CN1254273C - 药学上稳定的止血组合物 - Google Patents
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Abstract
本申请提供了新型止血组合物或止血制剂。提供了药学上稳定的溶液形式止血组合物，其特征在于包含在单个容器中的混合在一起的活化凝血因子VII(FVIIa)和凝血因子X(FX)。所述混合溶液pH值维持在5.0-6.5。
Description
发明领域
本发明属于医药领域，涉及含血浆蛋白的新型止血组合物及其药物制剂。更具体而言，本发明涉及治疗药物，其包含在单个容器中的活化凝血因子VII(下文也称作“FVIIa”)和凝血因子X(下文也称作“FX”)混合溶液。
背景技术
通过采用活化凝血酶原复合体浓缩物(APCC)或重组的活化凝血因子VII(rFVIIa)，已可控制具有抑制剂的血友病患者的止血。但是，在这些试剂中，前一试剂就安全性而言不能令人满意，而后一试剂就效力而言不能令人满意。为了克服这些缺陷，本发明人在日本专利公开No.2001-181204(日本专利申请No.368122/1999)公开了包含FVIIa和FX的药物组合物可用作止血剂。
包含蛋白活性成分的止血处理用药物组合物非常适宜以适合经由含所述组合物的容器施用的剂型静脉内给药，所述容器如为安瓿、注射器或小瓶。更普遍而言，使用一组两个容器，其中一个含冻干蛋白，另一个含用于溶解所述冻干蛋白的溶液。凝血因子相关蛋白的浓缩物已被配制成药物制剂，所述蛋白由血浆制得或使用遗传重组技术制得，其中所述药物制剂中大部分是以一冻干蛋白粉末和溶解用溶液组提供的。
发明内容
有两种方式可用于设计含FVIIa和FX的制剂剂型。一种方式是在分开的容器中各自提供FVIIa和FX，而另一种方式是在单个容器中提供FVIIa和FX的混合物。按照后一方式，将使用单一的两种蛋白质冻干粉末混合物和溶解用溶液组，因此共需要两个容器。另一方面，前一方式将需要为两种蛋白质中每一种提供独立的蛋白冻干粉末和溶解用溶液组，因此共需要四个容器。此外，在前一方式中，需要额外的将溶解用溶液移入蛋白冻干粉末容器中的装置或操作。在这点上，就方便性而言，前一方式是不利的。因此，如果可将FVIIa和FX混在一起容纳在单个容器中，就可得到既具药理有效性又具制药便利性的药物制剂。
如图1所示，FVIIa和FX作为酶和底物相互关联。在生理条件下，在磷脂和Ca2+存在下，FVIIa与血管损伤处存在的组织因子形成复合体，以活化FX。所得活化FX(FXa)引发后续酶促反应，通过形成不溶性血纤蛋白导致最终止血。当在血管损伤处局部出血时产生FXa，FXa实际是具有止血作用的有效因子。但是，据报道，当过量FXa存在于循环***中时，FXa可能引致全身性高凝固性(British Journal ofHaematology 69：491-497(1988))。有人提出FXa也可经由活化血管内皮细胞或系膜细胞(mesangial cell)参与引致炎症(Proc.Natl.Sci.USA 97：5255-5260(2000)；J.Am.Soc.Nephrol.12：891-899(2001))。
当FX和FVIIa蛋白均以高浓度存在时，不能对FVIIa水解FX产生FXa进行调节，由此产生大量FXa。此外，所得FXa可水解FVIIa作为底物，由此使FVIIa失活(Journal of Biological Chemistry 248：7729-7741(1973))。因而，提供在稳定溶液中的FX和FVIIa的混合物是极其困难的。在这样一种不稳定状态下，所述混合物不能配制成药物制剂，也不能对患者给药。
迄今为止，由于没有建立能克服上述问题的技术，尚没有任何已知的在单个容器中容纳有酶和其底物混合物的制剂，其中所述酶和其底物均是经纯化和制备得到的。
在这种情况下，本发明人进行了认真的研究以开发一种剂型，其中在单个容器中酶FVIIa和其底物FX混在一起。结果，本发明人出乎意料地发现了稳定包含所述酶和其底物混合物的混合组合物及其药物组合物的制备方法，并且基于该发现完成了本发明。
也就是说，本发明提供了包含在单个容器中的FVIIa和FX的液态组合物，其中FVIIa与FX在5.0-6.5的酸性pH值下混合，该pH值处于FVIIa的最佳pH范围6.5-10.0之外，本发明还提供了用作止血药物的所述组合物的冻干制剂。
本发明涉及包含FVIIa和FX混合物的液态组合物，以及所述组合物的冻干制剂。本发明的主要技术特征在于将所述液态组合物控制在特定的酸性pH范围。为此目的，可在本发明中使用任何缓冲剂溶液，使之能够将所述液态组合物控制在特定的酸性pH范围。可采用的示例性缓冲剂溶液包括如乙酸盐缓冲剂、酒石酸盐缓冲剂、柠檬酸盐缓冲剂等。
