CN107072956B - 一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途 - Google Patents
一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途 Download PDFInfo
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- CN107072956B CN107072956B CN201580060552.4A CN201580060552A CN107072956B CN 107072956 B CN107072956 B CN 107072956B CN 201580060552 A CN201580060552 A CN 201580060552A CN 107072956 B CN107072956 B CN 107072956B
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Abstract
一种含有达比加群酯的药用组合物、及其制备方法和用途，以及包含所述药用组合物的固体制剂。所述药用组合物包含维生素C层和达比加群酯层，且在两层之间通过半透膜层隔离，所述半透膜层包含水溶性化合物、水不溶性化合物以及任选的抗粘剂和/或增塑剂。
Description
技术领域
本发明涉及一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途，属于医药技术领域。
背景技术
本发明所述的达比加群酯活性物质的化学结构为3-[(2-{[4-(己氧羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1H-苯并咪唑-5-羰基)-吡啶-2-基-氨基]-丙酸乙酯，其化学结构如式I所示。该化合物可用于降低非瓣膜病心房颤动患者的中风和全身性栓塞风险、治疗已用胃肠外抗凝剂治疗5-10天的患者的深静脉血栓栓塞和肺栓塞、降低已接受过治疗的患者的深静脉血栓栓塞和肺栓塞的复发风险。
由于达比加群酯在pH＞4.0的介质中几乎不溶，故酸性环境有利于主要活性成分达比加群酯从药物制剂中溶出和体内吸收。专利公开号CN101632668 A公开了可采用医药上可接受的有机酸，如酒石酸、富马酸、琥珀酸、柠檬酸、苹果酸、谷氨酸或天冬氨酸作为达比加群酯溶解和溶出促进剂。该专利申请还公开了药物层与含酸的芯材料之间需要采用水溶性聚合物构成的隔离层进行隔离。该制剂要求所选酸的水溶性应至少大于1克/250ml水。
CN102793699A公开了一种包括维生素C和达比加群酯的组合物，相对于其它的有机酸，维生素C对人体的安全性更高，采用维生素C将提高药物的安全性。但由于维生素C在体内的代谢过程非常复杂，因此无论是将维生素C和达比加群酯简单混合，还是通过物理方式隔离，达比加群酯的溶出均不能达到预期的效果。
申请人意外地发现，通过采用半透膜层隔离的方式，解决了上述技术难题，并达到了预期的效果。
发明内容
作为本发明的第一方面，本发明提供了一种适于口服给药的达比加群酯药用组合物，其特征在于：所述组合物包含维生素C层和达比加群酯层，且在维生素C层与达比加群酯层之间通过半透膜层隔离。
作为本发明的第二方面，本发明还提供了一种制备适于口服给药的达比加群酯药用组合物的方法，所述方法包括：
(1)取颗粒维生素C置于流化床内，将包含粉末维生素C、水以及任选的粘合剂和/或填充剂的混悬液进行流化上药，筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯；
(2)将所述维生素C丸芯置于流化床内，将包含水溶性聚合物、水以及任选的分散剂和/或增塑剂的混悬液流化上药，制得具有水溶性聚合物层的颗粒1；
(3)将所述颗粒1置于流化床内，将包含水溶性化合物、水不溶性化合物、醇或醇溶液以及任选的抗粘剂和/或增塑剂的混悬液流化上药，筛选1mm以内的颗粒，作为具有半透膜层的颗粒2；
(4)将所述颗粒2置于流化床内，将包含达比加群酯或其可药用盐、醇以及任选的粘合剂和/或分散剂的混悬液流化上药，筛选1.5mm以内的颗粒作为具有达比加群酯层的颗粒3；以及
