TWI356051B - New crystalline form vi of agomelatine, a process - Google Patents

New crystalline form vi of agomelatine, a process Download PDF

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TWI356051B
TWI356051B TW097141871A TW97141871A TWI356051B TW I356051 B TWI356051 B TW I356051B TW 097141871 A TW097141871 A TW 097141871A TW 97141871 A TW97141871 A TW 97141871A TW I356051 B TWI356051 B TW I356051B
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agomelatine
disorders
formula
pharmaceutical composition
crystalline form
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TW200936548A (en
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Gerard Coquerel
Julie Linol
Pape Lionel Le
Jean-Pierre Lecouve
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Servier Lab
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Description

1356051 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種阿戈美拉汀（ag〇melatine)或結構式⑴ 之N-[2-(7-曱氧基-1-萘基）乙基]乙醯胺之新晶形（晶形VI)、 其製備方法及其醫藥組合物。
【先前技術】 阿戈美拉汀，或Ν-[2-(7·曱氧基_丨_萘基）乙基]乙醯胺具 有重要的藥理性質。 實際上’其具有雙重特徵’ 一方面’係褪黑激素能系統 受體的激動劑，另一方面，係5_HT2c受體之拮抗劑〇此等 性質在中枢神經系統中提供其活性，尤其治療重性抑鬱 症、季節性情緒失調、睡眠障礙、心血f病變、消化系統 病變、因時差引起的失眠與疲勞、食慾障礙與肥胖。 阿戈美拉汀、其製備及其在治療中之用途已在歐洲專利 説明書EP 0 447 285中描述。 基於該化合物的醫藥價值，得到高純度及尤其以具有溶 解性與易於製備使其在長期存儲下對溫度、光、濕度或含 氧量無特定需求之可再現型式係非常重要。 如今，本申請人已發展出一種可製得已完整定義且具可 再現性晶形之阿戈美拉汀的方法’因此具有溶解性與易於 製備之有價值之特性》而且， 該新形式具有明顯的長期穩 135586.doc
1356051 定性，不需要特定預防措施即可達到最佳儲存性，構成製 藥工業上最重要之優點。 更明確而言，本發明係關於結構式（I)化合物之晶形VI， 其特徵在於以下X-射線粉末繞射圖，其係利用Bruker D5 000matic繞射儀（銅陽極）測定，以平面間距d、Bragg角 2Θ及相對強度（以相對於最強線的百分比表示）表示： 2-Θ (°) 實驗值 d(A) 實驗值 強度(％) 5.73 15.411 11.4 10.22 8.645 11.6 20.10 4.413 10.2 23.69 3.751 59.0 29.48 3.027 14.8 結構式（I)化合物之晶形VI亦具有以下紅外光譜特徵：波 峰出現在 907.5 cm.1、866.7 cm·1、852.8 cm·1、827.4 cm.1、 754_6 cm·1、734.6 cm-丨、698.4 cm·1、672.1 cm.丨、650.9 cm·1、611.9 cm·1、588.1 cm·1。 【發明内容】 本發明係關於一種製備結構式⑴化合物之晶形VI的方 法，該方法特徵在於將阿戈美拉汀的異丙醚溶液在沸點下 加熱，然後迅速冷卻至〇t：。真空過濾後，得到純淨形式 之VI形。 根據本發明之結晶方法，可使用經任何方法得到的結構 式⑴化合物。 本發明亦關於另一種製備結構式（I)化合物之晶形V丨的方 法，該方法特徵在於將阿戈美拉汀在室溫，於高壓下24小 135586.doc 10 時，從水/乙醇混合物（50/50體積/體積）中結晶。 根據本發明之第二種任S古、土 ,^ α 種，·Ό日日方法，由阿戈美拉汀較佳在 kbar尚壓下進行再結 权佺在 可使用經任何方法得到 根據本發明之第二種結晶方法， 的結構式（I)化合物。 所付之该晶形有利於截供i^ ㈣Μ備具有-致且可再現之組合物並 〃有長期優越穩定性之醫藥調配物。 因此得到的晶㈣之藥理研究顯示對Μ神經系統與微 循環具有顯著活性，確定該„適用於治㈣力、睡眠障 礙、焦慮、重性抑臀症、季節性情緒失調、心血管病變、 消化系統病變、因時差引起的失眠與疲勞、精神分裂症、 恐慌症 '憂鬱症、食您障礙、肥胖、失眠、疼痛、精神失 調、癲癇纟、糖尿病、帕金森症、老年癡呆、與正常或病 變性老化相關的各種不同絲、偏頭痛、記憶損失、阿兹 海默氏病、及大腦循環病變。