CN109010249A - 注射用达比加群酯药物组合物及其制备方法和用途 - Google Patents
注射用达比加群酯药物组合物及其制备方法和用途 Download PDFInfo
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- CN109010249A CN109010249A CN201710425912.7A CN201710425912A CN109010249A CN 109010249 A CN109010249 A CN 109010249A CN 201710425912 A CN201710425912 A CN 201710425912A CN 109010249 A CN109010249 A CN 109010249A
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- dabigatran etcxilate
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- A61K31/33—Heterocyclic compounds
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Abstract
本发明涉及一种注射用达比加群酯药物组合物及其制备方法和用途。所述达比加群酯药物组合物包括：(1)如式I‑2所示的活性物质达比加群酯；(2)药学上可接受的溶媒；以及任选存在的(3)药学上可接受的其他辅料。试验表明，本发明的注射用达比加群酯药物组合物各项指标均符合相关药品规定，安全性、复溶性和长期稳定性都表现良好。药代试验显示，本发明的注射用达比加群酯药物组合物可保持给药后体内合适的血药浓度和治疗持续时间，并且pH值显示为中性，大大降低了对胃肠道的刺激作用。本发明制备工艺简单、方便可行，重复性好，生产成本较低，很容易实现工业化大规模生产。
Description
技术领域
本发明涉及已上市药物的缓释制剂，具体涉及一种注射用达比加群酯药物组合物及其制备方法和用途。
背景技术
目前，心血管疾病是导致人类死亡的主要原因之一，它的一个主要方面是血栓形成，其是由一系列复杂反应引起凝血而致。血液凝固是生物体的一种保护机制，借此可很快并且可靠地“密封”血管壁的缺损，因此可以避免失血或将其降到最低限度，维持正常止血作用，即出血和凝血平衡，受到一个复杂机制的调控。不受调控的活化凝血系统或缺乏活化过程的抑制作用都可能导致多种疾病和并发症，例如静脉血栓、深静脉血栓、肺栓塞、动脉粥样硬化、急性冠状综合征、脑血管疾病等。
现已上市的口服抗凝血药物主要有直接凝血酶抑制剂、Xa因子抑制剂、IX因子抑制剂、组织因子抑制剂和新型维生素K拮抗剂等。其中达比加群酯是一种口服、选择性的高效凝血酶抑制剂，临床已证明它能够替代华法林成为预防非瓣膜性心房纤维性颤动患者中风和全身栓塞并替代依诺肝素钠成为预防主要整形术后患者静脉血栓栓塞事件的首选用药。
达比加群(Dabigatran，结构如下式I-1所示)是一种选择性的高效凝血酶抑制剂物，但是由于其分子中强碱性脒基的存在，口服不能吸收。为提高其生物利用度，需要分别将达比加群分子中的游离羧基转变成乙酯、脒基转变成氨基甲酸己酯，得到其双前体药物--达比加群酯(Dabigatran Etexilate，结构如下式I-2所示)。达比加群酯口服后，经胃肠道吸收，然后在体内转化为活性物质达比加群，与凝血酶的纤维蛋白特异位点结合，阻止纤维蛋白原裂解为纤维蛋白，从而阻断凝血瀑布网络的最后步骤及血栓形成，发挥抗凝血作用。
基于上述研究，德国勃林格殷格翰公司又进一步开发出达比加群酯甲磺酸盐(结构如上式I-3所示)，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，它是一种直接凝血酶抑制剂，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宣布正式批准该药物上市销售，商品名为Pradaxa，中文名泰毕全，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。目前上市的达比加群酯制剂即为含该达比加群酯甲磺酸盐的微丸胶囊剂。
