TWI436760B - 阿利克侖之蓋崙(galenical)調配物 - Google Patents
阿利克侖之蓋崙(galenical)調配物 Download PDFInfo
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- TWI436760B TWI436760B TW097136655A TW97136655A TWI436760B TW I436760 B TWI436760 B TW I436760B TW 097136655 A TW097136655 A TW 097136655A TW 97136655 A TW97136655 A TW 97136655A TW I436760 B TWI436760 B TW I436760B
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Description
本發明係關於固體口服劑型,其包含作為在合適載劑中之活性成分之口服活性腎素抑制劑阿利克侖(aliskiren)或其醫藥學上可接受之鹽。詳言之,本發明提供包含單獨或與另一活性劑組合之阿利克侖(較佳為其半反丁烯二酸鹽或硝酸鹽)之蓋侖調配物。本發明亦係關於其製備方法及其作為藥劑之用途。
下文中若未特別定義,則術語"阿利克侖"應理解為其游離鹼與其鹽,尤其為其醫藥學上可接受之鹽,最佳為其半反丁烯二酸鹽。
自腎釋放之腎素在循環中分解血管張力素原以形成十酞血管緊張素I。十肽血管緊張素I又被肺、腎及其他器官中之血管緊張素轉化酶分解以形成八肽血管緊張素II。八肽藉由動脈血管收縮直接及藉由自腎上腺釋放鈉離子保持激素醛固酮而間接地增加血壓,伴隨細胞外液容積增加。腎素之酶活性抑制劑使血管緊張素I之形成減少。因此,產生較小量血管緊張素II。活性肽激素之濃度降低係(例如)腎素抑制劑之抗高血壓效應的直接原因。因此,可使用腎素抑制劑或其鹽例如作為抗高血壓劑或用於治療充血性心臟衰竭。
已知腎素抑制劑阿利克侖(詳言之,其半反丁烯二酸鹽)在降低血壓之治療中係有效的而與年齡、性別或種族無關且係良好耐受的。游離鹼形式之阿利克侖由下式表示
且化學定義為2(S
),4(S
),5(S
),7(S
)-N
-(3-胺基-2,2-二甲基-3-氧丙基)-2,7-二(1-甲基乙基)-4-羥基-5-胺基-8-[4-甲氧基-3-(3-甲氧基-丙氧基)苯基]-辛醯胺。如上所述,最佳為其半反丁烯二酸鹽,其於EP 678503 A中作為實例83特定揭示。
此藥劑經由口服路徑投藥優於腸胃外投藥,因為口服投藥允許患者自我投藥而腸胃外調配物在多數情況下必須由內科醫師或輔助醫務人員投藥。
然而,阿利克侖由於其物理化學性質而為難以調配之藥物且其以可靠且穩固方式製備錠劑形式之口服調配物成本昂貴。此外,在大劑量阿利克侖或其醫藥學上可接受之鹽(達到每錠劑300mg游離鹼)之特定情況下,必需高藥物負載以達成合理的錠劑尺寸。迄今為止,僅描述並開發出濕式粒狀阿利克侖調配物之實例,其使用基於口服劑型之總重量計大於46重量%之高藥物負載。阿利克侖之此固體口服劑型描述於(例如)WO 2005/089729中。然而,儘管其具有商業實用性,但由於需要使用造粒液體及額外乾燥步驟,所以濕式造粒法係欠佳的。
因此,需要開發克服上述與阿利克侖性質相關之問題的合適且穩固之蓋侖調配物。
另人驚奇地發現可使用滾輪壓實來便利地製備包含阿利克侖之穩固蓋侖調配物,因此避免濕式造粒法遭遇之溶劑問題且同時達成較高藥物負載以及具有至少與經濕式造粒法製得者等效之特徵的調配物。
因此,本發明係關於一種滾輪壓實之固體口服劑型,其包含治療有效量之阿利克侖或其醫藥學上可接受之鹽,其中活性成分以基於口服劑型之總重量計大於38重量%之量存在,此取決於或不取決於所使用之任何塗層或膠囊材料。
較佳地,基於口服劑型之總重量計之活性成分之量(重量%)未考慮所使用之任何塗層或膠囊重量。更佳地,活性成分以基於口服劑型之總重量計大於40重量%之量存在。
在本發明之一較佳實施例中,活性劑(較佳為諸如半反丁烯二酸鹽或硝酸鹽之鹽形式)以基於口服劑型之總重量計41重量%至80重量%、諸如41重量%至60重量%範圍內之量存在。
