CN1317964A - 新型组合物 - Google Patents
新型组合物 Download PDFInfo
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- CN1317964A CN1317964A CN99811010A CN99811010A CN1317964A CN 1317964 A CN1317964 A CN 1317964A CN 99811010 A CN99811010 A CN 99811010A CN 99811010 A CN99811010 A CN 99811010A CN 1317964 A CN1317964 A CN 1317964A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
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- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及含有第一种成分(a)(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物和第二种成分(b)游离碱或其可药用盐和/或溶剂化物形式的帕罗西丁的组合物、其制备方法、含有所述组合物的药物制剂、用所述组合物治疗情感障碍例如心境障碍和焦虑的用途和方法以及含有所述组合物的药盒。
Description
发明领域
本发明涉及含有第一种成分(a)(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物和第二种成分(b)帕罗西丁或其可药用盐和/或溶剂化物的组合物。本发明还涉及本发明组合物的制备方法、含有所述组合物的药物制剂以及通过合并给药或分别给药所述组合物来改善情感障碍如抑郁、焦虑、强迫症(OCD)等的治疗的用途。
发明背景
目前,普遍认为抗抑郁剂需要2-4周的时间才能达到全部的临床效果。相反,副作用却会立即出现。因此,抗抑郁剂的起效缓慢会使患者经历一段有药物的副作用但却没有治疗效果的脆弱时期。主治医师通常需要花很多功夫来劝说患者在这段时间内继续接受治疗。此外,在自杀性患者中,由于作用的起效是逐步的,在症状没有得到完全逆转之前可能会再次产生自杀动机,因此仍存在自杀的危险性并且需要反复住院。起效较快的抗抑郁剂不仅有利于症状的更迅速减轻,而且对于患者和医生来讲也更容易接受,并且还可以减少住院的需要以及住院的时间。在治疗其它情感障碍例如焦虑和OCD时,同样需要很长的时间来达到全部的临床效果。
现有技术
在WO96/33710中公开了化合物(R)-5-氨基甲酰基-8-氟-3-N,N-二环丁基氨基-3,4-二氢-2H-1-苯并吡喃,该化合物对5-HT受体具有高亲和性并且可以拮抗5-HT1A介导的反应,导致用血清素再摄取抑制剂治疗的抑郁患者迅速改善。
发明概述
本发明涉及新的组合物,该组合物含有第一种成分(a):特异性的5-HT1A拮抗剂(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物和第二种成分(b):游离碱或其可药用盐和/或溶剂化物形式的帕罗西丁。所述组合物能够较为迅速地起效,从而可以更有效地治疗患有情感障碍、特别是抑郁的患者。
在动物研究中证实,急性给药选择性的5-HT再摄取抑制剂(SSRIS)可以通过负反馈反应减少5-HT神经元内的电脉冲传播,所述负反馈反应可能是由侧突5-HT轴索在核缝释放5-HT所介导的。通过在核缝中抑制躯体树状(somatodendritic)5-HT1A自身受体,选择性拮抗剂抵消了由5-HT再摄取抑制剂所引起的传播的减少。这表明,选择性地阻断躯体树状自身受体、即5-HT1A拮抗剂可能具有改善5-HT再摄取抑制剂(SSRIS)之效力的临床潜力并使情感障碍的治疗效果、例如抗抑郁剂的作用产生新的、合理的迅速起效。
本文公开的化合物(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物(NAD299)作为选择性的5-HT1A受体拮抗剂记载于《药理学和实验治疗学杂志》(J.Pharmacol.Exp.Ther.),283,216-225,(1997)。
(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物对CNS中特异性的5-HT1A受体亚组具有高亲和性并可对作为拮抗剂对该5-HT1A受体起作用,而且在口服给药后还显示良好的生物利用度。
帕罗西丁是市售的5-HT再摄取抑制剂(SSRI)。帕罗西丁的可药用盐例如盐酸盐、氢溴酸盐、马来酸盐、酒石酸盐、乙酸盐等也包括在本发明的组合物范围内。此外还包括盐的溶剂化物形式,例如水合物和半水合物。
本发明的组合物可以是含有成分(a)和成分(b)的单一药物制剂的形式,或是一种含有成分(a)的制剂和一种含有成分(b)的制剂这样两种不同药物制剂的形式。药物制剂可以是片剂或胶囊、散剂、混合物、溶液剂或其它适宜的药物制剂形式例如贴剂和鼻制剂的形式。
本发明的组合物可以通过以例如常规的方式混合而制成将成分(a)和成分(b)掺入到同一药物制剂中的形式。
