TWI356702B - Process for the preparation of a solid, orally adm - Google Patents
Process for the preparation of a solid, orally adm Download PDFInfo
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- TWI356702B TWI356702B TW093136394A TW93136394A TWI356702B TW I356702 B TWI356702 B TW I356702B TW 093136394 A TW093136394 A TW 093136394A TW 93136394 A TW93136394 A TW 93136394A TW I356702 B TWI356702 B TW I356702B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Description
1356702 九、發明說明: 【發明所屬之技術領域】 本發明係關於製備固體口服之 法,其含有親水型5-氣-AK{(5S)-2^^胃又與醫藥組成物的方 5基)-苯基H,3-今唑院-5-基卜曱基)·2 _ '3,[4-(3_側氧冬嗎啉 疾病的預防和/或治療。 Μ羧醯胺’以及其用於 【先前技術】 5-氣-iV~({(5S)-2-側氧-3-[4-(3-側 g 噚唑烷_5-基}-甲基)_2_噻吩羧醯胺(1)為一、嗎啉基)-苯基]-1,3- 10 2 0 A因子Xa抑制劑,其可應用於各種血,低分子量的口服凝 wn δ η 1 μ7010 ,. 玉性疾病的預防和/或治 療(§月看胁趟/47919 ’此揭示為參考 氣-Ν-({(π)·2·侧氧_Η4·㈣氧冰嗎料)_苯基]·13二坐燒 -5-基}•曱基)-2·€吩賴胺(1)全部修飾物的活性化合 及另外包括其各自的水合物。 此活性化合物(1)的水溶性極低(約7毫克/升)。基於此,降 低其口服生物利用率並且增加吸收速率的生物變異性。 已曾提出各種增加口服生物利用率的觀念。 因此通^ Α活性化合物溶液裝填入例如軟膠囊内。基於 用於本目的之活性化合物⑴在溶射的溶解度極低之因素,此 方式不適$而為達到本發明所需的劑量強度可能使膠囊尺 寸無法被吞霜。 另類方法為將活性化合物非晶質化。但由於活性化合物(I) 亦不易溶解於例如乙醇或丙賴醫藥可接受溶劑中,故此處溶 1356702 液方法證明有問題。由於活性化合物的高熔點(約230。〇導致 製備過程中產生不希望之極高比例的裂解成分,因此藉由融合 方法之活性化合物的非晶質化方法亦不可行。 此外,曾利用己巴比妥和苯妥英為舉例說明將斥水性活性 化合物進行親水化作用(Lerk,Lagas,Fell,Nauta,t/owraw/ ο/' PAarwacewi/cfl/ Sdewces,第 68 卷第 7 號,1978 年 7 月,第 935〜939頁:斥水性藥物之親水化作用對膠囊釋放速率的影 響’,;Lerk,Lagas ’ Lie-A-Huen,Br〇ersma,Zuunnan,j⑽围;彳 10 15
Science,第 68 卷第 5 號,1979 年 5 月,第 634〜63 8頁:”從膠囊釋出之親水化苯妥英的活體外和活體内可 利用率”)。此處’錢拌機内將活性化合物顆粒混合曱基-或羥 乙基f維素溶液叫免其料,然後再加以賴。其後在不進 -步处理之下將所得之活性化合物充填人硬膠囊内。 議6驚奇f發現在濕顆粒化過程中特殊處理活性化合 程中使用:、其吸收速率。在製備固體口服醫藥組成物過 化合物(1)可明顯增加其配製物的生物可 【發明内容】 本發明係關於製備固體 法,其含有親水S 5遺〃^樂組成物的方 美飞芏其1 ” w^ 侧氧-3-[4-(3-侧氧-4-嗎啉 基)本基H,3,顿1基}甲基)_2嗔錢醯胺,其中: (a) 以濕造粒法製備含親水型活性 (b) 然後在適當時* …柳⑴的第顆拉, Ό醫樂上適當的添加物而將顆粒轉 20 1356702 變成醫藥組成物。 