TW201717930A - 經修飾釋放之口服投予之胺基酸製劑 - Google Patents
經修飾釋放之口服投予之胺基酸製劑 Download PDFInfo
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Abstract
本發明提供一種修飾釋放之胺基酸之方法與製劑,其具有改良之藥物動力學、代謝與利用性,用於治療或管理受到胺基酸代謝受損所界定之疾病。
Description
本發明係有關一種口服投予之胺基酸製劑與劑型,其具有改良之劑量精確性、改良之適口性、與改良之藥物動力學,以供最佳醫療效果。
胺基酸為人體合成蛋白質時之必要構件,主要來自於膳食蛋白質來源。人體使用19種不同L-組態胺基酸來合成蛋白質。其中有些胺基酸稱為「必需胺基酸」,因為身體無法獨立合成該等胺基酸。其他胺基酸不是「必需」,因為身體可以合成彼等。
膳食蛋白質於胃中開始分解成胺基酸,其中藉助於胃蛋白酶原、胃蛋白酶與鹽酸之組合活性分解成寡肽。從胃通過幽門進入十二指腸後仍繼續分解,其中膽汁分泌、碳酸氫鹽與胰臟酵素之組合活性能產生個別胺基酸。Montgomery R.等人1988;Baracos,2004。經釋出之胺基酸再依據胺基酸之特定立體專一性主動運輸過程被小腸吸收至門靜脈。胺基酸分泌進入小腸係一種同步機轉。二肽與三肽亦可被小腸吸收,但最後亦在腸細胞中水解成胺
基酸。此等過程主要為pH依賴性。當攝取食物時,胃分泌鹽酸,pH降至約2。經過幽門瓣後,隨鹼性膽汁分泌結果,pH逐漸從4上升至約7。緩衝系統即運作防止pH值超過約7.5-7.8。
分解膳食蛋白質所需的時間係胃排空期所耗費之時間與小腸中水解所需時間之總和。這兩種過程所需時間會隨食物攝取、蛋白質攝取、疾病、與同步之藥物治療而變化,其中以食物攝取為最常見的決定因素。Amidon等人1995報導在高脂肪餐後之胃排空時間為約3.5小時,在一般餐點後為約1.5小時,而在飲水250ml後為約10至20分鐘。Keohane等人1985報導小腸水解胺基酸之時間平均需約3小時,此時間隨個別蛋白質與胺基酸變化。在胃排空後,通過幽門瓣後,即開始發生此水解作用,並在第一段小腸中(亦即在空腸中)持續數小時。
胺基酸通常作為膳食補充品投予,促進蛋白質合成,特別當需要提高肌肉質量時。亦可投予特別調配之胺基酸組合來支持有特殊膳食攝取限制與要求之個體之營養健康。例如:在苯酮尿症中,身體因為缺乏必要的酵素而無法代謝苯基丙胺酸成為酪胺酸。以致苯基丙胺酸降解成數種毒性副產物。Montgomery等人1988;Waisbren等人2007。
苯基丙胺酸為一種必需胺基酸,通常會被苯基丙胺酸羥化酶酵素代謝成酪胺酸。苯酮尿症中缺乏此酵素或此酵素無法正常運作,而讓苯基丙胺酸脫羧基化成為
各種不同化合物,其中三種化合物有毒性:苯基丙酮酸鹽、苯基乳酸鹽與苯基乙酸鹽。基於此代謝抑制作用,必需降低苯基丙胺酸之膳食攝取,同時在膳食中提供不可或缺的酪胺酸胺基酸。Ney D.M.等人2014;Dioguardi,2011;Waisbren等人2007。
一種有效管理苯酮尿症之策略由特別調配之胺基酸製劑組成,其沒有苯基丙胺酸但補充酪胺酸。由於無法從大多數蛋白質膳食來源中排除苯基丙胺酸,因此通常會改用此等胺基酸補充品取代已完全從膳食中排除之膳食蛋白質。Vliet Van D.等人2014。然而此等患者亦可接受小心控制而含有極少量苯基丙胺酸之蛋白質膳食處理。Gropper S.S.等人1991。
市售用於管理苯酮尿症之胺基酸製劑實例包括以AntifenTM、Nutricia XP2TM(Maxamaid)與Milupa PKU2TM(Secunda)出售之製劑。Nutricia XP2TM與Milupa PKU2TM亦包含維生素與礦物質。下表A出示此等產品之配方,其係以各製劑含約100g胺基酸計算,其中省略維生素與礦物質含量。
可採用相同策略提供所有必需與非必需胺基酸,但省略身體無法代謝之胺基酸來製造特別調配之胺基酸製劑來投予之其他病症包括高酪胺酸血症、高白胺酸症、甲基丙二酸血症、高胱胺酸尿症、高甘胺酸血症、異戊酸血症、丙酸血症、與戊二酸血症(glutaric acidemia)(第II、IIA或IIB型)。
游離胺基酸可能比天然蛋白質存在許多缺點,因為胺基酸會被快速吸收,提高膳食酸負擔,尤其當投予更高劑量時。
再者,有些胺基酸製劑商品口味與氣味不佳,使得許多人(尤其是嬰兒與幼童)可能很難按時規律攝取。此外,此等製劑在攝入時會立即釋放,造成與攝取蛋白質時差異極大之吸收型態。
本發明目的之一係當攝入游離胺基酸且超過身體代謝能力時限制胺基酸分解代謝。
本發明另一目的為改良胺基酸製劑在口服攝取時之口味。
本發明又另一目的為提供一種獨特之胺基酸劑型,其不需要復水還原即可直接食用。
本發明再另一目的為提供一種具有經修飾釋放性質之胺基酸製劑,其更擬似蛋白質在口服攝入時之吸收型態。
已發展出經修飾釋放之胺基酸製劑來克服上
述缺點。該等製劑更適口,且最重要的是擬似來自天然食物來源之胺基酸之釋放概況。特定言之,該等製劑採用延遲釋放機轉,修飾製劑之胺基酸釋放來擬似天然蛋白質之胺基酸釋放速率。
