WO2010102554A1 - 阿戈美拉汀的新晶型ⅵ及其制备方法和应用 - Google Patents

阿戈美拉汀的新晶型ⅵ及其制备方法和应用 Download PDF

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WO2010102554A1
WO2010102554A1 PCT/CN2010/070931 CN2010070931W WO2010102554A1 WO 2010102554 A1 WO2010102554 A1 WO 2010102554A1 CN 2010070931 W CN2010070931 W CN 2010070931W WO 2010102554 A1 WO2010102554 A1 WO 2010102554A1
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Prior art keywords
agomelatine
crystal form
preparation
diseases
crystalline form
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PCT/CN2010/070931
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English (en)
French (fr)
Inventor
单汉滨
张鹏
袁哲东
蒋旭东
黄雨
王胡博
曹旭峰
程兴栋
俞雄
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上海医药工业研究院
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Priority to AU2010223720A priority Critical patent/AU2010223720B2/en
Priority to MA34144A priority patent/MA33100B1/fr
Priority to EP10750350A priority patent/EP2431355A4/en
Priority to JP2011553265A priority patent/JP2012519715A/ja
Priority to CA2754276A priority patent/CA2754276A1/en
Priority to AP2011005914A priority patent/AP3049A/xx
Priority to EA201101304A priority patent/EA019127B1/ru
Application filed by 上海医药工业研究院 filed Critical 上海医药工业研究院
Priority to MX2011009339A priority patent/MX2011009339A/es
Priority to US13/138,615 priority patent/US8614251B2/en
Priority to BRPI1013249A priority patent/BRPI1013249A2/pt
Priority to SG2011058559A priority patent/SG173692A1/en
Publication of WO2010102554A1 publication Critical patent/WO2010102554A1/zh
Priority to IL214683A priority patent/IL214683A0/en
Priority to ZA2011/06049A priority patent/ZA201106049B/en
Priority to TN2011000426A priority patent/TN2011000426A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the crystalline form is obtained by recrystallization of ethanol and water.
  • Method for the preparation of Form III Agomelatine is heated at 110 ° C until it is completely melted, and then slowly cooled until crystallization is obtained.
  • Preparation of Form IV Agomelatine is heated at 110 ° C until it is completely melted, then rapidly cooled between 50 and 70 ° C, and maintained at 70 ° C for about 5 hours until crystallization is obtained.
  • Preparation of crystal form V The so-called "high energy" mechanical grinding of agomelatine is obtained. Summary of invention
  • Another object of the present invention is to provide a process for preparing agomelatine crystal form VI which is simple in operation and good in reproducibility.
  • the crystal form of agomelatine, in the powder X-ray diffraction pattern, at the diffraction angle of 2 ⁇ is 11.13, 11.82, 17.49, 18.29, 19.48, 19.72, 20. 50 21. 76, 22.54, 22.97, 24.56, 25.36, 27.16, 31. There is a main peak at 93 degrees.
  • the crystal form of agomelatine in the powder X-ray diffraction pattern, corresponds to the relative intensity (in hundredths) at the diffraction angle 2 ⁇ of the main peak as follows:
  • a method for preparing agomelatine crystal form VI which first dissolves agomelatine in acetic acid, and then adds water at 0-25 ° C to crystallize.
  • the preparation method of the above-mentioned agomelatine crystal form VI is preferably added slowly when added to water, and the specific operation can be carried out by dropping, and stirring is continued to facilitate crystallization.
  • the agomelatine crystal form VI obtained by the present invention shows that it can be used for treating melatonin system diseases, sleep disorders, nervousness, anxiety, seasonal affective disorder or severe depression, heart Vascular disease, digestive system disease, insomnia or fatigue caused by jet lag, schizophrenia, phobia, depression, etc.
  • the agomelatine crystalline form VI provided by the invention can be used together with various pharmaceutically acceptable excipients or excipients to prepare various pharmaceutical dosage forms for oral or injectable use.
  • the invention obtains a new crystal form VI of agomelatine, which has good purity, stable crystal form and good reproducibility, and has advantages in preparation. In addition, it is better than the existing ones in stability and solubility. Crystal form.
  • Figure 1 is an X-ray diffraction pattern of a crystalline form VI obtained in Example 1 of the present invention. Using Bruker D8
  • the measurement conditions are as follows: CuKa 40Kv 40 mA is the light source, step size is 0. 02 °, scanning speed: 8 ° / min, scanning range: 3 ° ⁇ 80 °, room temperature.
  • the lg agomelatine was stirred and dissolved in 4 ml of acetic acid, slowly added dropwise to 80 ml of water, and stirred at 5 ° C for 3 hours, filtered, and the solid was washed with water 8 ml * 2 and dried under vacuum at 55 ° C to a constant weight.
  • White solid 0. 90g. Purity: 99.6%, melting point: 97-98 °C o
  • agomelatine 2 g was stirred and dissolved in 8 ml of acetic acid, slowly added dropwise to 160 ml of water, and stirred at 20 ° C for 3 hours, filtered, and the solid was washed with water 16 ml * 2 and dried under vacuum at 55 ° C to a constant weight.
  • White solid 1.76 g. Purity: 99.6%, melting point: 97-98 °C.
  • the crystal form of agomelatine obtained in Example 2 in the measured X-ray diffraction pattern of the dried powdery product, the interplanar spacing d, the Bragg 2 angle and the relative intensity values are: 2 ⁇ ° d (A) relative strength
  • Forms II, III, IV, and VI were placed in an incubator at 40 ° C for 20 days, and the stability of these crystal forms was investigated by high performance liquid chromatography.
  • Chromatographic conditions using octadecyl silicon germanium bonded silica as a filler; a mixed solution of 10 mM / L phosphate buffer salt (pH adjusted to 7.0 with sodium hydroxide) and acetonitrile volume ratio of 2: 7 as mobile phase ;
  • the column temperature was 40 ° C; the detection wavelength was 220 nm.
  • the purity was determined by an internal standard method.
  • the crystal forms II, III, IV, and VI were each placed in a lmg/mL solution using a mobile phase, and each was injected into a liquid chromatograph to record a chromatogram.
  • the measurement method refers to the method for determining the purity of the sample, and the measurement is performed by an external standard method.
  • the results are shown in Table 1:
  • the novel gemetastatin VI of the present invention is more advantageous in stability and solubility than several existing crystal forms. Moreover, in the preparation method, it has more industrial application value than the existing crystal forms III, IV and V.