在本發明之另一較佳實施例中,活性劑以基於口服劑型之總重量計大於42重量%直至55重量%之量存在。尤其較佳地,活性劑以基於口服劑型之總重量計大於48重量%或甚至50重量%至80重量%之量存在,以增加藥物負載。
在根據本發明之固體口服劑型中,其中活性劑完全由阿利克侖或其醫藥學上可接受之鹽組成,若活性劑以每單位劑型在約75mg至約600mg範圍內之游離鹼量存在,則為較佳的。
在本發明之一較佳實施例中,活性劑完全由阿利克侖或其醫藥學上可接受之鹽組成,且以每單位劑型在約75mg至約300mg範圍內之游離鹼量存在。
在本發明之另一較佳實施例中,阿利克侖劑量為其半反丁烯二酸鹽形式且以每單位劑型約83mg、約166mg、約332mg或約663mg之量存在,亦即,對應於每單位劑型75mg、150mg或300mg游離鹼。
根據本發明之固體口服劑型提供比關於給定單位劑量活性劑迄今為止可能之口服形式小之口服方式的活性成分之投藥。此外,所獲得之口服劑型在生產過程及儲存期間均為穩定的,例如,在習知封裝(例如,密封鋁發泡包裝)中儲存2年。
上文及下文給出之百分比係基於使用諸如半反丁烯二酸鹽或硝酸鹽之鹽計算,且若使用游離酸或其他鹽,百分比將相應修改。關於本文中所使用之百分比,數字係指阿利克侖,因此係指游離酸或鹽,詳言之,其係指半反丁烯二酸鹽或硝酸鹽。
術語"有效量"或"治療有效量"係指活性成分或活性劑停止或減緩所治療病症進程或另外完全或部分治癒或緩解病症的量。除非另有說明,否則本文中所使用之術語"藥物"、"活性物質"、"活性成分"、"活性劑"等係指組分a)及b)。組分a)或b)之每一者可被稱作"藥物"、"活性物質"、"活性成分"、"活性劑"等。
在上文及下文中,若未明確定義,則術語"阿利克侖"應理解為其游離鹼與其鹽,尤其為其醫藥學上可接受之鹽,諸如半反丁烯二酸鹽、硫酸氫鹽、乳清酸鹽或硝酸鹽,最佳為其半反丁烯二酸鹽。
可(例如)以本身已知之方式,尤其如EP 678503 A中(例如實例83中)所述來製備阿利克侖或其醫藥學上可接受之鹽。
固體口服劑型包含膠囊或更佳錠劑或薄膜塗覆錠劑。
根據本發明之固體口服劑型包含適於製備根據本發明之固體口服劑型之添加劑或賦形劑。可使用通常用於錠劑調配物中之壓片助劑且參考此主題之廣泛文獻,尤其參見Fiedler之"Lexicon der Hilfstoffe",第四版,ECV Aulendorf 1996,其以引用之方式併入本文中。此等醫藥學上可接受之添加劑包括(但不限於)填充劑或稀釋劑、黏合劑、崩解劑、潤滑劑、助流劑、穩定劑、界面活性劑、成膜劑、軟化劑、顏料及其類似物。醫藥口服固定劑量組合中每一添加劑之量可在此項技術中習知之範圍內變化。
合適填充劑包括(而不限於)微晶纖維素(例如纖維素MR)、甘露糖醇、蔗糖或其他糖或糖衍生物、磷酸氫鈣品質、澱粉品質(較佳為玉米澱粉)、低取代之羥基丙基纖維素、羥基乙基纖維素、羥基丙基甲基纖維素及其組合,較佳為微晶纖維素,例如可購得註冊商標AVICEL、VIVAPUR、FILTRAK、HEWETEN或PHARMACEL之產品。當存在時,填充劑之使用量可占劑型(在視需要選用任何薄膜塗佈之前)重量之約12%至約50%、較佳約10%至約45%、更佳約15%至約40%範圍內。較佳地,由於用滾輪壓實可能達成高藥物含量,因此填充劑之使用量可以占劑型(在視需要選用任何薄膜塗佈之前)重量之約3%至約50%、較佳約5%至約45%、更佳約7%至約40%範圍內。填充劑可包含在內相以及外相中,較佳為至少包含在內相中。較佳地,相較於經受滾輪壓實之典型混合物,填充劑之用量可保持相對較低。
合適黏合劑包括(而不限於)聚乙烯吡咯啶酮(PVP),諸如PVP K 30或PVP90F;聚乙二醇(PEG),例如PEG 4000;羥基丙基甲基纖維素;羥基丙基纖維素;預糊化澱粉及其組合。由於其物理化學性質,微晶纖維素(例如,纖維素MK)可作為"乾"黏合劑且可將其視為黏合劑。然而,為達成本發明之目的,將微晶纖維素歸類為填充劑而非黏合劑。當微晶纖維素存在且不視為黏合劑時,黏合劑在內相中之使用量為劑型(在視需要選用任何薄膜塗佈之前)重量之約0.01%至約10%、較佳約0.1%至約5%範圍內。較佳地,微晶纖維素不再使用額外黏合劑。
