CN101955440B - 一种阿戈美拉汀新晶型及其制备方法 - Google Patents
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Abstract
本发明涉及一种抗抑郁药物阿戈美拉汀的晶型X以及含有它的药物，该晶形以其X射线衍射图表征。
Description
技术领域
本发明涉及阿戈美拉汀的新的晶体形式，它在广泛适应症内具有活性，并且尤其可用于治疗抑郁症，本发明还涉及了相关制备方法和含有它的药物组合物。
背景技术
阿戈美拉汀具有极为有价值的药理和治疗特性、尤其是治疗抑郁症。阿戈美拉汀是褪黑色素1，2(MT1，MT2)受体激动剂，同时也是5羟色胺2c(5HT2C)受体拮抗剂，可直接与神经突触后膜的5HT2C受体结合，从而发挥其抗抑郁疗效，且不增加突触间的5HT浓度，因而没有5羟色胺再摄取抑制剂类药物和5羟色胺去甲肾上腺素再摄取抑制剂类药物的常见副作用。该药的另一独特作用靶点在MT受体，通过对MT1和MT2受体的激动作用，可调整患者的24小时节律、改善患者的睡眠质量，从而促进抑郁症患者整体临床状况的改善。
欧洲专利说明书EP 0447285中已经描述了阿戈美拉汀的制备方法。关于阿戈美拉汀的多晶型现象，EP0447285以及Yous等人(Journalof Medicinal Chemistry，1992，35(8)，1484-1486)首先公开了可以制备特殊晶型的阿戈美拉汀，这种晶型已由Tinant等人(Acta Cryst.(1994).C50，907-910)描述。另外法国Servier制药公司通过专利CN200610108396.7CN200610108394.8、CN200610108395.2以及CN200610108395.2分别公开了阿戈美拉汀II、III、IV以及V四种晶型的晶型数据以及相关组合物的方法。
发明内容
本发明的目的在于提供一种新的阿戈美拉汀X-晶型的晶体形式及其制备方式，其通过将阿戈美拉汀与异丙醚混合加热，直至溶解完全，蒸出异丙醚，残余物烘干即得。该晶体形式是完全区别于所有已公开晶型的新的晶体形态，虽然EP0447285以及Yous等人(Journal ofMedicinal Chemistry，1992，35(8)，1484-1486)通过异丙醚重结晶制备特殊晶型阿戈美拉汀，Tinant等人在Acta Cryst.(1994).C50，907-910上对其进行了描述，但是其熔点数据为109℃，与阿戈美拉汀X-晶型的99.1℃的熔点不同，另外通过粉末X射线衍射晶型数据比较也显著区别。本专利阿戈美拉汀X-晶型轮廓分明，可完美再现，并且就过滤、干燥、稳定性、方法配制和可加工性而言，其显示有价值的特征，可用作抗抑郁的药物中的用途。
阿戈美拉汀X-晶型，其特征在于如下粉末X射线衍射图，所述衍射图使用日本理学RigakuD/MAXRC衍射仪测定，并根据谱线位置(布拉格角2θ，以度表示)、谱线高度(以计数表示)、谱线面积(以计数×度表示)、半高处的谱线宽度(“FWHM”，以度表示)和晶面间距d表示，其中X-晶型表示如下：
另外阿戈美拉汀X-晶型的另一特征在于该晶型的DSC熔点为99.1℃。制备阿戈美拉汀X-晶型的方法，将使用由任何方法获得的阿戈美拉汀与异丙醚的混合物加热，直至溶解完全，蒸出异丙醚，即得产物。
本发明还涉及一种药物组合物，所述药物组合物包括作为活性成分的X-晶型形式的阿戈美拉汀和一种或多种合适的、惰性且无毒的赋形剂。在根据本发明的药物组合物中，可能更特别要提到的是那种适合于口服、肠胃外(静脉内或皮下)或经鼻施用的药片或糖衣丸、舌下用药片、胶囊、锭剂、栓剂、霜、软膏、皮肤凝胶、可注射制剂、可引用的混悬液。
可用剂量可根据疾病的性质和严重性、施药途径和患者的年龄和体重而有所不同。剂量在每天1至500mg之间变化，可以单次或分多次给药。
附图说明
本申请中包括的附图是说明书的一个构成部分，附图与说明书和权利要求书一起用于本发明的实质内容，用于更好地理解本发明。
图1为阿戈美拉汀晶型X的X-ray粉末衍射图谱。
图2为阿戈美拉汀晶型X的差示扫描量热法(DSC)热解曲线。
下面的实施例阐述了本发明。
下列实施例所采用的分析为下列型号：
X-ray：日本理光RigakuD/MAXRC型粉晶衍射仪
DSC：PerkinElmerThermalAnalysis。
实施例1：X晶型阿戈美拉汀的制备
将阿戈美拉汀1.0g加入到20mL异丙醚中加热回流溶解，浓缩蒸干溶剂异丙醚，残余物于40℃真空干燥至恒重。得到晶型X样品。以下列粉末X射线衍射图(见图1)和DSC图(见图)表征，X射线衍射表示：
实施例2：药物组合物
用于制备1000片药片、其中每片药片含有25mg剂量：
实施例1的化合物 25g
乳糖一水合物 62g
羟甲基纤维素钠 40g
硬酯酸镁 2.5g
无水胶体二氧化硅 0.3g
聚维酮 9g
硬脂酸 12g
1000片
Claims (1)
1.一种制备阿戈美拉汀晶型X的方法，其特征在于将阿戈美拉汀与异丙醚混合加热，直至溶解完全，蒸出异丙醚，即得阿戈美拉汀晶型X，所述阿戈美拉汀晶型X的DSC熔点为99.1℃；粉末X射线衍射布拉格角2θ、谱线高度、谱线面积、半高处的谱线宽度和晶面间距d如下表所示：