直到目前所進行之有限試驗中,數種個別胺基酸與胺基酸之組合當經修飾以達到特定之體外釋放標準時,已證實其血漿中之胺基酸濃度較相當之游離胺基酸製劑達到統計上優異之改良。因此,在第一項主要具體實施例中,本發明提供一種口服投予之胺基酸製劑,其包含一或多種經修飾釋放之胺基酸,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%或甚至40%。
在活體內動物生體可用率試驗中,已意外發現異白胺酸、白胺酸、酪胺酸、與纈胺酸當如本文所說明經修飾釋放時,會在血液中產生穩定之最高濃度,其仍顯著低於由相當之游離胺基酸製劑所產生之最高濃度。因此,在第二主要具體實施例中,本發明提供一種口服投予之胺基酸製劑,其包含選自精胺酸、異白胺酸、白胺酸、酪胺酸與纈胺酸之經修飾釋放之胺基酸,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)
中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。
另一項主要具體實施例係有關一組特別胺基酸:分支鏈胺基酸,且意外發現該等分支鏈胺基酸(呈集合物),當如本文所說明經修飾釋放時,比相當之游離胺基酸製劑產生之Cmax與C終點,產生顯著較低Cmax與較高C終點。因此在另一項主要具體實施例中,本發明提供一種包含一或多種經修飾釋放之分支鏈胺基酸之口服投予之胺基酸製劑,其中該包含2g經修飾釋放之分支鏈胺基酸於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。
再另一項主要具體實施例係有關另一組特別胺基酸:必需胺基酸,其等當如本文所說明經修飾釋放時,意外地比相當之游離胺基酸製劑產生顯著較低Cmax與顯著較高C終點。因此,再又另一項主要具體實施例中,本發明提供一種包含一或多種經修飾釋放之必需胺基酸之口服投予之胺基酸製劑,其中該包含2g經修飾釋放之必需胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、
或甚至40%。
再又另一項主要具體實施例係有關另一組特別胺基酸:大型中性胺基酸(不包括苯基丙胺酸、酪胺酸與甲硫胺酸),其等當如本文所說明經修飾釋放時,意外地比相當之游離胺基酸製劑產生顯著較低Cmax與顯著較高C終點。因此再又另一項主要具體實施例中,本發明提供一種包含一或多種經修飾釋放之大型中性胺基酸之口服投予之胺基酸製劑,其中該包含2g經修飾釋放之大型中性胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。
在第七項主要具體實施例中,本發明提供一種口服投予之胺基酸製劑,其包含經修飾釋放之非必需胺基酸之組合,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。
該製劑較佳係呈可食用之顆粒,其可與如優格之其他食物混合,或呈大粒可嚼式錠劑,其無法整粒吞嚥,但必需像吃餅乾一樣分小口食用。在單位劑量製劑中
之胺基酸含量將隨接受治療之個體之代謝需求而定,一般依個體年齡、性別、體重、與身體活力,及個體是否罹患限制攝取一或多種胺基酸之代謝病症而定,如本文中更詳細說明。
製劑可包含一種、所有或任何組合之必需與非必需胺基酸,且可特別設計用於任何需要補充胺基酸之應用。該等製劑特別適合治療罹患胺基酸處理病症的人,如:苯酮尿症、高酪胺酸血症、高白胺酸症、甲基丙二酸血症、高胱胺酸尿症、高甘胺酸血症、異戊酸血症、丙酸血症、與麩胺酸血症。
該經修飾釋放可採用本文中各種稱為延遲釋放劑之成份、選擇偏向於空腸中釋放之方式等達成。此等試劑可以讓製劑於食入後或試驗時溶解於介質中時造成胺基酸之修飾釋放。或者,其等可以延長或延緩胺基酸釋放,因此讓有些胺基酸直至後來的消化過程中(如:在製劑到達小腸之較高pH環境下時)才被釋放。此等試劑甚至可以在適當設計之製劑中,讓製劑中一小組胺基酸依不同於其他胺基酸之釋放速率釋放。該等製劑當在固定pH值試驗時,較佳係依據其經修飾釋放型態釋放。
本發明其他態樣涉及通常因胺基酸代謝受損而需要積極管理胺基酸攝取來治療或管理疾病之製劑之用法。因此另一項具體實施例中,本發明提供一種為有其需要之患者治療選自下列各物所組成群中之代謝病症之方法:苯酮尿症、高酪胺酸血症、高白胺酸症、甲基丙二酸
血症、高胱胺酸尿症、高甘胺酸血症、異戊酸血症、丙酸血症、與麩胺酸血症,其包括對患者經口投予本發明之胺基酸製劑。
另一項具體實施例提供一種製造本發明製劑之方法,且本具體實施例中,本發明提供一種製造本發明製劑之方法,其包括:(a)提供第一混合物,其包含單一或複數種胺基酸;(b)令該混合物與濕潤劑或溶劑(例如:醇與/或有機溶劑與/或水)及結合劑接觸,形成濕混合物;(c)視需要令該濕混合物通過篩網,形成均勻濕顆粒;(d)乾燥該均勻濕顆粒形成乾顆粒;(e)視需要令該乾顆粒通過篩網形成均勻乾顆粒,及(f)視需要使用一或多種包衣劑包覆乾顆粒,以提供該乾顆粒之修飾釋放。合適之包衣劑包括例如:纖維素聚合物類、脂肪酸類、蠟類與其他可以提供該乾顆粒之修飾釋放之包衣劑。合適之包覆技術包括例如:流化床包覆法與熔融造粒法。乾顆粒可併入任何常用之劑型中,但較佳係以無進一步修飾之劑型使用,其等很容易與其他成份(如:香料及無活性賦形劑或添加劑、或活性成份如:維生素、礦物質與碳水化合物)混合。或者,乾顆粒可壓縮成可嚼式錠劑。
