CN101429134B - 阿戈美拉汀的晶形vi、它的制备方法和包含它的药物组合物 - Google Patents

阿戈美拉汀的晶形vi、它的制备方法和包含它的药物组合物 Download PDF

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CN101429134B
CN101429134B CN2008101749182A CN200810174918A CN101429134B CN 101429134 B CN101429134 B CN 101429134B CN 2008101749182 A CN2008101749182 A CN 2008101749182A CN 200810174918 A CN200810174918 A CN 200810174918A CN 101429134 B CN101429134 B CN 101429134B
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G·科克雷尔
J·里诺尔
L·勒佩皮
J-P·勒库夫
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Abstract

本发明涉及式(I)化合物的晶形VI，该晶形以其X-射线粉末衍射图表征。

Description

阿戈美拉汀的晶形VI、它的制备方法和包含它的药物组合物
技术领域
本发明涉及阿戈美拉汀或式(I)的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的新晶形VI： 
Figure G2008101749182D00011
它的制备方法以及包含它的药物组合物。 
背景技术
阿戈美拉汀，或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺，具有有价值的药理性质。 
它确实具有双重的特征，一方面，它是褪黑素能***受体的激动剂，另一方面，它是5-HT2C受体的拮抗剂。这些性质使得它在中枢神经***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、心血管病理学、消化***病理学、由时差导致的失眠和疲劳、食欲障碍和肥胖症的治疗中有活性。 
阿戈美拉汀、它的制备和它的治疗用途在欧洲专利说明书EP0447285中已有描述。 
鉴于该化合物的药学价值，获得纯度优良且尤其是重现性极好的形式是最重要的，该形式在溶出和方便配制方面显示出有价值的特性，允许其长时间储存而没有对温度、光、湿度或氧气水平的特别要求。 
发明内容
本申请人现已开发了获得完好的、可重现的晶形的方法，所述晶形在溶出和方便配制方面显示出有价值的特性。另外，该新形式随着时间的过 去具有非常显著的稳定性，允许其最适宜储存而无需特别的防备，这在制药工业构成了最重要的优势。 
更特别的是，本发明涉及式(I)化合物的晶形VI，其通过以下X-射线粉末衍射图表征，应用Bruker D5000matic衍射计(铜对阴极)测定并且以术语晶面间距d、布拉格20角和相对强度(以相对于最强射线的百分数表示)表示： 
Figure G2008101749182D00021
式(I)化合物的晶形VI也通过以下红外光谱表征：可观察到的峰为907.5cm-1、866.7cm-1、852.8cm-1、827.4cm-1、754.6cm-1、734.6cm-1、698.4cm-1、672.1cm-1、650.9cm-1、611.9cm-1、588.1cm-1。 
本发明还涉及制备式(I)化合物的晶形VI的方法，该方法的特征在于将阿戈美拉汀的异丙醚溶液在沸腾下加热，然后快速冷却至0℃。真空过滤后获得纯形式的形式VI。 
在本发明的结晶方法中，可能应用通过任何方法获得的式(I)化合物。 
本发明还涉及制备式(I)化合物的晶形VI的另一种方法，该方法的特征在于在环境温度下、在高压下将阿戈美拉汀在水/乙醇混合物(50/50体积/体积)中结晶24小时。 
优选在本发明的第二种结晶方法中，在10kbar高压下将阿戈美拉汀重结晶。 
在本发明的第二种结晶方法中，可能应用通过任何方法获得的式(I)化合物。 
获得这种晶形的优点是其允许制备具有一致且可重现的组合物的药物制剂，其随着时间的过去具有极好的稳定性。 
对如此获得的形式VI的药理学研究已经显示它在中枢神经***和微 循环方面具有基本活性，这使其被确立可用于治疗下列疾病：紧张、睡眠障碍、焦虑、重症抑郁、季节性情感障碍、心血管病理学、消化***病理学、由时差导致的失眠和疲劳、精神***症、惊恐发作、忧郁症、食欲障碍、肥胖症、失眠、疼痛、精神病障碍、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性老化有关的多种障碍、偏头痛、记忆丧失、阿尔茨海默病以及脑循环障碍。在另一个活性领域中，表明阿戈美拉汀的形式VI可用于治疗性功能障碍，具有***抑制和免疫调节的性质，并且可潜在用于治疗癌症。 
阿戈美拉汀的晶形VI优选用于治疗重症抑郁、季节性情感障碍、睡眠障碍、心血管病理学、消化***病理学、由时差导致的失眠和疲劳、食欲障碍和肥胖症。 
本发明还涉及药物组合物，该药物组合物包含作为活性成分的式(I)化合物的晶形VI以及一种或多种适宜的惰性无毒赋形剂。在本发明的药物组合物中，可以更特别提及的是适于口服、非肠道(静脉内或皮下)或经鼻施用的那些，片剂或糖锭剂、颗粒剂、舌下片、胶囊剂、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶剂、可注射制剂、可饮用混悬剂和咀嚼胶。 
有用剂量可以根据障碍的性质和严重性、施用途径以及患者的年龄和体重而不同。剂量在每天0.1mg至1g之间变化，一次或多次施用。 
具体实施方式
下文实施例说明本发明，但不以任何方式限制本发明。 
实施例1：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的晶形VI
将0.74g的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺和36.06g的异丙醚装入试管中。将该悬浮液在沸腾下加热(温度73℃)2小时。然后快速冷却至0℃。在0℃下1小时后，经多孔3号玻璃滤器真空过滤。将获得的固体通过其熔点和以下X-射线粉末衍射图表征，应用Bruker D5000matic衍射计(铜对阴极)测定并且以术语晶面间距d、布拉格20角和相对强度(以相对于最强射线的百分数表示)表示：
Figure G2008101749182D00041
熔点：94℃ 
红外光谱：907.5cm-1、866.7cm-1、852.8cm-1、827.4cm-1、754.6cm-1、734.6cm-1、698.4cm-1、672.1cm-1、650.9cm-1、611.9cm-1、588.1cm-1。 
实施例2：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的晶形VI
在25℃下，将2g的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺加入至20mL水/乙醇混合物(50/50体积/体积)中。将该悬浮液经多孔4号玻璃滤器过滤。将该N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的饱和溶液置于10kbar压力下。24小时后，结晶完成并且将获得的固体通过其熔点和以下X-射线粉末衍射图表征，应用Bruker D5000matic衍射计(铜对阴极)测定并且以术语晶面间距d、布拉格20角和相对强度(以相对于最强射线的百分数表示)表示： 
熔点：94℃ 
红外光谱：907.5cm-1、866.7cm-1、852.8cm-1、827.4cm-1、754.6cm-1、734.6cm-1、698.4cm-1、672.1cm-1、650.9cm-1、611.9cm-1、588.1cm-1。 
实施例3：药物组合物 
制备1000片的配方，每片包含25mg活性成分： 
         实施例1或2化合物.........................25g 
         乳糖一水合物.............................62g 
         硬脂酸镁.................................1.3g
      玉米淀粉..................................26g 
      麦芽糖糊精................................9g 
      无水胶态二氧化硅..........................0.3g 
      预胶化玉米淀粉，A型.......................4g 
      硬脂酸....................................2.6g 
实施例4：药物组合物 
制备1000片的配方，每片包含25mg活性成分： 
      实施例1或2化合物..........................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 
      甘醇酸纤维素钠............................30g 
      硬脂酸....................................2.6g

