CN107530292A - 瑞博西尼片剂 - Google Patents
瑞博西尼片剂 Download PDFInfo
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Abstract
本发明关于瑞博西尼包括其盐的口服片剂。本发明的一个实施方式关于具有高载药量与即释曲线的瑞博西尼片剂。本发明的一个实施方式关于瑞博西尼的包衣片剂。本发明的另一实施方式关于瑞博西尼的包衣片剂，其中所述包衣是先进的防潮包衣(例如
Description
技术领域
本发明关于瑞博西尼(ribociclib)和/或其药学上可接受盐的片剂制剂，以及使用其进行治疗的方法。
背景技术
式(I)的化合物
已知是瑞博西尼。其化学名称为7-环戊基-N,N-二甲基-2-{[5-(哌嗪-1-基)吡啶-2-基]氨基}-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺，且其合成具体描述于WO 2010/020675 A1的实施例74中。
瑞博西尼的琥珀酸盐由式(II)描述：
且描述于WO2012/064805中。
瑞博西尼和其药学上可接受盐具有有价值的药理学特性，且可例如被用作(1)细胞周期蛋白依赖性激酶(尤其是选自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6和CDK9的细胞周期蛋白依赖性激酶)的抑制剂；和(2)糖原合成酶激酶-3(GSK-3)的调节剂和/或抑制剂。
瑞博西尼也以代码名称LEE011已知。
发明概述
本发明关于瑞博西尼(包括其盐和/或溶剂合物)的口服制剂。本发明的一个实施方式关于具有高载药量与即释曲线的瑞博西尼的片剂制剂。本发明的一个实施方式关于瑞博西尼的包衣片剂制剂。本发明的另一实施方式关于瑞博西尼的包衣片剂制剂，其中该包衣为先进的防潮包衣(例如amb II包衣，其中该包衣是以PVA为基础)。
附图说明
参考以下所描述的附图来说明本发明。
图1A和1B描绘制备瑞博西尼片剂的工艺流程图。未包衣片剂根据步骤1-8制备。包衣片剂根据步骤1-9制备。
图2展示采用(基于标准HPMC)和用amb II(基于PVA的先进防潮(AMB)包衣)制备的片剂图片。
图3展示采用标准和amb II包衣的瑞博西尼片剂的动态湿气吸附(DVS)数据。
图4展示通过100rpm的转篮和在37℃下具有不同pH值的溶解介质所获得的采用amb II包衣的瑞博西尼(LEE011)片剂的溶解曲线。
发明详述
本发明关于一种瑞博西尼或其药学上可接受盐的固体口服片剂剂型。该制剂具有良好的工艺性能和高稳定性。
本发明的片剂具有即释曲线。在处于标准溶解测试下45分钟后，这些片剂释放至少75％(Q)(其中Q是指由USP第<711>章定义的接受准则)的活性成分。在实施方式中，当使用100rpm的转篮且在37℃下以900ml的HCl pH 1作为溶解介质时，45分钟后片剂释放至少75％的活性成分。在另一实施方式中，当使用100rpm的转篮且在37℃下以900ml的HCl pH 2作为溶解介质时，45分钟后片剂释放至少75％的活性成分。在另一实施方式中，当使用100rpm的转篮且在37℃下以900ml的乙酸盐缓冲液pH 4.5作为溶解介质时，45分钟后片剂释放至少75％的活性成分。在另一实施方式中，当在37℃下使用100rpm的转篮且以900ml的磷酸盐缓冲液pH 6.8作为溶解介质时，45分钟后片剂释放至少75％的活性成分。
本发明的片剂可以是包衣的或未包衣的。
本发明片剂具有以核心片剂中瑞博西尼琥珀酸盐的w/w百分比进行测量时，至少40％、45％、50％、55％或60％的高载药量。
本发明片剂具有以核心片剂中瑞博西尼游离碱的w/w百分比进行测量时，至少32％、40％、44％、47％或52％的高载药量。
瑞博西尼琥珀酸盐的重量比(w/w)为核心片剂的至少40％。在一个实施方式中，瑞博西尼琥珀酸盐的重量比(w/w)为核心片剂的至少50％。在另一实施方式中，瑞博西尼琥珀酸盐的重量比(w/w)为核心片剂的至少55％。在另一实施方式中，瑞博西尼琥珀酸盐的重量比(w/w)为核心片剂的约55％至65％。在另一实施方式中，瑞博西尼琥珀酸盐的重量比(w/w)为核心片剂的约60％。
当就瑞博西尼游离碱来进行测量时，瑞博西尼的重量比(w/w)为核心片剂的至少32％。在一个实施方式中，瑞博西尼的重量比(w/w)为核心片剂的至少40％。在另一实施方式中，瑞博西尼的重量比(w/w)为核心片剂的至少44％。在另一实施方式中，瑞博西尼的重量比(w/w)为核心片剂的约44％至52％。在另一实施方式中，瑞博西尼的重量比(w/w)为核心片剂的约47％。
核心片剂也称作“片剂核心”。
在未包衣片剂中，片剂核心为整个片剂。在包衣片剂中，片剂核心为片剂排除包衣的部分。
根据本发明的片剂制剂可含有常用于药物制剂中的药学上可接受赋形剂，尤其例如用于口服施用的赋形剂，如填充剂、黏合剂、崩解剂和润滑剂。
