CN1290179A - 用于造影及治疗血栓的基于二聚阿帕西肽的药物组合物 - Google Patents
用于造影及治疗血栓的基于二聚阿帕西肽的药物组合物 Download PDFInfo
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Abstract
本发明是提供一种用于制造从阿帕西肽(spcitide)衍生的造影剂的新颖前驱试剂。利用本发明的前驱试剂制成的造影剂可用于活体内检测和诊断血栓。本发明的前驱试剂也可用于制造从阿帕西肽衍生的抗血栓剂。游离羧酸基的存在使前驱试剂在水介质中具有比二聚阿帕西肽更大的溶解度。
Description
本发明是关于血栓形成的诊断用造影的领域。更具体地说,本发明是关于用于血栓造影的药物组合物。本发明也关于使用由新颖前驱试剂制成的药物治疗血栓形成的范围。发明背景
血栓形成和血栓性栓塞症,尤其是深层静脉血栓形成(DVT)和肺栓塞(PE),是与发病率和死亡率密切有关的常见临床状况。据估计美国大约有500万病人每年经历一次或多次DVT发作,而有500,000以上的案例发生肺栓塞,造成100,000人死亡。据估计所有肺栓塞中有90%以上是起因于下肢DVT。若能尽早施用抗凝剂治疗即可有效地治疗这些病症。不过,这种治疗与阻止不必要的预防药物施用的危险性(如,内出血)有关。更先进的溶栓阻断技术(例如,施用重组体组织血纤蛋白溶酶原的活化剂或链激酶)能用于急性病例中,但这些技术的危险性甚至更大。此外,这些技术的临床有效施用需要确定患有血栓的部位以便监视治疗效果。
由于这些原因,迫切需要一种在体内定位血栓的快速方法,最好使用非侵入性的方法。过去,使用对比静脉造影术和压迫B-型超声波以确定深层静脉血栓形成的部位;选用的技术视血栓预期部位而定。然而,第一种技术是侵入性的,而且两种技术对病人都会感觉不舒服。此外,在许多病例中这些方法并不适用或产生不正确的结果。用于诊断PE的最新方法包括胸部X-光摄影、心电图(EKG)、动脉氧压、肺灌注和肺通气扫描及肺血管造影术。除了最后的(侵入性)的步骤,这些方法都不能提供明确的诊断。
最近,有一种99mTc-放射性标记的肽,阿帕西肽(apcitide),它结合到血小板上的GPIIb/IIIa受体中,血小板是血栓的成份之一,因而提供特别针对血栓的造影剂,并完成了用于急性DVT的闪烁造影的临床试验。制造99mTc-放射性标记的阿帕西肽的试剂合,ACUTECTTM,正在进行取得放射性药物产物销售许可的程序。
ACUTECTTM的主要成份是二聚阿帕西肽(bibapcitide),其化学结构列于下面。二聚阿帕西肽和其放射性标记描述于共同转让的美国专利第5,508,020和5,645,815;共同转让,待审查的专利USSN 08/253,317;及WO 93/23085;WO 93/25244;WO 94/23758和WO 95/33496。共同转让的WO 94/07918公开了二聚阿帕西肽也可用作未标记形式的抗血栓剂。
二聚阿帕西肽是阿帕西肽单体的二聚物,也公开于上述已认可的美国专利和申请书及国际专利申请书中。二聚阿帕西肽是由两个阿帕西肽单体的羧基端的胱氨酸的二顺丁烯二酰亚胺键合而形成的。阿帕西肽单体能与99Tc0复合,阿帕西肽/99Tc配合物的特性描述于1997年4月13-17日,Zheng等人的第213届美国化学学会会议的摘要336中。发明概要
本发明者已发现二种新颖阿帕西肽二聚物,二聚阿帕西肽单羧酸盐和二聚阿帕肽二羧酸盐,它存在于约pH5以上的二聚阿帕西肽水溶液中。这些新颖的阿帕西肽二聚物可用来作为制造99mTc-放射性标记阿帕西肽的前驱。
在一个具体实施方案中,本发明提供一种含二聚阿帕西肽单羧酸盐的前驱试剂。
在另一个具体实施方案中,本发明提供一种含二聚阿帕西肽二羧酸盐的前驱试剂。
在另一个具体实施方案中,本发明提供一种含二聚阿帕西肽单羧酸盐的组合物。
在另一个具体实施方案中,本发明提供一种含二聚阿帕西肽二羧酸盐的组合物。
在另一个具体实施方案中,本发明提供一种含二聚阿帕西肽单羧酸盐和药物上可接受的载体的药物组合物。