专利ZL 03805473.6公开了一种达比加群酯口服药物组合物，为硬质胶囊剂型，其内部是由酒石酸构成的芯材，在该芯材外部依次包裹隔离层和活性物质层。该硬质胶囊剂不仅在工艺上难度很大，并且在人体内生物利用度很低(3～7％)。与参比胶囊剂相比，在去除羟丙基甲基纤维素(HPMC)胶囊外壳直接服用其中的颗粒时的口服生物利用度可能会出现最高达75％的增加，导致出血，甚至生命危险。因此，在临床使用过程中需要始终注意保持HPMC胶囊的完整性以避免无意导致达比加群酯生物利用度的增高。所以应告知患者不可打开胶囊而单独服用其中的颗粒(例如分散在食物或置于饮料中服用)，以避免出血风险；由于其安全的有效浓度、半衰期较短(排泄很快)，病人需每天两次服用110mg或150mg的该胶囊药剂；并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，大量的未被吸收的达比加群易引起患者胃肠道不适，增加副作用(具体参看：达比加群酯的FDA申报资料和FDA的药品使用说明书)。
发明内容
针对以上原因，一方面，本发明设计一种缓慢释放达比加群酯的注射给药系统，具体是提供一种注射用达比加群酯药物组合物，从而保持给药后体内合适的血药浓度和治疗持续时间，这是提高达比加群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)、治疗已经形成的血栓性静脉炎(深静脉血栓)的有效途径；同时极大可能的降低胃肠道的副作用。
本发明意外的发现，本发明的注射给药系统，即所述注射用达比加群酯药物组合物的大鼠药代动力学曲线明显优于口服给药(达比加群酯)，口服给药8小时后，体内就已经完全检测不到达比加群血药浓度，而采用本发明的注射给药系统24小时后仍然在体内能够检测到达比加群的血药浓度；不仅暴露量大幅度提高，同时药时曲线也更加平缓。
具体地，本发明所述的注射用达比加群酯药物组合物包括如式I-2所示的活性物质达比加群酯，以及药学上可接受的溶媒，例如包括但不限于，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。
所述药学可接受的油相溶剂选自：橄榄油、芝麻油、聚氧乙烯蓖麻油、花生油、聚乙二醇(PEG-400)、聚乙二醇硬脂酸酯15(solutol)、油酸乙酯，以及它们的混合物。
此外，为了具有更好的药剂学特性，本发明的注射用达比加群酯药物组合物还可任选存在至少一种药学上可接受的其他辅料。所述其他辅料选自小分子或高分子化合物以及它们的混合物，例如包括但不限于，氯化钠、葡萄糖、甘油、甘露醇、乳糖、海藻糖、羧甲基纤维素钠、羟丙甲基纤维素、羟丙基-环糊精、吐温80、泊洛沙姆、泰洛沙姆、聚乙二醇、聚乙二醇硬脂酸酯15、PEG-胆固醇、PEG-胆固醇衍生物、PEG-维生素A、PEG-维生素E、醋酸乙烯酯、吡咯烷酮、明胶、酪蛋白、右旋糖酐40、胆固醇、丙三醇、胶体二氧化硅、阿拉伯树胶、黄芪胶、桃胶、卡波姆、硬脂酸、硬脂酸钙、十六醇-十八醇混合物、聚西托醇乳化蜡、脱水山梨糖醇、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物(cremophore EL)、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚氧乙烯硬脂酸酯、磷酸盐、十二烷基磺酸钠、羧甲基纤维素钙、羧丙基纤维素、甲基纤维素、羟乙基纤维素、非晶纤维素、硬酸铝镁、聚乙烯醇、琥珀酸二辛酯磺酸盐、钠磺基琥珀酸二烷基酯、十二烷基硫酸钠、烷基芳基聚醚磺酸酯、蔗糖硬脂酸酯与蔗糖二硬脂酸酯的混合物、乙烯吡咯烷酮-甲基丙烯酸-2-二甲氨基乙酯硫酸二甲酯、胺、氧化胺、胺盐、三乙醇胺、苯扎氯铵、聚甲基丙烯酸甲酯溴化三甲铵、溴化十二烷基三甲铵、溴化十六烷基三甲铵、氯化三(十六烷基)甲基铵、烷基-三甲铵盐、二烷基-二甲铵盐、氯化十二烷基三甲基铵、烷基二甲基铵卤化物、溴化癸基三甲基铵、溴化十二烷基三乙基铵、溴化四丁基铵、溴化苄基三甲基铵、季铵化聚氧乙基烷基胺、甲基化季铵聚合物、质子化季铵丙烯酰胺、溴化十六烷基吡啶鎓、十六烷基吡啶鎓、酰亚胺吡咯鎓盐、硫鎓化合物、阳离子瓜尔胶，以及它们的混合物。
在本发明的注射用达比加群酯药物组合物中，以重量百分数计，活性物质达比加群酯I-2的含量为注射用达比加群酯药物组合物总重量的0.001％～85％，优选0.1％～80％，更优选1％～50％；其余为药学上可接受的溶媒和任选存在的药学上可接受的其他辅料。
