CN101060860B - 用于治疗抑郁症的包含选择性5-羟色胺再摄取抑制剂和糖皮质激素受体拮抗剂的药物组合 - Google Patents
用于治疗抑郁症的包含选择性5-羟色胺再摄取抑制剂和糖皮质激素受体拮抗剂的药物组合 Download PDFInfo
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Abstract
本发明涉及包含一定量的SSRI或其药学上可接受的盐或溶剂合物和一定量的GR拮抗剂或其药学上可接受的盐或溶剂合物，任选与一种或多种药学上可接受的载体混合的组合，其用作用于抑郁症和相关障碍的疗法。
Description
本发明涉及用于治疗抑郁症和相关障碍的包含特异性5-羟色胺再摄取抑制剂的药物组合。
近期临床研究已经证实在患有下丘脑-垂体-肾上腺(HPA)轴障碍的患者中，选择性5-羟色胺再摄取抑制剂(SSRI)的抗抑郁症功效低于具有高应激激素水平的患者(Young等；HPA axis activation inmajor depression and response to fluoxetine：a pilot study，Psychoneuroendocrinology，2004，vol 29，pp 1198-1204)。提示那些患者可以用非SSRIs的抗抑郁药治疗。
其它公开文献中讨论了HPA在精神病理学中的作用或SSRI的作用机制，或提示糖皮质激素受体拮抗剂(GR-拮抗剂)在治疗具有活动过度的应激激素功能的患者中的应用(Blackburn-Munro和Blackburn-Munro，Chronic pain，chronic stress and depression：coincidence or consequence？J.Neuroendocrinology，2001，Vol13，pp 1009-1023；Str
hle和Holsboer，Stress responsiveneurohormones in depression and anxiety，Pharmacopsychiatry2003，vol 36，suppl 3pp S207-S214；Van Praag，Canstress causedepression？2004，Progress in Neuro-Psychopharmacol. & Biol.Psychiatry，2004，Vol 28，pp 891-907；Le Poul等，Fluoxetine-induced desensitization of somatodendritic 5-HT1Aautorecptors is independent of glucocorticoid(s)，Synapse，1997，vol 27，pp 303-312)。
本发明通过提供用一种组合疗法而提供了对抑郁症和相关疾病的改善的治疗方法，所述的组合包含一定量SSRI或其药学上可接受的盐或溶剂合物，和一定量的GR拮抗剂或其药学上可接受的盐或溶剂合物，任选混合有一种或多种药学上可接受的载体，其中一定量的SSRI和一定量的GR拮抗剂使得该组合在更多的患者中具有比单独使用每种药物更好的作用。更好的作用在于在个体患者或治疗组患者总体效果中较少的副作用或更为快速(早期或加速起效)或更完全地恢复。该组合的优选应用在于治疗耐治疗的抑郁症，也称作顽固性抑郁症或治疗顽固性抑郁症。
上述使用的下文说明书中的术语用于更好地澄清本发明提供的技术方案。
SSRI为具有选择性5-羟色胺再摄取抑制作用的药物。这意味着它在抑制5-羟色胺转运蛋白中的活性至少可以两倍于对去甲肾上腺素转运蛋白和多巴胺转运蛋白的抑制活性。可以通过许多公知技术测定这些转运蛋白的抑制。已知的SSRI为西酞普兰、S-西酞普兰、氯米帕明、氟西汀、氟伏沙明、帕罗西汀和舍曲林。GR拮抗剂为阻断皮质醇和皮质酮对糖皮质类固醇受体的作用的药物。已知的GR拮抗剂的实例为：RU 486(RU 38486＝(11β.17β)-11-[4-(二甲氨基)苯基]-17-羟基-17-(1-丙炔基)-雌-4，9-二烯-3-酮)；Org 34517，其为(11β，17β)-11-(1，3-苯并间二氧杂环戊烯-5-基)-17-羟基-17-(1-丙炔基)-雌-4，9-二烯-3-酮；Org 34850，其为(11β，17α)-11-[4-(二甲氨基)苯基-17-羟基-21-[4-(甲基磺酰基)苯基-19-去甲孕-4，9-二烯-20-炔-3-酮和酮康唑。Org 34517为用于本发明的优选的GR拮抗剂。
