CN109125274A - 注射用苯并咪唑类药用酸组合物及其制备方法和用途 - Google Patents
注射用苯并咪唑类药用酸组合物及其制备方法和用途 Download PDFInfo
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- CN109125274A CN109125274A CN201710504615.1A CN201710504615A CN109125274A CN 109125274 A CN109125274 A CN 109125274A CN 201710504615 A CN201710504615 A CN 201710504615A CN 109125274 A CN109125274 A CN 109125274A
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- benzimidazole
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Abstract
本发明公开了一种注射用苯并咪唑类药用酸组合物及其制备方法和用途。所述组合物包括如式I所示的苯并咪唑类药用酸,助溶剂,注射用水,和任选存在的药学上可接受的赋形剂、载体、佐剂或它们的组合,以及任选存在的pH调节剂。本发明的组合物在少量注射水中极易溶解,且在人体内可快速转化为具有抗凝活性的达比加群,见效快,且生物利用度高。本发明的苯并咪唑类药用酸组合物制备方法简单,易于工业化。
Description
技术领域
本发明涉及一种注射用苯并咪唑类药用酸组合物及其制备方法和用途。
背景技术
达比加群酯最早由德国勃林格殷格翰公司开发,于2008年4月在德国和英国率先上市,是继华法林之后50年来上市的首个新类别口服抗凝血药物,是直接凝血酶抑制剂,具有可口服、强效、无需特殊检测、药物相互作用少等优点。2010年10月19日,FDA宣布正式批准其上市销售,商品名为Pradaxa(泰毕全),具体产品是含达比加群酯甲磺酸盐(如下式II所示)的微丸胶囊剂,适应症为心房颤动引发的中风预防。此后,心房颤动适应症陆续获得加拿大、日本、欧盟等国家和地区的批准。
专利CN 100528157C公开了一种达比加群酯口服药物组合物,其为微丸型胶囊,微丸内部是由酒石酸构成的芯材,在该酒石酸芯材外部依次包裹隔离层和活性物质层。该微丸胶囊不仅工艺难度大并且在人体内的生物利用度也比较低(6.5%);而且该处方药酸性较强,容易刺激胃肠道,尤其对于一些患有消化道溃疡、胃食道反流等疾病的患者,易引起患者胃肠道不适,增加副作用。
由于达比加群酯的溶解性具有高度pH依赖性,在pH>5的介质中几乎不溶,在酸性环境中溶解度大大提高,因此导致达比加群酯在酸性环境下更为敏感,然而考虑到其对患者胃肠道的副作用,不可使其长时间暴露于酸性条件或溶液状态下,故至今未有达比加群酯注射剂型上市或相关报道。
综上,本领域技术人员仍然需要开发一种起效速度快、生物利用度高、副作用小,且易于制备的达比加群酯的非微丸胶囊剂型。
发明内容
本发明的目的之一是提供一种注射用苯并咪唑类药用酸组合物,其包括活性物质苯并咪唑类药用酸。所述组合物能在人体内迅速转化为直接有抗凝活性的达比加群,见效快,生物利用度高,且对人体副作用小。
具体地,一方面,本发明提供一种注射用苯并咪唑类药用酸组合物,其包括以下组分:
(a)如式I所示的苯并咪唑类药用酸;
(b)助溶剂;
(c)注射用水;和
(d)任选存在的药学上可接受的赋形剂、载体、佐剂或它们的组合;以及
(e)任选存在的pH调节剂。
所述药用酸选自:盐酸、甲磺酸、酒石酸、富马酸、硫酸、磷酸、乳酸、柠檬酸、马来酸、琥珀酸、苹果酸、谷氨酸、天冬氨酸或它们的组合。在本发明的一个实施方案中,所述药用酸优选选自盐酸、甲磺酸、酒石酸、柠檬酸。
