CN114533744A - 一种替格瑞洛-阿司匹林复方微丸制剂及其制备方法 - Google Patents
一种替格瑞洛-阿司匹林复方微丸制剂及其制备方法 Download PDFInfo
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Abstract
本公开提供了一种替格瑞洛‑阿司匹林复方微丸制剂及其制备方法，该制剂将阿司匹林肠溶微丸、替格瑞洛速释微丸和替格瑞洛缓释微丸使用胶囊填充机将三种微丸装于胶囊壳中制成。该制剂适用于每日服用一次，改善了患者的服药顺应性。本发明所述复方微丸制剂工艺简单，实操性强，适合于工业生产；采用微丸剂型释放药物，生物利用度高，血药浓度波动小，副作用更低。
Description
技术领域
本发明涉及一种含有替格瑞洛-阿司匹林复方微丸制剂及其制备方法，属于药物制药工程领域，适用于每日服用一次。
背景技术
进入二十一世纪，心血管疾病给人类带来新的严峻挑战。在《2002年世界卫生报告》中，世界卫生组织(WHO)与世界各地专家合作，收集并分析了当今世界对人类健康造成威胁的重大疾病，其中心血管疾病(包括脑血管病)的死亡率最高，全球每年因心血管死亡约1700万人，在心血管病因中3/4以上可归因于吸烟、高血压和高胆固醇血症。心脑血管疾病已成为全球性公共卫生问题。
在我国，随着经济水平的发展，人民生活水平的提高，心血管疾病发病率和死亡率迅速上升，成为全球上升较快的国家。《中国心血管病报告》中指出，目前全国有高血压患者1.6亿人(其中1.1亿是劳动人口)、现患血脂异常1.6亿人、超重2亿人、肥胖6000万人、糖尿病2000多万人、烟民3.5亿人、还有大量饮酒和缺乏体力活动者，这无疑是心血管病的巨大“后备军”。
阿司匹林是一种历史悠久的解热镇痛药，现多用于预防血栓等疾病。替格瑞洛用于急性冠脉综合征(不稳定性心绞痛、非ST段抬高心肌梗死或ST段抬高心肌梗死)患者，包括接受药物治疗和经皮冠状动脉介入(PCI)治疗的患者，降低血栓性心血管事件的发生率。
替格瑞洛片起始剂量为单次负荷量180mg(90mg×2片)，此后每次1片(90mg)，每日两次。本品推荐与阿司匹林联合用药，阿司匹林的维持剂量为每日1次，每次75～100mg。治疗中应尽量避免漏服。专利CN 101596166A提供了一种阿司匹林的肠溶微丸制剂制备方法，但该制剂只是单方制剂，并不能改善药物联合用药时一天服用2次带来的漏服现象。
本公开提供了一种含有替格瑞洛-阿司匹林复方微丸制剂及其制备方法，具体是将阿司匹林肠溶微丸和替格瑞洛缓释微丸装于胶囊中，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替格瑞洛-阿司匹林复方微丸制剂及其制备方法。
本发明提供的替格瑞洛-阿司匹林复方微丸制剂是由阿司匹林肠溶微丸、替格瑞洛速释微丸以及替格瑞洛缓释微丸组成，该制剂是将这三种微丸一同装入胶囊中形成复方微丸制剂。
本发明提供的阿司匹林肠溶微丸以阿司匹林微丸为含药丸芯，其外依次包隔离层及肠溶层。
本发明提供的阿司匹林肠溶微丸，所述阿司匹林微丸是由阿司匹林、填充剂以及粘合剂经挤出滚圆工艺制得；其中粘合剂选自聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素中的一种或多种组成，优选聚乙烯吡咯烷酮、羟丙基甲基纤维素。
本发明提供的阿司匹林肠溶微丸，所述隔离层包衣成分是由羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇中的一种或多种组成，其隔离层增重优选10％～30％，最优选15％～25％；肠溶包衣成分是由甲基丙烯酸、滑石粉、十二烷基硫酸钠、聚山梨醇酯80共聚物、枸橼酸酯系列、甘油醋酸酯、甘油三醋酸酯、柠檬酸三乙酯中的一种或多种组成，其肠溶层增重优选20％～45％，最优选30％～40％。
本发明提供的阿司匹林肠溶微丸，所述隔离层包衣溶剂选自乙醇、纯化水、异丙醇中的一种或多种，优选纯化水。