(5)任选地，对所述颗粒3包覆涂层。
作为本发明的第三方面，本发明还提供了包含上述达比加群酯药用组合物的固体制剂。
作为本发明的第四方面，本发明还涉及本发明的药用组合物在制备用于治疗血栓栓塞性疾病的药物中的用途。
附图说明
图1作为本发明优选实施方式之一的达比加群酯颗粒的断面示意图。
具体实施方式
作为本发明的第一方面，本发明提供了一种适于口服给药的达比加群酯药用组合物，其特征在于：所述组合物包含维生素C层和达比加群酯层，且在维生素C层与达比加群酯层之间通过半透膜层隔离。
本发明所述的半透膜层能够在溶出液中水化，产生孔道，使溶出液渗入酸性丸芯，酸性丸芯溶解并从孔道缓慢释放，产生酸性微环境，从而促进外层药物的溶出；且能够在溶出过程中包裹酸性丸芯，防止其与外层药物层的分离。
本发明的半透膜层优选包含水溶性化合物和水不溶性化合物。其中，水溶性化合物和水不溶性化合物通过醇或醇溶液进行溶解，所述醇或醇溶液优选异丙醇、无水乙醇或乙醇溶液。
所述水溶性化合物选自甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、邻苯二甲酸羟丙基甲基纤维素、果胶、环糊精、半乳甘露聚糖、平均分子量为4000以上的聚乙二醇、明胶、水溶性的单糖或多糖或上述两种以上的混合物；优选乳糖、蔗糖、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、PEG-6000、聚维酮或羧甲基纤维素钠；更进一步优选羟丙基纤维素或聚维酮。
所述水不溶性化合物选自乙基纤维素、HPMCAS、HPMCP、甲基丙烯酸共聚物或上述两种以上的混合物，其中，甲基丙烯酸共聚物包括但不限于Eudragit E、Eudragit R、Eudragit S、Eudragit L、Eudragit RS或Eudragit LD；优选乙基纤维素、HPMCAS、EudragitS100、Eudragit L100或HPMCP；进一步优选乙基纤维素。
所述半透膜层中，水溶性化合物与水不溶性化合物的质量比为1∶0.1～1∶10；优选1∶0.2～1∶5；进一步优选1∶0.5～1∶1。
所述半透膜层还可以进一步包含抗粘剂和/或增塑剂。所述抗粘剂可以选自滑石粉、硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯或上述两种以上的混合物；优选滑石粉。所述增塑剂可以选自柠檬酸三乙酯、柠檬酸三丁酯、甘油三乙酸酯、聚乙二醇或上述两种以上的混合物；优选聚乙二醇。
所述维生素C层可以仅包含维生素C，也可以进一步包括粘合剂和/或填充剂。所述维生素C可以是颗粒维生素C、粉末维生素C或者两者的组合。所述粘合剂可以选自羟丙基纤维素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素、果胶、阿拉伯胶或上述两种以上的混合物；优选羟丙基纤维素、羟丙基甲基纤维素、聚维酮或阿拉伯胶；进一步优选羟丙基纤维素或阿拉伯胶。所述填充剂可以选自微晶纤维素、乳糖、淀粉、甘露醇、预胶化淀粉、糊精或上述两种以上的混合物；优选微晶纤维素。
所述达比加群酯层可以仅包含达比加群酯，还可以进一步包括粘合剂和/或分散剂。所述粘合剂可以选自羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羟乙基纤维素、羧甲基纤维素钠、聚维酮、N-乙烯吡咯烷酮、阿拉伯胶或上述两种以上的混合物；优选羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚维酮或阿拉伯胶；进一步优选羟丙基纤维素或羧甲基纤维素钠；所述粘合剂优选通过醇、优选异丙醇进行溶解；上述分散剂可以是抗粘剂，例如滑石粉、硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯或上述两种以上的混合物；优选滑石粉。
上述半透膜层相对于维生素C层增重为0.5wt％～20wt％；优选地，上述半透膜层相对于维生素C层增重为2wt％～10wt％；进一步优选地，上述半透膜层相对于维生素C层增重为5wt％～10wt％。
