CN107530292B - 瑞博西尼片剂 - Google Patents
瑞博西尼片剂 Download PDFInfo
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- CN107530292B CN107530292B CN201680022122.8A CN201680022122A CN107530292B CN 107530292 B CN107530292 B CN 107530292B CN 201680022122 A CN201680022122 A CN 201680022122A CN 107530292 B CN107530292 B CN 107530292B
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- ribociclib
- crospovidone
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- magnesium stearate
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- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 title abstract description 36
- 229950003687 ribociclib Drugs 0.000 title abstract description 35
- 239000003826 tablet Substances 0.000 claims abstract description 95
- 238000000576 coating method Methods 0.000 claims abstract description 55
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- NHANOMFABJQAAH-UHFFFAOYSA-N butanedioic acid;7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound OC(=O)CCC(O)=O.N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 NHANOMFABJQAAH-UHFFFAOYSA-N 0.000 claims description 18
- 229950010518 ribociclib succinate Drugs 0.000 claims description 18
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 13
- 229960000913 crospovidone Drugs 0.000 claims description 13
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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 (14)
1.一种包衣药物口服片剂，具有片剂核心与包衣，所述片剂核心含至少50％(w/w)瑞博西尼琥珀酸盐，所述包衣包含45.52％聚乙烯醇(PVA)、20％滑石、2％卵磷脂和0.48％三仙胶且不含羟丙基甲基纤维素(HPMC)，并且，当根据USP第<711>章在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％的瑞博西尼琥珀酸盐。
2.如权利要求1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％。
3.如权利要求1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55％至65％。
4.如权利要求1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60％。
5.一种包衣片剂，具有片剂核心与包衣，所述片剂核心包含：
(a)内相，所述内相包含：
(i)瑞博西尼琥珀酸盐；
(ii)微晶纤维素；
(iii)羟丙基纤维素；
(iv)交聚维酮；
(v)胶态二氧化硅；和
(vi)硬脂酸镁；和
(b)外相，所述外相包含：
(i)交聚维酮；
(ii)胶态二氧化硅；
(iii)硬脂酸镁；且
其中，瑞博西尼琥珀酸盐含量为按所述片剂核心重量计至少50％，所述包衣包含45.52％聚乙烯醇(PVA)、20％滑石、2％卵磷脂和0.48％三仙胶且不含羟丙基甲基纤维素(HPMC)。
6.如权利要求5所述的包衣片剂，其中，
(a)所述内相包含：
(i)63.600mg瑞博西尼琥珀酸盐；
(ii)16.860mg微晶纤维素；
(iii)12.030mg羟丙基纤维素；
(iv)7.300mg交聚维酮；
(v)0.530mg胶态二氧化硅；和
(vi)1.590mg硬脂酸镁；且
(b)所述外相包含：
(i)3.210mg交聚维酮；
(ii)0.265mg胶态二氧化硅；和
(iii)2.115mg硬脂酸镁。
7.如权利要求5所述的包衣片剂，其中，
(a)所述内相包含：
(i)254.40mg瑞博西尼琥珀酸盐；
(ii)67.44mg微晶纤维素；
(iii)48.12mg羟丙基纤维素；
(iv)29.20mg交聚维酮；
(v)2.12mg胶态二氧化硅；和
(vi)6.36mg硬脂酸镁；且
(b)所述外相包含：
(i)12.84mg交聚维酮；
(ii)1.06mg胶态二氧化硅；和
(iii)8.46mg硬脂酸镁。
8.如权利要求5所述的包衣片剂，其中，
(a)所述内相包含：
(i)127.2mg瑞博西尼琥珀酸盐；
(ii)33.72mg微晶纤维素；
(iii)24.06mg羟丙基纤维素；
(iv)14.60mg交聚维酮；
(v)1.06mg胶态二氧化硅；和
(vi)3.18mg硬脂酸镁；且
(b)所述外相包含：
