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CN1149997C - 药物组合物 - Google Patents

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CN1149997C
CN1149997C CNB001224840A CN00122484A CN1149997C CN 1149997 C CN1149997 C CN 1149997C CN B001224840 A CNB001224840 A CN B001224840A CN 00122484 A CN00122484 A CN 00122484A CN 1149997 C CN1149997 C CN 1149997C
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J·R·克雷克莫雷
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N·A·维金斯
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Abstract

本发明涉及含有HMG CoA还原酶抑制剂(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐作为活性成分的药物组合物，该组合物在较长期间内保持稳定。

Description

药物组合物
本发明涉及药物组合物，更具体地说，本发明涉及含有(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐(下文称为“本发明试剂”)的药物组合物，其中所述的盐具体是钠盐和钙盐，尤其是钙盐：双[(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸]钙盐(如下面式I所示)。
在公开号为0521471的欧洲专利申请和生物有机和药物化学(Bioorganic and Medicinal Chemistry)(1997)，5(2)，第437-444页中公开了本发明试剂作为3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMG CoA还原酶)的抑制剂，并公开了其可用于治疗高胆甾醇血、高脂蛋白血和动脉粥样硬化。
同本发明试剂有关的一个问题是：在某些条件下，该试剂会降解。这使得难以配制产品，也难以提供足够储存期的药物组合物。形成的主要降解产物为相应的(3R，5S)内酯(下文称为“内酯”)和氧化产物(下文称为“B2”)，其中，碳-碳双键相邻的羟基被氧化成酮官能团。
因此，找到一种在一段较长时期内保持稳定的本发明试剂药物组合物是非常重要的。同样优选的是：这样的药物组合物具有良好的流速以有助于加工成口服单位剂型，例如片剂；以及当加工成可为不同剂量强度的口服片剂时，它们具有良好的崩解和溶解特性。还优选的是：这样的片剂具有合适的体积以易于给药。
在英国专利2 262 229中公开了为HMG CoA还原酶抑制剂的某些7-取代的-3，5-二羟基-6-庚烯酸盐的药物制剂。这些制剂需要存在能使组合物的水溶液或分散体的pH值至少为8的碱性介质(例如碳酸盐或碳酸氢盐)。
现在我们发现一种新的本发明试剂的药物组合物，其具有优良的特性，解决了与本发明试剂制剂有关的一种或多种问题。
因此，本发明首先一个方面包括一种药物组合物，其含有本发明试剂和其中阳离子为多价的三碱价磷酸盐。
本发明的第二方面包括应用其中阳离子为多价的三碱价磷酸盐稳定本发明试剂。
其中阳离子为多价的三碱价磷酸盐包括：例如三碱价磷酸钙、三碱价磷酸镁和三碱价磷酸铝。尤其优选三碱价磷酸钙。
在所述药物组合物中，三碱价磷酸盐和本发明试剂的比率按重量计为例如1∶80-50∶1、优选1∶50-50∶1、更优选1∶10-10∶1，特别更优选1∶5-10∶1。
优选地，本发明的药物组合物配制成口服剂型，例如片剂。因此，本发明的另一方面涉及药物组合物，其含有本发明试剂、其中阳离子为多价的三碱价磷酸盐和一种或多种填充剂、粘合剂、崩解剂或润滑剂。本发明还有一个方面涉及口服药物组合物，其含有本发明试剂、一种或多种填充剂、一种或多种粘合剂、一种或多种崩解剂、一种或多种润滑剂和其中阳离子为多价的三碱价磷酸盐。
合适的填充剂包括，例如：乳糖、糖、淀粉、改性淀粉、甘露糖醇、山梨糖醇、无机盐、纤维素衍生物(例如微晶纤维素、纤维素)、硫酸钙、木糖醇和乳糖醇。
合适的粘合剂包括例如：聚乙烯吡咯烷酮、乳糖、淀粉、改性淀粉、糖、阿拉伯树胶、黄芪胶、瓜尔胶、果胶、蜡粘合剂、微晶纤维素、甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羟丙基纤维素、copolyvidone、明胶和藻酸钠。