在另一个具体实施方案中,本发明提供一种含二聚阿帕西肽二羧酸盐和药物上可接受的载体的药物组合物。本发明的详细说明
本专利和本文参考的科学文献对本领域技术人员建立了可用的知识。所公布的美国专利和许可的申请书皆列入本文作为参考。
本发明的药物组合物提供一种新颖前驱试剂,二聚阿帕西肽单羧酸盐和二聚阿帕西肽二羧酸盐,可用于制备由二聚阿帕西肽衍生的造影剂和抗血栓剂。
有游离的羧酸盐基团存在时会使前驱试剂在水性介质中的溶解度大于二聚阿帕西肽在水介质中的溶解度。例如,二聚阿帕西肽和二聚阿帕西肽二羧酸盐在室温时的几个pH值的0.1M磷酸盐缓冲液中的溶解度的比较,示于下表1。
表1
溶解度
二聚阿帕西肽 | 二聚阿帕西肽-(COO-)2 | |
pH7 | <0.05毫克/毫升 | 1.3毫克/毫升 |
pH8 | <0.05毫克/毫升 | 1.3毫克/毫升 |
pH9 | <0.05毫克/毫升 | 1.3毫克/毫升 |
二聚阿帕西肽是购自Diatide公司,Londonderry,NH,USA。二聚阿帕西肽例如可按美国专利5,508,020;5,645,815;USSN 08/253,317和WO93/23085;WO 93/25244;WO 94/23758;WO 94/07918和WO 95/33496所示的固相肽合成法制造。二聚阿帕西肽最好在pH约4以下制造,而且以三氟乙酸盐分离。在调配前使用乙腈或乙醇和水或水溶液溶解二聚阿帕西肽三氟乙酸盐。哺乳动物,例如人类使用时,优选是以乙醇和水或水溶液溶解。
二聚阿帕西肽单羧酸盐和二聚阿帕西肽二羧酸盐最好通过使用适宜缓冲液,例如如实施例1所示的调整至所需pH的磷酸盐缓冲液,或实施例2公开的碳酸氢盐缓冲液,以提高已溶解二聚阿帕西肽的pH而由二聚阿帕西肽中制造。二聚阿帕西肽单羧酸盐和二聚阿帕西肽二羧酸盐是由冷冻干燥的二聚阿帕西肽三氟乙酸盐与适用于生理上pH的缓冲液再生而制成更好。任何缓冲液都可用于调节二聚阿帕西肽的pH值,以生成二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐。例如,磷酸盐缓冲液、碳酸氢盐缓冲液、硼酸盐缓冲液、柠檬酸盐缓冲液、硫酸盐缓冲液和其类似物,都可用于制造本发明的前驱试剂。此外,二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐能以酶催方法,例如,使用水解酶而制成。二聚阿帕西肽单羧酸盐和二聚阿帕西肽二羧酸盐可以使用已知方法,如实施例1和2所示的,诸如HPLC,进行分离和纯化。
二聚阿帕西肽、二聚阿帕西肽单羧酸盐和二聚阿帕西肽二羧酸盐在不同pH值下的稳定性列于下表2中。表2中的稳定性是以室温下95%的稳定性时间表示。
表2
稳定性
pH | 二聚阿帕西肽 | 二聚阿帕西肽-(COO-) | 二聚阿帕西肽-(COO-)2 |
<4 | >5小时 | 分钟 | 分钟 |
4-5 | 1-5小时 | 1小时 | 1小时 |
5-6 | 1小时 | >5小时 | >5小时 |
6-7 | 分钟 | >5小时 | >2天 |
7-8 | 分钟 | 1小时 | >5小时 |
>8 | 分钟 | 分钟 | 1小时 |
本发明的前驱试剂可以是药物组合物的形式。优选的是,本发明的药物组合物包含二聚阿帕西肽单羧酸盐或二聚阿帕西肽二羧酸盐。本发明的药物组合物包含二聚阿帕西肽单羧酸盐和二聚阿帕西肽二羧酸盐则更好。本发明的药物组合物包含二聚阿帕西肽单羧酸盐、二聚阿帕西肽二羧酸盐和二聚阿帕西肽则最佳。在药物组合物中二聚阿帕西肽单羧酸盐、二聚阿帕西肽二羧酸盐和二聚阿帕西肽的量可根据本发明的具体实施方案而改变。以ACUTECTTM出售的市售配制的二聚阿帕西肽,一般含有约10%和约50%之间的二聚阿帕西肽单羧酸盐以及约3%和约12%之间的二聚阿帕西肽二羧酸盐。
本发明的药物组合物还包含一种药物上可接受的稀释剂或载体,例如一种合适的白蛋白。本文中所用的“药物上可接受的稀释剂或载体”可包括任何和所有溶剂、分散介质、抗菌剂和抗真菌剂、等渗剂、酶抑制剂等等。这些用于药物活性物质的介质和制剂的用法是本领域所熟知的。例如,氯化钠注射液和林格氏注射液常用于作为稀释剂。前驱试剂可以冷冻干燥形式提供并经使用者重新配制成无菌、无热原、可注射的水溶液。这种具有适当相关的pH、等渗性、安定性等的可注射溶液的制备是本领域熟知的。
