CN104884051A - 包含吉格列汀和二甲双胍的组合药物及其制备方法 - Google Patents
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Abstract
本发明涉及一种包含作为活性组分的吉格列汀和二甲双胍的组合药物及其制备方法。本发明的由包含二甲双胍的第一层和包含吉格列汀的第二层组成的药物组合物对于预防和治疗糖尿病及其复杂疾病具有优异效果，并降低了每种组分的副作用。另外，本发明的组合物包含分离形式的吉格列汀和二甲双胍，以便保持这两种组分的固有溶出速率和改善患者顺应性。
Description
技术领域
本发明涉及一种包含作为活性组分的吉格列汀(Gemigliptin)和二甲双胍的组合药物及其制备方法。
背景技术
糖尿病分成两种类型——即，胰岛素依赖性1型糖尿病和非胰岛素依赖性(胰岛素抵抗性)2型糖尿病，后者占糖尿病患者的90％以上。
2型糖尿病是来源于包括胰岛素抗性和胰岛素分泌病症的双重内分泌作用的复杂病态生理学的慢性进行性疾病。2型糖尿病的治疗通常从饮食和锻炼开始，并通向其中使用口服抗糖尿病药的单独药物疗法。尽管在某些患者中，在初期阶段可利用单独的常规药物疗法来控制血糖水平，但是在大多数患者中，在诊断后数年需要组合治疗，因为他们的血糖水平不能通过单独的药物疗法来控制。然而，因为2型糖尿病是一种进行性疾病，所以对常规组合治疗表现出良好的始初反应的大多数患者在长期维持稳定的血糖水平上遇到困难，并需要增加给药量或另外的治疗。虽然目前使用的组合治疗具有增强血糖控制的可能性，但是它们具有自身的局限性以及副作用，比如低血糖症、体重增加等。而且，两种或更多种口服抗糖尿病药的组合引起许多患者不适，并且可能导致患者不愿意遵循药物方案从而治疗失败。
吉格列汀是一种新开发的DPP-IV抑制剂，其活化肠促胰岛素，以表现出稳定的血糖水平下降。而且，吉格列汀不具有常规口服抗糖尿病药的缺点比如低血糖症和体重增加，且表现出低心血管病症风险，从而其已经超越磺酰脲类。
考虑上述，为了增强疗效、减轻副作用并改善患者顺应性，本发明人对于具有不同作用机制的两种或更多种抗糖尿病药的组合进行了深入研究。作为这种努力的结果，本发明人发现可以通过吉格列汀和二甲双胍的组合来实现这样的目的，因此完成了本发明。
发明内容
技术问题
本发明的目的是提供用于预防和治疗糖尿病的药物组合物，其包含作为活性组分的具有不同作用机制的抗糖尿病药。
本发明的另一个目的是提供制备用于预防和治疗糖尿病的药物组合物的方法，所述药物组合物包含作为活性组分的具有不同作用机制的抗糖尿病药。
解决问题的技术方案
因此，本发明提供药物组合物，其由包含二甲双胍的第一层和包含吉格列汀的第二层组成。
在本发明的药物组合物中，可以用包含吉格列汀的第二层包覆包含二甲双胍的第一层。
本发明的另一个目的是通过制备包含吉格列汀和二甲双胍的组合药物的方法实现的，所述方法包括以下步骤：
(a)将吉格列汀与药学可接受的赋形剂混合；
(b)将二甲双胍与药学可接受的赋形剂混合，并将混合物制粒；和
(c)将步骤(a)中制备的混合物与步骤(b)中制备的颗粒混合。
在本发明的方法中，步骤(c)优选地通过将包含吉格列汀的混合物和包含二甲双胍的颗粒压制成双层片剂来进行。或者，步骤(c)可以通过用包含吉格列汀的混合物包覆由包含二甲双胍的颗粒制成的片剂来进行。
根据本发明，由于组合了作为具有不同的作用机制的抗糖尿病药的DPP-IV抑制剂吉格列汀和二甲双胍，因此药物的协同作用增强了疗效、减轻了副作用，并且改善了患者顺应性。