合適潤滑劑包括(而不限於)硬脂酸鎂、矽酸鋁或矽酸鈣、硬脂酸、CUTINA(氫化蓖麻油)、PEG 4000-8000、滑石、萮樹酸甘油酯、硬脂醯反丁烯二酸鈉(PRUV)及其組合,較佳為硬脂酸鎂。當潤滑劑存在時,其用量可占劑型(在視需要選用任何薄膜塗佈之前)重量之約0.1%至約5%、較佳約0.5%至約4%、更佳約1.1%至約3.3%範圍內。在一實施例中,潤滑劑可之使用量可占劑型(在視需要選用任何薄膜塗佈之前)重量之約0.1%至約8%、較佳約0.5%至約6%、更佳約1%至約6%範圍內。較佳地,在劑型之外相及內相中均含有潤滑劑。
合適崩解劑包括(而不限於)羧甲基纖維素鈣(CMC-Ca)、羧甲基纖維素鈉(CMC-Na)、交聯PVP(例如CROSPOVIDONE、POLYPLASDONE或KOLLIDON XL)、海藻酸、海藻酸鈉及瓜耳豆膠,最佳為交聯PVP(PVP XL、CROSPOVIDONE)、交聯CMC(Ac-Di-Sol)、羧甲基澱粉鈉(PlRIMOJEL及EXPLOTAB)或其組合。最佳崩解劑為交聯PVP,較佳為PVPP XL及/或交聯CMC(交聯羧甲基纖維素鈉、Vivasol、Ac-Di-Sol)。當存在時,崩解劑可以固體劑型(在視需要選用任何薄膜塗佈之前)重量之約5%至約30%、較佳約10%至約25%範圍內之量來使用。取決於組合物及其他添加劑,崩解劑可僅包含於內相中或包含於內相以及外相中。
合適助流劑包括(而不限於)膠狀二氧化矽(例如Aerosil 200)、三矽酸鎂、粉末狀纖維素、滑石及其組合。最佳為膠狀二氧化矽。當存在且不將澱粉視為助流劑時,助流劑可以劑型(在視需要選用任何薄膜塗佈之前)重量之約0.05%至約5%、較佳約0.1%至約3%、諸如約0.1%至約1%範圍內之量來使用。取決於組合物及其他添加劑,助流劑可僅包含於內相中或包含於內相以及外相中。較佳存在助流劑以增強經受滾輪壓實之材料之流動性質。
本發明之固體口服劑型具有不超過0.8%、較佳不超過0.6%之低易碎性。易碎性藉由熟習此項技術者已知之標準方法來量測,參看藥典USP<1216>及EP 2.9.7及JP中闡述之協調程序。
本發明之固體口服劑型亦具有合適硬度(例如,在約110N至約250N範圍內之平均硬度)。此平均硬度係在任何薄膜衣塗覆於固體劑型上之前測定。
就此而言,本發明之較佳實施例係針對經薄膜塗佈之固體口服劑型。合適之薄膜衣係已知的且可購得或可根據已知方法製備。通常,薄膜衣材料為親水聚合物,諸如聚乙二醇、聚乙烯吡咯啶酮、聚乙烯醇、羥基丙基纖維素、羥基甲基纖維素及羥基丙基甲基纖維素或其類似物,其中羥基丙基甲基纖維素係較佳的。薄膜衣組合物成分包括習知量之增塑劑,例如聚乙二醇(例如聚乙二醇6000)、檸檬酸三乙酯、鄰苯二甲酸二乙酯、丙二醇、甘油;以及不透明劑,諸如二氧化鈦;及著色劑,例如氧化鐵、鋁色澱等。通常,薄膜衣材料以提供固體口服劑型重量之約1%至約6%範圍內之薄膜衣的量來塗覆。較佳使用諸如由Colorcon Corp.製備之Sepifilm或Opadry混合物之乾燥混合物。此等產品為成膜聚合物、不透明劑、著色劑及增塑劑之單獨製備之乾燥預混合物,其經進一步加工為含水薄膜衣懸浮液。
薄膜衣通常可以達成固體口服劑型重量增加約1重量%至10重量%且較佳約2重量%至6重量%來塗覆。
薄膜衣可藉由習知技術在合適塗佈槽或流化床設備中使用水及/或習知有機溶劑(例如,甲醇、乙醇、異丙醇)、酮(丙酮)等來塗覆。
本發明之另一實施例為製造根據本發明之固體口服劑型之方法。此固體口服劑型可藉由以下方法來製備,其包含以下步驟:將阿利克侖或其醫藥上可接受之鹽與醫藥學上可接受之添加劑一起滾輪壓實,視需要與其他醫藥學上可接受之添加劑混合,及視需要將最終摻合物壓縮為錠劑。
詳言之,該方法包含以下步驟:
(a)摻合阿利克侖或其醫藥上可接受之鹽與醫藥學上可接受之添加劑;
(b)篩分經摻合之阿利克侖或其醫藥上可接受之鹽與醫藥學上可接受之添加劑;
(c)摻合經篩分之材料;
(d)滾輪壓實經摻合之材料以形成經壓實之材料;
(e)研磨經壓實之材料以形成經研磨之材料,稱作阿利克侖顆粒;
(f)視需要摻合經研磨之材料與外相,亦即與醫藥學上可接受之添加劑,以形成最終混合物;
(g)視需要壓縮最終摻合物以形成錠劑;及