本发明还包括通过将含有(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物和帕罗西丁的组合物合并给药来改善治疗作用起效的方法。
本发明的另一个实施方案是含有(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物的剂量单位和帕罗西丁的剂量单位的药盒,其中还可以选择性地含有使用说明书。药物制剂
根据本发明,组合物中的化合物通常以在可药用剂量形式中含有活性成分的药物制剂的形式口服、直肠、经皮、经鼻或通过注射给药。剂量形式可以是固体、半固体或液体的制剂。通常,活性成分在注射用的制剂中可以占制剂重量的0.1至99%,特别是占制剂重量的0.5至20%,在适用于口服给药的制剂中占制剂重量的0.2至50%。
药物制剂含有活性成分以及任意选择性地含有辅剂、赋形剂例如稀释剂和/或惰性载体。
为了生产口服应用的剂量单位形式的本发明组合物的药物制剂,可将选定的化合物与固体赋形剂如乳糖、蔗糖、山梨醇、甘露醇、淀粉如土豆淀粉、玉米淀粉或支链淀粉、纤维素衍生物、粘合剂如明胶或聚乙烯吡咯烷酮、崩解剂如淀粉甘醇酸钠、交联PVP和交联羧甲基纤维素钠(cross-caramellose sodium)和润滑剂如硬脂酸镁、硬脂酸钙、聚乙二醇、蜡、石蜡等以及抗粘剂例如滑石或胶态二氧化硅混合,然后压制成片剂。如果需要包衣片剂,可将按照上述方法制得的片芯用本领域技术人员已知的聚合物例如HPMC、HC或其它纤维素衍生物或PVP包衣,其中,将聚合物溶于水或易挥发的有机溶剂或有机溶剂的混合物中。或者,可将片剂用浓缩的糖溶液包衣,所述糖溶液可以含有例如阿拉伯胶、明胶、滑石、二氧化钛等。可以向这些包衣中加入染料例如以便于区分含有不同活性成分或不同量的活性化合物的片剂。
对于软明胶胶囊制剂,可将活性成分与例如植物油或聚乙二醇混合。硬明胶胶囊可以含有用上述片剂赋形剂例如乳糖、蔗糖、山梨醇、甘露醇、淀粉(例如土豆淀粉、玉米淀粉或支链淀粉)、纤维素衍生物、增塑剂、聚乙二醇、蜡、类脂或明胶制成的活性成分的颗粒。也可将药物的液体或半固体填充到硬明胶胶囊中。
用于直肠给药的剂量单位可以是溶液或混悬液,或者可以制成在中性脂肪基质中含有活性成分的栓剂形式或是含有活性成分与植物油或石蜡油的明胶直肠胶囊。口服应用的液体制剂可以是溶液、糖浆或混悬液的形式,例如含有约0.2%至约20%(重量)本文所述的活性成分的溶液,其余的物质为糖和乙醇、水、甘油和丙二醇的混合物。所述液体制剂还可以任意选择性地含有着色剂、矫味剂、糖精和作为增稠剂的羧甲基纤维素或本领域技术人员已知的其它赋形剂。
用于通过注射进行胃肠外应用的溶液剂可以制成活性成分的水溶性可药用盐的水溶液形式,优选浓度为约0.5%至约10%(重量)。这些溶液还可以含有稳定剂和/或缓冲剂,并且可以以各种剂量单位的安瓿的形式方便地提供。
在对人进行治疗时,本发明组合物中活性化合物的适宜每日剂量在口服给药时为约0.01-100mg/kg体重,在胃肠外给药时为0.001-100mg/kg体重。活性成分(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物的每日剂量可以和活性成分帕罗西丁的每日剂量有很大的不同,但两种活性成分的剂量也可以相同。医学和药物应用
另一方面,本发明提供了含有第一种成分(a)(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物和第二种成分(b)帕罗西丁的组合物在治疗5-羟色胺介导的疾病、例如情感障碍中的用途。情感障碍的例子是CNS的疾病例如心境障碍(抑郁、大抑郁发作、心境恶劣、季节性情感障碍、双重障碍的抑郁期)、焦虑症(强迫症、有或没有广场恐怖的恐慌症、社交恐怖症、特异性恐慌、全面焦虑、创伤后的紧张状态)、人格障碍(冲动控制障碍、拔毛癖)和睡眠障碍。其它CNS障碍例如饮食障碍(肥胖、厌食、食欲过盛)、经前期综合征、性欲障碍、酗酒、烟草滥用、孤独症、注意力缺陷、多动症、偏头痛、记忆力障碍(与衰老有关的记忆力损伤、早老性和老年性痴呆例如阿耳茨海默氏病)、病理学的攻击、精神分裂症、内分泌障碍(例如高摧乳素血症)、中风、运动障碍、帕金森氏症、体温调节障碍、疼痛和高血压也可以用本文所述的联用形式进行治疗。其它由羟基色胺介导的障碍的例子是尿失禁、血管痉挛和肿瘤(例如肺癌)生长的控制,也可以用本文所述的联用形式对其进行治疗。药理学(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物(NAD299)对帕罗西丁诱导的后缝神经冲动开始抑制的拮抗作用材料和方法
使用成年雄性Sprague Dawley大鼠(B&K Univesal,Sollentuna,Sweden)并将其在受控制的气候条件下饲养。按照标准方法对动物进行电生理记录的准备。简单地讲,将大鼠用水合氯醛深度麻醉然后固定在立体定位架上。通过立体定位坐标引导将细胞外记录电极插到后缝下,然后通过血清素神经元的神经冲动开始特性在该核中找出靶神经元。在整个实验中使动物保持麻醉并将药物通过尾静脉导管静脉给药。帕罗西丁(0.1mg/kg,静脉内)比NAD299(50nmol/kg,静脉内)早3分钟给药。结果
