CN113577067B - 一种甲磺酸达比加群酯药物制剂 - Google Patents
一种甲磺酸达比加群酯药物制剂 Download PDFInfo
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- CN113577067B CN113577067B CN202110617172.3A CN202110617172A CN113577067B CN 113577067 B CN113577067 B CN 113577067B CN 202110617172 A CN202110617172 A CN 202110617172A CN 113577067 B CN113577067 B CN 113577067B
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- Prior art keywords
- dabigatran etexilate
- etexilate mesylate
- compound
- organic acid
- mesylate
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Classifications
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
本发明涉及一种甲磺酸达比加群酯药物制剂，该药物制剂具体包括甲磺酸达比加群酯包衣复合物和有机酸或甲磺酸达比加群酯复合物和含有有机酸包衣颗粒，其中复合物中包含甲磺酸达比加群酯、水溶性稀释剂和胶类材料，胶类材料为黄原胶、瓜尔胶、槐豆胶和角叉菜胶中的一种或几种。本发明制得的甲磺酸达比加群酯药物制剂同时具有较好的溶出度和稳定性，且制备方法简单，易操作，适合工业化大规模生产。
Description
技术领域
本发明涉及一种直接凝血酶抑制剂的药物制剂，具体的为甲磺酸达比加群酯药物制剂，以及该制剂的制备方法。
背景技术
心房颤动(房颤)是临床上最常见的心律失常疾病，调查显示，目前我国房颤患病率高达0.77％，且患病率呈现随年龄增长显著增高的趋势。随着我国人口老龄化问题的日益突出，房颤患病率将持续增长。心源性卒中(主要是缺血性脑卒中)是房颤最为严重的并发症，其致死和致残率均较高，因此预防卒中对房颤患者十分重要。预防卒中的基础是抗凝治疗，华法林是临床证据最充分、使用最普遍的口服抗凝药物，但其存在治疗窗窄、剂量个体差异大、干扰因素多、需频繁监测凝血指标(INR)等缺陷，因此临床上亟需疗效可靠、安全性优的新型口服抗凝药物。
达比加群酯是一种新型直接凝血酶抑制剂，作为口服抗凝药使用，具有可口服、强效、无需特殊用药监测、药物相互作用少等特点。达比加群酯由德国勃林格殷格翰公司开发，于 2008年4月首次在英国上市。用于全膝关节或全髋关节置换术后静脉血栓形成的预防，口服为达比加群酯的主要给药途径，其经胃肠吸收后，在体内转化为具有直接抗凝血活性的达比加群。达比加群结合于凝血酶的纤维蛋白特异结合位点，阻止纤维蛋白原裂解纤维蛋白，从而阻断了凝血瀑布网络的最后步骤及血栓形成。
达比加群酯溶解性差，为了增加其溶解性，故以盐的形式开发成制剂在临床上使用(如甲磺酸盐)。甲磺酸达比加群酯化学名称为N-[2-[4-[N-(己氧羰基)脒基]苯氨基甲基]-1- 甲基-1H苯并咪唑-5-基羰基]-N-(2-吡啶基)-β-丙氨酸乙酯甲磺酸盐，结构式如下：
