CN102526737A - 二肽基肽酶iv抑制剂制剂 - Google Patents

二肽基肽酶iv抑制剂制剂 Download PDF

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CN102526737A
CN102526737A CN2012100684562A CN201210068456A CN102526737A CN 102526737 A CN102526737 A CN 102526737A CN 2012100684562 A CN2012100684562 A CN 2012100684562A CN 201210068456 A CN201210068456 A CN 201210068456A CN 102526737 A CN102526737 A CN 102526737A
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安贾.科尔劳希
帕特里克.罗默
格尔德.塞费尔特
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Abstract

本发明涉及具有氨基的DPP IV抑制剂的药物组合物，其制备及其治疗糖尿病的用途。

Description

二肽基肽酶IV抑制剂制剂
本申请是中国发明申请(发明名称：二肽基肽酶IV抑制剂制剂；申请日：2007年4月30日；申请号：200780016227.3)的分案申请。
技术领域
本发明涉及选定DPP IV抑制剂的药物组合物，其制备及其治疗选定医学病况的用途。
现有技术
亦称为CD26的酶DPP-IV(二肽基肽酶IV)为已知引起从许多在其N末端具有脯氨酸或丙氨酸残基的蛋白质的N末端二肽裂解的丝氨酸蛋白酶。由于具有此特性，DPP-IV抑制剂影响生物活性肽(包括肽GPG-1)的血浆含量且认为其为用于治疗糖尿病的有价值的药物。
在尝试制备选定DPP-IV抑制剂的药物组合物中，已观察到具有伯氨基或仲氨基的DPP-IV抑制剂显示与例如微晶纤维素、羟基乙酸淀粉钠、交联羧甲基纤维素钠、酒石酸、柠檬酸、葡萄糖、果糖、蔗糖、乳糖、麦芽糊精的许多常用赋形剂的不相容性、降解问题或萃取问题。尽管该化合物本身极其稳定，但其与固体剂型中所用的多种赋形剂及赋形剂的杂质(尤其在片剂中以紧密接触形式提供且呈高赋形剂/药物比率)反应。氨基似乎与还原糖及其他反应性羰基及(例如在微晶纤维素表面上经过氧化作用所形成的)羧酸官能基反应。这些未预见的困难主要在因选定抑制剂的惊人效能而需要的低剂量范围内观察到。因此，需要药物组合物以解决这些与选定DPP-IV抑制剂化合物出乎意料的效能相关的技术问题。
发明内容
本发明的药物组合物欲用于治疗I型糖尿病或II型糖尿病患者以实现血糖控制，且包含具有氨基(尤其游离氨基或伯氨基)的DPP-IV抑制剂作为活性成份、第一及第二稀释剂、粘合剂、崩解剂及润滑剂。进一步选择其他崩解剂及其他助流剂。另外，该组合物可用以治疗类风湿性关节炎、肥胖症及骨质疏松症，以及有助于同种异体移植物移植。
适于本发明的药物组合物的稀释剂为纤维素粉末、无水磷酸氢钙、二水合磷酸氢钙、赤藓醇、低取代羟丙基纤维素、甘露糖醇、预胶化淀粉或木糖醇。在这些稀释剂中，甘露糖醇及预胶化淀粉为优选。
优选作为第二稀释剂的稀释剂为上文所提及的稀释剂，预胶化淀粉及低取代羟丙基纤维素(L-HPC)，其显示辅助的粘合剂特性。
适于本发明的药物组合物的润滑剂为滑石粉、聚乙二醇、山萮酸钙、硬脂酸钙、氢化蓖麻油或硬脂酸镁。优选润滑剂为硬脂酸镁。
适于本发明的药物组合物的粘合剂为共聚乙烯吡咯烷酮(乙烯基吡咯烷酮与其他乙烯基衍生物的共聚物)、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、聚乙烯吡咯烷酮(聚维酮(Povidone))、预胶化淀粉、低取代羟丙基纤维素(L-HPC)，其中共聚乙烯吡咯烷酮及预胶化淀粉为优选。
上文所提及的粘合剂预胶化淀粉及L-HPC显示辅助的稀释剂及崩解剂特性且亦可用作第二稀释剂或崩解剂。
适于本发明的药物组合物的崩解剂为玉米淀粉、交联聚乙烯吡咯烷酮、低取代羟丙基纤维素(L-HPC)或预胶化淀粉，其中玉米淀粉为优选。
可使用胶体二氧化硅作为任选的助流剂。
本发明的例示性组合物包含稀释剂甘露糖醇、作为具有其他粘合剂特性的稀释剂的预胶化淀粉、粘合剂共聚乙烯吡咯烷酮、崩解剂玉米淀粉及作为润滑剂的硬脂酸镁。
以本发明的药物组合物制备的剂型含有0.1-100mg剂量范围的活性成份。优选的剂量为0.5mg、1mg、2.5mg、5mg及10mg。
典型药物组合物包含(重量％)：
0.5-20％    活性成份；
40-88％     稀释剂1；
3-40％      稀释剂2；
