TWI478733B - 突釋藥物釋放組合物 - Google Patents
突釋藥物釋放組合物 Download PDFInfo
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- TWI478733B TWI478733B TW099115137A TW99115137A TWI478733B TW I478733 B TWI478733 B TW I478733B TW 099115137 A TW099115137 A TW 099115137A TW 99115137 A TW99115137 A TW 99115137A TW I478733 B TWI478733 B TW I478733B
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- WFITUPFQQAGOBI-UHFFFAOYSA-M sodium;carbonochloridate Chemical compound [Na+].[O-]C(Cl)=O WFITUPFQQAGOBI-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
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- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
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- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
-
- 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
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Eyeglasses (AREA)
Description
由持續釋放親水基質錠劑突釋藥物之釋放法係醫藥學之進化領域。醫藥工業在錠劑調配物中使用各種方法來化合醫藥試劑。除活性成份以外，調配物包括其他賦形劑(諸如控制釋放劑、稀釋劑、黏合劑、崩解劑、界面活性劑、助滑劑、潤滑劑、著色劑、塗層物質、表面活化劑)及諸多其他對最終固體劑量產物提供不同性質之原料。
此外，某些加工步驟係用於調配及精確調配及/或製備固體劑量產物。與製備固體劑量調配物相關之最普遍的加工步驟概括如下：若化合物(諸如活性醫藥成份(「API」))之流動性質較差，當呈乾燥摻合物調配而引起裝量一致性問題時，可使用「濕法製粒」方法。通常使用濕法製粒以改良粉末摻合物之加工特性，包括經改良的流動性、裝量一致性及更均勻的粒度。
濕法製粒係用以改良流量、壓縮係數、生物可利用性、均質性、靜電性質及固體劑型之安定性。通常需要製粒法改良粉末混合物的流動及錠劑的機械特性。通常藉由添加液體(黏合劑或溶劑溶液)獲得顆粒。較大量的製粒液體產生較窄的粒度範圍及較粗及較硬的顆粒，亦即細顆粒之比例減小。顆粒粒度係藉由製粒液體之數量及進料速率決定。
若化合物(諸如活性醫藥成份「API」)之流動性質較差，當呈乾摻合物調配而引起裝量一致性問題時，可使用濕法製粒方法。濕法製粒通常用於改良粉末摻合物之加工特性，包括經改良的流動性、裝量一致性及更均勻的粒度。在濕法製粒中使用水及加熱會引起化學降解或物理形態轉變。
顆粒加工中所面臨的變數可導致重大的製錠問題。所形成顆粒之性質會受到製粒溶液的黏度、製粒溶液的添加速率、所使用攪拌器的類型及混合時間、乾式及濕式摻合之方法及速率影響。以上變數可改變所生成顆粒的密度及粒度，並可能對填充重量及壓縮品質產生重大影響。乾燥會導致不利的分離，因為可溶性API會移至乾燥顆粒之表面上。