可在混合機(混合造粒機)或流化床(=流化床製粒機)内 行步驟(a)的濕造粒法;其中以流化床製粒機較佳。 進 在濕造粒法中,可將固體或懸浮於顆粒之液體中的活性4 5合物⑴加入預混合物(原混合物)内。濕造粒法(懸浮製程)較^ 為加入懸浮於顆粒液體中之活性化合物⑴。 乂 在本發明之較佳具体例中,活性化合物⑴以結晶型式施 10 15 2 0 β取住的兴菔例甲,具結晶化合物(1)以微粒 用。此實例之活性化合物(1)具有平均粒# ^ 微米,更佳為介於1釦8拗卓#叫 平乂住為小於] J' V S ^〇^(9〇〇/〇,Μ,]), 兄川微未,更佳為小於15微米。 ) 根據本發明之齡液體含有—_、親水 备時加入制#卜此實例之親水 =以及3 或較佳為轉於H 粒液體f 用=顆粒液體内的溶劑可為有機溶劑,例如 或水或其齡物。較佳為彻水做為溶劑。知或丙綱 用於顆粒液体之親水性黏 加劑,較佳為可溶解於顆冑為4社適合的親水性ί 此處使用之親水Γ聚?::劑中者。 (HPMQ、羧甲基纖維素(:較佳丙基甲基纖維: 羥乙基纖維素、乙基羥^萁^)、乙基纖維素、甲基纖維素 L-HI>C(低取代Ηρα、: 土纖維素、羥丙基纖維素(HPC) 乙缚η比口各啤酮、聚乙稀醇、丙稀酸: 1356702 合物和其鹽類、乙烯吡咯啶酮-醋酸乙烯酯共聚物(例如 Kollidon® VA64、BASF)、凝膠、關華豆膠、部分水解澱粉、 褐藻酸鹽或三仙膠。最佳為使用HPMC做為親水性黏著劑。 親水性黏著劑的濃度為1至15%(根據醫藥組成物的總 5 重),較佳為1至8%。 視需要用於顆粒液體内的濕潤劑為醫藥上適合的濕潤劑 (表面活性劑)。常用者為,例如: 脂肪醇硫酸鹽類之納鹽如月桂基硫酸鈉、硫玻珀酸鹽如二 辛基硫琥拍酸鈉、多元醇的部分脂肪酸酯如單硬脂酸甘油酯、 10山梨聚醣的部分脂肪酸酯如山梨醇酐單月桂酸酯、聚羥基乙烯 山梨糖醇(polyhydroxyethylene sorbitan)的部分脂肪酸酯如聚 乙二醇山梨醇酐單月桂酸酯、單硬脂酸酯或單油酸酯、聚羥基 乙烯脂肪醇醚、聚羥基乙烯脂肪酸酯、氧化乙烯_氧化丙烯嵌 段共聚物(Plimmic®)或乙氧化三酸甘油酉旨。較佳的濕潤劑為月 15 桂基硫酸納(sodium lauryl sulphate)。 濕潤劑在需要時可加入濃度為〇」至5%(根據醫藥組成4 的總重)’較佳為0.1至2%。 在濕造粒法的預混合物(原混合物)中,可進— 上適合的添加物。常用者為,例如: v •填料和乾燥黏著劑如纖維素粉末、微晶纖 =維素、磷酸U酸三飼、三赠鎮、甘露 糖醇、山梨_、木_、乳糖(無水或水合,例 7 物)、右旋糖、麥芽糖、絲、葡萄糖、果糖或麥芽糖早糊^: 20 1356702
*分解促進劑(分解劑)如羧甲基纖維素、交聯羧甲基纖維 素(croscarmellose)(羧曱基纖維素的交聯物)、聚維酮 (crospovidone)(交聯之聚乙婦吡咯啶酮)、L-HPC(低取代羥丙基 纖維素)、羧甲基澱粉鈉、馬铃薯澱粉的乙醇酸鈉鹽(sodium 5 glycolate)、部分水解殿粉、小麥澱粉、玉米澱粉、米澱粉或馬 鈴薯澱粉。 在具有改良的(延遲)釋出活性化合物的錠劑配製物中,可φ 加入影響釋出速率的分解促進劑(分解劑)。下列為其常用者, 例如:羥丙基纖維素、羥丙基甲基纖維素、曱基纖維素、乙基 ίο 纖維素、叛甲基纖維素、聚半乳甘露糖(galactomannan)、三仙 膠(xanthan)、甘油酯、蠟、丙烯酸和/或曱基丙烯酸酯與三甲基 銨甲基丙烯酸酯的共聚物、二甲基胺甲基丙烯酸和中性曱基丙. 烯酸酯的共聚物、曱基丙烯酸或曱基丙烯酸酯之聚合物、乙基. 丙烯酸酯-曱基丙烯酸酯共聚物或甲基丙烯酸-甲基丙烯酸酯共 15 聚物。 接著將步驟(a)獲得之顆粒轉變成根據本發明步驟(b)的醫 ® 藥組成物。 步驟(b)包括根據熟習本技藝之人仕所習知的方法將其例 如壓錠或充填入膠囊’較佳為硬膠囊,或充填成藥袋(sachets),. 20 若需要時可進一步加入醫藥上適合的添加劑。 