CN101128198A - 沙贝马啉与安定药物联合治疗精神病 - Google Patents
沙贝马啉与安定药物联合治疗精神病 Download PDFInfo
- Publication number
- CN101128198A CN101128198A CNA2005800486536A CN200580048653A CN101128198A CN 101128198 A CN101128198 A CN 101128198A CN A2005800486536 A CNA2005800486536 A CN A2005800486536A CN 200580048653 A CN200580048653 A CN 200580048653A CN 101128198 A CN101128198 A CN 101128198A
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- Prior art keywords
- sabcomeline
- neuroleptic agent
- pharmaceutically acceptable
- acceptable salt
- treatment
- Prior art date
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- 230000000306 recurrent effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
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- 239000008215 water for injection Substances 0.000 description 1
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Abstract
本发明涉及其中沙贝马啉(sabcomeline)或其药学可接受盐和至少一种其他安定药物结合或同时给药的治疗精神病的结合和同时联合治疗。本发明提供利用所述结合或同时治疗性联合疗法治疗精神病的方法,本文用途的联合疗法和包含它们的药物组合物。
Description
本发明涉及治疗精神病和其他精神障碍的联合疗法、治疗性联合形式和含有它们的组合物,和治疗精神病和其他精神障碍的方法。
美国专利5278170公开了一类通过中枢神经系统内毒蕈碱受体的作用增强乙酰胆碱功能的化合物。本发明范围内的特别优选的化合物给出通用名称沙贝马啉,并且具有下列化学结构(I):
沙贝马啉(sabcomeline)的化学名称为R-(Z)-α-(甲氧基亚氨基)-α-(1-氮杂双环[.2.2]辛-3-基)乙睛。对于治疗性给药,优选以药学可接受盐的形式使用,典型地为盐酸盐,但沙贝马啉与药学可接受酸的其他盐还可以用于治疗性给药,例如由沙贝马啉游离碱与酸形成的盐,包括,但不限于氢溴酸、磷酸、乙酸、富马酸、水杨酸、柠檬酸、乳酸、草酸和对甲苯磺酸。
制备沙贝马啉的方法的一个实例如下:向叔丁醇钾(94.1g;0.84mol)在四氢呋喃(250ml)中的搅拌溶液内在氮气下在10分钟内加入3-(氰基甲基)喹核碱(60g;0.4mol)在四氢呋喃(150ml)中的溶液。将该反应搅拌10分钟,随后冷却至0℃。以内温不超过25℃的速度加入亚硝酸异戊基酯(51.5g 0.44mol)。将该反应搅拌20分钟,随后用二甲级亚砜(500ml)稀释。以使内温不超过35℃的速度加入甲苯磺酸甲酯(134g;0.72mol)在二甲基亚砜(100ml)内的溶液。20分钟后加入碳酸钾水溶液(约5wt%500ml)并且该反应用乙酸乙酯萃取(5x200ml)。乙酸乙酯萃取液用5wt%碳酸钾水溶液洗涤(4x250ml),随后用饱和碳酸钾洗涤(50ml)。合并的水层再用乙酸乙酯萃取(500ml),萃取方法如上。合并的有机萃取液用无水碳酸钾干燥(200g)和真空浓缩得到含有约80wt%3-[(氰基)(甲氧基亚氨基)-甲基]喹核碱的褐色油,其是Z∶E异构体的4∶1混合物,(47.4g;0.245mol;61%)。
另一种制备沙贝马啉的药学可接受盐的方法包括其在EP0626961中所说的中间体并且在此引入作为参考。
首先评估沙贝马啉的是其在治疗痴呆中的用途。随后,许多文献公开了沙贝马啉治疗精神病的用途,例如WO 98/46226。WO 02/03684进一步公开了通过施用毒蕈碱激动剂与典型或非典型安定药的联合形势治疗精神病。虽然沙贝马啉在WO 02/03684中作为许多适合与许多典型或非典型抗精神病药物联合的毒蕈碱激动剂之一公开,但举例只限于一种毒蕈碱激动剂(xanomeline)与少量安定药联合,并且没有具体信息或数据记录有关包括沙贝马啉的联合疗法。仍然需要进一步确定和改进的药物用于精神病的治疗,并且特别是提高现有安定药物疗法的功效的组合物和方法。
现已发现沙贝马啉或其药学可接受盐可以适当地与至少一种安定药物联合来产生改进的精神病治疗。与本发明的联合形式、用途和方法有个的特别优点包括在低于其常规单组分的用量的剂量下等效或提高的效价。也可以观察到对精神病的正性症状和/或负性症状和/或认知症状的改进疗法。本发明的治理的联合形式、用途和方法还可以给某些安定(neuroleptic)药物的治疗反应不够或耐受的患者的治疗提供益处。
术语安定(neuroleptic)是指减轻精神病患者的混乱、错觉、幻觉和精神运动性兴奋的安定药对认识和行为的影响。还知道作为主要的镇定药和安定药,安定药物含有一组下列7类的药物:吩噻嗪类,进一步分为脂肪族,哌啶类,和哌嗪类,噻吨类(例如氟哌里多),丁酰苯类(例如氟哌啶醇),二苯并氮杂类(例如洛沙平),二氢吲哚酮类(例如吲茚酮),二苯基丁基哌啶(例如哌咪清),苯并异唑(例如利哌利酮).
