CN1754878A - α晶形的雷奈酸锶、其制备方法和含有它的药物组合物 - Google Patents

α晶形的雷奈酸锶、其制备方法和含有它的药物组合物 Download PDF

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CN1754878A
CN1754878A CNA2005100753929A CN200510075392A CN1754878A CN 1754878 A CN1754878 A CN 1754878A CN A2005100753929 A CNA2005100753929 A CN A2005100753929A CN 200510075392 A CN200510075392 A CN 200510075392A CN 1754878 A CN1754878 A CN 1754878A
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S·霍瓦特
I·德米恩克
G·达米安
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Abstract

本发明涉及α晶形的式(I)的雷奈酸锶，其特征在于其X射线粉末衍射图谱和水含量为22至24％。本发明还涉及药物。

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α晶形的雷奈酸锶、其制备方法和含有它的药物组合物
本发明涉及α晶形的雷奈酸锶(strontium ranelate)、其制备方法以及含有它的药物组合物。
式(I)所示的雷奈酸锶：
或5-[二(羧甲基)-氨基]-3-羧甲基-4-氰基-2-噻吩甲酸的二锶盐及其水合物具有非常有价值的药理学和治疗特性，尤其是显著的抗骨质疏松特性，使得这些化合物可用于治疗和预防骨病。
雷奈酸锶及其水合物还具有使它们可用于治疗和预防关节病的特性。
在欧洲专利说明书EP0415850中已经描述了雷奈酸锶及其四水合物、七水合物和八水合物的制备和治疗用途。
在欧洲专利说明书EP 0 813 869中已经描述了雷奈酸锶在预防和治疗关节病中的用途。
本申请人现已发现雷奈酸锶可以以一种确定的晶形被获得，该晶形重现性良好，并且鉴于这一事实，该晶形在过滤和制剂制备容易性方面具有有价值的性质。
更具体而言，本发明涉及α晶形的雷奈酸锶，其特征在于水含量为22至24％和以下的X射线粉末衍射图谱，该衍射图谱用PANalytical X’Pert Pro衍射计和X’Celerator检测器测定并且以衍射峰位置(布拉格角2θ，以度表示)、衍射峰高(以计数表示)、衍射峰面积(以计数×度表示)、衍射峰半高宽(“FWHM”，以度表示)和晶面间距d(以_表示)表示：
  衍射峰编号   2θ角(度)   峰高(计数)   峰面积(计数×度)   FWHM(度)   晶面间距(_)
  1   7.6   4527   448   0.1004   11.649
  2   8.0   1438   142   0.1004   11.069
  3   8.3   3522   349   0.1004   10.642
  4   8.6   11347   1123   0.1004   10.272
  5   8.9   7332   726   0.1004   9.889
  6   11.0   1047   104   0.1004   8.072
  7   11.3   1655   164   0.1004   7.840
  8   12.0   2186   216   0.1004   7.355
  9   13.2   2887   381   0.1338   6.703
  10   13.5   1705   169   0.1004   6.557
  11   14.1   154   30   0.2007   6.275
  12   14.7   803   79   0.1004   6.035
  13   14.9   1346   178   0.1338   5.942
  14   15.8   1556   154   0.1004   5.613
  15   16.0   3339   441   0.1338   5.527
  16   16.7   1845   183   0.1004   5.308
  17   17.3   2835   281   0.1004   5.127
  18   17.6   1252   124   0.1004   5.049
  19   18.0   2183   216   0.1004   4.939
  20   19.2   2303   228   0.1004   4.622
  21   19.8   1298   128   0.1004   4.475
  22   20.3   788   78   0.1004   4.373
  23   20.6   1039   103   0.1004   4.317
  24   21.1   882   116   0.1338   4.211
  25   21.7   390   38   0.1004   4.103