本发明所述的如式I-2所示活性物质达比加群酯，同时还包括其药学可接受的盐。所述药学可接受的盐是指该化合物可以与无机酸或有机酸形成可药用盐，其中无机酸诸如盐酸、氢溴酸、氢碘酸、硝酸、高氯酸、硫酸或磷酸；所述有机酸诸如甲磺酸、三富甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、草酸、马来酸、柠檬酸、酒石酸、乳酸、琥珀酸、苹果酸。
另一方面，本发明还提供一种注射用达比加群酯药物组合物的制备方法，包括以下步骤：
称取处方量的如式I-2所示的活性物质达比加群酯，和/或药学上可接受的其他辅料，向其中加入适量的药学上可接受的溶媒，搅拌溶解，继续添加至处方量，搅拌均匀后，加入适量药用活性炭进行吸附，然后用微孔滤膜过滤脱碳，再经微孔滤膜过滤除菌，即得。
所述药用活性炭的添加量为溶液总体积的0.01％～0.5％，优选0.01％～0.5％，更优选0.1％～0.3％，最优选0.1％～0.2％，w/v。
优选用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜过滤除菌。
任选的，过滤除菌后，进行冻干处理。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达比加群酯药物组合物，可以是油状液体，也可以是固体粉末例如颗粒物、或冻干粉形式，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。
第三方面，本发明还提供所述注射用达比加群酯药物组合物在制备治疗或预防如下病症的药剂中的用途，所述病症包括但不限于，例如：
(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。
本发明所述的“注射用”是指不同于口服给药，而是通过注射方式的给药途径，所述注射方式可包括但不限于，例如静脉注射、皮下注射、皮内注射、肌肉注射、脊椎腔注射等。本领域技术人员可根据具体情况适当选择不同的注射给药途径，将本发明的达比加群酯药物组合物进行注射给药。
如无特殊说明，本发明所述的药学上可接受的溶媒，以及任选存在的药学上可接受的其他辅料均为“注射用”医用/药用规格，例如注射用水、注射用生理盐水、注射用PBS缓存液、注射用油(例如注射用橄榄油、注射用蓖麻油)等，它们均为本领域常规用品，均可市售获得。
试验表明，本发明的注射用达比加群酯药物组合物各项指标均符合相关药品规定，安全性、复溶性和长期稳定性都表现良好。药代试验显示，本发明的注射用达比加群酯药物组合物可保持给药后体内合适的血药浓度和治疗持续时间。并且本发明的注射用达比加群酯药物组合物pH值为中性，相对于表现为较强酸性的市售产品Pradaxa胶囊剂，大大降低了对胃肠道的刺激作用，具有广阔的应用前景。并且本发明产品制备工艺简单、方便可行，重复性好，生产成本较低，很容易实现工业化大规模生产。
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为在不同给药途径(大鼠灌胃或皮下注射)下的各药品的药代动力学变化曲线。
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。
化合物I-1、I-2、I-3、I-4、I-5均可按照现有已知文献合成，其他实验试剂，如无特殊说明，均为市售产品。
实施例1制备注射用达比加群酯药物组合物1
1)处方：按1000瓶计(规格：40mg/瓶)
活性物质达比加群酯I-2 40g
聚乙二醇硬脂酸酯15 150mL
PBS缓冲液 850mL
2)制备方法：
称取处方量的活性物质达比加群酯I-2与聚乙二醇硬脂酸酯15，加入PBS缓冲液适量，搅拌溶解后，继续添加至处方量，搅拌均匀后，添加溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜过滤除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得本发明的注射用达比加群酯药物组合物1。
实施例2制备注射用达比加群酯药物组合物2
1)处方：按1000瓶计(规格：40mg/瓶)
活性物质达比加群酯I-2 40g
橄榄油 1000mL