所述助溶剂选自:甘露醇、吐温40(聚氧乙烯脱水山梨醇单棕榈酸酯)、吐温60(聚氧乙烯脱水山梨醇单硬脂酸酯)、吐温80(聚氧乙烯脱水山梨醇单油酸酯)、卖泽49(聚氧乙烯单脂酸酯)、Cremophor-EL(聚氧乙烯蓖麻油酸酯)、Pluronic F68(聚氧丙烯-聚氧乙烯二醇共聚物)、胆酸钠、十二烷基硫酸钠、蔗糖的高级脂肪酸酯、羧甲基纤维素、羧甲基纤维素钠、山梨醇,或它们的组合。在本发明的一个实施方案中,所述助溶剂优选为甘露醇、羧甲基纤维素、羧甲基纤维素钠或它们的组合。
在本发明的一个实施方案中,所述组合物优选包含0.5wt%~5wt%的如式I所示的苯并咪唑类药用酸。
在本发明的一个实施方案中,所述组合物优选包含0.01wt%~5wt%的助溶剂。
在本发明的另一个实施方案中,所述组合物优选包含0.01wt%~5wt%的甘露醇、羧甲基纤维素、羧甲基纤维素钠或它们的组合。
另一方面,本发明提供一种如本发明所述的组合物的制备方法,所述方法包括以下步骤:
(1)提供助溶剂和注射用水的混合溶液;和
(2)将如式I所示的苯并咪唑类药用酸,和任选存在的药学上可接受的赋形剂、载体、佐剂或它们的组合加入到步骤(1)的混合溶液中;
(3)任选的,将上述获得的含有如式I所示的苯并咪唑类药用酸的溶液进行冻干处理,即得。
根据本发明方法制得的组合物可以是注射用粉针、注射液或冻干粉形式。
第三方面,本发明还提供一种上述组合物的用途,即本发明所述的注射用苯并咪唑类药用酸组合物可用于制备治疗或预防具有如下病症的药剂,所述病症包括:
(a)深静脉血栓及肺栓塞;和/或
(b)已经形成的静脉血栓栓塞、急性冠状动脉综合症、急性深静脉血栓、肺栓塞和复发深静脉血栓。
主要优势:
(1)本发明的注射用苯并咪唑类药用酸组合物在注射用水中有很好的溶解度,且在人体内迅速转化为直接有抗凝活性的达比加群,见效快,生物利用度高,有效地避开了现有药物口服生物利用度小和个体吸收差异大的弊端。
(2)本发明的注射用苯并咪唑类药用酸组合物克服了目前市售的达比加群酯甲磺酸盐微丸胶囊剂生物利用度低,且对于一些患有消化道溃疡、胃食道反流等疾病的患者,易引起患者胃肠道不适,增加副作用等的缺陷。
(3)本发明的注射用苯并咪唑类药用酸组合物可通过静脉滴注或静脉注射的给药方式,可减少给药量和血药浓度的波动,缩小个体差异,减少不良反应。也可针对不同肾代谢患者,给予相应剂量的注射,大大降低因肾代谢差异导致的出血风险。
(4)本发明的注射用苯并咪唑类药用酸组合物的制备方法,工艺流程简单,可操作性强,易于工业化大批量生产,克服了目前市售的达比加群酯甲磺酸盐微丸胶囊制备工艺过于复杂、上药量难以控制、上药层不均匀,批间重现性较差,成品收率较低等缺点。并且根据本发明方法制得的产品具有复溶性好、临床使用方便、贮存期长等优点。
附图说明
此处所说明的附图仅用来提供对本发明的进一步理解,构成本申请的一部分,并不构成对本发明的不当限定,其中:
图1为单次静脉给药后,本发明的含式IA药用酸的组合物在大鼠血浆中的达比加群浓度随时间变化的曲线。
图2为单次给药后,含式II药用酸的组合物在大鼠血浆中的达比加群浓度随时间变化的曲线。
具体实施方式
下面结合所附附图和具体实施例来详细说明本发明,应理解,示例性实施例仅用来解释本发明,但并不作为对本发明的限定。本领域技术人员还应当理解,本发明不受下述实施例的限制,下述实施例和说明书中描述的只是本发明的基本原理、主要特征和优势,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入本发明的范围内。本发明要求保护的范围由所附权利要求书及其等同物界定。
除非另有说明,本文所使用的专业术语与科学用语均为本领域常规用语。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明中。所述百分比通常为重量%,除非另有明确说明。
术语
如本文所用,术语“包括”涵盖了“包括”、“包含”、“基本上由……构成”和“由……构成”等,他们具有相同的含义,可互换使用。