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3466923A1 (en) * | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Process for the preparation of agomelatine in crystalline form |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050756A (zh) * | 2009-11-09 | 2011-05-11 | 北京利乐生制药科技有限公司 | 阿戈美拉汀新晶型及其制备方法 |
| CN102557979B (zh) * | 2010-12-16 | 2014-11-26 | 北大方正集团有限公司 | 一种阿戈美拉汀的晶型、其制备方法、用途及药物组合物 |
| 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 |
| FR2978916B1 (fr) | 2011-08-10 | 2013-07-26 | Servier Lab | Composition pharmaceutique solide pour administration buccale d'agomelatine |
| WO2013082302A1 (en) | 2011-11-30 | 2013-06-06 | Ratiopharm Gmbh | Agomelatine-urea complex and crystalline forms thereof |
| FR3001894A1 (fr) | 2013-02-08 | 2014-08-15 | Servier Lab | Composition pharmaceutique solide pour administration buccale d'agomelatine |
| 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 |
| EP3075724B1 (en) | 2015-03-31 | 2023-07-12 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Solid form of agomelatine |
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|---|---|---|---|---|
| US5194614A (en) * | 1990-02-27 | 1993-03-16 | Adir Et Compagnie | Compounds having a naphthalene structure |
| CN101429134A (zh) * | 2007-11-09 | 2009-05-13 | 瑟维尔实验室 | 阿戈美拉汀的新晶形vi、它的制备方法和包含它的药物组合物 |
| CN101585779A (zh) * | 2009-03-10 | 2009-11-25 | 上海医药工业研究院 | 阿戈美拉汀的新晶型ⅵ及其制备方法和应用 |
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- 2009-07-17 CN CN200910089360.2A patent/CN101955440B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5194614A (en) * | 1990-02-27 | 1993-03-16 | Adir Et Compagnie | Compounds having a naphthalene structure |
| CN101429134A (zh) * | 2007-11-09 | 2009-05-13 | 瑟维尔实验室 | 阿戈美拉汀的新晶形vi、它的制备方法和包含它的药物组合物 |
| CN101585779A (zh) * | 2009-03-10 | 2009-11-25 | 上海医药工业研究院 | 阿戈美拉汀的新晶型ⅵ及其制备方法和应用 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3466923A1 (en) * | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Process for the preparation of agomelatine in crystalline form |
| WO2019072864A1 (en) | 2017-10-09 | 2019-04-18 | Krka, D.D., Novo Mesto | PROCESS FOR THE PREPARATION OF AGOMÉLATINE IN CRYSTALLINE FORM |
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