Abstract

本发明提供了阿戈美拉汀的一种新晶型及其制备方法和应用。阿 戈美拉汀的晶型粉末X射线衍射图中，在衍射角度2θ为11.13、11.82、17.49、18.29、19.48、19.72、20.50、21.76、22.54、22.97、24.56、25.36、27.16、31.93度处有主峰。该新的晶型纯度好、晶形稳定且重现性好， 在制剂方面具有优势。 另外在稳定性和溶解度上更优于现有的几种晶型。

Description

阿戈美拉汀的新晶型 VI及其制备方法和应用 技术领域 型 ， 及其制备方法和应用。 技术背景
阿戈美拉汀（agomelatine) , 化学名为 N_ [2 - (7 -甲氧基- 1 -萘基) 乙基]乙酰胺， 化学结构如下式 （ I ) 所示， 商品名 Valdoxar
Figure imgf000003_0001
它具有双重作用，不仅是褪黑激素能系统受体的激动剂，还有拮抗 5HT2C 受体的作用， 其性质使其在中枢神经系统具备活性， 尤其在严重抑郁症、 季节性情感障碍、 睡眠障碍、 心血管疾病、 消化系统疾病、 飞行时差引起 的失眠和疲劳、 食欲紊乱和肥胖症的治疗中具有活性。 它是第一个褪黑激 素类抗抑郁药， 能有效治疗抑郁症， 改善睡眠参数和不影响性功能。 阿戈 美拉汀的制备方法和治疗用途在欧洲专利说明书 EP0447285中已有报道。
鉴于该化合物的药学价值， 获得纯度好、 晶形稳定且重现性好的该化 合物是重要的， 使其在制剂方面具有优势， 并且足够稳定可以长期存储， 且对温度、 光、 湿度或氧气水平没有特定要求。
在 中 国 专 利 CN200510071611. 6 、 CN200610108396. 7 、 CN200610108394. 8、 CN200610108395. 2说明书中分别公开了三种阿戈美拉 汀的 II、 III、 IV、 V晶形及其制备方法。
其中晶型 Π是通过乙醇与水重结晶制得。 晶形 III的制备方法： 在 110 °c加热阿戈美拉汀直至完全熔化， 然后缓慢冷却直至结晶得到。 晶形 IV的 制备方法： 在 110°C加热阿戈美拉汀直至完全熔化， 然后在 50和 70°C之间 迅速冷却， 并在 70°C维持约 5小时直至结晶得到。 晶形 V的制备方法： 对 阿戈美拉汀进行所谓的 "高能"机械研磨制得。 发明概要
本发明的目的是提供一种新的阿戈美拉汀的晶型， 即晶型 VI， 该晶型 在制剂方面显示出有价值的特性。
本发明的另一目的是提供阿戈美拉汀晶型 VI的制备方法， 该制备方法 操作简单， 重现性好。
阿戈美拉汀的晶型 ，其粉末 X射线衍射图中，在衍射角度 2 Θ为 11. 13、 11. 82、 17. 49、 18. 29、 19. 48、 19. 72、 20. 50、 21. 76、 22. 54、 22. 97、 24. 56、 25. 36、 27. 16、 31. 93度处有主峰。
阿戈美拉汀的晶型 ， 其粉末 X射线衍射图中， 在有主峰的衍射角度 2 Θ处对应的相对强度 （以百分百计） 如下表示：
Figure imgf000004_0001
19. 48 66. 8
19. 72 100
20. 50 14. 5
21. 76 19. 7
22. 54 22. 0
22. 97 26. 2
24. 56 13. 1
25. 36 16. 7
27. 16 12. 2
31. 93 10. 1
阿戈美拉汀晶型 VI的制备方法， 该方法是先将阿戈美拉汀溶于醋酸， 然后加入 0-25°C的水中， 结晶析出。
上述阿戈美拉汀晶型 VI的制备方法， 加入水中时最好缓慢加入， 具体 操作可以采用滴加的方法， 并不停的进行搅拌， 以利于结晶析出。