(h)視需要塗覆膜衣以獲得薄膜包衣之錠劑。或者,製程步驟(b)及(f)可以兩個步驟執行,包含阿利克侖或阿利克侖顆粒分別與添加劑之第一摻合(無潤滑劑)及第一摻合物與潤滑劑之第二(最終)摻合。
應注意用於此項技術中之許多已知造粒、篩分及混合方法,例如在自由下落或滾筒摻合器中混合、在單一衝壓機或旋轉式製錠機上壓縮為錠劑或在滾輪壓實設備上壓實。可使用任何合適構件完成篩分步驟,例如使用振盪篩分或手動/振動篩。可使用任何合適構件完成摻合步驟。通常,將阿利克侖或阿利克侖顆粒及醫藥學上可接受之添加劑配送至諸如擴散摻合器或擴散混合器之適當容器中。
可使用任何合適構件完成壓實步驟。通常,使用壓實力約1kN/cm至約20kN/cm i.O.、較佳約2kN/cm至10kN/cm範圍內(對於開發規模機器而言)之滾輪壓實機完成壓實。在一實施例中,使用約2kN/cm至約6kN/cm i.O.、較佳約3kN/cm至5kN/cm範圍內之壓實力(對於開發規模機器而言)。亦可藉由使經摻合之粉末結塊形成較大錠劑來進行壓實,隨後減小較大錠劑之尺寸。較佳地,所使用之裝置為Freund Corporation;TF Mini型滾輪壓實機。使用此設備,適當地調節螺桿速度以確保滾輪壓實材料之適當品質。較佳地,螺桿速度大於15rpm,諸如20rpm至30rpm。此外,使用此設備,適當地調節滾輪速度以確保滾輪壓實材料之適當品質。較佳地,滾輪速度為3rpm至5rpm。亦較佳地,不施加預壓縮力。
可使用任何合適構件完成研磨/篩分步驟。通常,壓實材料(內相)通過具有至少1.0篩孔尺寸(諸如1.0或1.2毫米)之篩的篩磨或振動篩/研磨機來研磨。較佳地,在擴散摻合器中將經研磨之材料通常與諸如潤滑劑、填充劑、崩解劑及助流劑之醫藥學上可接受之添加劑(外相)摻合。
對於壓實及研磨/篩分更佳者為Gerteis 3-W-Polygran PACTOR(例如Minipactor 250/25/3),其具有以下典型特性:間隙寬度為1.0mm至5.0mm,較佳為2.0mm至4..0mm;滾輪速度為2.5rpm至15rpm,較佳為2.5rpm至10rpm;篩孔尺寸為0.8mm至2.00mm,較佳為1.0mm至1.5mm。
根據本發明之所得調配物顯示下列優點:
‧可易於達成相對高之藥物負載;
‧使具有足夠硬度、抗易碎性、崩解時間等之醫藥口服固定劑量組合之調配成為可能;
‧將藥物物質之黏著趨勢及不良流動降至最小;
‧達成穩固製造方法;
‧達成調配物之按比例增加及產生可再生性能之方法;及
‧達成足夠穩定性以實現合理存放期;
‧達成較短加工時間,尤其歸因於無任何乾燥步驟,且因此使製程更具經濟性;
˙錠劑尺寸較小而具有相同量之活性成分;
˙封裝成本較低;
˙每批次錠劑數目較大。
與先前技術濕式造粒相比,本文所述之滾輪壓實提供更具經濟性之方法,其不使用溶劑及額外乾燥步驟且同時達成具有高藥物負載之固體口服劑型,藥物負載較佳甚至高於目前用濕式造粒法所製備者,因此總體提供較小錠劑尺寸之可能性,這增加患者順應性。
本發明同樣係關於製備上文所述之固體口服劑型之方法。此固體口服劑型可藉由處理上文界定之組分以適當量來生產,以形成單位固體口服劑型。
本發明之固體口服劑型可用於降低血壓,收縮壓或舒張壓或兩者。本發明可適用之病症包括(而不限於)高血壓(無論惡性、本質性、腎血管性、糖尿病性、獨立收縮性還是其他繼發型)、充血性心臟衰竭、絞痛(無論穩定性還是不穩定性)、心肌梗塞、動脈粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不全、周邊血管疾病、左心室肥大、認知功能障礙(諸如阿茲海默氏症(Alzheimer's))及中風、頭痛及慢性心臟衰竭。
本發明同樣係關於治療高血壓(無論惡性、本質性、腎血管性、糖尿病性、獨立收縮性還是其他繼發型)、充血性心臟衰竭、絞痛(無論穩定性還是不穩定性)、心肌梗塞、動脈粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不全、周邊血管疾病、左心室肥大、認知功能障礙(例如阿茲海默氏症)、中風、頭痛及慢性心臟衰竭之方法,此治療方法包含向需要該治療之動物(包括人類患者)投與治療有效之根據本發明之固體口服劑型。
