CN114848604A - 一种恩格列净和盐酸二甲双胍复方制剂及其制备方法 - Google Patents
一种恩格列净和盐酸二甲双胍复方制剂及其制备方法 Download PDFInfo
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- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 87
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- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- -1 metformin hydrochloride compound Chemical class 0.000 title abstract description 8
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 80
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 21
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- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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Abstract
本发明公开了一种恩格列净和盐酸二甲双胍复方制剂及其制备方法,复方制剂包括恩格列净颗粒和盐酸二甲双胍颗粒;所述恩格列净颗粒包括恩格列净,波拉克林钾,麦芽糖‑环糊精,崩解剂,粘合剂;盐酸二甲双胍颗粒包括盐酸二甲双胍,稀释剂,崩解剂,粘合剂;其中恩格列净粒径d0.9不大于30μm。本发明复方制剂能够解决恩格列净和盐酸二甲双胍用量悬殊而不易控制含量均匀度的问题;同时能有效克服恩格列净溶解性差的问题,实现恩格列净和盐酸二甲双胍的溶出曲线与原研上市产品一致的效果。
Description
技术领域
本发明属于医药制剂技术领域,具体地说,涉及一种恩格列净和盐酸二甲双胍复方制剂及其制备方法。
背景技术
恩格列净作为SGLT-2抑制剂药物,已被证实能够阻断肾脏中葡萄糖的再吸收作用,将过多的葡萄糖排泄到体外,从而达到降低血糖水平的效果,而且该降糖效果不依赖于β细胞功能和胰岛素抵抗。与安慰剂相比,恩格列净除了能有效降低血糖外,还有助于减轻体重和降低血压。临床上,恩格列净用于改善2型糖尿病患者的血糖控制。恩格列净可与盐酸二甲双胍联合使用,在饮食和运动基础上改善2型糖尿病患者的血糖控制。恩格列净/盐酸二甲双胍片是由勃林格殷格翰公司开发用于治疗糖尿病的复方制剂。2015年5月,欧盟批准恩格列净/盐酸二甲双胍的上市申请。2015年8月,FDA批准恩格列净盐酸二甲双胍复方上市。
恩格列净化学名称为:(1S)-1,5-脱水-1-(4-氯-3-{4-[(3S)-四氢呋喃-3-氧基]苄基}苯基]-D-葡萄糖醇,其结构式为:
恩格列净是白色至浅黄色,无吸湿性粉末。极微溶于水,难溶于甲醇,微溶于乙醇和乙腈,可溶于50%乙腈水溶液,几乎不溶于甲苯。恩格列净溶解性较低,而盐酸二甲双胍易溶于水;并且已上市的恩格列净盐酸二甲双胍复方制剂中,单位制剂中盐酸二甲双胍用量为500-1000mg,恩格列净用量为5-12.5mg,二者用量差异非常大,很容易发生不能完全混匀,造成含量均匀度差的问题。在实际生产中,如何使恩格列净和盐酸二甲双胍复方制剂中恩格列净同盐酸二甲双胍一起快速溶出,并且具有较好的含量均匀度仍是非常具有挑战性。