本發明額外優點一部份示於下文說明中,一部份顯然可由本說明中了解,或可從本發明之操作中學習。可採用附錄之申請專利範圍中特別指出之元素與組合來了解及達成本發明。咸了解,上述一般說明與下文詳細說明僅供舉例說明,並未如申請專利範圍中限制本發明。
第1圖列表說明人體用來合成蛋白質之19種胺基酸,其等依據結構與性質(亦即脂系、芳香系、酸性、鹼性、硫化與pKa)分類。
第2圖列表說明必需胺基酸,亦即無法在身體內透過生化合成法產生,但必需經過膳食攝入之彼等胺基酸,如Montgomery等人1988所報導。
第3圖係圖示說明依據實例7方法製造之無包覆色胺酸,在採用兩種槳板速度,隨時間之釋放概況,並與根據本發明調配之色胺酸比較。
第4圖係圖示說明實例8製劑採用pH 1.2之溶解介質與50rpm之槳板速度,其中色胺酸隨時間之釋放概況。
第5圖係圖示說明實例9製劑當採用實例8說明之實驗條件,但改用籃子法替代槳板時,色胺酸隨時間之釋放概況。
第6圖係圖示說明實例10製劑在實例10說明之實驗條件下時,該包含胺基酸混合物之製劑隨時間之龐德羅(Ponderal)釋放概況。
第7圖係圖示說明實例11表10b說明之游離胺基酸製劑依據實例11說明之方法試驗時之龐德羅溶解概況。
第8圖繪圖說明APR AA混合物(bkT037/71)中18種不同胺基酸之溶解概況。
第9圖係圖示說明依實例11與表10d與10e報導之方法與配方製造及試驗之經四種不同乙基纖維素包覆之經修飾釋放之胺基酸製劑之龐德羅溶解概況。
第10圖繪圖說明APR批次2(bkT037/72-2),表10f,當依據實例11說明之方法試驗時,其中18種不同胺基酸之溶解概況。
第11圖繪圖說明APR批次4(bkT037/72-4),表10g,當依據實例11說明之方法試驗時,其中18種不同胺基酸之溶解概況。
第12圖繪圖說明具有表11a所說明之組成,依實例12之說明製造及試驗之經四種不同乙基纖維素/二山嵛酸甘油酯包覆之經修飾釋放之胺基酸製劑中,胺基酸集合物之龐德羅溶解概況。
第13圖繪圖說明APR批次5(bkT037/73-5)(表11c)當依據實例12報導之方法試驗時,其中18種不同胺基酸之溶解概況。
第14圖繪圖說明APR批次7(bkT037/72-7)(表11d)當依據實例12報導之方法試驗時,其中18種不同胺基酸之溶解概況。
第15圖說明依實例11與12之說明製造及試驗之四種不同本發明試驗製劑(APR批次2/bkT037/72-2、APR批次4/bkT037/72-4、APR批次5/bkT037/73-5、APR批次7/bkT037/72-7)與游離胺基酸混合物bkT037/71中,胺基酸集合物之龐德羅溶解概況。
第16圖報導如實例14所說明兩種不同本發明之經修飾釋放之胺基酸製劑、一種游離胺基酸製劑、與酪蛋白中14種胺基酸在豬中之平均血漿濃度隨時間之變化(以集合物計)。
第17圖報導如實例14所說明兩種不同本發明之經修飾釋放之胺基酸製劑、一種游離胺基酸製劑、與酪蛋白中必需胺基酸在豬中之平均血漿濃度隨時間之變化。
第18圖報導如實例14所說明兩種不同本發明之經修飾釋放之胺基酸製劑、一種游離胺基酸製劑、與酪蛋白中分支鏈胺基酸在豬中之平均血漿濃度隨時間之變化(以集合物計)。
第19圖報導如實例14所說明兩種本發明之經修飾釋放之胺基酸製劑、一種游離胺基酸製劑、與酪蛋白中大型中性鏈胺基酸在豬中之平均血漿濃度隨時間之變化(以集合物計)。
當本文採用單數型式「一個」、「一種」與「該」或類似術語時,咸了解其等包括複數指稱物,除非內文另有明確指示。因此例如:提及「烴」時,包括兩種或更多種此等烴之混合物,等等。本文所採用之術語「或」或類似術語,意指特定列表之任何一種成員,亦包括該列表成員之組合。
當本文採用術語「約(about或ca.)」時,將彌補製藥業及存在於製藥產品中所容許之變異,如:因製造變異與時間所誘發產品降解造成之產品強度與生體可用率差異。該術語容許製藥操作時之任何變異,若內文中要求,可讓所分析之產品在所主張專利權之產品所指示強度上視為醫藥上之等效物或生物上之等效物、或在此二者上為等效物。咸了解,此文件中表述之所有數值之前均可冠上術語「約」。
術語「分別獨立」係用於指被一組可能變數修飾之特定元件可能或可能不會被相同變數界定。因此例如:若組成物包含z%之元件A與z%之元件B,且z可分別獨立為10%或20%,則該組成物可包含10%之元素A與10%之元素B,或10%之元素A與20%之元素B,等等。
術語「胺基酸」係指可參與合成肽與蛋白質之任何天然胺基酸。為了方便表達,胺基酸經常沒有寫出其立體組態,但咸了解,胺基酸應呈其天然立體異構物。
本發明製劑中,胺基酸可呈游離鹼、呈鹽酸鹽、或呈另一種合適之鹽。術語必需胺基酸係指在體內無法自行製造,而必需衍生自外部來源之任何胺基酸。可包括在本發明製劑中之必需胺基酸包括L-異白胺酸、L-白胺酸、L-離胺酸、L-蘇胺酸、L-色胺酸、L-纈胺酸、L-甲硫胺酸、L-苯基丙胺酸、L-組胺酸與L-精胺酸或任何其醫藥上可接受之鹽類(最後兩種胺基酸被認為係僅針對嬰兒之必需胺基酸,但為了簡便,仍稱其等為「本文之必需胺基
酸」)。
術語非必需胺基酸係指必需胺基酸以外之任何其他胺基酸,因此包括例如:L-丙胺酸、L-天冬胺酸、L-胱胺酸、L-麩醯胺與/或L-麩胺酸、甘胺酸、L-脯胺酸、L-絲胺酸、牛磺酸、L-酪胺酸、與L-肉鹼或任何其醫藥上可接受之鹽類。任何此等胺基酸均可呈游離鹼、鹽酸鹽、或任何其他合適鹽類。