如本文所用,术语“药学上可接受的赋形剂、载体、佐剂”指的是一种或多种相容性固体或液体填料或凝胶物质,适合用于人使用,它们本身并不是必要的活性成分,且施用后没有过分的毒性。“相容性”在此指的是组合物中各组份能与本发明的活性成分苯并咪唑类药用酸以及它们之间相互掺和,而不明显降低活性成分苯并咪唑类药用酸的药效。合适的药学上可接受的赋形剂、载体、佐剂是本领域普通技术人员所熟知的。在Remington′sPharmaceutical Sciences(Mack Pub.Co.,N.J.1991)中可找到关于药学上可接受的赋形剂、载体、佐剂的充分讨论。本发明的组合物中的药学上可接受的赋形剂、载体、佐剂可含有液体,如水、盐水、甘油和乙醇。另外,这些赋形剂、载体、佐剂中还可存在其它辅助性物质,例如润湿剂或乳化剂、pH缓冲物质等,其他非必要成分,例如其他辅助性药材,也都包括在药学上可接受的赋形剂、载体、佐剂的定义中。
常见的药学上可接受的赋形剂、载体、佐剂包括但不限于,例如纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述药学上可接受的赋形剂、载体、佐剂或它们的组合的用量没有特别限制,本领域技术人员可根据常规技术适当调整,只要能够实现本发明的技术方案即可。
如本文所用,术语“pH调节剂”又称作pH值调节剂、酸度调节剂或pH值控制剂等,是用来调整或保持体系pH值(呈酸、呈碱或呈中性)的一种物质。本发明可使用的pH调节剂包括但不限于,例如有机酸或无机酸、碱、中和剂或缓冲剂等,示例性的实例如柠檬酸、乙酸、乳酸,稀盐酸、稀硫酸,氢氧化钠、氢氧化钾,碳酸钠、碳酸钾,PBS缓冲液等。
本发明的组合物
本发明人经过广泛而深入的研究,意外地发现一种注射用苯并咪唑类药用酸组合物,该组合物在pH>5的水溶液中易溶解,且在体内可快速转化为具有直接抗凝活性的达比加群,见效快,生物利用度高,在此基础上完成了本发明。
具体地,本发明的组合物包含安全有效量范围内的如式I所示的苯并咪唑类药用酸、助溶剂、注射用水,和任选存在的药学上可接受的赋形剂、载体、佐剂,以及任选存在的pH调节剂等。其中“安全有效量”指的是组合物的量足以明显改善病情,而不至于产生严重的副作用。
在本发明的一个实施方案中,所述组合物优选包含0.5wt%~5wt%的如式I所示的苯并咪唑类药用酸。
在本发明的一个实施方案中,所述组合物优选包含0.01wt%~5wt%的助溶剂。
在本发明的一个实施方案中,所述组合物优选包含0.01wt%~5wt%的甘露醇、羧甲基纤维素、羧甲基纤维素钠或它们的组合。
溶解试验显示,本发明的组合物在注射用水中的溶解度完全能够满足临床要求,其中所述组合物在水中的动力学溶解度为5mg/mL~50mg/mL,在水中的热力学溶解度为5mg/mL~30mg/mL。药代试验表明,本发明的组合物在大鼠体内的最大血药浓度Cmax值高达4795.8ng/mL,具有很好的抗凝活性。
本发明组合物的制备
本发明的注射用苯并咪唑类药用酸组合物的制备方法非常简单,可操作性强。例如只需将如式I所示的苯并咪唑类药用酸和任选存在的药学上可接受的赋形剂、载体、佐剂或它们的组合充分溶解于助溶剂和注射用水的混合溶液中,搅拌均匀,再任选使用pH值调节剂调节体系pH值,即得。
任选地,调整体系pH值后还可将上述获得的含有式I的苯并咪唑类药用酸组合物的溶液进行冻干处理。
所述药学上可接受的赋形剂、载体、佐剂或它们的组合的加入方式和用量没有特别限制,本领域技术人员可根据常规技术进行选择和操作,只要能够实现本发明的技术方案即可。
所述冻干处理是本领域技术人员公知的制药工艺,其中预冻温度为-20℃~-60℃,预冻时间为2h~10h;升华干燥温度为-40℃~0℃,升华干燥时间为10h~40h;解析干燥温度为0℃~30℃,解析干燥时间为3h~40h。
根据本发明方法制得的注射用苯并咪唑类药用酸组合物,可以是注射用粉针、注射液,或冻干粉形式。例如当为冻干粉形式时,在使用时只需将其与注射用溶媒例如注射用水、生理盐水、PBS缓冲液或药学可接受的油相溶剂以及它们的混合物等复溶即可。