「直接壓縮」係定義為直接由API及合適的賦形劑之粉末混合物壓縮成錠劑的過程。不需要藉由濕法或乾法製粒步驟前處理粉末摻合物。其僅涉及摻合及壓縮。由於此需要較少的單元操作，較少的機器及通常較少的加工時間，另外在某些情況中，增加的產品安定性，所以此呈現快速生產的優點。
經過直接壓縮的錠劑會在崩解後釋放出各主要藥物粒子。而藉由壓縮顆粒製備錠劑時，具有較大表面積之小型藥物顆粒會共同黏附成為較大的聚結物，因此減小了可用於溶解的表面積。
雖然具有所有益處，製粒過程可提供(諸如)改良的材料流動性及裝量一致性，但是「輥筒壓縮」在濕度、溶劑或針對熱敏感化合物上，比濕法製粒提供更獨特的優點。
在輥筒壓縮中，將粉末送進兩個依相反方向輥轉之輥筒中，由於摩擦牽引粉末進入輥筒之間，其壓縮粉末。輥筒壓縮法表面上係簡單的過程，但是基本機轉複雜，因為其涉及諸多材料性質及機器變數(諸如材料流動性質、對輥筒表面的摩擦、壓縮係數、壓塑性、彈性、透氣性、輥筒表面、輥筒尺寸、輥筒壓力、輥筒間隙、輥筒速度、進料方法及條件)。
通常在輥筒壓縮過程中存在三個控制參數：輥筒壓力、輥筒間隙及輥筒速度。由於輥筒壓縮期間之粉末會因機械壓力(垂直應力及剪切應力)造成粉末摻合物共同固化形成帶狀物，因此應檢查其與垂直(壓縮)應力及剪切應力的關聯性，來探討所有參數。
黏度係與固體劑量醫藥組合物相關的另一特性，儘管通常認為黏度係流體流動性質的特性。在醫藥技術中，固體劑型(諸如錠劑及膠囊)一旦經口投與且暴露於消化道(包括口、咽喉、胃及腸)之流體中時，即變成與黏度相關。
醫藥調配物中通常包括控制釋放劑作為賦形劑。該等持續釋放劑，較佳為經取代的纖維素衍生物(諸如羥丙基甲基纖維素(HPMC))促使調配物延時釋放醫藥活性成份，因此較不需要經常對患者投與調配物，諸如每日一次。其較佳含量應為允許形成可逐漸釋放活性成份的凝膠基質之量。此外，本文涵蓋的組合物可包含其他持續釋放劑，較佳為彼等在與水接觸時會膨脹者，諸如聚乙烯吡咯啶酮、羥乙基纖維、羥丙基纖維素、其他纖維素醚及酯(如甲基纖維素、甲基乙基纖維素、羥丙基甲基纖維素、羧甲基纖維素、澱粉、預糊化澱粉、聚甲基丙烯酸酯、聚乙酸乙烯酯、微晶質纖維素、葡聚糖或其混合物)。
本發明者已發現，對包括醫藥活性劑及具有某些表觀黏度的控制釋放劑之調配物中之成份進行某些加工法時，對活性成份的溶解具有明顯的作用。在醫藥科學中，控制活性成份的溶解速率對所期望的釋放時間及活性成份的功能性而言很重要。如此，本文揭示的發現內容及組合物提供新穎的方法，透過成份的獨特組合及在組合物中使用經特定加工的活性成份來控制活性成份溶解。
本文揭示的本發明一項特定的觀察結果及優點係醫藥活性成份加上控制釋放劑之混合物的濕法製粒過程所製成之固體調配物在醫藥活性成份於某種黏度下之突釋特性上造成令人驚訝的結果。明確言之，若使用濕法製粒法處理醫藥活性成份加上控制釋放劑之混合物，則該較高黏度的調配物具有一致之較快速突釋速率。
相反，本文揭示的本發明另一特定的觀察結果及優點係直接壓縮及輥筒壓縮之過程在處於特定黏度之醫藥活性成份的突釋特性方面出現彼此相似的特性。明確言之，若使用直接壓縮及輥筒壓縮處理醫藥活性成份加上控制釋放劑之混合物時，該較高黏度的調配物比彼等使用濕法製粒法處理者一致具有較慢的突釋速率。
本發明將可以調配可調節釋放曲線之藥品，以產生同時具有立即釋放(IR)及持續釋放(ER)兩種特性之組合物。對於疼痛處理之產品而言，較佳實施例之關鍵需求在於預先釋放初始劑量以先止痛，並在一段時間內持續提供有效血液濃度。本文示例的組合物提供該等有利的特性。
本發明例舉的組合物之另一優點係IR/ER調配物可製成單一、單片設計。與IR/ER調配物常用的多層方式相反，由製造業觀點而言，單片原型具有明顯的優勢。由於壓縮過程比較不複雜，因此錠劑/膠囊壓製法運轉速度較快。此外，若使用雙面錠劑壓製，生產速率可加倍。同樣，由於使用者僅處理單層，錠劑規格說明更簡單。如此，無須擔心可能發生在雙層錠劑上之層體彼此黏合問題。此外，雙層錠劑可能具有較高的易碎性。