本发明提供的阿司匹林肠溶微丸，所述肠溶层包衣溶剂选自乙醇、纯化水、异丙醇中的一种或多种，优选70％的乙醇溶液。
本发明提供的一种阿司匹林肠溶微丸的制备方法包括以下步骤：
(1)阿司匹林微丸制备：先将阿司匹林使用气流粉碎机粉碎后优选0.20mm～0.45mm之间粒径的原料与填充剂以及粘合剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得阿司匹林微丸用流化床干燥，控制水分在3％以内；
(2)阿司匹林隔离层包衣：配置3％的HPMC水溶液，加入聚乙二醇得到隔离层包衣液，将阿司匹林微丸置于流化床中，对其流化包衣并干燥；
(3)阿司匹林肠溶层包衣：选用甲基丙烯酸酯做包衣材料，并添加柠檬酸三乙酯及滑石粉混和均匀，对步骤(2)产物流化包衣并干燥；
本发明提供的替格瑞洛缓释微丸是由替格瑞洛、填充剂、粘合剂、骨架材料、致孔剂、助流剂以及润滑剂经挤出滚圆工艺制得；所述替格瑞洛速释微丸是由替格瑞洛、填充剂、粘合剂以及润滑剂经挤出滚圆工艺制得。其中所述缓释微丸与速释微丸中替格瑞洛的占比优选6:1～1:1，最优选4:1～3:2。
本发明提供的一种替格瑞洛微丸的制备方法包括以下步骤：
(4)替格瑞洛速释微丸制备：先将替格瑞洛过30目筛后与填充剂、粘合剂以及润滑剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得替格瑞洛速释微丸用流化床干燥，控制水分在3％以内；
(5)替格瑞洛缓释微丸制备：先将替格瑞洛过30目筛后与填充剂、粘合剂、骨架材料、致孔剂、助流剂以及润滑剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得替格瑞洛速释微丸用流化床干燥，控制水分在3％以内；
本发明的替格瑞洛-阿司匹林复方微丸制剂，所述微丸的平均粒径在0.25mm～0.85mm之间，优选0.35mm～0.55mm。
本发明的替格瑞洛-阿司匹林复方微丸制剂及其制备方法，所述阿司匹林肠溶微丸、替格瑞洛速释微丸和替格瑞洛缓释微丸使用胶囊填充机将三种微丸装于胶囊壳中。
本发明的替格瑞洛-阿司匹林复方微丸制剂及其制备方法，活性药物成分由阿司匹林和替格瑞洛组成，二者联用，可以显著改善ACS患者的临床症状，减少了出血的风险，且均采用微丸制剂剂型释放药物，生物利用度高，血药浓度波动小，副作用更低。
本发明的替格瑞洛-阿司匹林复方微丸制剂及其制备方法，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。
附图说明
附图1实施例1阿司匹林与参比制剂释放曲线累积释放度(％)图
附图2实施例1替格瑞洛释放曲线累积释放度(％)图
附图3实施例1替格瑞洛-阿司匹林释放曲线累积释放度(％)图
具体实施方式
为便于理解，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。
一种替格瑞洛-阿司匹林复方微丸制剂及其制备方法。
实施例1
阿司匹林微丸制备：先将阿司匹林使用气流粉碎机粉碎后优选0.20mm～0.45mm之间粒径的原料与处方量的填充剂以及粘合剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得阿司匹林微丸用流化床干燥，控制水分在3％以内；
阿司匹林隔离层包衣：配置3％的HPMC水溶液，加入聚乙二醇得到隔离层包衣液，将阿司匹林微丸置于流化床中，对其流化包衣并干燥；
阿司匹林肠溶层包衣：选用甲基丙烯酸酯做包衣材料，并添加柠檬酸三乙酯及滑石粉混和均匀，对步骤(2)产物流化包衣并干燥；
替格瑞洛速释微丸制备：先将替格瑞洛过30目筛后与填充剂、粘合剂以及润滑剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得替格瑞洛速释微丸用流化床干燥，控制水分在3％以内。
替格瑞洛缓释微丸制备：先将替格瑞洛过30目筛后与填充剂、粘合剂、骨架材料、致孔剂、助流剂以及润滑剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得替格瑞洛速释微丸用流化床干燥，控制水分在3％以内。