因此,如何解决药物成分用量悬殊导致含量均匀度差和恩格列净溶解性差的问题是目前丞待解决的问题。
发明内容
鉴于此,本发明提供一种恩格列净和盐酸二甲双胍复方制剂,该复方制剂能够解决恩格列净和盐酸二甲双胍用量悬殊而不易控制含量均匀度的问题,获得含量均匀的复方制剂;同时能有效克服恩格列净溶解性差的问题,使恩格列净能快速溶出,实现恩格列净和盐酸二甲双胍的溶出曲线与原研上市产品一致的效果。本发明还提供一种制备恩格列净和盐酸二甲双胍复方制剂的方法,该方法简单、易操作,常规设备即可满足生产要求,质量可控,适合工业化大规模生产。
本发明提供一种恩格列净和盐酸二甲双胍复方制剂,该复方制剂包括恩格列净颗粒和盐酸二甲双胍颗粒;所述恩格列净颗粒包括恩格列净,波拉克林钾,麦芽糖-环糊精,崩解剂,粘合剂;盐酸二甲双胍颗粒包括盐酸二甲双胍,稀释剂,崩解剂,粘合剂;其中恩格列净粒径d0.9不大于30μm。
本发明为了解决恩格列净和盐酸二甲双胍用量差异悬殊,将恩格列净和盐酸二甲双胍分别制成颗粒,得到恩格列净和盐酸二甲双胍复方制剂具有良好的含量均匀度。并且由于恩格列净溶解性差,为了使恩格列净与盐酸二甲双胍一起快速溶出,本发明控制恩格列净粒径d0.9不大于30μm,在恩格列净颗粒中加入波拉克林钾和麦芽糖-环糊精,通过恩格列净粒径控制,以及波拉克林钾和麦芽糖-环糊精的配合,能很好的促进恩格列净的溶出,克服恩格列净溶解性差的问题。
上述的恩格列净和盐酸二甲双胍复方制剂中,优选的,恩格列净粒径d0.9为8-30μm。
为了更好的控制恩格列净的溶出,对恩格列净颗粒中波拉克林钾和麦芽糖-环糊精的用量进行考察,得到波拉克林钾和麦芽糖-环糊精的质量用量比为1-5:1。
上述的恩格列净和盐酸二甲双胍复方制剂中,崩解剂为羧甲基淀粉钠,低取代羟丙基纤维素,交联聚维酮,交联羧甲基纤维素钠中的一种或几种。
上述恩格列净和盐酸二甲双胍复方制剂中,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,聚维酮中的一种或几种。
上述恩格列净和盐酸二甲双胍复方制剂中,恩格列净颗粒还包括稀释剂。
上述恩格列净和盐酸二甲双胍复方制剂中,稀释剂为微晶纤维素,预胶化淀粉,乳糖,磷酸氢钙,山梨醇,淀粉,蔗糖中的一种或几种。
上述恩格列净和盐酸二甲双胍复方制剂中,恩格列净颗粒和\或盐酸二甲双胍颗粒还包括润滑剂。
上述恩格列净和盐酸二甲双胍复方制剂中,润滑剂为硬脂酸镁,微粉硅胶,滑石粉中的一种或几种。
上述恩格列净和盐酸二甲双胍复方制剂中,复方制剂各组分用量以质量份数计为:
恩格列净颗粒包括恩格列净5-12.5份,波拉克林钾30-70份,麦芽糖-环糊精10-30份,崩解剂2-5份,粘合剂2-5份;
盐酸二甲双胍颗粒包括盐酸二甲双胍500-1000份,稀释剂24-50份,崩解剂20-50份,粘合剂6-18份;
其中盐酸二甲双胍用量以二甲双胍计算。
本发明还提供一种恩格列净和盐酸二甲双胍复方制剂的制备方法,所述方法包括以下步骤:
(1)将恩格列净,波拉克林钾,麦芽糖-环糊精,崩解剂和粘合剂混合均匀,湿法制粒,干燥,得恩格列净颗粒;
(2)将盐酸二甲双胍,稀释剂,崩解剂和粘合剂混合均匀,湿法制粒,干燥,得盐酸二甲双胍颗粒;