上述达比加群酯层和维生素C层的重量比1∶0.15～1∶1.8，优选1∶0.6～1∶1.1。
在某些特定的实施例中，在维生素C与达比加群酯层之间，除了包括上述半透膜层之外，还可以进一步包括水溶性聚合物层；所述水溶性聚合物可以选自羟丙基纤维素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素、果胶、阿拉伯胶或上述两种以上的混合物；优选羟丙基纤维素、羧甲基纤维素钠、聚维酮或阿拉伯胶；进一步优选羟丙基纤维素或阿拉伯胶。在某些特定的实施例中，所述水溶性聚合物为阿拉伯胶。
上述水溶性聚合物层还可以进一步包括分散剂和/或增塑剂。所述分散剂可以是抗粘剂，例如滑石粉、硬脂酸镁、硬脂酸、氢化植物油、山嵛酸甘油酯或上述两种以上的混合物，优选滑石粉。所述增塑剂可以选自柠檬酸三乙酯，柠檬酸三丁酯，甘油三乙酸酯、聚乙二醇或上述两种以上的混合物；优选聚乙二醇。
上述水溶性聚合物层增重与半透膜层增重比值为1∶0.1～1∶10；优选比值为1∶0.2～1∶5；进一步优选比值为1∶1～1∶1.1。
本发明的药用组合物包括但不限于颗粒剂、片剂、丸剂、微丸；所述颗粒剂、片剂、丸剂或微丸可以是多层结构；所述多层结构中，维生素C层和达比加群酯层的相对位置可以任意调换，例如维生素C层位于较内层、达比加群酯层隔着半透膜层或者隔着水溶性聚合物层和半透膜层位于较外层；或者达比加群酯层位于较内层、维生素C层隔着半透膜层或者隔着水溶性聚合物层和半透膜层位于较外层。在此情况下，所述维生素C层或达比加群酯层还可以包衣形式包覆于所述隔离层(即，半透膜层、或者水溶性聚合物层和半透膜层)外。
本发明一个优选实施方式为多粒状制剂，其中各个颗粒是如图1的结构。该颗粒的大致球状或球状的酸芯中包含维生素C；接着，有一层由水溶性聚合物层和半透膜层构成的隔离层，用于隔离维生素C酸芯与达比加群酯层；接着，该隔离层再被达比加群酯的相同球形层包围；任选地，该达比加群酯层可进一步被涂层包围。
上述涂层可以包含药物上常用的成膜剂和/或增塑剂和/或色素。所述的成膜剂可以是羟丙基纤维素、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素或上述两种以上的混合物。所述增塑剂可以是柠檬酸三乙酯，柠檬酸三丁酯，甘油三乙酸酯、聚乙二醇或上述两种以上的混合物。所述色素可以是二氧化钛、氧化铁黄、氧化铁红或上述两种以上的混合物。
作为本发明的第二方面，本发明还提供了一种制备适于口服给药的达比加群酯药用组合物的方法，所述方法包括如下步骤：
(1)取颗粒维生素C置于流化床内，将包含粉末维生素C、水以及任选的粘合剂和/或填充剂的混悬液进行流化上药，筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯；
(2)将所述维生素C丸芯置于流化床内，将包含水溶性聚合物、水以及任选的分散剂和/或增塑剂的混悬液流化上药，制得具有水溶性聚合物层的颗粒1；
(3)将所述颗粒1置于流化床内，将包含水溶性化合物、水不溶性化合物、醇或醇溶液以及任选的抗粘剂和/或增塑剂的混悬液流化上药，筛选1mm以内的颗粒，作为具有半透膜层的颗粒2；
(4)将所述颗粒2置于流化床内，将包含达比加群酯或其可药用盐、醇以及任选的粘合剂和/或分散剂的混悬液流化上药，筛选1.5mm以内的颗粒作为具有达比加群酯层的颗粒3；以及
(5)任选地，对所述颗粒3包覆涂层。
作为一种优选的实施方式，所述方法包括如下步骤：
取颗粒维生素C，置于流化床内，将包含阿拉伯胶、粉末维生素C和水的混悬液进行流化上药，筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯；
将维生素C丸芯置于流化床内，将包含阿拉伯胶、滑石粉和水的混悬液流化上药，制得具有水溶性聚合物层的颗粒1；
取羟丙基纤维素和乙基纤维素，加异丙醇搅拌溶解，再加入滑石粉，搅拌使充分混悬，得到混悬液；
将颗粒1置于流化床内，将包含羟丙基纤维素、乙基纤维素和滑石粉的混悬液流化上药，筛选1mm以内的颗粒作为进一步具有半透膜层的颗粒2；
将颗粒2置于流化床内，将包含羟丙基纤维素、滑石粉、达比加群酯和异丙醇的混悬液流化上药，筛选1.5mm以内的颗粒作为进一步具有达比加群酯层的颗粒3。
