物的混合物的药学组合物从DE-A-2530372获知。对这些药物来说含有游离富马酸是必须的。
DE-A-2621214描述了治疗牛皮癣的含有作为活性成分的富马酸单乙酯及其天然盐的药物。出版物“Hautarzt(Dermatologist)(1987)279-285”讨论了富马酸单乙酯盐的用途。从EP 0312697 Bl已知用于治疗牛皮癣、牛皮癣关节炎、神经性皮炎和节段性回肠炎(enteritisregionalis Crohn)的含有富马酸单烷酯盐和富马酸二酯的混合物的药学制剂。
具体实施方案
具体说，本发明的目的是通过使用一种或多种分子式如下的富马酸二烷基酯制备用于移植医学或治疗自体免疫疾病的药学制剂来实现的：
其中，R1和R2可以相同或不同，独立地代表直链的、支链的或环状的饱和或不饱和的C1-20烷基，这些烷基可以任选地被卤素(氯、氟、碘、溴)、羟基、C1-4烷氧基、硝基或氰基取代。
C1-20的烷基，优选是C1-8的烷基，最优选是C1-5烷基，例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、环戊基、2-乙基己基、己基、环己基、庚基、环庚基、辛基、乙烯基、烯丙基、2-羟乙基、2或3-羟丙基、2-甲氧基乙基、甲氧基甲基或2-或3-甲氧基丙基。优选R1或R2中至少一个为C1-5的烷基，尤其是甲基或乙基。更优选R1和R2为相同或不同的C1-5的烷基如甲基、乙基、正丙基或叔丁基，特别优选是甲基和乙基。最优选的是R1和R2相同并且是甲基或乙基。特别优选是富马酸二甲酯、富马酸甲基乙基酯和富马酸二乙酯。
本发明所用的富马酸二烷基酯由本领域已知的方法制备(参见例如EP 0312697)。
优选将该活性成分用于制备任选地在胶囊或小药囊中的片剂、微片剂、丸剂或者颗粒剂形式的口服制剂。任选地装填在胶囊或小药囊中的微片剂或丸剂形式的制剂是优选的，并且也是本发明的主题。口服制剂可以被肠溶包衣包被。胶囊可以是软或硬明胶胶囊。
根据本发明的富马酸二烷基酯可以单独或以几种化合物的混合物使用，任选地与常规载体和赋形剂组合。通过以下方式选择用量：所得的制剂含有的活性成分的量相当于10-300毫克富马酸。
优选的本发明的制剂含有总量为10-300毫克富马酸二甲酯和/或富马酸二乙酯。
根据优选的实施方案，丸剂的大小或微片剂的平均直径在300-2000微米的范围内，特别是在500或1000微米的范围内。
除了移植物抗宿主反应(参见上述)以外，以下被治疗的自体免疫疾病可以被命名为：多关节炎、多发性硬化、移植物抗宿主反应、幼年发病性糖尿病、桥本甲状腺炎、格雷夫斯病、系统性红斑狼疮(SLE)、斯耶格伦综合征、恶性贫血和慢性活动型(类狼疮)肝炎。自体免疫疾病在更广意义上也包括牛皮癣、牛皮癣关节炎、神经性皮炎和节段性回肠炎。
除了上述的微丸剂、微片剂、胶囊(如软或硬胶明胶胶囊)、颗粒剂和片剂形式的口服给予的制剂以外，适宜的药学制剂为软膏剂、硬膏药、洗剂或淋洗(shower)剂形式的皮肤和经皮给予的制剂，含水微分散体、水包油型乳剂形式的非肠道给予的制剂，或者栓剂或微灌肠剂形式的用于直肠给药的油性溶液，微片剂或微丸剂形式的药学制剂对上述包括牛皮癣、牛皮癣关节炎、神经性皮炎和节段性回肠炎的自体免疫疾病的治疗是优选的，并且它也是本发明的主题。
根据本发明，用富马酸二烷基酯的治疗也可以与一种或多种在器官移植中常规使用的三联药物治疗制剂组合或只与环孢菌素A组合进行。为此目的，给予的制剂可以分别含有已知剂量或数量的活性成分的组合。同样，组合治疗可以由通过相同或不同途径平行给予单独的制剂组成。任选地，除根据本发明给予的富马酸衍生物的剂量之外，可有利地将含有的活性成分的剂量减小。
根据本本发明的用途的另一实施方案为顺序应用上述富马酸二烷基酯来改变采用免疫抑制剂如环孢菌素的药物治疗。这意味着在应用以上定义的富马酸衍生物一周或数周后可以接着进行一周或数周的环孢菌素的治疗。这使得环孢菌素A的剂量减少，结果使长期治疗的副作用出现的比率显著降低。
通过给予优选的微片剂形式的富马酸二烷基酯，则与富马酸衍生物和盐相比，在给予常规片剂时已经减少但仍被观察到的胃肠刺激和副作用可以进一步地减少。
推测在给予常规的片剂时，片剂的成分在肠中以过高的浓度释放，造成肠粘膜的局部刺激。这种局部刺激导致短期内很高浓度的TNF-α的释放，这可能是形成胃肠副作用的原因。另一方面，在应用胶囊中的肠溶包衣的微片剂的情况下，在肠上皮细胞中形成很低的活性成分的局部浓度。微片剂由胃增量释放并通过蠕动进入小肠，从而改善活性成分的分布。
这意味着相同剂量的肠溶包衣微片剂已分布在胃中并分部分进入肠中，其中活性成分以较小的剂量释放。这就避免了肠上皮细胞的局部刺激和TNF-α的释放。推测这导致与常规的片剂相比微片剂的改善的在胃肠道中的耐受性。
此外吸收得以改善，因为根据本发明使用的富马酸二烷基酯本身不是活性成分，而是所谓的前药，它必须在体内转化成活性成分。
为了说明根据本发明的用途，以下给出了不同的用于制备优选的药物的实施例。
制备实施例
大体上，可以采用典型的制片方法制备片剂或微片剂形式的本发明的口服制剂。也可以采用其它制备片剂的方法代替典型的制片方法，如直接压片和根据熔化法和喷雾干燥法制备固体分散体的方法。
片剂可以被肠溶包衣包被。肠溶包衣可以在典型的包衣锅中施加，或在流化床设备中喷施或施加。片剂也可以被薄膜包衣包被。
实施例1
制备在胶囊内的含有120.0毫克富马酸二甲基酯，相当于96毫克富 马酸的肠溶包衣的微片剂
采取必要的预防措施(口罩、手套、防护衣等)，将12.000千克富马酸二甲酯粉碎、混合并用筛网800均化。然后制备具有以下组成的赋形剂混合物：17.50千克淀粉衍生物(STA-RX1500)、0.30千克微晶纤维素(AvicelPH 101)、0.75千克PVP(Kollidon120)、4.00千克Primogel、0.25千克胶态硅酸(Aerosil)。将活性成分加至整个粉末混合物中，混合，用筛网200均化，采用2％的聚乙烯吡咯烷酮(KollidonK25)水溶液以常规方式加工以得到粘合剂颗粒，然后在干燥状态下与外相混合。所述外相由0.50千克硬脂酸镁和1.50千克滑石组成。
然后以常规的方式压制该粉末混合物得到毛重为10.0毫克且直径为2.0毫米的凸形片剂。
实现抵抗胃酸的一个例子是将2.250千克羟丙基甲基纤维素邻苯二甲酸酯(HPMCP，PharmacoatHP50)溶液分部分溶于以下溶剂的混合物中：13.00升丙酮、13.50升乙醇(94wt.-％，用2％的甲酮变性)和1.50升软化水。在最终溶液中加入作为增塑剂的蓖麻油(0.240千克)并以常规方式分部分施加于片芯上。
干燥完成后，在同一设备中施加组成如下的悬浮液作为薄膜包衣：0.340千克滑石、0.400千克钛(VI)、氧化物Cronus RN56、0.324千克着色漆L-Rot-Lack 86837、4.800千克Eudragit E12.5％和0.120千克聚乙二醇6000、在组成如下的溶剂混合物中的pH11XI：8.170千克2-丙醇、0.200千克软化水和0.600千克三醋酸甘油酯(三醋精)。