安定药可以根据其结构分类,也可以根据其药理学、其对受体的作用及其临床性质来分类。常用(也称为常规)安定药主要作用于多巴胺受体。非典型安定药作用于其他受体和多巴胺,并且可能不会像安定药那样引起运动性疾病的副作用。非典型安定药的实例包括氨磺必利(商标名Solian),aripiprazole(Abilify),氯氮平(Clozaril),奥氮平(Zyprexa),喹噻平(Seroquel),利哌利酮(Risperdal)和泽坦平(Zoleptil).
可以相信沙贝马啉和安定药的联合形式的临床应用可能在不同成员的非典型安定药类型之间差异很大,这取决于其对不同亚型的神经化学受体的不同亲和性。例如,除了其对多巴胺和5-羟色胺受体的亲和性,许多非典型安定药种类可能对于毒蕈碱和组胺受体亚型的亲和性也不同。非典型安定药物对于毒蕈碱受体亚型的活性在于已经报道了非典型安定药类型的许多成员的可忽略亲和性、弱激动活性和弱拮抗活性的性质。
例如,沙贝马啉的M1/M4受体激动性质可以提高功能胆碱能活性,并且当联合给药时,通过下列产生益处:
i)与本身对毒蕈碱受体很少或没有亲和性的非典型安定药(例如利哌利酮)联合提高功能性胆碱能活性
ii)与具有弱毒蕈碱受体激动剂作用的非典型安定药(例如氯氮平或N-去甲基氯氮平)联合提供附加功能性胆碱能活性
iii)竞争毒蕈碱受体并由此降低具有毒蕈碱受体拮抗性质的非典型安定药(例如奥氮平)的抗胆碱能功能作用。
对于毒蕈碱和组胺受体,存在对于认知具有有益或副作用的其它受体。例如,具有5-HT6受体拮抗和肾上腺能α2受体拮抗性质的药物也可以是有益的。一些非典型药物也可以具有这样的益处。
本发明的联合疗法适宜结合给药。所谓结合给以是指各个组分以分开的药物组合物或装置的形式连续或重叠给药。这种两种或多种治疗剂的治疗性给药方案是本领域技术人员一般了解的并且在此称作结合治疗性给药;也称作附加治疗性给以。本发明的范围包括任何和所有其中患者分开接受但沙贝马啉或其药学可接受盐和至少一种安定药连续或重叠治疗性给药的治疗方案。在结合治疗性给药的一个实施方式中,患者通常通过治疗性施用一种或多种组分达到一段时间来稳定化并且随后接受另一组分的给药。在本发明的范围内,优选沙贝马啉或其药学可接受盐作为结合治疗性疗法施用给接受至少一种安定药物给药的患者,而本发明的范围还包括将至少一种安定药物结合治疗性施用给接受沙贝马啉或其药学可接受盐的给药的患者。
本发明的联合疗法还可以同时给药。所谓同时给药是指各个组分一起同时给药的治疗方案,或以包含或含有两种组分的单一治疗组合物或装置的形式,或者作为分开的各自含有一种组分的组合物或装置。分开的各组分同时联合给药的这种联合形式可以以多部分的试剂盒形式提供。
因此在第一方面,本发明提供一种通过沙贝马啉或其药学可接受盐对接受至少一种安定药物的治疗性给药的患者的结合治疗性给药治疗精神病的方法。另一方面,本发明提供沙贝马啉或其药学可接受盐在制备用于结合治疗性给药以治疗接受至少一种安定药物的治疗性给药的患者中的精神病的药物中的应用。本发明还提供沙贝马啉或其药学可接受盐以结合治疗性给药在治疗接受至少一种安定药物的治疗性给药的患者的精神病中的应用。本发明进一步提供沙贝马啉或其药学可接受盐用于结合治疗性给药以治疗接受至少一种安定药物的治疗性给药的患者的精神病。
另一方面,本发明提供通过一种通过将至少一种安定药物结合治疗性施用给接受沙贝马啉或其药学可接受盐的治疗性给药的患者以治疗精神病的方法。另一方面,本发明提供至少一种安定药物在制备用于结合治疗性给药治疗接受沙贝马啉或其药学可接受盐的治疗性给药的患者中的精神病的药物中的应用。本发明还提供至少一种安定药物用于结合治疗性给药以治疗接受沙贝马啉或其药学可接受盐的治疗性给药的患者中的精神病的应用。
另一方面,本发明提供一种通过同时治疗性施用沙贝马啉或其药学可接受盐和至少一种安定药物治疗精神病的方法。本发明进一步提供沙贝马啉或其药学可接受盐和至少一种安定药物的联合形式在制备用于在精神病的治疗中同时治疗性给药的药物中的应用。本发明进一步提供沙贝马啉或其药学可接受盐和至少一种安定药物的联合形式用于在精神病但治疗中同时治疗性给药的应用。本发明进一步提供沙贝马啉或其药学可接受盐在制备与至少一种安定药物同时治疗性给药治疗精神病的药物中的应用。本发明进一步提供沙贝马啉或其药学可接受盐用于与至少一种安定药物在精神病治疗中同时治疗性给药中的应用。本发明进一步提供沙贝马啉或其药学可接受盐用于在精神病的治疗中与至少一种安定药物同时治疗性给药。本发明进一步提供至少一种安定药物在制备治疗精神病重与沙贝马啉或其药学可接受盐同时治疗性给药的药物中的应用。本发明进一步提供至少一种安定药物与沙贝马啉或其药学可接受盐同时治疗性给药以治疗精神病的应用。