甲磺酸达比加群酯分子结构中含两个弱碱性中心，pKa值4.0±0.1(苯并咪唑基团)和6.7 ±0.1(氨基甲酸己酯基团)。甲磺酸达比加群酯的溶解性具有强烈的pH依耐性，在pH小于3时，其溶解性较好，在pH大于3的溶液中，其溶解度迅速降低，在中性及碱性条件下几乎不溶解。甲磺酸达比加群酯分子结构中有多个酯健或酰胺键，对水分和温度较为敏感，在酸性条件下其水解加快，故甲磺酸达比加群酯的稳定性差，现有技术中针对其稳定性和溶解性的研究很多，但仍存在诸多问题待解决。
专利CN101632668A公开了一种达比加群酯的口服药物组合物，其制备方法是在有机酸丸芯表面包隔离层和药物层，达到有机酸与活性药物的物理学分离。该工艺采用丸芯上药法，将活性药物悬浮液包覆于有机酸丸芯上。该方法需要多层包衣，制备方法复杂，同时上药过程中会存在上药层不均匀，批间重现性差，原料药损失较大，成品收率低等问题。
专利CN108261409A公开了一种达比加群酯的口服药物组合物及其制备方法，该专利中将有机酸晶体利用空心胶囊I隔离，然后与含药颗粒按比例混合均匀后填充至空心胶囊II中。该专利中含药颗粒与有机酸晶体是以独立个体填充于胶囊中，进入体内后可能会分离较远，影响药物的溶出。
现有技术为了提高甲磺酸达比加群酯的溶解速率，在制剂中加入了另一种有机酸为甲磺酸达比加群酯溶解提供低pH的酸性环境，且将甲磺酸达比加群酯和有机酸制备在同一颗粒或微丸上。但甲磺酸达比加群酯在酸性环境中不稳定，如果在酸性环境中遇到水分，其稳定性更差。因此，如何在保证甲磺酸达比加群酯具有良好的稳定性的前提下还能达到优异的溶出效果，是现有甲磺酸达比加群酯制剂需进一步改进的问题。
发明内容
本发明提供一种甲磺酸达比加群酯药物制剂，旨在克服甲磺酸达比加群酯的溶出和稳定性。本发明制得的甲磺酸达比加群酯药物制剂同时具有较好的溶出度和稳定性，且制备方法简单，易操作，适合工业化大规模生产。该药物制剂具体包括甲磺酸达比加群酯包衣复合物和有机酸或甲磺酸达比加群酯复合物和含有有机酸包衣颗粒，其中复合物中包含甲磺酸达比加群酯、水溶性稀释剂和胶类材料，胶类材料为黄原胶、瓜尔胶、槐豆胶和角叉菜胶中的一种或几种。
甲磺酸达比加群酯的溶解性具有高度的pH依赖性，在酸性环境中溶解度大大提高，但甲磺酸达比加群酯在酸性溶液中不稳定，本发明针对甲磺酸达比加群酯这一特殊的性质，进行大量研究开发出一种既能保证甲磺酸达比加群酯稳定又能实现具有较好溶出效果的药物制剂。本发明将甲磺酸达比加群酯与水溶性稀释剂和胶类材料制成复合物，复合物可以显著提高甲磺酸达比加群酯的溶出，再加入少量的有机酸进一步提高甲磺酸达比加群酯的溶出，即可实现较好的溶出效果，同时为了保证甲磺酸达比加群酯的稳定，本发明采用包衣手段将甲磺酸达比加群酯复合物与有机酸隔离，避免有机酸与甲磺酸达比加群酯的接触。
具体的，本发明提供一种甲磺酸达比加群酯药物制剂，所述药物制剂包含：
a)甲磺酸达比加群酯包衣复合物，该复合物包含甲磺酸达比加群酯、水溶性稀释剂和胶类材料，复合物表面包被隔离层；
b)有机酸；
其中，胶类材料为黄原胶、瓜尔胶、槐豆胶和角叉菜胶中的一种或几种。
本发明还提供另一种甲磺酸达比加群酯药物制剂的技术方案，所述药物制剂包含：
a)甲磺酸达比加群酯复合物，该复合物包含甲磺酸达比加群酯、水溶性稀释剂和胶类材料；