除非另作陈述，否则活性成分的所有量均意旨作为碱或酸的化合物重量，而不指盐的重量。按照本说明书中的术语，称作SSRI或GR拮抗剂的药物为活性成分或组合形式的活性组分。
药学上可接受的盐包括酸加成的盐，所述的酸例如盐酸、富马酸、马来酸、柠檬酸或琥珀酸，这些酸仅作为例示提及，但不意味着起限定作用。
术语药学上可接受的载体和赋形剂意旨那些本领域中公知可允许作为添加剂或载体物质在丸剂、片剂、胶囊等中使用的物质。这些物质通常由卫生保健部门批准用于该目的并且为无活性的药理学试剂。药学上可接受的载体和赋形剂的编辑内容可以在Handbook ofPharmaceutical excipients(2nd edition edited by A.Wade和P.J.Weller；Published by the American Pharmaceutical Association，Washington和The Pharmaceutical Press，London，1994)中找到。特别地，可以将乳糖、淀粉、纤维素衍生物等或其混合物用作本发明组合中活性成分的载体。辅助组分包括那些本领域中常用的物质，诸如着色剂、粘合剂、稀释剂、崩解剂、润滑剂、调味剂和湿润剂。一般而言，可以使用不干扰活性化合物功能的任意药学上可接受的添加剂。
术语组合意旨任意呈现形式，其可以视为目的在于SSRI和GR拮抗剂的联合应用。
SSRI和GR拮抗剂的这类组合在本说明书中还意旨本发明的组合。
可以理解可以同时在相同或不同的药物制剂中一起给予或依次给予组合中的化合物。如果依次给药，那么在给予第二种(或额外的)活性组分中的延缓不应使得组合中活性组分功效作用的有益性丧失。本说明书的组合的最低要求在于该组合的目的应在于提供活性组分组合的功效作用的有益性。可以通过有助于使用本发明组合的设备、供应(provisions)、适应性(adaptation)和/或其它方式推断联合用药的预期应用。例如，可以通过加入联合应用的说明书或助剂乃至决定物适当形成所述组合。例如，用于联合应用的决定物可以归属于组合活性成分的单位剂型的配药器的特性。活性成分由此可以在单独的单位剂型中，但所述的组合仍然可以具有根据配药器特性诱导按预定顺序和/或在预定时间使用单位剂型的组合的决定物。联合应用的优选决定物当然为在一种药物组合物中组合的两种活性成分的制剂。
因此，本发明的一个方面提供了包含SSRI或其药学上可接受的盐或溶剂合物和GR拮抗剂或其药学上可接受的盐或溶剂合物的药物组合物。
术语‘抑郁症和相关障碍’意旨本领域技术人员可以理解的医学领域。将已知对使用分类为SSRI的药物治疗有正面反应的那些障碍视为本发明描述的与抑郁症相关。这类障碍例如为：焦虑症，诸如惊恐性障碍、强迫观念与行为障碍、创伤后应激障碍、慢性疼痛综合征或双相性精神障碍。众所周知SSRI对并不严格限于对抑郁症的作用的行为和精神功能具有更一般性的有益作用。本发明还包括所述的联合用药在焦虑中的应用，在使用SSRI的应用方式中，为长效作用将其扩大范围使用，其不同于典型的具有急性焦虑缓解且通常是镇静作用的抗焦虑药的应用，也称作弱安定剂。后一种抗焦虑/镇静作用通常归因于与脑中GABA-受体的相互作用。
尽管能够将联合用药中的活性组分作为纯化学物质给药，但是优选将它们制成药物组合物，也本文中称作药物制剂。合适的组合物包括那些适合于口服或直肠给药的组合物。在本发明实施方案中的药物组合物包含SSRI或GR拮抗剂或其组合和一种或多种药学上可接受的载体或赋形剂以及任选其它治疗剂。本发明进一步提供了本发明组合物在抑郁症和相关障碍疗法中的应用。此外，本发明包括SSRI或GR拮抗剂在制备包含SSRI或GR拮抗剂的药剂中的应用，该药剂具有精神调节活性的对疗法、特别是针对抑郁症和相关障碍而言改善的功效。该药剂具有强化的作用或较低的副作用或与每种药物单独使用相比起效较早。该药剂的优选应用在于治疗耐治疗抑郁症。本发明还包括SSRI或GR拮抗剂在制备用于联合给予具有GR拮抗剂或SSRI的药物(同时或依次)或相应地在治疗抑郁症或相关障碍中的应用。