(3)将恩格列净颗粒和盐酸二甲双胍颗粒混合均匀,压片。
上述恩格列净和盐酸二甲双胍复方制剂的制备方法中,步骤(1)还包括加入稀释剂和\或润滑剂的步骤;步骤(2)还包括加入润滑剂的步骤。
与现有技术相比,本发明的有益效果为:
1.本发明通过在恩格列净颗粒中,限定恩格列净粒径d0.9不大于30μm,再在处方中加入波拉克林钾和芽糖-环糊精辅料,并配合崩解剂和粘合剂,能促进恩格列净快速溶出。
2.本发明将恩格列净和盐酸二甲双胍分别制成颗粒,再混合压片,能够很好解决恩格列净与盐酸二甲双胍用量悬殊而不易控制含量均匀度的问题。
具体实施方式
实施例1
恩格列净d0.9=18μm。
制备方法:
(1)将恩格列净,波拉克林钾,麦芽糖-环糊精,低取代羟丙基纤维素和羟丙基纤维素混合均匀,湿法制粒,干燥,得恩格列净颗粒;
(2)将盐酸二甲双胍,微晶纤维素,低取代羟丙基纤维素和羟丙基纤维素混合均匀,湿法制粒,干燥,得盐酸二甲双胍颗粒;
(3)恩格列净颗粒和盐酸二甲双胍颗粒混合均匀,压片。
实施例2
恩格列净d0.9=20μm。
制备方法:
(1)将恩格列净,波拉克林钾,麦芽糖-环糊精,交联聚维酮和羟丙基甲基纤维素混合均匀,湿法制粒,干燥,得恩格列净颗粒;
(2)将盐酸二甲双胍,预胶化淀粉,山梨醇,羧甲基淀粉钠和羟丙基纤维素混合均匀,湿法制粒,干燥,得盐酸二甲双胍颗粒;
(3)恩格列净颗粒和盐酸二甲双胍颗粒混合均匀,压片。
实施例3
恩格列净d0.9=30μm。
制备方法:
(1)将恩格列净,波拉克林钾,麦芽糖-环糊精,低取代羟丙基纤维素,羧甲基纤维素钠和乳糖混合均匀,湿法制粒,干燥,得恩格列净颗粒;
(2)将盐酸二甲双胍,磷酸氢钙,淀粉,低取代羟丙基纤维素,交联羧甲基纤维素钠和羟丙基纤维素混合均匀,湿法制粒,干燥,得盐酸二甲双胍颗粒;
(3)恩格列净颗粒,盐酸二甲双胍颗粒和硬脂酸镁混合均匀,压片。
实施例4
恩格列净d0.9=12μm。
制备方法:
(1)将恩格列净,波拉克林钾,麦芽糖-环糊精,低取代羟丙基纤维素,聚维酮和微粉硅胶混合均匀,湿法制粒,干燥,得恩格列净颗粒;
(2)将盐酸二甲双胍,微晶纤维素,低取代羟丙基纤维素和羟丙基纤维素,聚维酮和滑石粉混合均匀,湿法制粒,干燥,得盐酸二甲双胍颗粒;
(3)恩格列净颗粒和盐酸二甲双胍颗粒混合均匀,压片。
实施例5
恩格列净d0.9=10μm。
制备方法:
(1)将恩格列净,波拉克林钾,麦芽糖-环糊精,羧甲基淀粉钠,低取代羟丙基纤维素,羟丙基纤维素和硬脂酸镁混合均匀,湿法制粒,干燥,得恩格列净颗粒;
(2)将盐酸二甲双胍,微晶纤维素,山梨醇,低取代羟丙基纤维素和羟丙基纤维素混合均匀,湿法制粒,干燥,得盐酸二甲双胍颗粒;
(3)恩格列净颗粒和盐酸二甲双胍颗粒混合均匀,压片。
实施例6
恩格列净d0.9=8μm。
制备方法:
(1)将恩格列净,波拉克林钾,麦芽糖-环糊精,交联羧甲基纤维素钠和聚维酮混合均匀,湿法制粒,干燥,得恩格列净颗粒;
(2)将盐酸二甲双胍,微晶纤维素,蔗糖,低取代羟丙基纤维素,羟丙基纤维素和微粉硅胶混合均匀,湿法制粒,干燥,得盐酸二甲双胍颗粒;
(3)恩格列净颗粒,盐酸二甲双胍颗粒和硬脂酸镁混合均匀,压片。
对比例
制备方法同实施例1。
含量均匀度试验
采用HPLC法测定实施例,对比例所得样品及市售品(商品名为Synjardy;规格:以恩格列净、盐酸二甲双胍计5mg/500mg)中恩格列净的含量均匀度,结果如下:
本发明考察了用量较小的恩格列净的含量均匀度,由上述试验数据可知,按照本发明制得的样品的恩格列净具有很好的含量均匀度,符合中国药典规定。
溶出度考察
取实施例、对比例所得样品及市售品,根据中国药典2020年版四部9031溶出度与溶出度测定法,以pH6.8磷酸盐缓冲液作为溶出介质,转速为每分钟75rpm,于5min、10min、15min、20min、30min测定恩格列净和盐酸二甲双胍的溶出度(%)。所得结果如下:
由上述实验数据可知,本发明实施例中加入波拉克林钾和麦芽糖-环糊精,并且恩格列净粒径d0.9控制不大于30μm,能够促进恩格列净溶出,得到恩格列净和盐酸二甲双胍的溶出曲线与原研上市产品一致的效果。而对比例1中采用羟丙基-β-环糊精代替麦芽糖-环糊精,对比例2-3不同时含有波拉克林钾和麦芽糖-环糊精,以及对比例4中恩格列净粒径d0.9大于30μm,得到样品的溶出效果差。
Claims (10)
1.一种恩格列净和盐酸二甲双胍复方制剂,其特征在于,所述复方制剂包括恩格列净颗粒和盐酸二甲双胍颗粒;所述恩格列净颗粒包括恩格列净,波拉克林钾,麦芽糖-环糊精,崩解剂,粘合剂;盐酸二甲双胍颗粒包括盐酸二甲双胍,稀释剂,崩解剂,粘合剂;其中恩格列净粒径d0.9不大于30μm。
2.根据权利要求1所述的恩格列净和盐酸二甲双胍复方制剂,其特征在于,所述波拉克林钾和麦芽糖-环糊精的质量用量比为1-5:1。
3.根据权利要求1所述的恩格列净和盐酸二甲双胍复方制剂,其特征在于,所述崩解剂为羧甲基淀粉钠,低取代羟丙基纤维素,交联聚维酮,交联羧甲基纤维素钠中的一种或几种。
4.根据权利要求1所述的恩格列净和盐酸二甲双胍复方制剂,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,聚维酮中的一种或几种。
5.根据权利要求1所述的恩格列净和盐酸二甲双胍复方制剂,其特征在于,所述恩格列净颗粒还包括稀释剂。
6.根据权利要求1或5所述的恩格列净和盐酸二甲双胍复方制剂,其特征在于,所述稀释剂为微晶纤维素,预胶化淀粉,乳糖,磷酸氢钙,山梨醇,淀粉,蔗糖中的一种或几种。
7.根据权利要求1所述的恩格列净和盐酸二甲双胍复方制剂,其特征在于,所述恩格列净颗粒和\或盐酸二甲双胍颗粒还包括润滑剂。
8.根据权利要求7所述的恩格列净和盐酸二甲双胍复方制剂,其特征在于,所述润滑剂为硬脂酸镁,微粉硅胶,滑石粉中的一种或几种。
9.根据权利要求1所述的恩格列净和盐酸二甲双胍复方制剂,其特征在于,所述复方制剂各组分用量以质量份数计为:
恩格列净颗粒包括恩格列净5-12.5份,波拉克林钾30-70份,麦芽糖-环糊精10-30份,崩解剂2-5份,粘合剂2-5份;
盐酸二甲双胍颗粒包括盐酸二甲双胍500-1000份,稀释剂24-50份,崩解剂20-50份,粘合剂6-18份;
其中盐酸二甲双胍用量以二甲双胍计算。
10.一种权利要求1所述恩格列净和盐酸二甲双胍复方制剂的制备方法,其特征在于,所述方法包括以下步骤:
(1)将恩格列净,波拉克林钾,麦芽糖-环糊精,崩解剂和粘合剂混合均匀,湿法制粒,干燥,得恩格列净颗粒;
(2)将盐酸二甲双胍,稀释剂,崩解剂和粘合剂混合均匀,湿法制粒,干燥,得盐酸二甲双胍颗粒;
(3)将恩格列净颗粒和盐酸二甲双胍颗粒混合均匀,压片。
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