然后将肠溶包衣的微片剂装填到净重为400毫克硬明胶胶囊中并封口。
实施例2
制备在胶囊内的含有120.0毫克富马酸二甲酯，相当于96毫克富马 酸的肠溶包衣的微片剂
将12.000千克富马酸二甲酯如上粉碎并均化。然后制备组成如下的赋形剂混合物：23.20千克微晶纤维素(AvicelPH 200)、3.00千克Croscarmellose钠(AC-Di-SOL-SD-711)、2.50千克滑石、0.10千克无水二氧化硅(Aerosil200)和1.00千克硬脂酸镁。然后将活性成分加至整个粉末混合物中并均匀地混合。接着通过直接压片将该粉末混合物压成毛重为10.0毫克且直径为2.00毫米的凸形片剂。
然后，制备还含有0.07千克邻苯二甲酸二丁酯的0.94 Eudragit的异丙醇溶液。将该溶液喷至片芯上。接着，制备在水中的17.32千克EudragitLD-55和2.80千克微滑石、2.00千克Macrogol 6000与0.07千克dimeticon的混合物的悬浮液并将其喷至该芯上。
接着，将肠溶包衣的微片剂装填至具有净重为650毫克硬明胶胶囊中并封口。
实施例3
制备在胶囊内的含有50.0毫克富马酸二甲酯，相当于40毫克富马酸 的微丸剂
将5.000千克富马酸二甲酯如上粉碎并均化。此外，制备2升20％(m/v)的聚乙烯吡咯烷酮乙醇溶液(Kollidon K-30)。向包衣锅中的7.250千克非球形(nonpareilles)小丸喷施部分Kollidon K-30溶液直至轻微湿润。然后分部分加入活性成分直至该小丸干燥。该湿润/干燥过程持续到已加入所有的活性成分的混合物。接着摇动该小丸直至完全干燥。
之后，将该小丸装填至硬明胶胶囊中(126.5毫克小丸/胶囊)。
实施例4
制备含有110.0毫克富马酸二甲酯，相当于88毫克富马酸的肠溶包 衣胶囊
将11.000千克富马酸二甲酯在由14.00千克淀粉、5.65千克乳糖、2.00千克微晶纤维素(Avicel)、1.00千克聚乙烯吡咯烷酮(Kollidon25)和2.443千克Primogel组成的混合物中剧烈混合，采取必要的预防措施(口罩、手套、防护衣)，用筛网800均化。
以常规方式采用2％的聚乙烯吡咯烷酮(KollidonK25)水溶液将整个粉末混合物加工成粘合剂颗粒，并在干燥时与外相混合。所述外相由0.350千克胶态硅酸(Aerosil)、0.500千克硬脂酸镁和1.500千克滑石组成。将该均匀的混合物以400毫克分部分地装填到适宜的胶囊中，然后以常规的方式使其被由硬脂酸羟丙基甲基纤维素酯和作为增塑剂的蓖麻油组成的肠溶包衣包被。也可以将产物装填至适宜的由乙酸邻苯二甲酸纤维素(CAP)和羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)的混合物组成的的肠溶包衣胶囊中来代替采用硬明胶胶囊。
与现有技术的物质如可能导致大量肾病或淋巴增生系统疾病的环孢菌素相比，采用本发明的富马酸衍生物治疗以上所列的适应症很少导致严重的副作用。
其中，环孢菌素的免疫抑制作用是由Th-1细胞形成的抑制导致的。本申请人的进行的体外试验已表明富马酸酯导致Th1型的细胞素模式向Th2型的细胞素模式的转换。
特别是考虑到在移植物抗宿主反应和宿主抗移植物反应或其它自体免疫疾病如多发性硬化中通常需要的长期治疗和预防，本发明的用途的未预期的效果是最令人感兴趣的。在采用环孢菌素与富马酸衍生物的组合治疗中，前一化合物的毒副作用可以未预期地被显著降低。此外，本发明的用途在取代已知的伴有严重副作用的自体免疫疾病的皮质甾类治疗方面也是有意义的。

Claims (20)

1.一种或多种富马酸二烷基酯在制备用于治疗在器官和细胞移植中的宿主抗移植物反应或移植物抗宿主反应的药学制剂中的用途。
2.一种或多种富马酸二烷基酯在制备用于治疗自体免疫疾病的药学制剂中的用途，所述自体免疫疾病选自幼年发病性糖尿病、桥本甲状腺炎、格雷夫斯病、系统性红斑狼疮(SLE)、斯耶格伦综合征、恶性贫血和慢性活动型(类狼疮)肝炎。
3.一种或多种分子式如下的富马酸二烷基酯的根据权利要求1或2的在制备用于移植医学或治疗自体免疫疾病的药学制剂中的用途，所述自体免疫疾病选自幼年发病性糖尿病、桥本甲状腺炎、格雷夫斯病、系统性红斑狼疮(SLE)、斯耶格伦综合征、恶性贫血和慢性活动型(类狼疮)肝炎，
其中，R1和R2可以相同或不同，独立地代表直链的、支链的或环状的饱和或不饱和的C1-20烷基，这些烷基可以任选地被卤素(氯、氟、碘、溴)、羟基、C1-4烷氧基、硝基或氰基取代。
4.根据权利要求3的用途，特征在于自由基R1和R2为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、环戊基、2-乙基己基、己基、环己基、庚基、环庚基、辛基、乙烯基、烯丙基、2-羟乙基、2和/或3-羟丙基、2-甲氧基乙基、甲氧基乙基或2-或3-甲氧基丙基。
5.根据权利要求3或4的用途，特征在于R1和R2相同并代表甲基或乙基。
6.根据权利要求1-5的任一项权利要求的用途，其中的活性成分被配方成任选地在胶囊或小药囊中的片剂、微片剂、丸剂或者颗粒剂形式的口服制剂。
7.根据权利要求6的用途，特征在于所述丸剂的大小或微片剂的平均直径在300-2000微米的范围内。
8.根据权利要求1-7的用途，特征在于所述制剂以软或硬明胶胶囊的形式存在。
9.根据权利要求1-8的任一项权利要求的用途，其中所述制剂含有相当于10-300毫克富马酸的量的活性成分。
10.根据权利要求6-9的用途，特征在于单位剂量的药物被肠溶包衣包被。
11.根据权利要求1-5的用途，特征在于所述药物以皮肤和经皮给予的制剂、非肠道给予的制剂以及直肠给予的制剂的形式使用。
12.一种或多种富马酸二烷基酯在制备微片剂或丸剂形式的用于治疗自体免疫疾病的药学制剂中的用途，所述自体免疫疾病选自多关节炎、多发性硬化、幼年发病性糖尿病、桥本甲状腺炎、格雷夫斯病、系统性红斑狼疮(SLE)、斯耶格伦综合征、恶性贫血和慢性活动型(类狼疮)肝炎。
13.一种或多种分子式如下的富马酸二烷基酯的根据权利要求15的在制备用于治疗自体免疫疾病的药学制剂中的用途，所述自体免疫疾病选自多关节炎、多发性硬化、幼年发病性糖尿病、桥本甲状腺炎、格雷夫斯病、系统性红斑狼疮(SLE)、斯耶格伦综合征、恶性贫血和慢性活动型(类狼疮)肝炎，
其中，R1和R2可以相同或不同，独立地代表直链的、支链的或环状的饱和或不饱和的C1-20烷基，这些烷基可以任选地被卤素(氯、氟、碘、溴)、羟基、C1-4烷氧基、硝基或氰基取代。
14.根据权利要求13的用途，特征在于自由基R1和R2为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、环戊基、2-乙基己基、己基、环己基、庚基、环庚基、辛基、乙烯基、烯丙基、2-羟乙基、2和/或3-羟丙基、2-甲氧基乙基、甲氧基乙基或2-或3-甲氧基丙基。