2)制备：
称取处方量的活性物质达比加群酯I-2，加入橄榄油适量，搅拌溶解后，继续添加至处方量，搅拌均匀后，添加溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，然后再用Φ0.22μm的微孔滤膜滤过除菌。最后经分装、压塞、轧盖、全检合格后包装，即得本发明的注射用达比加群酯药物组合物2。
实施例3制备注射用达比加群酯药物组合物3
1)处方：按1000瓶计(规格：40mg/瓶)
活性物质达比加群酯I-2 40g
聚乙二醇PEG-400 1000mL
2)制备：
称取处方量的活性物质达比加群酯I-2，加入聚乙二醇PEG-400适量，搅拌溶解后，继续添加至处方量，搅拌均匀后，添加溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜滤过除菌。最后经分装、压塞、轧盖、全检合格后包装，即得本发明的注射用达比加群酯药物组合物3。
实施例4制备注射用达比加群酯药物组合物4
1)处方：按1000瓶计(规格：40mg/瓶)
活性物质达比加群酯I-2 40g
聚氧乙烯蓖麻油 150mL
PBS缓冲液 850mL
2)制备：
称取处方量的活性物质达比加群酯I-2与聚氧乙烯蓖麻油，加入PBS缓冲液适量，搅拌溶解后，继续添加至处方量，搅拌均匀后，添加溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜过滤除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得本发明的注射用达比加群酯药物组合物4。
实施例5制备注射用达比加群酯药物组合物5
1)处方：按1000瓶计(规格：40mg/瓶)
活性物质达比加群酯I-2 40g
右旋糖酐40 100mL
生理盐水 900mL
2)制备：
称取处方量的活性物质达比加群酯I-2与右旋糖酐40，加入生理盐水适量，搅拌溶解后，继续加至处方量，搅拌均匀后，然后添加溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜过滤除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得本发明的注射用达比加群酯药物组合物5。
实施例6制备注射用达比加群酯药物组合物6
1)处方：按1000瓶计(规格：133mg/瓶)
活性物质达比加群酯I-2 133.3g
聚乙二醇硬脂酸酯15 150mL
PBS缓冲液 850mL
2)制备：
称取处方量的活性物质达比加群酯I-2与聚乙二醇硬脂酸酯15，加入PBS缓冲水溶液适量，搅拌溶解后，继续添加至处方量，搅拌均匀，然后加入溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜过滤除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得本发明的注射用达比加群酯药物组合物6。
实施例7制备注射用达比加群酯药物组合物7
1)处方：按1000瓶计(规格：267mg/瓶)
活性物质达比加群酯I-2 266.7g
聚乙二醇硬脂酸酯15 150mL
PBS缓冲水溶液 850mL
2)制备：
称取处方量的活性物质达比加群酯I-2与聚乙二醇硬脂酸酯15，加入PBS缓冲水溶液适量，搅拌溶解后，继续添加至处方量，搅拌均匀，然后加入溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm微孔滤膜过滤脱炭，之后再用Φ0.22μm微孔滤膜过滤除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得本发明的注射用达比加群酯药物组合物7。
对比例1制备达比加群酯甲磺酸盐针剂
1)处方：按1000瓶计(规格：40mg/瓶，以达比加群计)
活性物质达比加群酯甲磺酸盐I-3 46g
注射用水 1000mL
2)制备：
称取处方量的活性物质达比加群酯甲磺酸盐I-3，加入注射用水适量，搅拌溶解后，继续添加至处方量，搅拌均匀，然后添加溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜过滤除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得达比加群酯甲磺酸盐针剂。