術語「分支鏈胺基酸」係指纈胺酸、異白胺酸、與白胺酸、或任何其醫藥上可接受之鹽類。
一項具體實施例中,術語「大型中性胺基酸」係指色胺酸、蘇胺酸、纈胺酸、異白胺酸、白胺酸、與組胺酸、或任何其醫藥上可接受之鹽類。另一項具體實施例中,該術語亦包括苯基丙胺酸、甲硫胺酸與酪胺酸。
術語「製劑」係指醫藥或醫學食品或食品成份之成品或半成品組合,其包括活性成份與無活性賦形劑或添加劑二者。該術語係指半成品製劑、成品製劑、及封裝成最終單位劑量之製劑。
本說明書全文及申請專利範圍中,術語「包含」與該術語之變化型,如:「涵括」與「包括」意指「包括,但不限於」,且無意排除例如:其他添加劑、組份、整數或步驟。
術語「治療」與「處理」當用於本文時,意指希望可以為患者治癒、緩解、安定、或預防疾病、病理症狀或病變之醫學處理。此術語包括積極治療,亦即明確
針對改善疾病、病理症狀或病變之治療,亦包括病因治療,亦即直接針對排除該相關疾病、病理症狀或病變之病因。此外,此術語包括緩和治療,亦即該治療之設計在於解除症狀,而非治癒該疾病、病理症狀或病變;預防性治療,亦即指向儘量達最小化或部份或完全抑制該相關疾病、病理症狀或病變之發展;及支持性治療,亦即該治療係用於補充另一種指向改善該相關疾病、病理症狀或病變之特定療法。該術語亦包括患者之膳食管理,該患者之進食、消化、吸收或代謝食物或營養素的能力因為特定疾病或醫學病症而受到限制或損傷,或該患者經過醫學判斷而有其他特殊營養素需求,但無法單靠修改正常膳食來達到膳食管理。
術語「經修飾釋放」係指任何醫藥製劑,其中釋放速率經有意地改變以達到所需之醫療或藥物動力學反應。因此該術語包括延長釋放製劑,其中藥物隨時間延長釋放,或釋放速率不受周圍環境之pH影響。該術語亦包括延緩釋放製劑,其中該製劑(或其一部份)之活性成份在開始食入後延緩釋出。延緩釋放製劑通常設計成主要讓製劑到達小腸時才開始釋放。
本文所採用「醫療有效量」係指其用量足以引發所需之生物效應。該醫療有效量或劑量將依患者之年齡、性別與體重、及患者當前醫學病況而定。習知此相關技藝者咸了解可依此等因素及本說明書以外之額外因素決定適當劑量。當用於指營養素,如:胺基酸、礦物質、維
生素等等時,該術語係指其用量一般認可為支持人體代謝需求時之需要量。
「醫藥上可接受」意指其適用於製備醫藥組成物,亦即通常為安全、無毒且並非生物上或其他方面所不期望者,且包括獸醫用途、人類醫用食品、食物與藥學用途上可接受者。「醫藥上可接受之鹽類」意指如上述定義係醫藥上或醫用食品或食物上可接受者,且具有所需之藥學或營養學活性。
當本文中之範圍係以指明範圍之交替上限與下限表述時,咸了解,其端點可依任何數學上可行之方式組合。因此例如:50或80至100或70之範圍亦可改用50至100、50至70、及80至100之一系列範圍表述。當一系列上限值與下限值有關於採用詞語與/或時,咸了解,上限值不受下限值限制或可與下限值組合,反之亦然。因此例如:超過40%與/或低於80%之範圍包括超過40%、低於80%、及超過40%但低於80%之範圍。
當本文中試驗方法出示來自美國藥典(United States Pharmacopoeia)或其他業界已接受之綱要之特定試驗方法時,咸了解,根據習知此相關技藝者之習知技術,該試驗方法可在不改變基本物理原則或最終結果下,依據一般及習知之操作法修飾,因此例如:可能需要本文所提供實例測試不同劑型。
當本文中出示百分比時,咸了解,該百分比為重量百分比,且該比例係以重量計,除非另有相反說明。
本發明係於主要具體實施例與次項具體實施例中定義,且咸了解,主要具體實施例可以組合來定義其他主要具體實施例,而該等次項具體實施例可以組合來定義額外次項具體實施例,而該等次項具體實施例與次項具體實施例之組合可以與所有主要具體實施例組合來定義本發明其他具體實施例。組合具體實施例與次項具體實施例之能力僅受到數學上或物理上不可能性之限制。
第一項主要具體實施例中,本發明提供一種口服投予之胺基酸製劑,其包含一或多種經修飾釋放之胺基酸,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。
第二項主要具體實施例中,本發明提供一種口服投予之胺基酸製劑,其包含選自下列之經修飾釋放之胺基酸:精胺酸、異白胺酸、白胺酸、酪胺酸與纈胺酸,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。
第三項主要具體實施例中,本發明提供一種
口服投予之胺基酸製劑,其包含經修飾釋放之分支鏈胺基酸,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。在較佳具體實施例中,該製劑包括經修飾釋放之纈胺酸、異白胺酸與白胺酸。
第四項主要具體實施例中,本發明提供一種口服投予之胺基酸製劑,其包含經修飾釋放之必需胺基酸之組合,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。在較佳具體實施例中,該經修飾釋放之胺基酸包括精胺酸、組胺酸、異白胺酸、白胺酸、蘇胺酸、離胺酸與色胺酸。
第五項主要具體實施例中,本發明提供一種口服投予之胺基酸製劑,其包含經修飾釋放之大型中性胺基酸,其中該包含2g經修飾釋放之大型中性胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不