醫藥上適合的添加劑常用者為,例如: •潤滑劑、滑動劑、流動調節劑例如反丁烯二酸、硬脂酸、 硬脂酸鎂、硬脂酸鈣、硬脂醯反丁烯二酸鈉、高分子量脂肪醇、 9 mi 聚乙二醇、澱粉(小麥、米、玉伞 〆 八邱r拫能、访β仆木或馬鈐薯澱粉)、滑石粉、俜 ~散(《)♦、氧_、碳酸鎮或發酸舞。 ♦分解促進劑(分解劑)如幾 素(羧甲基纖維素的交聯物)、:„、交聯羧甲Ϊ 酮)、L-HPC(低取代羥丙美纖唯夸、、嗣(父聯之聚乙烯^比哈疋 殿粉、小麥澱粉、玉米甲絲油 '部分水解 '粉水殿粉或馬鈴薯澱粉。 本發明進一步係關於一種 ^ . Λ 5,ν,& 服醫樂組成物,其含有親· ,型5-亂善(《聊2,氧_3* 十坐烧_5_基}曱基)_2•喧吩緩酿胺(1)。馬琳基)-本基] 括顆^由;根據本發明的固體°服1藥組成物包 i 填顆粒的藥袋、以及鍵劑,其釋出活性化 口物⑴為快速或改⑽物式。其中 生化,。在本發明的内文二:釋出变. 值(3〇分鐘)為75%者。說明於實驗部分第5.2.2章之具有Q € 根據本發明之醫藥組成: 製物總重的(U至60%,較佳^ 口物(1)/辰度為根據配 化合物(I)的劑量較佳為i至為1至桃。此處,活性 根據本發明之錠劑顆粒 的習知方法下進行包衣。可利右用需 ==習本技藝之人仕 材料或薄膜形成劑進行包覆广%本技衣之人仕常用的包衣 纖維素、乙基纖4 = 丙基纖維素,丙基甲基 、乙烯吡咯啶酮、乙烯吡咯啶__醋酸 1356702 乙酯共聚物(例如Kollidon⑧VA64、BASF)、蟲膝(shellac) 烯酸和/或曱基丙烯酸酯與三曱基銨甲基丙烯酸酯的共聚物丙 二甲基胺甲基丙烯酸和中性曱基丙烯酸酯的共聚物、甲基 酸或甲基丙婦酸酿聚合物、乙基丙婦酸酯-曱基丙缔酸甲於共 5 聚物、曱基丙烯酸-曱基丙烯酸酯共聚物、丙二醇、聚乙二 三醋酸甘油酯、檸檬酸三乙酯,和/或染色劑/顏料如二氧化鈦、 氧化鐵、靛藍或適當的沈澱色料。 本發明進一步係關於利用根據本發明之醫藥組成物預防_ 和/或治療疾病,其特別指血栓性疾病如心肌梗塞、心絞痛(包 10 括不穩定心絞痛)、血管或冠狀動脈分路手術後再梗塞和再狹 窄、大腦血管梗塞、暫時性腦缺血、周邊動脈阻塞疾病、肺栓 塞或深靜脈血栓。 下述將藉由較佳之舉例性具體例做更詳細的說明,然而本 發明並非僅侷限於所列舉的具體例。除非另有說明,否則下述 I5 全部數量資料均指重量百分比。 « 【實施方式】 實驗部分 1.利用親水型/流化庆造粒法之釔合活柹化合物(I)之顆粒製備 鍵劑 20 1.1錠劑組成分(毫克/錠) 活性化合物(I),微粒化 20.0毫克 微晶纖維素 35.0毫克 乳糖單水化合物 22.9毫克 交聯羧甲基纖維素(Ac-Di-Sol®,FMC) 3.0毫克 11 羥丙基曱基纖維素,5釐泊 月桂基硫酸鈉 硬脂酸鎂 羥丙基曱基纖維素,15釐泊 聚乙二醇3.350 ~~氧化敍 製備方法 丙基?基纖維素(5釐泊)和月桂基硫酸鈉溶解於水 水備懸汙為顆粒化液體噴塗於微晶纖維素、|丨 讓甲基纖維素之原始混合物表面。:二 (〇.8亳米網孔)製得的顆粒後,加入硬月匕酸糕*、3入_及師慮 之欲壓槊的榀厭制芡力入硬月曰i鎂並混合之。將獲得 裂強度的錠劑。利用懸浮於 =牛頓抗斷 10 3·〇毫克 0.5亳克 0.6毫克 1.5毫克 〇·5亳克 〇.5毫克 87.5毫克 二醇水溶液内的二氧化欽進r包=維著素色(1:_^ 包含活性化合垫⑴之拥餘勒備錠 2·: 鍵劑組成分(亳克/矣) 活性化合物(I),微粒化 微晶纖維素 乳糖單水化合物 交聯羧甲基纖維素(Ac-Di S P 羥丙基甲基纖維素,3釐泊, 月桂基硫酸鈉 ' 硬脂酸鎂 羥丙基曱基纖維素,15鰲、、6 聚乙二醇400 氡化鐵黃 FMC) 5.0毫克 40.0毫克 33.9毫克 3.0毫克 2.0毫克 〇.5毫克 0.6毫克 1.5毫克 0.5毫克 〇.1毫克 12 1356702