而且，为了克服由于吉格列汀和二甲双胍的组合引起的问题并获得与单独药物相同的溶出度，本发明提供包含呈分离形式的吉格列汀和二甲双胍的组合药物。
因此，本发明的第一方面涉及药物组合物，其由包含二甲双胍的第一层和包含吉格列汀的第二层组成的双层。
本发明的另一方面涉及药物组合物，其中用包含吉格列汀的第二层包覆包含二甲双胍的第一层。
为了制备本发明的包含呈分离形式的吉格列汀和二甲双胍的组合药物，将吉格列汀制备成与赋形剂的混合物，将二甲双胍制粒，然后可以通过将二者混合来制备吉格列汀和二甲双胍的组合药物。
特别地，本发明的组合药物的制备方法包括以下步骤：
(a)将吉格列汀与药学可接受的赋形剂混合；
(b)将二甲双胍和药学可接受的赋形剂的混合物湿法制粒，并将颗粒干燥；和
(c)将步骤(a)中制备的包含吉格列汀的混合物与步骤(b)中制备的包含二甲双胍的颗粒混合。
在本发明的方法的一个实施方案中，分别制备包含吉格列汀的混合物和包含二甲双胍的颗粒，然后将其压制成由吉格列汀层和二甲双胍层组成的双层片剂。该组合药物表现出快速释放吉格列汀和持续释放二甲双胍的溶出模式，并且这两种溶出模式不会相互影响。
在本发明的另一个实施方案中，用吉格列汀层包覆包含二甲双胍的片剂。该包衣的组合药物可以通过将二甲双胍颗粒压制成片剂，将其进一步用与包衣基质混合的吉格列汀包覆来制备。
本发明的药物组合物可以包含药学可接受的载体或添加剂。在本发明的一个实施方案中，所述药物组合物可以包含药学可接受的赋形剂、崩解剂、粘合剂、润滑剂等。所述赋形剂可以包括但不限于微晶纤维素。所述崩解剂可以包括但不限于交联羧甲纤维素钠、交聚维酮、淀粉羟乙酸钠等。所述粘合剂可以包括但不限于聚乙烯吡咯烷酮、共聚维酮(copovidone)等。所述润滑剂可以包括但不限于胶态二氧化硅、水合二氧化硅(hydrous silicon dioxide)、硬脂酸镁、硬脂酰基富马酸钠山嵛酸甘油酯硬脂酸钙、硬脂酸、滑石等。
在本发明的另一个实施方案中，包含吉格列汀的第二层可以不包含粘合剂。
另外，本发明的药物组合物可以是薄膜包衣的。薄膜包衣中可用的物质可以包括常规物质，比如羟丙基甲基纤维素、聚乙烯吡咯烷酮、共聚维酮、系列、系列，但不限于此。
在本发明的组合药物中，作为活性组分的吉格列汀可以吉格列汀酒石酸盐·1.5水合物的形式被包含，用量为基于吉格列汀层的总重量的10至80重量％，优选10至70重量％。作为另一活性组分的二甲双胍可以二甲双胍盐酸盐的形式被包含，用量为基于二甲双胍层总重量的40至80重量％，优选50至70重量％。
在本发明中，吉格列汀层可以包含20至90重量％的药学可接受的添加剂，并且二甲双胍层可以包括20至60重量％的药学可接受的添加剂。这样的比例适用于包括分离颗粒剂在内的本发明的所有制剂。如果制剂具有偏离上述范围的比例，则可能产生过大的片剂，因而降低给药便利性。为了给药便利性，吉格列汀层可以优选地为基于二甲双胍层的40重量％或更少，更优选30重量％或更少，最优选20重量％或更少。
在本发明中，二甲双胍层显示持续释放的溶出模式，并且可以使用用于该溶出模式的各种药学可接受的组分。最优选地，使用预胶化淀粉构建用于该目的的持续释放基质。所述持续释放基质组分以基于二甲双胍盐酸盐重量的40至80重量％，更优选50至70重量％，最优选55至65重量％的量被包含。
对于本发明的药物组合物而言，可以使用多种药学可接受的吉格列汀盐，其中吉格列汀酒石酸盐·1.5水合物是最优选的形式。吉格列汀酒石酸盐·1.5水合物的结构和制备方法公开在韩国专利第0776623号中，其公开内容援引加入本文。另外，对于本发明的药物组合物而言，可以使用多种药学可接受的二甲双胍盐，其中二甲双胍盐酸盐是最优选的形式。