15.根据权利要求12或13的用途，特征在于R1和R2相同并代表甲基或乙基。
16.根据权利要求12-15的任一项权利要求的用途，其中将活性成分配方成在胶囊或小药囊中的片剂、微片剂、丸剂形式的口服制剂。
17.根据权利要求12-16的任一项权利要求的用途，特征在于丸剂的大小或微片剂的平均直径在300-2000微米的范围内。
18.根据权利要求16的用途，特征在于制剂以软或硬明胶胶囊的形式存在。
19.根据权利要求12-18的任一项权利要求的用途，其中的制剂含有相当于10-300毫克富马酸的量的活性成分。
20.根据权利要求16-19的用途，特征在于单位剂量的药物被肠溶包衣包被。
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Families Citing this family (115)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19853487A1 (de) * 1998-11-19 2000-05-25 Fumapharm Ag Muri Verwendung von Dialkylfumaraten
DE10000577A1 (de) 2000-01-10 2001-07-26 Fumapharm Ag Muri Verwendung von Fumarsäurederivaten zur Behandlung mitochondrialer Krankheiten
US6912052B2 (en) * 2000-11-17 2005-06-28 Cymer, Inc. Gas discharge MOPA laser spectral analysis module
DE10101307A1 (de) * 2001-01-12 2002-08-01 Fumapharm Ag Muri Fumarsäurederivate als NF-kappaB-Inhibitor
ATE447945T1 (de) * 2001-01-12 2009-11-15 Biogen Idec Internat Gmbh Verwendung von fumarsäureamiden
US20050259709A1 (en) * 2002-05-07 2005-11-24 Cymer, Inc. Systems and methods for implementing an interaction between a laser shaped as a line beam and a film deposited on a substrate
DE10217314A1 (de) 2002-04-18 2003-11-13 Fumapharm Ag Muri Carbocyclische und Oxacarboncyclische Fumarsäure-Oligomere
AU2003236156A1 (en) * 2003-04-24 2005-01-04 Shin-Jen Shiao Pharmaceutical compositions used for immune disease treatment and improvement
US7277188B2 (en) * 2003-04-29 2007-10-02 Cymer, Inc. Systems and methods for implementing an interaction between a laser shaped as a line beam and a film deposited on a substrate
CA2526586C (en) * 2003-09-09 2010-03-16 Fumapharm Ag The use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
DE10360869A1 (de) * 2003-09-09 2005-04-07 Fumapharm Ag Verwendung von Fumarsäurederivaten zur Therapie der Herzinsuffizienz, der Hyperkeratose und von Asthma
DE10342423A1 (de) * 2003-09-13 2005-04-14 Heidland, August, Prof. Dr.med. Dr.h.c. Verwendung von Fumarsäurederivaten zur Prophylaxe und zur Behandlung von Genomschäden
US6873418B1 (en) 2003-09-30 2005-03-29 Cymer, Inc. Optical mountings for gas discharge MOPA laser spectral analysis module
US6894785B2 (en) * 2003-09-30 2005-05-17 Cymer, Inc. Gas discharge MOPA laser spectral analysis module
CA2478458A1 (en) * 2004-08-20 2006-02-20 Michael Panzara Treatment of pediatric multiple sclerosis
ES2582942T3 (es) * 2004-10-08 2016-09-16 Forward Pharma A/S Composiciones farmacéuticas de liberación controlada que comprenden un éster de ácido fumárico
US20080004344A1 (en) * 2004-11-10 2008-01-03 Aditech Pharma Ab Novel Salts of Fumaric Acid Monoalkylesters and Their Pharmaceutical Use
US7653095B2 (en) * 2005-06-30 2010-01-26 Cymer, Inc. Active bandwidth control for a laser
EP1915334A2 (en) * 2005-07-07 2008-04-30 Aditech Pharma AB Novel salts of fumaric acid monoalkylesters and their pharmaceutical use