另一方面,本发明提供一种通过同时治疗性施用含有沙贝马啉或其药学可接受盐和至少一种情感稳定或抗躁狂药物的组合物治疗精神病的方法、含有沙贝马啉或其药学可接受盐和至少一种情感稳定或抗躁狂药物的药物组合物、含有沙贝马啉或其药学可接受盐和至少一种情感稳定或抗躁狂药物在治疗精神病中的应用、含有沙贝马啉或其药学可接受盐和至少一种情感稳定或抗躁狂药物的药物组合物在制备用于治疗精神病药物中的用途,和用于治疗精神病的含有沙贝马啉或其药学可接受盐和至少一种情感稳定或抗躁狂药物的药物组合物.
另一方面,本发明提供用于治疗精神病的多部分试剂盒,其中包括含有沙贝马啉或其药学可接受盐的第一剂型和一个或多个含有安定药物的用于同时治疗性给药的其他剂型。
在本文中,术语精神病包括精神分裂症,精神分裂症样疾病,分裂情感性障碍,妄想性疾病,情感障碍,孤独症,抽搐疾病,具有精神病特征的抑郁,慢性精神分裂性精神病,分裂情感性精神病,和暂时性急性精神病。上述病症表示多种疾病状态。例如,精神分裂症是指多种形式例如紧张症、混乱、妄想狂样、无差别(undifferential)、残余形式等。上述疾病的所有不同形式被认为是本发明的组成部分。
下列进一步举例说明洗涤这样的疾病状态,其中许多在AmericanPsychiatric Association(DSM IV)出版的Diagnostic and Statistical Manualof Mental Disorders,第4版中分类:妄想狂型精神分裂症,混乱型精神分裂症,紧张型精神分裂症,无差别(Undifferentiated)型精神分裂症,残余型精神分裂症,精神分裂症样障碍,分裂情感共有型精神病,由常规医学病症造成的精神病,物质引起的精神病,具有精神病症状的精神病,精神分裂样人格疾病和精神分离性人格疾病。目录还包括耐受现有技术的治疗方法和方式的精神分裂症的形式。
本发明的使用沙贝马啉或其药学可接受盐和安定药物的精神病治疗可以与其他药物疗法一起进行。特别是,镇定药可以用于治疗激动、焦虑或睡眠紊乱。优选使用劳拉西泮,它属于苯并二氮杂类。也可以使用抗抑郁药物和焦虑药物,例如SSRI抗抑郁药物,如帕罗西汀或氟西汀。
本发明中使用的安定药物的实例包括,但不限于:丁酰苯类,例如氟哌啶醇,匹莫齐特,和氟哌利多;吩噻嗪类,例如氯丙嗪,美索哒嗪,三氟拉嗪,奋乃静,氟奋乃静,氟丙嗪,普鲁氯嗪,和乙酰奋乃静;噻吨类,例如替沃噻吨和氯普噻吨;噻吩并苯并二氮杂类;二苯并二氮杂类;苯并异唑类;二苯并硫杂类;咪唑烷酮类;苯并异噻唑基-哌嗪类;三嗪类例如拉莫三嗪;二苯并氧杂类,例如洛沙平;二氢吲哚酮,例如吗茚酮;aripiprazole;和具有抗精神病活性的衍生物。本发明可以使用的安定药物的其他实例包括卡马西平,丙戊酸钠,加巴喷丁,托吡酯,奥卡西平和锂。本发明优选使用的安定药物的特别实例及其常规给药途径和剂量范围如表1所示。
表1
安定药物
通用名 | 商品名 | 给药途径 | 剂型 | 剂量范围和(中间)a |
氯氮平 | CLOZARIL | 口服 | 片剂 | 12-900mg/天(300-900mg/天) |
奥氮平 | ZYPREXA | 口服 | 片剂 | 5-25mg/天(10-25mg/天) |
齐拉西酮 | GEODON | 口服 | 胶囊 | 20-80/天两次(80-160mg/天) |
维思通 | RISPERDAL | 口服 | 溶液,片剂 | 2-16mg/天片剂(4-12mg/天) |
维思通 | RISPERDAL | 静脉内 | 长效注射剂型 | |
富马酸喹噻平 | SEROQUEL | 口服 | 片剂 | 50-900mg/天(300-900mg/天) |
舍吲哚 | SERDILECT | (4-24mg/天) | ||
阿米舒必利 | ||||