本发明的新颖前驱试剂可用于制造由二聚阿帕西肽衍生的诊断剂或治疗用制剂。这种制剂包括用于检测和诊断血栓的闪烁造影剂,其详情描述于美国专利5,508,020;5,645,815;USSN 08/253,317和WO 93/23085;WO 93/25244;WO 94/23758;及WO 95/33496。二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐也可用于制造抗血栓制剂,其说明见WO94/07918。本发明的前驱试剂也可用于制造含有由二聚阿帕西肽衍生的目标肽的抗血栓剂,它是与溶血栓的蛋白酶共价连接。其详细说明见共同申请专利的USSN 08/753,781和USSN 08/982,981。
当本发明的前驱试剂用于制造由二聚阿帕西肽衍生的有标记的诊断剂或治疗制剂时,可以使用任何产生讯号的标记。这种标记可以适于特定标记的任何方法通过与前驱试剂直接共价或非共价键合,或通过与其间接共价或非共价键合而掺入或与本发明的前驱试剂复合。适宜的标记包括放射性标记、荧光标记、顺磁标记、适用于计算机处理的X线断层术的重金属元素或稀土元素离子和其类似物。以放射性标记较佳。本发明方法中更优选地使用发射γ-射线的放射性核素,例如123I、67Ga、111In和99mTc。最好使用99mTc以标记本发明的前驱试剂。当使用99mTc作为标记时,99mTc是在pH大于约5时加至含有二聚阿帕西肽单羧酸盐和/戒二聚阿帕西肽二羧酸盐的药物组合物内,加热生成的混合物一段时间后,并使温度足以形成阿帕西肽单体和该单体的放射标记。包含二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐以及99mTc的药物组合物的混合物最好在沸水浴中加热约15分钟,以形成含经99mTc-标记的阿帕西肽的闪烁照相造影剂。
使用本发明的前驱试剂制成的标记或未标记的血栓造影或抗血栓剂最好与药物上可接受的载体一起由静脉注射给药予活的哺乳动物。根据本发明的教导,由含二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐的药物组合物制成的造影剂或抗血栓剂最好以单一单位的可注射剂量,溶于任何传统介质,例如盐水溶液介质或于血液血浆介质内而进行施药。以单位剂量注射溶液的量是约0.01毫升至约10毫升。
由含二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐的药物组合物制成的诊断剂和治疗剂,最好以诊断或治疗有效量对可能与血栓有关的疾病状态或患有这种疾病状态的哺乳动物施药。本文中的“诊断有效量”一词是指由二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐制成的诊断剂的药物组合物中的每种活性组份的总量,或以使用足以在体内血栓部位产生可测得讯号的诊断剂的方法给予这种组合物的总量。本文中,“治疗有效量”一词是指由二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐制成的治疗剂的药物组合物中每种活性组成的总量,或以使用足以显示对病人有意义的效用,即与由医师决定的不接受治疗剂的病人的比较组相比,使用其血栓发生率和严重性都有降低的治疗剂的方法中所给予这种组合物的总量。当只施予个别活性成份时,该词仅指成份。当施予组合物时,该词是指一起、连续或同时施予时,造成诊断或治疗效果的活性成份的结合量,例如,由二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐制成的造影剂或治疗剂能以约0.1至约10毫克/公斤体重的剂量投药,在灌输1-2小时以上后,全部作为浓缩药团或部分作为浓缩药团而进行静脉内投药。在由二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐制成的放射性标记诊断剂或治疗剂时,投药的单位剂量的放射活性为约0.01mCi至约100mCi;最好是约1mCi至约20mCi。某些具体实施例中,以体内放射性造影监测静脉内投药后的血栓部位。