二氧化鈦 2.2製備方法 在高速混合機内混合纖維素、乳糖單水化合物和交 基纖維素(原顆粒混合物)。將羥丙基甲基纖維素(3釐泊)和羧曱 基硫酸鈉溶解於水中。將微粒化活性化合物(1)懸浮於該=桂 5内。將製備之懸浮液做為顆粒化液體加入原顆粒混合物§内',然 後利用快速旋轉攪拌機將其和原顆粒混合物均勻地混合。在= 成徹底的此合之後,在流化床内進行濕顆粒的筛滤(4毫米網孔) 和乾燥。在篩濾乾燥顆粒(〇.8毫米網孔)之後,加入硬脂酸鎂並 混合之。將獲得之欲壓製的混合物壓製成具有6毫米直徑和 ίο 50〜100牛頓抗斷裂強度的錠劑。利用懸浮於羥丙基曱基纖維 素(15釐泊)和聚乙二醇水溶液内之二氧化鈥和氧化鐵黃的色 素進行包衣錠劑的著色。 3·製備含親水型活性化合物⑴及充填成藥袋的顧齟 3.1顆粒組成分(毫克/包) 50.0毫克 662.0毫克 15.0毫克 15.0毫克 1.0毫克 2,0毫克 5.0毫克 活性化合物(I),微粒化 甘露糖醇 交聯羧甲基纖維素(Ac-Di-Sol®,FMC) 羥丙基甲基纖維素,5釐泊 月桂基硫酸鈉 两分散石夕(Aerosil® 200, Degussa) 草莓香料,喷霧乾燥 750.0毫克 3·2製備方法 將羥丙基甲基纖維素(5釐泊)和月桂基硫酸鈉溶解於水 13 1356702 中。將微粒化活性化合物⑴懸浮於該溶液内。在流化床的造粒 法過程中將製備之懸浮液做為顆粒化液體噴塗於甘露糖醇和 父聯敌曱基纖維素之原混合物表面。乾燥及篩遽(〇 8毫米網孔) 製付的顆粒後,然後加入南分散發(Aerosil®)和草莓香料並混合 5之。利用裝填機將750毫克獲得之混合物充填入藥袋内。 4· |僙含親水型活悻化合物(I)及充填成硬膠囊的顆粉 4.1顆粒組成分(毫克/膠囊) 20.0毫克 30.0毫克 79.5毫克 25.0毫克 4.5毫克 0.5毫克 0.5毫克 活性化合物(I),微粒化 微晶纖維素 乳糖單水化合物 玉米澱粉 羥丙基甲基纖維素,5釐泊 月桂基硫酸鈉 高分散矽(Aerosil® 200, Degussa) 160.0毫克 4.2製備方法 將羥丙基甲基纖維素(5釐泊)和月桂基硫酸鈉溶解於水 1〇中。將微粒化活性化合物(I)懸浮於該溶液内。在流化床的造粒 法過程中將製備之懸浮液做為顆粒化液體喷塗於微晶纖維 素、乳糖單水化合物和玉米澱粉之原混合物表面。乾燥及篩濾 (0.8毫米網孔)製得的顆粒後’然後加入高分散矽(Aer〇sii®)並 混合之。將160毫克獲得之混合物充填入2號尺寸膠囊的硬膠 15 囊内。 5.含/不含親水型活性化合物(I)之餘拜]的比較 5.1錠劑組成分,製備方法 1356702 為檢測錠劑性質及改善含親水型活性化合物(i)之配製物 的生物可利用率,製備下列含10毫克活性化合物(I)之未包衣 的錠劑(毫克/錠): 活性化合物(I),微粒化 10.0毫克 微晶纖維素 40.0毫克 乳糖單水化合物 27.9毫克 交聯羧曱基纖維素(Ac-Di-Sol®,FMC) 3.0毫克 羥丙基曱基纖維素,5釐泊 3.0毫克 月桂基硫酸鈉 0.5毫克 硬脂酸鎂 0.6毫克 85.0毫克 鍵劑A ·未經造粒直接製鍵 5 錠劑B :藉由流化床製粒機/1.2中所述之懸浮製程製備 利用錠劑A的混合物及錠劑B的顆粒壓製成具有直徑6 毫米和70〜80牛頓抗斷裂強度的錠劑。 5.2錠劑性質 5.2.1水中的分解時間(USP崩解儀,Erweka): 10 錠劑A :約1.5分鐘 鍵劑B :約6.5分鐘 5.2.2活體外釋出量 根據錠劑總含量所釋出之活性化合物含量示於下表1 : 表1 :活體外釋出量 15分 30分 45分 60分 錠劑A 87% 92% 93% 94% 錠劑B 94% 95% 96% 96% 15 (USP漿葉,900毫升之pH4.5醋酸緩衝液+0.5%月桂基硫酸鈉,75rpm) 15 1356702 5.2.3生物可利用率 為測定生物可利用率,以交又方式將三顆錠劑A或三顆 錠劑B分別投與各組的三隻犬。