CN1407890A - 牛皮癣的治疗 - Google Patents
牛皮癣的治疗 Download PDFInfo
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- CN1407890A CN1407890A CN01805911A CN01805911A CN1407890A CN 1407890 A CN1407890 A CN 1407890A CN 01805911 A CN01805911 A CN 01805911A CN 01805911 A CN01805911 A CN 01805911A CN 1407890 A CN1407890 A CN 1407890A
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- Prior art keywords
- nri
- psoriasis
- tomoxetine
- acid
- treatment
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Abstract
用甲肾上腺素再摄取抑制剂治疗牛皮癣。
Description
发明领域
本发明属于药物化学和皮肤病药物领域,提供一种治疗称作牛皮癣的皮肤病的方法。
发明背景
牛皮癣是一种令人痛苦的慢性皮肤病,它侵袭了超过7百万的美国人。每年发生多达250,000个新病例,牛皮癣典型地与受害者的年龄或性别没有太大的关系。女性的发病率略高于男性,据报道目前从初生婴儿到90岁的人均可能患此病。患者的痛苦和治疗费用,使牛皮癣成为一种沉重的社会负担。据估计,1999年牛皮癣门诊病人的治疗费用约为16-32亿美元,在美国每年约有超过150万的患者会因为此病而看医生。
目前,有一些治疗方案可供牛皮癣患者选择,这包括局部药物治疗、光疗法和内服药物治疗。局部治疗包括类固醇、煤焦油、地蒽酚、维生素D3及其类似物、维甲酸类和日光浴。与这些局部治疗有关的副作用包括皮肤变薄、抓痕、灼伤、刺激和光敏性。类固醇的应用也会产生抗药性,这可导致后续的类固醇治疗失效。光疗法包括在医师指导下施用紫外线B或补骨脂素和紫外线A的结合。长期的光疗法可使皮肤过早衰老并增加皮肤癌的发生率。典型地用于治疗最严重牛皮癣的内服药物治疗,包括施用氨甲蝶呤、口服维甲酸类和环孢霉素。应谨慎控制氨甲蝶呤的施用以避免肝损害。由于口服维甲酸类有可能导致严重的先天性缺陷,必须小心控制女性的应用。这种风险在停药之后还可持续几年。环孢霉素是一种免疫抑制剂,可用来治疗内服治疗失败的患者或者有其他内服治疗禁忌的人群。业已发现,不同疗法之间的转换,以及局部药物治疗与光疗法的联合,也是牛皮癣治疗的有效方案。
由于目前无法治愈牛皮癣,而且也没有使所有患者反应或耐受的可行疗法,因此需要一种治疗牛皮癣的新方法,该方法应对治疗效力、安全性和副作用均有改善。
发明简述
本发明提供一种治疗牛皮癣的方法,包括将有效量的去甲肾上腺素再摄取抑制剂给予需要这种治疗的病人。
本发明也提供去甲肾上腺素再摄取抑制剂在制备用于治疗牛皮癣的药物的中的用途。此外,本发明提供一种用于牛皮癣治疗的药物制剂,所述制剂中包含去甲肾上腺素再摄取抑制剂。
发明详述
许多化合物(包括下面详细讨论的化合物)均是去甲肾上腺素再摄取抑制剂,并且将来还会鉴定出更多的去甲肾上腺素再摄取抑制剂。在本发明的实践中,所述去甲肾上腺素再摄取抑制剂包括那些50%有效浓度为约1000nM或更低的再摄取抑制剂(采用Wong等在Drug Development Research,6,397(1985)中描述的方法测定)。用于本发明方法的去甲肾上腺素再摄取抑制剂,其特征在于:相对于其作为其他受体直接激动剂或拮抗剂的能力,它可选择性地抑制神经递质再摄取。适用于本发明方法的去甲肾上腺素再摄取抑制剂包括但不限于:
托莫西汀(Tomoxetine),即(R)-(-)-N-甲基-3-(2-甲基苯氧基)-3-苯基丙胺,通常以其盐酸盐形式施用。US4,314,081首先公开了托莫西汀。在此所用的术语“托莫西汀”是指该分子的任何酸加成盐或游离碱。有关托莫西汀作为去甲肾上腺素再摄取抑制剂的活性的讨论,例如参见Gehlert等,NeuroscienceLetters,157,203-206(1993);
式I化合物或其可药用盐:其中X为C1-C4烷基硫基,且Y为C1-C2烷基。Gehlert、Robertson和Wong在US5,281,624中,以及Gehlert等在Life Sciences,55(22),1915-1920,(1995)中描述了式I化合物。他们教导这些化合物可用作脑内去甲肾上腺素再摄取抑制剂。这些化合物也存在着立体异构体,它们不仅包括外消旋体,而且还包括可分离的单独异构体以及这些单独异构体的混合物。例如,式I化合物包括以下示例性化合物:
N-乙基-3-苯基-3-(2-甲硫基苯氧基)丙胺苯甲酸盐;
(R)-N-甲基-3-苯基-3-(2-丙硫基苯氧基)-丙胺盐酸盐;
(S)-N-乙基-3-苯基-3-(2-丁硫基苯氧基)丙胺;
N-甲基-3-苯基-3-(2-乙硫基苯氧基)丙胺丙二酸盐;
(S)-N-甲基-3-苯基-3-(2-叔-丁硫基苯氧基)-丙胺萘-2-磺酸盐;
(R)-N-甲基-3-(2-甲硫基苯氧基)-3-苯基-丙胺;
瑞波西汀(Reboxetine)(EdronaxTM),即2-[α-(2-乙氧基)苯氧基苄基]吗啉,通常以其外消旋体形式施用。US4,229,449首先提出该化合物用于治疗抑郁症。瑞波西汀是选择性的去甲肾上腺素再摄取抑制剂。术语“瑞波西汀”是指外消旋体或对映体形式分子的任何酸加成盐或者游离碱;
度洛西汀(Duuloxetine),即N-甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺,通常以其盐酸盐和(+)对映体形式施用。US4,956,388首先教导了这种化合物的高效力。术语“度洛西汀”是指该分子的酸加成盐或游离碱。优选的度洛西汀肠溶制剂是小丸剂,其中包括:a)度洛西汀与可药用赋形剂组成的核心;b)任选隔离层;c)包括醋酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)和可药用赋形剂的肠衣层;d)任选抛光层。US5,508,074教导了该制剂;
文拉法辛(Venlafaxine)在文献中已知,US4,761,501教导了其合成方法及其用作5-羟色胺和去甲肾上腺素摄取抑制剂的活性。在该专利中,文拉法辛被鉴定为化合物A;和
米那普仑(Milnacipran)(N,N-二乙基-2-氨基甲基-1-苯基环丙烷羧酰胺),US4,478,836在实施例4中制备了该化合物。该专利描述该化合物可用作抗抑郁药。Moret等在Neuropharmacology 24,1211-19(1985)中描述其做为5-羟色胺和去甲肾上腺素再摄取的抑制剂的药理学活性。
上述与本发明所用化合物和制剂有关的所有美国专利,均在此引入作为参考。
虽然所有具有去甲肾上腺素再摄取抑制活性的化合物均可用于本发明方法,但也有必要进行一定的优选。优选地,该去甲肾上腺素再摄取抑制剂能选择性作用于去甲肾上腺素(相对于其他神经递质)。同时,所述去甲肾上腺素再摄取抑制剂优选选自托莫西汀、瑞波西汀或式I化合物。尤其优选该去甲肾上腺素再摄取抑制剂选自托莫西汀、瑞波西汀或(R)-N-甲基-3-(2-甲硫基-苯氧基)-3-***。采用盐酸托莫西汀治疗牛皮癣是本发明最优选实施方案。
本领域普通技术人员可以理解,本发明所用的大多数或所有化合物均能成盐,并且通常可采用其药用盐形式,这是由于它们比游离碱更易于结晶和提纯。在所有的情况下,在本文上下文中通常优选采用上述药用盐,并且所有化合物的可药用盐均包括在其中。