填充剂例如可单独为纤维素、甘露醇、磷酸二钙、乳糖、微晶纤维素或其组合。
黏合剂例如可单独为羟丙基纤维素、聚乙烯吡咯烷酮或其组合。
崩解剂例如可单独为交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羟基乙酸淀粉钠或其组合。
润滑剂例如可单独为硬脂酸镁、硬脂酸、滑石、二氧化硅、硬脂酰富马酸钠或其组合。
举例而言，附图1A和1B展示制备瑞博西尼片剂的工艺流程图。未包衣片剂是根据步骤1-8制备。包衣片剂是根据步骤1-9制备。
在一个实施方式中，核心瑞博西尼片剂具有内相和外相，该内相包含瑞博西尼或其盐。
包衣材料：
本发明的瑞博西尼片剂为即释片剂且可采用任何即释的包衣材料包衣。例如包衣材料可为200、amb II、fxTM、II、或其混合物。200、amb II、fxTM、II和都可购自Colorcon,Inc。
在一个实施方式中，包衣材料为是HPMC(羟丙基甲基纤维素)包衣材料且具有下列组成：HPMC(Pharmacoat 603)71.4％、聚乙二醇7.15％、滑石7.15％和氧化铁14.3％。
在另一实施方式中，包衣材料为amb II。amb II是以PVA(聚乙烯醇)为基础的包衣材料且具有下列组成：聚乙烯醇45.52％、氧化铁32％、滑石20％、卵磷脂(大豆)2％和三仙胶0.48％。
当瑞博西尼片剂采用amb II包衣时，该片剂显示改良的外观且基本上没有开裂缺陷。
本发明在以下实施例中进一步描述。下列非限制性实施例说明本发明且不视为限制所附权利要求书的范围。
实施例1未包衣的50mg和200mg瑞博西尼片剂
下表1详述未包衣的50mg和200mg瑞博西尼片剂的组成。这些片剂是根据工艺流程图(图1A-1B)的步骤1-8制备。
表1.每剂型单位的组成
1盐因子为1.272。若药物物质含量为≤99.5％，其量增加，并相应减少微晶纤维素含量。
2植物来源
实施例2未包衣的100mg、150mg和300mg瑞博西尼片剂
下表2详述未包衣的100mg、150mg和300mg瑞博西尼片剂的组成。这些片剂根据工艺流程图(图1A-1B)的步骤1-8制备。
表2.每剂型单位的组成
1盐因子为1.272。若药物物质含量为≤99.5％，其量增加，并相应减少微晶纤维素含量。
2植物来源
实施例3(采用amb II包衣)包衣的50mg和200mg瑞博西尼片剂
下表3详述薄膜包衣的50mg和200mg瑞博西尼片剂的组成。这些片剂根据工艺流程图(图1A-1B)的步骤1-9制备。包衣材料为amb II，其为市售可得的且是以PVA为基础的先进防潮(AMB)包衣。
表3.每剂型单位的组成
1盐因子为1.272。若药物物质含量为≤99.5％，其量增加，并相应减少微晶纤维素含量。
2植物来源
3制备过量包衣以补偿包衣过程期间的损耗
4该包衣预混物为市售可得产品
5在加工期间去除
实施例4(采用amb II包衣)包衣的100mg、150mg和300mg瑞博西尼片剂
下表4详述薄膜包衣的100mg、150mg和300mg瑞博西尼片剂的组成。这些片剂根据工艺流程图(图1A-1B)的步骤1-9制备。包衣材料为ambII，其为市售可得的且是以PVA为基础的先进防潮(AMB)包衣。
表4.每剂型单位的组成
1盐因子为1.272。若药物物质含量为≤99.5％，其量增加，并相应减少微晶纤维素含量。
2植物来源
3制备过量包衣以补偿包衣过程期间的损耗
4包衣预混物为市售可得产品
5在加工期间去除
实施例5
比较采用不同包衣((基于标准HPMC)相比amb II(基于PVA的先进防潮(AMB)包衣材料))包衣的瑞博西尼片剂。在Bohle包衣机(1Kg规模)中以3g/min的喷雾速率进行包衣。用标准包衣时观察到片剂标识桥接问题和片剂开裂的缺陷。相比之下，用以PVA为基础的amb II包衣的片剂并未观察到开裂。
图2展示采用(基于标准HPMC)和采用amb II(基于PVA的先进防潮(AMB)包衣材料)制备的片剂的图像。
实施例6
采用标准和amb II包衣的瑞博西尼片剂的动态湿气吸附(DVS)数据显示于图3中。在50mg和200mg剂量单位下，与标准片剂相比，采用AMB包衣(amb II)包衣的片剂展示出更好的性能。
实施例7
在不同pH值的介质中评估采用amb II包衣的瑞博西尼片剂的溶解曲线。装置：离心篮，旋转：100rpm，体积：900mL，介质：HCl pH 1、HCl pH 2、乙酸盐缓冲液pH 4.5、磷酸盐缓冲液pH 6.8。图4展示在不同pH值的介质中，采用amb II薄膜包衣的瑞博西尼片剂的溶解曲线。
实施例8采用不同包衣预混物组合的(amb II包衣)包衣的50mg和200mg瑞博西尼片剂
下表5详述相比于实施例3，采用不同包衣预混物组合的薄膜包衣的50mg和200mg瑞博西尼片剂的组成。这些片剂根据工艺流程图(图1A-1B)的步骤1-9制备。包衣材料为amb II，其为市售可得的且是以PVA为基础的先进防潮(AMB)包衣。