EP1915387B1 (en) 2005-07-07 2010-01-20 Aditech Pharma AG Novel glucopyranose esters and glucofuranose esters of alkyl- fumarates and their pharmaceutical use
EP1940382A2 (en) * 2005-10-07 2008-07-09 Aditech Pharma AB Combination therapy with fumaric acid esters for the treatment of autoimmune and/or inflammatory disorders
JP2009510137A (ja) * 2005-10-07 2009-03-12 アディテック・ファルマ・アクチボラゲット フマル酸エステルを含む制御放出医薬組成物
US7317179B2 (en) * 2005-10-28 2008-01-08 Cymer, Inc. Systems and methods to shape laser light as a homogeneous line beam for interaction with a film deposited on a substrate
US7679029B2 (en) * 2005-10-28 2010-03-16 Cymer, Inc. Systems and methods to shape laser light as a line beam for interaction with a substrate having surface variations
US20100130607A1 (en) 2007-02-08 2010-05-27 Ralf Gold Neuroprotection in demyelinating diseases
PL2137537T3 (pl) 2007-02-08 2013-10-31 Biogen Ma Inc Kompozycje i zastosowania do leczenia stwardnienia rozsianego
RU2361605C2 (ru) * 2007-08-01 2009-07-20 Федеральное агентство по высокотехнологичной медицинской помощи Федеральное государственное учреждение "Уральский научно-исследовательский институт дерматовенерологии и иммунопатологии" (ФГУ УрНИИДВиИ Росмедтехнологий) Способ лечения псориаза
DE102008030023A1 (de) 2008-06-16 2009-12-17 Eberhard-Karls-Universität Tübingen Universitätsklinikum Arzneimittel zur Behandlung einer durch Parasiten verursachten Krankheit
PL2334378T3 (pl) 2008-08-19 2014-09-30 Xenoport Inc Proleki wodorofumaranu metylu, ich kompozycje farmaceutyczne i sposoby zastosowania
ES2411972T5 (es) 2009-01-09 2021-10-27 Fwp Ip Aps Formulación farmacéutica que comprende uno o más ésteres de ácido fumárico en una matriz de erosión
JP2012525385A (ja) 2009-04-29 2012-10-22 バイオジェン・アイデック・エムエイ・インコーポレイテッド 神経変性および神経炎症の治療
PL2533634T3 (pl) * 2010-02-12 2016-04-29 Biogen Ma Inc Neuroprotekcja w chorobach demielinizacyjnych
EA201290808A1 (ru) 2010-02-18 2013-03-29 ХАЙ ПОЙНТ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи Замещенные конденсированные производные имидазола, фармацевтические композиции и способы их применения
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
WO2011116091A1 (en) 2010-03-17 2011-09-22 Novartis Ag Dispenser
LT2558499T (lt) 2010-04-16 2017-07-25 Biogen Ma Inc. Antikūnai prieš vla-4
US20140163100A1 (en) * 2011-05-26 2014-06-12 Biogen Idec Ma Inc. Methods of Treating Multiple Sclerosis and Preserving and/or Increasing Myelin Content
RS56972B1 (sr) 2011-06-08 2018-05-31 Biogen Ma Inc Postupak za pripremu visoko-čistog i kristalnog dimetil fumarata
RU2014125430A (ru) 2011-11-24 2015-12-27 Синтон Бв Контролируемое высвобождение частиц, содержащих диметилфумарат
US9504679B2 (en) 2011-12-19 2016-11-29 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and Nrf2 activators
US20130158077A1 (en) 2011-12-19 2013-06-20 Ares Trading S.A. Pharmaceutical compositions
JP5918395B2 (ja) 2012-02-07 2016-05-18 ゼノポート，インコーポレイティド モルホリノアルキルフマレート化合物、医薬組成物及び使用方法