本發明同樣係關於根據本發明之固體口服劑型對於製造用於治療高血壓(無論惡性、本質性、腎血管性、糖尿病性、獨立收縮性還是其他繼發型)、充血性心臟衰竭、絞痛(無論穩定性還是不穩定性)、心肌梗塞、動脈粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不全、周邊血管疾病、左心室肥大、認知功能障礙(例如阿茲海默氏症)、中風、頭痛及慢性心臟衰竭之藥劑的用途。
本發明同樣係關於用於治療高血壓(無論惡性、本質性、腎血管性、糖尿病性、獨立收縮性還是其他繼發型)、充血性心臟衰竭、絞痛(無論穩定性還是不穩定性)、心肌梗塞、動脈粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不全、周邊血管疾病、左心室肥大、認知功能障礙(例如阿茲海默氏症)、中風、頭痛及慢性心臟衰竭之醫藥組合物,其包含根據本發明之固體口服劑型。
最終,待投與之活性劑及特定調配物之精確劑量取決於多種因素,例如所治療之病症、所要之治療持續時間及活性劑之釋放速率。舉例而言,所需活性劑之量及其釋放速率可基於已知之活體外或活體內技術來確定,測定就治療效果而言,特定活性劑在血漿中以可接受之濃度水平維持多久。
以上描述完全揭示了本發明,包括其較佳實施例。本文特定揭示之實施例之修改及改良係在以下申請專利範圍之範疇之內。無需進一步詳細描述,咸信熟習此項技術者使用先前描述可最大程度地利用本發明。因此,應將本文中之實例看作僅是說明性的且不以任何方式限制本發明之範疇。
阿利克侖300mg(游離鹼)錠劑之組成,毫克/單位。
如本文中所述混合、顆粒化及壓縮阿利克侖錠劑之組分以使用Freund Corporation;TF Mini型之滾輪壓實機製備滾輪壓實之阿利克侖錠劑,製程參數描述如下:
阿利克侖300mg(游離鹼)錠劑之組成,毫克/單位。
如本文中所述混合、顆粒化及壓縮阿利克侖錠劑之組分以使用Gerteis MINIPACTOR滾輪壓實機製備滾輪壓實之阿利克侖錠劑;製程參數描述如下:
Claims (18)
- 一種固體口服劑型,其係藉由包含滾輪壓實步驟之製造方法獲得,該劑型包含作為活性成分之治療有效量之阿利克侖(Aliskiren)或其醫藥學上可接受之鹽,其中該活性成分基於該口服劑型總重量計之含量係大於38重量%,且其中該劑型進一步包含-選自磷酸氫鈣之填充劑;及-選自交聯羧甲基纖維素之崩解劑。
- 如請求項1之固體口服劑型,其中該崩解劑為交聯羧甲基纖維素鈉。
- 如請求項1之固體口服劑型,其中該活性成分之含量大於40重量%。
- 如請求項1或2之固體口服劑型,其中該活性成分之含量為41重量%至80重量%範圍內。
- 如請求項1或2之固體口服劑型,其中該活性成分之含量為41重量%至60重量%範圍內。
- 如請求項1或2之固體口服劑型,其中該活性成分以基於口服劑型之總重量計大於50重量%至80重量%之量存在。
- 如請求項1或2中任一項之固體口服劑型,其中該活性成分完全由阿利克侖或其醫藥學上可接受之鹽組成,且其含量為每單位劑型75mg至300mg範圍內之游離鹼。
- 如請求項1或2中任一項之固體口服劑型,其中阿利克侖為其半反丁烯二酸鹽形式,且其含量為每單位劑型83 mg、166mg或332mg。
- 如請求項1或2中任一項之固體口服劑型,其中該劑型進一步包含潤滑劑,該潤滑劑之含量為該劑型之0.5重量%至6重量%。
- 如請求項1或2中任一項之固體口服劑型,其中該劑型進一步包含潤滑劑,該潤滑劑之含量為該劑型之0.5重量%至4重量%。
- 如請求項1或2中任一項之固體口服劑型,其中該劑型進一步包含助流劑,該助流劑之含量為該劑型之0.1重量%至3.0重量%。
- 如請求項1或2中任一項之固體口服劑型,其中該劑型進一步包含助流劑,該助流劑之含量為該劑型之0.1至1.0重量%。
- 如請求項11之固體口服劑型,其中該助流劑為二氧化矽膠體。
- 如請求項12之固體口服劑型,其中該助流劑為二氧化矽膠體。
- 如請求項1或2中任一項之固體口服劑型,其係用於治療高血壓、充血性心臟衰竭、心絞痛、心肌梗塞、動脈粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不全、周邊血管疾病、左心室肥大、認知功能障礙、中風、頭痛及慢性心臟衰竭。