b)含有有机酸包衣颗粒；
其中，胶类材料为黄原胶、瓜尔胶、槐豆胶和角叉菜胶中的一种或几种。
为了实现更好的溶出效果，本发明中甲磺酸达比加群酯包衣复合物或甲磺酸达比加群酯复合物的粒径d0.9为250-800μm。
在一些实施例中，为了获得更好的溶出效果，甲磺酸达比加群酯复合物或甲磺酸达比加群酯包衣复合物中，胶类材料为黄原胶和瓜尔胶的组合。进一步的，所述黄原胶和瓜尔胶的质量用量比为1:0.5-2。
上述水溶性稀释剂为蔗糖、乳糖、甘露醇和山梨醇中的一种或几种。
上述甲磺酸达比加群酯、水溶性稀释剂和胶类材料的质量用量比为75-150:50-120:10-40，其中甲磺酸达比加群酯用量以达比加群酯计。
在一些实施例中，甲磺酸达比加群酯包衣复合物或甲磺酸达比加群酯复合物还包含表面活性剂。所述表面活性剂为十二烷基硫酸钠、卵磷脂、吐温80和聚氧乙烯40氢化蓖麻油中的一种或几种。
上述有机酸选自酒石酸、富马酸、柠檬酸、琥珀酸、苹果酸、谷氨酸或天冬氨酸。更进一步的，为了保证活性成分的稳定性，本发明可以加入少量的有机酸也能实现更好的溶出效果，其中，甲磺酸达比加群酯与有机酸的质量用量比为1：0.3-0.8，优选的为1：0.3-0.65，进一步优选的为1:0.3-0.5，甲磺酸达比加群酯用量以达比加群酯计。
上述含有有机酸包衣颗粒的粒径d0.9为250-800μm。上述含有有机酸包衣颗粒包含有机酸和粘合剂。所述粘合剂为羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和聚维酮中的一种或几种。
本发明还提供上述甲磺酸达比加群酯药物制剂的制备方法，包括如下步骤：
(1)将甲磺酸达比加群酯、水溶性稀释剂和胶类材料分散到溶剂中，喷雾干燥制得甲磺酸达比加群酯复合物，在甲磺酸达比加群酯复合物表面包隔离层，得甲磺酸达比加群酯包衣复合物；
(2)将甲磺酸达比加群酯包衣复合物与有机酸混合，填充到胶囊。
在一些实施例中，本发明还提供另一种制备甲磺酸达比加群酯药物制剂的制备方法，包括如下步骤：
(1)将甲磺酸达比加群酯、水溶性稀释剂和胶类材料分散到溶剂中，喷雾干燥制得甲磺酸达比加群酯复合物；
(2)将粘合剂配制成粘合剂溶液，将粘合剂溶液加入到有机酸中，制粒，干燥，包衣，得含有有机酸包衣颗粒；
(3)将甲磺酸达比加群酯复合物和含有有机酸包衣颗粒混合，填充到胶囊。
上述溶剂为水、乙醇、丙酮、异丙醇、二氯甲烷和甲醇中的一种或几种。
本发明中涉及的隔离层或是对有机酸进行包衣形成包衣颗粒所用的包衣材料为本领域中常用的可实现将甲磺酸达比加群酯与有机酸隔离的材料，如羟丙基纤维素、羟丙甲纤维素、阿拉伯胶、丙烯酸树脂、欧巴代等薄膜包衣材料。
与现有技术相比，本发明的有益效果为：
1.甲磺酸达比加群酯具有pH依赖性，在酸性环境中溶解性好，本发明为了减少有机酸的使用，将甲磺酸达比加群酯与水溶性稀释剂和胶类材料制成复合物，并且对胶类材料进行研究，选择胶类材料为黄原胶、瓜尔胶、槐豆胶和角叉菜胶中的一种或几种，从而提高甲磺酸达比加群酯的溶出。
2.本发明为了实现更好的溶出效果，采用黄原胶和瓜尔胶为胶类材料配合水溶性稀释剂制成复合物，更进一步的，所用黄原胶和瓜尔胶的质量用量比为1:0.5-2时，溶出效果更优。
3.本发明通过控制酸的用量来增加甲磺酸达比加群酯的稳定性，甲磺酸达比加群酯与有机酸的质量用量比为1：0.3-0.8。