該活性之另…冶療領域，阿 戈美拉汀晶形VI可用於性功能障礙，其具有抑制排卵及免 疫調節性質，且具有用於治療螽症之潛力。 阿戈美拉汀晶形VI較佳用於治療重性抑鬱症、季節性情 緒失調、睡眠障礙、心血管病變、消化系統病變、因時差 引起的失眠與疲勞、食慾障礙與肥胖。 本發明亦關於包含作爲活性成分的結構式（1)化合物之晶 形VI與一種或多種適宜之無活性且無毒性的賦形劑之醫藥 組合物。在根據本發明之醫藥組合物中，可更特別提及適 宜經口、非經腸道（靜脈内或皮下）或經鼻投與之錠劑或糖 135586.doc • 8 - 1356051 衣丸劑、粒劑、舌下錠劑、膠囊、糖錠、栓劑、乳霜、軟 膏、皮膚用凝膠、注射製劑、可飲用懸浮液與口香糖。 適用之劑量可根據症狀特性與嚴重性、投與途徑及患者 年齡與重量變化。劑量為每天投藥一次或多次之〇i 至 1 g之間。 【實施方式】 以下實例闡述但不以任何方法限制本發明。
實例1 : N-【2-(7·甲氧基_1_萘基）乙基】乙醯胺之晶形VI 取0.74 g N-[2-(7-甲氧基_卜萘基）乙基]乙醯胺與刊〇6 g 異丙醚加入試管中。在沸點（溫度73。〇處加熱該懸浮液2小 時。然後迅速冷卻至〇°C。在丨小時後，在孔率3的玻璃 料上進行真空過濾《得到的固體特徵在於其熔點與以下的 X-射線粉末繞射圖’其係利用Bruker D5000matic繞射儀 (銅極）測定’以平面間距d、Bragg角2Θ及相對強度（以相 對於最強線的百分比表示）表示： 2-Θ (°) 實驗值 d(A) 實驗值 強度(％) 5.73 15.411 11.4 10.22 8.645 11.6 20.10 4.413 10.2 23.69 3.751 59.0 29.48 3.027 14.8
溶點：94〇C 紅外光譜：907.5 cm·1、866.7 cm·1、852.8 cm·1、827.4 cm 、754.6 cm 1、734.6 cm_1、698.4 cnT1、672.1 cm·1、 650.9 cm·1、611.9 cm·1、588.1 cm-1。 135586.doc •9- 1356051
實例2 : N-【2-(7-甲氧基-1-萘基*)乙基〗乙醯胺之晶形VI 在25°C ’將2 g Ν-[2-(7·甲氧基-1-萘基）乙基]乙醯胺加入 20 ml水/乙醇混合物（50/50體積/體積）中。在孔率4的玻璃 料上過濾該懸浮液。在該N-[2-(7-甲氧基-1-萘基）乙基]-乙 酿胺之飽和溶液上施加1〇 kbar麼力。24小時後，完全結 晶’得到的固體特徵在於其熔點與以下的χ_射線粉末繞射 圖’其係利用Bruker D5000matic繞射儀（銅陽極）測定，以 平面間距d、Bragg角2Θ及相對強度（以相對於最強線的百 分比表示）表示： 2-θ(°) 實驗值 d(A) 實驗值 強度(％) 5.73 15.411 11.4 10.22 8.645 11.6 20.10 4.413 10.2 23.69 3.751 59.0 29.48 3.027 14.8 紅外光譜：907_5 cm·1、866.7 cm·1、852.8 cm-1、827.4 cm·1、 754.6 cm·1、734.6 cm·1 ' 698.4 cm-1、672.1 cm·1、650.9 cnT1、611.9 cm-1、588.1 cm·1。
熔點：94〇C 實例3 :醫藥組合物 製備每個包含25 mg活性成分的1000個錠劑之調配物： 實例1或2之化合物 25 g 乳糖單水合物 62 g 硬脂酸鎂 1.3 g 玉米澱粉 26 g 135586.doc •10- 1356051 麥芽糖糊精 9 g 脫水膠態矽石 0.3 g 預糊化玉米澱粉，A型 4 g 硬脂酸 2.6 g 實例4 :醫藥組合物 製備每個包含25 mg活性成分的1000個錠劑之調配物： 實例1或2之化合物 25 g 乳糖單水合物 62 g 硬脂酸鎂 1-3 g 聚乙烯吡咯啶酮 9 g 脫水膠態矽石 0.3 g 纖維素羥乙酸鈉 30 g 硬脂酸 2.6 g
135586.doc -11 -

Claims (1)

1356051 十、申請專利範圍： 1. 一種結構式（I)的阿戈美拉汀（agomelatine)晶形VI :
其特徵在於具有以下之X-射線粉末繞射圖：其係利用 Bruker D5000matic繞射儀（銅陽極）測定，以平面間距d、 Bragg角2Θ及相對強度（以相對於最強線的百分比表示）表 示： 2-Θ (°) 實驗值 d(A) 實驗值 強度(％) 5.73 15.411 11.4 10.22 8.645 11.6 20.10 4.413 10.2 23.69 3.751 59.0 29.48 3.027 14.8 2. 一種結構式⑴的阿戈美拉汀晶形VI :