- 一種如請求項1至15中任一項之固體口服劑型之用途,其係用於製造用以治療高血壓、充血性心臟衰竭、心絞 痛、心肌梗塞、動脈粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不全、周邊血管疾病、左心室肥大、認知功能障礙、中風、頭痛及慢性心臟衰竭之藥劑。
- 一種製造如請求項1至15中任一項之固體口服劑型之方法,其包含以下步驟:滾輪壓實一種組合物,其係阿利克侖或其醫藥上可接受之鹽及醫藥學上可接受之添加劑,在篩分該組合物後,視需要與其他醫藥學上可接受之添加劑混合,及視需要將最終摻合物壓縮為錠劑。
- 如請求項17之方法,其包含以下步驟:(a)摻合阿利克侖或其醫藥上可接受之鹽與醫藥學上可接受之添加劑;(b)篩分經摻合之阿利克侖或醫藥上可接受之鹽及醫藥學上可接受之添加劑;(c)摻合經篩分之材料;(d)滾輪壓實經摻合之材料以形成壓實之材料;(e)研磨該經壓實之材料以形成研磨之材料,稱作阿利克侖顆粒;(f)視需要摻合該研磨之材料與外層相,亦即與醫藥學上可接受之添加劑,以形成最終混合物;(g)視需要壓縮最終摻合物以形成錠劑;及(h)視需要塗覆薄膜衣以獲得薄膜包衣之錠劑,或者,製程步驟(a)及(f)可分成兩個步驟執行,其包括先由阿利克侖或阿利克侖顆粒分別與添加劑形成第一摻合物(無潤滑劑),並由第一摻合物與該潤滑劑形成第二(最終)摻合物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY119161A (en) | 1994-04-18 | 2005-04-30 | Novartis Ag | Delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides with enzyme especially renin inhibiting activities |
US6521647B2 (en) * | 2000-04-04 | 2003-02-18 | Pfizer Inc. | Treatment of renal disorders |
JP2004514703A (ja) * | 2000-12-01 | 2004-05-20 | ノバルティス アクチエンゲゼルシャフト | 有機化合物の組合せ剤 |
RU2183116C1 (ru) * | 2001-07-10 | 2002-06-10 | Жаров Олег Владимирович | Фармацевтическая композиция, обладающая болеутоляющим, противовоспалительным, антипиретическим и спазмолитическим действием |
WO2004100871A2 (en) * | 2003-05-09 | 2004-11-25 | Pharmacia Corporation | Combination of an aldosterone receptor antagonist and a renin inhibitor |
MY144477A (en) * | 2004-03-17 | 2011-09-30 | Novartis Ag | Galenic formulations of organic compounds |
US20050220865A1 (en) * | 2004-04-02 | 2005-10-06 | Koleng John J | Compressed composition comprising magnesium salt |
MY146830A (en) * | 2005-02-11 | 2012-09-28 | Novartis Ag | Combination of organic compounds |
JP2008539250A (ja) * | 2005-04-27 | 2008-11-13 | ノバルティス アクチエンゲゼルシャフト | アテローム性動脈硬化症を処置するための方法 |
CN101300030A (zh) * | 2005-11-08 | 2008-11-05 | 诺瓦提斯公司 | 血管紧张素ⅱ受体阻滞剂、钙通道阻滞剂和另一活性物质的组合产品 |