超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。在較佳具體實施例中,該製劑包括經修飾釋放之色胺酸、蘇胺酸、纈胺酸、異白胺酸、白胺酸、與組胺酸。
第六項主要具體實施例中,本發明提供一種為有其需要之患者治療選自由苯酮尿症、高酪胺酸血症、高白胺酸症、甲基丙二酸血症、高胱胺酸尿症、高甘胺酸血症、異戊酸血症、丙酸血症、與麩胺酸血症所組成群中之代謝病症之方法,其包括對該患者經口投予如主要具體實施例或次項具體實施例中任一項所定義之本發明製劑。
第七項主要具體實施例中,本發明提供一種口服投予之胺基酸製劑,其包含經修飾釋放之非必需胺基酸之組合,其中該包含2g經修飾釋放之胺基酸之製劑依<711>USP 39 NF 34,在攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中該x%為90%、80%、70%、60%、50%、或甚至40%。
各種不同次項具體實施例中,該製劑可包含一種、所有、或任何必需與非必需胺基酸之組合,且可針對需要補充胺基酸之任何用途特別設計。該等製劑特別適合治療罹患胺基酸處理病症(如:苯酮尿症、高酪胺酸血症、高白胺酸症、甲基丙二酸血症、高胱胺酸尿症、高甘胺酸血症、異戊酸血症、丙酸血症、與麩胺酸血症)之患者。其他更特定次項具體實施例更明確說明於表B-D。然而咸
了解,此等製劑應考慮併入某些彈性,例如:嬰兒與兒童之胺基酸需求,其可能使某些胺基酸落在所示比例範圍之外。
表B出示在一般計畫用於補充胺基酸、及苯酮尿症與高酪胺酸血症之製劑中作為經修飾釋放之胺基酸之十九種胺基酸之相對重量份數。A欄出示胺基酸之合適比例之較佳範圍,而B欄出示合適之比例之更佳範圍。表B僅說明製劑中胺基酸之相對比例。因此,可包括其他成份。從表B所述任何製劑釋放之胺基酸集合物比例較佳係如第一項主要具體實施例所示。
其他具體實施例係定義第一項主要具體實施例包括表B一般製劑(經A或B欄定義)所涵括之三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表B一般製劑(經A或B欄定義)所涵括之必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施
例包括表B之苯酮尿症製劑(經A或B欄定義)所涵括之三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表B之苯酮尿症製劑(經A或B欄定義)所涵括之必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表B之高酪胺酸血症製劑(經A或B欄定義)所涵括之三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義在第一項主要具體實施例中,包括表B之高酪胺酸血症製劑(經A或B欄定義)所涵括之必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
表C出示用於高白胺酸症、甲基丙二酸血症、丙酸血症、與戊二酸血症中作為經修飾釋放之胺基酸之十九種胺基酸之相對重量份數。A欄出示分別針對此等代謝病症之胺基酸之合適比例之較佳範圍,而B欄出示合適比例之更佳範圍。表C僅說明製劑中胺基酸之相對比例。因此,可包括其他成份。從表C所述任何製劑釋放之胺基酸集合物比例較佳係如第一項主要具體實施例所示。
其他具體實施例係定義第一項主要具體實施例包括表C之高白胺酸症製劑(經A或B欄定義)所涵括之三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表C之高白胺酸症製劑(經A或B欄定義)所涵括之必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表C之甲基丙二酸血症製劑(經A或B欄定義)所涵括之三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表C之甲基丙二酸血症製劑(經A或B欄定義)所涵括之必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表C之丙酸血症製劑(經A或B欄定義)所涵括之三
種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表C之丙酸血症製劑(經A或B欄定義)所涵括之必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表C之戊二酸血症製劑(經A或B欄定義)所涵括之三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表C之戊二酸血症製劑(經A或B欄定義)所涵括之必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
表D出示於異戊酸血症、高胱胺酸尿症、與高甘胺酸血症中作為經修飾釋放之胺基酸使用之十九種胺基酸之相對重量份數。A欄出示分別針對此等代謝病症之胺基酸之合適比例之較佳範圍,而B欄出示合適比例之更佳範圍。表D僅說明製劑中胺基酸之相對比例。因此可包括其他成份。從表D所述任何製劑釋放之胺基酸集合物比例較佳係如第一項主要具體實施例所示。
