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CN103476406B - 安它可朋组合物 - Google Patents

安它可朋组合物 Download PDF

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CN103476406B
CN103476406B CN201180070146.8A CN201180070146A CN103476406B CN 103476406 B CN103476406 B CN 103476406B CN 201180070146 A CN201180070146 A CN 201180070146A CN 103476406 B CN103476406 B CN 103476406B
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sds
pvp
antacropone
mannitol
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CN103476406A (zh
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郝为华
王钟靓
陈蕙筠
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Innopharmax Inc
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Abstract

本发明公开了一种安他可朋组合物，其包含安它可朋或其医药可接受盐，PVPK30及SDS；其中安它可朋：PVP K30：SDS的质量比为1：0.05～0.6：0.06～0.1。本发明还公开了安他可朋组合物的制备方法和应用。

Description

安它可朋组合物
技术领域
本发明是关于一种安它可朋(Entacapone)组合物，其包含安它可朋、PVP K30及SDS。此外，本发明亦关于所述安它可朋组合物的制备方法及其用途。
背景技术
安它可朋即(E)-2-氰基-3-(3，4-二羟基-5-硝基-苯基)-N，N-二乙基-2-丙烯酰胺((E)-2-cyano-3-(3，4-dihydroxy-5-nitro-phenyl)-N，N-diethyl-2-propenamide)，是目前已知可用于治疗帕金森氏症(Parkinson′s Disease)的药物。
由于安它可朋的溶离率及生体可用率低，目前已知的安它可朋组合物多以研磨或粉碎的方式将之制成尺寸较小的颗粒，以提高其溶离率及生体可用率。举例来说，US 2010/0104634 A1是使90％的安它可朋颗粒粒径小于40μm，而WO 2009098661 A1则是将安它可朋与糖醇的颗粒经微粒化工艺而使其粒径小于30μm。
然而，研磨或微粒化这类工艺往往会产生高热，而使药物变质，另外，此类工艺仍有产率低及成本高的问题。因此，如何在毋须研磨、粉碎或微粒化等工艺的情况下制备出溶离率或生体可用率高的安它可朋组合物，是业界亟待解决的课题。
发明内容
为解决上述问题，发明人开发出一种改良方法，能够在毋须研磨、粉碎或微粒化等工艺的情况下提高安它可朋的溶离率，并使工艺简化以提高产率及降低生产成本。
本发明目的之一是提供一种安它可朋组合物，其包含安它可朋或其医药可接受盐、PVP K30(Polyvinylpyrrolidone K30)、SDS(sodium dodecyl sulfate)，以及至少一种医药上可接受的赋形剂。
为达上述目的，本发明提供了一种安它可朋组合物，其包含安它可朋或其医药可接受盐、PVP K30及SDS；其中安它可朋∶PVP K30∶SDS的质量比为1∶0.05～0.6∶0.06～0.1，且其溶离率大于88％。
在本发明的较佳实施态样中，所述安它可朋组合物中的安它可朋∶PVPK30∶SDS的质量比为1∶0.05～0.2∶0.06；更佳者，其质量比为1∶0.2∶0.06。
在本发明的较佳实施态样中，所述安它可朋组合物的溶离率大于90％；更佳者，其溶离率大于95％。
在本发明的较佳实施态样中，所述安它可朋组合物进一步包含至少一种赋形剂，且所述赋形剂是选自聚维酮(Povidone)、交联聚维酮(Crospovidone)、糖类、交联羧甲基纤维素钠(Croscarmellose Sodium)，或其组合。所述糖类例如可选自微晶纤维素(Microcrystalline Cellulose，MCC)、甘露糖醇(Mannitol)、纤维素、羟丙基甲基纤维素(Hydroxypropyl Methylcellulose)、淀粉或乳糖。
本发明还提供了一种如前文所述的安它可朋组合物的制备方法，其包含下列步骤：
(a)将安它可朋或其医药可接受盐、PVP K30及SDS混合，其中安它可朋∶PVP K30∶SDS的质量比为1∶0.05～0.6∶0.06～0.1；
(b)使步骤(a)所得的混合物通过筛网，且该筛网的网目在180μm以下，更佳者，在150μm以下；
(c)将步骤(b)所得的混合物进行造粒；
(d)将步骤(c)所得的颗粒烘干，直至水分含量介于1％～3％，得出所述的安它可朋组合物；
以上方法不包含使安它可朋或其医药可接受盐、PVP K30及SDS的混合物的粒径小于30μm的研磨、粉碎或微粒化步骤。
在本发明的较佳实施态样中，所述方法步骤(a)中的安它可朋∶PVP K30∶SDS的质量比为1∶0.05～0.2∶0.06；更佳者，其质量比为1∶0.2∶0.06。
在本发明的较佳实施态样中，所述方法步骤(c)的造粒为湿式造粒。
在本发明的较佳实施态样中，所述方法不包含使安它可朋或其医药可接受盐、PVPK30及SDS的混合物的粒径小于40μm的研磨、粉碎或微粒化步骤。
在本发明的较佳实施态样中，所述方法步骤(a)进一步包含至少一种赋形剂，且所述赋形剂选自聚维酮、交联聚维酮、糖类、交联羧甲基纤维素钠，或其组合。所述糖类例如可选自微晶纤维素、甘露糖醇、纤维素、羟丙基甲基纤维素、淀粉或乳糖。
本发明另提供一种医药组合物，其包含如前文所述的安它可朋组合物；较佳者，是治疗帕金森氏症的医药组合物。
在本发明的较佳实施态样中，所述医药组合物进一步包含左多巴(Levodopa)及羟苯丝肼(Benserazide)、或进一步包含左多巴及卡比多巴(Carbidopa)。
本发明又提供一种将如前文所述的安它可朋组合物用于制备医药组合物的用途；较佳者，是用于制备治疗帕金森氏症的医药组合物。
在本发明的较佳实施态样中，所述用途所制备的医药组合物进一步包含左多巴及羟苯丝肼、或进一步包含左多巴及卡比多巴。
由上可知，本发明所提供的安它可朋组合物可在毋须研磨、粉碎或微粒化等工艺的情况下将安它可朋的溶离率提高到88％以上，与习知方法相较之下，不但省略研磨相关步骤而简化工艺，同时不会因为研磨相关步骤而导致高热而引发安它可朋变质的风险，亦可使产率提高，成本降低。
具体实施方式
下列实施例仅为最佳实施态样的例示，非意图限制本发明的范围。所属领域的技术人员可藉由本发明的揭露，在不背离本发明的精神的范围内做出适度的变更和修正。
实施例
首先依照下表1的组合物配比，制得安它可朋组合物1～6的颗粒。
将MCC、SDS、PVP K30、甘露糖醇及安它可朋依序混合5分钟，之后使混合物粉末通过150μm(100目)的筛网；再将通筛后的粉末倒入造粒机中，喷洒去离子水，以进行造粒。所得颗粒置于50℃烘箱中烘干，直至水分含量介于1％～3％，之后充入胶囊或是打锭，得出安它可朋组合物1～6。
表1
依据在FDA网站上提供的溶离方法数据库(Dissolution Methods Database)中检索得到安它可朋的药物溶离方法(http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm)进行溶离试验，其中溶离是使用USP标准搅拌桨式装置(paddle)，转速为50rpm，所用溶媒为900mL的pH5.5的磷酸缓冲溶液，试验时间为120分钟，之后利用HPLC进行分析，所得溶离率如下表2所示。
表2
由上可知，安它可朋本身的溶离率大约是81.15％，当安它可朋∶PVPK30∶SDS的质量比为1∶0.05～0.6∶0.06～0.1之时，所得安它可朋组合物的溶离率大幅增加，可达88％以上；当安它可朋∶PVP K30∶SDS的质量比为1∶0.05～0.2∶0.06之时，所得安它可朋组合物的溶离率可达90％以上；而当安它可朋∶PVP K30∶SDS的质量比为1∶0.2∶0.06时，其溶离率可达95％以上。
因此，利用上述配比在毋须研磨、粉碎或微粒化等工艺的情况下所得出的安它可朋组合物不但具有溶离率高、工艺简便等优点，亦没有因为研磨时产生高热而导致安它可朋变质的疑虑。

