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TWI520753B - Ｄｐｐ ｉｖ抑制劑調配物 - Google Patents

Ｄｐｐ ｉｖ抑制劑調配物 Download PDF

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TWI520753B
TWI520753B TW103100247A TW103100247A TWI520753B TW I520753 B TWI520753 B TW I520753B TW 103100247 A TW103100247 A TW 103100247A TW 103100247 A TW103100247 A TW 103100247A TW I520753 B TWI520753 B TW I520753B
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pharmaceutical composition
methyl
diluent
dpp
disintegrant
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TW201417844A (zh
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安佳 柯爾勞斯齊
派翠克 羅莫
賈德 雪夫特
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百靈佳殷格翰國際股份有限公司
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Description

DPP IV抑制劑調配物
本發明係關於選定DPP IV抑制劑之醫藥組合物，其製備及其治療選定醫學病況之用途。
亦稱為CD26之酶DPP-IV(二肽基肽酶IV)為已知引起二肽自許多在其N末端具有脯胺酸或丙胺酸殘基之蛋白質之N末端裂解的絲胺酸蛋白酶。歸因於此特性，DPP-IV抑制劑影響生物活性肽(包括肽GLP-1)之血漿含量且認為其為用於治療糖尿病之極具價值的藥物。
在嘗試製備選定DPP-IV抑制劑之醫藥組合物中，已觀察到具有一級胺基或二級胺基之DPP-IV抑制劑展示與諸如微晶纖維素、羥基乙酸澱粉鈉、交聯羧甲基纖維素鈉、酒石酸、檸檬酸、葡萄糖、果糖、蔗糖、乳糖、麥芽糊精之許多習用賦形劑之不相容性、降解問題或萃取問題。儘管該等化合物本身極其穩定，但其與固體劑型中所用之多種賦形劑及賦形劑之雜質(尤其以緊密接觸形式提供於錠劑中且呈高賦形劑/藥物比率)反應。胺基似乎與還原糖及其他反應性羰基及羧酸官能基(例如在微晶纖維素表面上藉由氧化作用所形成)反應。此等未預見之困難主要在因選定抑制劑之驚人效能而需要之低劑量範圍內觀察到。因此，需要醫藥組合物以解決此等與選定DPP-IV抑制劑化合物出乎意料之效能相關的技術問題。
本發明之醫藥組合物欲用於治療第一型糖尿病或第二型糖尿病患者以達成血糖控制，且包含具有胺基(尤其游離胺基或一級胺基)之DPP-IV抑制劑作為活性成份、第一及第二稀釋劑、黏合劑、崩解劑及潤滑劑。另一選擇為其他崩解劑及其他助流劑。另外，該等組合物可用以治療類風濕性關節炎、肥胖症及骨質疏鬆症，以及可用以支持同種異體移植物移植。
適於本發明之醫藥組合物之稀釋劑為纖維素粉末、無水磷酸氫二鈣、二水合磷酸氫二鈣、赤藻糖醇、低取代羥丙基纖維素、甘露糖醇、預糊化澱粉或木糖醇。在彼等稀釋劑中，甘露糖醇及預糊化澱粉為較佳。
較佳作為第二稀釋劑之稀釋劑為上文所提及之稀釋劑預糊化澱粉及低取代羥丙基纖維素(L-HPC)，其展示其他黏合劑特性。
適於本發明之醫藥組合物之潤滑劑為滑石粉、聚乙二醇、萮樹酸鈣、硬脂酸鈣、氫化蓖麻油或硬脂酸鎂。較佳潤滑劑為硬脂酸鎂。
適於本發明之醫藥組合物之黏合劑為共聚乙烯吡咯啶酮(乙烯基吡咯啶酮與其他乙烯基衍生物之共聚物)、羥丙基甲基纖維素(HPMC)、羥丙基纖維素(HPC)、聚乙烯吡咯啶酮(聚維酮(Povidone))、預糊化澱粉、低取代羥丙基纖維素(L-HPC)，其中共聚乙烯吡咯啶酮及預糊化澱粉為較佳。