其他具體實施例係定義第一項主要具體實施例包括表D之異戊酸血症製劑(經A或B欄定義)所涵括之三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表D之異戊酸血症製劑(經A或B欄定義)所涵括之必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表D之高胱胺酸尿症製劑(經A或B欄定義)所涵括三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表D之高胱胺酸尿症製劑(經A或B欄定義)所涵括必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施例包括表D之高甘胺酸血症製劑(經A或B欄定義)所涵括三種或更多種、五種或更多種、10種或更多種、或15種或更多種、或甚至所有胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
其他具體實施例係定義第一項主要具體實施
例包括表D之高甘胺酸血症製劑(經A或B欄定義)所涵括必需胺基酸、分支鏈胺基酸、或大型中性胺基酸作為經修飾釋放之胺基酸,其比例示於A或B欄。
額外次項具體實施例係定義第三項主要具體實施例係受到於表E1-E3中所示分支鏈胺基酸之相對比例之限制。
額外次項具體實施例係定義第四項主要具體實施例受到表F1-F3中所示必需胺基酸(精胺酸、組胺酸、異白胺酸、白胺酸、離胺酸、蘇胺酸、色胺酸與纈胺酸)之相對比例之限制。
額外次項具體實施例係定義第五項主要具體實施例受到表G1-G3中所示大型中性胺基酸之相對比例之限制。
另一項次項具體實施例係治療苯酮尿症,其定義不考慮胺基酸之比例,本發明製劑包含以下三種或更多種、五種或更多種、或所有胺基酸:精胺酸、組胺酸、異白胺酸、白胺酸、離胺酸、甲硫胺酸、蘇胺酸、色胺酸、與纈胺酸,或一或多種其醫藥上可接受之鹽類,作為經修飾釋放之必需胺基酸。
另一項次項具體實施例係治療苯酮尿症,其定義再次不考慮胺基酸之比例,本發明製劑包含以下三種或更多種、五種或更多種、或所有胺基酸:精胺酸、組胺酸、異白胺酸、白胺酸、離胺酸、甲硫胺酸、蘇胺酸、色胺酸、與纈胺酸,或一或多種其醫藥上可接受之鹽類,作為經修飾釋放之必需胺基酸;與以下三種或更多種、五種或更多種、或所有胺基酸:丙胺酸、天冬胺酸、肉鹼、胱
胺酸、麩醯胺與/或麩胺酸、甘胺酸、脯胺酸、絲胺酸、牛磺酸、與酪胺酸,或一或多種其醫藥上可接受之鹽類,作為經修飾釋放之非必需胺基酸。
一項特別次項具體實施例中,其適合治療本文說明之任何代謝病症,其定義不考慮成份比例,該製劑包含精胺酸與組胺酸、或一或多種其醫藥上可接受之鹽類,作為經修飾釋放之必需胺基酸;與丙胺酸、天冬胺酸、肉鹼、胱胺酸、麩醯胺與/或麩胺酸、脯胺酸、絲胺酸、與牛磺酸,或一或多種其可接受之鹽類,作為經修飾釋放之非必需胺基酸。
特別佳具體實施例中,該製劑係呈單一劑量之單位劑型提供,其包含1至40克胺基酸,其中當每天投予3至4次該製劑時,該製劑在醫療上有效符合人類患者胺基酸膳食需求。亦即針對該製劑中真正存在之胺基酸,該製劑適當符合患者之膳食需求。
另一項主要具體實施例中,本發明提供一種製造如本發明任一項主要具體實施例或次項具體實施例所定義之製劑之方法,其包括:(a)提供第一混合物,其包含單一或複數種胺基酸;(b)令該混合物與濕潤劑及結合劑接觸,形成濕混合物;(c)視需要令該濕混合物通過篩網,形成均勻濕顆粒;(d)乾燥該均勻濕顆粒形成乾顆粒;(e)視需要令該乾顆粒通過篩網形成均勻乾顆粒,及(f)視需要使用經修飾釋放之組成物包覆該均勻乾顆粒。
該方法特別適合混合大量胺基酸,且可進一
步使用胺基酸之不同混合物製備超過一個之顆粒,並組合該等不同顆粒,製成最終製劑。因此,在製造方法之較佳具體實施例中,第一混合物可包含僅一種胺基酸,或多達6種胺基酸,其進一步包括使用僅包含一種胺基酸,或多達6種胺基酸之不同之第二胺基酸混合物,重覆步驟(a)-(d),及視需要(e)與(f),形成第二均勻乾顆粒,並組合均勻乾顆粒,製成製劑。一項具體實施例中,該等顆粒係壓縮形成可嚼式錠劑。另一項具體實施例中,在形成顆粒混合物後,進一步加工處理,例如:添加調味料或營養素。
該等製劑亦可依據製劑中胺基酸百分比定義。因此例如:本發明進一步提供一種製劑,其包含超過20wt%、70wt%或90wt%之胺基酸,其中(a)該胺基酸包含約10wt%至約80wt%、約20wt%至約60wt%、約30至約50%、或約35至約45%之必需胺基酸;與(b)該必需胺基酸包括以下所有胺基酸或任何組合:L-異白胺酸、L-白胺酸、L-離胺酸、L-蘇胺酸、L-色胺酸、L-纈胺酸、L-甲硫胺酸、L-組胺酸與L-精胺酸(最後兩種胺基酸被認為係僅針對嬰兒之必需胺基酸)。
或者,該經修飾釋放之製劑可依據製劑中必需胺基酸對非必需胺基酸之比例來定義。因此,各種不同具體實施例中,本發明提供一種經修飾釋放之口服投予之胺基酸製劑,其包含超過20wt%、50%、70wt%或90wt%之胺基酸,其中該(a)該胺基酸包含重量比為約10:90、20:80、30:70、40:60、50:50、60:40、70:30、80:20