1-5％       粘合剂；
5-15％      崩解剂，及
0.1-4％     润滑剂。
优选的药物组合物包含(重量％)：
0.5-7％    活性成份；
50-75％    稀释剂1；
5-15％     稀释剂2；
2-4％      粘合剂；
8-12％     崩解剂，及
0.5-2％    润滑剂。
本发明的药物组合物欲用于口服用途且可以胶囊、片剂或膜包衣片剂的剂型使用。一般膜包衣是该组合物的2-4％，优选3％，且包含成膜剂、增塑剂、助流剂及任选的一种或多种颜料。例示性包衣组合物可包含羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)、滑石粉、二氧化钛及任选的氧化铁。
本发明的上下文中的优选活性成份为具有伯氨基的DPP-IV抑制剂及其盐，例如由式(I)或式(II)定义的任何DPP-IV抑制剂及其盐：
Figure BDA0000143705620000031
其中R1为([1，5]二氮杂萘-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、(3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基或(4，6-二甲基-嘧啶-2-基)甲基，且R2为3-(R)-氨基-哌啶-1-基、(2-氨基-2-甲基-丙基)-甲氨基或(2-(S)-氨基-丙基)-甲氨基。
优选的DPP IV抑制剂化合物为以下化合物及其盐：
●1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(142))：
Figure BDA0000143705620000041
●1-[([1，5]二氮杂萘-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(252))：
Figure BDA0000143705620000042
●1-[(喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-氨基-哌啶-1-基)-黄嘌呤(参见WO 2004/018468，实施例2(80))：
●2-((R)-3-氨基-哌啶-1-基)-3-(丁-2-炔基)-5-(4-甲基-喹唑啉-2-基甲基)-3，5-二氢-咪唑并[4，5-d]哒嗪-4-酮(参见WO 2004/050658，实施例136)：
Figure BDA0000143705620000044
●1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(2-氨基-2-甲基-丙基)-甲基氨基]-黄嘌呤(参见WO 2006/029769，实施例2(1))：
Figure BDA0000143705620000045
●1-[(3-氰基-喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(30))：
Figure BDA0000143705620000051
●1-(2-氰基-苄基)-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(39))：
●1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-(2-氨基-丙基)-甲基氨基]-黄嘌呤(参见WO 2006/029769，实施例2(4))：
Figure BDA0000143705620000053
●1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(52))：
Figure BDA0000143705620000054
●1-[(4-甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(81))：
Figure BDA0000143705620000061
●1-[(4，6-二甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(82))：
●1-[(喹喔啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参见WO 2005/085246，实施例1(83))：
Figure BDA0000143705620000063
为制备本发明的组合物，可经过湿法造粒方法来制备颗粒。使用造粒液体以粒造粒成份及赋形剂的其它方法为流化床造粒法或一锅(one-pot)造粒法。
