TW561056B - Oral immediate release formulation of the thrombin inhibitor - Google Patents
Oral immediate release formulation of the thrombin inhibitor Download PDFInfo
- Publication number
- TW561056B TW561056B TW088114460A TW88114460A TW561056B TW 561056 B TW561056 B TW 561056B TW 088114460 A TW088114460 A TW 088114460A TW 88114460 A TW88114460 A TW 88114460A TW 561056 B TW561056 B TW 561056B
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- 229940122388 Thrombin inhibitor Drugs 0.000 title claims abstract description 19
- 239000003868 thrombin inhibitor Substances 0.000 title claims abstract description 19
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 title claims abstract description 13
- 239000012729 immediate-release (IR) formulation Substances 0.000 title claims description 4
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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561056 五、發明說明（2) 咸發現具pH依賴溶解度之低分子量以胜肽為基礎之凝血 酶抑制劑一包括其鹽，可被調配成無或極低口!！依賴溶解力 之I R鍵劑。 因此，本發明目的是提供新穎之醫藥調配物，其包括調 配成I R錠劑之低分子量以胜狀為基礎之凝血酶抑制劑，其 為無或極低p Η依賴溶解力，和製備此種調配物之方法。 此申請書中提及之凝血酶抑制劑是pH依賴溶解度之低分 子量以胜肽為基礎的凝血酶抑制劑。”低分子量以胜肽為 基礎之凝血酶抑制劑” 一詞對熟諳此技藝者應熟知其包括 具一至四個胜肽鍵聯，和/或具分子量低於1〇〇〇之凝血酶 抑制劑，且包括一般描述者和較佳為特別是克雷森 (Claesson)在Blood Coagul· Fibrin ( 1 994 ) 5，411 之評 論文章，和揭示在美國專利第4, 346, 078 ;國際專利申請 案WO 97/23499 、W0 97/02284 、W0 97/46577 、W0 98/01422 、W0 93/05069 、W0 93/11152 、W0 95/23609 、 WO 95/35309 、W0 96/25426 、W0 94/29336 、W0 93/18060WO 和 95/01168 ;和歐洲專利申請案623 596、648 780 、 468 231 、 559 046 、 641 779 、 185 390 、 526 877 、 542 525 、195 212 、362 002 、364 344 、530 167 、293 881 、686 642 、669 317 和601 459 。 較佳之低分子量以胜肽為基礎之凝血酶抑制劑包括總稱 為”賈壯"（gatrans)者。所提及之特別賈壯包括 11000(：112(1〇(：1^-？1(3 18运-11(已知之伊諸賈壯 (inogatran);見國際專利申請案W0 93/ 1 1 1 52和文中縮寫
第5頁 561056 五、發明說明（4) 之：儘管化合物A還是具極大 =本發明之調配物包括凝血酶抑制劑、-解度。 之真充劑，該填充劑/埴# u y 、充劑或組合 需要之非抽e = 填充劑們具散解特性（因賸胝、4鉬 iif膨膜填充劑散解劑、結合劑和/或潤Λ )和 35%(重量比），較佳Α #們的里構成超過調配物之 鞏此抽 1又佳為超過50%(重量比）。 二賦形劑可具多重目 劑。使用量較35%為高之賦為填充劑和散解 但其可對調配物提供其：重开要明中意為填充劑， 作用或潤滑作用。 寺丨，例如散解作用、結合 具散解特性之填充 素、微細纖維辛）H i //維素本身（例如微粒纖维 納、馬鈐薯：中/以身(例如玉米殿粉。殿粉乙1^ 非胗胳f焱私、未澱粉、麥澱粉）。 ％ 旌糖真充劑是選自糖（例如甘露糖醇、山利π 方疋，、木糖醇、乳糖）。 料山柒糖醇、右 ，θ丨疋選自纖維素本身（例如微彳_ 素、父聯羧甲Α输绐丰知」戈械粒纖維素、微細纖％ 身（例如戮於:素鈉、父聯羥丙基纖維素）、澱於士 叔扮乙酵酸鈉、預先 叔私本 馬釦著澱粉、米澱粉匕之J又扣、玉米澱粉、 氫、陽離子交換樹脂) 例如交聯聚乙埽四, 基是= Ϊ身(例如竣甲基纖維素鈉、一