对比例2制备达比加群针剂
1)处方：按1000瓶计(规格：40mg/瓶，以达比加群计)
活性物质达比加群I-1 30g
聚乙二醇硬脂酸酯15 150mL
PBS缓冲液 850mL
2)制备：
称取处方量的活性物质达比加群I-1与聚乙二醇硬脂酸酯15，加入PBS缓冲液适量，搅拌溶解后，继续添加至处方量，搅拌均匀，然后加入溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜过滤除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得达比加群针剂。
对比例3制备达比加群酯中间体针剂1
1)处方：按1000瓶计(规格：40mg/瓶，以达比加群计)
活性物质达比加群酯中间体I-4 38.2g
聚乙二醇硬脂酸酯15 150mL
PBS缓冲液 850mL
2)制备：
称取处方量的活性物质达比加群酯中间体I-4与聚乙二醇硬脂酸酯15，加入PBS缓冲水溶液适量，搅拌溶解后，继续添加至处方量，搅拌均匀，然后加入溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm微孔滤膜过滤脱炭，之后再用Φ0.22μm微孔滤膜过滤除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得达比加群酯中间体针剂1。
对比例4制备达比加群酯中间体针剂2
1)处方：按1000瓶计(规格：40mg/瓶，以达比加群计)
活性物质达比加群酯中间体I-5 31.8g
聚乙二醇硬脂酸酯15 150mL
PBS缓冲液 850mL
2)制备：
称取处方量的活性物质达比加群酯中间体I-5与聚乙二醇硬脂酸酯15，加入PBS缓冲水溶液适量，搅拌溶解后，继续添加至处方量，搅拌均匀，然后加入溶液量0.1％(w/v)的药用活性炭，搅拌吸附30分钟后，用Φ0.45μm的微孔滤膜过滤脱炭，之后再用Φ0.22μm的微孔滤膜滤过除菌。
然后将上述过滤除菌后制品放入labconco FreeZone冻干机中进行冻干处理。最后经分装、压塞、轧盖、全检合格后包装，即得达比加群酯中间体针剂2。
药代动力学评价
对上述实施例1～7和对比例1～4制得的样品进行药代动力学试验，采用的方法和仪器如下：
健康成年SD大鼠(雄性，6-8周龄，购自上海西普尔-必凯实验室动物有限公司，动物生产许可证号SCXK(沪)2013-0016)，给药前一天禁食不禁水。3只大鼠皮下(或灌胃)给药3mg/kg(以达比加群计)，以相应的溶媒(或配方)配制成0.6mg/mL(0.3mg/mL)(以达比加群计)的溶液(或混悬液)，于给药前(0h)和给药后5min、15min、30min、1.0、2.0、4.0、8.0、24.0h由眼眶采血200uL，肝素抗凝，4℃下8000rpm离心6min，然后将血浆转移到另一个样品管中，存储于-20℃下。
HPLC：超高效液相色谱系统(Waters公司，ACQUITY UPLC)，包括二元溶剂管理器(ACQUITY UPLC Binary Solvent Manager)、样品管理器(ACQUITY UPLC AutosamplerMod.)、高通量样品组织管理器(ACQUTIY UPLC Sample Organizer)、高温柱温箱(ACQUITYUPLC Column Heater HT)。
MS：(API 4000，美国应用生物系统公司)，电喷雾离子源(ESI)，串联四极杆质量分析器。数据处理系统为Analyst软件(美国应用生物系统公司，软件版本号1.5.1)。
柱子：ACQUITY UPLC BEH C18 1.7μm(50mm×2.10mm)
流动相：0.1％甲酸水溶液和0.1％甲酸甲醇溶液
定量方法：内标法
mpk：毫克/千克
1、考察不同给药途径(大鼠灌胃或皮下注射)后的各药品的药代动力学变化
结果参看图1和表1，其中图1为在不同给药途径例如大鼠灌胃或皮下注射后的各药品的药代动力学变化曲线，表1示出了不同给药途径(大鼠灌胃或皮下注射)后的各药品的药代动力学数据(达比加群浓度)。
表1
从图1和表1可以看出，皮下给药在体内产生的达比加群的半衰期明显长于灌胃给药，特别是在实施例2的橄榄油溶媒配方中达到了2倍以上的效果；并且皮下给药的体内达比加群暴露量远高于灌胃给药，达到了3～6倍；相比灌胃给药，皮下注射给药的药时曲线更加平缓，体内达比加群的血药浓度更加平稳。
