CN108938586B - 一种含有喹啉衍生物或其盐的药物组合物的制备方法 - Google Patents

一种含有喹啉衍生物或其盐的药物组合物的制备方法 Download PDF

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CN108938586B
CN108938586B CN201811023692.6A CN201811023692A CN108938586B CN 108938586 B CN108938586 B CN 108938586B CN 201811023692 A CN201811023692 A CN 201811023692A CN 108938586 B CN108938586 B CN 108938586B
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卢韵
张新华
王晨阳
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Jiangsu Hengrui Medicine Co Ltd
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Abstract

本发明提供了一种含有喹啉衍生物或其盐的药物组合物的制备方法。具体而言，本发明提供了一种含有(R,E)‑N‑(4‑(3‑氯‑4‑(吡啶‑2‑基甲氧基)苯基氨基)‑3‑氰基‑7‑乙氧基喹啉‑6‑基)‑3‑(1‑甲基吡咯烷基‑2‑基)‑丙烯酰胺或其药理学上可接受的盐的药物组合物的制备方法，包括在本发明所述的药物组合物的制备过程中，使用含有至少一种有机溶剂的润湿剂进行湿法制粒。采用本发明所述方法制备的药物组合物具有制备过程中的颗粒分布均匀，组合物溶出迅速而且均一的特点。