本发明的一个重要方面在于提供了一种治疗患有抑郁症或相关障碍脊椎动物物种个体，例如哺乳动物，包括人类患者的方法，该治疗方法包含给予有效量的SSRI与GR拮抗剂的组合。用于治疗的所需每日剂量优选作为单剂量提供或在全天中的适当间隔给予的两次或三次亚剂量提供。在实际中，这意味着为治疗以组合形式提供对接受者给药或接受者摄取的包含SSRI的单位剂型和包含GR拮抗剂的单位剂型或提供包含SSRI和GR拮抗剂的单位剂型。
因此，在本发明的一个实施方案中，可以将SSRI和GR拮抗剂的混合物制成单位剂型形式的药物制剂，例如以片剂、丸剂、胶囊等形式给药。这类剂型及其制剂为本领域中公知的，例如描述在标准参考文献中：Gennaro等，Remmington：The science and practice ofpharmacy(20th ed.，Lippincott Williams & Wilkins，Baltimore，Philadelphia，2000，尤其是参见第5部分：Pharmaceuticalmanufacturing)。合适的助剂描述在例如Handbook ofPharmaceutical Excipients(2nd Edition，Editors A.Wade和P.J.Weller；American Pharmaceutical Association；Washington；ThePharmaceutical Press；London，1994)中。这类方法包括使活性组分与构成一种或多种辅助组分的载体混合的步骤。本发明由此还提供了制备药物组合物的方法，且更具体地说，是提供了制备包含SSRI和GR拮抗剂的给药单位剂量的方法，该方法包含使一定量的SSRI(或其药学上可接受的盐)和一定量的GR拮抗剂(或其药学上可接受的盐)混入一种或多种药物赋形剂。
更通常的是将这些日用药物制剂对患者开据处方为“患者用药包”，它们含有在单一包装、通常为泡罩包中的不同治疗期中应用的编号的给药单位剂量或其它给予计量的单位剂量的用具。患者用药包具有超过药剂师可以给患者分发来自批量供应的药物供给的传统处方的优点，即患者始终可以使用患者用药包中包含的包装说明书，而传统的处方中没有。包含的包装说明书中已经显示可以改善患者对临床医师指示的依从性。因此，本发明进一步包括如上文所述的药物制剂与适合于该制剂的包装材料。在这类患者用药包中，可以通过有助于使用最适合于治疗的技术说明、设备、供应、适应性和/或其它方式推断所述制剂在联合治疗抑郁症或相关障碍中的预期应用。这类措施使得患者用药包特别适合于和适用于使用本发明组合治疗。
特别地，另一个实施方案包括含有单独剂量单位的包装，其中的一种或多种含有SSRI或其药学上可接受的盐，并且其中的一种或多种含有GR拮抗剂或其药学上可接受的盐。该包装含有足够的片剂、胶囊等以便将患者治疗预定的时间期限，例如2周，1个月或3个月。
就本发明组合的应用而言，它应提供活性组分，使得可以获得有效量。当然，产生有效作用所需的SSRI(或其药学上可接受的盐或溶剂合物)和GR拮抗剂(或其药学上可接受的盐或溶剂合物)的用量可以改变并且最终由医务人员决定。所考虑的因素包括给药途径和制剂的性质、接受者的体重、年龄和一般情况以及所治疗疾病的性质和严重程度。一般而言，用于对人体给药的SSRI的合适剂量在0.05-5mg/千克体重接受者/天的范围，优选在0.1-1.0mg/千克体重接受者/天的范围。用于对人体给药的GR拮抗剂的合适剂量通常在0.01-5mg/千克体重接受者/天的范围，优选0.05-0.7mg/千克体重接受者/天的范围。
可以将适合于口服给药的制剂制成分散单位，诸如各自含有预定量活性成分的片剂或胶囊。活性组分在给药剂型中的合适用量为，例如包含1-50mg SSRI和一般为5-100mg GR拮抗剂的片剂。
实施例
认为存在于脊神经元上的5-HT1A自身受体的脱敏为基于SSRI的作用的重要机制之一。在实验动物中，可以使用额前皮质中的微量渗析和在阻断局部摄取的探针区中局部给予SSRI(氟西汀)和影响所有吸收部位并且导致5-HT1A自身受体活化的全身注射联用来测定这种脱敏作用。
方法
对3只一组居留的可随意摄取食物和饮水的Hooded Lister大鼠进行研究。将动物保持在受控环境条件下：温度(20℃)和湿度(30-50％)，12小时光照/黑暗循环(在07.00a.m.光照)。每个笼子接受相同的治疗并且在同一天研究各个笼子以避免群居隔绝。对动物进行两种治疗：作为每日在07:00-07:30和19:00-19:30给予两次载体或GR拮抗剂(15mg/kg Org 34850，腹膜内(i.p.))。所有动物均接受在早晨给予的每日单次注射的氟西汀(在无菌水中10mg/kg，i.p.)。治疗期为0(对照组)，3，7或14天。