本发明所得到的阿戈美拉汀晶型 VI， 对其进行药理研究结果显示， 可 用于治疗褪黑素能系统疾病， 睡眠障碍、 紧张、 焦虑症、 季节性情感障碍 或严重抑郁症、 心血管疾病、 消化系统疾病、 飞行时差引起的失眠或疲劳、 精神分裂症、 恐惧症、 抑郁症等。
本发明所提供的阿戈美拉汀晶型 VI， 可与药学上的各种辅料或赋性剂 一起制得各种药物剂型， 用于口服或注射使用。
本发明得到了一种新的阿戈美拉汀晶型 VI， 纯度好、 晶形稳定且重现 性好， 在制剂方面具有优势。 另外在稳定性和溶解度上更优于现有的几种 晶型。 附图说明
图 1是本发明实施例 1所得晶型 VI的 X射线衍射图谱。 采用 Bruker D8
ADVANCE仪测定。 测定条件如下： CuKa 40Kv 40mA为光源， 步长 0. 02 ° ， 扫描速度： 8 ° /min， 扫描范围： 3 ° 〜80 ° ， 室温。
发明内容
实施例 1
将 lg阿戈美拉汀搅拌溶解于 4ml醋酸中， 缓慢滴加入水 80ml中， 维 持在0 搅拌3. 5小时， 过滤， 固体用水 8ml*2洗涤， 55°C下真空干燥至恒 重， 得到白色固体 0. 91g。 纯度： 99. 6%, 熔点： 97-98°C。 实施例 2
将 lg阿戈美拉汀搅拌溶解于 4ml醋酸中， 缓慢滴加入水 80ml中， 维 持在 5°C搅拌 3小时，过滤，固体用水 8ml*2洗涤， 55°C下真空干燥至恒重， 得到白色固体 0. 90g。 纯度： 99. 6%, 熔点： 97-98 °C o
实施例 3
将 2g阿戈美拉汀搅拌溶解于 8ml醋酸中， 缓慢滴加入水 160ml中， 维 持在 20°C搅拌 3小时， 过滤， 固体用水 16ml*2洗涤， 55°C下真空干燥至恒 重， 得到白色固体 1. 76g。 纯度： 99. 6%, 熔点： 97-98°C。 实施例 2中所得阿戈美拉汀的晶型 ， 其干燥后的粉末状产品实测 X射 线衍射图中， 晶面间距 d、 布拉格 2 Θ角和相对强度值为： 2 θ ° d (A) 相对强度
11. 13 7. 942 12. 4
11. 82 7. 481 17. 8
17. 49 5. 066 20. 7
18. 29 4. 846 17. 9
19. 48 4. 553 66. 8
19. 72 4. 498 100
20. 50 4. 328 14. 5
21. 76 4. 080 19. 7
22. 54 3. 941 22. 0
22. 97 3. 868 26. 2
24. 56 3. 621 13. 1
25. 36 3. 509 16. 7
27. 16 3. 280 12. 2
31. 93 2. 800 10. 1
使用的测试仪器？
实验结果测试：
分别将晶型 II、 III、 IV、 VI分别放入 40°C的恒温箱中， 放置 20天， 通 过高效液相色谱法对这些晶型的稳定性进行研究。
1、 样品纯度测定
色谱条件： 用十八垸基硅垸键合硅胶为填充剂； 以 10mM/L磷酸缓冲盐 (用氢氧化钠调节 pH至 7. 0 )和乙腈体积比为 2: 7的混合溶液作为流动相； 柱温为 40°C ; 检测波长为 220nm。 通过内标法测定纯度。
用流动相分别将晶型 II、 III、 IV、 VI配置成 lmg/mL 的溶液， 各取 10 注入液相色谱仪， 记录色谱图。
2、 样品含量测定
测定方法参考样品纯度测定的方法， 用外标法进行测定， 结果见表一：
Figure imgf000008_0001
Figure imgf000008_0002
3、 水溶性测定
测定方法采用 HPLC方法， 用外标法进行测定。 结果如下表二:
表二
Figure imgf000008_0003
根据测试结果看到， 本发明的阿戈美拉汀新晶型 VI在稳定性和溶解度 上比现有的几个晶型更有优势。 且在制备方法上， 也比现有的晶型 III、 IV、 V更有工业应用价值。

