CN114533694A - 一种含有替格瑞洛和阿司匹林的复方胶囊制剂及其制备方法 - Google Patents
一种含有替格瑞洛和阿司匹林的复方胶囊制剂及其制备方法 Download PDFInfo
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- CN114533694A CN114533694A CN202011345937.4A CN202011345937A CN114533694A CN 114533694 A CN114533694 A CN 114533694A CN 202011345937 A CN202011345937 A CN 202011345937A CN 114533694 A CN114533694 A CN 114533694A
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- ticagrelor
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- cellulose
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- Medicinal Preparation (AREA)
Abstract
本发明属于医药技术制剂领域，涉及一种含有替格瑞洛和阿司匹林的复方胶囊制剂及其制备方法，适用于每日服用一次。本公开提供了一种替格瑞洛和阿司匹林的复方胶囊制剂，具体是由替格瑞洛缓释片和相同形状的阿司匹林肠溶片灌装硬胶囊组成。该制剂每日只需服用一次，减少了服用次数，大大减少了患心梗和中风的风险，改善了患者服药的依从性。与阿司匹林肠溶片的联合使用，减少了出血的风险，毒副作用小，有效降低血小板聚集率，安全性更佳。
Description
技术领域
本发明属于制药技术工业领域，涉及一种含有替格瑞洛和阿司匹林的复方制剂，每片含有替格瑞洛180mg、阿司匹林100mg，适用于每日服用一次。
背景技术
据统计，现阶段世界上死亡率最高的疾病是冠心病，在最新十大死亡疾病排名中居首位，占12.9％。到目前为止，美国心脑血管疾病死亡人数占总死亡人数的1/3-1/2，其中冠心病占心脏病死亡人数的50％-75％。随着国内人们生活环境和饮食习惯的变化，心脑血管疾病发病率也逐年升高。据不完全统计，我国每年有38％的中国人死于心血管疾病，其中CHD占心血管疾病死亡人数的25％-50％。
冠心病是冠状动脉粥样硬化性心脏病的简称，是由于冠状动脉粥样硬化或者其他一些因素引起的心肌血流量减少,导致心肌缺血、缺氧而引起的心肌损伤性变化。其临床主要表现以稳定型心绞痛、不稳定型心绞痛、心律失常、心源性休克等。由于本病发病较慢,多数患者病史较长。目前临床上常用的治疗手段有:冠心病药物治疗、经皮冠状动脉介入治疗和冠状动脉旁路移植术等主要治疗手段。但是目前临床上仍以药物治疗为主。
目前临床上有多种治疗冠心病的药物，其中抗血小板类药物在冠心病的治疗中具有重要的作用，它可以有效的抑制血小板在血管内的聚集，防止血小板聚集收缩，从而达到抑制血栓形成。
目前市面上的抗血小板聚集的药物有阿司匹林、替格瑞洛和硫酸氢氯吡格雷阿司匹林片。但有医者指出硫氢氯吡格雷虽为血小板聚集抑制剂，其抗血小板功效个体差异较大，影响治疗效果。替格瑞洛作为新型二磷酸腺苷P2Y12受体拮抗剂，其疗效及安全性均得到血小板抑制和患者结局验证与支持，PLATO研究指出替格瑞洛疗效优于硫氢氯吡格雷，同时可规避硫氢氯吡格雷抵抗性，选择性抑制ADP与血小板受体结合，抑制ADP介导糖蛋白GPⅡb/Ⅲa复合物活化，从而抑制血小板聚集及非ADP引发的血小板聚集，且该药与阿司匹林合用，毒副作用较小，安全性佳，在临床范围内得到了广泛推广。
