CN1319015A - 含有二膦酸类化合物的组合物 - Google Patents
含有二膦酸类化合物的组合物Info
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Abstract
本发明涉及含有二膦酸或其生理相容性盐作为活性物质的给药固体药物剂型,其中活性物质以颗粒形式与任选药物辅剂一起存在于内相中,并且外相含有小于5%(重量)的硬脂酸形式的润滑剂,以该给药剂型的总重量计。
Description
本发明涉及一种含有二膦酸或其生理相容性盐作为活性物质和硬脂酸作为外相润滑剂的给药固体药物制剂。本发明还涉及一种制备所述给药剂型的方法。
已知二膦酸类化合物的给药药物剂型可用于治疗钙代谢性疾病。含有这些活性物质的药物能够有效治疗高钙血症,并且也适用于治疗由骨转移灶所致的肿瘤骨质溶解。它们还可以有效治疗骨质疏松症和由此引起的疼痛。
由于治疗此类疾病的活性物质常常需要长时间给药,所以口服用药非常适宜,因为这一般更容易被患者接受。
业已公开了某些二膦酸类化合物及其盐的口服给药剂型。例如EP-B 275468、EP-B 0625355(均属于Boehringer Mannheim)和WO93/21907(Leiras Oy)公开了含有氯屈双磷酸(二氯甲烷二磷酸)或其盐的药物制剂。WO 93/09785(Procter&Gamble Pharmaceuticals)公开了利塞膦酸盐(3-吡啶基-1-羟基亚乙基-1,1-二膦酸的盐)的口服给药剂型。WO 93/21907和WO 93/09785描述了带有包衣的口服给药剂型,该剂型仅在pH高于5或5.5的条件下才溶解。目的是区别给药的剂型通过胃部并且只在肠道中释放出活性成分。
现有技术中公开的二膦酸类化合物或其盐的固体剂型在内相中含有活性物质和选定的与活性成分相容的药物辅剂,并且在外相中含有选定的药物辅剂,特别是确保制剂在胶囊填装机或压片机中易于加工的药物辅剂。例如,EP-B 0275468描述了含氯屈双磷酸盐的药物,其颗粒中含有80-95%的高比例活性物质,含量为2-10%的填充剂和含量为0-5%的润滑剂,所述颗粒附加有一个润滑剂形式的外相,该润滑剂优选是硬脂酸镁和滑石,比例为1-5%。
在胶囊或片剂或其它固体给药剂型的开发过程中,人们通常特别关注外相中所用的辅剂。
对外相中适当润滑剂的选择和比例非常重要,因为在开发条件下它对给药剂型的物理性质影响极大。上述选择和比例决定了填充在胶囊或片剂中的物质是否可以在适当机器中在长时间内不难于加工,或片剂是否粘着在机器内的压型模中。因此必须向外相中加入足够的润滑剂。但如果润滑剂的比例过高,可能会出现其它副作用。例如,颗粒如此疏水致使所得药物只能缓慢崩解,并且无法达到预期的溶解速率(特别是30分钟后完全是否活性物质)。
下列已知润滑剂可用于外相中:硬脂酸镁、硬脂酸钙、滑石、硬脂基富马酸钠、聚乙二醇或脂肪酸和甘油的氢化酯和硬脂酸。
例如在EP-B 0275468中,公开了氯屈双磷酸盐的口服给药剂型,其中硬脂酸镁和滑石在外相中一起用作润滑剂。EP-B 0625355(Boehringer Mannheim GmbH)公开了在氯屈双磷酸盐的给药剂型的外相中只采用硬脂酸镁作为润滑剂。WO 93/21907(Leiras Oy,氯屈双磷酸盐)的实施例1中,公开了应用滑石和硬脂酸镁作为外相中的润滑剂并且用硬脂酸作为内相的润滑剂。WO 93/09785(Procter&Gamble,利塞膦酸盐)的实施例3公开了硬脂酸润滑剂的比例是片芯的5.8%(重量)。
然而业已发现,特别是当活性物质的比例较低时,润滑剂或其浓度无法最佳化,因为在30分钟后无法获得85%的溶解率,这样的溶解率表明可均匀和几乎完全释放出活性物质,或通过加热加压至室温以上后该溶解率迅速降低。
因此,本发明的一个目的是开发一种给药的药物剂型,其中活性物质是二膦酸化合物或其生理相容性盐,并且该制剂使活性物质足够稳定地在30分钟内被均匀和几乎完全释放出来,同时在变温加压后溶解率不出现降低。给药剂型中活性物质在高含量和低含量时都适用。
令人惊奇地发现,以给药剂型的总重量计,外相中含有小于5%(重量)如0.1-4.9%(重量)硬脂酸润滑剂的固体给药剂型具有的溶解率在30分钟后至少为85%,并且该溶解率在40-50℃下暴露数周后不改变。这同时适用于低含量和高含量活性物质的给药剂型。