应用
本发明的苯并咪唑类药用酸组合物可用于预防深静脉血栓及肺栓塞(在进行髋关节或膝关节置换手术之后)、治疗已经形成的静脉血栓栓塞、急性冠状动脉综合症、急性深静脉血栓、肺栓塞、复发深静脉血栓。
实施例
除非另有说明,下列实施例所用试剂和原料均可市售获得(例如式IA化合物、式II化合物、式IV化合物均可市售获得),其中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
实施例1式III化合物【3-(2-(((4-甲脒基-苯基)氨基)-甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-羰基氨基)-丙酸乙酯】的制备
将式IA化合物(0.60g,1.12mmol)溶于乙醇(20mL)中,室温搅拌5分钟后过滤,滤液用饱和碳酸氢钠调pH>7,减压浓缩至有固体析出,趁热过滤,用少量的水洗涤,烘干后得到白色固体179mg(即式III化合物)。
1H NMR(400MHz,DMSO-d6):d 8.39(d,J=4.8Hz,1H),7.55(d,J=4.8Hz,3H),7.46(s,1H),7.39(d,J=8.4Hz,1H),7.14(q,J=4.8Hz,2H),6.88(d,J=8.0Hz,1H),6.76(br s,1H),6.74(d,J=8.8Hz,2H),4.56(s,2H),4.22(t,J=7.2Hz,2H),3.97(q,J=6.8Hz,2H),3.76(s,3H),2.68(t,J=6.8Hz,2H),1.12(t,J=7.2Hz,3H)。
LCMS:Rt=2.757min。
[M+H]+=500。
实施例2化合物式IB【3-(2-(((4-甲脒基-苯基)氨基)-甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-羰基氨基)-丙酸乙酯甲磺酸盐】的制备
室温下将0.25mL的1M甲磺酸水溶液滴加到式III化合物(125mg,0.25mmol)的20mL水溶液中,将该反应液在40℃下搅拌10min,反应液浑浊,然后慢慢加入20mL甲醇直到反应体系变澄清,反应液减压浓缩,冻干,得到白色固体148mg(即式IB化合物),收率99%。
1H NMR(400MHz,DMSO-d6):d 8.46(d,J=4.8Hz,1H),7.57(d,J=4.8Hz,3H),7.469(s,1H),7.44(d,J=8.4Hz,1H),7.30(q,J=4.8Hz,2H),6.78(d,J=8.0Hz,1H),6.75(br s,1H),6.73(d,J=8.8Hz,2H),4.52(s,2H),4.26(t,J=7.2Hz,2H),3.95(q,J=6.8Hz,2H),3.74(s,3H),3.30(s,3H),2.63(t,J=6.8Hz,2H),1.11(t,J=7.2Hz,3H)。
LCMS:Rt=2.757min。
[M+H]+=500。
对比例1式V化合物【3-(2-(((4-甲脒基-苯基)氨基)-甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-羰基氨基)-丙酸盐酸盐】的制备
室温下将0.25mL的1M HCl滴加到式IV化合物(达比加群,118mg,0.25mmol)的20mL的水溶液中,反应液在40℃下搅拌10min,反应液变浑浊,然后慢慢加入20mL甲醇直到反应体系澄清,将该反应液减压浓缩,冻干,得到白色固体124mg(即式V化合物),收率98%。
1H NMR(300MHz,DMSO-d6):8.96-8.94(m,2H),8.70(s,2H),8.36-8.35(m,1H),7.82(d,J=8.7Hz,2H),7.62-7.54(m,3H),7.26-7.23(m,1H),7.15-7.13(m,1H),7.02(d,J=8.1Hz,1H),6.89-6.86(m,2H),4.78(s,2H),4.16(t,J=7.5Hz,2H),3.85(s,3H),2.64-2.59(m,2H)。
