CN112402392A - 一种甲磺酸达比加群酯缓释制剂及其制备方法 - Google Patents
一种甲磺酸达比加群酯缓释制剂及其制备方法 Download PDFInfo
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- CN112402392A CN112402392A CN202011520981.4A CN202011520981A CN112402392A CN 112402392 A CN112402392 A CN 112402392A CN 202011520981 A CN202011520981 A CN 202011520981A CN 112402392 A CN112402392 A CN 112402392A
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Abstract
本发明涉及一种甲磺酸达比加群酯缓释微丸制剂及其制备方法。该微丸的结构包括丸芯、包裹在丸芯外层的含药层、包裹在含药层外层的隔离层1和隔离层2、包裹在隔离层2外层的缓释层。本发明制备的微丸具有稳定性好、制剂间差异小、生物利用度高、减少每日给药次数等优点，并且显著降低制剂带来的窄治疗窗药物体内暴露量高变异的风险。
Description
技术领域
本发明涉及医药制剂技术领域，具体涉及一种甲磺酸达比加群酯缓释制剂及其制备方法。
背景技术
达比加群酯，是由德国柏林格殷格翰公司开发的一种新型的合成的直接凝血酶抑制剂，在体内代谢成达比加群后，发挥抗凝血作用，其结构如式I所示。目前市售的为达比加群酯甲磺酸盐，剂型仅有口服速释剂型，商品名为Pradaxa。服用时，应用水整粒吞服，餐时或餐后服用均可，且不能打开胶囊。成人的推荐剂量为每日口服300mg，即每次1粒150mg的胶囊，每日两次，应维持终生治疗。甲磺酸达比加群酯最大的特点就是不用检测INR，还具有强效、无需特殊用药监测、药物相互作用少等特点，具有良好的临床应用前景。
式 
。
达比加群酯属于生物药剂学分类系统II类，水中溶解度极低，其表观溶解度随溶液pH 值的增加而减小，在pH1.0、pH2.0、pH3.0时溶解度分别为13.49mg/ml 、1.89mg/ml 、156μg/ml，在pH>4的缓冲液中几乎不溶。达比加群酯在pH1~3的胃液中溶解度较高，但是透膜性不够，难以被吸收，到达肠中后，随着环境pH升高药物大量析出，影响其生物利用度。
上市的达比加群酯制剂是含有酒石酸的达比加群酯甲磺酸盐微丸胶囊，专利（WO03/04056）公开了该制剂的组合物形式，是通过将达比加群酯制成盐以及加入有机酸的途径来提高达比加群酯的溶解度，促进药物吸收，但是研究表明，该市售制剂的生物利用度仅约6.5%。并且，根据FDA的BE指南和中国食品药品检定所的《甲磺酸达比加群酯生物等效性试验指导意见草案》可知，达比加群酯为高变异、窄治疗窗药物，在安全性和有效性方面的暴露-反应关系曲线非常陡峭，因此在临床应用上存在较大风险，可能会导致大出血等危及生命的后果。另外，该制剂每天需服药2次，且需长期给药，患者顺应性差。
现有甲磺酸达比加群酯胶囊还有一个问题一直没能得到很好的解决，即甲磺酸达比加群酯原料遇湿极其不稳定，需要采用HPMC胶囊壳防潮。HPMC胶囊壳在体内包裹原料药，导致了体内更高的变异，导致体内暴露量波动很大。