上述颗粒维生素C的制备方法包括但不限于流化床、包衣槽或挤出滚圆设备；上述颗粒3可进一步包覆涂层，所述涂层包覆方法包括但不限于流化床、包衣槽或常用的涂膜装置。
作为本发明的第三方面，本发明还提供了包含上述达比加群酯药用组合物的固体制剂，所述的固体制剂形式可以是颗粒剂、片剂或胶囊；在某些特定的实施例中，所述的固体制剂呈胶囊形式。
作为本发明的第四方面，本发明还涉及本发明的药用组合物在制备用于治疗血栓栓塞性疾病的药物中的用途。
本发明中，除特别说明外，达比加群酯是指式I所示的达比加群酯及其可药用盐；所述的可药用盐包括但不限于甲磺酸达比加群酯。
本发明中，流化上药是指用流化床将混悬液涂敷于固体颗粒表面的方法。
本发明中，HPMCP是指羟丙甲基纤维素邻苯二甲酸酯。
本发明中，HPMCAS是指醋酸羟丙基甲基纤维素琥珀酸酯。
本发明中，除特别说明外，所述半透膜层指在溶出介质中具有一定的强度且能够产生孔道的包衣层。
发明人在对维生素C层、隔离层和达比加群酯层的大量深入研究中，发现采用半透膜层隔离维生素C层和达比加群酯层，能够为达比加群酯的溶出提供良好的酸性微环境，显著改善达比加群酯的体外溶出。
实施例
以下以具体的实施例说明本发明的技术方案，但本发明的保护范围不限于所述实施例的范围。所采用的试剂均为市售产品。实施例中，除非特殊说明，“％”是指重量百分含量。
比较实施例1
处方：
制备方法：
1.1)取处方量阿拉伯胶a，加水57ml搅拌溶解，再加入处方量粉末维生素C，搅拌使充分混悬，得到混悬液；
1.2)取处方量颗粒维生素C，置于流化床内，将步骤1.1)制备得到的混悬液进行流化上药；工艺参数：雾化压力为1500mbar～1700mbar，进风温度在60℃～70℃之间，物料温度保持在40℃～50℃之间；
1.3)上药结束后筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯，水分应≤0.7％；
2.1)取处方量阿拉伯胶b，加水搅拌溶解，再加入处方量滑石粉a，搅拌使充分混悬，得到混悬液；
2.2)取处方量步骤1.3)制备得的维生素C丸芯(维生素C芯材料中粉末维生素C、颗粒维生素C和阿拉伯胶a的处方量之和)，置于流化床内，将步骤2.1)制备得的混悬液流化上药；工艺参数：雾化压力为1300mbar～1500mbar，进风温度在50℃～60℃之间，物料温度保持在35℃～45℃之间，制得具有水溶性聚合物层的颗料1；
3.1)取处方量羟丙基纤维素，加异丙醇搅拌溶解，再加入处方量滑石粉b，搅拌使充分混悬，将得到的混悬液降温，使温度低于5℃；
3.2)取处方量甲磺酸达比加群酯，搅拌下加入步骤3.1)制备得的混悬液中，搅拌使均匀分散；
3.3)取上述步骤2.2)制备得的颗粒1，置于流化床内，将步骤3.2)制备得的混悬液流化上药；工艺参数：雾化压力为1800mbar～2200mbar；进风温度在35℃～55℃之间，物料温度保持在28℃～40℃；颗粒干燥失重应≤0.7％；
3.4)上药结束后筛选1.5mm以内的颗粒。
比较实施例2
处方：
制备方法：
参照比较实施例1的制备方法，先用粉末维生素C、颗粒维生素C和阿拉伯胶a制备维生素C丸芯，再将包含阿拉伯胶b和滑石粉a的混悬液流化上药，然后将包含羟丙基纤维素a和滑石粉b的混悬液流化上药，最后再将包含达比加群酯、羟丙基纤维素b和滑石粉c的混悬液流化上药，并筛选制得的颗粒。
比较实施例3达比加群酯胶囊的制备
取比较实施例1中微丸287.01mg，灌装入1号植物空心胶囊内，得110mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
比较实施例4达比加群酯胶囊的制备
取比较实施例1中微丸195.68mg，灌装入2号植物空心胶囊内，得75mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
比较实施例5达比加群酯胶囊的制备
取比较实施例2中微丸291.71mg，灌装入2号植物空心胶囊内，得110mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
实施例1
处方：
制备方法：