制造二聚阿帕西肽单羧酸盐和/或二聚阿帕西肽二羧酸盐的方法在下列实施例中更详细说明,而该方式仅供说明但不受限于此。实施例1二聚阿帕西肽单羧酸盐的合成
将二聚阿帕西肽三氟乙酸盐(100毫克)悬浮在10毫升乙腈(CH3CH)中,声波处理1分钟,然后以40毫升水(H2O)稀释。在加水(H2O)时肽完全溶解。将40毫升pH7 0.05M磷酸盐加至该溶液内,使溶液变得稍有混浊。肽溶液的pH为7.2。在沸水浴中放置溶液3分钟形成清澈溶液。HPLC分析表明分别约有26%、54%与14%的二聚阿帕西肽二羧酸盐、二聚阿帕西肽单羧酸盐和二聚阿帕西肽的量存在。直接将反应溶液倒入以固态CO2调整至pH6-6.5的10mM碳酸氢铵(NH4HCO3)(移动相C)平衡后的47×300mm δ-Pak C18柱。柱以移动相C冲洗5分钟,接着以100/0 C/D至90/10 C/D梯度液冲洗5分钟以上,继而以90/10 C/D至80/20 C/D冲洗30分钟以上(移动相D=在pH6-6.5下的10mM NH4HCO3在75/25CH3CN/H2O中)。HPLC缓冲液不断的以固态CO2保持在pH6-6.5。根据在220nm下监视流出液而收集馏份。然后以分析用的HPLC分析馏份,收集并冷冻干燥含纯(≥98%)的二聚阿帕西肽单羧酸盐的馏份,以提供约30毫克的二聚阿帕西肽单羧酸盐(30%产量)作为白色粉末状碳酸铵盐。这样制成的二聚阿帕西肽单羧酸盐的NMR分析(20%CD3CN/80%H2O,pH6,T=20℃)说明于下表3中。
*非对映的共振实施例2二聚阿帕西肽二羧酸盐的合成
将二聚阿帕西肽三氟乙酸盐(100毫克)悬浮在5毫升CH3CN中,声处理1分钟,然后以25毫升水H2O稀释。加水(H2O)时肽完全溶解。将1毫升饱和碳酸氢钠(NaHCO3)和0.5毫升1M碳酸钾(K2CO3)加入该溶液内。利用pH试纸以估计该肽溶液的pH为8.5。在加入K2CO3时,溶液变得混浊,但在室温下放置两小时后慢慢变成清澈。3小时后以分析用的HPLC测量,发现反应含有84%二聚阿帕西肽二羧酸盐。将反应溶液直接倒进用固态CO2调节至pH6-6.5的10mM碳酸氢铵(NH4HCO3)(移动相C)平衡后的47×300mm δ -Pak C18柱。以100%移动相C冲洗柱5分钟,接着以100/0C/D至90/10 C/D梯度液冲洗5分钟以上,再以90/10 C/D至70/30 C/D冲洗30分钟以上。HPLC缓冲液不断的以固态CO2保持在pH6-6.5。根据在220nm下监测流出液而收集馏份。然后以分析用的HPLC分析馏份,收集并冷冻干燥含纯(≥98%)的二聚阿帕西肽二羧酸盐的馏份,得到约54毫克二聚阿帕西肽二羧酸盐(肽含量86%,分离出的产量53%)的白色粉末状碳酸铵盐。制成的二聚阿帕西肽二羧酸盐的NMR分析(20%CD3CN/80%H2O,pH6,T=20℃)列于下表4。
*非对映的共振
应当理解,上述公开的实施例只是强调本发明的某些特殊具体实施例,但其所有改良或同等物则都属于所附权利要求书中的本发明精神及范围内。
Claims (10)
1.一种前驱试剂,它包含二聚阿帕西肽单羧酸盐。
2.一种前驱试剂,它包含二聚阿帕西肽二羧酸盐。
3.一种组合物,它包含二聚阿帕西肽单羧酸盐。
4.根据权利要求3的组合物,它还包含二聚阿帕西肽二羧酸盐。
5.根据权利要求4的组合物,它还包含二聚阿帕西肽。
6.一种组合物,它包含二聚阿帕西肽二羧酸盐。
7.一种药物组合物,它包含二聚阿帕西肽单羧酸盐和药物上可接受的载体。
8.根据权利要求7的药物组合物,它还包含二聚阿帕西肽二羧酸盐。
9.根据权利要求8的药物组合物,它还包含二聚阿帕西肽。
10.一种药物组合物,它包含二聚阿帕西肽二羧酸盐和药物上可接受的载体。
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