  26   22.3   1919   253   0.1338   3.990
  27   22.7   1805   179   0.1004   3.923
  28   23.0   4043   467   0.1171   3.861
  29   23.5   650   86   0.1338   3.792
  30   24.0   8677   1002   0.1171   3.711
  31   24.7   229   30   0.1338   3.600
  32   25.1   1246   164   0.1338   3.543
  33   25.6   1659   219   0.1338   3.473
  34   25.9   1773   175   0.1004   3.442
  35   26.3   695   69   0.1004   3.385
  36   26.6   401   46   0.1171   3.355
  37   27.0   2800   370   0.1338   3.300
  38   27.6   1415   140   0.1004   3.230
  衍射峰编号   2θ角(度)   峰高(计数)   峰面积(计数×度)   FWHM(度)   晶面间距(_)
  39   28.0   3250   429   0.1338   3.186
  40   28.4   1513   250   0.1673   3.144
  41   29.1   1456   144   0.1004   3.068
  42   29.6   1943   192   0.1004   3.022
  43   30.1   3637   540   0.1506   2.967
  44   30.5   707   117   0.1673   2.929
  45   30.9   596   59   0.1004   2.897
  46   31.8   577   76   0.1338   2.816
  47   32.0   1080   107   0.1004   2.796
  48   32.5   512   51   0.1004   2.756
  49   32.9   1268   167   0.1338   2.726
  50   33.4   1180   117   0.1004   2.685
本发明还涉及制备α晶形的雷奈酸锶的方法，其特征在于将雷奈酸锶或其水合物在水中的溶液加热至回流，然后冷却直至结晶完全，并通过过滤收集产物。
·在本发明的制备方法中，可以使用通过任何方法获得的雷奈酸锶或其水合物，例如通过专利说明书EP 0 415 850中所述的制备方法获得的雷奈酸锶八水合物。
·获得所述晶形的一个优势是使得过滤非常迅速且有效，并且还使得可制备具有一致的且可重现的组成的药物制剂，当制剂用于口服施用时尤其有利。
·由此获得的晶形十分稳定，使得其在对温度、光、湿度或氧水平无特殊要求的条件下也可以贮存相当长的时间。
本发明还涉及包含作为活性成分的α晶形的雷奈酸锶以及一种或多种适宜的、惰性且无毒的赋形剂的药物细合物。在本发明的药物组合物中，可更特别地提及的是那些适于口服、胃肠外(静脉内或皮下)或鼻腔施用的药物组合物，如片剂或糖衣丸、颗粒剂、舌下片剂、胶囊剂、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶剂、注射用制剂、可口服的混悬剂和口香糖。
有效剂量可根据病症的性质和严重程度、施用途径以及患者的年龄和体重而变化。剂量可以为每天0.2g至10g，一次或多次施用。
以下实施例对本发明进行了举例说明。
X射线粉末衍射图谱在以下实验条件下测定：
-PANalytical X’Pert Pro衍射计，X’Celerator检测器，
-电压45kV，电流强度40mA，
-支架(mounting)θ-θ，
-Kβ(Ni)滤波器，
-入射光和衍射光Soller狭缝：0.04rad，
-发散狭缝：自动，照射长度：10mm，
-掩膜(mask)：10mm，
-防散射狭缝：1/2°，
-测定模式：连续，从3°至34°，增量0.017°，
-每步测定时间：31.1秒，
-总时间：8分07秒，
-测定速度：0.068°/秒，
-旋转器：以1周/秒的速度旋转，
-测定温度：环境温度。
实施例1：α晶形的雷奈酸锶
将200g根据专利说明书EP 0 415 850中所述的方法获得的雷奈酸锶八水合物与2升水混合并加热至回流。然后将混合物冷却至20℃。通过过滤收集所获得的固体。
通过干燥失重法测得的所获得的产物的水含量为22至24％，相当于每分子雷奈酸锶含有8.1至9分子水。
X射线粉末衍射图谱：
α晶形的雷奈酸锶的X射线粉末衍谢图谱(衍射角)以汇总在下表中的重要衍射峰给出：
  衍射峰编号   2θ角(度)   峰高(计数)   峰面积(计数×度)   FWHM(度)   晶面间距(_)
  1   7.6   4527   448   0.1004   11.649
  2   8.0   1438   142   0.1004   11.069
