CN1927193B - 阿戈美拉汀在获得用于治疗抑郁患者睡眠障碍的药物中的用途 - Google Patents
阿戈美拉汀在获得用于治疗抑郁患者睡眠障碍的药物中的用途 Download PDFInfo
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Abstract
本发明涉及阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺在获得用于治疗抑郁患者睡眠障碍的药物中的用途。
Description
技术领域：
本发明涉及式(I)的阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺或其水合物、晶体形式和可药用酸或碱的加成盐单独或联合在获得用于治疗抑郁患者睡眠障碍的药物中的用途，
背景技术：
阿戈美拉汀，或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺，具有褪黑激素能系统受体激动剂和5-HT2C受体拮抗剂的双重特征。这些特征使得它在中枢神经系统中具有活性，更特别是在重症抑郁、季节性情感障碍、睡眠障碍、心血管疾病、消化系统疾病、由时差导致的失眠和疲劳、食欲紊乱和肥胖症的治疗中有活性。
欧洲专利说明书EP 0447285中已经描述了阿戈美拉汀、其制备方法和在治疗中的用途。
发明内容：
现在，本申请人已经发现阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺或其水合物、晶体形式和可药用酸或碱的加成盐具有有价值的特性，该特性允许其用于治疗抑郁患者的睡眠障碍。
睡眠是人类最重要的昼夜生物节律。该节律在抑郁患者中受到了严重的影响并且目前没有令人满意的减轻那些障碍的公认治疗方法。现有的抗抑郁剂治疗(氟西汀、帕罗西汀、文拉法辛...)对抑郁患者的睡眠障碍有很小或没有特定作用。作为导致受治疗者的日认知能力(diurnal cognitivecapacities)下降的强效非特异性镇静作用的结果，那些有效的抗抑郁剂治疗也如此。这对于例如米安色林和米氮平是真实的(Ridout等人.2001，Fawcett等人，1998)。
现在，申请人已经发现阿戈美拉汀特别适合治疗抑郁患者的睡眠障碍。实际上，抑郁患者睡眠的改善不必损害睡眠结构：具有非特异性镇静作用的抗抑郁剂扰乱了该结构，特别是通过改变快速眼动睡眠或慢深度睡眠(Zarifian等人.1982)来扰乱该结构。与其相反，现在，本申请人已经发现阿戈美拉汀与常规的抗抑郁剂表现不同，它的作用不妨害抑郁患者的睡眠结构，由此不妨害内环境稳定的睡眠响应。这些结果导致允许在抑郁患者的睡眠障碍中考虑它的使用，甚至是长期使用。
因此，本发明涉及阿戈美拉汀或其水合物、晶体形式和可药用酸或碱的加成盐在获得用于治疗抑郁患者睡眠障碍的药物组合物中的用途。
药物组合物将以适于经口服、胃肠道外、经皮、经鼻、直肠或经舌途径给药的形式存在，特别是以可注射的制剂、片剂、舌下片、glossettes、明胶胶囊、胶囊、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶等等。
除了阿戈美拉汀之外，本发明的药物组合物还包含一种或多种选自稀释剂、润滑剂、粘合剂、崩解剂、吸收剂、着色剂、甜味剂等等的赋形剂或载体。
以举例方式且无任何限制意义可被提及的有：
◆稀释剂：乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素、甘油，
◆润滑剂：二氧化硅、滑石粉、硬脂酸及其镁盐和钙盐、聚乙二醇，
◆粘合剂：硅酸镁铝、淀粉、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮，
◆崩解剂：琼脂、海藻酸及其钠盐、泡腾混合物。
有用剂量根据患者的性别、年龄及体重、给药途径、障碍的性质以及任何所联合的治疗的不同而不同，为每24小时1mg至50mg阿戈美拉汀。
阿戈美拉汀的日剂量优选为每天25mg。
具体实施方式：
药物组合物：
制备1000片片剂的处方，每片包含25mg活性成分：
阿戈美拉汀..........................................25g
乳糖一水合物.........................................62g
硬脂酸镁............................................1.3g
聚维酮..............................................9g
无水胶态二氧化硅....................................0.3g
纤维素羟乙酸钠......................................30g
硬脂酸..............................................2.6g
临床研究：
阿戈美拉汀对抑郁患者睡眠障碍的特定作用通过与米氮平的比较来确定。本研究以双盲法进行6周治疗，以睡眠的多导睡眠描记记录作为其效力的主要标准。汉密尔顿抑郁量表(Hamilton Scale of Depression)可证明抗抑郁效力。所得结果表明阿戈美拉汀在治疗抑郁患者的睡眠障碍中特别有效。