如聚乙稀四基纖維素、甲基纖維素）、聚合G 勝）、和傳人聚乙二醇）、明膠（例如水解之明例 得統之結合劑（例如澱粉、天然膠）。解之明
O:\60\60070.PTD 第7頁 561056 五、發明說明（5) 潤滑劑是選自不溶之潤滑劑（例如硬脂酸鎂、硬脂 和可Ϊ月曰酸辞、硬脂酸、油、滑石、硬脂酿富馬酸納）， 之潤滑劑(例如聚乙二醇、苯甲酸納、月桂基硫酸 其ΐ = t發明之調配物中不同組成物較佳是為以下比例， 八疋乂製成鍵劑的重量％計算： 綾血酶抑制劑：1—35%，較佳為1-15%。 時，車父佳為45_80%，當微粒纖維素為5 0—9 0% 〇:5〇%且：：、最佳為72_76% ’當非膨脹填 。田甘路糖醇為0 一 15%時，較佳為5 - 1〇%。 當澱粉乙醇酸鈉為3-20% 當聚乙烯四氫吡咯酮為 政解劑：〇-35%，較佳為7-35% 時’較佳為5 -1 0 %。 結合劑··0-15%，較佳為4-12% 3- 15%時，較佳為5 —。 ，較佳為0.5-1.5%，當硬脂酿富馬酸納為 5-1· 5%時，較佳為高於1%。 来本：：t現調配物包含之活性組份顆粒大小小於300微 ΐ ‘ ΐί,於150微米且較佳之平均顆粒大小小於80微 ί播Ϊ/5 微粒纖維素（5〇_9〇%，較佳為Η%))，甘 3^〇Π〇Γ _ 1 5%，較佳為8 ‘ 5% )散解劑（例如澱粉乙醇酸鈉 四盼吹狀5%) ’以適當之結合劑濕调（例*聚乙烯 二匕酮Κ 90(3-15%，較佳為8%))，最終再與適當之潤 =合（例如硬脂醯富馬酸納（〇5_15%，較佳為丨％))者 之錢劑具良好之工業特性和極低之pH依賴性溶解度。 561056
根據本發明 製備。 之調配物較佳是以直接壓縮或以濕粒化技術 直接壓縮 將低分子量；^麻 合。混合物再抑制劑與填充劑且若需要與散解劑混 濕粒化作用一调b劑混合並壓縮成錠劑。 將低分子曹/ rnriuj 劑混合。混抑制劑與填充劑，且若需要則與散解 粒劑後，將溶解結合劑之適當溶劑濕潤。乾燥 ^ ^ ^研磨再與潤滑劑混合並壓縮成錠劑。 貝際範例
i根/康本發明之錠劑的藥劑溶解力 乂備凝血酶抑制劑，化合物a之丨R錠劑是將化合 粒纖維素、•粉乙醇酸鈉和甘露糖醇混合。以適當旦、々微 水中之聚乙烯四氫吡咯酮K 9 0濕潤混合物。乾燥穩里’各在 顆粒再與硬脂酿富馬酸鈉混合並壓縮成錠劑。 ’研磨 化合物A 毫克/錠劑 24 微粒纖維素（MCC pH ιοί J 丨 140 澱粉乙醇酸鈉 16 甘露糖醇 16 聚乙烯四氫啦咯_^ 90 15 水 適量 硬脂醯富馬酸鈉 2 打孔器： 9毫米
第9頁 561056 五、發明說明（7) 鍵劑重詈· 里· 213 ί 1 硬度· 八· π 11 〇牛頓 9 ί所得> 鍵劑有關化合物Α之溶解力是使用u s ρ溶解裝置 0;ϋ水）’每分鐘100轉，500毫升。所用溶解基質為37 使用兩種不同之溶解基質，〇· 1 M HC1 pH 1和磷酸鹽 緩衝液ρΗ 6· 8(離子強度〇· 1 )。釋出化合物A之量是以UV分 光光度計測定。
結果示在圖1。30分鐘後，化合物A溶解量在〇.1 μ HC1 是94%(平均η = 3)和磷酸鹽緩衝液ρΗ 6·8是94%(平均η = 3)。 Mlb 根據本發明之錠劑的藥劑溶解力 製備凝血酶抑制劑，化合物A之I R錠劑，是將化合物a、 微粒纖維素和玉米澱粉混合，再將混合物以適量玉米澱粉 (糊）濕潤。乾燥後，研磨顆粒再與交聯之聚乙烯四氫卩比咯 酮混合。最後與硬脂醯富馬酸鈉混合再將顆粒壓縮成錠 劑。
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化合物A 毫克/錠劑 30 微粒纖維素 1 15 玉米澱粉 55 玉米殺粉（糊） 6 水 適量 交聯聚乙烯四氫吡咯酮 10 硬脂酿富馬酸納 2. 2 打孔器： 8. 5毫米 $ 10頁 561056 五、發明說明（8) 鍵劑重量： 219毫克 硬度： 1 1 0牛頓 根據例1所述法分析所得錠劑化合物A之溶解力。結果示 在圖2。30分鐘後，化合物A溶解量在〇· 1 M HC1為1 00% (平 均η = 3)和在磷酸鹽緩衝液ρΗ 6.8為97%(平均η = 3)。 ^ 根據參考文獻之錠劑的藥劑溶解力
雷奇蒙（理論和實際之工業藥學1986，343，附錄Α)描述 另一種組合物與製造I R鍵劑之”標準”粒化法。製備凝血酶 抑制劑，化合物Α之IR錠劑是根據此法將化合物a、磷酸三 辦混合，再將此混合物以溶在水中之預膠凝化玉米澱粉濕 潤。乾燥後，研磨粒劑再與滑石混合。最後，與礦物油混 合再將顆粒壓縮成錠劑。 化合物A 24 磷酸三鈣 丨〇 〇 預膠凝化澱粉 15 適量 滑石 6 0 輕礦物油 4