还发现NAD299可以拮抗由帕罗西丁所诱导的对大鼠血清素能后缝神经元神经冲动开始的抑制作用(见图)。图中给出了从每组5只动物的记录结果计算出的中值±半-四分位数间距(medians±semi-interquartile range)。在图中还给出了通过Mann-Whitney μ-试验进行的治疗组和对照组之间差异的统计学评估。此外,用NAD299处理对帕罗西丁诱导的抑制作用产生了有统计学意义的拮抗作用(p<0.05)。讨论和结论
一般认为,选择性的血清素再摄取抑制剂(SSRIS)例如帕罗西丁是由于其可以增强血清素在中脑核缝的前脑血清素能投射靶区域的突触有效性的能力而具有抗抑郁作用。但是,受影响的5-羟色胺(5-HT)转运蛋白同时存在于躯体树状和末端区域,血清素在前一区域有效性的增加将会通过抑制性5-HT1A自身受体的激活而抑制神经元活性以及前脑的5-HT合成和释放。正如在动物研究中所证实的,由于这些受体会逐渐脱敏,前脑的血清素释放将会逐渐增加,这该现象的时程可能可以解释抗抑郁剂在临床上的起效延迟。
目前有这样的推测,通过阻断抑制性5-HT1A自身受体来消除SSRIS的自身抑制作用将会产生快速起效,并且还会增加这些药物的效力。
数据表明,(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物(NAD299)可以在大鼠中有效地拮抗通过急性给药帕罗西丁所产生的对血清素能神经元神经冲动开始的抑制作用。
以下非限定性实施例用来说明本发明。
实施例
在单一剂量形式中含有第一种成分(a)和第二种成分(b)的适宜的药物组合物含有如下成分:
组成 mg/片
活性药物成分(a) 5
活性药物成分(b) 20
微晶纤维素 100
玉米淀粉 40
聚烯吡酮 4
水 50
淀粉甘醇酸钠 8
硬脂酸镁 1
权利要求书
按照条约第19条的修改
1、含有第一种成分(a)(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物和第二种成分(b)游离碱或其可药用盐和/或溶剂化物形式的帕罗西丁的组合物。
2、权利要求1的组合物在生产用于治疗由5-HT所介导之疾病的药物中的用途。
3、权利要求2的用途,用于生产治疗情感障碍的药物。
4、权利要求3的用途,用于生产治疗心境障碍的药物。
5、权利要求4的用途,用于生产治疗抑郁的药物。
6、权利要求2的用途,用于生产预防或治疗尿失禁的药物。
7、治疗由5-HT介导的疾病的方法,该方法包括向患有该疾病的患者施用权利要求1所定义的组合物。
8、权利要求7的方法,用于治疗情感障碍。
9、权利要求7的方法,用于治疗心境障碍。
10、权利要求9的方法,用于治疗抑郁;
11、权利要求7的方法,用于预防或治疗尿失禁。
12、通过合并给药权利要求1所定义的组合物来改善治疗作用起效的方法。
13、药物制剂,其中的活性成分为权利要求1所定义的组合物中的活性成分,还任意选择性地含有辅剂、赋形剂和/或惰性载体。
14、权利要求13的药物制剂,其中,第一种成分(a)与第二种成分(b)合并给药。
15、权利要求13-14中任意一项所述的药物制剂用于治疗5-HT介导的疾病。
16、权利要求13-14中任意一项所述的药物制剂用于治疗情感障碍。
17、权利要求13-14中任意一项所述的药物制剂用于治疗心境障碍。
18、权利要求13-14中任意一项所述的药物制剂用于治疗抑郁。
19、权利要求13-14中任意一项所述的药物制剂用于治疗尿失禁。
20、权利要求1所述组合物的制备方法,该方法包括,将第一种成分(a)和第二种成分(b)掺入到相同药物制剂中。
21、权利要求1所述组合物的制备方法,其中,第一种成分(a)在一种药物制剂中并与在另一种不同药物制剂中的第二种成分(b)合并。
22、含有第一种成分(a)(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物的剂量单位和第二种成分(b)游离碱或其可药用盐和/或溶剂化物形式的帕罗西丁的剂量单位的药盒,其中还可以任意选择性地含有使用说明书。
Claims (19)
1、含有第一种成分(a)(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物和第二种成分(b)游离碱或其可药用盐和/或溶剂化物形式的帕罗西丁的组合物。
2、权利要求1的组合物在生产用于治疗由5-HT所介导之疾病的药物中的用途。
3、权利要求2的用途,用于生产治疗情感障碍的药物。
4、权利要求3的用途,用于生产治疗心境障碍的药物。
5、权利要求4的用途,用于生产治疗抑郁的药物。
6、治疗由5-HT介导的疾病的方法,该方法包括向患有该疾病的患者施用权利要求1所定义的组合物。
7、权利要求6的方法,用于治疗情感障碍。
8、权利要求6的方法,用于治疗心境障碍。
9、权利要求8的方法,用于治疗抑郁。
10、通过合并给药权利要求1所定义的组合物来改善治疗作用起效的方法。
11、药物制剂,其中的活性成分为权利要求1所定义的组合物中的活性成分,还任意选择性地含有辅剂、赋形剂和/或惰性载体。
12、权利要求11的药物制剂,其中,第一种成分(a)与第二种成分(b)合并给药。