AU2013203445C1 (en) * 2012-02-07 2017-04-20 Biogen Ma Inc. Pharmaceutical compositions containing dimethyl fumarate
CA2873098A1 (en) * 2012-05-23 2013-11-28 Cellixbio Private Limited Compositions and methods for the treatment of multiple sclerosis
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
JP2015527372A (ja) * 2012-08-22 2015-09-17 ゼノポート，インコーポレイティド 副作用を低減させるモノメチルフマレートおよびそのプロドラッグの投与方法
US20200000758A1 (en) * 2012-08-22 2020-01-02 Xenoport, Inc. Oral Dosage Forms Of Methyl Hydrogen Fumarate And Prodrugs Thereof
CN103483194B (zh) * 2012-11-30 2016-03-09 杨寅柯 一种2-氟代富马酸酯(结构式i)及其制备方法及应用
US20140171504A1 (en) 2012-12-14 2014-06-19 Georgia Regents Research Institute, Inc. Methods of Treating Sickle Cell Disease and Related Disorders Using Fumaric Acid Esters
TW201436790A (zh) 2012-12-21 2014-10-01 Biogen Idec Inc 經氘取代之反丁烯二酸酯衍生物類
KR101379427B1 (ko) * 2013-02-13 2014-03-28 경북대학교병원 디메틸푸마레이트를 유효성분으로 포함하는 신섬유증의 예방 또는 치료용 조성물
SG10201707543PA (en) 2013-03-14 2017-11-29 Alkermes Pharma Ireland Ltd Prodrugs of fumarates and their use in treating various deseases
US8669281B1 (en) 2013-03-14 2014-03-11 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
WO2014160633A1 (en) 2013-03-24 2014-10-02 Xenoport, Inc. Pharmaceutical compositions of dimethyl fumarate
WO2014197860A1 (en) 2013-06-07 2014-12-11 Xenoport, Inc. Method of making monomethyl fumarate
WO2014205392A1 (en) 2013-06-21 2014-12-24 Xenoport, Inc. Cocrystals of dimethyl fumarate
US20160206586A1 (en) 2013-08-26 2016-07-21 Forward Pharma A/S Pharmaceutical composition containing dimethyl fumarate for administration at a low daily dose
CN104415026A (zh) * 2013-08-31 2015-03-18 成都渊源生物科技有限公司 氘代富马酸衍生物在治疗多发性硬化症中的应用
US9416096B2 (en) 2013-09-06 2016-08-16 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US20150079180A1 (en) 2013-09-18 2015-03-19 Xenoport, Inc. Nanoparticle compositions of dimethyl fumarate
CN104434904B (zh) * 2013-09-22 2018-09-04 深圳翰宇药业股份有限公司 一种复方微丸胶囊的制备方法及其制备的复方微丸胶囊
UY35748A (es) * 2013-09-27 2015-04-30 Teva Pharma Terapia combinada con laquinimod para el tratamiento de la esclerosis múltiple
CA3135273A1 (en) * 2013-12-12 2015-06-18 Almirall, S.A. Pharmaceutical compositions comprising dimethyl fumarate
EP3079663A1 (en) 2013-12-13 2016-10-19 Biogen MA Inc. Controlled release dosage form for once daily administration of dimethyl fumarate
ES2753361T3 (es) 2014-02-24 2020-04-08 Alkermes Pharma Ireland Ltd Sulfonamida y profármacos de fumaratos de sulfinamida y su uso en el tratamiento de diversas enfermedades
EP3501510B1 (en) 2014-02-28 2020-07-01 Banner Life Sciences LLC Controlled release enteric soft capsules of fumarate esters
US9326947B1 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US9636318B2 (en) 2015-08-31 2017-05-02 Banner Life Sciences Llc Fumarate ester dosage forms
US10098863B2 (en) 2014-02-28 2018-10-16 Banner Life Sciences Llc Fumarate esters
MX389474B (es) 2014-03-14 2025-03-20 Biogen Ma Inc Dimetilfumarato y regimenes de vacunacion.