1.1)取阿拉伯胶a，加水57ml搅拌溶解，再加入处方量粉末维生素C，搅拌使充分混悬，得到混悬液；
1.2)取处方量颗粒维生素C，置于流化床内，将步骤1.1)制备得的混悬液进行流化上药；工艺参数：雾化压力为1500mbar～1700mbar，进风温度在60℃～70℃之间，物料温度保持在40℃～50℃之间；
1.3)上药结束后筛出粒径在0.6mm～0.8mm之间的颗粒作为维生素C丸芯，水分应≤0.7％。
2.1)取处方量阿拉伯胶b，加水搅拌溶解，再加入处方量滑石粉a，搅拌使充分混悬，得到混悬液；
2.2)取处方量的步骤1.3)制备得的维生素C丸芯(维生素C芯材料中粉末维生素C、颗粒维生素C和阿拉伯胶a的处方量之和)，置于流化床内，将步骤2.1)制备得的混悬液流化上药；工艺参数：雾化压力为1300mbar～1500mbar，进风温度在50℃～60℃之间，物料温度保持在35℃～45℃之间，制得具有水溶性聚合物层的颗粒1；
3.1)取处方量羟丙基纤维素a和乙基纤维素，加异丙醇搅拌溶解，再加入处方量滑石粉b，搅拌使充分混悬，得到混悬液；
3.2)取步骤2.2)制得的颗粒1，置于流化床内，将步骤3.1)制备得的混悬液流化上药。工艺参数：雾化压力为1800mbar～2000mbar，进风温度在50℃～60℃之间，物料温度保持在35℃～50℃之间；
3.3)上药结束后筛选1mm以内的颗粒作为具有半透膜层的颗粒2；
4.1)取处方量羟丙基纤维素b，加异丙醇搅拌溶解，再加入处方量滑石粉c，搅拌使充分混悬，将混悬液降温，使温度低于5℃；
4.2)取处方量甲磺酸达比加群酯，搅拌下加入步骤4.1)制备得的混悬液中，搅拌使均匀分散；
4.3)取步骤3.3)制备得的颗粒2，置于流化床内，将步骤4.2)制备得的混悬液流化上药；工艺参数：雾化压力为1800mbar～2200mbar，进风温度在35℃～55℃之间，物料温度保持在28℃～40℃，颗粒干燥失重应≤0.7％；
4.4)上药结束后筛选1.5mm以内的颗粒。
参照实施例1的制备方法制备实施例2～7的处方颗粒。
实施例2
处方：
制备方法：
参照实施例1的制备方法，先用粉末维生素C、颗粒维生素C和羟丙基甲基纤维素a制备维生素C丸芯；再将包含羟丙基甲基纤维素b和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含乳糖和HPMCAS的包衣液流化上药(分散介质为80％乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、羟丙基甲基纤维素c和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例3
处方：
制备方法：
参照实施例1的制备方法，筛分出粒径在0.6mm～0.8mm的颗粒维生素C作为维生素C丸芯；再将包含聚维酮(K30)a和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含蔗糖(d50≤5μm，d90≤15μm)和Eugragit S100的混悬液流化上药(分散介质为无水乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、聚维酮(K30)b和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例4
处方：
制备方法：
参照实施例1的制备方法，筛分出粒径在0.6mm～0.8mm的颗粒维生素C作为维生素C丸芯；再将包含羧甲基纤维素钠a和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含羟丙基纤维素和Eugragit L100的混悬液流化上药(分散介质为无水乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、羧甲基纤维素钠b和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例5
处方：
制备方法：