上文所提及之黏合劑預糊化澱粉及L-HPC展示其他稀釋劑及崩解劑特性且亦可用作第二稀釋劑或崩解劑。
適於本發明之醫藥組合物之崩解劑為玉米澱粉、交聯聚乙烯吡咯啶酮、低取代羥丙基纖維素(L-HPC)或預糊化澱粉，其中玉米澱粉為較佳。
可使用膠狀二氧化矽作為可選助流劑。
本發明之例示性組合物包含稀釋劑甘露糖醇、作為具有其他黏 合劑特性之稀釋劑之預糊化澱粉、黏合劑共聚乙烯吡咯啶酮、崩解劑玉米澱粉及作為潤滑劑之硬脂酸鎂。
以本發明之醫藥組合物製備之劑型含有0.1-100mg劑量範圍之活性成份。較佳劑量為0.5mg、1mg、2.5mg、5mg及10mg。
典型醫藥組合物包含(重量%)：0.5-20% 活性成份、40-88% 稀釋劑1、3-40% 稀釋劑2、1-5% 黏合劑、5-15% 崩解劑，及0.1-4% 潤滑劑。
較佳醫藥組合物包含(重量%)：0.5-7% 活性成份、50-75% 稀釋劑1、5-15% 稀釋劑2、2-4% 黏合劑、8-12% 崩解劑，及0.5-2% 潤滑劑。
本發明之醫藥組合物欲用於口服用途且可以膠囊、錠劑或膜衣錠劑之劑型使用。一般膜衣構成組合物之2-4%，較佳3%，且包含成膜劑、增塑劑、助流劑及視情況一或多種顏料。例示性塗佈組合物可包含羥丙基甲基纖維素(HPMC)、聚乙二醇(PEG)、滑石粉、二氧化鈦及視情況之氧化鐵。
本發明上下文中之較佳活性成份為具有一級胺基之DPP-IV抑制劑及其鹽，諸如由式(I)或式(II)定義之任何DPP-IV抑制劑及其鹽：
其中R1為([1,5]萘啶-2-基)甲基、(喹唑啉-2-基)甲基、(喹喏啉-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為3-(R)-胺基-哌啶-1-基、(2-胺基-2-甲基-丙基)-甲胺基或(2-(S)-胺基-丙基)-甲胺基。
較佳之DPP IV抑制劑化合物為以下化合物及其鹽：˙1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤(對照WO 2004/018468，實例2(142))： ˙1-[([1,5]萘啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-哌啶-1-基)-黃嘌呤(對照WO 2004/018468，實例2(252))： ˙1-[(喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-哌啶-1-基)-黃嘌呤(對照WO 2004/018468，實例2(80))： ˙2-((R)-3-胺基-哌啶-1-基)-3-(丁-2-炔基)-5-(4-甲基-喹唑啉-2-基甲基)-3,5-二氫-咪唑幷[4,5-d]噠嗪-4-酮(對照WO 2004/050658，實例136)： ˙1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(2-胺基-2-甲基-丙基)-甲胺基]-黃嘌呤(對照WO 2006/029769，實例2(1))： ˙1-[(3-氰基-喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺 基-哌啶-1-基)-黃嘌呤(對照WO 2005/085246，實例1(30))： ˙1-(2-氰基-苄基)-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-哌啶-1-基)-黃嘌呤(對照WO 2005/085246，實例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-胺基-丙基)-甲胺基]-黃嘌呤(對照WO 2006/029769，實例2(4))： ˙1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-哌啶-1-基)-黃嘌呤(對照WO 