一方面,以给药剂型的总重量计,外相中硬脂酸少于5%可以产生足够的润滑作用,使片剂或胶囊填充剂不粘着在加工机器上,另一方面,颗粒化的活性物质不会变得疏水。
本发明的这个方面涉及给药的固体药物剂型,其中活性物质是二膦酸类化合物或其生理相容性盐,其中颗粒形式的活性物质任选与药物辅剂一起存在于内相中,并且外相含有比例小于5%(重量)的硬脂酸形式的润滑剂,以给药剂型的总重量计。
外相优选含有0.1至3%(重量),特别是0.9至3%(重量)比例的硬脂酸,以给药剂型的总重量计。在释放率至少是90%(按照USP通过桨式搅拌方法测定)的情况中,特别优选硬脂酸的加入比例是给药剂型总重量的1.5至2.7%(重量)。
微粒化活性物质可以含有可药用辅剂和/或添加剂,例如乳糖、淀粉、葡萄糖、甘露糖醇、碳酸钙、磷酸钙、微晶纤维素、羟丙基甲基纤维素或其它所属领域这种目的的其它物质。
按照本发明的给药剂型在外相中也可以含有其它药物辅剂,特别是崩解剂,所有已知崩解剂均适用。更特别是交联聚乙烯吡咯烷酮(Crospovidone USPNF)是适用于本发明目的的良好崩解剂。
下列双膦酸盐是可用于本发明的活性物质,它们可以是游离酸或药物相容性盐或水合物形式,特别是钠盐:(4-氨基-1-羟基亚丁基)双膦酸盐(阿仑膦酸盐(alendronate)),(二氯亚甲基)双膦酸盐(氯屈二磷酸盐(clodronate)),[1-羟基-3-(1-吡咯烷基)-亚丙基]双膦酸盐(EB-1053),(1-羟基亚乙基)双膦酸盐(羟乙二磷酸盐(etidronate)),[1-羟基-3-(甲基戊基氨基)亚丙基]双膦酸盐(伊班膦酸盐(ibandronate)),[环庚基氨基-亚甲基]双膦酸盐(英卡膦酸盐(incadronate)),(6-氨基-1-羟基亚己基)双膦酸盐(奈立膦酸盐),[3-(二甲基氨基)-1-羟基亚丙基]双膦酸盐(奥帕膦酸盐(olpadronate)),(3-氨基-1-羟基亚丙基)双膦酸盐(氨羟二磷酸二钠),[1-羟基-2-(3-吡啶基)亚乙基]双膦酸盐(利塞膦酸盐),[[(4-氯苯基)巯基]-亚甲基]双膦酸盐(替鲁膦酸盐),[1-羟基-2-咪唑-(1,2-a)吡啶-3-基亚乙基]双膦酸盐(YH 529),[1-羟基-2-(1H-咪唑-1-基)-亚甲基]双膦酸盐(佐利膦酸盐(zoledronate))。
本发明的活性物质优选是伊班膦酸盐(ibandronate)、羟乙二磷酸盐、氯屈二磷酸盐、利塞膦酸盐、氨羟二磷酸二钠、阿仑膦酸盐或其游离酸。这些物质机器制备方法是已知并且公开在例如下列参考文献:美国专利号4705651(阿仑膦酸盐),美国专利号4927814(伊班膦酸盐),美国专利号3468935、3400147、3475486(羟乙二磷酸盐),O.T.Quimby等人,《有机化学杂志》32,4111(1967)(氯屈二磷酸盐),美国专利号4505321(利塞膦酸盐)和美国专利号4134969和3962432(氨羟二磷酸二钠)。
活性物质在本发明给药剂型中的比例可以高达该剂型总重量的95%(重量)。特别优选活性物质的含量是0.2-30%(重量),以该给药剂型的总重量计。本发明的方法特别适用于制备每单位剂量含有0.25-100mg的活性物质的口服给药剂型。术语“单位剂量”表示不连续的给药剂型,即单独片剂或胶囊。
本发明特别优选其中活性物质是伊班膦酸(1-羟基-3-(N-甲基-N-戊基)氨基-丙基-1,1-二膦酸)或其生理相容性盐(例如钠盐)的给药剂型。
为了制备本发明的给药剂型,将所述组分干混。将活性物质,优选与常规粘合剂如淀粉糊或聚乙烯吡咯烷酮K25和选择性加入的可药用添加剂和辅剂(内相的赋形剂)一起湿法制粒。随后将湿的颗粒干燥并且过筛。
此后向该混合物中加入外相。首先将外相的组分(硬脂酸和辅剂)混合并且在下一步骤中加入到颗粒中,或者分别并且直接将外相中的硬脂酸和任何其它辅剂加入颗粒中。
利用自动设备可以很容易地加工本发明的混合物并且随后压缩成为片剂或填充到常规明胶胶囊中。由此制备的片剂可以用常规薄膜包衣,例如WO 97/39755所述。
所以,本发明还涉及一种制备其中活性物质是二膦酸或其生理相容性盐的给药固体药物剂型的方法,其中通过已知方法活性物质与药物辅剂一起加工得到颗粒,向所得内相加入少于5%(重量)的硬脂酸润滑剂,并且选择性地进一步向该混合物中加入辅剂,并且将该混合物填充到胶囊中或压缩为片剂。