表5.每剂型单位的组成
1盐因子为1.272。若药物物质含量为≤99.5％，其量增加，并相应减少微晶纤维素含量。
2植物来源
3制备过量包衣以补偿包衣过程期间的损耗
4包衣预混物为市售可得产品
5在加工期间去除
实施例9不同包衣预混物组合的(采用amb II包衣)包衣的100mg、150mg和300mg瑞博西尼片剂
下表6详述相比于实施例4，采用不同包衣预混物组合的薄膜包衣的100mg、150mg和300mg瑞博西尼片剂的组成。这些片剂根据工艺流程图(图1A-1B)的步骤1-9制备。包衣材料为amb II，其为市售可得的且是以PVA为基础的先进防潮(AMB)包衣。
表6.每剂型单位的组成
1盐因子为1.272。若药物物质含量为≤99.5％，其量增加，并相应减少微晶纤维素含量。
2植物来源
3制备过量包衣以补偿包衣过程期间的损耗
4包衣预混物为市售可得产品
5在加工期间去除
Claims (26)
1.一种药物口服片剂，其包含瑞博西尼或其药学上可接受盐。
2.如权利要求1的片剂，其包含瑞博西尼琥珀酸盐。
3.如权利要求1的片剂，其包含瑞博西尼或其盐，其中当根据USP<711>在37℃下以100rpm的转篮和900ml pH 2或pH 4.5的溶解介质测试时，45分钟后所述片剂释放至少75％的该瑞博西尼或其盐。
4.如权利要求1的片剂，其在片剂核心中包含瑞博西尼或其盐，其中就瑞博西尼游离碱进行测量时，所述片剂核心包含至少32％重量比(w/w)的瑞博西尼。
5.如权利要求4的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的至少40％。
6.如权利要求5的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的至少44％。
7.如权利要求6的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的约44％至52％。
8.如权利要求4的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的约47％。
9.一种包含瑞博西尼琥珀酸盐的药物口服片剂，其中瑞博西尼琥珀酸盐的重量比(w/w)为片剂核心的至少40％。
10.如权利要求9的片剂，其中瑞博西尼琥珀酸盐的重量比(w/w)为所述片剂核心的至少50％。
11.如权利要求10的片剂，其中瑞博西尼琥珀酸盐的重量比(w/w)为所述片剂核心的至少55％。
12.如权利要求11的片剂，其中瑞博西尼琥珀酸盐的重量比(w/w)为所述片剂核心的约55％至65％。
13.如权利要求9的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的约60％。
14.一种包衣药物口服片剂，其包含瑞博西尼或其药学上可接受盐，其中所述包衣包含聚乙烯醇(PVA)。
15.一种包衣药物口服片剂，其包含瑞博西尼琥珀酸盐，其中所述包衣包含PVA。
16.一种包含瑞博西尼或其盐的包衣药物口服片剂，其中当根据USP<711>在37℃下以100rpm的转篮和900ml pH 2或pH 4.5的溶解介质测试时，45分钟后所述片剂释放至少75％的所述瑞博西尼或其盐，且其中所述包衣包含PVA。
17.一种包含瑞博西尼或其盐的包衣药物口服片剂，其中就瑞博西尼游离碱来进行测量时，瑞博西尼的重量比(w/w)为所述片剂核心的至少32％，且其中所述包衣包含PVA。
18.如权利要求17的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的至少40％。
19.如权利要求18的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的至少44％。
20.如权利要求19的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的约44％至52％。
21.如权利要求17的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的约47％。
22.一种包含瑞博西尼琥珀酸盐的包衣药物口服片剂，其中瑞博西尼琥珀酸盐的重量比(w/w)为所述片剂核心的至少40％。
23.如权利要求22的片剂，其中瑞博西尼琥珀酸盐的重量比(w/w)为所述片剂核心的至少50％。
24.如权利要求23的片剂，其中瑞博西尼琥珀酸盐的重量比(w/w)为所述片剂核心的至少55％。
25.如权利要求24的片剂，其中瑞博西尼琥珀酸盐的重量比(w/w)为所述片剂核心的约55％至65％。
26.如权利要求22的片剂，其中瑞博西尼的重量比(w/w)为所述片剂核心的约60％。
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