至約90:10、80:20、70:30、60:40、50:50、40:60、30:70或20:80之必需與非必需胺基酸;及(b)該必需胺基酸包括以下胺基酸之所有或任何組合:L-異白胺酸、L-白胺酸、L-離胺酸、L-蘇胺酸、L-色胺酸、L-纈胺酸、L-甲硫胺酸、L-組胺酸與L-精胺酸(最後兩種胺基酸被認為係僅針對嬰兒之必需胺基酸)。
製劑較佳包括一或多種可以控制製劑中所有胺基酸或一小組胺基酸釋放之賦形劑或添加劑。此等賦形劑或添加劑在本文中一般稱為「延遲釋放之賦形劑或添加劑」,且可以提供延長釋放形態、延緩釋放形態、立即釋放與延長釋放或延緩釋放形態之組合。一項具體實施例中,賦形劑或添加劑為延緩釋放之賦形劑或添加劑,較佳稱為「選擇偏向在pH 4至7之間釋放該胺基酸之方式」或「當口服投予時選擇偏向在空腸中釋放胺基酸之方式」。此等例子中,賦形劑通常係以有效造成該製劑選擇偏向在pH 4至7之間釋放胺基酸之含量存在。
術語「選擇偏向釋放」不排除有些賦形劑會在較低pH環境下釋放胺基酸,或甚至在較低pH環境下之釋放速率等於在較高pH環境下之釋放速率之可能性。重點在於該賦形劑可以使原本在胃中低pH環境下釋放胺基酸總量比立即釋放劑型之釋放量減少。因此,例如:當製劑通過GI道時,賦形劑隨時間所產生之釋放概況可以比原本可能發生在立即釋放型製劑之釋放概況更減緩,或可在合適之活體外環境中建立模式。或者,賦形劑可延遲直到
製劑到達空腸之較高pH環境時才釋放。
修飾釋放之賦形劑或添加劑/包衣劑係習知此相關技藝者所習知,且包括例如:乙基纖維素、乙酸纖維素、乙酸乙烯酯/乙烯氯共聚物、丙烯酸酯/甲基丙烯酸酯共聚物、聚環氧乙烷、羥丙基甲基纖維素、鹿角菜膠、藻酸與其鹽類、羥乙基纖維素、羥丙基纖維素、刺梧桐樹膠、金合歡膠、黃蓍膠、刺槐豆膠、關華豆膠、黃原膠、羧甲基纖維素鈉、甲基纖維素、蜂蠟、巴西棕櫚蠟、鯨蠟醇、氫化植物油、硬脂醇、丙烯酸共聚物、鹿角菜膠、果膠、一羧甲基纖維素鈉、脂肪酸之單與二甘油酯、脂肪酸與其酯或衍生物,包括山嵛酸甘油酯與硬脂酸二棕櫚酸甘油酯、澱粉與其衍生物,如:玉米乙酸酯。
此等本發明組成物可採用製藥及食品補充品技藝上習知之方式製備,並可依是否需要局部或全身處理,採用各種不同途徑投藥。最佳投藥途徑為口服。該組成物除了胺基酸外,通常可包含一或多種可接受之載劑(賦形劑或添加劑)。製造本發明組成物時,活性成份通常與賦形劑混合、經賦形劑稀釋、或囊封在如:呈例如:膠囊、藥囊、紙、或其他容器之載劑中。當賦形劑作為稀釋劑時,其可為固體、半固體、或液體材料,其作用為活性成份之媒劑、載劑或介質。因此,組成物可呈錠劑、丸劑(包括軟式與硬式明膠囊)、粉末、顆粒、微球粒、含錠、藥囊(亦即封裝之粉末或顆粒或微球粒)藥囊、酏劑、懸浮液、乳液、
溶液、與糖漿,其中包含例如:至高90%重量比之胺基酸。
採用此技術即可設計各種不同胺基酸產品,其中所有或僅一部份選定之胺基酸具有經修飾釋放概況。例如:可能設計一種製劑,其中:製劑中所有或僅一部份胺基酸經調配成經修飾釋放。亦即超過20%、40%、60%或80%、及/或低於80%、60%、40%、或20%之胺基酸經調配成經修飾釋放。
製劑中所有或僅一部份必需胺基酸調配成經修飾釋放。亦即超過20%、40%、60%或80%、及/或低於80%、60%、40%、或20%之必需胺基酸經調配成經修飾釋放。
沒有任何必需胺基酸經調配成經修飾釋放。
製劑中所有或僅一部份非必需胺基酸經調配成經修飾釋放。亦即超過20%、40%、60%或80%,及/或低於80%、60%、40%、或20%之非必需胺基酸經調配成經修飾釋放。
沒有任何一種非必需胺基酸經調配成經修飾釋放。
上述策略之任何組合。
例如:採用本申請案說明之調配策略,可能調配胺基酸劑型,因而僅讓必需胺基酸,但不讓非必需胺基酸經調配成經修飾釋放。或者,可能調配胺基酸劑型,因而僅讓非必需胺基酸,但不讓必需經調配成經修飾釋放。或者,依特定製劑之釋放試驗結果而定,可能最好保留某些胺基酸,如:酪胺酸,作為立即釋放胺基酸。
有各種策略可用於控制製劑釋放胺基酸,其隨所需之藥物動力學形態而定。此等策略通常涉及非pH
依賴性賦形劑或添加劑,因此製劑釋放胺基酸不受其在胃腸道中之位置影響,或若涉及pH依賴性賦形劑或添加劑時,則製劑將延緩至到達小腸中較高pH環境時才釋放胺基酸。
可包括在組成物中之非pH依賴性持續釋放劑/包衣包括但不限於:乙基纖維素、乙酸纖維素、乙酸乙烯酯/乙烯氯共聚物、丙烯酸酯/甲基丙烯酸酯共聚物、聚環氧乙烷、羥丙基甲基纖維素、鹿角菜膠、藻酸與其鹽類、羥乙基纖維素、羥丙基纖維素、黃原膠、刺梧桐樹膠、金合歡膠、黃蓍膠、刺槐豆膠、關華豆膠、羧甲基纖維素鈉、甲基纖維素、蜂蠟、巴西棕櫚蠟、鯨蠟醇、氫化植物油、硬脂醇、脂肪酸與其酯或衍生物,包括例如:山嵛酸甘油酯與硬脂酸二棕櫚酸甘油酯、黃原膠、澱粉、與澱粉之衍生物,如:玉米乙酸酯。
通常組成物中存在有至少一種非pH依賴性經修飾釋放劑,其含量為約1wt%或5wt%至約50wt%或25wt%,較佳為約1wt%至約30wt%。然而咸了解,本發明範圍不限於任何特定之非pH依賴性持續釋放劑。
在pH超過5.5提高製劑之胺基酸釋放速率之pH依賴性劑包括但不限於:在pH超過5.5膨脹之聚合物、包覆胺基酸之腸溶性包衣、及藉由維持製劑在酸性微環境下(例如:有機酸)而提高胺基酸在pH超過5.5之溶解度之試劑。合適之有機酸包括例如:甲酸、乙酸、丙酸、丁酸、戊酸、己酸、草酸、乳酸、蘋果酸、檸檬酸、苯甲酸、與