舒必利 | ||||
氟哌啶醇 | HALDOL | 口服 | 片剂 | 1-100mg/天(1-15mg/天) |
氟哌啶醇癸酸盐 | HALDOLDecanoate | 非肠道 | 溶液 | |
氟哌啶醇乳酸盐 | HALDOLINTENSOL | 口服 | ||
非肠道 | 注射液 | |||
氯丙嗪 | THORAZINE | 直肠 | 栓剂 | 30-800mg/天 |
口服 | 胶囊,溶液,片剂 | (200-500mg/天) | ||
非肠道 | 注射液 | |||
氟奋乃静 | PROLIXIN | 0.5-40mg/天(1-5mg/天) | ||
氟奋乃静癸酸盐 | PROLIXINDecanoate | 非肠道 | 注射液 | (约口服剂量的一半) |
氟奋乃静庚酸盐 | PROLIXIN | 非肠道 | 注射液 | (同上) |
氟奋乃静盐酸盐 | PROLIXIN | 口服 | 酏剂溶液 | |
非肠道 | 注射液 | |||
替沃噻吨 | NAVANE | 口服 | 胶囊 | 6-60mg/天(8-30mg/天) |
替沃噻吨盐酸盐 | NAVANE | 口服 | 溶液 | |
非肠道 | 注射液 | |||
三氟拉嗪 | STELAZINE | (2-40mg/天) | ||
奋乃静 | TRILAFON | 口服 | 溶液,片剂 | 12-64mg/天(16-64mg/天) |
非肠道 | 注射液 | |||
奋乃静和阿米替林盐酸盐 | ETRAFONTRIAVIL | 口服 | 片剂 | |
硫利哒嗪 | NELLARIL | 口服 | 混悬剂,溶液,片剂 | 150-800mg/天(100-300mg/天) |
美索哒嗪 | (30-400mg/天) | |||
吗茚酮 | MOBAN | 50-225mg/天(15-150mg/天) | ||
吗茚酮盐酸盐 | MOBAN | 口服 | 溶液 | |
洛沙平盐酸盐 | LOXITANE | 20-250mg/天(60-100mg/天) | ||
洛沙平琥珀酸盐 | LOXITANE | 口服 | 溶液 | |
非肠道 | 注射液 | |||
匹莫齐特 | 口服 | 胶囊 | ||
氟哌噻吨 | (1-10mg/天) | |||
丙嗪 | SPARINE |
三氟丙嗪 | VESPRIN | |||
氯普噻吨 | TARACTAN | |||
氟哌利多 | INAPSINE | |||
乙酰奋乃静 | TINDAL | |||
普鲁氯嗪 | COMPAZINE | |||
左美丙嗪 | NOZINAN | |||
哌泊噻嗪 | PIPOTRIL | |||
Aripiprazole | ABILIFY | |||
Hoperidone |
所选安定药物的商品名和供应商如下:氯氮平(在商品名为CLOZARIL,购自Mylan,Zenith Goldline,UDL,Novartis);奥氮平(商品名ZYPREXA,购自Lilly;齐拉西酮(商品名GEODON,购自Pfizer);利哌利酮(商品名RISPERDAL,购自Janssen);富马酸喹噻平(商品名SEROQUEL,购自AstraZeneca);氟哌啶醇(商品名HALDOL),购自Ortho-McNeil);氯丙嗪(商品名THORAZINE,购自GlaxoSmithKline;氟奋乃静(商品名PROLIXIN,购自Apothecon,Copley,Schering,Teva,和American Pharmaceutical Partners,Pasadena);替沃噻吨(商品名NAVANE;,购自Pfizer);三氟拉嗪(10-[-(4-甲基-1-哌嗪基)丙基]-2-(三氟甲基)吩噻嗪二盐酸盐,商品名STELAZINE,购自GlaxoSmithKline;奋乃静(商品名TRILAFON(R);购自Schering);吗茚酮(商品名MOBAN,购自Endo);和洛沙平(商品名LOXITANE;购自Watson)。另外,也可以使用苯哌利多(Glianimon)、培拉嗪(Taxilan)或美哌隆(Eunerpan))。本发明特别优选的安定药物是奥氮平、利哌利酮、喹噻平、氟哌啶醇、氯氮平、齐拉西酮和osanetant.