13、权利要求11-12中任意一项所述的药物制剂用于治疗5-HT介导的疾病。
14、权利要求11-12中任意一项所述的药物制剂用于治疗情感障碍。
15、权利要求11-12中任意一项所述的药物制剂用于治疗心境障碍。
16、权利要求11-12中任意一项所述的药物制剂用于治疗抑郁。
17、权利要求1所述组合物的制备方法,该方法包括,将第一种成分(a)和第二种成分(b)掺入到同一药物制剂中。
18、权利要求1所述组合物的制备方法,其中,第一种成分(a)在一种药物制剂中并与在另一个不同药物制剂中的第二种成分(b)合并。
19、含有第一种成分(a)(R)-3-N,N-二环丁基氨基-8-氟-3,4-二氢-2H-1-苯并吡喃-5-甲酰胺(2R,3R)酒石酸氢盐一水合物的剂量单位和第二种成分(b)游离碱或其可药用盐和/或溶剂化物形式的帕罗西丁的剂量单位的药盒,其中还可以任意选择性地含有使用说明书。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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SE9803156A SE9803156D0 (sv) | 1998-09-16 | 1998-09-16 | A new composition |
SE9803156-0 | 1998-09-16 |
Publications (1)
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CN1317964A true CN1317964A (zh) | 2001-10-17 |
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Application Number | Title | Priority Date | Filing Date |
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CN99811010A Pending CN1317964A (zh) | 1998-09-16 | 1999-09-13 | 新型组合物 |
Country Status (21)
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EP (1) | EP1128825A1 (zh) |
JP (1) | JP2002524508A (zh) |
KR (1) | KR20010099647A (zh) |
CN (1) | CN1317964A (zh) |
AR (1) | AR021808A1 (zh) |
AU (1) | AU6378099A (zh) |
BR (1) | BR9913748A (zh) |
CA (1) | CA2342341A1 (zh) |
CZ (1) | CZ2001961A3 (zh) |
EE (1) | EE200100157A (zh) |
HU (1) | HUP0103544A3 (zh) |
ID (1) | ID28785A (zh) |
IL (1) | IL141519A0 (zh) |
IS (1) | IS5879A (zh) |
NO (1) | NO20011312L (zh) |
PL (1) | PL346763A1 (zh) |
SE (1) | SE9803156D0 (zh) |
SK (1) | SK3262001A3 (zh) |
TR (1) | TR200100779T2 (zh) |
WO (1) | WO2000015218A1 (zh) |
ZA (1) | ZA200101946B (zh) |
Families Citing this family (2)
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DK1358177T3 (da) | 2000-10-13 | 2006-12-04 | Neurosearch As | Behandling af affektbetonede lidelser ved den kombinerede virkning af en nikotinreceptoragonist og et monoaminergt stof |
WO2006093192A1 (ja) * | 2005-03-04 | 2006-09-08 | Tokyo Medical And Dental University | 覚醒剤精神病及び統合失調症の再発防止治療薬 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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SE9501567D0 (sv) * | 1995-04-27 | 1995-04-27 | Astra Ab | A new combination |
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1998