其特徵在於以下紅外光譜：907.5 cm·1、866_7 cm·1、 852.8 cm·1、827.4 cm·1、754.6 cm·1、734.6 cm·1、698.4 cm-1、672.1 cm-1、650.9 cm-1、611.9 cm-1、588.1 cm·1 o 3. —種製備如請求項1或2之結構式⑴化合物的晶形VI之方 法，其特徵在於： 將含阿戈美拉汀的異丙醚溶液在沸點下加熱，迅速冷 135586.doc 1356051 卻至o°c及然後真空過濾。 4. 一種製備如請求項1或2之結構式⑴化合物的晶形VI之方 法，其特徵在於： 由阿戈美拉丁在周溫及高壓下24小時，從水/乙醇混合 物（50/50體積/體積）中結晶。 5. 一種醫藥組合物，其包含作爲活性成分的如請求項丨或2 之阿戈美拉汀晶形VI與一種或多種醫藥可接受之無活性 及無毒性載體。 6. 如請求項5之醫藥組合物，其係用於製造醫藥品，供治 療褪黑激素能系統失調。 7. 如睛求項5之醫藥組合物’係係用於製造醫藥品，供治 療睡眠障礙、壓力、焦慮、季節性情緒失調或重性抑鬱 症、心血管病變、消化系統病變、因時差引起的失眠與 疲勞、精神分裂症、恐慌症、憂鬱症、食慾障礙、肥 胖、失眠、疼痛、精神失調、癲癇症、糖尿病、帕金森 症、老年癡呆、與正常或病變老化相關的各種不同症 狀、偏頭痛、記憶損失、阿茲海默氏病、大腦循環障礙 或性功能障礙、作爲排卵抑制劑或免疫調節劑、或治療 癌症。 135586.doc
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Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2934856B1 (fr) * 2008-08-05 2010-08-13 Servier Lab Nouveau procede d'obtention de la forme cristalline v de l'agomelatine
CN101585779B (zh) 2009-03-10 2014-04-02 上海医药工业研究院 阿戈美拉汀的晶型vi及其制备方法和应用
WO2011006387A1 (zh) * 2009-07-11 2011-01-20 浙江华海药业股份有限公司 阿戈美拉汀的制备方法、阿戈美拉汀晶形及其制备方法
CN101955440B (zh) * 2009-07-17 2014-04-09 江苏万特制药有限公司 一种阿戈美拉汀新晶型及其制备方法
CN102001959B (zh) * 2009-09-01 2014-07-02 北京本草天源药物研究院 一种药物晶体及其制备方法和用途
EP2319827A1 (en) 2009-11-09 2011-05-11 Ratiopharm GmbH Process for the production of polymorph form I of agomelatine
CN101781226B (zh) 2009-12-23 2012-03-28 天津泰普药品科技发展有限公司 阿戈美拉汀及其药物组合物
EP2558440B1 (en) 2010-04-15 2016-11-16 ratiopharm GmbH Process for the production of polymorph form i of agomelatine
WO2012046253A2 (en) * 2010-10-08 2012-04-12 Msn Laboratories Limited Process for the preparation of n-[2- (7-methoxy-l-naphthyl) ethyl] acetamide and its novel crystalline forms
CZ303787B6 (cs) 2011-01-21 2013-05-02 Zentiva, K.S. Metastabilní krystalové formy agomelatinu a jejich farmaceutické kompozice
CN102690209A (zh) * 2011-03-23 2012-09-26 上海医药工业研究院 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物
WO2012130837A1 (en) 2011-03-28 2012-10-04 Ratiopharm Gmbh Solid agomelatine in non-crystalline form
CN102206864B (zh) * 2011-04-13 2012-10-03 吉林省博大伟业制药有限公司 阿戈美拉汀的ⅵ晶型单晶及混合晶型和制备方法
PH12012000132A1 (en) * 2011-06-09 2014-10-20 Servier Lab New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them
ES2634243T3 (es) 2011-11-30 2017-09-27 Ratiopharm Gmbh Complejo de agomelatina-urea y formas cristalinas del mismo
CZ2012108A3 (en) 2012-02-15 2013-02-27 Zentiva Ks A method for the manufacture of a polymorphously stable pharmaceutical composition containing agomelatine
EP2872129B1 (en) 2012-07-16 2017-03-08 ratiopharm GmbH Complex of agomelatine and cyclodextrin