本发明的一个特别优选的方面是提供一种通过给接受奥氮平给药的患者结合治疗性施用沙贝马啉或其药学可接受盐的治疗精神病的方法。本发明的另一优选方面是提供沙贝马啉或其药学可接受盐在制备用于在接受奥氮平的患者中结合治疗性给药治疗精神病的药物中的应用。本发明的另一优选方面提供沙贝马啉或其药学可接受盐在接受奥氮平的患者中结合治疗性给药治疗精神病中的应用。本发明的另一优选方面提供用于在接受奥氮平的患者中结合治疗性给药治疗精神病的沙贝马啉或其药学可接受盐。
本发明的一个特别优选的方面是提供一种通过给接受利哌利酮给药的患者结合治疗性施用沙贝马啉或其药学可接受盐的治疗精神病的方法。本发明的另一优选方面是提供沙贝马啉或其药学可接受盐在制备用于在接受利哌利酮的患者中结合治疗性给药治疗精神病的药物中的应用。本发明的另一优选方面提供沙贝马啉或其药学可接受盐在接受利哌利酮的患者中结合治疗性给药治疗精神病中的应用。本发明的另一优选方面提供用于在接受利哌利酮的患者中结合治疗性给药治疗精神病的沙贝马啉或其药学可接受盐。
本发明的一个特别优选的方面是提供一种通过给接受喹噻平给药的患者结合治疗性施用沙贝马啉或其药学可接受盐的治疗精神病的方法。本发明的另一优选方面是提供沙贝马啉或其药学可接受盐在制备用于在接受喹噻平的患者中结合治疗性给药治疗精神病的药物中的应用。本发明的另一优选方面提供沙贝马啉或其药学可接受盐在接受喹噻平的患者中结合治疗性给药治疗精神病中的应用。本发明的另一优选方面提供用于在接受喹噻平的患者中结合治疗性给药治疗精神病的沙贝马啉或其药学可接受盐。
本发明的一个特别优选的方面是提供一种通过给接受aripiprazole给药的患者结合治疗性施用沙贝马啉或其药学可接受盐的治疗精神病的方法。本发明的另一优选方面是提供沙贝马啉或其药学可接受盐在制备用于在接受aripiprazole的患者中结合治疗性给药治疗精神病的药物中的应用。本发明的另一优选方面提供沙贝马啉或其药学可接受盐在接受aripiprazole的患者中结合治疗性给药治疗精神病中的应用。本发明的另一优选方面提供用于在接受aripiprazole的患者中结合治疗性给药治疗精神病的沙贝马啉或其药学可接受盐。
本发明的一个特别优选的方面是提供一种通过给接受氟哌啶醇给药的患者结合治疗性施用沙贝马啉或其药学可接受盐的治疗精神病的方法。本发明的另一优选方面是提供沙贝马啉或其药学可接受盐在制备用于在接受氟哌啶醇的患者中结合治疗性给药治疗精神病的药物中的应用。本发明的另一优选方面提供沙贝马啉或其药学可接受盐在接受氟哌啶醇的患者中结合治疗性给药治疗精神病中的应用。本发明的另一优选方面提供用于在接受氟哌啶醇的患者中结合治疗性给药治疗精神病的沙贝马啉或其药学可接受盐。
本发明的一个特别优选的方面是提供一种通过给接受氯氮平给药的患者结合治疗性施用沙贝马啉或其药学可接受盐的治疗精神病的方法。本发明的另一优选方面是提供沙贝马啉或其药学可接受盐在制备用于在接受氯氮平的患者中结合治疗性给药治疗精神病的药物中的应用。本发明的另一优选方面提供沙贝马啉或其药学可接受盐在接受氯氮平的患者中结合治疗性给药治疗精神病中的应用。本发明的另一优选方面提供用于在接受氯氮平的患者中结合治疗性给药治疗精神病的沙贝马啉或其药学可接受盐。
本发明的一个特别优选的方面是提供一种通过给接受齐拉西酮给药的患者结合治疗性施用沙贝马啉或其药学可接受盐的治疗精神病的方法。本发明的另一优选方面是提供沙贝马啉或其药学可接受盐在制备用于在接受齐拉西酮的患者中结合治疗性给药治疗精神病的药物中的应用。本发明的另一优选方面提供沙贝马啉或其药学可接受盐在接受齐拉西酮的患者中结合治疗性给药治疗精神病中的应用。本发明的另一优选方面提供用于在接受齐拉西酮的患者中结合治疗性给药治疗精神病的沙贝马啉或其药学可接受盐。
本发明的一个特别优选的方面是提供一种通过给接受osanetant给药的患者结合治疗性施用沙贝马啉或其药学可接受盐的治疗精神病的方法。本发明的另一优选方面是提供沙贝马啉或其药学可接受盐在制备用于在接受osanetant的患者中结合治疗性给药治疗精神病的药物中的应用。本发明的另一优选方面提供沙贝马啉或其药学可接受盐在接受osanetant的患者中结合治疗性给药治疗精神病中的应用。本发明的另一优选方面提供用于在接受osanetant的患者中结合治疗性给药治疗精神病的沙贝马啉或其药学可接受盐。
对于本发明的治疗性给药,沙贝马啉组分可以以其游离碱的形式使用,但优选以药学可接受盐的形式使用,通常是盐酸盐。沙贝马啉与药学可接受酸的其他盐还可以用于治疗性给药,例如衍生自沙贝马啉或其药学可接受盐游离碱和酸的盐包括,但不限于,氢溴酸盐,磷酸盐,乙酸,富马酸,马来酸,水杨酸,柠檬酸,草酸,乳酸,苹果酸,甲磺酸和对甲苯磺酸。本发明的沙贝马啉或其药学可接受衍生物的所有溶剂化物和所有其他物理形式,包括但不限于其他结晶形式,无定形形式和多晶型也属于本发明的范围内,并且所有在此涉及沙贝马啉的包括其所有药学可接受盐,所有溶剂化物和全部物理形式。
一种或多种安定药物也可以适当地以其碱性或酸性形式给药,或者如果适宜,以其药学可接受盐或其他衍生物的形式。在此所述的一种或多种安定药物或其药学可接受盐或衍生物的所有溶剂化物和所有物理形式包括但不限于其他晶体形式、无定形形式和多晶型,也属于本发明的范围内。在一种或多种安定药物的情况中,优选的形式和衍生物是那些在单一疗法中被证实可以治疗性给药的,包括表I中提及的那些,但本文中所有涉及安定药物的均包括其所有药学可接受盐或其他衍生物,和其所有溶剂化物和其物理形式。