在湿法造粒方法中，造粒液体为例如水、乙醇、甲醇、异丙醇、丙酮的溶剂，优选地为纯水，且含有例如共聚乙烯吡咯烷酮的粘合剂。溶剂为挥发性组份，其并不保留于最终产物中。将活性成份及除润滑剂以外的其他赋形剂预混合且用水性造粒液体使用高切应力(shear)造粒机造粒。湿法造粒步骤之后的颗粒任选用湿法筛分步骤、干燥及干法筛分。接着可使用例如流化床干燥器进行干燥。
将干燥的颗粒经适当筛进行筛分。在添加除润滑剂以外的其他赋形剂之后，将混合物在例如自由下落式混合器的合适常规混合器中混合，随后添加例如硬脂酸镁的润滑剂且最终在混合器中混合。
因此，用于制备本发明的药物组合物的示例性湿法造粒方法包含：
a.在周围温度下将例如共聚乙烯吡咯烷酮的粘合剂溶解于例如纯水的溶剂中以产生造粒液体；
b.将DPP-IV抑制剂、稀释剂及崩解剂于合适混合器中混合以产生预混物；
c.将该预混物以造粒液体润湿且随后将经润湿的预混物例如于高切应力混合器中造粒；
d.任选地将经造粒的预混物经筛孔尺寸至少1.0mm且优选地为3mm的筛进行筛分；
e.将颗粒例如在流化床干燥器中于约40-75℃且优选地为55-65℃的入口空气温度下干燥，直至所需干燥失重值达到1-5％的范围内为止；
f.任选地将干燥颗粒例如经过筛孔尺寸为0.6mm-1.6mm，优选地为1.0mm的筛进行筛分以去除结块；及
g.优选将经筛分的润滑剂添加至颗粒中，以最终例如在立方形的混合器中进行混合。
在另一方法中，可在步骤g的最终混合之前添加作为外加颗粒(extragranular)的部分赋形剂，例如部分崩解剂(例如玉米淀粉)或稀释剂(例如预胶化淀粉)或其他崩解剂(交联聚乙烯吡咯烷酮)。
在此方法的另一替代形式中，步骤a至e中所产生的颗粒在一锅高切应力造粒方法中产生且随后在一锅造粒机中干燥。
对于制备胶囊而言，将最终混合物进一步填充至胶囊中。
对于制备片剂或片芯而言，使用适当制片机将最终混合物进一步压制成具有适当尺寸及抗压强度的目标片芯重量的片剂。
对于制备膜包衣片剂而言，制备涂布悬浮液且使用标准膜包衣机以该包衣悬浮液将压制片芯包衣至重量增加约2-4％，优选约3％。膜-包衣溶剂为挥发性组份，其并不保留于最终产物中。为减少片剂中所需润滑剂的量，可选择使用外部润滑系统。
实施例
实施例1-用于直接压制的制剂
将具有伯氨基的活性DPP IV抑制剂成份及除硬脂酸镁以外的所有其他赋形剂在高切应力混合器中混合。将此预混物经1mm筛进行筛分。在添加硬脂酸镁之后，将预混物于自由下落式混合器中混合以产生最终混合物。使用合适制片机将最终混合物压制成片剂。可获得以下组合物：
Figure BDA0000143705620000081
Figure BDA0000143705620000082
实施例2-用于直接压制的另一种制剂
将具有伯氨基的活性DPP IV抑制剂成份及除硬脂酸镁以外的所有其他赋形剂在高切应力混合器中混合。将此预混物经1mm筛进行筛分。在添加硬脂酸镁之后，将预混物于自由下落式混合器中混合以产生最终混合物。使用合适制片机将最终混合物压制成片剂。可获得以下组合物：
Figure BDA0000143705620000083
Figure BDA0000143705620000091
实施例3-片剂制剂
在周围温度下将共聚乙烯吡咯烷酮溶解于纯水中以产生造粒液体。将具有伯氨基的活性DPP IV抑制剂成份、甘露糖醇及部分预胶化淀粉在合适混合器中混合以产生预混物。将该预混物以造粒液体润湿且随后造粒。将湿颗粒任选地经由筛孔尺寸为1.6-3.0mm的筛进行筛分。将颗粒在合适干燥器中于55℃下干燥至残留水份含量相当于2-5％的干燥失重。将干燥颗粒经过筛孔尺寸为1.0mm的筛进行筛分。将颗粒与部分预胶化淀粉于合适混合器中混合。在使硬脂酸镁通过1.0mm筛去除结块之后，将其添加至此混合物中。随后经过在合适混合器中最终混合产生最终混合物且将其压制成片剂。可获得以下片剂组合物：
  组份   毫克/片   ％/片
  活性成份   10.000   1.667
  预胶化淀粉   210.000   35.000
  甘露糖醇   236.000   39.333
  共聚乙烯吡咯烷酮   18.000   3.000
  总计(颗粒)   474.000   79.000
  预胶化淀粉   120.000   20.000
  硬脂酸镁   6.000   1.000
  总计   600.000   100.000
实施例4-包衣片剂制剂
在周围温度下将共聚乙烯吡咯烷酮溶解于纯水中以产生造粒液体。将具有伯氨基的活性DPP IV抑制剂成份、甘露糖醇、预胶化淀粉及玉米淀粉在合适混合器中混合以产生预混物。将该预混物以造粒液体润湿且随后使用高切应力混合器造粒。将湿颗粒任选地经筛孔尺寸为16-30mm的筛进行筛分。将颗粒在流化床干燥器中于约60℃下干燥直至获得2-4％的干燥失重值。将最终混合物压制成片芯。