另一项评价睡眠改善的研究在处于典型抑郁状态的患者中以双盲法进行6周，与文拉法辛进行比较。一周安慰剂后，332名患者被随机给药：165名接受2周的25mg/天阿戈美拉汀，167名接受2周的75mg/天文拉法辛。治疗2周后，如果发现所得临床改善不够，那么在随后的治疗中某些患者的剂量将加倍至50mg/天的阿戈美拉汀或150mg/天的文拉法辛。
汉密尔顿抑郁量表可证明抗抑郁效力，所得结果表明阿戈美拉汀与文拉法辛的效力相当。
对睡眠的作用采用Leeds睡眠评价问卷(Leeds Sleep EvaluationQuestionnaire(LSEQ))来评价：在“进入睡眠容易度”(GTS)一项中，阿戈美拉汀比米氮平的作用更显著并且出现得更快，该作用从第一周起显著不同(p＝0.007)并在6周治疗期间对于阿戈美拉汀而言持续。关于“睡眠质量”(QOS)一项，阿戈美拉汀显示了比米氮平略高的效力(p＝0.015)。在“日间欲睡”和“健康感觉”的现象中阿戈美拉汀被报道相对于米氮平有同样显著的改善(p小于或等于0.001)。那些结果证明阿戈美拉汀在治疗抑郁患者睡眠障碍中的效力的优势。
最后，阿戈美拉汀对多导睡眠描记参数的作用通过在15名具有典型抑郁状态的患者中进行的初步研究来评价。给予25mg阿戈美拉汀可以观察到睡眠生理结构的恢复。脑电描记活性记录的第3和4周期的绝对和相对持续时间被显著增加而REM(快速眼动)睡眠未改变。此外，阿戈美拉汀增加睡眠的总持续时间，减少夜间醒来的次数，并因而改善睡眠效力。那些有益的作用从治疗的第一周起被观察到。
Claims (2)
1.N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺或其可药用酸或碱的加成盐在制备用于在抑郁患者中恢复睡眠生理结构的药物中的用途。
2.包含单独或与一种或多种可药用赋形剂组合的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺或其可药用酸或碱的加成盐的药物组合物在制备用于在抑郁患者中恢复睡眠生理结构的药物中的用途。
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| FR0509207 | 2005-09-09 | ||
| FR0509207A FR2890562B1 (fr) | 2005-09-09 | 2005-09-09 | Utilisation de l'agomelatine pour l'obtention de medicaments destines au traitement des troubles du sommeil chez le patient deprime |
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| FR2918370B1 (fr) * | 2007-07-02 | 2009-08-28 | Servier Lab | Nouveaux derives naphtaleniques,leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR2918372B1 (fr) * | 2007-07-02 | 2009-08-28 | Servier Lab | Nouveaux derives naphtaleniques,leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| CN102190595A (zh) * | 2010-03-17 | 2011-09-21 | 上海医药工业研究院 | 阿戈美拉汀溴化氢水合物及其制备方法 |
| CN102190594A (zh) * | 2010-03-17 | 2011-09-21 | 上海医药工业研究院 | 阿戈美拉汀氯化氢水合物及其制备方法 |
| CN101991559B (zh) * | 2010-11-25 | 2012-04-18 | 天津市汉康医药生物技术有限公司 | 一种稳定的阿戈美拉汀胶囊药物组合物 |
| FR2978916B1 (fr) * | 2011-08-10 | 2013-07-26 | Servier Lab | Composition pharmaceutique solide pour administration buccale d'agomelatine |
| WO2013119605A1 (en) * | 2012-02-07 | 2013-08-15 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Promoting sleep using at1 receptor blockers |
| CN102552211B (zh) * | 2012-02-16 | 2013-07-17 | 福建广生堂药业股份有限公司 | 一种阿戈美拉汀的制剂组合物及其制备方法 |