2005/085246，實例1(52))： ˙1-[(4-甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-哌啶-1-基)-黃嘌呤(對照WO 2005/085246，實例1(81))： ˙1-[(4,6-二甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-哌啶-1-基)-黃嘌呤(對照WO 2005/085246，實例1(82))： ˙1-[(喹喏啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-哌啶-1-基)-黃嘌呤(對照WO 2005/085246，實例1(83))：
為製備本發明之組合物，可藉由濕式造粒方法來製備顆粒。由 活性成份及賦形劑使用造粒液體進行造粒之替代性方法為流化床造粒法或同爐造粒法。
在濕式造粒方法中，造粒液體為諸如水、乙醇、甲醇、異丙醇、丙酮之溶劑，較佳為純水，且含有諸如共聚乙烯吡咯啶酮之黏合劑。溶劑為揮發性組份，其並不保留於最終產物中。將活性成份及除潤滑劑以外之其他賦形劑預混合且用水性造粒液體使用高剪切造粒機造粒。濕式造粒步驟之後之顆粒可視需要選用濕式篩分步驟、乾燥及乾式篩分。接著可使用例如流化床乾燥器來進行乾燥。
將乾燥顆粒經由適當篩進行篩分。在添加除潤滑劑以外之其他賦形劑之後，將混合物在諸如自由下落式摻合器之合適習知摻合器中摻合，隨後添加諸如硬脂酸鎂之潤滑劑且最終在摻合器中摻合。
因此，用於製備本發明之醫藥組合物之濕式造粒方法實例包含：a.在周圍溫度下將諸如共聚乙烯吡咯啶酮之黏合劑溶解於諸如純水之溶劑中以產生造粒液體；b.將DPP-IV抑制劑、稀釋劑及崩解劑於合適混合器中摻合以產生預混物；c.將該預混物以造粒液體潤濕且隨後將經潤濕之預混物例如於高剪切混合器中造粒；d.視情況將經造粒之預混物經由篩孔尺寸為至少1.0mm且較佳為3mm之篩進行篩分；e.將顆粒例如在流化床乾燥器中於約40-75℃且較佳為55-65℃之入口空氣溫度下乾燥，直至所需乾燥失重值達到1-5%之範圍內為止；f.視情況將乾燥顆粒例如藉由經由篩孔尺寸為0.6mm-1.6mm，較佳為1.0mm之篩進行篩分來去塊；及 g.將最好經篩分之潤滑劑添加至顆粒中，例如在立方體混合器中進行最終摻合。
在一替代性方法中，可在步驟g之最終摻合之前添加特細粒狀(extragranular)之部分賦形劑，諸如部分崩解劑(例如玉米澱粉)或稀釋劑(例如預糊化澱粉)或其他崩解劑(交聯聚乙烯吡咯啶酮)。
在此方法之另一替代形式中，步驟a至e中所產生之顆粒係以同爐高剪切造粒方法產生且隨後在同爐造粒機中乾燥。
對於製備膠囊而言，將最終摻合物進一步填充至膠囊中。
對於製備錠劑或錠劑核心而言，使用適當製錠機將最終摻合物進一步壓縮成具有適當尺寸及抗壓強度，具有目標錠劑核心重量之錠劑。
對於製備膜衣錠劑而言，製備塗佈懸浮液且使用標準薄膜塗佈機以該塗佈懸浮液將壓縮錠劑核心塗佈至重量增加約2-4%，較佳約3%。薄膜-塗佈溶劑為揮發性組份，其並不保留於最終產物中。為減少錠劑中所需潤滑劑之量，選擇使用外部潤滑系統。
實例
實例1-用於直接壓縮之調配物
將具有一級胺基之活性DPP IV抑制劑成份及除硬脂酸鎂以外之所有其他賦形劑在高剪切摻合器中摻合。將此預混物經由1mm篩進行篩分。在添加硬脂酸鎂之後，將預混物於自由下落式摻合器中摻合以產生最終摻合物。使用合適製錠機將最終摻合物壓縮成錠劑。可獲得以下組合物：
實例2-用於直接壓縮之替代性調配物
將具有一級胺基之活性DPP IV抑制劑成份及除硬脂酸鎂以外之所有其他賦形劑在高剪切摻合器中摻合。將此預混物經由1mm篩進行篩分。在添加硬脂酸鎂之後，將預混物於自由下落式摻合器中摻合以產生最終摻合物。使用合適製錠機將最終摻合物壓縮成錠劑。可獲得以下組合物：
實例3-錠劑調配物