因此，亟需一种稳定性好、制剂间变异小、生物利用度高、患者顺应性好的达比加群酯制剂。
发明内容
为解决现有现有产品的不足，本发明提供了一种甲磺酸达比加群酯缓释制剂及其制备方法，该制剂稳定性好、制剂间变异小、生物利用度高、减少给药次数等优点，并且显著降低制剂带来的窄治疗窗药物体内暴露量高变异的风险。采用的技术方案如下：
本发明为一种结构如图1所示的甲磺酸达比加群酯缓释微丸，其特征在于，所述微丸结构包括空白丸芯、包裹在丸芯外层的含药层、包裹在含药层外层的隔离层1和隔离层2、包裹在隔离层2外层的缓释层。
本发明所述空白丸芯选自蔗糖丸芯、纤维素丸芯、甘露醇丸芯、酒石酸丸芯、二氧化硅丸芯中的至少一种。所述空白丸芯的平均粒径为0.1~1.0mm。
本发明所述缓释微丸中，含药层、隔离层1和隔离层2分别包括甲磺酸达比加群酯、粘合剂、pH调节剂中的一种或多种的混合物。
本发明所述缓释微丸中，含药层包括甲磺酸达比加群酯、粘合剂、抗粘剂中的一种或多种的混合物。
本发明所述缓释微丸中，所述粘合剂选自阿拉伯胶、黄原胶、羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、甲基纤维素、羟乙基纤维素、羧甲基纤维素、聚乙烯吡咯烷酮、N-乙烯吡咯烷酮、醋酸乙烯酯的共聚物中的至少一种；所述抗粘剂选自滑石粉、微粉硅胶、二氧化钛、硬脂酸镁、单硬脂酸甘油酯中的至少一种；所述pH调节剂选自柠檬酸、酒石酸、富马酸、琥珀酸、抗坏血酸、苹果酸中的至少一种。
本发明所述缓释微丸中，缓释层聚合物增重5%~20%；其中缓释层包括缓释材料、增塑剂、致孔剂、抗粘剂中的一种或多种的混合物。
本发明所述缓释微丸的缓释层中，所述缓释材料选自乙基纤维素、醋酸纤维素、聚（甲基乙烯基醚）顺丁烯二酸苷、聚氧乙烯、乙烯-醋酸乙烯酯共聚物、丙烯酸树脂中的至少一种；所述增塑剂选自柠檬酸三乙酯、甘油、丙二醇、聚乙二醇类、邻苯二甲酸酯类的至少一种；所述抗粘剂选自滑石粉、微粉硅胶、二氧化钛、硬脂酸镁、单硬脂酸甘油酯中的至少一种；所述致孔剂选自羟丙基甲基纤维素、海藻酸钠、糖和糖醇、低分子量聚乙二醇、聚乙烯醇、氯化钠、吐温、司盘中的至少一种。
本发明所述缓释微丸含有以下重量份的组分：
本发明第一方面的一个优选实例中，所述缓释微丸含有以下重量份的组分：
本发明第一方面的一个优选实例中，所述缓释微丸含有以下重量份的组分：
本发明第一方面的一个优选实例中，所述缓释微丸含有以下重量份的组分：
所述缓释微丸的制备方法包括：
（1）将甲磺酸达比加群酯、羟丙纤维素、滑石粉溶解或分散于溶剂中，得含药层包衣液；将羟丙甲纤维素和滑石粉溶解或分散于溶剂中，得隔离层1包衣液；将柠檬酸、羟丙甲纤维素和滑石粉溶解或分散于溶剂中，得隔离层2包衣液；将乙基纤维素、柠檬酸三乙酯、低粘度羟丙甲基纤维素和滑石粉溶解或分散于溶剂中，得缓释层包衣液；
（2）采用流化床底喷包衣工艺，在空白丸芯上依次喷含药层、隔离层1、隔离层2和缓释层包衣液，得到缓释微丸。
上述缓释微丸可进一步填充胶囊、压制成片或其他剂型。
附图说明
图1 甲磺酸达比加群酯缓释微丸结构示意图。
图2 实施例6中达比加群的血浆药物浓度-药时曲线。
具体实施方式
本发明人经过研究，获得了一种稳定性好、生物利用度高、可以减少给药次数的甲磺酸达比加群酯缓释制剂，可以显著降低制剂带来的窄治疗窗药物体内暴露量高变异的风险。