  3   8.3   3522   349   0.1004   10.642
  4   8.6   11347   1123   0.1004   10.272
  5   8.9   7332   726   0.1004   9.889
  6   11.0   1047   104   0.1004   8.072
  7   11.3   1655   164   0.1004   7.840
  8   12.0   2186   216   0.1004   7.355
  9   13.2   2887   381   0.1338   6.703
  10   13.5   1705   169   0.1004   6.557
  11   14.1   154   30   0.2007   6.275
  12   14.7   803   79   0.1004   6.035
  13   14.9   1346   178   0.1338   5.942
  14   15.8   1556   154   0.1004   5.613
  15   16.0   3339   441   0.1338   5.527
  16   16.7   1845   183   0.1004   5.308
  17   17.3   2835   281   0.1004   5.127
  18   17.6   1252   124   0.1004   5.049
  19   18.0   2183   216   0.1004   4.939
  20   19.2   2303   228   0.1004   4.622
  21   19.8   1298   128   0.1004   4.475
  22   20.3   788   78   0.1004   4.373
  23   20.6   1039   103   0.1004   4.317
  24   21.1   882   116   0.1338   4.211
  25   21.7   390   38   0.1004   4.103
  26   22.3   1919   253   0.1338   3.990
  27   22.7   1805   179   0.1004   3.923
  28   23.0   4043   467   0.1171   3.861
  29   23.5   650   86   0.1338   3.792
  30   24.0   8677   1002   0.1171   3.711
  31   24.7   229   30   0.1338   3.600
  32   25.1   1246   164   o.1338   3.543
  33   25.6   1659   219   0.1338   3.473
  34   25.9   1773   175   0.1004   3.442
  35   26.3   695   69   0.1004   3.385
  36   26.6   401   46   0.1171   3.355
  37   27.0   2800   370   0.1338   3.300
  38   27.6   1415   140   0.1004   3.230
  衍射峰编号   2θ角(度)   峰高(计数)   峰面积(计数×度)   FWHM(度)   晶面间距(_)
  39   28.0   3250   429   0.1338   3.186
  40   28.4   1513   250   0.1673   3.144
  41   29.1   1456   144   0.1004   3.068
  42   29.6   1943   192   0.1004   3.022
  43   30.1   3637   540   0.1506   2.967
  44   30.5   707   117   0.1673   2.929
  45   30.9   596   59   0.1004   2.897
  46   31.8   577   76   0.1338   2.816
  47   32.0   1080   107   0.1004   2.796
  48   32.5   512   51   0.1004   2.756
  49   32.9   1268   167   0.1338   2.726
  50   33.4   1180   117   0.1004   2.685
实施例2：药物组合物
制备1000片每片含有0.5g活性成分的片剂的处方：
实施例1的化合物 ……………………………………………………658g
羧甲基淀粉钠…………………………………………………………25.5g
微晶纤维素……………………………………………………………119.4g
聚乙烯吡咯烷酮………………………………………………………38g
无水胶态二氧化硅……………………………………………………1.5g
硬脂酸镁………………………………………………………………7.6g。