将以上所述阿司匹林肠溶微丸、替格瑞洛速释微丸和替格瑞洛缓释微丸使用胶囊填充机将三种微丸分别装于明胶胶囊壳和羟丙基甲基胶囊壳中，溶出数据如下：
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 (8)
1.一种替格瑞洛-阿司匹林复方微丸制剂，其特征在于，具体是由阿司匹林肠溶微丸、替格瑞洛速释微丸和替格瑞洛缓释微丸组成，该制剂是将这三种微丸一同装入胶囊中形成复方微丸制剂。
2.根据权利要求1所述的替格瑞洛-阿司匹林复方微丸制剂，其特征在于，所述阿司匹林肠溶微丸以阿司匹林微丸为含药丸芯，其外依次包隔离层及肠溶层；其中阿司匹林微丸是由阿司匹林、填充剂以及粘合剂经挤出滚圆工艺制得；其中粘合剂选自聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素中的一种或多种组成，优选聚乙烯吡咯烷酮和羟丙基甲基纤维素。
3.根据权利要求1-2所述的替格瑞洛-阿司匹林复方微丸制剂，其特征在于，所述隔离层包衣成分是由羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇中的一种或多种组成，其隔离层增重优选10％～30％，最优选15％～25％；肠溶包衣成分是由甲基丙烯酸、滑石粉、十二烷基硫酸钠、聚山梨醇酯80共聚物、枸橼酸酯系列、甘油醋酸酯、甘油三醋酸酯、柠檬酸三乙酯中的一种或多种组成，其肠溶层增重优选20％～45％，最优选30％～40％。
4.根据权利要求1-3所述的替格瑞洛-阿司匹林复方微丸制剂，其特征在于，所述阿司匹林用气流粉碎机粉碎，其粉碎后平均粒径在0.15mm～0.88mm之间，优选0.20mm～0.45mm。
5.根据权利要求1所述的替格瑞洛-阿司匹林复方微丸制剂，其特征在于，所述替格瑞洛缓释微丸是由替格瑞洛、填充剂、粘合剂、骨架材料、致孔剂、助流剂以及润滑剂经挤出滚圆工艺制得；所述替格瑞洛速释微丸是由替格瑞洛、填充剂、粘合剂以及润滑剂经挤出滚圆工艺制得；其中所述缓释微丸与速释微丸中替格瑞洛的占比优选6:1～1:1，最优选4:1～3:2。
6.根据权利要求1-5所述的替格瑞洛-阿司匹林复方微丸制剂，其特征在于，所述微丸的平均粒径在0.25mm～0.85mm之间，优选0.35mm～0.55mm。
7.根据权利要求1-6所述的替格瑞洛-阿司匹林复方微丸制剂，其特征在于，制备方法如下：
(1)阿司匹林微丸制备：先将阿司匹林使用气流粉碎机粉碎后优选0.20mm～0.45mm之间粒径的原料与填充剂以及粘合剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得阿司匹林微丸用流化床干燥，控制水分在3％以内；
(2)阿司匹林隔离层包衣：配置3％的HPMC水溶液，加入聚乙二醇得到隔离层包衣液，将阿司匹林微丸置于流化床中，对其流化包衣并干燥；
(3)阿司匹林肠溶层包衣：选用甲基丙烯酸酯做包衣材料，并添加柠檬酸三乙酯及滑石粉混和均匀，对步骤(2)产物流化包衣并干燥；
(4)替格瑞洛速释微丸制备：先将替格瑞洛过30目筛后与填充剂、粘合剂以及润滑剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得替格瑞洛速释微丸用流化床干燥，控制水分在3％以内；
(5)替格瑞洛缓释微丸制备：先将替格瑞洛过30目筛后与填充剂、粘合剂、骨架材料、致孔剂、助流剂以及润滑剂混合均匀后，采用湿法制粒制备软材，所制软材应比片剂要求湿度略高，将软材倒入挤出机中挤出条状物，将条状物导入滚圆机中滚圆，最后将所得替格瑞洛速释微丸用流化床干燥，控制水分在3％以内。
8.根据权利要求1-7所述的替格瑞洛-阿司匹林复方微丸制剂，其特征在于，所述阿司匹林肠溶微丸、替格瑞洛速释微丸和替格瑞洛缓释微丸使用胶囊填充机将三种微丸装于胶囊壳中。
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