本发明实施例说明书中所提到的各组分的重量不仅仅可以指代各组分的具体含量，还可以表示各组分间重量的比例关系，因此，只要是按照本发明实施例说明书胃滞留缓释制剂各组分的含量按比例放大或缩小均在本发明实施例说明书公开的范围内。具体的，本发明实施例说明书中所述的重量份可以是μg、mg、g、kg等医药领域公知的重量单位，当然也可以看作是重量百分比。
实施例1~3：甲磺酸达比加群酯缓释微丸组成及制备
制备步骤如下：
（1）将甲磺酸达比加群酯、羟丙纤维素、滑石粉溶解或分散于异丙醇中，得含药层包衣液；将羟丙甲纤维素和滑石粉溶解或分散于水中，得隔离层1包衣液；将柠檬酸、羟丙甲纤维素和滑石粉溶解或分散于水中，得隔离层2包衣液；将乙基纤维素、柠檬酸三乙酯和滑石粉溶解或分散于乙醇中，得缓释层包衣液；
（2）采用流化床底喷包衣工艺，在空白丸芯上依次喷含药层、隔离层1、隔离层2和缓释层包衣液，得到缓释微丸。
实施例4：缓释制剂制备
取适量实施例2微丸直接以150mg规格手动填充明胶空心胶囊，得到甲磺酸达比加群酯缓释胶囊。
取适量实施例2微丸，与适量微晶纤维素、交联羧甲基纤维素钠、硬脂酸镁混合均匀后，采用旋转压片机以150mg规格进行压片，得到甲磺酸达比加群酯缓释片。
实施例5：溶出实验
采用实施例4制备的甲磺酸达比加群酯缓释胶囊与缓释片作为实验样品，以pH6.8磷酸盐缓冲液为溶出介质，篮法100rpm，n=6，考察缓释制剂的体外释放度，结果如下：
以上释放曲线可以看出，将甲磺酸达比加群酯制成缓释微丸后，填充胶囊或压制成片，均可达到缓释效果。并且，本发明意外的发现，甲磺酸达比加群酯缓释制剂释放均一性非常好，说明本发明批内差异性小，工艺稳健且产品质量稳定。
实施例6：体内药代动力学
采用实施例4制备的甲磺酸达比加群酯缓释胶囊和市售甲磺酸达比加群酯胶囊（泰必全150mg）作为实验样品，对比进行了动物体内实验。具体如下：6只比格犬，雄性，体重（10±2）kg，分成2组：（a）实验组、（b）对照组，每组3只，比较其药代动力学差异。
各组比格犬先禁食禁水12h，a组服用实施例4中甲磺酸达比加群酯胶囊剂，一日一次；b组服用市售甲磺酸达比加群酯胶囊（商品名：泰必全150mg），一日两次（第一次给药后间隔12h进行第二次给药）。于给药前0h及给药后2h、3h、4h、6h、8h、10h、12h、14h、15h、16h、18h、20h、22h、24h，由腿静脉分别取血1ml，经相关处理后测定达比加群的血浆药物浓度，得到其药时曲线，如图2所示。
以上动物实验可以看出，本发明实施例4制备的甲磺酸达比加群酯缓释胶囊在体内可以缓慢释放，一天给药1次（150mg）即可达到市售品一天给药2次（300mg）的AUC，且Cmax没有明显变化。说明本发明的甲磺酸达比加群酯缓释胶囊不仅在体内可以缓慢释放，而且生物利用度是市售制剂的200%以上，不仅可以减少每日给药次数和剂量，体内变异系数也显著降低。
本发明针对窄治疗窗药物达比加群酯，显著降低了制剂带来的体内暴露量高变异的风险，潜在降低了临床应用上可能会导致大出血等危及生命的后果的不良反应。
以上通过实施例形式的具体实施方式，对本发明的上述内容再做进一步的详细说明。但不应此理解为本发明上述主题的范围仅限于以上的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
Claims (10)