欧洲心脏病学年会上公布数据显示，50％的冠心病患者每月至少漏服药1次，病人忘记服药的次数越多，将会大大增加患心梗和中风的风险。为了减少该风险，改善患者服药的依从性，现开发出一种一日一次联合给药的药物是十分有必要的。中国专利文献专利CN106619549 A公开了一种替格瑞洛与阿司匹林复合片剂及其制备方法，该专利中为替格瑞洛片与阿司匹林片的复方口服制剂，每日服用2次，增加了漏服的风险。目前还没有替格瑞洛缓释与阿司匹林肠溶片的复方口服制剂上市。
本公开提供了一种含有替格瑞洛和阿司匹林的复方制剂，该制剂为胶囊制剂，具体是由替格瑞洛缓释片和阿司匹林肠溶片灌装胶囊组成。该制剂每日只需服用一次，减少了患心梗和中风的风险，改善了患者服药的依从性。
发明内容
本发明的目的是提供一种含有替格瑞洛和阿司匹林的复方制剂。
本发明的替格瑞洛和阿司匹林的复方制剂，提供了一种新型的组合方式，该发明将替格瑞洛缓释片和阿司匹林肠溶片灌装胶囊，组成复方制剂，实现了替格瑞洛和阿司匹林在同一制剂中的联合使用，一天只需服用一次，改善了患者用药的顺应性，防止漏服带来的风险，可以显著改善ACS患者的临床症状，减少了出血的风险，有效降低血小板聚集率，毒副作用小，安全性更佳。
本发明的替格瑞洛和阿司匹林的复方制剂，单位制剂中包括替格瑞洛180mg，阿司匹林100mg。该制剂每日只需服用一次，减少了服用次数，大大减少了患心梗和中风的风险，改善了患者服药的依从性。
为实现上述发明目的，本发明主要通过分开制粒、混合、压片、灌装等方式使得替格瑞洛和阿司匹林在最终固体制剂产品中不直接接触，达到各自同时释药的效果。
一种替格瑞洛和阿司匹林的复方制剂，该制剂是由替格瑞洛缓释片，替格瑞洛速释片和阿司匹林肠溶片组成，通过灌装胶囊组合成一个完整制剂。
本发明的替格瑞洛缓释固体组合物含有的组分包括：替格瑞洛、甘露醇、预胶化淀粉、微晶纤维素、无水磷酸氢钙、羟丙甲纤维素、羟丙基纤维素、聚维酮、胶态二氧化硅和硬脂酸镁。
本发明的替格瑞洛速释组合物含有的组分包括：替格瑞洛、甘露醇、预胶化淀粉、微晶纤维素、无水磷酸氢钙、羟丙甲纤维素、羟丙基纤维素、聚维酮、羧甲基淀粉钠、红氧化铁、胶态二氧化硅和硬脂酸镁。
本发明的阿司匹林肠溶片含有的组分包括：阿司匹林、微晶纤维素、玉米淀粉、甲基丙烯酸树脂、滑石粉、柠檬酸三乙酯。
本发明的替格瑞洛和阿司匹林的复方制剂，先将阿司匹林原辅料混合后进行压片，然后采用高效薄膜包衣机进行肠溶包衣；替格瑞洛缓释固体组合物和速释固体组合物为：将替格瑞洛和内加辅料进行混合，采用高剪切湿法制粒，然后加入外加辅料进行混合，最后采用普通压片机或双层压片机进行压片。
本发明的替格瑞洛和阿司匹林的复方制剂，替格瑞洛和阿司匹林固体组合物片剂压片时选用的是圆形片，且阿司匹林和替格瑞洛采用压片冲模大小形状相同。
本发明的替格瑞洛和阿司匹林的复方制剂，提供了一种新型的替格瑞洛和阿司匹林组合方式，在00号明胶空心硬胶囊中，分别填入阿司匹林肠溶片(规格100mg)1片，替格瑞洛缓释片(规格180mg或126mg)2片，含有或不含替格瑞洛速释片(规格54mg)1片。
本发明的替格瑞洛和阿司匹林的复方胶囊制剂，单位制剂示意图如图1所示，本发明包括但不仅限于图1形式，示意图仅提供一种示例。
图1.