参照实施例1的制备方法，先用粉末维生素C、颗粒维生素C和阿拉伯胶a制备维生素C丸芯；再将包含甲基纤维素a和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含甲基纤维素b和羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)的包衣液流化上药(分散介质为80％乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、阿拉伯胶b和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例6
处方：
制备方法：
参照实施例1的制备方法，筛分出粒径在0.6mm～0.8mm的颗粒维生素C作为维生素C丸芯；再将包含羧甲基纤维素钠a、滑石粉a和聚乙二醇-6000a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将聚乙二醇-6000b和乙基纤维素的混悬液流化上药(分散介质为无水乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、羧甲基纤维素钠b和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例7
处方：
制备方法：
参照实施例1的制备方法，先用粉末维生素C、颗粒维生素C和阿拉伯胶制备维生素C丸芯；再将包含羧甲基纤维素钠a和滑石粉a的混悬液流化上药(分散介质为水)，获得具有水溶性聚合物层的颗粒；然后将包含羧甲基纤维素钠b和乙基纤维素的包衣液流化上药(分散介质为无水乙醇溶液)，获得具有半透膜层的颗粒；最后再将包含达比加群酯、羧甲基纤维素钠c和滑石粉b的混悬液流化上药，筛选，制得具有达比加群酯层的颗粒。
实施例8 达比加群酯胶囊的制备
取实施例2中微丸291.71mg，灌装入1号植物空心胶囊内，得110mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
实施例9 达比加群酯胶囊的制备
取实施例2中微丸198.88mg，灌装入1号植物空心胶囊内，得75mg(以C34H41N7O5计)规格甲磺酸达比加群酯胶囊。
实施例10 达比加群酯胶囊体外溶出特性比较
分别取比较实施例3、比较实施例4、比较实施例5、实施例8、实施例9和市售参比制剂，照溶出度测定法(中国药典2010年版二部附录X C第一法)，加溶出介质900ml，转速为每分钟100转，依法操作，分别于10、20、30、45、60分钟时取样测定溶出度。
结果如表1、2所示：
表1 溶出特性比较(规格：110mg(以C34H41N7O5计))
表2 溶出特性比较(规格：75mg(以C34H41N7O5计))
Claims (16)
1.一种适于口服给药的达比加群酯药用组合物，其特征在于：所述组合物包含维生素C层丸芯和达比加群酯层，且维生素C层丸芯和达比加群酯层之间依次通过水溶性聚合物层和半透膜层隔离；所述半透膜层包含水溶性化合物、水不溶性化合物以及抗粘剂和/或增塑剂；
所述水溶性聚合物选自阿拉伯胶；
所述水溶性化合物选自羟丙基纤维素；
所述水不溶性化合物选自乙基纤维素。
2.如权利要求1所述的药用组合物，其特征在于，所述半透膜层中的水溶性化合物与所述水不溶性化合物的质量比为1:0.1～1:10。
3.如权利要求2所述的药用组合物，其特征在于，所述半透膜中的水溶性化合物与所述水不溶性化合物的质量比为1:0.2～1:5。
4.如权利要求3所述的药用组合物，其特征在于，所述半透膜中的水溶性化合物与所述水不溶性化合物的质量比为1:0.5～1:1。
5.如权利要求1所述的药用组合物，其特征在于，所述半透膜层相对于所述维生素C层增重为0.5wt％～20wt％。
6.如权利要求5所述的药用组合物，其特征在于，所述半透膜层相对于所述维生素C层增重为2wt％～10wt％。
7.如权利要求6所述的药用组合物，其特征在于，所述半透膜层相对于所述维生素C层增重为5wt％～10wt％。
8.如权利要求1所述的药用组合物，其特征在于，所述达比加群酯层和所述维生素C层的重量比为1:0.15～1:1.8。
9.如权利要求8所述的药用组合物，其特征在于，所述达比加群酯层和所述维生素C层的重量比为1:0.6～1:1.1。