Claims

权利要求
1. 阿戈美拉汀的晶型 ， 其粉末 X射线衍射图中， 在衍射角度 2 Θ 为 11.13、 11.82、 17.49、 18.29、 19.48、 19.72、 20.50、 21.76、 22.54、 22.97、 24.56、 25.36、 27.16、 31.93度处有主峰。
2. 如权利要求 1所述的阿戈美拉汀的晶型 ，其粉末 X射线衍射图中， 在有主峰的衍射角度 2 Θ 处对应的相对强度如下：
2 θ ° 相对强度
11.13 12.4
11.82 17.8
17.49 20.7
18.29 17.9
19.48 66.8
19.72 100
20.50 14.5
21.76 19.7
22.54 22.0
22.97 26.2
24.56 13.1
25.36 16.7
27.16 12.2
31.93 10.1
3. 如权利要求 1或 2所述的阿戈美拉汀晶型的制备方法， 该方法是 先将阿戈美拉汀溶于醋酸， 然后加入 0-25 °C的水中， 结晶析出。
4. 如权利要求 3所述的阿戈美拉汀晶型的制备方法， 其特征在于： 是将阿戈美拉汀的醋酸溶液缓慢加入水中， 同时不停搅拌。
5. 一种药物组合物， 由权利要求 1或 2所述的阿戈美拉汀晶型和药 学上可接受的辅料或赋性剂组成。
6. 权利要求 1或 2所述的阿戈美拉汀晶型在治疗褪黑素能系统疾病， 睡眠障碍、 紧张、 焦虑症、 季节性情感障碍或严重抑郁症、 心血 管疾病、 消化系统疾病、 飞行时差引起的失眠或疲劳、 精神分裂 症、 恐惧症、 抑郁症疾病的药物中的应用。
PCT/CN2010/070931 2009-03-10 2010-03-09 阿戈美拉汀的新晶型ⅵ及其制备方法和应用 WO2010102554A1 (zh)

Priority Applications (14)