附图说明
图1.本发明示例图
图2.实施例1阿司匹林释放曲线累积释放度(％)图
图3.实施例1替格瑞洛释放曲线累积释放度(％)图
具体实施方式
接下来结合具体实施例可以对本发明进行进一步详细描述，以下描述均是实际示例，仅用于详细阐述本发明，而不是对本发明的限制。
一种含有替格瑞洛和阿司匹林的复方制剂。
实施例1
阿司匹林处方组成
按照上表所述处方准备原辅料。
原辅料称量混合：按质量比例称取阿司匹林、微晶纤维素、玉米淀粉，混合均匀；
检测：检测中间体颗粒的含量，计算应压实际片重；
压片：使用单层压片机，调节压片机装量及压力，总体片剂控制硬度为50±20N；
包衣：配置好肠溶包衣液，待物料温度到达35.0℃时，开始喷包衣液；控制物料温度为30.0℃±5.0℃，素片增重为素片重量的17.0％～20.0％，停止包衣；在烘箱内60℃干燥20h，即得阿司匹林肠溶片。
替格瑞洛缓释片
按照上表所述处方准备原辅料。
原辅料称量：按质量比例称取替格瑞洛、甘露醇、微晶纤维素、羟丙甲纤维素；
粘合剂的配制：将羟丙基纤维素加入纯化水中，搅拌至溶液澄清透明完全溶解，即得粘合剂；
制粒过程：将称量好的替格瑞洛、甘露醇、微晶纤维素、羟丙甲纤维素置于湿法制粒机内混合均匀，加入粘合剂制软材，软材成型后置于整粒机中过24目筛筛整粒，然后于50℃～60℃进行干燥，控制水分≤3.00％，待水分合格后进行干整粒；
混合：将上述颗粒分别按比例加入外加辅料，混合均匀；
检测：检测中间体颗粒的含量，计算应压实际片重；
压片：使用高速旋转式压片机，采用8mm浅凹圆形冲模、进行压片，控制片重为理论片重的±2％，控制片子硬度为30-80N，控制片子厚度为3.5-4.5mm；
包衣：包衣控制包衣液的浓度为15.0％，待物料温度到达45.0℃时，开始喷包衣液；控制物料温度为40.0℃±5.0℃，素片增重为素片重量的2.0％～5.0％，停止包衣；
胶囊填充：采用胶囊填充剂分别在4种料斗中加入00号明胶空心硬胶囊、阿司匹林肠溶片和替格瑞洛缓释片，其中1个料斗中加入阿司匹林肠溶片，1个料斗加入00号明胶空心硬胶囊，另两个料斗加入替格瑞洛缓释片，调节转速20-30rpm，进行胶囊填充，即得最终产品。
产品体外释放曲线如下表格和图谱所示。
图2.实施例1阿司匹林释放曲线累积释放度(％)图
图3.实施例1替格瑞洛释放曲线累积释放度(％)图
由以上结果可知，本发明复方制剂阿司匹林与参比制剂体外释放行为基本一致，替格瑞洛能够长效释放，且阿司匹林与替格瑞洛释放互不干扰。
举例，并不是对实施方式的限定。在上述说明的基础上还可以做出其他不同形式的变化或变动。这里无需也无法对所有的实施方式予以举例。由此索引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之内。
Claims (13)
1.一种替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，该复方制剂含有替格瑞洛缓释片和阿司匹林肠溶片，含有或不含替格瑞洛速释片，其中替格瑞洛缓释片的一种形式是胃漂浮制缓释剂，填装在“0”号或“00”号空心胶囊中组成。
2.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，所述替格瑞洛缓释固体组合物含有替格瑞洛、乳糖、甘露醇、磷酸氢钙、微晶纤维素、预胶化淀粉、羟丙基纤维素、羟乙基纤维素、甲基纤维素、山嵛酸甘油酯、丙烯酸树脂、海藻酸钠、聚氧乙烯、卡波姆、羟丙基甲基纤维素、聚乙烯吡咯烷酮、硬脂酸镁、胶态二氧化硅中的一种或多种。
3.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，所述替格瑞洛缓释固体组合物采用的缓释骨架材料为羟丙甲纤维素、羟乙基纤维素、羟丙基纤维素、甲基纤维素、卡波姆、海藻酸钠、聚氧乙烯、山嵛酸甘油酯、尤特奇中的一种或多种，其中缓释骨架材料含有或不含致孔剂，致孔剂可以选择甘露醇、乳糖、微晶纤维素、羟丙甲纤维素中的一种。
4.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，可以是一种胃漂浮缓释制剂，替格瑞洛缓释片为双层片，包含含药层和产气层；含药层替格瑞洛缓释固体组合物含有替格瑞洛、乳糖、甘露醇、磷酸氢钙、微晶纤维素、预胶化淀粉、羟丙基纤维素、羟乙基纤维素、甲基纤维素、山嵛酸甘油酯、丙烯酸树脂、海藻酸钠、聚氧乙烯、卡波姆、羟丙基甲基纤维素、聚乙烯吡咯烷酮、硬脂酸镁、胶态二氧化硅中的一种或多种；产气层含有乳糖、甘露醇、磷酸氢钙、微晶纤维素、预胶化淀粉、羟丙基纤维素、羟乙基纤维素、甲基纤维素、丙烯酸树脂、海藻酸钠、聚氧乙烯、卡波姆、羟丙基甲基纤维素、聚乙烯吡咯烷酮、碳酸氢钠、枸橼酸、酒石酸、硬脂酸镁、胶态二氧化硅中的一种或多种。