对于本发明的结合或同时治疗性给药,沙贝马啉或其药学可接受盐或溶剂化物和一种或多种安定药物或其药学可接受盐、衍生物或溶剂化物分别可以以纯净形式给药,但各组分应优选配制为药学可接受的和有效的组合物,该组合物在机体内提供有效水平的各个组分。大多数适当药学组合物对各个组分的选择属于本领域技术人员的范围内,并且各个组分可以是相同或不同的形式。适当的制剂包括,但不限于片剂、胶囊、散剂、颗粒剂、锭剂、栓剂、重构散剂和液体制剂,例如口服或灭菌非肠道溶液或混悬液。
为了将本发明的沙贝马啉和安定药物的联合组合物同时给药,沙贝马啉或其药学可接受盐或溶剂化物和一种或多种安定药物及其药学可接受盐、衍生物或溶剂化物可以以纯净形式一起给药,但该联合组合物应优选配制为药学可接受的和有效的组合物,该组合物在机体内提供有效水平的各个组分。大多数适当药学组合物对各个组分的选择属于本领域技术人员的范围内。适当的制剂包括,但不限于片剂、舌下片剂、经颊组合物、胶囊、散剂、颗粒剂、锭剂、栓剂、重构散剂和液体制剂,例如口服或灭菌非肠道溶液或混悬液。
为了达到结合给药和同时给药的一致性,优选各组分的组合物,或者各组分联合形式的组合物是单位剂量的形式。
组分或者组分联合形式的单位剂量呈递形式,对于口服给药可以是片剂和胶囊并且可以含有常规赋形剂,例如粘合剂,例如糖浆、阿拉伯胶、明胶、山梨糖醇、黄芪胶或聚乙烯吡咯烷酮;填充剂,例如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸;片剂润滑剂,例如硬脂酸镁;崩解剂,例如淀粉、聚乙烯吡咯烷酮、乙醇酸淀粉钠或微晶纤维素;或药物可接受湿润剂,例如十二烷基硫酸钠。
固体口服组合物可以通过混合、填充、制片等的常规方法来制备。反复混合操作可以用于使活性剂分布在采用大量填充剂的整个组合物内。此类操作是本领域的常规过程。片剂可以按照普通药学实践中的熟知方法进行包衣,特别是用肠溶包衣。
组分或组分联合形式的口服液体制剂,可以是例如乳液、糖浆、混悬液或酏剂的形式,或者可以是用水或其他适当载体在使用之前重构的干燥产物。这样的液体制剂可以含有常规添加剂,例如助悬剂,如山梨糖醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化可食用脂肪;乳化剂,例如卵磷脂、脱水山梨糖醇一油酸酯或阿拉伯胶;非水性载体(可以包括可食用油),例如杏仁油、分级椰子油、油性酯例如甘油、丙二醇或乙醇的酯;防腐剂,例如对羟基苯甲酸甲基或丙基酯或山梨酸;和如果需要可以使用常规矫味或着色剂。
对于组分或组合联合形式的非肠道给药(例如静脉内、肌肉内或皮下给药),可以理由组分或组分的联合形式与灭菌载体制备液体单位剂型,并且,根据所用的浓度,可以悬浮或溶解在载体中。在制备溶液时,组分或组分的联合形式可以溶解在注射用水中并且过滤灭菌,之后填充到适当小瓶或安瓿内并密封。适宜地,佐剂例如局部麻醉剂、防腐剂和缓冲剂可以溶解在载体内。为了提高稳定性,该组合物可以在填充后冷冻到瓶内并且在真空下除去水。非肠道混悬液的制备基本上以相同方式,除了组分是悬浮在载体中而不是溶解之外,并且灭菌无法通过过滤完成。组分或组分的联合形式可以通过暴露在环氧乙烷下类灭菌,之后悬浮在灭菌载体中。适宜地,组合物中含有表面活性剂或湿润剂以促进组分或组分的联合形式的均匀分布。
组分或组分的联合形式还可以配制为贮库制剂。此类长效制剂可以通过植入(例如皮下或肌肉内)给药或通过肌肉内注射给药。所以,例如,本发明的组分和组分联合形式可以用适当的聚合物或疏水性材料(例如在可接受油中的溶液)或离子交换树脂中配制,或者不易溶解的衍生物中配制,例如微溶盐。
各个组分和组分的联合形式的组合物可以含有0.1%-99%重量,优选10-60%重量的活性物质,这取决于给药的方法。
对于结合或同时给药,单位剂量的沙贝马啉组分是在10-300微克的范围内,各个单位剂量至多每天给药4次。优选沙贝马啉组分的单位剂量是在25-100微克的范围内,各单位剂量可以每天至多给药4次。安定药物的日剂量和单位剂量应取决于所用的安定药物,但通常是给具体安定药物在单一疗法中推荐或批准的剂量。在本发明的优选方面中,沙贝马啉的结合给药可以允许安定药物的剂量低于该安定药物在单一疗法中通常推荐时的剂量。通常适用于本发明的结合或同时给药的安定药物的日剂量如表1所示。
本文所述的至少一种安定药物和沙贝马啉的结合或同时给药还可以用于治疗或预防主要抑郁疾病,包括双极性抑郁症、单极抑郁、具有或不具有精神病特征、紧张症特征、忧郁特征或产后发作的单次或复发性严重抑郁发作,治疗焦虑和治疗恐慌疾病。其他情感障碍属于术语主要抑郁疾病的范畴内,包括早期和晚期发作并且具有或不具有非典型特征的心境恶劣、神经质抑郁、创伤后应激障碍、手术后应激和社会恐怖症;阿尔茨海默氏型的痴呆,早期或完全发作,具有抑郁情感;具有抑郁情感的血管痴呆;酒精、苯丙胺、可卡因、致幻剂、吸入剂、阿片类、苯环利定、镇静剂、催眠剂和其他物质;抑郁型的分裂情感性疾病;和抑郁情感的调整障碍。主要抑郁障碍还可以由于常规医疗条件造成,包括但不限于,心肌梗塞、糖尿病、流产或堕胎等。