CN102988315B (zh) * 2012-09-28 2017-11-17 浙江华海药业股份有限公司 阿戈美拉汀固体制剂的制备方法
WO2014072998A1 (en) 2012-11-07 2014-05-15 Cadila Healthcare Limited An improved process for preparation of agomelatine
WO2014096373A1 (en) 2012-12-21 2014-06-26 Laboratorios Lesvi, S. L. Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof
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
CZ2013621A3 (cs) 2013-08-13 2015-02-25 Zentiva, K.S. Termodynamicky stabilní tuhý roztok agomelatinu pro použití ve farmaceutické formulaci
WO2015124496A1 (en) 2014-02-19 2015-08-27 Synthon B.V. Pharmaceutical composition comprising amorphous agomelatine
EP3075724B1 (en) 2015-03-31 2023-07-12 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Solid form of agomelatine
EP3466413A1 (en) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Pharmaceutical composition containing agomelatine and process for the preparation thereof
EP3466923A1 (en) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Process for the preparation of agomelatine in crystalline form
CN114028335A (zh) * 2021-12-24 2022-02-11 山东京卫制药有限公司 一种阿戈美拉汀溶液鼻喷剂及其应用

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1146164B (it) 1980-07-16 1986-11-12 Selenia Ind Elettroniche Dispositivo di filtraggio doppler adattivo alla situazione di clutter ed ecm esterna per impianti radar
FR2658818B1 (fr) * 1990-02-27 1993-12-31 Adir Cie Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
DK1309547T3 (da) * 2000-07-27 2007-05-21 Teva Pharma Krystallinsk og ren modafinil og fremgangsmåde til fremstilling af samme
US6992219B2 (en) * 2002-08-09 2006-01-31 Cephalon France Modafinil polymorphic forms
FR2866335B1 (fr) * 2004-02-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'agomelatine
FR2889522B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
US7645905B2 (en) * 2005-08-03 2010-01-12 Les Laboratoires Servier Crystalline form IV of agomelatine, a process for its preparation and pharmaceutical compositions containing it
US7358395B2 (en) * 2005-08-03 2008-04-15 Les Laboratories Servier Crystalline form V of agomelatine, a process for its preparation and pharmaceutical compositions containing it
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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