4.本发明通过将甲磺酸达比加群酯与水溶性稀释剂和胶类材料制成复合物，并对甲磺酸达比加群酯和有机酸进行包衣隔离，可以使得到的甲磺酸达比加群酯制剂同时具有良好的溶出和稳定性，保证药物的疗效。
具体实施方式
实施例1
制备方法：
(1)将甲磺酸达比加群酯、乳糖、黄原胶和瓜尔胶分散到水中，喷雾干燥制得甲磺酸达比加群酯复合物，在甲磺酸达比加群酯复合物表面包隔离衣，得甲磺酸达比加群酯包衣复合物，甲磺酸达比加群酯包衣复合物粒径d0.9为300μm；
(2)将甲磺酸达比加群酯包衣复合物与酒石酸混合，填充到胶囊。
实施例2
制备方法：
(1)将甲磺酸达比加群酯、甘露醇、黄原胶和瓜尔胶分散到30％乙醇水溶液中，喷雾干燥制得甲磺酸达比加群酯复合物，在甲磺酸达比加群酯复合物表面包隔离衣，得甲磺酸达比加群酯包衣复合物，甲磺酸达比加群酯包衣复合物粒径d0.9为250μm；
(2)将甲磺酸达比加群酯包衣复合物与富马酸混合，填充到胶囊。
实施例3
制备方法：
(1)将甲磺酸达比加群酯、乳糖、蔗糖、黄原胶、瓜尔胶和十二烷基硫酸钠分散到二氯甲烷中，喷雾干燥制得甲磺酸达比加群酯复合物，在甲磺酸达比加群酯复合物表面包隔离衣，得甲磺酸达比加群酯包衣复合物，甲磺酸达比加群酯包衣复合物粒径d0.9为460μm；
(2)将甲磺酸达比加群酯包衣复合物与琥珀酸混合，填充到胶囊。
实施例4
制备方法：
(1)将甲磺酸达比加群酯、甘露醇、黄原胶和瓜尔胶分散到30％乙醇水溶液中，喷雾干燥制得甲磺酸达比加群酯复合物，在甲磺酸达比加群酯复合物表面包隔离衣，得甲磺酸达比加群酯包衣复合物，甲磺酸达比加群酯包衣复合物粒径d0.9为250μm；
(2)将甲磺酸达比加群酯包衣复合物与富马酸混合，填充到胶囊。
实施例5
制备方法：
(1)将甲磺酸达比加群酯、乳糖、山梨醇、槐豆胶、角叉菜胶和吐温80分散到水中，喷雾干燥制得甲磺酸达比加群酯复合物，在甲磺酸达比加群酯复合物表面包隔离衣，得甲磺酸达比加群酯包衣复合物，甲磺酸达比加群酯包衣复合物粒径d0.9为800μm；
(2)将甲磺酸达比加群酯包衣复合物与苹果酸混合，填充到胶囊。
实施例6
制备方法：
(1)将甲磺酸达比加群酯、甘露醇和黄原胶分散到异丙醇中，喷雾干燥制得甲磺酸达比加群酯复合物，在甲磺酸达比加群酯复合物表面包隔离衣，得甲磺酸达比加群酯包衣复合物，甲磺酸达比加群酯包衣复合物粒径d0.9为540μm；
(2)将甲磺酸达比加群酯包衣复合物与柠檬酸混合，填充到胶囊。
实施例7
制备方法：
(1)将甲磺酸达比加群酯、乳糖、黄原胶和瓜尔胶分散到丙酮中，喷雾干燥制得甲磺酸达比加群酯复合物，甲磺酸达比加群酯复合物粒径d0.9为280μm；
(2)将羟丙基纤维素配制成羟丙基纤维素溶液，将羟丙基纤维素溶液加入到酒石酸中，制粒，干燥，包衣，得含有有机酸包衣颗粒，含有有机酸包衣颗粒的d0.9为360μm；
(3)将甲磺酸达比加群酯复合物和含有有机酸包衣颗粒混合，填充到胶囊。
实施例8
制备方法：
(1)将甲磺酸达比加群酯、甘露醇、黄原胶和瓜尔胶分散到25％乙醇水溶液中，喷雾干燥制得甲磺酸达比加群酯复合物，甲磺酸达比加群酯复合物粒径d0.9为350μm；
(2)将羟丙基甲基纤维素配制成羟丙基甲基纤维素溶液，将羟丙基甲基纤维素溶液加入到谷氨酸中，制粒，干燥，包衣，得含有有机酸包衣颗粒，含有有机酸包衣颗粒的d0.9为480μ m；
(3)将甲磺酸达比加群酯复合物和含有有机酸包衣颗粒混合，填充到胶囊。