2、检测在不同给药途径(灌胃和皮下注射给药)和不同溶媒下给药8小时后，体内达比加群的血药浓度
表2示出了在不同给药途径(灌胃给药和皮下注射)下，给药8小时后大鼠血浆中的达比加群浓度。
表2
从表2可以看出，皮下注射给药途径下的大鼠血浆中的达比加群浓度远远高于灌胃给药途径。
3、不同剂量药物组合物皮下注射的药代动力学数据比较(达比加群浓度)
表3示出了不同剂量药物组合物皮下注射的药代动力学数据(达比加群浓度)。
表3
从表3可以看出，皮下注射给药不同剂量的本发明的达比加群酯药物组合物，它们的体内达比加群的半衰期和暴露量均呈现出很好的量效关系。
4、皮下注射不同药品的药代数据比较(达比加群浓度)
表4示出了皮下注射不同药品(如本发明实施例1的达比加群酯药物组合物以及对比例1～3的不同达比加群酯针剂)的药代动力学数据(达比加群浓度)。
表4
从表4可以看出，在皮下注射给药方式下，本发明的药物组合物在大鼠体内的达比加群的暴露量均高于对比例1、对比例2和对比例3。
5、长期稳定性试验
对实施例1～7和对比例1～4制备的产品进行长期12个月的质量稳定性检测，具体检测方法参看《中华人民共和国药典》2005版第二部，结果参看表5。
表5
结果表明，本发明的达比加群酯药物组合物的各项指标均符合相关规定，且优于对比例1～4制得的药品。
6、安全性试验
将本发明实施例1～7和对比例1～4制得的产品，按照现行的药品注册法规要求(《化学药物刺激性、过敏性盒溶血性研究技术指导原则》)进行血管刺激性试验、溶血试验、过敏性试验，结果显示，本发明实施例1～7的测试样品均符合血管刺激性试验、溶血试验和过敏性试验的规定，且各项指标均优于对比例1～4的测试样品。例如，本发明实施例1～7的测试样品的注射部位皮肤、静脉均呈现相似的变化，未见充血、水肿、硬结及坏死等异常现象。
7、溶解性考察
分别取实施例1～7和对比例1～4制得的产品，加注射用水(添加量为试样重量的2～5倍)，用秒表记录复溶时间，每批样品测试3次，取平均值。结果显示，本发明的注射用达比加群酯药物组合物具有较快的临床基本可接受的复溶性能(所有测试样品的复溶时间均在15～50秒之间，溶液澄清透明无杂质)，优于对比例1～4(复溶时间60～90秒，且伴有颗粒物)。
Claims (10)
1.一种注射用达比加群酯药物组合物，其特征在于，包括以下组分：
(1)如式I-2所示的活性物质达比加群酯；
(2)药学上可接受的溶媒；以及任选存在的
(3)药学上可接受的其他辅料。
2.根据权利要求1所述的药物组合物，其特征在于，所述药学上可接受的溶媒包括注射用水、生理盐水、PBS缓冲液或药学上可接受的油相溶剂，以及它们的混合物。
3.根据权利要求2所述的药物组合物，其特征在于，所述药学上可接受的油相溶剂选自：橄榄油、芝麻油、聚氧乙烯蓖麻油、花生油、聚乙二醇、聚乙二醇硬脂酸酯15、油酸乙酯，以及它们的混合物。
4.根据权利要求1所述的药物组合物，其特征在于，所述药学上可接受的其他辅料选自：氯化钠、葡萄糖、甘油、甘露醇、乳糖、海藻糖、羧甲基纤维素钠、羟丙甲基纤维素、羟丙基-环糊精、吐温80、泊洛沙姆、泰洛沙姆、聚乙二醇、聚乙二醇硬脂酸酯15、PEG-胆固醇、PEG-胆固醇衍生物、PEG-维生素A、PEG-维生素E、醋酸乙烯酯、吡咯烷酮、明胶、酪蛋白、右旋糖酐40、胆固醇、丙三醇、胶体二氧化硅、阿拉伯树胶、黄芪胶、桃胶、卡波姆、硬脂酸、硬脂酸钙、十六醇-十八醇混合物、聚西托醇乳化蜡、脱水山梨糖醇、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚氧乙烯硬脂酸酯、磷酸盐、十二烷基磺酸钠、羧甲基纤维素钙、羧丙基纤维素、甲基纤维素、羟乙基纤维素、非晶纤维素、硬酸铝镁、聚乙烯醇、琥珀酸二辛酯磺酸盐、钠磺基琥珀酸二烷基酯、十二烷基硫酸钠、烷基芳基聚醚磺酸酯、蔗糖硬脂酸酯与蔗糖二硬脂酸酯的混合物、乙烯吡咯烷酮-甲基丙烯酸-2-二甲氨基乙酯硫酸二甲酯、胺、氧化胺、胺盐、三乙醇胺、苯扎氯铵、聚甲基丙烯酸甲酯溴化三甲铵、溴化十二烷基三甲铵、溴化十六烷基三甲铵、氯化三(十六烷基)甲基铵、烷基-三甲铵盐、二烷基-二甲铵盐、氯化十二烷基三甲基铵、烷基二甲基铵卤化物、溴化癸基三甲基铵、溴化十二烷基三乙基铵、溴化四丁基铵、溴化苄基三甲基铵、季铵化聚氧乙基烷基胺、甲基化季铵聚合物、质子化季铵丙烯酰胺、溴化十六烷基吡啶鎓、十六烷基吡啶鎓、酰亚胺吡咯鎓盐、硫鎓化合物、阳离子瓜尔胶，以及它们的混合物。