合适的崩解剂包括例如：交联羧甲基纤维素钠(crosscarmellosesodium)、聚乙烯聚吡咯烷酮(crospovidone)、聚乙烯吡咯烷酮、淀粉羟基乙酸钠、玉米淀粉、微晶纤维素、羟丙基甲基纤维素和羟丙基纤维素。
合适的润滑剂包括例如：硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石、巴西棕榈蜡、氢化植物油、矿物油、聚乙二醇和十八烷基富马酸钠。
可以加入的其它常规赋形剂包括防腐剂、稳定剂、抗氧化剂、二氧化硅流动调节剂(silica flow conditioners)、防粘剂或助流剂(glidant)。
其它可以应用的适宜填充剂、粘合剂、崩解剂、润滑剂和其它赋形剂记载于下列文献中：“药物赋形剂手册(Handbook ofPharmaceutical Excipients)”第2版，美国药学协会编；“工业制药的理论与实践”(The Theory and Practice of IndustrialPharmacy)，第2版，Lachman，leon，1976；药物剂型：片剂卷1(Pharmaceutical Dosage Forms：Tablets Volume 1)，第2版，Lieberman，Hebert  A，等编，1989；现代药物学(ModernPharmaceutics)，Banker，Gilbert和Rhodes，Christopher T，1979；和雷明顿药物科学(Reminton’s Pharmaceutical Sciences)，第15版，1975年。
一般地，本发明试剂的含量按组合物重量计为1-80％，优选1-50％，更优选1-20％(特别是2-15％)。
一般地，三碱价磷酸盐例如三碱价磷酸钙的含量按重量计为1-50％，例如1-25％，优选1-20％，特别优选5-18％。
一般地，一种或多种填充剂的含量按重量计为30-90％。
一般地，一种或多种粘合剂的含量按重量计为2-90％。
一般地，一种或多种崩解剂的含量按重量计为2-10％、尤其是4-6％。
应该理解：一种具体的赋形剂可以同时充当粘合剂和填充剂，或充当粘合剂、填充剂和崩解剂。一般地，填充剂、粘合剂和崩解剂的总量为例如组合物重量的70-90％。
一般地，一种或多种润滑剂的含量按重量计为0.5-3％，特别是1-2％。
本发明优选的组合物包括例如那些含有本发明试剂、三碱价磷酸钙和赋形剂的药物组合物，其中所述赋形剂选自：乳糖、甘露糖醇、微晶纤维素、聚乙烯吡咯烷酮(povidone)、聚乙烯聚吡咯烷酮、淀粉羟基乙酸钠和硬脂酸镁。本发明优选的独立组合物包括例如：那些含有本发明试剂、三碱价磷酸钙、微晶纤维素、乳糖、淀粉羟基乙酸钠、2，6-二叔丁基对甲酚和硬脂酸镁的组合物；含有本发明试剂、聚乙烯吡咯烷酮、三碱价磷酸钙、微晶纤维素、甘露糖醇、淀粉羟基乙酸钠、2，6-二叔丁基对甲酚和硬脂酸镁的组合物；含有本发明试剂、三碱价磷酸钠、聚乙烯聚吡咯烷酮、微晶纤维素、乳糖和硬脂酸镁的组合物；以及含有本发明试剂、聚乙烯吡咯烷酮、三碱价磷酸钠、微晶纤维素、乳糖、淀粉羟基乙酸钠、硬脂酸镁和2，6-二叔丁基对甲酚的组合物。但应用乳糖和微晶纤维素时，它们优选的重量比为约1∶1-3∶1。
特别关心的本发明组合物包括例如下列实施例中所列出的具体实施方案。
本发明的药物组合物可以应用本领域通常已知的标准技术和制备方法制备，例如通过把各组分干混。例如，可以把本发明试剂、三碱价磷酸盐(例如三碱价磷酸钙)、一种或多种填充剂、一种或多种粘合剂和一种或多种崩解剂以及其它附加的赋形剂(如果需要)混合在一起。可以把混合前的混合物组分或混合物本身通过筛网过滤，例如通过400-700μm筛网。然后把润滑剂，也可以将其通过筛网，加入到混合物中，继续混合直至得到均匀混合物。然后把混合物压成片剂。或者，可以应用湿法制粒技术。例如，可以把本发明试剂、三碱价磷酸盐、一种或多种填充剂、一种或多种粘合剂和一部分崩解剂以及其它附加的赋形剂(如果需要)混合在一起，例如通过制粒机，把该粉末混合物同一小部分净化水一起制粒。干燥得到的颗粒，进行研磨。把剩余的崩解剂和润滑剂加入到研磨后的颗粒中，混合后，把得到的均相混合物压制成片剂。应该理解：可以把干燥混合和湿法制粒技术进行改动，包括各成分的加入顺序和它们在压成片之前的筛选和混合，这些改动按照本领域熟知的原理进行。
然后可以应用片剂包衣，例如通过用水基膜包衣制剂进行喷雾包衣。所述包衣剂可以含有，例如：乳糖、羟丙基甲基纤维素、甘油三乙酸酯、二氧化钛和氧化铁。包衣成分混合物可以市售得到，例如在下文实施例中记载的成分。在该包衣剂中，例如片剂组合物的含量为0.5-10％重量、特别是1-6％、和优选2-3％。含有氧化铁的包衣剂是特别优选的，因为它们能够降低本发明试剂的光降解产品的形成速率。