附图简述
图1显示由内部和外部两种路径构成的凝血级联。
图2显示在几种pH值下包含FVIIa和FX混合物的本发明液态组合物中(如果有的话)产生的FXa水平。
图3显示在冻干前和后，在几种pH值下包含FVIIa和FX混合物的本发明冻干制剂中(如果有的话)产生的FXa水平。
实施本发明的最佳方式
在pH为5.0-10.0下，可适当地制备缓冲剂。在较此范围更加酸性的pH下，溶液中FVIIa和/或FX的稳定性受损，其中FVIIa和/或FX逐渐失活。在较此范围更加碱性的pH下，溶液中FVIIa和/或FX的稳定性也是不足的，因而蛋白质逐渐失活。而在6.5-10.0的pH下，由FVIIa将底物FX转化成FXa。因此，可以使用5.0-6.5、优选5.4-6.1的pH，由此不会损害各组分的活性或者将FX转化成FXa。
用于本发明的FVIIa和FX可通过任何已知方法制备，例如，通过从人血中分离得到，或通过遗传重组技术得到。
FVIIa可通过文献中公开的已知方法由血制备得到，这些文献包括如日本专利公开No.155797/1991、日本专利公开No.059866/1998和日本专利公开No.059867/1998。或者，FVIIa也可通过如下方式制备：通过冷融人新鲜冷冻血浆并离心除去冷沉淀物(cryoprecipitate)制得贫含冷沉淀物血浆(cryo-poor plasma)，将贫含冷沉淀物血浆采用阴离子交换层析得到粗制FVII，将粗制FVII经固定化抗FVII单克隆抗体亲合柱层析纯化，然后用其他血浆蛋白如活化凝血因子XII或者FXa活化FVII。为确保安全，所得FVIIa优选含有尽可能少的凝血酶原、凝血酶、FIX和FIXa。
FX可通过如下方式制备：通过冷融人新鲜冷冻血浆并离心除去冷沉淀物制得贫含冷沉淀物血浆，将贫含冷沉淀物血浆采用阴离子交换层析得到粗制FX，然后将粗制FX经固定化抗FX单克隆抗体亲合柱层析纯化。类似于FVIIa的情况，为确保安全，所得FX优选含有尽可能少的凝血酶原、凝血酶、FIX和FIXa。
本发明的液态组合物可适宜包含1-20μM的FVIIa和5-400μM的FX。在优选实施方案中，本发明的液态组合物可另外包含0.001-1重量％的非离子表面活性剂和不低于0.01重量％的一种或多种选自白蛋白、糖和氨基酸的化合物，以便使所述组合物具有储存稳定性以及万一所述液态组合物被冻干，在复原时易于溶解。
本发明的组合物或止血制剂可对任何患有各种止血障碍和显示出血倾向的患者给药。
本发明提供了具有改善的安全性、有效性和便利性的新型止血制剂。
通过下面的实施例对本发明进行更详细描述，但这些实施例在任何情况下都不意在限制本发明的范围。
实施例1
为研究缓冲溶液中FVIIa/FX混合物的稳定性，在规定pH的缓冲溶液(不含CaCl2的MES缓冲剂：100mM MES，100mM NaCl)中将0.4mg/mLFVIIa和1.0mg/mL FX混在一起，混合物在37℃温育。在每一规定时间测量样品中FVIIa、FX和FXa各自的活性，该测量在其中上述各因子不彼此影响的***中进行。此处所用FVIIa是如日本专利公开155797/1991所述方式制得的血液制品。
作为结果，在测试的缓冲剂每一pH值下温育24小时后，FVIIa和FX都保留大于90％的活性。FXa含量基于其对一合成底物(S2222)的特异性水解活性来计算，FXa含量对FX的摩尔比如图2所示。在pH5.6和6.0的缓冲剂中没有观察到FXa含量增加，而在pH7.0和8.0的缓冲剂中测出FXa含量显著增加。
实施例2
为研究冻干之后缓冲溶液中FVIIa/FX混合物的稳定性，在规定pH的缓冲溶液(不含CaCl2的柠檬酸盐缓冲剂：10mM柠檬酸钠、120mMNaCl、0.5％甘氨酸、2％白蛋白和50ppm Tween 80)中将0.4mg/mLFVIIa和1.0mg/mL FX混在一起，以便制备冻干的母料。如实施例1所述，此处所用FVIIa是如日本专利公开155797/1991所述方式制得的血液制品。
在冻干前后，如实施例1所述测量各因于的活性，FXa含量如图3所示。作为结果，在测试的缓冲剂每一pH值下，在冻干之前和之后，FVIIa和FX均保留大于80％的活性。在pH5.5和6.0的缓冲剂中没有观察到FXa含量增加，而在pH7.0的缓冲剂中测出FXa含量显著增加。
Claims (4)
1.药学上稳定的止血液态组合物，其包含在单个容器中的活化的凝血因子VII(FVIIa)和凝血因子X(FX)的混合溶液，其中所述混合溶液具有5.0-6.5的pH值。
2.权利要求1的液态止血组合物，其中所述组合物包含1-20μM的FVIIa和5-400μM的FX。