對於活性成份而言，較佳的實施例包括NSAID，其以可誘發止痛或減輕疼痛之量存在。適用於本發明操作法的環氧化酶-1抑制劑(包括彼等較佳之布洛芬(ibuprofen))可呈約50至約800 mg之間之量存在於所主張的組合物中。較佳係以約200至600 mg之間之量存在。最佳係以約600 mg之量存在。如本文提供的術語活性劑之「有效量」或「治療上有效量」之定義為至少足以提供所期望的治療作用之製劑用量。如上所述，本發明之發現基礎在於若投與正常劑量的NSAID，則可降低減充血劑及/或抗組胺之有效劑量。所需要的準確數量將隨個體之間變化，其取決於年齡、個體之整體條件、所治療病症的嚴重度及所投與的特定活性劑，等等。
如本文提供的術語活性試劑之「正常許可劑量」之定義為美國食品與藥物管理局(United States Food and Drug Administration)許可以特定劑型投與人體之安全且有效製劑的用量。因此以經過許可的劑量作為出現於醫藥產物中之劑量，即每單位劑型之活性劑用量。在本發明中，許可劑量之比例意指針對相同患者群體(例如，成年人之間或幼兒之間)及針對相同劑型(例如，酏劑、錠劑、膠囊、膜衣錠、控制釋放劑等)許可的劑量。
在本發明之操作法中，習此相關技藝之人士可使用任何非處方(OTC)或處方減充血劑及/或抗組胺之許可劑型，減少(例如)25%至50%或更多，並與許可劑量之NSAID共同投與，以達到有效緩解鼻炎及減少副作用。在一實施例中，相對於相當於約100%正常強度之NSAID劑型中NSAID之存在量而言，本發明涵蓋使用少於或等於約75%及高於1%之許可劑量之一或多種減充血劑、止咳劑或抗組胺含量。另一範圍係約10%至約65%之間。另一範圍係約30%至約55%之間。亦可能約35%至約50%之間。
本發明涵蓋一種包含單一或多種醫藥活性成份(例如，減充血劑、抗組胺及NSAID)之組合物。
醫藥組合物及本發明之使用方法中所使用之非類固醇消炎藥物(NSAID)可選自以下任何種類：
(1) 丙酸衍生物；
(2) 乙酸衍生物；
(3) 芬那酸(fenamic acid)衍生物；
(4) 聯苯基羧酸衍生物；
(5) 昔康類(oxicams)，及
(6) Cox-2抑制劑
因此，本文使用的術語「NSAID」意指任何非類固醇消炎化合物，其包括其醫藥上可接受的無毒鹽，屬於以上六種結構類型之一。
本發明所使用的屬於先前定義之非類固醇消炎藥物之特定化合物係習此項技術者所熟知且有關其等化學結構、醫藥活性、副作用、正常劑量範圍等可參照各種文獻參考來源。參見(例如)Physician's Desk Reference及The Merek Index。
本文使用的丙酸衍生物中，特定涵蓋布洛芬(ibuprofen)、萘普生(naxproxen)、氟比洛芬(flurbiprofen)、非諾洛芬(fenoprofen)、酮基布洛芬(ketoprofen)、蘇普芬酸(suprofen)、芬布芬(fenbufen)及氟洛芬(fluprofen)。在乙酸衍生物中，示例性化合物包括托麥汀鈉(tolmetin sodium)、佐美酸(zomepirac)、舒林酸(sulindac)及吲哚美辛(indomethacin)。在芬那酸衍生物中，示例性化合物包括甲滅酸(mefenamic acid)及甲氯滅酸鈉。本發明使用的示例性聯苯基羧酸衍生物包括雙氟尼酸(diflunisal)及氟苯沙酸(flufenisal)。示例性昔康類包括吡羅昔康(piroxicam)、舒多昔康(sudoxicam)及伊索昔康(isoxicam)。示例性Cox-2抑制劑包括塞來考昔(celecoxib)、羅非考昔(rofecoxib)、美儂西康(meloxicam)及尼美舒利(nimesulide)。操作本發明實施例時，上述非類固醇消炎藥物之實例為布洛芬(ibuprofen)。