本发明的另一方面包括制备稳定的药物组合物的方法，具包括把本发明试剂和其中阳离子为多价的三碱价磷酸盐混合。本发明还有一个方面包括制备稳定的药物组合物的方法，其包括把其中阳离子为多价的三碱价磷酸盐加入到含有本发明试剂的药物组合物中。
下列药物组合物，其中本发明试剂为式I的钙盐，是为了举例说明本发明，它们不是以任意方式对本发明进行限制。
实施例1
本发明试剂                      2.50mg
三碱价磷酸钙                    20.0mg
微晶纤维素                      47.0mg
乳糖一水合物                    47.0mg
淀粉羟基乙酸钠                  3.00mg
2，6-二叔丁基对甲酚             0.05mg
硬脂酸镁                        1.00mg
将本发明试剂、微晶纤维素、乳糖一水合物、淀粉羟基乙酸钠、三碱价磷酸钙和2，6-二叔丁基对甲酚混合10分钟。把硬脂酸镁经#40目(425μm)筛过筛后，加入到上述混合物中，再继续混合3分钟。将得到的均匀混合物压成片剂。
在70℃/80％相对湿度下把该片剂储存1周。1周后，发现仅仅形成0.11％w/w的氧化产物B2，仅仅形成0.50％w/w的内酯。比较起来，其中用20.0mg二碱价磷酸钙代替20.0mg三碱价磷酸钙的类似制剂，形成0.23％w/w的B2，和15.61％w/w的内酯。
实施例2
本发明试剂              2.50mg
聚烯吡酮                2.50mg
三碱价磷酸钙            20.0mg
微晶纤维素              47.0mg
甘露糖醇                47.0mg
淀粉羟基乙酸钠          3.00mg
2，6-二叔丁基对甲酚     0.05mg
硬脂酸镁                1.00mg
将本发明试剂、聚烯吡酮、甘露糖醇、微晶纤维素、2，6-二叔丁基对甲酚、三碱价磷酸钙和淀粉羟基乙酸钠(按照上面给出的量)混合5-60分钟。把硬脂酸镁经#40目(425μm)筛过筛后，加入到上述混合物中，再继续混合3分钟。将得到的均匀混合物压成片剂。应用羟丙基甲基纤维素、聚乙二醇400、二氧化钛和氧化铁(由Warner-Jenkinson以Spectrablend出售)和水的混合物在包衣盘中喷雾，对压成的片剂进行包衣。包衣后增重为1-6％w/w，优选2-3％w/w。
在70℃/80％相对湿度下把该片剂储存1周。1周后，发现仅仅形成0.06％w/w的氧化产物B2，仅仅形成2.22％w/w的内酯。
实施例3
本发明试剂                  2.60mg
聚乙烯聚吡咯烷酮            3.75mg
三碱价磷酸钙                5.66mg
微晶纤维素                  15.5mg
乳糖一水合物                46.5mg
硬脂酸镁                    0.94mg
将本发明试剂和聚乙烯聚吡咯烷酮混合在一起5分钟，然后把混合物通过400-700μm筛。再把一小部分微晶纤维素过筛。过筛后的物质同除润滑剂以外的其它成分混合10分钟。把硬脂酸镁经#40目(425μm)筛过筛后，加入到上述混合物中，再继续混合3分钟。将得到的均匀混合物压成片剂。应用乳糖一水合物、羟丙基甲基纤维素、甘油三乙酸酯和氧化铁(由Colorcon以Opadry II出售)和水的混合物在包衣盘中喷雾，对压成的片剂进行包衣。包衣后增重为1-6％w/w，优选2-3％w/w。
在70℃/80％相对湿度下把该片剂储存1周。此时发现仅仅形成0.19％w/w的氧化产物B2，仅仅形成2.71％w/w的内酯。
实施例4
本发明试剂                      2.50mg
聚烯吡酮                        2.50mg
三碱价磷酸钙                    20.0mg
微晶纤维素                      34.5mg
乳糖一水合物                    34.0mg
淀粉羟基乙酸钠                  6.00mg
硬脂酸镁             1.00mg
2，6-二叔丁基对甲酚  0.05mg
把一部分三碱价磷酸钙和2，6-二叔丁基对甲酚在袋子中混合30秒。将本发明试剂、聚烯吡酮、剩余的三碱价磷酸钙、微晶纤维素、乳糖一水合物、三碱价磷酸钙/2，6-二叔丁基对甲酚混合物和一部分淀粉羟基乙酸钠在制粒机中混合30秒。用净化水把粉末混合物制粒1分钟，加入速度为70mg/片/分钟。在流化床干燥器中把颗粒在50℃下干燥直至干燥后损失小于2％w/w。将干燥的颗粒通过磨机(例如通过Comil)。把研磨后的颗粒和剩余的淀粉羟基乙酸钠混合约5分钟。把硬脂酸镁经#40目(425μm)筛过筛后，加入到上述混合物中，再继续混合3分钟。将得到的均匀混合物压成片剂。