本发明所用的许多化合物是胺类化合物,因此可与任何无机酸和有机酸反应而形成可药用酸加成盐。本发明化合物的一些游离胺在室温下典型地为油类,因此优选将游离胺转化成其可药用酸加成盐(室温下通常为固体),以便于处置和施用。用于形成上述盐的酸通常为无机酸,例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸等,和有机酸,例如对-甲苯磺酸、甲磺酸、草酸、对-溴苯基磺酸、碳酸、丁二酸、柠檬酸、苯甲酸、醋酸等。因此,示例性的可药用盐包括:硫酸盐,焦硫酸盐,硫酸氢盐,亚硫酸盐,亚硫酸氢盐,磷酸盐,磷酸一氢盐,磷酸二氢盐,偏磷酸盐,焦磷酸盐,氯化物,溴化物,碘化物,醋酸盐,丙酸盐,癸酸盐,辛酸盐,丙烯酸盐,甲酸盐,异丁酸盐,己酸盐,庚酸盐,丙炔酸盐,草酸盐,丙二酸盐,丁二酸盐,辛二酸盐,癸二酸盐,富马酸盐,顺丁烯二酸盐,丁炔-1,4-二酸盐,己炔-1,6-二酸盐,苯甲酸盐,氯苯甲酸盐,甲基苯甲酸盐,二硝基苯甲酸盐,羟基苯甲酸盐,甲氧基苯甲酸盐,邻苯二甲酸盐,磺酸盐,二甲苯磺酸盐,苯乙酸盐,苯丙酸盐,苯丁酸盐,柠檬酸盐,乳酸盐,β-羟基丁酸盐,乙醇酸盐,酒石酸盐,甲磺酸盐,丙磺酸盐,萘-1-磺酸盐,萘-2-磺酸盐,扁桃酸盐等。优选的可药用盐是与盐酸形成的盐。给药方案
在最终的分析中,必须由主治医师根据临床试验中联合用药的知识和药物特性,以及所治疾病以外的其他疾病等病人特征,来确定本发明所用药物的剂量。这里将提供剂量的常规范围和某些优选剂量。
托莫西汀:约5-200mg/天;优选约60-150mg/天;更优选约60-130mg/天;和更优选约60-120mg/天;
式I化合物:约0.01mg/kg-20mg/kg;优选每日剂量约0.05mg/kg-10mg/kg;更理想地约0.1mg/kg-5mg/kg;
瑞波西汀:约1-30mg,1-4次/天;优选约5-30mg,1次/天;
度洛西汀:约1-30mg 1次/天;优选约5-20mg,1次/天;
文拉法辛:约10-150mg,1-3次/天;优选约25-125mg,3次/天;和
米那普仑:约10-100mg,1-2次/天;优选约25-50mg,2次/天。
所有有关化合物适于口服,通常经口服给药,并优选经口服给药。然而,口服给药不是唯一途径,甚不是唯一优选的途径。例如,经皮施用比较适于那些口服给药时健忘或烦躁的患者。在特殊情况下,上述药物也可经皮、静脉内、肌内、鼻内或直肠内途径给药。给药途径可以变化,这取决于药物的物理特性以及患者和护理者的便利性。以下实施例旨在描述用于施用去甲肾上腺素再摄取抑制剂的制剂,对本发明的范围不作任何限定。
制剂实施例1:硬明胶胶囊
成分
用量(mg/胶囊)
盐酸托莫西汀 30.0
淀粉 305.0
硬脂酸镁 5.0
混合上述成分,并填入硬明胶胶囊中,340mg/胶囊。
制剂实施例2:片剂
成分
用量(mg/片)
盐酸托莫西汀 25.0
微晶纤维素 200.0
胶体二氧化硅 10.0
硬脂酸 5.0
混合上述组分,并压制成片剂,每片重240mg。
制剂实施例3:干粉吸入剂
成分
重量%
盐酸托莫西汀 5
乳糖 95
将活性成分与乳糖混合,并将所得混合物加到干粉吸入装置中。
制剂实施例4:片剂
成分
用量(mg/片)
盐酸托莫西汀 30.0
淀粉 45.0
微晶纤维素 35.0
聚乙烯吡咯烷酮 4.0
(10%水溶液)
羧甲基纤维素淀粉钠 4.5
硬脂酸镁 0.5
滑石粉
1.0
总计 120mg
将活性成分、淀粉和纤维素过20目US筛,并混合完全。聚乙烯吡咯烷酮溶液与所得粉末混合,然后过16目US筛。所得颗粒于50-60℃干燥,并过16目US筛。然后,将前述已过30目筛的羧甲基纤维素淀粉钠、硬脂酸镁、和滑石粉加至颗粒中,混合之后,经压片机压成片剂,每片重120mg。
制剂实施例5:胶囊
成分
用量(mg/胶囊)
盐酸托莫西汀 40.0
淀粉 109.0
硬脂酸镁
1.0
总计 150.0mg
将活性成分、纤维素、淀粉和硬脂酸镁混合,过20目US筛后填入硬明胶胶囊中,150mg/胶囊。
制剂实施例6:栓剂
成分
用量
盐酸托莫西汀 25mg
饱和脂肪酸甘油酯 加至2,000mg
将活性成分过60目US筛,并混悬于预先稍微加热熔融的饱和脂肪酸甘油酯中。然后,将所得混合物倾入2.0g容量的栓剂模子中并使之冷却。
制剂实施例7:混悬剂