在周圍溫度下將共聚乙烯吡咯啶酮溶解於純水中以產生造粒液體。將具有一級胺基之活性DPP IV抑制劑成份、甘露糖醇及部分預糊化澱粉在合適混合器中摻合以產生預混物。將該預混物以造粒液體潤濕且隨後造粒。將潮濕顆粒視情況經由篩孔尺寸為1.6-3.0mm之篩進行篩分。將顆粒在合適乾燥器中於55℃下乾燥至殘留水份含量相當於2-5%之乾燥失重。將乾燥顆粒經由篩孔尺寸為1.0mm之篩進行篩分。將顆粒與部分預糊化澱粉於合適混合器中摻合。在使硬脂酸鎂通過1.0mm篩去塊之後，將其添加至此摻合物中。隨後藉由在合適混合器中最終摻合產生最終摻合物且將其壓縮成錠劑。可獲得以下錠劑組合物：
實例4-包衣錠劑調配物
在周圍溫度下將共聚乙烯吡咯啶酮溶解於純水中以產生造粒液體。將具有一級胺基之活性DPP IV抑制劑成份、甘露糖醇、預糊化澱粉及玉米澱粉在合適混合器中摻合以產生預混物。將該預混物以造粒液體潤濕且隨後使用高剪切混合器造粒。將潮濕顆粒視情況經由篩孔尺寸為1.6-3.0mm之篩進行篩分。將顆粒在流化床乾燥器中於約60℃下乾燥直至獲得2-4%之乾燥失重值。將最終摻合物壓縮成錠劑核心。
在周圍溫度下於合適混合器中，將羥丙基甲基纖維素、聚乙二醇、滑石粉、二氧化鈦及氧化鐵懸浮於純水中以產生塗佈懸浮液。將錠劑核心以塗佈懸浮液塗佈至重量增加約3%以產生膜衣錠劑。可獲得以下錠劑組合物：
實例5-錠劑調配物
在周圍溫度下將共聚乙烯吡咯啶酮溶解於純水中以產生造粒液體。將具有一級胺基之活性DPP IV抑制劑成份、甘露糖醇及預糊化澱 粉在合適混合器中摻合以產生預混物。將該預混物以造粒液體潤濕且隨後造粒。將潮濕顆粒視情況經由合適篩進行篩分。將顆粒在合適乾燥器中於約50℃下乾燥直至獲得3-5%之乾燥失重值。將乾燥顆粒經由篩孔尺寸為1.0mm之篩進行篩分。
使硬脂酸鎂通過1.0mm篩且將其添加至顆粒中。隨後，藉由在合適摻合器中最終摻合產生最終摻合物且將最終摻合物壓縮成錠劑。可獲得以下錠劑組合物：
實例6-錠劑調配物變體
在周圍溫度下將共聚乙烯吡咯啶酮溶解於純水中以產生造粒液體。將具有一級胺基之活性DPP IV抑制劑成份及一部分甘露糖醇、預糊化澱粉及玉米澱粉在合適混合器中摻合以產生預混物。將該預混物以造粒液體潤濕且隨後造粒。將潮濕顆粒經由合適篩進行篩分。將顆粒在流化床乾燥器中於約60℃入口空氣溫度下乾燥直至獲得1-4%之乾燥失重值。將乾燥顆粒經由篩孔尺寸為1.0mm之篩進行篩分。
使硬脂酸鎂過篩以去塊且將其添加至顆粒中。另外，在此方法步驟下添加特細粒狀之剩餘部分賦形劑。隨後藉由在合適摻合器中最終摻合產生最終摻合物且將其壓縮成錠劑核心。
在周圍溫度下在合適混合器中，將羥丙基甲基纖維素、聚乙二 醇、滑石粉、二氧化鈦及氧化鐵懸浮於純水中以產生塗佈懸浮液。將錠劑核心以塗佈懸浮液塗佈至重量增加約3%以產生膜衣錠劑。可獲得以下調配物變體：實例6.1-具有特細粒狀賦形劑之調配物變體
實例6.2-具有其他特細粒狀崩解劑之調配物變體
實例6.3-高劑量調配物D

Claims (26)

  1. 一種醫藥組合物，其包含作為活性成份之具有游離胺基或一級胺基之DPP IV抑制劑化合物或其鹽、第一稀釋劑、第二稀釋劑、黏合劑、崩解劑及潤滑劑；其中該DPP IV抑制劑係以0.5mg至10mg的劑量被含有，且該等稀釋劑係選自纖維素粉末、無水磷酸氫二鈣、二水合磷酸氫二鈣、赤藻糖醇、低取代羥丙基纖維素、甘露糖醇、預糊化澱粉及木糖醇。
  2. 如請求項1之醫藥組合物，其另包含其他崩解劑。
  3. 如請求項1或2之醫藥組合物，其另包含其他助流劑。
  4. 如請求項1之醫藥組合物，其中該等稀釋劑係選自低取代羥丙基纖維素、甘露糖醇、及預糊化澱粉。
  5. 如請求項1之醫藥組合物，其中該潤滑劑為滑石粉、聚乙二醇、萮樹酸鈣、硬脂酸鈣、氫化蓖麻油或硬脂酸鎂。
  6. 如請求項1之醫藥組合物，其中該黏合劑為共聚乙烯吡咯啶酮(乙烯基吡咯啶酮與其他乙烯基衍生物之共聚物)、羥丙基甲基纖維素(HPMC)、羥丙基纖維素(HPC)或聚乙烯吡咯啶酮(聚維酮(Povidone))。
  7. 如請求項1之醫藥組合物，其中該崩解劑為玉米澱粉。
  8. 如請求項2之醫藥組合物，其中該其他崩解劑為交聯聚乙烯吡咯啶酮。
  9. 如請求項3之醫藥組合物，其中該可選用之助流劑為膠體狀二氧化矽。