Description

一种含有喹啉衍生物或其盐的药物组合物的制备方法
本申请是申请号为201780000924.3，申请日为2017年1月23日，发明名称为“一种含有喹啉衍生物或其盐的药物组合物的制备方法”的中国专利申请的分案申请。
技术领域
本发明属于药物制剂领域，具体涉及一种药物组合物的制备方法，所述组合物含有化学名为(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺的活性药物或其药理学上可接受的盐及至少一种药学上可接受的赋形剂，在本发明所述的药物组合物的制备过程中，使用含有至少一种有机溶剂的润湿剂进行湿法制粒。采用本发明所述方法制备的药物组合物具有制备过程中的颗粒分布均匀，组合物溶出迅速而且均一的特点。。
背景技术
CN102471312B公开了一种小分子化合物(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺，该化合物具有式I所示的结构，
Figure BDA0001787976480000011
已知其为小分子受体酪氨酸激酶抑制剂，抑制表皮生长因子受体(EGFR)和人表皮因子受体2(ERBB2)。其可以与细胞内EGFR和ERBB2的激酶区的ATP结合位点共价结合，阻止肿瘤细胞内EGFR和ERBB2的同质和异质二聚体形成，抑制其自身的磷酸化，阻断下游信号通路的激活，从而抑制肿瘤细胞生长。临床上可用于胃癌、肺癌、乳腺癌等多种肿瘤的治疗。
CN102933574B公开了式I化合物的马来酸盐形式，其相对于其他盐和式I化合物本身在溶解度以及生物利用度和药代动力学方面更具优势。
CN103974949B公开了式I化合物二马来酸盐的I型结晶。该晶型具有良好的晶型稳定性和化学稳定性，可用于制备治疗与EGFR受体酪氨酸激酶或HER-2受体酪氨酸激酶有关的疾病的药物。
但是，在将(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药学上可接受的盐制备成药物固体组合物时，由于活性成分溶解于水后在局部产生较大的粘性，不利于制成药物制剂，同时也造成了药物溶出度下降且不同个体的药物制剂溶出速度不均一。
发明内容
本发明的目的在于提供一种制备出溶出迅速、均一的药物组合物的方法，并且该药物组合物制备工艺简单，更适合工艺化大生产。
本发明提供了一种药物组合物的制备方法，包括：
将活性药物(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐与润湿剂混合并制粒。
其中药理学上可接受的盐可以是盐酸盐、马来酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐，优选马来酸盐，更优选二马来酸盐。基于组合物的总重量，所述活性成分的含量范围可以是基于组合物总重量剂计5％-70％，优选10％-50％，更优选20-40％。
在本发明提供的药物组合物的制备方法中，在制粒过程中，润湿剂最后可通过干燥过程去除。所述润湿剂可包含至少一种有机溶剂，还可包含水，其中有机溶剂可以是低毒性的有机溶剂，优选乙醇、丙酮等，更优选乙醇。基于润湿剂的总重量，所述有机溶剂的含量可以是20～100％，优选50～95％，更优选50～80％。
本发明提供了的药物组合物的制备方法，还包括将制得颗粒干燥，然后压片制成片剂或灌装制成胶囊，获得便于临床给药的口服固体制剂。
在本发明提供的药物组合物的制备方法中，药物组合物中可以含有一种或多种药学上可接受的赋形剂，例如填充剂、崩解剂、粘合剂、润滑剂等。
所述的填充剂可以是微晶纤维素、磷酸氢钙、甘露醇、预胶化淀粉、乳糖等中的一种或多种。基于组合物的总重量，所述填充剂含量为约5-80％。
所述的粘合剂可以是羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素等中的一种或多种，基于组合物的总重量，所述粘合剂含量为约0.5-15％。
所述的崩解剂可以是低取代羟丙基纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮中的一种或多种，其中优选交联聚乙烯吡咯烷酮，崩解剂的含量为基于组合物总重量的2-20％，优选4-15％，更优选6-10％。
所述的润滑剂可以是滑石粉、硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、胶体二氧化硅等中的一种或多种。基于组合物的总重量，润滑剂的含量为约0.5-5％。
在本发明提供的药物组合物的制备方法中，赋形剂中的一种或多种(例如填充剂、崩解剂、粘合剂)可以与润湿剂以及活性成分一起混合后制粒，然后干燥；或者在将仅有活性成分与润湿剂混合制得的颗粒干燥后加入一种或多种赋形剂；也可以将赋形剂的一部分与活性成分以及润湿剂一起混合而另一部分在制粒干燥后加入。优选地，将填充剂、崩解剂以及粘合剂与活性成分以及润湿剂一起混合，然后制粒干燥，再加入润滑剂。
本发明还提供了一种药物组合物的制备方法，包括：
将活性药物(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐与润湿剂混合，制粒，干燥，压片制成片剂或灌装制成胶囊，其中，所述润湿剂可以是乙醇与水的混合溶剂，所述乙醇的含量可以是基于润湿剂的总重量的50～80％，所述药物组合物还可以包含：
1)2-20wt％的崩解剂，所述崩解剂为交联聚乙烯吡咯烷酮；
2)5-80wt％的填充剂，所述填充剂选自乳糖和微晶纤维素中的一种或多种；
3)0.5-15wt％的粘合剂，所述粘合剂选自聚乙烯吡咯烷酮、羟丙基甲基纤维素及羟丙基纤维素中的一种或多种；
4)0.5-5wt％的润滑剂，所述润滑剂选自硬脂酸镁和滑石粉的一种或多种。
其中，所述各组分的含量百分比均以药物组合物总重量计。
根据本发明提供的药物组合物的制备方法，相较于纯水，包含了乙醇等低毒性有机溶剂的润湿剂在湿法制粒时制备出的颗粒粒径分布更加理想，制成口服固体制剂后，活性药物溶出更加迅速完全而且均一，更有利于药物发挥药效。
通过本发明提供的制备方法制得的药物组合物溶出迅速，起效显著，可用于胃癌、肺癌或乳腺癌等癌症的治疗。
附图说明
图1显示实施例1～5以及比较例1颗粒粒径分情况。
图2显示比较例1多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图3显示实施例1多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图4显示实施例2多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图5显示实施例3多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图6显示实施例4多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图7显示实施例5多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图8显示实施例6～11的片剂在0.1mol/L盐酸溶液中的溶出曲线。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1～5，比较例1
以表1的处方比例，将(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺的马来酸盐(以下简称为化合物A)、乳糖、微晶纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮混合，分别以适量纯化水、20wt％乙醇的水溶液、50wt％乙醇的水溶液、80wt％乙醇的水溶液、93.75wt％乙醇的水溶液和无水乙醇为润湿剂湿法制粒，干燥至水分小于2％进行干整粒，加入处方量的硬脂酸镁，采用旋转总混机进行混合。将得到的总混颗粒分装100g用于筛分，其余颗粒压片、包衣，制备成片剂。
表1
Figure BDA0001787976480000041
单位：质量％
实验例1：筛分实验
选取50目、100目筛网对实施例1～5以及比较例1得到的100g分装颗粒进行震荡筛分。比例较例1用纯化水作为润湿剂，制备的颗粒，大颗粒和细粉均较多，粒径分布不理想，实施例1～5使用含有乙醇的润湿剂，制备的颗粒粒径分布较均一，大颗粒和细粉均较少。
筛分结果见图1。
实验例2：溶出实验
根据中国药典2010版二部附录溶出度测定第二法(桨法)，对实施例1～5和比较例1的片剂进行溶出度测定。使用900ml的0.1mol/L盐酸溶液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例1～5用20wt％乙醇、50wt％乙醇、80wt％乙醇的水溶液、93.75wt％乙醇、无水乙醇作为润湿剂，制备的颗粒，粒径分布较理想，化合物A溶出迅速完全。比例较例1用纯化水作为润湿剂，制成的片剂中，化合物A溶出均一性不好。实施例1～5使用含有乙醇的润湿剂，制成的片剂中，化合物A溶出均一性较好。
溶出曲线图见图2～7，图中所示R1～R6为试验样品片1～片6。
实施例6～11
以表2的处方比例，将化合物A、乳糖、微晶纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮混合，以适量93.75wt％乙醇的水溶液为润湿剂进行湿法制粒，干燥至水分小于2％进行干整粒，加入处方量的硬脂酸镁，采用旋转总混机进行混合。将得到的总混颗粒压片、包衣，制备成片剂。
表2
Figure BDA0001787976480000051
单位：质量％
实验例3：溶出实验
根据中国药典2010版二部附录溶出度测定第二法(桨法)，对实施例6～11的片剂进行溶出度测定。使用900ml的0.1mol/L盐酸溶液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，处方中含有不同比例崩解剂的实施例6～9的片剂和处方中含有不同比例化合物A的实施例10、11的片剂中，化合物A溶出迅速完全。
溶出曲线图见图8。