对微量渗析而言，用水合氯醛(500mg/kg i.p.+根据需要的增补剂量)麻醉动物。在右侧额前皮质(脑功能区定位坐标：来自前卤和硬脑脊膜表面的嘴侧+3.2mm，外侧0.5mm，前侧-4.6mm)实施手术以便进行微量渗析探针定位。用人工脑脊液(aCSF)灌注探针3小时，直到获得稳定基础水平的5-HT。每隔20分钟采集一次样品并且通过HPLC使用电化学检测进行分析。实验方案包含三个阶段：i)将基础胞外5-HT水平测定60分钟；ii)将氟西汀(10μM)加入到aCSF中以便阻断局部吸收，从而测定总释放率。采集80分钟样品；和iii)i.p.注射氟西汀(10mg/kg)以便阻断所有的吸收部位，包括自身受体，并且采集120分钟样品。将该注射后测定的5-HT水平的下降等级用作自身受体敏感性的测量值。
结果
表：用给予氟西汀或氟西汀与Org 34850的组合3，7或14天的预治疗对i.p.注射氟西汀后5-HT水平下降的作用。
如表中所示的结果表明，在接受所述组合治疗的组中，下降的等级低于单独使用氟西汀的组。
结论
结果表明在使用SSRI和GR拮抗剂联合治疗后，自身受体已经经历了比单独SSRI更大的脱敏作用。
Claims (2)
1.选择性5-羟色胺再摄取抑制剂在制备用于治疗抑郁症和相关障碍的药物中的应用，其中所述药物包含一定量的所述选择性5-羟色胺再摄取抑制剂或其药学上可接受的盐或溶剂合物，以及一定量的糖皮质激素受体拮抗剂或其药学上可接受的盐或溶剂合物，任选混合有一种或多种药学上可接受的载体，其中所述的选择性5-羟色胺再摄取抑制剂为氟西汀，并且所述的糖皮质激素受体拮抗剂为(11β，17α)-11-[4-(二甲氨基)苯基]-17-羟基-21-[4-(甲基磺酰基)苯基]-19-去甲孕-4，9-二烯-20-炔-3-酮。
2.糖皮质激素受体拮抗剂在制备用于治疗抑郁症和相关障碍的药物中的应用，其中所述药物包含一定量的选择性5-羟色胺再摄取抑制剂或其药学上可接受的盐或溶剂合物，以及一定量的所述糖皮质激素受体拮抗剂或其药学上可接受的盐或溶剂合物，任选混合有一种或多种药学上可接受的载体，其中所述的选择性5-羟色胺再摄取抑制剂为氟西汀，并且所述的糖皮质激素受体拮抗剂为(11β，17α)-11-[4-(二甲氨基)苯基]-17-羟基-21-[4-(甲基磺酰基)苯基]-19-去甲孕-4，9-二烯-20-炔-3-酮。
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| WO2003037354A1 (en) * | 2001-10-26 | 2003-05-08 | Akzo Nobel N.V. | USE OF (11β, 17β)-11-(1,3-BENZODIOXOL-5-YL)-17-HYDROXY-17-(1-PROPYNYL)-ESTRA-4,9-DIEN-3-ONE IN THE TREATMENT OF MAJOR DEPRESSIVE DISORDER |
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| WO2003037354A1 (en) * | 2001-10-26 | 2003-05-08 | Akzo Nobel N.V. | USE OF (11β, 17β)-11-(1,3-BENZODIOXOL-5-YL)-17-HYDROXY-17-(1-PROPYNYL)-ESTRA-4,9-DIEN-3-ONE IN THE TREATMENT OF MAJOR DEPRESSIVE DISORDER |
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| EP1814589B1 (en) | 2015-04-15 |
| CN103316019A (zh) | 2013-09-25 |
| EP1814589A1 (en) | 2007-08-08 |
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