LCMS:Rt=2.730min。
[M+H]+=472。
实施例3本发明的含式IA药用酸的组合物的制备
分别称取8.6mg的式IA化合物和5mg甘露醇,溶于注射用水中,搅拌混合均匀,调节体系pH值=6~7,然后进行冻干处理,即获得含式IA药用酸的组合物,为粉针状物。
将上述获得的含式IA药用酸的组合物溶于1mL注射用水中,进行溶解。室温震荡24小时后,观察完全溶解,未有沉淀析出,溶液呈澄清透明状。测得该组合物在水中的溶解度>5mg/mL。
实施例4本发明的含式IB药用酸的组合物的制备
分别称取9.5mg的式IB化合物和5mg甘露醇,溶于注射用水中,搅拌混合均匀,调节体系pH值=6~7,然后进行冻干处理,即获得含式IB药用酸的组合物,为粉针状物。
将上述获得的含式IB药用酸的组合物溶于1mL注射用水中,进行溶解。室温震荡24小时后,观察完全溶解,未有沉淀析出,溶液呈澄清透明状。测得该组合物在水中的溶解度>5mg/mL。
实施例5本发明的含式IA药用酸的组合物的制备
分别称取8.6mg的式IA化合物、6.5mg羧甲基纤维素,以及适量的明胶,溶于注射用水中,搅拌混合均匀,调节体系pH值=6~7,然后进行冻干处理,即获得含式IA药用酸的组合物,为粉针状物。
将上述获得的含式IA药用酸的组合物溶于1mL注射用水中,进行溶解。室温震荡24小时后,观察完全溶解,未有沉淀析出,溶液呈澄清透明状。测得该组合物在水中的溶解度>5mg/mL。
实施例6本发明的含式IB药用酸的组合物的制备
分别称取9.5mg的式IB化合物、6.5mg羧甲基纤维素,以及适量的滑石,溶于注射用水中,搅拌混合均匀,调节体系pH值=6~7,然后进行冻干处理,即获得含式IB药用酸的组合物,为粉针状物。
将上述获得的含式IB药用酸的组合物溶于1mL注射用水中,进行溶解。室温震荡24小时后,观察完全溶解,未有沉淀析出,溶液呈澄清透明状。测得该组合物在水中的溶解度>5mg/mL。
对比例2含式IV的组合物的制备
分别称量7.5mg的IV化合物式和5mg甘露醇,溶于注射用水中,搅拌混合均匀,然后进行冻干处理,即获得含式IV的组合物,为粉针状物。
将上述获得的含式IV的组合物溶于1mL注射用水中,未能完全溶解,室温震荡24小时后,观察仍未完全溶解,溶液呈浑浊悬浮状。测得该组合物在水中的溶解度<5mg/mL。
对比例3含式V药用酸的组合物的制备
分别称取8.1mg的式V化合物和5mg甘露醇,溶于注射用水中,搅拌混合均匀,调节体系pH值=6~7,然后进行冻干处理,即获得含式V药用酸的组合物,为粉针状物。
将上述获得的含式V药用酸的组合物溶于1mL注射用水中,发现未能完全溶解,室温震荡24小时后,观察仍未完全溶解,溶液呈浑浊悬浮状。测得其溶解度为4.69mg/mL,<5mg/mL。
对比例4含式II药用酸的组合物的制备
分别称量11.6mg的式II化合物和5mg甘露醇,溶于注射用水中,搅拌混合均匀,调节体系pH值=6~7,然后进行冻干处理,即获得含式II的药用酸组合物,为粉针状物。
将上述获得的含式II药用酸的组合物溶于1mL注射用水中,未能完全溶解,室温震荡24小时后,观察仍未完全溶解,溶液呈浑浊悬浮状。测得该组合物在水中的溶解度<5mg/mL。
药理试验
1、热力学和动力学溶解度测试
对各化合物进行热力学和动力学溶解度测试,结果参看表1。
表1
注:“-”表示未测试。
结果显示,无论是在注射用水还是在猴子血浆中,本发明的苯并咪唑类药用酸的热力学溶解度远远高于其它化合物;无论是在胃肠道环境(pH=6.5)还是血液环境(pH=7.4),本发明的苯并咪唑类药用酸的动力学溶解度也均远远高于其它化合物。