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
CN104027311A (zh) * 2014-05-09 2014-09-10 万特制药(海南)有限公司 一种含有富马酸二甲酯的肠溶缓释微丸
WO2016061393A1 (en) 2014-10-15 2016-04-21 Xenoport, Inc. Fumarate compounds, pharmaceutical compositions, and methods of use
DE102014015314A1 (de) 2014-10-17 2016-04-21 Ppm-Medical Holding Gmbh Mittel zur unterstützenden Immunmodulation
MA40985A (fr) 2014-11-17 2017-09-26 Biogen Ma Inc Méthodes de traitement de la sclérose en plaques
CN104490849A (zh) * 2014-11-24 2015-04-08 广东东阳光药业有限公司 一种高密度的富马酸二甲酯肠溶颗粒及其制备方法
WO2016089648A1 (en) 2014-12-01 2016-06-09 Vtv Therapeutics Llc Bach 1 inhibitors in combination with nrf2 activators and pharmaceutical compositions thereof
HK1245010A1 (zh) 2014-12-10 2018-08-24 明尼苏达大学董事会 用於治疗疾病的遗传修饰的细胞、组织和器官
MA41139A (fr) 2014-12-11 2017-10-17 Actelion Pharmaceuticals Ltd Combinaison pharmaceutique comportant un agoniste sélectif du récepteur sip1
PL3256125T3 (pl) 2014-12-11 2022-05-09 Actelion Pharmaceuticals Ltd Schemat dawkowania ponesimodu, selektywnego agonisty receptora s1p1
KR102283582B1 (ko) 2014-12-23 2021-07-30 한미약품 주식회사 푸마르산 에스테르를 함유하는 미니-정제 형태의 약제학적 제제
HK1253050A1 (zh) * 2015-02-02 2019-06-06 英仕柏集团有限责任公司 稳定的富马酸二烷基酯组合物
KR102487136B1 (ko) * 2015-02-08 2023-01-10 엘커메스 파마 아일랜드 리미티드 모노메틸푸마레이트 전구약물 조성물
US20180064653A1 (en) * 2015-03-17 2018-03-08 Hetero Labs Limited Pharmaceutical compositions of dimethyl fumarate
DK3273951T3 (da) 2015-03-27 2020-11-02 Symbionyx Pharmaceuticals Inc Sammensætninger og fremgangsmåder til behandling af psoriasis
CA2987895A1 (en) 2015-06-01 2016-12-08 Sun Pharmaceutical Industries Ltd. Pharmaceutical compositions of dimethyl fumarate
EP3310341A1 (en) 2015-06-17 2018-04-25 Biogen MA Inc. Dimethyl fumarate particles and pharmaceutical compositions thereof
US10213411B2 (en) 2015-08-27 2019-02-26 Vijaykumar Rajasekhar Use of prodrugs of fumarates in treating heart failure diseases
WO2017056107A1 (en) 2015-09-28 2017-04-06 Natco Pharma Ltd Pharmaceutical compositions of dimethyl fumarate
WO2017060400A1 (en) 2015-10-07 2017-04-13 Neurovive Pharmaceutical Ab Protected carboxylic acid-based metabolites for the treatment of disesases related to mitochondrial dysfunctions
DE102016103242A1 (de) * 2016-02-24 2017-08-24 Flexopharm Brain Gmbh & Co. Kg Mittel zur unterstützenden Immunmodulation
CA3003237A1 (en) * 2015-10-28 2017-05-04 Sun Pharmaceutical Industries Limited Pharmaceutical compositions of dimethyl fumarate
US10463642B2 (en) 2016-02-01 2019-11-05 Vijaykumar Rajasekhar Methods of treating heart failure diseases using prodrugs of methyl hydrogen fumarate
WO2017145036A1 (en) * 2016-02-25 2017-08-31 Aurobindo Pharma Ltd Pharmaceutical compositions comprising dimethyl fumarate
CN106265621B (zh) * 2016-09-19 2019-05-17 苏州大学 富马酸二甲酯在制备预防和治疗移植物抗宿主病及移植物抗白血病药物中的应用
GR1009149B (el) 2016-10-25 2017-10-31 Φαρματεν Αβεε Φαρμακευτικα σκευασματα που περιλαμβανουν εναν εστερα φουμαρικου οξεως και μεθοδος παραγωγης αυτων
TR201616998A1 (en) 2016-11-23 2018-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi DELAYED RELEASE DOSING FORMS WITH DIMETHYL FUMARATE
DE102017105036A1 (de) 2017-03-09 2018-09-13 Flexopharm Brain Gmbh & Co. Kg Mittel zur Anwendung bei der Behandlung der Dyslipidämie
EP3641736A1 (en) 2017-06-23 2020-04-29 Almirall, S.A. Pharmaceutical compositions comprising dimethyl fumarate
US12037398B2 (en) 2018-06-04 2024-07-16 Biogen Ma Inc. Anti-VLA-4 antibodies having reduced effector function
CA3135946C (en) 2019-05-31 2022-08-09 Myung-Hwa Kim Enteric tablet containing dimethyl fumarate
EP4003338A1 (en) 2019-07-22 2022-06-01 Actelion Pharmaceuticals Ltd Methods of treating multiple sclerosis
RU2742745C1 (ru) * 2019-09-24 2021-02-10 Акционерное общество "Исследовательский Институт Химического Разнообразия" Лекарственная форма в виде капсулы, содержащая таблетки с диметилфурмаратом
WO2021142062A1 (en) 2020-01-10 2021-07-15 Banner Life Sciences Llc Fumarate ester dosage forms with enhanced gastrointestinal tolerability
BR112022017754A2 (pt) 2020-03-06 2022-10-18 Actelion Pharmaceuticals Ltd Métodos para retardar a perda de volume cerebral
EP4117785A4 (en) 2020-03-13 2024-04-17 Marc J. Simard METHODS OF TREATMENT OF MULTIPLE SCLEROSIS
CN111418675A (zh) * 2020-04-23 2020-07-17 王坤全 一种幼儿保健茶
EP4146190A2 (en) 2020-05-06 2023-03-15 Imcyse SA Combination treatment for fumarate-related diseases
WO2022203432A1 (ko) 2021-03-25 2022-09-29 주식회사 큐라클 특정 약동학적 매개변수를 나타내는 디메틸푸마레이트를 유효성분으로 함유한 약학적 조성물
US20240216330A1 (en) * 2021-04-02 2024-07-04 Biogen Ma Inc. Combination treatment methods of multiple sclerosis
WO2022254356A1 (en) 2021-06-04 2022-12-08 Zim Laboratories Limited Delayed release compositions of dimethyl fumarate
US12357616B2 (en) 2021-10-11 2025-07-15 Vanda Pharmaceuticals Inc. Methods of treating multiple sclerosis
CA3221343A1 (en) 2021-10-11 2023-04-20 Allitia DIBERNARDO Methods of treating multiple sclerosis
CA3220702A1 (en) 2022-02-11 2023-08-17 Actelion Pharmaceuticals Ltd Methods of slowing an increase in brain ventricular volume
CN115590831A (zh) * 2022-10-26 2023-01-13 力品药业（厦门）股份有限公司（Cn） 一种富马酸二甲酯缓释微片及其制备方法

Family Cites Families (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1972109U (de) 1965-10-20 1967-11-09 Qualitrol Corp Schnellventil zum schutz elektrischer geraete.