旋劑重量： 19 8毫克 硬度： 1 2牛頓 根據例1所述之法分析所得錠劑之化合物A溶解力。社果 不在圖2。30分鐘後，化合物入溶解量在〇1 M HC1 s 40%(平均n = 3)和在磷酸鹽緩衝液pH 6 8中是(平^
561056 五、發明說明（9) η = 3 )。 例3 根據參考文獻之鍵劑的藥劑溶劑力 雷奇蒙（理論和實際之工業藥學1 9 86，343，附錄Α)描述 另一種’’標準"粒化IR錠劑之組合物和製法。凝血酶抑制 劑，化合物Α之IR錠劑是根據此法將化合物a，乳糖混合， 再將混合物以溶在水中之澱粉濕潤。 物油混合再將顆粒壓縮成錠劑。 化合物A 24 乳糠 110 澱粉（糊） 5 澱粉 28 滑石 28 礦物油5 0 c p s 11 打孔器： 9毫米 錠劑重量： 20 6毫克 硬度： 13牛頓 乾燥後，研磨顆粒再與乾燥澱粉和滑石混合。最終與礦
根據例1所述之法分析所得錠劑之化合物溶解力。結果 示在圖3。30分鐘後，化合物α溶解量在〇. i Μ Η。中為 一10 0°/〇(平均n=3)和磷酸鹽緩衝液ρΗ 6· 8中是。 — 厂圖形簡述 疋 〇 ° 根據本發明旋劑 根據參考文獻錠 圖1 :如例1所述，凝血酶抑制劑化合物八自 之溶解力。（例1 b並無圖形）。 圖2 :如例2所述，凝血酶抑制劑化合物α自 561056 五、發明說明（10) 劑之溶解力。. 圖3 ··如例3所述，凝血酶抑制劑化合物A自根據參考文獻鍵 劑之溶解力。 卷論（範例） 由範例中，顯然當使用”標準"粒劑時並不能獲得足量產 任一者之工業特性均不良（例2和3 )，且/或在磷酸鹽 Ξ ϊ ΪΡΗ -6義8之ΐ解力並不能達到工業指引中快速溶解藥 幻產物之疋義。威弗之活體内生物效性和生物 的即釋固體藥劑型包含根攄4物薤與八步 田性研九
份/活性^。μ ^ <某些活性部 r王风根據本發明之調配物溶解力在兩滁A哲县 快速的且工業特性極佳。 啤種基吳疋
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Claims (1)
- 561056 案號 88114460 六、申請專利範圍 1 . 一種pH依賴性溶解 血酶抑制劑的固體型式 酶抑制劑之平均顆粒大 一或多種散解特性之填 調配物重，其選自纖維 2 .根據申請專利範圍 配物視需要含有糖、散 該糖為甘露糖醇、山梨 散解劑為微粒纖維素、 鈉、交聯經丙基纖維素 粉、玉米澱粉、馬鈴薯 烯四氫吼σ各酮或陽離子 素鈉、羥丙基纖維素、 聚乙稀四氫吼σ各酮、聚 膠；及該潤滑劑為硬脂 酸、油、滑石、硬脂醯 月桂基硫酸鈉。 3 .根據申請專利範圍 凝血酶抑制劑之平均顆 4.根據申請專利範圍 血酶抑制劑之平均顆粒 5 .根據申請專利範圍 其包括微粒纖維素和甘 6 .根據申請專利範圍 其特徵為 特徵為凝 其特徵為 度之低分子量、以胜肽為基礎之凝 之口服即釋型調配物，特徵為凝血 小為小於3 0 0微米，調配物包括具 充劑，其含量為高於35重量％之該 素本身和殿粉本身所組成之群。 第1項之口服調配物，其特徵為調 解劑、結合劑和/或潤滑劑，其中 糖醇、右旋糖、木糖醇或乳糖；該 微細纖維素、交聯羧曱基纖維素 、澱粉乙醇酸鈉、預先膠凝化之澱 澱粉、米澱粉、麥澱粉、交聯聚乙 交換樹脂；該結合劑為羧甲基纖維 羥丙基甲基纖維素、甲基纖維素、 乙二醇、水解之明膠、澱粉或天然 酸鎂、硬脂酸鈣、硬脂酸鋅、硬脂 富馬酸鈉、聚乙二醇、苯甲酸鈉或 第1或2項之口月良調配物 粒大小為小於1 5 0微米。 第1或2項之口服調配物 大小為小於8 0微米。 第1或2項之口服調配物 露糖醇之組合。 第5項之口服調配物，其特徵為微0:\60\60070-920829.ptc 第15頁 561056 _案號88114460 年P月 日 修正__ 六、申請專利範圍 粒纖維素占調配物之5 0 - 9 0 % (重量比） 7 ·根據申請專利範圍第5項之口服調配物，其特徵為甘 露糖醇占調配物之0 - 1 5 % (重量比）。 8 ·根據申請專利範圍第1或2項之口服調配物，其中凝血 酶抑制劑是甘胺酸，N-[卜環己基-2-[2-[ [ [ [4-[(羥基亞 胺基）胺基甲基]-苯基]甲基]胺基]羰基]-1-吖丁啶基]- 2 -氧基乙基]-，乙 3旨，[S-(R*， S*)] -）。 9 ·根據申請專利範圍第1或2項之口服調配物，其係用於 治療 1 0.根據申請專利範圍第1項之口服即釋型調配物，其係 用於製備、用於預防及/或治療血栓性栓塞之調配物。O:\60\60070-920829.ptc 第16頁
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| PT (1) | PT1109537E (zh) |
| RU (2) | RU2252751C2 (zh) |
| SA (1) | SA99200683B1 (zh) |
| SE (1) | SE9802973D0 (zh) |
| SK (1) | SK285507B6 (zh) |