在周围温度下于合适混合器中，将羟丙基甲基纤维素、聚乙二醇、滑石粉、二氧化钛及氧化铁悬浮于纯水中以产生包衣悬浮液。将片芯以包衣悬浮液包衣至重量增加约3％以产生膜包衣片剂。可获得以下片剂组合物：
  组份   mg   mg   mg   mg   mg
  活性成份   0.500   1.000   2.500   5.000   10.000
  甘露糖醇   67.450   66.950   65.450   130.900   125.900
  预胶化淀粉   9.000   9.000   9.000   18.000   18.000
  玉米淀粉   9.000   9.000   9.000   18.000   18.000
  共聚乙烯吡咯烷酮   2.700   2.700   2.700   5.400   5.400
  硬脂酸镁   1.350   1.350   1.350   2.700   2.700
  总质量(片芯)   90.000   90.000   90.000   180.000   180.000
  HPMC   1.500   1.500   1.500   2.500   2.500
  PEG   0.150   0.150   0.150   0.250   0.250
  二氧化钛   0.750   0.750   0.750   1.250   1.250
  滑石粉   0.525   0.525   0.525   0.875   0.875
  氧化铁，黄色   0.075   0.075   0.075   0.125   0.125
  总质量(包衣片剂)   93.000   93.000   93.000   185.000   185.000
实施例5-片剂制剂
在周围温度下将共聚乙烯吡咯烷酮溶解于纯水中以产生造粒液体。将具有伯氨基的活性DPP IV抑制剂成份、甘露糖醇及预胶化淀粉在合适混合器中混合以产生预混物。将该预混物以造粒液体润湿且随后造粒。将湿颗粒任选地经合适筛进行筛分。将颗粒在合适干燥器中于约50℃下干燥直至获得3-5％的干燥失重值。将干燥颗粒经筛孔尺寸为1.0mm的筛进行筛分。
使硬脂酸镁通过1.0mm筛且将其添加至颗粒中。随后，经过在合适混合器中最终混合而产生最终混合物且将最终混合物压制成片剂。可获得以下片剂组合物：
  组份   mg   mg   mg   mg   mg
  活性成份   0.500   1.000   2.500   5.000   10.000
  甘露糖醇   27.500   27.000   67.500   135.000   130.000
  预胶化淀粉   20.000   20.000   50.000   100.000   100.000
  共聚乙烯吡咯烷酮   1.500   1.500   3.750   7.500   7.500
  硬脂酸镁   0.500   0.500   1.250   2.500   2.500
  总片剂质量   50.000   50.000   125.000   250.000   250.000
实施例6-片剂制剂变体
在周围温度下将共聚乙烯吡咯烷酮溶解于纯水中以产生造粒液体。将具有伯氨基的活性DPP IV抑制剂成份及部分的甘露糖醇、预胶化淀粉及玉米淀粉在合适混合器中混合以产生预混物。将该预混物以造粒液体润湿且随后造粒。将湿颗粒经合适筛进行筛分。将颗粒在流化床干燥器中于约60℃入口空气温度下干燥直至获得1-4％的干燥失重值。将干燥颗粒经筛孔尺寸为1.0mm的筛进行筛分。
使硬脂酸镁过筛以去除结块且将其添加至颗粒中。另外，在这方法步骤中添加作为外加颗粒的剩余部分赋形剂。随后经过在合适混合器中最终混合产生最终混合物且将其压制成片芯。
在周围温度下在合适混合器中，将羟丙基甲基纤维素、聚乙二醇、滑石粉、二氧化钛及氧化铁悬浮于纯水中以产生包衣悬浮液。将片芯以包衣悬浮液包衣至重量增加约3％以产生膜包衣片剂。可获得以下制剂变体：
实施例6.1-具有外加颗粒赋形剂的制剂变体
Figure BDA0000143705620000121
实施例6.2-具有其他外加颗粒崩解剂的制剂变体
  组份   mg   mg   mg   mg   mg
  活性成份   0.500   1.000   2.500   5.000   10.000
  甘露糖醇   67.450   66.950   65.450   130.900   125.900
  预胶化淀粉   9.000   9.000   9.000   18.000   18.000
  玉米淀粉   9.000   9.000   9.000   18.000   18.000
  共聚乙烯吡咯烷酮   2.700   2.700   2.700   5.400   5.400