实施例9
制备方法：
(1)将甲磺酸达比加群酯、蔗糖、山梨醇、黄原胶、瓜尔胶和聚氧乙烯40氢化蓖麻油分散到甲醇中，喷雾干燥制得甲磺酸达比加群酯复合物，甲磺酸达比加群酯复合物粒径d0.9为 250μm；
(2)将羧甲基纤维素钠配制成羧甲基纤维素钠溶液，将羧甲基纤维素钠溶液加入到天冬氨酸中，制粒，干燥，包衣，得含有有机酸包衣颗粒，含有有机酸包衣颗粒的d0.9为250μm；
(3)将甲磺酸达比加群酯复合物和含有有机酸包衣颗粒混合，填充到胶囊。
实施例10
制备方法：
(1)将甲磺酸达比加群酯、乳糖、黄原胶和瓜尔胶分散到丙酮中，喷雾干燥制得甲磺酸达比加群酯复合物，甲磺酸达比加群酯复合物粒径d0.9为280μm；
(2)将羟丙基纤维素配制成羟丙基纤维素溶液，将羟丙基纤维素溶液加入到酒石酸中，制粒，干燥，包衣，得含有有机酸包衣颗粒，含有有机酸包衣颗粒的d0.9为360μm；
(3)将甲磺酸达比加群酯复合物和含有有机酸包衣颗粒混合，填充到胶囊。
实施例11
制备方法：
(1)将甲磺酸达比加群酯、乳糖、山梨醇、黄原胶、角叉菜胶、卵磷脂和吐温80分散到水中，喷雾干燥制得甲磺酸达比加群酯复合物，甲磺酸达比加群酯复合物粒径d0.9为800μm；
(2)将羟丙基纤维素配制成羟丙基纤维素溶液，将羟丙基纤维素溶液加入到酒石酸和富马酸中，制粒，干燥，包衣，得含有有机酸包衣颗粒，含有有机酸包衣颗粒的d0.9为800μm；
(3)将甲磺酸达比加群酯复合物和含有有机酸包衣颗粒混合，填充到胶囊。
实施例12
制备方法：
(1)将甲磺酸达比加群酯、乳糖、槐豆胶和瓜尔胶分散到异丙醇中，喷雾干燥制得甲磺酸达比加群酯复合物，甲磺酸达比加群酯复合物粒径d0.9为620μm；
(2)将聚维酮配制成聚维酮溶液，将聚维酮溶液加入到酒石酸中，制粒，干燥，包衣，得含有有机酸包衣颗粒，含有有机酸包衣颗粒的d0.9为700μm；
(3)将甲磺酸达比加群酯复合物和含有有机酸包衣颗粒混合，填充到胶囊。
对比实施例1
制备方法同实施例1。
对比实施例2
制备方法同实施例7。
溶出度考察
取实施例1-12和对比处方1-8制得的样品，以pH6.8磷酸盐缓冲液+1.5％SDS作为溶出介质，照溶出度测定法(中国药典2010年版二部附录X C第二法)，转速为每分钟100转，于15、30、 45、60、90、120min取溶出液进行HPLC测定，实验结果如下：
由上述实验结果可知，本发明实施例和对比实施例中对甲磺酸达比加群酯复合物中的辅料进行考察，并进一步确定复合物中选取的胶类材料具体为黄原胶、瓜尔胶、槐豆胶和角叉菜胶中的一种或几种时，具有很好的溶出效果，更进一步的，当胶类材料为是黄原胶和瓜尔胶的组合，并且质量用量比为1:0.5-2时，有更优异的溶出效果，而当胶类材料选择阿拉伯胶时，或选择水溶性聚合物聚乙二醇6000或聚维酮时，溶出效果较差。
稳定性考察
取实施例1-12制得的样品，测定样品的最大单杂(％)和总杂质(％)，实验结果如下：
由上述实验结果可知，本发明实施例中将有机酸和甲磺酸达比加群酯采用包衣隔离的方式进行物理隔离，并且所用甲磺酸达比加群酯(以达比加群酯计)与有机酸质量用量比为1： 0.3-0.8，所用有机酸量较少，能够保证制得制剂的稳定性，所得制剂的杂质远低于产品质量要求的限度，保证了患者用药的安全性。
Claims (14)
1.一种甲磺酸达比加群酯药物制剂，其特征在于，所述药物制剂包含：