DE1618162B1 (de) 1967-05-20 1971-05-19 Basf Ag Verfahren zur Herstellung con Cyclohexan-1.2.3.4.5.6-hexan-carbonsäure
US3832287A (en) * 1972-03-02 1974-08-27 Lilly Co Eli Dipeptide antibiotic and method for the production thereof
DE2212369A1 (de) 1972-03-15 1973-09-20 Basf Ag Cyclohexanhexacarbonsaeure
DE2530372A1 (de) * 1975-07-08 1977-01-13 Walter Dr Schweckendiek Pharmazeutische zubereitungen zur behandlung von psoriasis
DE2621214C3 (de) * 1976-05-13 1981-11-12 Koronis Gmbh Chemisch-Pharmazeutische Praeparate, 5441 Sassen Verwendung von Stabilisatoren in Arzneimitteln mit Fumarsäuremonoäthylester und desen Mineralsalzen
DE2840498C2 (de) * 1978-09-18 1980-04-10 Walter Dr. 6700 Ludwigshafen Schweckendiek Pharmazeutische Zubereitungen zur Behandlung von Psoriasis
DE3127432A1 (de) 1981-07-11 1983-02-03 Bayer Ag, 5090 Leverkusen Verfahren zur herstellung von fumarsaeuremonoester
US4894366A (en) 1984-12-03 1990-01-16 Fujisawa Pharmaceutical Company, Ltd. Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same
US5149695A (en) * 1985-01-15 1992-09-22 Speiser Peter P Fumaric acid derivatives, process for the production thereof and pharmaceutical compositions containing same
CH664150A5 (de) * 1985-01-15 1988-02-15 Peter Paul Prof Dr Speiser Fumarsaeureprodrug, verfahren zu seiner herstellung und dieses enthaltende darreichungsformen.
JPS61194020A (ja) 1985-02-22 1986-08-28 Dai Ichi Seiyaku Co Ltd 網膜症治療剤
GB2176999B (en) 1985-06-22 1989-07-12 Stanley Stewart Davis Sustained release medicament
DE3531597A1 (de) 1985-09-04 1987-03-05 Bioferon Biochem Substanz Verwendung von interferon-gamma (ifn-gamma) enthaltenden praeparationen zur behandlung psoriatischer erkrankungen
IL83775A (en) 1987-09-04 1991-12-15 Dexter Chemical Corp Amino acid esters and amides of fumaric acid and pharmaceutical compositions containing them for use in the treatment of psoriasis
US5242905A (en) * 1987-09-04 1993-09-07 Dexter Chemical Corporation Pharmaceutical compositions for the treatment of psoriasis
US5214196A (en) 1987-09-04 1993-05-25 Dexter Chemical Corporation Diethyl ester of di-glycyl fumaramide
US4959389A (en) 1987-10-19 1990-09-25 Speiser Peter P Pharmaceutical preparation for the treatment of psoriatic arthritis
US5424332A (en) 1987-10-19 1995-06-13 Speiser; Peter P. Pharmaceutical composition and process for the production thereof
DE3834794A1 (de) 1988-10-12 1990-04-19 F Schielein Oral zu verabreichendes mittel zur behandlung von psoriasis
AU1271592A (en) 1991-01-18 1992-08-27 Dexter Chemical Corporation Malic acid derivatives and compositions for the treatment of psoriasis
IT1251166B (it) 1991-08-09 1995-05-04 Chiesi Farma Spa Derivati di geneserina,loro preparazione e composizioni farmaceutiche che li contengono
WO1994028883A1 (en) 1993-06-08 1994-12-22 Brown Raymond K Therapeutic compositions and methods of use
CA2125763C (en) * 1993-07-02 2007-08-28 Maurice Kent Gately P40 homodimer of interleukin-12
US5407772A (en) 1993-11-30 1995-04-18 Xerox Corporation Unsaturated polyesters
US7888458B1 (en) 1993-11-30 2011-02-15 John B. Harley Diagnostics and therapy of epstein-barr virus in autoimmune disorders
DK0750616T3 (da) 1994-03-16 2001-07-23 Cenes Ltd Syreadditionssalte af 2,3,4,5-tetrahydro-1H-3-benzazapinforbindelser
US6576236B1 (en) 1994-07-01 2003-06-10 Dana Farber Cancer Institute Methods for stimulating T cell responses by manipulating a common cytokine receptor γ chain
GB2291422A (en) 1994-07-18 1996-01-24 Fujisawa Pharmaceutical Co 4-phenyl-pyrido[2,3-b]pyrazin-4-ones
IL110380A0 (en) 1994-07-20 1994-10-21 Agis Ind 1983 Ltd Antiviral topical pharmaceutical compositions
US5589504A (en) * 1994-07-26 1996-12-31 Cornell Research Foundation, Inc. Treatment of newborn jaundice
CN1125141A (zh) 1994-12-22 1996-06-26 杭州中美华东制药有限公司 一种含环孢菌素a的固体分散物及其外用剂型上的用途
US6011000A (en) 1995-03-03 2000-01-04 Perrine; Susan P. Compositions for the treatment of blood disorders
EP0850061A1 (en) 1995-09-13 1998-07-01 Takeda Chemical Industries, Ltd. Immunosuppressant
JPH1067658A (ja) * 1995-09-13 1998-03-10 Takeda Chem Ind Ltd 免疫抑制剤
JP4004567B2 (ja) 1996-02-14 2007-11-07 アステラス製薬株式会社 Ｗｂ２６６３ｂ物質を含有する免疫抑制剤