Claims (7)

1.一种药物组合物的制备方法，包括：将活性药物(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐与润湿剂混合并制粒的步骤，还包括将制得颗粒干燥，然后压片制成片剂的步骤，
其中所述润湿剂为乙醇与水的混合溶剂，所述乙醇的含量为基于润湿剂总重量计的80-95wt％，
所述活性药物的含量为基于组合物总重量的10％-40％，
所述药物组合物还包含：
1)4-20wt％的崩解剂，所述崩解剂为交联聚乙烯吡咯烷酮；
2)5-80wt％的填充剂，所述填充剂选自乳糖和微晶纤维素中的一种或多种；
3)0.5-15wt％的粘合剂，所述粘合剂选自聚乙烯吡咯烷酮、羟丙基甲基纤维素及羟丙基纤维素中的一种或多种；
4)0.5-5wt％的润滑剂，所述润滑剂选自硬脂酸镁和滑石粉的一种或多种。
2.根据权利要求1所述的药物组合物的制备方法，其中所述活性药物的含量为基于组合物总重量的20-40％。
3.根据权利要求1所述的药物组合物的制备方法，其中所述药理学上可接受的盐为马来酸盐。
4.根据权利要求3所述的药物组合物的制备方法，其中所述药理学上可接受的盐为二马来酸盐。
5.通过权利要求1到4任一项所述的制备方法得到的药物组合物。
6.权利要求5所述的药物组合物在制备治疗癌症的药物中的用途。
7.根据权利要求6所述的用途，其中所述癌症选自胃癌、肺癌或乳腺癌。
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