對於本發明組合物中之非類固醇消炎藥物之劑量而言，儘管特定劑量將取決於患者之年齡及重量、症狀之嚴重度、副作用之發生率及類似因素改變，但是對於人體而言，NSAID之典型有效鎮痛量係約200至1000 mg雙氟尼酸，約50至200 mg佐美酸鈉，約100至800 mg布洛芬，較佳600 mg布洛芬，約250至1000 mg萘普生，約50至200 mg氟比洛芬，約100至400 mg非諾洛芬，約20至40 mg吡羅昔康，約250至500 mg甲滅酸，約200至800 mg芬布芬或約50至100 mg酮基布洛芬；但是，若需要可使用更多或更少量。
在與過敏症或感冒相關之鼻症狀之相關治療中所使用的術語「抗組胺」通常意指組胺H1
受體拮抗劑。已知諸多化學物質具有組胺H1
受體拮抗劑活性。多數有用的化合物可分類為乙醇胺類、乙二胺類、烷基胺類、吩噻嗪類或哌啶類。代表性的組胺H1
受體拮抗劑包括(但不限於)：阿司咪唑(astemizole)、呱吡康唑(azatadine)、氮單斯汀(azelastine)、阿伐司丁(acrivastine)、溴苯拉敏(brompheniramine)、氯苯拉敏(chlorpheniramine)、氯苯苄咯(clemastine)、賽克利嗪(cyclizine)、卡瑞斯汀(carebastine)、賽庚啶(cyproheptadine)、氯苯吡醇胺(carbinoxamine)、脫羧氯雷他定(descarboethoxyloratadine)(亦稱為SCH-34117)、地洛瑞林(desloratadine)、多西拉敏(doxylamine)、二甲茚定(dimethindene)、依巴斯汀(ebastine)、依匹斯汀(epinastine)、乙氟利嗪(efletirizine)、非索那定(fexofenadine)、羥嗪(hydroxyzine)、酮替芬(ketotifen)、氯雷他定(loratadine)、左卡巴斯汀(levocabastine)、咪唑斯汀(mizolastine)、美喹他嗪(mequitazine)、米安色林(mianserin)、諾柏斯汀(noberastine)、美克洛嗪(meclizine)、諾司咪唑(norastemizole)、匹庫馬特(picumast)、吡拉明(pyrilamine)、異丙嗪(promethazine)、特非那定(terfenadine)、去敏靈(tripelennamine)、替美斯汀(temelastine)、異丁嗪(trimeprazine)及曲普立定(triprolidine)。很容易藉由已知方法(包括針對單離的天竺鼠迴腸組胺之收縮性回應的特異性阻斷性)評估其他化合物，以確定對H1
受體之活性。
本文特別涵蓋氯苯拉敏(Chlorpheniramine)。普通成人之氯苯拉敏劑量係依需要，每4至6小時口服4 mg，最多量達24 mg/天。普通幼兒的氯苯拉敏劑量係每4至6小時口服2 mg，最多量達12 mg/天。較佳的鹽係氯苯拉敏馬來酸鹽。根據本發明，普通成人劑量可因此降至3 mg，或進一步降至2 mg，依需要每4至6小時口服一次，最多量達12至18 mg/天。同樣，在本發明之實施例中，幼兒劑量係每4至6小時口服1.5 mg或1 mg，最多量達6至9 mg/天。在另一實施例中，本發明允許幼兒劑量之氯苯拉敏與成人劑量之NSAID(諸如布洛芬)組合。
本發明醫藥組合物及使用方法中所使用之減充血劑包括(但不限於)假麻黃鹼、苯基麻黃鹼、苯丙醇胺。熟習此項技術者可瞭解諸多其他合適的減充血劑及其等許可劑量。
本文特別涵蓋假麻黃鹼及苯基麻黃鹼。普通成人之假麻黃鹼劑量係每4至6小時60 mg，最多量達240 mg/天。2至5歲普通幼兒之假麻黃鹼劑量係每6小時15 mg，最多量達60 mg/天，及6至12歲係每6小時30 mg，最多量達120 mg/天。因此，在操作本發明之特定實施例中，每4至6小時成人劑量可降至45或30 mg，最多量120至180 mg/天，及每6小時幼兒劑量可降至約11或7.5 mg，最多量達30至45 mg/天。上述明顯看出本發明涵蓋將雙倍幼兒劑量與標準成人劑量之NSAID投與成人。