1.一种甲磺酸达比加群酯缓释微丸，其特征在于，所述微丸结构包括空白丸芯、包裹在丸芯外层的含药层、包裹在含药层外层的隔离层1和隔离层2、包裹在隔离层2外层的缓释层；其中含药层、隔离层1和隔离层2分别包括甲磺酸达比加群酯、粘合剂、pH调节剂中的一种或多种的混合物；其中缓释层聚合物增重5%~20%；其中缓释层包括缓释材料、增塑剂、致孔剂、抗粘剂中的一种或多种的混合物。
2.根据权利要求1所述缓释微丸，其特征在于，所述空白丸芯选自蔗糖丸芯、纤维素丸芯、甘露醇丸芯、酒石酸丸芯、二氧化硅丸芯中的至少一种；所述空白丸芯的平均粒径为0.1~1.0mm。
3.根据权利要求1所述缓释微丸，其特征在于，所述含药层包括甲磺酸达比加群酯、粘合剂、抗粘剂中的一种或多种的混合物。
4.根据权利要求1~3所述缓释微丸，其特征在于，所述粘合剂选自阿拉伯胶、黄原胶、羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、甲基纤维素、羟乙基纤维素、羧甲基纤维素、聚乙烯吡咯烷酮、N-乙烯吡咯烷酮、醋酸乙烯酯的共聚物中的至少一种；所述抗粘剂选自滑石粉、微粉硅胶、二氧化钛、硬脂酸镁、单硬脂酸甘油酯中的至少一种；所述pH调节剂选自柠檬酸、酒石酸、富马酸、琥珀酸、抗坏血酸、苹果酸、磷酸、磷酸二氢钠、磷酸二氢钾中的至少一种。
5.根据权利要求1所述缓释微丸，其特征在于，缓释层中，所述缓释材料选自乙基纤维素、醋酸纤维素、聚（甲基乙烯基醚）顺丁烯二酸苷、聚氧乙烯、乙烯-醋酸乙烯酯共聚物、丙烯酸树脂中的至少一种；所述增塑剂选自柠檬酸三乙酯、甘油、丙二醇、聚乙二醇类、邻苯二甲酸酯类的至少一种；所述抗粘剂选自滑石粉、微粉硅胶、二氧化钛、硬脂酸镁、单硬脂酸甘油酯中的至少一种；所述致孔剂选自羟丙基甲基纤维素、海藻酸钠、糖和糖醇、低分子量聚乙二醇、聚乙烯醇、氯化钠、吐温、司盘中的至少一种。
6.根据权利要求1-5所述缓释微丸，其特征在于，含有以下重量份的组分：
7.根据权利要求1-5所述缓释微丸，其特征在于，含有以下重量份的组分：
8.根据权利要求1-7所述缓释微丸，其特征在于，含有以下重量份的组分：
9.根据权利要求1-8所述缓释微丸，其特征在于，含有以下重量份的组分：
10.一种制备权利要求1-9所述缓释微丸的方法，其特征在于，所述制备方法包括：
（1）将甲磺酸达比加群酯、羟丙纤维素、滑石粉溶解或分散于溶剂中，得含药层包衣液；将羟丙甲纤维素和滑石粉溶解或分散于溶剂中，得隔离层1包衣液；将柠檬酸、羟丙甲纤维素和滑石粉溶解或分散于溶剂中，得隔离层2包衣液；将乙基纤维素、柠檬酸三乙酯、低粘度羟丙甲基纤维素和滑石粉溶解或分散于溶剂中，得缓释层包衣液；
（2）采用流化床底喷包衣工艺，在空白丸芯上依次喷含药层、隔离层1、隔离层2和缓释层包衣液，得到缓释微丸；
（3）将缓释微丸进一步填充明胶胶囊（囊壳不含HPMC）、压制成片或其他剂型。
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| CN115227663A (zh) * | 2021-04-22 | 2022-10-25 | 石药集团恩必普药业有限公司 | 一种甲磺酸达比加群酯胶囊及其制备方法 |
| CN115227663B (zh) * | 2021-04-22 | 2023-12-12 | 石药集团恩必普药业有限公司 | 一种甲磺酸达比加群酯胶囊及其制备方法 |
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