  10. 如請求項1之醫藥組合物，其中該第一稀釋劑為甘露糖醇且該第 二稀釋劑為預糊化澱粉。
  11. 如請求項1之醫藥組合物，其包含：0.5-20% 活性成份、40-88% 稀釋劑1、3-40% 稀釋劑2、1-5% 黏合劑、5-15% 崩解劑，及0.1-4% 潤滑劑。
  12. 如請求項1之醫藥組合物，其包含：0.5-7% 活性成份、50-75% 稀釋劑1、5-15% 稀釋劑2、2-4% 黏合劑、8-12% 崩解劑，及0.5-2% 潤滑劑。
  13. 如請求項1之醫藥組合物，其係呈膠囊、錠劑或膜衣錠劑之劑型。
  14. 如請求項13之醫藥組合物，其包含2-4%之膜衣。
  15. 如請求項14之醫藥組合物，其中該膜衣包含成膜劑、增塑劑、助流劑及視情況選用之一或多種顏料。
  16. 如請求項15之醫藥組合物，其中該膜衣包含羥丙基甲基纖維素(HPMC)、聚乙二醇(PEG)、滑石粉、二氧化鈦及氧化鐵。
  17. 如請求項1、2、4-8及10-16中任一項之醫藥組合物，其中該黏合劑係選自共聚乙烯吡咯啶酮(乙烯基吡咯啶酮與其他乙烯基衍生物之共聚物)、羥丙基甲基纖維素(HPMC)、羥丙基甲基纖維素(HPMC)、羥丙基纖維素(HPC)、聚乙烯吡咯啶酮(聚維酮 (povidone)、預糊化澱粉及低取代羥丙基纖維素(L-HPC)；該崩解劑係選自玉米澱粉、交聯聚乙烯吡咯啶酮、低取代羥丙基纖維素(L-HPC)及預糊化澱粉；及/或該潤滑劑係選自滑石粉、聚乙二醇、萮樹酸鈣、硬脂酸鈣、氫化蓖麻油及硬脂酸鎂。
  18. 如請求項1、2、4-8及10-16中任一項之醫藥組合物，其中該DPP IV抑制劑為1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤。
  19. 如請求項1、2、4-8及10-16中任一項之醫藥組合物，其中該DPP IV抑制劑係以0.5mg、1mg、2.5mg、5mg或10mg的劑量被含有。
  20. 一種製備如請求項1之醫藥組合物之方法，其包含：a.將黏合劑溶解於溶劑中以產生造粒液體；b.將DPP-IV抑制劑、稀釋劑及崩解劑摻合以產生預混物；c.將該預混物以該造粒液體潤濕且隨後將該經潤濕之預混物造粒；d.視情況將該經造粒之預混物經由篩孔尺寸為至少1.0mm之篩進行篩分；e.於約40-75℃下乾燥該顆粒，直至所需乾燥失重值達到1-5%之範圍內為止；f.藉由將該乾燥顆粒經由篩孔尺寸為至少0.6mm之篩進行篩分而將該乾燥顆粒去塊；g.將潤滑劑添加至該顆粒中，以進行最終摻合。
  21. 如請求項20之方法，其進一步包含：h.將該最終摻合物壓縮成錠劑核心；i.製備塗佈懸浮液； j.將該等錠劑核心以該塗佈懸浮液塗佈至重量增加約2-4%以產生膜衣錠劑。
  22. 如請求項20之方法，其中在步驟g之最終摻合之前添加一部份特細粒狀之該等賦形劑。
  23. 如請求項20之方法，其中步驟a-e中所產生之該顆粒係於同爐高剪切造粒方法中產生，且隨後於同爐造粒機中乾燥。
  24. 如請求項20-23中任一項之方法，其中該黏合劑係選自共聚乙烯吡咯啶酮(乙烯基吡咯啶酮與其他乙烯基衍生物之共聚物)、羥丙基甲基纖維素(HPMC)、羥丙基甲基纖維素(HPMC)、羥丙基纖維素(HPC)、聚乙烯吡咯啶酮(聚維酮(povidone)、預糊化澱粉及低取代羥丙基纖維素(L-HPC)；該崩解劑係選自玉米澱粉、交聯聚乙烯吡咯啶酮、低取代羥丙基纖維素(L-HPC)及預糊化澱粉；及/或該潤滑劑係選自滑石粉、聚乙二醇、萮樹酸鈣、硬脂酸鈣、氫化蓖麻油及硬脂酸鎂。
  25. 如請求項20-23中任一項之方法，其中該DPP IV抑制劑為1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤。
  26. 如請求項20-23中任一項之方法，其中該DPP IV抑制劑係以0.5mg、1mg、2.5mg、5mg或10mg的劑量被含有。
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