TW200804241A (en) * | 2006-02-24 | 2008-01-16 | Novartis Ag | New salt |
GB0605688D0 (en) * | 2006-03-21 | 2006-05-03 | Novartis Ag | Organic compounds |
GB0612540D0 (en) * | 2006-06-23 | 2006-08-02 | Novartis Ag | Galenical formulations of organic compounds |
EP1891937A1 (en) * | 2006-08-25 | 2008-02-27 | Novartis AG | Galenic formulations of aliskiren |
JP2010509254A (ja) * | 2006-11-09 | 2010-03-25 | ノバルティス アーゲー | アリスキレンとオロチン酸の塩 |
EP1972335A1 (en) * | 2007-03-23 | 2008-09-24 | Krka | Solid dosage forms comprising aliskiren and pharmaceutically acceptable salts thereof |
US20100209480A1 (en) * | 2007-09-28 | 2010-08-19 | Ralf Altenburger | Galenical formulations of organic compounds |
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Also Published As
Publication number | Publication date |
---|---|
BRPI0817586A2 (pt) | 2015-03-31 |
MA31768B1 (fr) | 2010-10-01 |
WO2009040373A2 (en) | 2009-04-02 |
JP5378384B2 (ja) | 2013-12-25 |
TN2010000120A1 (en) | 2011-09-26 |
CA2697229A1 (en) | 2009-04-02 |
EP2205232A2 (en) | 2010-07-14 |
MY148266A (en) | 2013-03-29 |
CO6270216A2 (es) | 2011-04-20 |
RU2483718C2 (ru) | 2013-06-10 |
WO2009040373A3 (en) | 2009-08-20 |
AR068539A1 (es) | 2009-11-18 |
MX2010003260A (es) | 2010-04-29 |
ZA201001144B (en) | 2011-12-28 |
GT201000064A (es) | 2012-03-30 |
RU2010116530A (ru) | 2011-11-10 |
AU2008303504B2 (en) | 2012-03-22 |
JP2010540489A (ja) | 2010-12-24 |
KR20100076996A (ko) | 2010-07-06 |
CN101808630A (zh) | 2010-08-18 |
EP2548553A1 (en) | 2013-01-23 |
US20110033533A1 (en) | 2011-02-10 |
PE20091203A1 (es) | 2009-09-11 |
TW200922546A (en) | 2009-06-01 |
CL2008002828A1 (es) | 2009-05-15 |
AU2008303504C1 (en) | 2013-05-16 |
AU2008303504A1 (en) | 2009-04-02 |
NZ584005A (en) | 2012-08-31 |
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