口服3毫克活性化合物(I)/公 斤之後得相關藥動學參數列於下述的表2 : 5 表2 :活性化合物(I)的藥動學參數 錠劑A 動物 幾何 平均數 幾何 標準差 算數 平均數 算數 標準差 1 2 3 AUC(0 〜24) [毫械州 1.39 2.31 3.34 2.21 1.55 2.35 0.974 AUC(0~24)norm [imm 0.464 0.770 1.11 0.735 1.55 0.782 0.325 Cmax [毫_ 0.299 0.398 0.430 0.371 1.21 0.376 0.0684 Cmax.norm [公_ 0.0997 0.133 0.143 0.124 1.21 0.125 0.0228 C(24)/C舰 (%] 12.2 2.99 55.1 12.6 4.29 23.4 27.8 ^max [小瑚 1.00 1.50 0.750 1.04 1.42 1.08 0.382 錠劑B AUC(0 〜24) 2.82 3.03 3.73 3.17 1.16 3.19 0.476 AUC(0~24)norm [毫_升1 0.938 1.01 1.24 1.06 1.16 1.06 0.159 Cmax [毫_ 0.478 0.513 0.321 0.428 1.29 0.437 0.102 [公斤/升] 0.159 0.171 0.107 0.143 1.29 0.146 0.0341 C(24)/C隱 (%] 26.4 1.17 93.4 14.2 9.53 40.3 47.7 ^max [小蝴 1.00 1.50 0.750 1.04 1.42 1.08 0.382 結果:和錠劑A比較儘管分解速度較慢(請看5.2.1)並且 極類似活體外錠劑B的釋出速率(請看5.2.2),錠劑B的吸收 速率明顯較優而因此其生物可利用率增加約35%。同時,其變 1〇 異性明顯降低。錠劑A和錠劑B之間的唯一差異為濕造粒法 的懸浮製程中錠劑B之活性化合物(I)的親水化作用。 【圖式簡單說明】 無 【元件代表符號簡單說明】 無 15
Claims (1)
1356702
專利申請案第931 36394號 ROC Patent Application No. 93 1 3 63 94 修正之申請專利範圍中文本·附件(二) Amended Claims in Chinese-Encl. (II) (民國100年9月28曰送呈) (Submitted on September 28, 2011) 十、申請專利範圍: 1. 一種製備固體口服之可投與醫藥組成物的方 法,其含有親水型5-氯-W-({(5S)_2-側氧(oxo)-3-[4-(3-側氧-4 -嗎♦基)-苯基]-1,3-σ亏0坐燒-5-基}-甲基)-2-σ塞吩 羧醯胺(I),其特徵為: (a) 以濕造粒法製備含親水型活性化合物(I)的第 一顆粒; (b) 然後在需要時加入醫藥上適當的添加物而將 顆粒轉變成醫藥組成物; 其中濕造粒法為混合機造粒或流化床造粒;活 性化合物(I)具低於10微米之平均粒徑x5G且造粒液體 含有溶劑、親水性黏合劑及,若適當,濕潤劑。 2. 根據申請專利範圍第1項之方法,其特徵為該 濕造粒法為流化床造粒。 3. 根據申請專利範圍第1或2項之方法,其特徵 為該活性化合物(I)為以結晶型式施用。 4. 根據申請專利範圍第3項之方法,其特徵為該 活性化合物(I)為以微粒化型式施用。 5. 根據申請專利範圍第1或2項之方法,其特徵 為懸浮於造粒液體内的活性化合物(I)被引入濕造粒法 中〇
17 1356702 6.根據t請專利範圍第】或2項之 為該醫樂組成物為快速釋出活性化合師)的鍵劑、。“ 固體7口服醫til請專利範圍第1項之方法製備的 亏’元基)-甲基)-2-噻吩竣醯胺(i)。 9. 根據申請專利範圍第8項之醫藥組成物,其含 有結晶型式的活性化合物(I)。 10. 根據申料利範圍帛9項之醫藥組成物,其含 有微粒化型式的活性化合物(I)。 —U.根據申請專利範圍第7至1〇項中任一項之醫 樂組成物,其特徵為活性化合物(⑽度為根據配製物辑 重的1至60%。 “ 12. 根據申請專利範圍第7至1〇項中任一項之醫 藥組成物’其包含月桂基硫酸鈉做為濕潤劑。 13. 根據申請專利範圍第12項之醫藥組成物,包 含月桂基硫酸鈉的濃度為根據總重的0.1至5%。 