- 1998-09-16 SE SE9803156A patent/SE9803156D0/xx unknown
-
1999
- 1999-09-13 EP EP99951319A patent/EP1128825A1/en not_active Withdrawn
- 1999-09-13 TR TR2001/00779T patent/TR200100779T2/xx unknown
- 1999-09-13 JP JP2000569802A patent/JP2002524508A/ja active Pending
- 1999-09-13 WO PCT/SE1999/001597 patent/WO2000015218A1/en not_active Application Discontinuation
- 1999-09-13 HU HU0103544A patent/HUP0103544A3/hu unknown
- 1999-09-13 BR BR9913748-8A patent/BR9913748A/pt not_active Application Discontinuation
- 1999-09-13 CN CN99811010A patent/CN1317964A/zh active Pending
- 1999-09-13 CA CA002342341A patent/CA2342341A1/en not_active Abandoned
- 1999-09-13 KR KR1020017003337A patent/KR20010099647A/ko not_active Application Discontinuation
- 1999-09-13 CZ CZ2001961A patent/CZ2001961A3/cs unknown
- 1999-09-13 EE EEP200100157A patent/EE200100157A/xx unknown
- 1999-09-13 AU AU63780/99A patent/AU6378099A/en not_active Abandoned
- 1999-09-13 IL IL14151999A patent/IL141519A0/xx unknown
- 1999-09-13 ID IDW20010581A patent/ID28785A/id unknown
- 1999-09-13 SK SK326-2001A patent/SK3262001A3/sk unknown
- 1999-09-13 PL PL99346763A patent/PL346763A1/xx unknown
- 1999-09-15 AR ARP990104626A patent/AR021808A1/es not_active Application Discontinuation
-
2001
- 2001-03-07 IS IS5879A patent/IS5879A/is unknown
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Also Published As
Publication number | Publication date |
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JP2002524508A (ja) | 2002-08-06 |
HUP0103544A3 (en) | 2003-12-29 |
ID28785A (id) | 2001-07-05 |
TR200100779T2 (tr) | 2001-10-22 |
IL141519A0 (en) | 2002-03-10 |
AR021808A1 (es) | 2002-08-07 |
PL346763A1 (en) | 2002-02-25 |
NO20011312L (no) | 2001-05-16 |
SE9803156D0 (sv) | 1998-09-16 |
CZ2001961A3 (cs) | 2001-08-15 |
ZA200101946B (en) | 2002-06-10 |
BR9913748A (pt) | 2001-07-10 |
WO2000015218A1 (en) | 2000-03-23 |
KR20010099647A (ko) | 2001-11-09 |
EP1128825A1 (en) | 2001-09-05 |
EE200100157A (et) | 2002-08-15 |
NO20011312D0 (no) | 2001-03-15 |
HUP0103544A2 (hu) | 2002-05-29 |
CA2342341A1 (en) | 2000-03-23 |
SK3262001A3 (en) | 2001-08-06 |
AU6378099A (en) | 2000-04-03 |
IS5879A (is) | 2001-03-07 |
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