成分
用量
盐酸托莫汀 50.0mg
黄原胶 4.0mg
羧甲基纤维素钠(11%)
微晶纤维素(89%) 50.0mg
蔗糖 1.75g
苯甲酸钠 10.0mg
香料和着色剂 适量
纯净水 加至5.0ml
将活性成分、蔗糖和黄原胶混合并过10目US筛,然后与预制的微晶纤维素和羧甲基纤维素钠的水溶液混合。搅拌下加入用水稀释的苯甲酸钠、香料和着色剂,然后加入足量水至要求的体积。
制剂8实施例:胶囊
成分
用量(mg/胶囊)
盐酸托莫西汀 15.0
淀粉 407.0
硬脂酸镁
3.0
总计 425.0mg
将活性成分、纤维素、淀粉,和硬脂酸镁混合,并过20目US筛,然后填入硬明胶胶囊中,425mg/胶囊。
制剂实施例9:静脉内制剂
成分
用量
盐酸托莫西汀 250.0mg
等渗盐水 1000ml
制剂实施例10:局部制剂
成分
用量
盐酸托莫西汀 1-10g
乳化蜡 30g
液体石蜡 20g
白色软石蜡 加至100g
将白色软石蜡加热熔化。掺入液体石蜡和乳化蜡并搅拌至溶解。加入活性成分,并继续搅拌至分散。然后将混合物冷却凝固。
制剂实施例11:舌下或颊部含片
成分
用量(mg/片)
盐酸托莫西汀 10.0
甘油 210.5
水 143.0
枸橼酸钠 4.5
聚乙烯醇 26.5
聚乙烯吡咯烷酮
5.5
总计 410.0mg
保持温度为90℃,采用连续搅拌,将甘油、水、枸橼酸钠、聚乙烯醇和聚乙烯吡咯烷酮混合。聚合物加入溶液后,将所得溶液冷却至约50-55℃并缓慢掺入活性成分。将均匀的混合物倾入由惰性物质制成的模中,得到含药的分散基质(约2-4mm厚)。然后将分散基质切成适宜大小的独立片剂。
牛皮癣是一种病因不明的慢性皮肤病,其特征在于出现炎性皮肤损害。目前已识别出许多不同类型的牛皮癣,下面将分别加以描述。
红皮病性牛皮癣是一种伴有细碎鳞屑的皮肤炎性损害,并常伴有重度痛、瘙痒和可能的肿胀。
滴状牛皮癣的特征在于出现小红点状的牛皮癣,典型地存在于患者的臂部、腿部和躯干。
皮褶牛皮癣是无鳞屑的炎性损害,典型地出现在腋窝、腹股沟、***下和其他皮肤襞褶处。
斑块(Plaque)牛皮癣是最常见的类型,其特征在于炎症损害被银屑所覆盖。尽管斑块牛皮癣可以发生在任何皮肤表面,但以膝盖、肘、头皮和躯干最常见。
脓疱性牛皮癣的特征在于出现非传染性脓液的水疱样损害。这种损害可能集中或分布于皮肤上。
脚趾甲和手指甲上也会出现牛皮癣麻点(pit)。这些麻点会使指甲变色并增厚,并可使指甲从甲床脱落。
牛皮癣也可根据损害侵袭的程度进行分类。损害不超过身体2%的牛皮癣可认为上轻度牛皮癣。损害占身体2-10%的牛皮癣视为中度牛皮癣,损害超过身体10%的牛皮癣视为重度牛皮癣。
本发明方法适于治疗所有类型和程度的牛皮癣。抑制去甲肾上腺素再摄取
采用Wong等,supra.的常规方法,可测定化合物对去甲肾上腺素再摄取的抑制能力。
将雄性Sprague-Dawley鼠(重150-250g)断头处死并立即取出脑。将大脑皮质置于包含0.32M蔗糖和10mM葡萄糖的9体积介质中匀化。经差速离心(1000×g离心10分钟,和17,000×g离心28分钟),将粗制的突触体标本分离出来。将所得的沉淀物混悬于相同介质中,并在当天使用之前保存于冰中。
如下测定3H-去甲肾上腺素的突触体摄取:在含有10mM葡萄糖、0.1mM异丙异烟肼、1mM抗坏血酸、0.17mM EDTA和50nM3H-去甲肾上腺素的Krebs-碳酸氢盐介质中(1mL),将皮质突触体(相当于1mg蛋白质)于37℃保温5分钟。反应混合物立即用2mL冰冷的Krebs-碳酸氢盐缓冲液稀释,并用细胞收集器(Brandel,Gaithersburg,MD)真空过滤。滤器用约5mL冰冷的0.9%盐水清洗2次,用液体闪烁计数器测定3H-去甲肾上腺素的摄取。以3H-去甲肾上腺素在4时℃的蓄积为本底,并将其从所有测量值中扣除。通过线性回归分析,可测定抑制50%3H-去甲肾上腺素蓄和所需的待试化合物浓度(IC50值)。
实施例1