3.冻干的止血药物制剂，其通过冻干权利要求1-2任一项所述的止血液态组合物而制得。
4.稳定液态组合物的方法，所述液态组合物包含在单个容器中的FVIIa和FX的混合溶液，所述方法包括将所述液态组合物维持在5.0-6.5的pH值。
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| IL162239A0 (en) | 2001-12-21 | 2005-11-20 | Novo Nordisk Healthcare Ag | Liquid composition of factor vii polypeptides |
| ES2523655T5 (es) * | 2002-06-21 | 2018-04-23 | Novo Nordisk Health Care Ag | Composiciones sólidas estabilizadas de polipéptidos del Factor VIIa |
| DE602004023848D1 (de) * | 2003-07-01 | 2009-12-10 | Novo Nordisk Healthcare Ag | Von factor vii polypeptiden |
| WO2005034990A1 (ja) * | 2003-10-09 | 2005-04-21 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | アンチトロンビンｉｉｉ含有止血用組成物 |
| GB0324044D0 (en) | 2003-10-14 | 2003-11-19 | Astrazeneca Ab | Protein |
| RU2373953C2 (ru) * | 2003-12-19 | 2009-11-27 | Ново Нордиск Хелс Кеа Аг | Стабилизированная композиция, содержащая полипептид фактора vii |
| CN101198696B (zh) | 2005-04-13 | 2014-02-26 | 阿斯利康(瑞典)有限公司 | 包含产生需要γ-羧化的蛋白质用的载体的宿主细胞 |
| EP1728798A1 (en) | 2005-06-01 | 2006-12-06 | ZLB Behring GmbH | Coagulation factor X polypeptides with modified activation properties |
| EP1820508A1 (en) | 2006-02-21 | 2007-08-22 | CSL Behring GmbH | Coagulation factor X polypeptides with modified activation properties |
| EP1958618A1 (de) * | 2007-02-15 | 2008-08-20 | Octapharma AG | Verfahren zur Gefriertrocknung mit optimierter Rekonstitution von Biopolymeren |
| US8206967B2 (en) | 2007-07-06 | 2012-06-26 | Medimmune Limited | Method for production of recombinant human thrombin |
| EP3151662B1 (en) | 2014-06-09 | 2020-10-21 | Terumo BCT, Inc. | Lyophilization |
| JP7110360B2 (ja) | 2017-10-09 | 2022-08-01 | テルモ ビーシーティー バイオテクノロジーズ，エルエルシー | 凍結乾燥方法 |
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| AU2008203028B2 (en) | 2011-08-11 |
| EP1407780B1 (en) | 2013-05-01 |
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| ES2407134T3 (es) | 2013-06-11 |
| KR101067400B1 (ko) | 2011-09-27 |
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