本申请的至少一种安定药物和沙贝马啉的结合或同时给药还可以用于治疗睡眠障碍,包括dysomnia、失眠、睡眠窒息、发作性睡眠和生物钟紊乱。
本申请的至少一种安定药物和沙贝马啉的结合或同时给药还可以用于对许多物质的耐受和依赖。例如,治疗对尼古丁、酒精、咖啡因、苯环利定(苯环利定样化合物)依赖性的治疗中,或在阿片(例如大麻,海洛因,吗啡)或苯并二氮杂类依赖性的治疗中;在可卡因、镇静催眠剂、苯丙胺或苯丙胺有关药物(例如右苯丙胺,甲基苯丙胺)成瘾或其联合形式的治疗中。
本发明可以通过适当的患者研究举例说明。适当的患者研究的下列实施例出于举例说明的目的并且不以任何方式限定本发明的范围。该研究是沙贝马啉的功效的双盲、安慰剂对照、随机研究,其中沙贝马啉在治疗中分别结合性施用三种安定药物用于治疗精神分裂症和分裂情感性精神病中的认知作用。
选择具有认知缺损的约50名患有精神分裂症和分裂情感性精神病的年龄18-55岁的患者(根据DSM-IV定义的标准诊断)。合格的患者是那些在筛选访问之前3个月内对于安定药物稳定的患者。在举例试验中患者能够被稳定化的安定药物是氟哌啶醇、利哌利酮或奥氮平。所选患者随机接受在先施用的安定药物加安慰剂并且在校施用安定药物加沙贝马啉(50微克盐酸盐,bid)达12周。治疗12周后,停止药物并且患者在2周后进行总结。与氟哌啶醇、利哌利酮和奥氮平结合治疗的沙贝马啉的神经认知效果用Cogtest(认知功能测试)电池通过Neurocognitive Global评分(NGS)进行评估并且与氟哌啶醇、利哌利酮和奥氮平加安慰剂的进行对比。在研究结束时还可评估PANSS(总的阳性和阴性症状比例)、CDSS(精神分裂症的Calgary抑郁比例)和CGI(临床皮质印象改进)与基线相比的变化。另外,也可以使用cogtest电池例如Bacs和matrics。此外,预期可以存在第二初级定位社会功能(addressing social functioning)。进行研究和试验的最佳持续时间是6个月。
Claims (36)
1.一种含有沙贝马啉(sabcomeline)或其药学可接受盐和至少一种安定药物药物组合物。
2.权利要求1的药物组合物,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
3.含有沙贝马啉或其药学可接受盐和至少一种安定药物的药物组合物在治疗精神病中的应用。
4.按照权利要求3的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
5.沙贝马啉或其药学可接受盐在结合治疗性给药以治疗接受至少一种安定药物的治疗性给药的患者中的精神病的应用。
6.按照权利要求5的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
7.沙贝马啉或其药学可接受盐在制备用于结合治疗性给药以治疗接受至少一种安定药物的治疗性给药的患者的精神病的药物中的应用。
8.按照权利要求7的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
9.至少一种安定药物在结合治疗性给药以治疗接受沙贝马啉或其药学可接受盐的治疗性给药的患者中的精神病的应用。
10.按照权利要求9的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
11.至少一种安定药物在制备用于结合治疗性给药以治疗接受沙贝马啉或其药学可接受盐的治疗性给药的患者的精神病的药物中的应用。
12.按照权利要求9的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
13.沙贝马啉或其药学可接受盐和至少一种安定药物的联合形式在同时治疗性给药治疗精神病中的应用。
14.按照权利要求13的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
15.沙贝马啉或其药学可接受盐和至少一种安定药物的联合形式在制备用于同时治疗性给药治疗精神病的药物中的应用。
16.按照权利要求15的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
17.沙贝马啉或其药学可接受盐在用于在精神病的治疗中与至少一种安定药物同时治疗性给药中的应用。
18.按照权利要求17的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
19.沙贝马啉或其药学可接受盐在制备用于在精神病的治疗中与至少一种安定药物同时治疗性给药以治疗精神病的药物中的应用。
20.按照权利要求19的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
21.至少一种安定药物在用于在精神病的治疗中与沙贝马啉或其药学可接受盐同时治疗性给药中的应用。
22.按照权利要求21的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
23.至少一种安定药物在制备用于在精神病的治疗中与沙贝马啉或其药学可接受盐同时治疗性给药以治疗精神病的药物中的应用。
24.按照权利要求23的用途,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