受验者为39岁的男性高加索人,腿部出现中度严重的斑块样牛皮癣。该受验者几乎一生遭受牛皮癣的痛苦,并在本研究之前病情恶化。曾采用类固醇,包括TemovateTM(11β,16β)-21-氯-9-氟-11,17-二羟基-16-甲基孕烷-1,4-二烯-3,20-二酮,Glaxo公司)局部治疗其损伤,但在本研究之前未能成功治愈。对该受验者进行60mg盐酸托莫西汀治疗,每日施用2次,连续12天。对受验者的最终评估证明改善显著,在以前的损害部位仅出现少量的鳞屑和微弱的皮肤红斑。
Claims (10)
1.一种治疗牛皮癣的方法,包括对需此治疗的患者施用有效量的去甲肾上腺素再摄取抑制剂。
3.如权利要求2的方法,其中去甲肾上腺素再摄取抑制剂为托莫西汀、瑞波西汀、或式I化合物。
4.如权利要求3的方法,其中去甲肾上腺素再摄取抑制剂为托莫西汀。
5.如权利要求3的方法,其中去甲肾上腺素再摄取抑制剂为盐酸托莫西汀。
6.如权利要求3的方法,其中去甲肾上腺素再摄取抑制剂为瑞波西汀。
7.如权利要求3的方法,其中去甲肾上腺素再摄取抑制剂为(R)-N-甲基-3-(2-甲硫基-苯氧基)-3-苯基丙胺。
8.如权利要求1的方法,其中治疗斑块牛皮癣。
9.如权利要求8的方法,其中去甲肾上腺素再摄取抑制剂为托莫西汀。
10.如权利要求8的方法,其中去甲肾上腺素再摄取抑制剂为盐酸托莫西汀。
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- 2001-02-20 IL IL15047901A patent/IL150479A0/xx unknown
-
2002
- 2002-07-01 ZA ZA200205266A patent/ZA200205266B/en unknown
- 2002-09-05 HR HR20020729A patent/HRP20020729A2/xx not_active Application Discontinuation
- 2002-09-05 NO NO20024236A patent/NO20024236D0/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
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WO2001066101A2 (en) | 2001-09-13 |
MXPA02008659A (es) | 2003-02-24 |
WO2001066101A3 (en) | 2002-02-07 |
NO20024236L (no) | 2002-09-05 |
HRP20020729A2 (en) | 2004-02-29 |
EA200200948A1 (ru) | 2003-02-27 |
SK12812002A3 (sk) | 2003-08-05 |
US20030045585A1 (en) | 2003-03-06 |
BR0108980A (pt) | 2003-06-03 |
DZ3282A1 (fr) | 2001-09-13 |
HUP0204551A2 (hu) | 2003-06-28 |
JP2003525899A (ja) | 2003-09-02 |
CA2400571A1 (en) | 2001-09-13 |
AU4529101A (en) | 2001-09-17 |
PL357042A1 (en) | 2004-07-12 |
US6683114B2 (en) | 2004-01-27 |
ZA200205266B (en) | 2003-10-01 |
EP1267859A2 (en) | 2003-01-02 |
NO20024236D0 (no) | 2002-09-05 |
IL150479A0 (en) | 2002-12-01 |
KR20020081403A (ko) | 2002-10-26 |
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