a）甲磺酸达比加群酯包衣复合物，该复合物包含甲磺酸达比加群酯、水溶性稀释剂和胶类材料，复合物表面包被隔离层；
b）有机酸；
其中，所述水溶性稀释剂为蔗糖、乳糖、甘露醇和山梨醇中的一种或几种；所述胶类材料为黄原胶和瓜尔胶的组合；所述甲磺酸达比加群酯、水溶性稀释剂和胶类材料的质量用量比为75-150:50-120:10-40，其中甲磺酸达比加群酯用量以达比加群酯计。
2.一种甲磺酸达比加群酯药物制剂，其特征在于，所述药物制剂包含：
a）甲磺酸达比加群酯复合物，该复合物包含甲磺酸达比加群酯、水溶性稀释剂和胶类材料；
b）含有有机酸包衣颗粒;
其中，所述水溶性稀释剂为蔗糖、乳糖、甘露醇和山梨醇中的一种或几种；所述胶类材料为黄原胶和瓜尔胶的组合；所述甲磺酸达比加群酯、水溶性稀释剂和胶类材料的质量用量比为75-150:50-120:10-40，其中甲磺酸达比加群酯用量以达比加群酯计。
3.根据权利要求1或2所述的药物制剂，其特征在于，所述甲磺酸达比加群酯包衣复合物或甲磺酸达比加群酯复合物的粒径d0.9为250-800μm。
4.根据权利要求1或2所述的药物制剂，其特征在于，所述黄原胶和瓜尔胶的质量用量比为1:0.5-2。
5.根据权利要求1或2所述的药物制剂，其特征在于，所述甲磺酸达比加群酯包衣复合物或甲磺酸达比加群酯复合物还包含表面活性剂。
6.根据权利要求5所述的药物制剂，其特征在于，所述表面活性剂为十二烷基硫酸钠、卵磷脂、吐温80和聚氧乙烯40氢化蓖麻油中的一种或几种。
7.根据权利要求1或2所述的药物制剂，其特征在于，所述有机酸选自酒石酸、富马酸、柠檬酸、琥珀酸、苹果酸、谷氨酸或天冬氨酸。
8.根据权利要求1或2所述的药物制剂，其特征在于，甲磺酸达比加群酯与有机酸的质量用量比为1：0.3-0.8，其中甲磺酸达比加群酯用量以达比加群酯计。
9.根据权利要求2所述的药物制剂，其特征在于，所述含有有机酸包衣颗粒的粒径d0.9为250-800μm。
10.根据权利要求2所述的药物制剂，其特征在于，所述含有有机酸包衣颗粒包含有机酸和粘合剂。
11.根据权利要求10所述的药物制剂，其特征在于，所述粘合剂为羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和聚维酮中的一种或几种。
12.一种制备权利要求1所述甲磺酸达比加群酯药物制剂的制备方法，其特征在于，包括如下步骤：
（1）将甲磺酸达比加群酯、水溶性稀释剂和胶类材料分散到溶剂中，喷雾干燥制得甲磺酸达比加群酯复合物，在甲磺酸达比加群酯复合物表面包隔离层，得甲磺酸达比加群酯包衣复合物；
（2）将甲磺酸达比加群酯包衣复合物与有机酸混合，填充到胶囊。
13.一种制备权利要求2所述甲磺酸达比加群酯药物制剂的制备方法，其特征在于，包括如下步骤：
（1）将甲磺酸达比加群酯、水溶性稀释剂和胶类材料分散到溶剂中，喷雾干燥制得甲磺酸达比加群酯复合物；
（2）将粘合剂配制成粘合剂溶液，将粘合剂溶液加入到有机酸中，制粒，干燥，包衣，得含有有机酸包衣颗粒；
（3）将甲磺酸达比加群酯复合物和含有有机酸包衣颗粒混合，填充到胶囊。
14.根据权利要求12或13所述的制备方法，其特征在于，所述溶剂为水、乙醇、丙酮、异丙醇、二氯甲烷和甲醇中的一种或几种。
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