止咳劑對大腦起作用以抑制咳嗽反射。該等咳嗽抑制劑係用於緩解持續乾咳。最常用的藥物係右美沙芬(dextromethorphan)(NMDA受體拮抗劑)、可待因(codeine)及福爾可定(pholcodine)(其係類鴉片)。但是，熟習此項技術者應瞭解，仍有許多種諸多其他熟知且常見的止咳劑可以使用。本發明係視需要關於止咳劑之用途。該止咳劑可使用少於或等於75%許可劑量之量。
本發明之組合物係調配成固體單一劑型(諸如錠劑、膠囊、藥囊、片劑及類似物)。通常固體化合物係經口投與。
本發明示例性組合物係關於一種固體劑型(諸如散裝粉末、錠劑、膜衣錠、丸劑、膠囊、藥囊、粒劑及任何其他適於經口投藥之劑型)。對於本說明書及附屬請求項之目的而言，術語「錠劑」同樣意指錠劑、膜衣錠或任何其他適於經口投藥之劑型。
本發明組合物亦涵蓋含有一或多種非醫藥活性賦形劑。此等包括(但不限於)：控制釋放劑、稀釋劑、黏合劑、崩解劑、界面活性劑、助滑劑、潤滑劑、著色劑、塗層物質、表面活性劑及諸多其他對最終固體劑量產物提供不同性質之原料。
醫藥調配中通常包括控制釋放劑作為賦形劑。該等持續釋放劑，較佳為經取代的纖維素衍生物(諸如羥丙基甲基纖維素(HPMC))，促使調配物延遲釋放醫藥活性成份，因此較不需要經常對患者投與調配物(諸如每日一次)。其較佳含量應為允許形成可逐漸釋放活性成份的凝膠基質之量。此外，本文涵蓋的組合物可包含其他持續釋放劑，較佳為彼等在與水接觸時會膨脹者，諸如聚乙烯吡咯啶酮、羥乙基纖維、羥丙基纖維素、其他纖維素醚及酯(如甲基纖維素、甲基乙基纖維素、羥丙基甲基纖維素、羧甲基纖維素、澱粉、預糊化澱粉、聚甲基丙烯酸酯、聚乙酸乙烯酯、微晶質纖維素、葡聚糖或其混合物)。通常，控制釋放劑係以最終組合物重量之約0.5%至約50%及更明確言之，以最終組合物重量之約10%至約30%之量存在。
黏合劑係用於對經粉末狀材料提供內聚性質之製劑。黏合劑對錠劑調配物提供黏合性，確保壓縮後之錠劑仍維持完整，並藉由調配所需硬度及尺寸之顆粒而改良自由流動性質。合適的黏合劑材料包括(但不限於)：澱粉(包括玉米澱粉及預糊化澱粉)、明膠、糖(包括蔗糖、葡萄糖、右旋糖、乳糖及山梨糖醇)、聚乙二醇、蠟、天然及合成膠質，例如，阿拉伯膠、黃蓍膠、海藻酸鈉、纖維素(諸如微晶質纖維素)及合成聚合物(諸如聚甲基丙烯酸酯及聚乙烯吡咯啶酮)。
潤滑劑在錠劑製備中具有諸多功能。其等預防錠劑材料黏附至模具及衝壓機表面，減少微粒間摩擦，促使錠劑自模具空腔中釋出並可改良錠劑製粒的流動速率。合適的潤滑劑之實例包括(但不限於)：硬脂酸鎂、硬脂酸鈣、硬脂酸、山萮酸甘油酯、滑石、月桂基硫酸鈉、硬脂富馬酸鈉、聚乙二醇或其混合物。通常，該潤滑劑係以最終組合物重量之約0.25%至約5%及更明確言之，以最終組合物重量約0.5%至約1.5%之量存在。
崩解劑係添加至錠劑以促使其在投藥後分裂或崩解之物質或物質之混合物。已將用作崩解劑之材料在化學上分為澱粉、黏土、纖維素、褐藻膠、膠質及交聯聚合物。合適的崩解劑之實例包括(但不限於)：交聯羧甲基纖維素鈉、澱粉羥乙酸鈉、澱粉、矽酸鎂鋁、膠體二氧化矽、甲基纖維素、瓊脂、膨潤土、海藻酸、瓜耳膠、柑橘果肉、羧甲基纖維素、微晶質纖維素或其混合物。通常，崩解劑係以最終組合物重量之0%至約30%及更明確言之，以最終組合物重量之約0%至15%之量存在。
助滑劑係改良粉末混合物流動特性之物質。助滑劑之實例包括(但不限於)：膠體二氧化矽、滑石或其混合物。通常，助滑劑係以最終組合物重量之約0.1%至約10%及更明確言之，以最終組合物重量之約0.1%至約5%之量存在。
吸附劑可係(例如)膠體二氧化矽、微晶質纖維素、矽酸鈣或其混合物。通常，吸附劑係以最終組合物重量之約0.05%至約42%及更明確言之，以最終組合物重量之約0.05%至約37%之量存在。
若需要，在本發明調配物中可包括其他常用於醫藥調配物之成份(諸如稀釋劑、安定劑及抗黏附劑)。視需要選用的成份包括相關技術中熟知的著色劑及調味劑。
可調配描述於本發明之醫藥組合物，依持續釋放方法釋放活性成份。此等組分之劑型涵蓋多種調配物。
本發明係進一步藉由以下實例描述，其不以任何方式限制本發明主張的範圍。