25.一种用于治疗精神病的多部分试剂盒,其中包括含有沙贝马啉或其药学可接受盐的第一剂型和至少一个同时治疗性给药的含有安定药物的其他剂型。
26.权利要求25的多部分试剂盒,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
27.一种通过沙贝马啉或其药学可接受盐在接受至少一种安定药物的治疗性给药的患者中结合治疗性给药治疗精神病的方法。
28.按照权利要求27的方法,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
29.沙贝马啉或其药学可接受盐用于结合治疗性给药治疗接受至少一种安定药物的治疗性给药的患者中的精神病。
30.沙贝马啉或其药学可接受盐用于结合治疗性给药治疗接受至少一种安定药物的治疗性给药的患者中的精神病,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
31.一种通过至少一种安定药物在接受沙贝马啉或其药学可接受盐的治疗性给药的患者中结合治疗性给药治疗精神病的方法。
32.按照权利要求31的治疗方法,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
33.一种沙贝马啉或其药学可接受盐联合至少一种安定药物同时治疗性给药治疗精神病的方法。
34.按照权利要求33的治疗方法,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
35.沙贝马啉或其药学可接受盐用于在精神病的治疗中与至少一种安定药物同时治疗性给药。
36.沙贝马啉或其药学可接受盐用于在精神病的治疗中与至少一种安定药物同时治疗性给药,其中所述的安定药物选自奥氮平、利哌利酮、喹噻平、aripiprazole、氟哌啶醇、氯氮平、齐拉西酮和osanetant。
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EP2258359A3 (en) * | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
JP2009506069A (ja) * | 2005-08-26 | 2009-02-12 | ブレインセルス,インコーポレイティド | ムスカリン性受容体調節による神経発生 |
GB0607952D0 (en) * | 2006-04-21 | 2006-05-31 | Minster Res Ltd | Novel treatment |
GB0607946D0 (en) * | 2006-04-21 | 2006-05-31 | Minster Res The Ltd | Mono and combination therapy |
GB0822077D0 (en) * | 2008-12-03 | 2009-01-07 | Minster Res Ltd | Novel treatments |
PL3061821T3 (pl) | 2009-07-22 | 2020-01-31 | PureTech Health LLC | Kompozycje do leczenia zaburzeń łagodzonych przez aktywację receptora muskarynowego |
US10265311B2 (en) | 2009-07-22 | 2019-04-23 | PureTech Health LLC | Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation |
JP5758900B2 (ja) | 2009-09-30 | 2015-08-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | グルコピラノシル置換ベンジルベンゼン誘導体の調製方法 |
US10610489B2 (en) * | 2009-10-02 | 2020-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20140303097A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
HUE041709T2 (hu) | 2013-04-05 | 2019-05-28 | Boehringer Ingelheim Int | Az empagliflozin terápiás alkalmazásai |
US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
CN113181161A (zh) | 2013-04-18 | 2021-07-30 | 勃林格殷格翰国际有限公司 | 药物组合物、治疗方法及其用途 |
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US20090281078A1 (en) | 2009-11-12 |
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