CN1319396A - 药物组合物 - Google Patents

药物组合物 Download PDF

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CN1319396A
CN1319396A CN00122485A CN00122485A CN1319396A CN 1319396 A CN1319396 A CN 1319396A CN 00122485 A CN00122485 A CN 00122485A CN 00122485 A CN00122485 A CN 00122485A CN 1319396 A CN1319396 A CN 1319396A
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J·R·克雷克莫雷
N·A·维金斯
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Abstract

本发明涉及药物组合物,更具体地说,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－烯酸或其可药用盐作为活性成分和其中阳离子为多价的无机盐的药物组合物。

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，该试剂特别容易降解。形成的主要降解产物为相应的(3R,5S)内酯(下文称“内酯”)和氧化产物(下文称“B2”)，其中，碳-碳双键相邻的羟基被氧化成酮官能团。本发明试剂具有明显降解的倾向使得难以配制和提供一种具有市售产品能接受的储存期的药物组合物。
在英国专利2262229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，这些化合物对pH降解敏感。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)。
然而，我们发现：单独控制制剂的pH值，还不足以提高本发明试剂的稳定性。我们已经发现：通过选择无机盐，将其加入到含有一种或多种多价无机阳离子的组合物中，可以提高本发明试剂的稳定性。不愿为理论所束缚，我们认为：所述多价无机阳离子稳定了本发明试剂的结构，使其更难以被氧化和/或内酯化。
因此，我们提供的本发明含有以下内容：(1)含有作为活性成分的本发明试剂和其中阳离子为多价的无机盐的药物组合物。(2)其中阳离子为多价的无机盐在含有本发明试剂的药物组合物中作为稳定剂的应用。
优选的本发明特征为：(1)其中本发明的试剂在组合物中的含量超过5mg、优选超过10mg。但本发明试剂含量为1mg、2mg、5mg和10mg的组合物除外。在优选的组合物中，本发明试剂的含量为20mg、40mg或80mg。(2)其中稳定化合物不为合成的水滑石。(3)形成的药物组合物为片剂或粉剂。
本发明药物组合物优选为片剂。
在无机盐中发现的多价阳离子可以选自下列物质：钙、镁、锌、铝和铁或其混合物。优选的多价阳离子为钙、铝和镁或其混合物。特别优选的多价阳离子为铝和镁或其混合物。
无机盐中的抗衡离子可以选自：磷酸根、碳酸根、硅酸根(silicate)、氧化物和偏硅酸根(metasilicate)。优选的抗衡离子选自碳酸根、硅酸根(silicate)、氧化物和偏硅酸根(metasilicate)。特别优选的抗衡离子选自硅酸根(silicate)、氧化物或偏硅酸根(metasilicate)。
本发明的各个方面包括含有选自上述任意阳离子的多价阳离子和也选自上述任意阴离子的抗衡离子的无机盐。
本发明所用的无机盐优选为：偏硅酸铝镁(NeusolinTM,FujiChemical Industry Limited)、磷酸氢钙或正磷酸钙、三碱价磷酸镁和三碱价磷酸铝。特别优选偏硅酸铝镁和三碱价磷酸钙。
还优选这样的组合物具有良好的流速以有助于加工成单位口服剂型，例如片剂；当加工成可为不同剂量强度的口服片剂时，还优选这样的组合物具有良好的崩解特性和溶解特性。
在药物组合物中，无机盐与本发明试剂的重量比为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无机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无机盐。
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 of PharmaceuticalExcipients)”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 Industrial Pharmacy)，第2版，Lachman,Leon,1976；药物剂型：片剂卷1(Pharmaceutical DosageForms:Tablets Volume 1)，第2版，Lieberman,Hebert A，等编，1989；现代药物学(Modern Pharmaceutics),Banker,Gilbert和Rhodes,Christopher T,1979；和雷明顿药物科学(Reminton’sPharmaceutical sciences)，第15版，1975年。
一般地，本发明试剂的重量含量为1-50％、优选1-25％、更优选1-20％、特别优选5-18％。
一般地，无机盐例如三碱价磷酸钙的重量含量为1-25％、例如1-20％，优选5-18％。
一般地，一种或多种填充剂的重量含量为30-90％。
一般地，一种或多种粘合剂的重量含量为2-90％。
一般地，一种或多种崩解剂的重量含量为2-10％、优选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重量含量为0.5-3％，特别是1-2％。
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，可以把本发明试剂和其中阳离子为多价的无机盐、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，持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，可以把本发明试剂和其中阳离子为多价的无机盐、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那些成分。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％。含有氧化铁的包衣是特别优选的，因为它们能够降低本发明试剂的光降解产物的形成速率。
因此，我们提供含有本发明试剂的药物组合物作为本发明的特征，所述组合物含有氧化铁光保护性包衣。
本发明的另一方面包括制备稳定的药物组合物的方法，其包括把本发明试剂和其中阳离子为多价的无机盐混合。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无机盐加入到含有本发明试剂的药物组合物中。
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        3.00mg2,6-二叔丁基对甲酚    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在一起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。
实施例2本发明试剂            2.50mg聚烯吡酮(Povidone)    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        3.00mg2,6-二叔丁基对甲酚    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(按照下面给出的量)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-Jenlkinson以SpectrablendTM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，再将混合物混合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 ⅡTM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            1.00mg2,6-二叔丁基对甲酚  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。用净化水将粉末混合物制粒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ComilTM)。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。
Figure A0012248500101
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无机盐。
2．权利要求1所述的药物组合物，其中无机盐中的阳离子选自钙、镁、锌、铝和铁。
3．权利要求1所述的药物组合物，其中无机盐选自偏硅酸铝镁、三碱价磷酸钙、三碱价磷酸镁和三碱价磷酸铝。
4．权利要求3所述的药物组合物，其中无机盐为偏硅酸铝镁。
5．片剂或粉剂形式的权利要求1-4任意一项所述的药物组合物。
6．权利要求1-5任意一项所述的药物组合物，其中活性成分的含量高于5mg。
7．权利要求1-6任意一项所述的药物组合物，其中活性成分的含量高于10mg。
8．权利要求1-7任意一项所述的药物组合物，其中阳离子为多价的无机盐不为合成的水滑石。
9．权利要求1-8任意一项所述的药物组合物，其中无机盐与活性成分的重量比为1∶80-50∶1。
10．上述任意一项权利要求所述的药物组合物，其还包括一种或多种填充剂、粘合剂、崩解剂或润滑剂。
11．上述权利要求1-6任意一项所述的药物组合物，其中活性成分的含量为组合物重量的1-50％。
12．上述权利要求1-6任意一项所述的药物组合物，其中无机盐的含量为组合物重量的1-50％。
13．权利要求10所述的药物组合物，其中填充剂的含量为组合物重量的30-90％。
14．权利要求10或13所述的药物组合物，其中粘合剂的含量为组合物重量的2-90％。
15．权利要求10、13或14所述的药物组合物，其中崩解剂的含量为组合物重量的2-10％。
16．权利要求10、13、14或15所述的药物组合物，其中润滑剂的含量按重量计为0.5-3％。
17．上述任意一项权利要求所述的药物组合物，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。
18．阳离子为多价的无机盐稳定化合物(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。
19．权利要求18所述的用途，其中阳离子为多价的无机盐选自偏硅酸铝镁、三碱价磷酸钙、三碱价磷酸镁和三碱价磷酸铝。
20．权利要求19所述的用途，其中阳离子为多价的无机盐为偏硅酸铝镁。
21．一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无机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。
22．权利要求21所述的方法，其中阳离子为多价的无机盐为偏硅酸铝镁。
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