发明的有益效果
由于具有不同作用机制的两种组分的协同组合，本发明的包含吉格列汀和二甲双胍的药物组合物对于预防和治疗糖尿病及其复杂疾病具有优异功效，并降低了每种组分的副作用。另外，本发明提供包含呈分离形式的吉格列汀和二甲双胍的组合药物，从而可以克服由于组合引起的问题，并且与单一组分的药物相比可以获得这两种组分的相同溶出速率。
附图简述
图1为显示与比较例1的单一组分药物相比，实施例1和2的组合药物的吉格列汀的溶出试验结果的图。
图2为显示与比较例1的单一组分药物相比，实施例1和2的组合药物的二甲双胍的溶出试验结果的图。
发明的实施方式
通过下述实施例更详细地解释本发明。然而，这些实施例仅用于例示本发明，而本发明的范围不限于此。
实施例1和2：制备包含吉格列汀和二甲双胍的双层片剂
在这些实施例中制备其中快速释放吉格列汀而不会影响持续释放二甲双胍的吉格列汀和二甲双胍的组合药物。
[表1]
通过使用聚乙烯吡咯烷酮作为粘合剂，将二甲双胍盐酸盐、微晶纤维素和预胶化淀粉的混合物制粒，将制备的颗粒干燥，并与卡波姆和硬脂酸镁混合，以制备二甲双胍层物质。制备包括吉格列汀酒石酸盐·1.5水合物的所有组分的简单混合物作为吉格列汀层物质。将二甲双胍层物质和吉格列汀层物质两者压制成双层片剂，并使用Opadry II对该片剂进行薄膜包衣。
比较例1：吉格列汀的单一组分药物和二甲双胍的单一组分药物
使用LG Life Sciences Ltd.生产的吉格列汀50mg片剂作为吉格列汀的单一组分药物，并且使用市售可获得的Glucophage XR 500mg片剂作为二甲双胍的单一组分药物。
试验例1：实施例和比较例的制剂的吉格列汀和二甲双胍的溶出试验
对于实施例1和2的双层片剂和比较例1的单一组分药物，在下述条件下进行溶出试验并比较。
[溶出条件]
洗出液：pH 1.2(900mL)
仪器：美国药典篮法(USP Basket Method)，100rpm
温度：37℃
[结果]
图1和图2为显示与比较例1的单一组分药物相比，实施例1和2的组合药物的吉格列汀和二甲双胍的溶出试验结果的图。
如图1和图2所证实的，与比较例1的单一组分药物相比，实施例1和2中制备的包含吉格列汀和二甲双胍的包衣双层片剂表现出类似的溶出速率。
Claims (8)
1.药物组合物，其由包含二甲双胍的第一层和包含吉格列汀的第二层组成。
2.根据权利要求1的组合物，其中用所述包含吉格列汀的第二层包覆所述包含二甲双胍的第一层。
3.根据权利要求1的组合物，其中所述第一层还包含预胶化淀粉。
4.根据权利要求1或3的组合物，其中所述第二层还包含微晶纤维素。
5.制备包含吉格列汀和二甲双胍的组合药物的方法，其包括以下步骤：
(a)将吉格列汀与药学可接受的赋形剂混合；
(b)将二甲双胍与药学可接受的赋形剂混合，并将混合物制粒；和
(c)将步骤(a)中制备的混合物与步骤(b)中制备的颗粒混合。
6.根据权利要求5的方法，其中步骤(c)是通过将步骤(a)中制备的包含吉格列汀的混合物和步骤(b)中制备的包含二甲双胍的颗粒压制成双层片剂来进行的。
7.根据权利要求5的方法，其中步骤(c)是通过用步骤(a)中制备的包含吉格列汀的混合物包覆由步骤(b)中制备的包含二甲双胍的颗粒制成的片剂来进行的。
8.根据权利要求5的方法，其中所述药学可接受的赋形剂选自聚乙烯吡咯烷酮、微晶纤维素、预胶化淀粉、卡波姆、硬脂酸镁、交联羧甲纤维素钠和硬脂酰基富马酸钠。
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