Claims (5)

1.α晶形的式(I)的雷奈酸锶：
其特征在于水含量为22至24％和以下的X射线粉末衍射图谱，该衍射图谱用PANalytical X’Pert Pro衍射计和X’Celerator检测器测定并且以衍射峰位置(布拉格角2θ，以度表示)、衍射峰高(以计数表示)、衍射峰面积(以计数×度表示)、衍射峰半高宽(“FWHM”，以度表示)和晶面间距d(以_表示)表示：   衍射峰编号   2θ角(度)   峰高(计数) 峰面积(计数×度)   FWHM(度)   晶面间距(_)   1   7.6   4527 448   0.1004   11.649   2   8.0   1438 142   0.1004   11.069   3   8.3   3522 349   0.1004   10.642   4   8.6   11347 1123   0.1004   10.272   5   8.9   7332 726   0.1004   9.889   6   11.0   1047 104   0.1004   8.072   7   11.3   1655 164   0.1004   7.840   8   12.0   2186 216   0.1004   7.355   9   13.2   2887 381   0.1338   6.703   10   13.5   1705 169   0.1004   6.557   11   14.1   154 30   0.2007   6.275   12   14.7   803 79   0.1004   6.035   13   14.9   1346 178   0.1338   5.942   14   15.8   1556 154   0.1004   5.613   15   16.0   3339 441   0.1338   5.527   16   16.7   1845 183   0.1004   5.308   17   17.3   2835 281   0.1004   5.127   18   17.6   1252 124   0.1004   5.049   19   18.0   2183 216   0.1004   4.939   20   19.2   2303 228   0.1004   4.622   21   19.8   1298 128   0.1004   4.475
  衍射峰编号   2θ角(度)   峰高(计数) 峰面积(计数×度)   FWHM(度)   晶面间距(_)   22   20.3   788 78   0.1004   4.373   23   20.6   1039 103   0.1004   4.317   24   21.1   862 116   0.1336   4.211   25   21.7   390 38   0.1004   4.103   26   22.3   1919 253   0.1338   3.990   27   22.7   1805 179   0.1004   3.923   28   23.0   4043 467   0.1171   3.861   29   23.5   650 86   0.1338   3.792   30   24.0   8677 1002   0.1171   3.711   31   24.7   229 30   0.1338   3.600   32   25.1   1246 164   0.1338   3.543   33   25.6   1659 219   0.1338   3.473   34   25.9   1773 175   0.1004   3.442   35   26.3   695 69   0.1004   3.385   36   26.6   401 46   0.1171   3.355   37   27.0   2800 370   0.1338   3.300   38   27.6   1415 140   0.1004   3.230   39   28.0   3250 429   0.1338   3.186   40   28.4   1513 250   0.1673   3.144   41   29.1   1456 144   0.1004   3.068   42   29.6   1943 192   0.1004   3.022   43   30.1   3637 540   0.1506   2.967   44   30.5   707 117   0.1673   2.929   45   30.9   596 59   0.1004   2.897   46   31.8   577 76   0.1338   2.816   47   32.0   1080 107   0.1004   2.796   48   32.5   512 51   0.1004   2.756   49   32.9   1268 167   0.1338   2.726   50   33.4   1180 117   0.1004   2.685
2.制备权利要求1的α晶形的雷奈酸锶的方法，其特征在于将雷奈酸锶或其水合物在水中的溶液加热至回流，然后冷却直至结晶完全，并通过过滤收集产物。
3.包含作为活性成分的权利要求1的α晶形的雷奈酸锶以及与之组合的一种或多种可药用的、惰性且无毒的载体的药物组合物。
4.权利要求1的α晶形的雷奈酸锶在制备用于治疗或预防骨质疏松的药物中的用途。
5.权利要求1的α晶形的雷奈酸锶在制备用于治疗或预防关节病的药物中的用途。
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CN102241663A (zh) * 2010-05-10 2011-11-16 山东方明药业股份有限公司 一种雷奈酸锶八水合物的制备方法
CN102503931A (zh) * 2011-09-20 2012-06-20 浙江华海药业股份有限公司 一种雷尼酸锶晶形h的制备方法

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CN102241663A (zh) * 2010-05-10 2011-11-16 山东方明药业股份有限公司 一种雷奈酸锶八水合物的制备方法
CN102241663B (zh) * 2010-05-10 2013-02-13 山东方明药业集团股份有限公司 一种雷奈酸锶八水合物的制备方法
CN102503931A (zh) * 2011-09-20 2012-06-20 浙江华海药业股份有限公司 一种雷尼酸锶晶形h的制备方法

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