以下實施例顯示本發明之優點。
為了研究該方法的效用，藉由濕法製粒(WG)、輥筒壓縮(RC)及直接壓縮(DC)製備小規模實驗室批次的單片原型。為了研究聚合物的作用，評估不同黏度級別(K100LV及K4M)及羥丙基甲基纖維素含量(20及25%HPMC)的基質。以下特定實例中使用的預混合製劑參見表1。
然後調配以下組合物。摻合預混合物A至H(表1中)及各取一部份預混合物分配於三種製備方法。直接壓縮用之預混合物係與二氧化矽及硬脂酸摻合並壓縮(如以下描述)。輥筒壓縮用之預混合物係在實驗室規模之裝置上製粒及磨碎，然後與顆粒外層之二氧化矽及硬脂酸摻合並壓縮。濕法製粒用之預混合物在實驗室規模之裝置上製粒、乾燥並磨碎，然後與顆粒外層之二氧化矽及硬脂酸摻合並壓縮。
測定特定實例之黏度*並總結於下表2中。
*2% w/w HPMC於水中之溶液的黏度，cps
突釋釋放之數量係以下示比率表示，其中分母係由60至720分鐘之間區域之線性釋放速率計算。圖2至9顯示經濕法製粒、輥筒壓縮及直接壓縮處理的組合物之曲線及比較。
圖1概括利用濕法製粒、輥筒壓縮及直接壓縮方法加工的組合物中API釋放及組合物黏度之比較。
結果：較高的聚合物含量係與較低的釋放速率及較低程度的突釋藥物釋放有關。當聚合物含量增加時，API釋放速率及突釋速率降低，因為其產生較穩定的凝膠基質。
聚合物黏度與突釋量亦具有緊密的聯繫。較高黏度聚合物的比例提高會增加突釋量，其係HPMC之水合速率函數。聚合物水合程度降低使得在凝膠基質發展前即允許釋放API。
加工因素對突釋具有最顯著的作用。乾法加工的突釋程度低於濕法製粒。此等結果顯示濕法製粒方法之水合/脫水步驟增加突釋量。
結論：此套II級BCS、高載藥量原型顯示，可藉由使用較高量HPMC，選擇較低黏度聚合物級別及使用乾法加工方法減少突釋。
圖1顯示在利用濕法製粒、輥筒壓縮及直接壓縮方法加工的組合物中API釋放及組合物表觀黏度之比較結果概述。
圖2顯示使用預混合批料A：20% HPMC(100:0 K100LV:K4M)進行濕法製粒、輥筒壓縮及直接壓縮加工組合物之分佈曲線及比較。
圖3顯示使用預混合批料B：20% HPMC(67:33 K100LV:K4M)經濕法製粒、輥筒壓縮及直接壓縮加工的組合物之分佈曲線及比較。
圖4顯示使用預混合批料C：20% HPMC(33:67 K100LV:K4M)經濕法製粒、輥筒壓縮及直接壓縮加工的組合物之分佈曲線及比較。
圖5顯示使用預混合批料D：20% HPMC(0:100 K100LV:K4M)經濕法製粒、輥筒壓縮及直接壓縮加工的組合物之分佈曲線及比較。
圖6顯示使用預混合批料E：25% HPMC(100:0 K100LV:K4M)經濕法製粒、輥筒壓縮及直接壓縮加工的組合物之分佈曲線及比較。
圖7顯示使用預混合批料F：25% HPMC(67:33 K100LV:K4M)經濕法製粒、輥筒壓縮及直接壓縮加工的組合物之分佈曲線及比較。
圖8顯示使用預混合批料G：25% HPMC(33:67 K100LV:K4M)經濕法製粒、輥筒壓縮及直接壓縮加工的組合物之分佈曲線及比較。
圖9顯示使用預混合批料H：25% HPMC(0:100 K100LV:K4M)經濕法製粒、輥筒壓縮及直接壓縮加工的組合物之分佈曲線及比較。
(無元件符號說明)
Claims (2)
- 一種製備固體劑量組合物之方法，該固體劑量組合物包含至少一種醫藥活性成份，該至少一種醫藥活性成份由布洛芬(ibuprofen)、微晶質纖維素及羥丙基甲基纖維素(HPMC)組成，其中該HPMC以最終組合物重量之10%至30%之量存在，且其中於製錠前以濕法製粒預混合布洛芬。
- 一種固體劑量組合物，其包含至少一種醫藥活性成份，該至少一種醫藥活性成份由布洛芬、微晶質纖維素及HPMC組成，其中該HPMC以最終組合物重量之10%至30%之量存在且其中布洛芬係藉由濕法製粒加工。
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