Claims (10)

1.式(I)的阿戈美拉汀的晶形VI
其通过以下X-射线粉末衍射图表征，应用具有铜对阴极的BrukerD5000matic衍射计测定并且以术语晶面间距d、布拉格2θ角和以相对于最强射线的百分数表示的相对强度表示：
Figure FSB00000709433400012
2.根据权利要求1的式(I)的阿戈美拉汀的晶形VI
其通过以下红外光谱表征：907.5cm-1、866.7cm-1、852.8cm-1、827.4cm-1、754.6cm-1、734.6cm-1、698.4cm-1、672.1cm-1、650.9cm-1、611.9cm-1、588.1cm-1。
3.药物组合物，该药物组合物包含作为活性成分的权利要求1或2的阿戈美拉汀的晶形VI，以及一种或多种可药用惰性无毒载体。
4.权利要求3的药物组合物，其用于制备治疗褪黑素能***障碍的药物。
5.权利要求3的药物组合物，其用于制备治疗睡眠障碍、紧张、焦虑、心血管疾病、消化***疾病、忧郁症、食欲障碍、肥胖症、疼痛、精神病障碍、癫痫、糖尿病、与正常或病理性老化有关的多种障碍、偏头痛、记忆丧失、脑循环障碍或性功能障碍，作为***抑制剂或免疫调节剂或治疗癌症的药物。
6.根据权利要求5的药物组合物，其中所述的睡眠障碍是失眠。
7.根据权利要求6的药物组合物，其中所述的失眠是由时差导致的失眠和疲劳。
8.根据权利要求5的药物组合物，其中所述的焦虑是惊恐发作。
9.根据权利要求5的药物组合物，其中所述的精神病障碍是精神***症、季节性情感障碍或重症抑郁。
10.根据权利要求5的药物组合物，其中所述的与正常或病理性老化有关的多种障碍是老年性痴呆、帕金森病、阿尔茨海默病。
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