片剂和胶囊的大小适宜选择为使每单位剂量中的活性物质浓度为0.25-100mg。这决定了本发明给药剂型的大小,取决于活性物质的生理功效和任何增效的辅剂。
本发明制备的给药剂型在外相中含有小于5%(重量)的硬脂酸,得到自由流动、可倾泻组合物并且当压缩或填充于胶囊中时不粘着在模型和工具上。
在外相中利用相同质量的硬脂酸镁润滑剂的对比试验中,发现30分钟后体外释放率是56%。如果将这些胶囊另外在40-50℃下在干燥橱柜中热压数周后并且重新测定释放率,30分钟后的数值降低到30%以下。
本发明将在下列实施例中进一步说明,这些实施例不对本发明构成限定。对比实施例1:
含有1.8%(重量)硬脂酸镁润滑剂的5.0mg胶囊的制备
项目 | 组成 | (mg/个胶囊) |
1 | 伊班二膦酸钠一水合物 | 5.63 |
2 | 乳糖200(D80) | 19.37 |
3 | 乳糖D30 | 249.00 |
4 | 聚乙烯吡咯烷酮K25 | 9.00 |
5 | 乳糖D30 | 128.00 |
6 | 交联聚乙烯吡咯烷酮 | 25.00 |
7 | 硬脂酸镁 | 8.00 |
重量 | 444.00 |
活性物质的含量相当于5.0mg游离酸。制备方法:
由活性物质(第1项)和乳糖200(第2项)制备预混混合物。利用聚乙烯吡咯烷酮粘合剂(第4项),随后将预混混合物与辅剂附聚乳剂乳糖D30(第3项)一起制粒,在干燥和过筛后将颗粒与另外的乳糖(第5项)混合。将外相的添加剂(第6和7项)分别加入该混合物。
在适当机器中将所得物质填充到胶囊内。对胶囊的测试应作为工序间控制的一部分,并且在制备后立刻进行30分钟后体外释放率的试验。按照USP通过桨式搅拌法测定释放率。对比实施例1:
含有0.91%(重量)硬脂酸镁润滑剂的5.0mg胶囊的制备
项目 | 组成 | (mg/个胶囊) |
1 | 伊班二膦酸钠一水合物 | 5.63 |
2 | 乳糖D80 | 19.37 |
3 | 乳糖D30 | 249.00 |
4 | 聚乙烯吡咯烷酮K25 | 9.00 |
5 | 乳糖D30 | 128.00 |
6 | 交联聚乙烯吡咯烷酮 | 25.00 |
7 | 硬脂酸镁 | 4.00 |
重量 | 440.00 |
活性物质的含量相当于5.0mg游离酸。
胶囊按照对比实施例1所述方法制备。
30分钟后的体外释放结果是56%。
将对比实施例1和2中的胶囊在50℃下在干燥橱柜中热压数周,随后再测定释放率。30分钟后的释放率值降低到30%以下。
实施例1:
含有0.9和1.8%(重量)硬脂酸润滑剂的5.0mg本发明胶囊的制备
项目 | 组成 | a)(mg/个胶囊) | a)(mg/个胶囊) |
1 | 伊班二膦酸钠一水合物 | 5.63 | 5.63 |
2 | 乳糖D80 | 19.37 | 19.37 |
3 | 乳糖D30 | 249.00 | 249.00 |
4 | 聚乙烯吡咯烷酮K25 | 9.00 | 9.00 |
5 | 乳糖D30 | 128.00 | 128.00 |
6 | 交联聚乙烯吡咯烷酮 | 25.00 | 25.00 |
7 | 硬脂酸 | (0.9%)4.00 | (1.8%)8.00 |
重量 | 440.00 | 444.00 |
胶囊填充原料按照对比实施例1和2所述方法制备。在这些实施例中,添加剂6和7构成外相。
在干燥和过筛后,将原料填充到0号胶囊中。
30分钟后的体外释放结果是:a)含有4.0mg硬脂酸的批次是90%,和b)含有8.0mg硬脂酸的批次是101%。
将本发明实施例1的胶囊也在50℃下在干燥烘箱内热压数周。随后测定溶解率,所得溶解率与热压之前的相同。
实施例2:
含有2.5%(重量)硬脂酸润滑剂的20mg本发明片剂的制备
项目 | 组成 | (mg/个胶囊) |
1 | 伊班二膦酸钠 | 21.38 |
2 | 乳糖D30 | 45.52 |
3 | 羟丙基甲基纤维素 | 2.00 |
4 | 微晶纤维素 | 3.00 |
6 | 交联聚乙烯吡咯烷酮 | 5.50 |
7 | 硬脂酸 | (2.5%)2.00 |
重量 | 79.40 |
活性物质的量相当于20.0mg游离酸。制备方法:
将活性物质与辅剂混合(第2、3和4项)并且用水湿法制粒。将构成外相的混合物(第5和6项)加入到干燥和过筛后的颗粒中。随后将易于压缩的原料压缩为片剂。
制备后立刻测试所得片剂的体外释放率。30分钟后的数值为102%。