5.根据权利要求1所述的药物组合物，其特征在于，以重量百分数计，活性物质达比加群酯I-2的含量为注射用达比加群酯药物组合物总重量的0.001％～85％，优选0.1％～80％，更优选1％～50％；其余为药学上可接受的溶媒和任选存在的药学上可接受的其他辅料。
6.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物为固体粉末、颗粒物、冻干粉或油状物。
7.一种注射用达比加群酯药物组合物的制备方法，其特征在于，包括以下步骤：
称取处方量的活性物质达比加群酯I-2，以及任选存在的药学上可接受的其他辅料，向其中加入适量的药学上可接受的溶媒，搅拌溶解，继续添加至处方量，搅拌均匀后，加入适量药用活性炭进行吸附，然后用微孔滤膜过滤脱碳，再经微孔滤膜过滤除菌，即得。
8.根据权利要求7所述的方法，其特征在于，任选的，过滤除菌后，进行冻干处理。
9.根据权利要求7所述的方法，其特征在于，所述药用活性炭的添加量为溶液总体积的0.01％～0.5％，优选0.01％～0.5％，更优选0.1％～0.3％，最优选0.1％～0.2％，w/v。
10.权利要求1～6任一项所述的达比加群酯药物组合物在制备治疗或预防如下病症的药剂中的用途，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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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020180489A1 (en) * | 2019-03-06 | 2020-09-10 | University Of Rochester | Anticoagulant compositions and uses thereof |
| CN113893356A (zh) * | 2020-11-27 | 2022-01-07 | 上海博志研新药物技术有限公司 | 甲磺酸达比加群酯包合物、制备方法及应用 |
| CN114025746A (zh) * | 2019-05-10 | 2022-02-08 | 福多兹制药公司 | 抗血栓形成剂的可注射聚合物纳米颗粒组合物及其方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1248251A (zh) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | 二取代双环杂环,其制备法及作为药物的用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1248251A (zh) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | 二取代双环杂环,其制备法及作为药物的用途 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020180489A1 (en) * | 2019-03-06 | 2020-09-10 | University Of Rochester | Anticoagulant compositions and uses thereof |
| CN114025746A (zh) * | 2019-05-10 | 2022-02-08 | 福多兹制药公司 | 抗血栓形成剂的可注射聚合物纳米颗粒组合物及其方法 |
| CN114025746B (zh) * | 2019-05-10 | 2023-08-25 | 福多兹制药公司 | 抗血栓形成剂的可注射聚合物纳米颗粒组合物及其方法 |
| CN113893356A (zh) * | 2020-11-27 | 2022-01-07 | 上海博志研新药物技术有限公司 | 甲磺酸达比加群酯包合物、制备方法及应用 |
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