在70℃/80％相对湿度下把该片剂储存1周。此时，发现仅仅形成0.23％w/w的氧化产物B2，仅仅形成0.28％w/w的内酯。比较起来，其中用20.0mg二碱价磷酸钙代替20.0mg三碱价磷酸钙的类似制剂，形成0.19％w/w的B2和28.15％w/w的内酯。
式I

Claims (22)

1、一种药物组合物，含有(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐作为活性成分和其中阳离子为多价的三碱价磷酸盐。
2、权利要求1所述的药物组合物，其中阳离子为多价的三碱价磷酸盐选自三碱价磷酸钙、三碱价磷酸镁和三碱价磷酸铝。
3、权利要求1或2所述的药物组合物，其中阳离子为多价的三碱价磷酸盐为三碱价磷酸钙。
4、权利要求1或2所述的药物组合物，其中三碱价磷酸盐与活性成分的比率按重量计为1∶5-10∶1。
5、权利要求1或2所述的药物组合物，其还包含一种或多种填充剂、粘合剂、崩解剂或润滑剂。
6、权利要求1所述的药物组合物，该组合物口服使用，包括(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐作为活性成分、一种或多种填充剂、一种或多种粘合剂、一种或多种崩解剂、一种或多种润滑剂和其中阳离子为多价的三碱价磷酸盐。
7、权利要求6所述的药物组合物，其中活性成分的含量按组合物重量计为1-80％，和药物组合物各组分的含量之和为100％重量。
8、权利要求6或7所述的药物组合物，其中三碱价磷酸盐的含量按组合物重量计为1-50％，和药物组合物各组分的含量之和为100％重量。
9、权利要求6或7所述的药物组合物，其中填充剂的含量按组合物重量计为30-90％，和药物组合物各组分的含量之和为100％重量。
10、权利要求6或7所述的药物组合物，其中粘合剂的含量按组合物重量计为2-90％，和药物组合物各组分的含量之和为100％重量。
11、权利要求6或7所述的药物组合物，其中崩解剂的含量按组合物重量计为2-10％，和药物组合物各组分的含量之和为100％重量。
12、权利要求6或7所述的药物组合物，其中润滑剂的含量按重量计为0.5-3％，和药物组合物各组分的含量之和为100％重量。
13、权利要求6或7所述的药物组合物，其中：
(i)三碱价磷酸盐的含量按组合物重量计为1-50％；
(ii)填充剂的含量按组合物重量计为30-90％；
(iii)粘合剂的含量按组合物重量计为2-90％；
(iv)崩解剂的含量按组合物重量计为2-10％；和
(v)润滑剂的含量按重量计为0.5-3％；且
其中组合物各组分的含量之和为100％重量。
14、权利要求6所述的药物组合物，含有(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐作为活性成分、三碱价磷酸钙、微晶纤维素、乳糖、淀粉羟基乙酸钠、2，6-二叔丁基对甲酚和硬脂酸镁。
15、权利要求6所述的药物组合物，含有(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐作为活性成分、三碱价磷酸钙、聚乙烯吡咯烷酮、微晶纤维素、甘露糖醇、淀粉羟基乙酸钠、2，6-二叔丁基对甲酚和硬脂酸镁。
16、权利要求6所述的药物组合物，含有(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐作为活性成分、三碱价磷酸钙、聚乙烯聚吡咯烷酮、微晶纤维素、乳糖和硬脂酸镁。
17、权利要求6所述的药物组合物，含有(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐作为活性成分、三碱价磷酸钙、聚乙烯吡咯烷酮、微晶纤维素、乳糖、淀粉羟基乙酸钠、2，6-二叔丁基对甲酚和硬脂酸镁。
18、权利要求1、2、6、7或14至17中任意一项所述的药物组合物，其中活性成分为(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸的钙盐。
19、阳离子为多价的三碱价磷酸盐稳定化合物(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐的用途。
20、权利要求19所述的用途，其中阳离子为多价三碱价磷酸盐选自三碱价磷酸钙、三碱价磷酸镁和三碱价磷酸铝。
21、权利要求19或20所述的用途，其中阳离子为多价的三碱价磷酸盐为三碱价磷酸钙。
22、一种生产稳定的药物组合物的方法，包括把其中阳离子为多价的三碱价磷酸盐加入到含有化合物(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸或其可药用盐的药物组合物中。
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