10.如权利要求1所述的药用组合物，其特征在于，所述水溶性聚合物层增重与所述半透膜层增重比值为1:0.1～1:10。
11.如权利要求10所述的药用组合物，其特征在于，所述水溶性聚合物层增重与所述半透膜层增重比值为1:0.2～1:5。
12.如权利要求11所述的药用组合物，其特征在于，所述水溶性聚合物层增重与所述半透膜层增重比值为1:1～1:1.1。
13.如权利要求1所述的药用组合物，其特征在于，所述药用组合物为多粒状制剂，其中，各个颗粒的球状或球状的酸芯中包含所述维生素C；接着，有一层依次由所述水溶性聚合物层和所述半透膜层构成的隔离层，用于隔离所述维生素C酸芯与所述达比加群酯层；接着，所述隔离层再被达比加群酯的相同球形层包围；任选地，所述达比加群酯层进一步被涂层包围。
14.一种包含权利要求1～13任一项所述的药用组合物的固体制剂，其特征在于，所述固体制剂形式是片剂、颗粒剂或胶囊。
15.权利要求14所述的固体制剂，其特征在于，所述固体制剂呈胶囊形式。
16.权利要求1～13任一项所述的药用组合物在制备用于治疗血栓栓塞性疾病的药物中的用途。
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| CN2014106507861 | 2014-11-14 | ||
| CN201410650786.1A CN105640909B (zh) | 2014-11-14 | 2014-11-14 | 一种含有达比加群酯的药用组合物 |
| PCT/CN2015/094499 WO2016074640A1 (zh) | 2014-11-14 | 2015-11-13 | 一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途 |
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| CN201580060552.4A Active CN107072956B (zh) | 2014-11-14 | 2015-11-13 | 一种含有达比加群酯的药用组合物、其制备方法、固体制剂和用途 |
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| EP3771465A1 (en) * | 2019-08-01 | 2021-02-03 | Zaklady Farmaceutyczne Polpharma SA | Pharmaceutical composition comprising dabigatran etexilate |
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- 2015-11-13 CN CN201580060552.4A patent/CN107072956B/zh active Active
- 2015-11-13 WO PCT/CN2015/094499 patent/WO2016074640A1/zh active Application Filing
- 2015-11-13 US US15/525,860 patent/US10881615B2/en active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| CN105640909A (zh) | 2016-06-08 |
| WO2016074640A1 (zh) | 2016-05-19 |
| CN105640909B (zh) | 2019-09-20 |
| EP3219311A4 (en) | 2018-07-11 |
| EP3219311A1 (en) | 2017-09-20 |
| US10881615B2 (en) | 2021-01-05 |
| CN107072956A (zh) | 2017-08-18 |
| US20170333350A1 (en) | 2017-11-23 |
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