14_根據申請專利範圍第7至1〇項中任一項之醫 藥組成物,其包含羥丙基甲基纖維素做為親水性黏著 劑。 15.根據申請專利範圍第14項之醫藥組成物,包 含羥丙基 16. 藥組成物 甲基纖維素的濃度為根據總重的1至15%。 根據申請專利範圍第7至10項中任一項之醫 ’其為鍵劑的型式。 組成物,其 组成物,其 17.根據申請專利範圍第16項之醫藥 為逮釋鍵劑的型式。 ^ I8·根據申請專利範圍第16項之醫藥 特徵為該錢劑被包覆包衣。 種利用親水型 iy, -(3-側氧_4_嗎淋基)_苯基]_i,3_ σ寻嗤烷_5 =2嗜錢醯胺㈣備供預防和/或治療血 : <樂物的用途。 妖涡
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2003
- 2003-11-27 DE DE10355461A patent/DE10355461A1/de not_active Withdrawn
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2004
- 2004-10-29 AR ARP040103985A patent/AR047844A1/es not_active Application Discontinuation
- 2004-11-13 DK DK04797879.6T patent/DK1689370T4/da active
- 2004-11-13 UA UAA200607192A patent/UA85693C2/ru unknown
- 2004-11-13 KR KR1020067010283A patent/KR101151117B1/ko active IP Right Review Request
- 2004-11-13 RU RU2006122599/15A patent/RU2379036C2/ru active
- 2004-11-13 IL IL175860A patent/IL175860B2/en active IP Right Grant
- 2004-11-13 CN CN200480035106XA patent/CN1886120B/zh active Active
- 2004-11-13 AT AT04797879T patent/ATE385782T1/de active
- 2004-11-13 PT PT04797879T patent/PT1689370E/pt unknown
- 2004-11-13 WO PCT/EP2004/012897 patent/WO2005060940A2/de active IP Right Grant
- 2004-11-13 BR BRPI0416404A patent/BRPI0416404B8/pt active IP Right Grant
- 2004-11-13 DE DE502004006218T patent/DE502004006218D1/de active Active
- 2004-11-13 US US10/580,711 patent/US20080026057A1/en not_active Abandoned
- 2004-11-13 SI SI200430675A patent/SI1689370T2/sl unknown
- 2004-11-13 PL PL04797879T patent/PL1689370T5/pl unknown
- 2004-11-13 NZ NZ547466A patent/NZ547466A/en unknown
- 2004-11-13 ES ES04797879.6T patent/ES2300845T5/es active Active
- 2004-11-13 CA CA2547113A patent/CA2547113C/en active Active