5.根据权利要求1和4所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，替格瑞洛缓释片为双层片剂，采用粉末直压或湿法制粒压片，采用双层压片机进行压制；湿法制粒润湿剂采用水或乙醇水，乙醇水比例为10:0-1:1。
6.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，、含有替格瑞洛速释片，替格瑞洛速释固体组合物含有替格瑞洛、乳糖、甘露醇、磷酸氢钙、微晶纤维素、预胶化淀粉、羟丙基纤维素、羟丙甲纤维素、聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、二氧化硅和硬脂酸镁中的一种或多种。
7.根据权利要求1-6所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，含有胃溶型薄膜包衣，其中薄膜包衣材料选择防潮型PVA欧巴代预混剂或羟丙甲纤维素欧巴代预混剂。
8.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，该制剂为片剂，具体包括：圆形片、椭圆形片、胶囊形、三角形、四边形、五边形、六边形等，优选圆形片和椭圆形片。
9.根据权利要求1、4、5所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，双层片剂，具体包括：圆形片、椭圆形片、胶囊形、三角形、四边形、五边形、六边形等，优选圆形片和椭圆形片。
10.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，阿司匹林固体组合物中含有微晶纤维素、玉米淀粉、丙烯酸树脂、十二烷基硫酸钠、吐温80、滑石粉、柠檬酸三乙酯、羟丙甲纤维素、巴西棕榈蜡。
11.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，所述复方制剂中每单位含有替格瑞洛60mg、90mg、120mg或180mg，优选120mg和180mg，其中速释固体组合物与缓释固体组合物中替格瑞洛的质量比为5:1～1:5，优选3:1～1:3；每单位含有阿司匹林75mg或100mg，优选100mg。
12.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，采用湿法制粒或粉末直接压片方法，压制性状相同或不同片剂，其中替格瑞洛缓释片2-6片、阿司匹林肠溶片1-2片，填装进胶囊中。
13.根据权利要求1所述的替格瑞洛和阿司匹林的复方胶囊制剂，其特征在于，“0”号或“00”号胶囊所选用的材质为明胶、羟丙甲基纤维素、多糖聚合物中的一种。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107260700A (zh) * | 2016-04-09 | 2017-10-20 | 厦门恩成制药有限公司 | 一种替格瑞洛复方口服固体制剂的制备方法 |
| CN110876750A (zh) * | 2018-09-06 | 2020-03-13 | 江苏恒瑞医药股份有限公司 | 一种含有替格瑞洛或其可药用盐的缓释组合物 |
| CN111939136A (zh) * | 2020-09-07 | 2020-11-17 | 乐普（北京）医疗器械股份有限公司 | 一种含有替格瑞洛和阿司匹林的复方制剂及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107260700A (zh) * | 2016-04-09 | 2017-10-20 | 厦门恩成制药有限公司 | 一种替格瑞洛复方口服固体制剂的制备方法 |
| CN110876750A (zh) * | 2018-09-06 | 2020-03-13 | 江苏恒瑞医药股份有限公司 | 一种含有替格瑞洛或其可药用盐的缓释组合物 |
| CN111939136A (zh) * | 2020-09-07 | 2020-11-17 | 乐普（北京）医疗器械股份有限公司 | 一种含有替格瑞洛和阿司匹林的复方制剂及其制备方法 |
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