| PT2810656T (pt) | 2013-06-06 | 2017-11-13 | Zentiva As | Formulações de agomelatina compreendendo agomelatina na forma de cocristais |
| EP2810647A1 (en) | 2013-06-06 | 2014-12-10 | Zentiva, a.s. | Pharmaceutical formulations comprising agomelatine in the form of agomelatine co-crystal with an organic acid |
| EP2856934A1 (en) * | 2013-10-04 | 2015-04-08 | Les Laboratoires Servier | Biomarkers for the prediction of long term remission in depression |
| CN103690499B (zh) * | 2013-12-23 | 2015-05-06 | 天津泰普药品科技发展有限公司 | 一种稳定的晶i型阿戈美拉汀片剂及其制备方法 |
| CN103655499B (zh) * | 2013-12-23 | 2015-07-22 | 天津泰普药品科技发展有限公司 | 一种稳定的晶x型阿戈美拉汀片剂及其制备方法 |
| CN104523639B (zh) * | 2014-12-11 | 2017-03-22 | 扬子江药业集团四川海蓉药业有限公司 | 一种阿戈美拉汀片剂及其制备方法 |
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| JP2007517040A (ja) * | 2003-12-24 | 2007-06-28 | セプレイコー インコーポレイテッド | 睡眠の質を改善するためのメラトニン併用療法 |
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| US7635721B2 (en) * | 2005-08-03 | 2009-12-22 | Les Laboratoires Servier | Crystalline form III of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
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| Publication number | Publication date |
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| FR2890562A1 (fr) | 2007-03-16 |
| KR20070029608A (ko) | 2007-03-14 |
| NZ549726A (en) | 2008-03-28 |
| SG146451A1 (en) | 2008-10-30 |
| KR20080103043A (ko) | 2008-11-26 |
| EP2295050A1 (fr) | 2011-03-16 |
| GEP20094602B (en) | 2009-02-10 |
| GT200600409A (es) | 2007-04-30 |
| WO2007028905A1 (fr) | 2007-03-15 |
| AU2006209372A1 (en) | 2007-03-29 |
| JP2007077148A (ja) | 2007-03-29 |
| FR2890562B1 (fr) | 2012-10-12 |
| NO20064050L (no) | 2007-03-12 |
| EA014288B1 (ru) | 2010-10-29 |
| UA81573C2 (en) | 2008-01-10 |
| PE20070333A1 (es) | 2007-06-02 |
| CN1927193A (zh) | 2007-03-14 |
| MA28506B1 (fr) | 2007-04-03 |
| TW200800148A (en) | 2008-01-01 |
| HK1100481A1 (en) | 2007-09-21 |
| BRPI0603762A (pt) | 2007-05-15 |
| CA2558762A1 (fr) | 2007-03-09 |
| AP2008004379A0 (en) | 2008-04-30 |
| AR056063A1 (es) | 2007-09-19 |
| EA200601449A1 (ru) | 2007-04-27 |
| UY29777A1 (es) | 2006-10-31 |
| MXPA06010233A (es) | 2007-03-08 |
| EP1762237A1 (fr) | 2007-03-14 |
| US20070060655A1 (en) | 2007-03-15 |
| ZA200607531B (en) | 2008-05-28 |
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