| TR (2) | TR200100666T2 (zh) |
| TW (1) | TW561056B (zh) |
| UA (1) | UA75567C2 (zh) |
| WO (1) | WO2000013671A1 (zh) |
| ZA (1) | ZA200101762B (zh) |
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| US7129233B2 (en) | 2000-12-01 | 2006-10-31 | Astrazeneca Ab | Mandelic acid derivatives and their use as thrombin inhibitors |
| AR034517A1 (es) * | 2001-06-21 | 2004-02-25 | Astrazeneca Ab | Formulacion farmaceutica |
| SE0103369D0 (sv) * | 2001-10-09 | 2001-10-09 | Astrazeneca Ab | Pharmaceutical formulation |
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| CN101836978B (zh) * | 2002-03-28 | 2013-09-11 | 帝人制药株式会社 | 含有单一晶型的固体制剂 |
| SE0201658D0 (sv) * | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | Immediate release pharmaceutical formulation |
| SE0201661D0 (sv) * | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | New salts |
| SE0201659D0 (sv) | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | Modified release pharmaceutical formulation |
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| US7781424B2 (en) * | 2003-05-27 | 2010-08-24 | Astrazeneca Ab | Modified release pharmaceutical formulation |
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| US8022053B2 (en) * | 2004-11-02 | 2011-09-20 | Bayer Schering Pharma Aktiengesellschaft | Oral solid dosage forms containing a low dose of estradiol |
| US7524354B2 (en) * | 2005-07-07 | 2009-04-28 | Research Foundation Of State University Of New York | Controlled synthesis of highly monodispersed gold nanoparticles |
| KR101426754B1 (ko) * | 2006-06-29 | 2014-08-07 | 가부시키가이샤 쓰무라 | 한방 엑기스 함유 정제 조성물 |
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| US20090061000A1 (en) * | 2007-08-31 | 2009-03-05 | Astrazeneca Ab | Pharmaceutical formulation use 030 |
| DE102008014237A1 (de) * | 2008-03-14 | 2009-09-17 | J. Rettenmaier & Söhne Gmbh + Co. Kg | Direktverpressbares Tablettierhilfsmittel |
| US8513261B2 (en) * | 2009-03-13 | 2013-08-20 | Toyama Chemical Co., Ltd. | Tablet and granulated powder containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide |
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