KR970064620A (ko) * 1996-03-05 1997-10-13 임성기 사이클로스포린-함유 외용약제 조성물
ATE199083T1 (de) 1996-04-22 2001-02-15 Shionogi & Co Terphenylverbindungen und sie enthaltende arzneimittel
KR20000015895A (ko) 1996-05-22 2000-03-15 유니버시티 오브 알버타 타입-2 케모카인 결합 단백질 및 그 이용방법
US6046180A (en) 1996-06-17 2000-04-04 Guilford Pharmaceuticals Inc. NAALADase inhibitors
EP1886677A1 (en) 1996-07-26 2008-02-13 Susan P. Perrine Use of an inducing agent for the treatment of blood, viral and cellular disorders
DE19651551C2 (de) * 1996-12-11 2000-02-03 Klinge Co Chem Pharm Fab Opioidantagonisthaltige galenische Formulierung
WO1998027970A2 (en) 1996-12-24 1998-07-02 National Research Council Of Canada Treatment of diseases or prevention of cellular damage caused by oxygen-containing free radicals
US5972363A (en) 1997-04-11 1999-10-26 Rohm And Haas Company Use of an encapsulated bioactive composition
DE19721099C2 (de) 1997-05-20 1999-12-02 Fumapharm Ag Muri Verwendung von Fumarsäurederivaten
ATE555780T1 (de) 1997-10-24 2012-05-15 John P Blass Nahrungsergänzungsmittel für metabolische hirnleistungsstörungen
DE19814358C2 (de) * 1998-03-31 2002-01-17 Fumapharm Ag Muri Verwendung von Alkylhydrogenfumaraten zur Behandlung von Psoriasis, psoriatischer Arthritis, Neurodermitis und Enteritis regionalis Crohn
DE19839566C2 (de) * 1998-08-31 2002-01-17 Fumapharm Ag Muri Verwendung von Fumarsäurederivaten in der Transplantationsmedizin
DE19848260C2 (de) 1998-10-20 2002-01-17 Fumapharm Ag Muri Fumarsäure-Mikrotabletten
DE19853487A1 (de) * 1998-11-19 2000-05-25 Fumapharm Ag Muri Verwendung von Dialkylfumaraten
DE10000577A1 (de) * 2000-01-10 2001-07-26 Fumapharm Ag Muri Verwendung von Fumarsäurederivaten zur Behandlung mitochondrialer Krankheiten
CA2399623A1 (en) 2000-02-11 2001-08-16 Philadelphia Health And Education Corporation Differentiation of bone marrow cells into neuronal cells and uses therefor
WO2002002190A2 (en) 2000-07-05 2002-01-10 Johns Hopkins School Of Medicine Prevention and treatment of neurodegenerative diseases by glutathione and phase ii detoxification enzymes
DE10101307A1 (de) 2001-01-12 2002-08-01 Fumapharm Ag Muri Fumarsäurederivate als NF-kappaB-Inhibitor
ATE447945T1 (de) 2001-01-12 2009-11-15 Biogen Idec Internat Gmbh Verwendung von fumarsäureamiden
US20050043408A1 (en) 2001-10-15 2005-02-24 Faustinus Yeboah Anti-glycation agents for preventing age- diabetes- and smoking-related complications
DE10217314A1 (de) 2002-04-18 2003-11-13 Fumapharm Ag Muri Carbocyclische und Oxacarboncyclische Fumarsäure-Oligomere
SI1477166T1 (sl) 2003-04-28 2006-12-31 Biofrontera Bioscience Gmbh Uporaba riluzola, kombiniranega s primernimi pomoznimi in dodatnimi snovmi, za zdravljenje bolezni,za katere je znacilna hiperproliferacija keratinocitov, se zlasti nevrodermitisa in psoriaze
CA2526586C (en) 2003-09-09 2010-03-16 Fumapharm Ag The use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
DE10342423A1 (de) 2003-09-13 2005-04-14 Heidland, August, Prof. Dr.med. Dr.h.c. Verwendung von Fumarsäurederivaten zur Prophylaxe und zur Behandlung von Genomschäden
US20050096369A1 (en) 2003-11-04 2005-05-05 Hoang Ba X. Compositions and methods for treating cellular proliferation disorders
EP1781303A4 (en) * 2004-06-30 2008-07-02 Combinatorx Inc METHOD AND REAGENTS FOR THE TREATMENT OF METABOLISM DISEASES
ES2582942T3 (es) 2004-10-08 2016-09-16 Forward Pharma A/S Composiciones farmacéuticas de liberación controlada que comprenden un éster de ácido fumárico
EP1812374A1 (en) 2004-11-10 2007-08-01 Aditech Pharma AB Novel salts of fumaric acid monoalkylesters and their pharmaceutical use
US20090202527A1 (en) 2004-11-19 2009-08-13 Biogen Idec Ma Inc. Treatment for multiple sclerosis
DE102005022845A1 (de) 2005-05-18 2006-11-23 Fumapharm Ag Thiobernsteinsäurederivate und deren Verwendung
US20100130607A1 (en) 2007-02-08 2010-05-27 Ralf Gold Neuroprotection in demyelinating diseases
PL2137537T3 (pl) 2007-02-08 2013-10-31 Biogen Ma Inc Kompozycje i zastosowania do leczenia stwardnienia rozsianego
JP2012525385A (ja) 2009-04-29 2012-10-22 バイオジェン・アイデック・エムエイ・インコーポレイテッド 神経変性および神経炎症の治療

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