- 2004-11-13 SI SI200430675T patent/SI1689370T1/sl unknown
- 2004-11-13 AU AU2004305226A patent/AU2004305226B2/en active Active
- 2004-11-13 JP JP2006540276A patent/JP4852423B2/ja active Active
- 2004-11-13 EP EP04797879.6A patent/EP1689370B2/de active Active
- 2004-11-23 GT GT200400239A patent/GT200400239A/es unknown
- 2004-11-25 MY MYPI20044891A patent/MY138386A/en unknown
- 2004-11-25 HN HN2004000490A patent/HN2004000490A/es unknown
- 2004-11-26 TW TW093136394A patent/TWI356702B/zh active
- 2004-11-26 PE PE2004001166A patent/PE20050666A1/es active IP Right Grant
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- 2006-05-24 ZA ZA200604166A patent/ZA200604166B/en unknown
- 2006-05-24 MA MA29056A patent/MA28178A1/fr unknown
- 2006-05-25 EC EC2006006584A patent/ECSP066584A/es unknown
- 2006-05-29 CU CU20060109A patent/CU23551B7/es active IP Right Grant
- 2006-06-23 NO NO20062942A patent/NO340156B1/no unknown
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2007
- 2007-06-22 HK HK07106689.6A patent/HK1099518A1/xx unknown
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2008
- 2008-03-27 CY CY20081100352T patent/CY1107369T1/el unknown
- 2008-04-01 HR HRP20080150TT patent/HRP20080150T4/hr unknown
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2009
- 2009-07-16 RU RU2009127302/15A patent/RU2493850C2/ru active Protection Beyond IP Right Term
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2014
- 2014-03-10 US US14/202,481 patent/US9402851B2/en active Active
- 2014-04-11 US US14/250,863 patent/US9415053B2/en active Active
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2016
- 2016-02-10 US US15/040,169 patent/US20170007612A1/en not_active Abandoned
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