Claims (7)

1.一种安它可朋组合物的制备方法，其包含下列步骤：
(a)将MCC、SDS、PVP K30、甘露糖醇及安它可朋依序混合5分钟，其中每200mg的安它可朋，PVP K30、SDS、MCC及甘露糖醇的含量分别为10mg、12mg、0.5mg及168mg；或每200mg的安它可朋，PVP K30、SDS、MCC及甘露糖醇的含量分别为20mg、12mg、0.5mg及168mg；
(b)使步骤(a)所得的混合物通过150μm的筛网；
(c)将步骤(b)所得的混合物喷洒去离子水进行造粒；
(d)将步骤(c)所得的颗粒于50℃烘干，直至水分含量介于1％～3％，得出颗粒形式的安它可朋组合物；
以上方法不包含使安它可朋、PVP K30及SDS的混合物的粒径小于30μm的研磨、粉碎或微粒化步骤。
2.如权利要求1所述的方法，其中步骤(c)的造粒为湿式造粒。
3.如权利要求1所述的方法，其不包含使安它可朋、PVP K30及SDS的混合物的粒径小于40μm的研磨、粉碎或微粒化步骤。
4.一种安它可朋组合物，其包含安它可朋、PVP K30、SDS、MCC及甘露糖醇；其中每200mg的安它可朋，PVP K30、SDS、MCC及甘露糖醇的含量分别为10mg、12mg、0.5mg及168mg；或每200mg的安它可朋，PVP K30、SDS、MCC及甘露糖醇的含量分别为20mg、12mg、0.5mg及168mg；并且，所述安它可朋组合物为颗粒形式，且该组合物是以权利要求1-3中任一项所述的方法所制得的。
5.一种医药组合物，其包含如权利要求4所述的安它可朋组合物。
6.如权利要求5所述的医药组合物，其是治疗帕金森氏症的医药组合物。
7.一种将如权利要求4所述的安它可朋组合物用于制备用于治疗帕金森氏症的医药组合物的用途。
CN201180070146.8A 2011-04-26 2011-04-26 安它可朋组合物 Expired - Fee Related CN103476406B (zh)

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