此外,还对本发明的组合物进行了热力学和动力学溶解度测试,结果表明,本发明的苯并咪唑类药用酸组合物在水中的动力学溶解度在5mg/mL~50mg/mL范围内,在水中的热力学溶解度在5mg/mL~30mg/mL范围内。
2、体外血浆转化试验
将本发明的含式IA药用酸的组合物、含式IB药用酸的组合物分别溶于DMSO溶液,然后将其加入到新鲜采集的大鼠血浆中,使之在血浆中的浓度为5μM(以达比加群计),将该样品立即经甲醇沉淀后HPLC分析,结果发现,样品中检测到约5μM的达比加群,且未检测到任何式IA(IB)化合物和/或式III化合物。
结论:在体外条件下,本发明的含式IA(式IB)药用酸的组合物在大鼠血浆内瞬时完全转化为达比加群。
3、大鼠药代动力学试验
SD大鼠三只分别静脉注射给予1mg/Kg(以达比加群计)的含式IA药用酸的组合物、含式IB药用酸的组合物、含式II药用酸的组合物,给药后分别于2min、5min、15min、30min、1h、2h、4h、8h和24h眼眶静脉丛采血约0.2mL,离心分离血浆样品,用LC/MS/MS分析其中达比加群的浓度。试验平行3次,统计数据,绘制血药浓度随时间变化曲线,结果分别如图1、图2所示。
从图1、图2可知,本发明的组合物在SD大鼠体内瞬时(2min内)达到最高浓度的达比加群,药效速度非常快;而含式II药用酸的组合物在SD大鼠体内需要近30min才达到最高浓度的达比加群,见效比较慢。经计算,本发明的组合物的最大血药浓度Cmax值可达4795.8ng/mL。
结论:本发明的组合物在大鼠体内可快速转化为直接有抗凝活性的达比加群。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落入本申请所附权利要求书限定的范围内。
Claims (9)
1.一种注射用苯并咪唑类药用酸组合物,其特征在于,包括以下组分:
(a)如式I所示的苯并咪唑类药用酸;
(b)助溶剂;
(c)注射用水;和
(d)任选存在的药学上可接受的赋形剂、载体、佐剂或它们的组合;以及
(e)任选存在的pH调节剂。
2.如权利要求1所述的组合物,其特征在于,所述药用酸选自:盐酸、甲磺酸、酒石酸、富马酸、硫酸、磷酸、乳酸、柠檬酸、马来酸、琥珀酸、苹果酸、谷氨酸、天冬氨酸或它们的组合;优选所述药用酸选自盐酸、甲磺酸、酒石酸、柠檬酸。
3.如权利要求1所述的组合物,其特征在于,所述助溶剂选自:甘露醇、吐温40、吐温60、吐温80、卖泽49、Cremophor-EL、Pluronic F68、胆酸钠、十二烷基硫酸钠、蔗糖的高级脂肪酸酯、羧甲基纤维素、羧甲基纤维素钠、山梨醇或它们的组合;优选所述助溶剂选自甘露醇、羧甲基纤维素、羧甲基纤维素钠或它们的组合。
4.如权利要求1所述的组合物,其特征在于,所述组合物优选包含0.5wt%~5wt%的如式I所示的苯并咪唑类药用酸。
5.如权利要求1所述的组合物,其特征在于,所述组合物优选包含0.01wt%~5wt%的助溶剂。
6.如权利要求5所述的组合物,其特征在于,所述组合物优选包含0.01wt%~5wt%的甘露醇、羧甲基纤维素、羧甲基纤维素钠或它们的组合。
7.如权利要求1至6任一项所述的组合物,其特征在于,所述组合物为注射用粉针、注射液或冻干粉。
8.一种如权利要求1所述的组合物的制备方法,其特征在于,包括以下步骤:
(1)提供助溶剂和注射用水的混合溶液;和
(2)将如式I所示的苯并咪唑类药用酸,和任选存在的药学上可接受的赋形剂、载体、佐剂或它们的组合加入到步骤(1)的混合溶液中,搅拌均匀;
(3)任选的,用pH调节剂调节体系pH值;
(4)任选的,将上述获得的含有如式I所示的苯并咪唑类药用酸的溶液进行冻干处理,即得。
9.权利要求1~6任一项所述的组合物在制备治疗或预防如下病症的药剂中的的用途,所述病症包括:
(a)深静脉血栓及肺栓塞;和/或
(b)已经形成的静脉血栓栓塞、急性冠状动脉综合症、急性深静脉血栓、肺栓塞和复发深静脉血栓。
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