Application Number Priority Date Filing Date Title
SG2011058559A SG173692A1 (en) 2009-03-10 2010-03-09 New crystalline form vi of agomelatine, preparation method and application thereof
EA201101304A EA019127B1 (ru) 2009-03-10 2010-03-09 Новая кристаллическая форма vi агомелатина, ее получение и применение
EP10750350A EP2431355A4 (en) 2009-03-10 2010-03-09 NOVEL VI-CRYSTALLINE FORM OF AGOMÉLATINE ITS PREPARATION METHOD AND APPLICATION
JP2011553265A JP2012519715A (ja) 2009-03-10 2010-03-09 アゴメラチンの新規結晶形態ｖｉ、製造方法及びその応用
MX2011009339A MX2011009339A (es) 2009-03-10 2010-03-09 Nueva forma cristalina iv de la agomelatina, preparacion y uso de la misma.
AP2011005914A AP3049A (en) 2009-03-10 2010-03-09 New crystalline form VI of agomelatine, preparation method and application thereof
MA34144A MA33100B1 (fr) 2009-03-10 2010-03-09 Nouvelle forme cristalline vi de l'agomelatine son procede de preparation et son application
AU2010223720A AU2010223720B2 (en) 2009-03-10 2010-03-09 New crystalline form VI of Agomelatine, preparation method and application thereof
CA2754276A CA2754276A1 (en) 2009-03-10 2010-03-09 New crystalline form vi of agomelatine, preparation method and application thereof
US13/138,615 US8614251B2 (en) 2009-03-10 2010-03-09 Crystalline form VI of agomelatine, preparation method and application thereof
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US20140088197A1 (en) * 2011-03-23 2014-03-27 Les Laboratories Servier Mixed crystal agomelatine (form viii), preparation method and use thereof and pharmaceutical composition containing same
WO2014122405A1 (fr) 2013-02-08 2014-08-14 Les Laboratoires Servier Composition pharmaceutique solide pour l'administration buccale d'agomélatine
EP2705023A4 (en) * 2011-01-04 2014-11-19 Symed Labs Ltd PROCESSES FOR THE PREPARATION OF N- [2- (7-METHOXY-1-NAPHTHYLLELYHYL) ACETAMIDE
WO2015124496A1 (en) 2014-02-19 2015-08-27 Synthon B.V. Pharmaceutical composition comprising amorphous agomelatine
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ES2634243T3 (es) 2011-11-30 2017-09-27 Ratiopharm Gmbh Complejo de agomelatina-urea y formas cristalinas del mismo
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

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EP2705023A4 (en) * 2011-01-04 2014-11-19 Symed Labs Ltd PROCESSES FOR THE PREPARATION OF N- [2- (7-METHOXY-1-NAPHTHYLLELYHYL) ACETAMIDE
US20140088197A1 (en) * 2011-03-23 2014-03-27 Les Laboratories Servier Mixed crystal agomelatine (form viii), preparation method and use thereof and pharmaceutical composition containing same
JP2014516921A (ja) * 2011-03-23 2014-07-17 上海医薬工業研究院 混晶アゴメラチン（ｖｉｉｉ型）、その調製方法及び使用、並びにこれを含有する医薬組成物
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EP2556824A1 (fr) 2011-08-10 2013-02-13 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
WO2013021139A1 (fr) 2011-08-10 2013-02-14 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
WO2014122405A1 (fr) 2013-02-08 2014-08-14 Les Laboratoires Servier Composition pharmaceutique solide pour l'administration buccale d'agomélatine
WO2015124496A1 (en) 2014-02-19 2015-08-27 Synthon B.V. Pharmaceutical composition comprising amorphous agomelatine
EP3075724A1 (en) 2015-03-31 2016-10-05 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Solid form of agomelatine

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CA2754276A1 (en) 2010-09-16
CO6410293A2 (es) 2012-03-30
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UA100476C2 (en) 2012-12-25
US8614251B2 (en) 2013-12-24
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PE20120653A1 (es) 2012-06-14
ZA201106049B (en) 2012-10-31
EA201101304A1 (ru) 2012-04-30
AP3049A (en) 2014-11-30
EP2431355A4 (en) 2012-08-08
EP2431355A1 (en) 2012-03-21
CU20110162A7 (es) 2012-02-15
CR20110457A (es) 2011-09-21
BRPI1013249A2 (pt) 2016-04-05
AP2011005914A0 (en) 2011-10-31
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