实施例3:
含有2.5%(重量)硬脂酸润滑剂的50mg本发明片剂的制备
项目 | 组成 | (mg/个胶囊) |
1 | 伊班二膦酸钠 | 53.45 |
2 | 乳糖D30 | 113.80 |
3 | 羟丙基甲基纤维素 | 5.00 |
4 | 微晶纤维素 | 7.50 |
6 | 交联聚乙烯吡咯烷酮 | 13.75 |
7 | 硬脂酸 | (2.5%)5.00 |
重量 | 198.50 |
活性物质的量相当于50.0mg游离酸。制备方法:
将活性物质与辅剂混合(第2、3和4项)并且用水湿法制粒。干燥和过筛后,将构成外相的原料(第5和6项)分别与干燥和过筛的颗粒混合。随后将易于压缩的原料压缩为片剂。
在高达40℃的不同温度下对稳定性进行试验,在不同的时间间隔后反复测定释放率。即使在40℃下26周后,观察不到与起始释放率有明显区别。
Claims (13)
1.一种含有二膦酸或其生理相容性盐或水合物作为活性物质的给药的固体药物剂型,其中活性物质是以颗粒的形式任选与药物辅剂一起存在于内相中,并且外相含有相当于给药剂型总重量的小于5%重量的硬脂酸形式的润滑剂。
2.按照权利要求1的给药剂型,其中在外相中含有相当于给药剂型总重量0.1-3%重量的硬脂酸。
3.按照权利要求1的给药剂型,其中在外相中含有相当于给药剂型总重量0.9-3%重量的硬脂酸。
4.按照权利要求1-3任一项的给药剂型,其中外相中含有相当于给药剂型总重量1.5-2.7%重量的硬脂酸。
5.按照权利要求1-4任一项的给药剂型,其中活性物质是伊班膦酸盐、羟乙二磷酸盐、氯屈二磷酸盐、利塞膦酸盐、氨羟二磷酸二钠、阿仑膦酸盐或其相应的游离酸。
6.按照权利要求1-5任一项的给药剂型,其中所述活性物质的存在比例是每单位剂量0.25-100mg。
7.按照权利要求1-5任一项的给药剂型,其中所述活性物质的存在比例是每单位剂量0.5-50mg。
8.按照权利要求1-7任一项的给药剂型,其中外相中含有崩解剂形式的另外的药物辅剂。
9.按照权利要求8的给药剂型,其中崩解剂是交联聚乙烯吡咯烷酮(Crospovidone USPNF)。
10.一种制备权利要求1-9的给药固体药物剂型的方法,其中通过已知方法将活性物质与药物辅剂一起转化为颗粒,将小于5%重量的硬脂酸润滑剂和任选其它辅剂加入得到的内相中,并且将该混合物填充在胶囊中或压缩形成片剂。
11.按照权利要求10的方法,其中外相中的硬脂酸和任何其它辅剂分别与颗粒混合。
12.按照权利要求10的方法,其中所述硬脂酸先与其它外相所用的辅剂混合,然后将得到的混合物与颗粒混合。
13.如本申请特别是实施例中所述的给药药物剂型及其产品。
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EP98119102A EP0998932A1 (de) | 1998-10-09 | 1998-10-09 | Feste pharmazeutische Darreichungsform enthaltend Diphosphonsäure oder deren Salze und Verfahren zu ihrer Herstellung |
EP98119102.6 | 1998-10-09 |
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CN1150000C CN1150000C (zh) | 2004-05-19 |
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EP (2) | EP0998932A1 (zh) |
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CN1649598B (zh) * | 2002-12-20 | 2011-12-07 | 弗·哈夫曼-拉罗切有限公司 | 高剂量伊班膦酸制剂 |
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CN1649598B (zh) * | 2002-12-20 | 2011-12-07 | 弗·哈夫曼-拉罗切有限公司 | 高剂量伊班膦酸制剂 |
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