(i)6.420mg交聚维酮；
(ii)0.53mg胶态二氧化硅；和
(iii)4.23mg硬脂酸镁。
9.如权利要求5所述的包衣片剂，其中，
(a)所述内相包含：
(i)190.8mg瑞博西尼琥珀酸盐；
(ii)50.58mg微晶纤维素；
(iii)36.09mg羟丙基纤维素；
(iv)21.9mg交聚维酮；
(v)1.59mg胶态二氧化硅；和
(vi)4.77mg硬脂酸镁；且
(b)所述外相包含：
(i)9.63mg交聚维酮；
(ii)0.795mg胶态二氧化硅；和
(iii)6.345mg硬脂酸镁。
10.如权利要求5所述的包衣片剂，其中，
(a)所述内相包含：
(i)381.6mg瑞博西尼琥珀酸盐；
(ii)101.6mg微晶纤维素；
(iii)72.18mg羟丙基纤维素；
(iv)43.8mg交聚维酮；
(v)3.18mg胶态二氧化硅；和
(vi)9.54mg硬脂酸镁；且
(b)所述外相包含：
(i)19.26mg交聚维酮；
(ii)1.59mg胶态二氧化硅；和
(iii)12.69mg硬脂酸镁。
11.如权利要求1至4中任一项所述的片剂，其中，所述包衣包含32％氧化铁。
12.如权利要求5至10中任一项所述的包衣片剂，其中，所述包衣包含32％氧化铁。
13.如权利要求5至10中任一项所述的包衣片剂，当根据USP第<711>章在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％的瑞博西尼琥珀酸盐。
14.如权利要求12所述的包衣片剂，当根据USP第<711>章在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％的瑞博西尼琥珀酸盐。
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| CN1360612A (zh) * | 1999-07-09 | 2002-07-24 | 伯温德药品服务公司 | 基于聚乙烯醇的涂膜和涂膜组合物 |
| WO2012064805A1 (en) * | 2010-11-10 | 2012-05-18 | Novartis Ag | Salt(s) of 7-cyclopentyl-2 -(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| EP2742940A1 (en) * | 2012-12-13 | 2014-06-18 | IP Gesellschaft für Management mbH | Salts of aza-bicyclo-di-aryl ethers for adminstration once daily, twice daily or thrice daily |
| WO2014097125A1 (en) * | 2012-12-20 | 2014-06-26 | Novartis Ag | Pharmaceutical combination comprising binimetinib |
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| JPS5428812A (en) * | 1977-08-09 | 1979-03-03 | Yoshitomi Pharmaceut Ind Ltd | Preparation of coated tablet |
| GB9414045D0 (en) | 1994-07-12 | 1994-08-31 | Berwind Pharma Service | Moisture barrier film coating composition, method, and coated form |
| BRPI0917791B1 (pt) | 2008-08-22 | 2022-03-22 | Novartis Ag | Compostos de pirrolopirimidina como inibidores de cdk, bem como composição farmacêutica e combinação |
| US9283230B2 (en) * | 2011-02-11 | 2016-03-15 | Wista Laboratories Ltd. | Phenothiazine diaminium salts and their use |
| KR102122941B1 (ko) * | 2012-07-13 | 2020-06-15 | 지티엑스, 인코포레이티드 | 선택적 안드로겐 수용체 조절자(sarms)를 이용한 안드로겐 수용체(ar) 양성 유방암의 치료 방법 |
| SG10201906270VA (en) * | 2013-03-21 | 2019-08-27 | Novartis Ag | Combination therapy comprising a b-raf inhibitor and a second inhibitor |
| EP2810644A1 (en) * | 2013-06-06 | 2014-12-10 | Ferrer Internacional, S.A. | Oral formulation for the treatment of cardiovascular diseases |
| US10799506B2 (en) * | 2015-04-16 | 2020-10-13 | Novartis Ag | Ribociclib tablet |
| CN109953966A (zh) * | 2017-12-26 | 2019-07-02 | 天津耀辰实业发展有限公司 | 一种含有瑞博西尼的药物组合物及其制备方法 |
| JP7347388B2 (ja) | 2020-09-25 | 2023-09-20 | 信越化学工業株式会社 | 紫外線硬化型有機変性シリコーン組成物および硬化物 |
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