  总质量(颗粒)   88.650   88.650   88.650   177.300   177.300
  硬脂酸镁   1.350   1.350   1.350   2.700   2.700
  交联聚乙烯吡咯烷酮   2.000   2.000   2.000   4.000   4.000
  总质量(片芯)   92.000   92.000   92.000   184.000   184.000
  HPMC   1.500   1.500   1.500   2.500   2.500
  PEG   0.150   0.150   0.150   0.250   0.250
  二氧化钛   0.750   0.750   0.750   1.250   1.250
  滑石粉   0.525   0.525   0.525   0.875   0.875
  氧化铁，黄色   0.075   0.075   0.075   0.125   0.125
  总质量(包衣片剂)   95.000   95.000   95.000   189.000   189.000
实施例6.3-高剂量制剂D
Figure BDA0000143705620000131

Claims (20)

1.药物组合物，其包含作为活性成份的具有氨基的DPP IV抑制剂化合物或其盐、第一稀释剂、第二稀释剂、粘合剂、崩解剂及润滑剂。
2.如权利要求1所述的药物组合物，其包含其他崩解剂。
3.如权利要求1或2所述的药物组合物，其包含其他助流剂。
4.如权利要求1所述的药物组合物，其中该稀释剂为纤维素粉末、无水磷酸氢钙、二水合磷酸氢钙、赤藓醇、低取代羟丙基纤维素、甘露糖醇、预胶化淀粉或木糖醇。
5.如权利要求1所述的药物组合物，其中该润滑剂为滑石粉、聚乙二醇、山萮酸钙、硬脂酸钙、氢化蓖麻油或硬脂酸镁。
6.如权利要求2所述的药物组合物，其中该粘合剂为共聚乙烯吡咯烷酮(乙烯基吡咯烷酮与其他乙烯基衍生物的共聚物)、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)或聚乙烯吡咯烷酮(聚维酮)。
7.如权利要求1所述的药物组合物，其中该崩解剂为玉米淀粉。
8.如权利要求2所述的药物组合物，其中该其他崩解剂为交联聚乙烯吡咯烷酮。
9.如权利要求1所述的药物组合物，其中任选的助流剂为胶体二氧化硅。
10.如权利要求1所述的药物组合物，其中该第一稀释剂为甘露糖醇，该第二稀释剂为预胶化淀粉，该粘合剂为共聚乙烯吡咯烷酮，该崩解剂为玉米淀粉，且该润滑剂为硬脂酸镁。
11.如权利要求1所述的药物组合物，其包含：
0.5-20％        活性成份；
40-88％         稀释剂1；
3-40％          稀释剂2；
1-5％           粘合剂；
5-15％          崩解剂，及
0.1-4％         润滑剂。
12.如权利要求1所述的药物组合物，其包含：
0.5-7％         活性成份；
50-75％    稀释剂1；
5-15％     稀释剂2；
2-4％      粘合剂；
8-12％     崩解剂，及
0.5-2％    润滑剂。
13.如权利要求1所述的药物组合物，其剂型为胶囊、片剂或膜包衣片剂。
14.如权利要求13所述的药物组合物，其包含2-4％的膜包衣。
15.如权利要求1所述的药物组合物，其中该膜包衣包含成膜剂、增塑剂、助流剂及任选的一种或多种颜料。
16.如权利要求15所述的药物组合物，其中该膜包衣包含羟丙基甲基纤维素(HPMC)、聚乙二醇(PEG)、滑石粉、二氧化钛及氧化铁。
17.一种制备如权利要求1所述的药物组合物的方法，其包含：
a.在将粘合剂溶解于溶剂中以产生造粒液体；
b.将DPP-IV抑制剂、稀释剂及崩解剂混合以产生预混物；
c.将该预混物以造粒液体润湿且随后将经润湿的预混物造粒；
d.任选地将经造粒的预混物经筛孔尺寸为至少1.0mm的筛进行筛分；
e.将颗粒于约40-75℃下干燥，直至所需干燥失重值达到1-5％的范围内为止；
f.将干燥颗粒经筛孔尺寸至少为0.6mm的筛进行筛分；
g.将润滑剂添加至颗粒中进行最终混合。
18.如权利要求17所述的方法，其进一步包含：
h.将该最终混合物压制成片芯；
i.制备包衣悬浮液；
j.将该片芯以该包衣悬浮液包衣至重量增加约2-4％以产生膜包衣片剂。
19.如权利要求17所述的方法，其中在步骤g的最终混合之前添加作为外加颗粒的部分赋形剂。
20.如权利要求17所述的方法，其中步骤a-e中所产生的颗粒在一锅高切应力造粒方法中产生，且随后于一锅造粒机中干燥。
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