碳酸。可採用此等策略之任何組合來促進胺基酸在pH超過5.5釋放。組成物中該至少一種pH依賴性劑之含量通常為約0.5wt.%至約40wt.%,較佳為約1wt.%至約20wt.%。
在pH超過5.5膨脹之聚合物包括但不限於:丙烯酸共聚物、甲基丙烯酸共聚物(包括例如:彼等以Eudragit®品牌出售者)、藻酸鈉、鹿角菜膠、藻酸、果膠、與羧甲基纖維素鈉。
腸溶性包衣包括但不限於:乙酸纖維素酞酸酯、羥丙基甲基纖維素酞酸酯、聚乙酸乙烯酯酞酸酯、甲基丙烯酸共聚物、乙酸纖維素偏苯三酸酯、羥丙基甲基纖維素乙酸酯、琥珀酸酯、蟲膠、與玉米蛋白。
提高胺基酸在pH超過5.5之溶解度之試劑包括但不限於:有機酸。此等有機酸維持錠劑在酸性微環境中,且包括但不限於:檸檬酸、富馬酸、酒石酸、己二酸、葡萄糖酸-δ-內酯、與蘋果酸。
本發明組成物通常先採用濕式造粒法製備,包覆包衣,及若需要呈餅型時,隨後在與其他合適賦形劑或添加劑(如:潤滑劑、抗黏著劑與崩解劑)混合後,壓縮成餅型劑型。調味劑可在造粒期間添加,因此其等成為顆粒之一部份或「顆粒內」,或隨後與顆粒混合,然後壓縮顆粒,且可視需要壓縮成錠劑/餅型。
濕式造粒法中,至少一種胺基酸與其他成份使用造粒液體(例如:異丙醇、乙醇、三氯甲烷或水),於環繞式混合機、高剪切混合機、或流化床造粒機中製成顆
粒。結合劑可包含在造粒液體中,或可含在乾混合物中。濕粒於烘箱或流化床乾燥機中乾燥,然後通過合適篩網過篩,得到自由流動顆粒,其等隨後可包覆功能性賦形劑或添加劑,可提供修飾或延長或延緩釋放概況。
增積劑可包括在顆粒或餅型製劑中,且包括但不限於:微晶纖維素、甘露糖醇、木糖醇、磷酸二鈣、硫酸鈣、澱粉、乳糖、蔗糖、右旋糖、山梨糖醇、果糖、與纖維素粉末。當組成物存在有增積劑時,其含量可為約5wt.%至約90wt.%,較佳為約10wt.%至約50wt.%。
可包括在製劑中之崩解劑包括但不限於:微晶纖維素、澱粉、交聚維酮(crospovidone)、甘醇酸澱粉鈉、與交聯羧甲基纖維素鈉。當組成物中存在有崩解劑時,其含量可為約0.5wt.%至約30wt.%,較佳為約1wt.%至約15wt.%。
可用於組成物中之抗黏著劑與助滑劑包括但不限於:滑石、玉米澱粉、二氧化矽、月桂基硫酸鈉、與硬脂酸金屬鹽。當組成物中存在有抗黏著劑與助滑劑時,其含量為約0.2wt.%至約15wt.%,較佳為約0.5wt.%至約5wt.%。
可用於組成物中之潤滑劑包括但不限於:硬脂酸鎂、硬脂酸鈣、硬脂酸鈉、硬脂酸、硬脂基富馬酸鈉、氫化玉米籽油、滑石、與蠟類,包括但不限於:蜂蠟、巴西棕櫚蠟、鯨蠟醇、硬脂酸甘油酯、棕櫚酸甘油酯、山嵛酸甘油酯、氫化植物油、與硬脂醇。當存在有潤滑劑時,
其含量為約0.2wt.%至約20wt.%,較佳為約0.5wt.%至約5wt.%。
可使用之結合劑(「結合料」)包括但不限於:聚乙烯基吡咯烷酮、澱粉、甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素、蔗糖溶液、右旋糖溶液、關華豆膠、黃原膠、金合歡膠、黃蓍膠、刺槐豆膠與藻酸鈉或任何其他藻酸鹽。當組成物中存在有結合劑時,其含量為約0.2wt.%至約10wt.%,較佳為約0.5wt.%至約5wt.%。
可包括在組成物中之包衣劑包括但不限於:乙基纖維素、乙酸纖維素、乙酸乙烯酯/乙烯氯共聚物、丙烯酸酯/甲基丙烯酸酯共聚物、聚環氧乙烷、羥丙基甲基纖維素、鹿角菜膠、藻酸與其鹽類、羥乙基纖維素、羥丙基纖維素、刺梧桐樹膠、金合歡膠、黃蓍膠、刺槐豆膠、關華豆膠、羧甲基纖維素鈉、甲基纖維素、蜂蠟、巴西棕櫚蠟、鯨蠟醇、氫化植物油、硬脂醇、脂肪酸與其酯或衍生物,包括山嵛酸甘油酯與硬脂酸二棕櫚酸甘油酯、黃原膠、澱粉、與澱粉衍生物,包括玉米乙酸酯。
胺基酸本身帶有苦味,在本發明一項具體實施例中,此等苦味胺基酸使用遮味劑材料微囊封。適用於遮蔽醫藥製劑味道之材料包括彼等可以微囊封胺基酸之材料,藉以防止察覺到其苦味。本發明遮味劑材料藉由例如:製造比醫藥製劑更可口之醫藥製劑,及/或藉由製造減少傳統調味料或遮味劑用量之劑型,而提供更優異之醫藥製劑。
遮味劑材料包括例如:纖維素羥丙基醚(HPC);經低度取代之羥丙基醚(L-HPC);纖維素羥丙基甲基醚(HPMC);甲基纖維素聚合物;乙基纖維素(EC)與其混合物;聚乙烯基醇(PVA);羥乙基纖維素;羧甲基纖維素與羧甲基纖維素(CMC)之鹽類;聚乙烯基醇與聚乙二醇共聚物;單酸甘油酯類、三酸甘油酯類、聚乙二醇類、經改質食用澱粉、丙烯酸系聚合物及丙烯酸系聚合物與纖維素醚類之混合物;乙酸纖維素酞酸酯;西比薄膜(sepifilm),如:HPMC與硬脂酸之混合物、環糊精、及此等材料之混合物。
除了使用本文所說明之遮味劑材料或加強製劑貨架壽命之材料微囊封胺基酸外,本發明醫藥製劑亦可包含一或多種調味劑。適用於本發明醫藥製劑之「調味劑」或「甜味劑」包括例如:金合歡膠糖漿、乙醯磺胺酸鉀(acesulfame K)、阿力糖(alitame)、茴香、蘋果、阿斯巴甜(aspartame)、香蕉、巴伐利亞奶油(Bavarian cream)、莓果、黑醋栗、奶油糖、檸檬酸鈣、樟腦、焦糖、櫻桃、櫻桃奶油、巧克力、肉桂、泡泡糖、柑橘、柑橘甜酒、柑橘奶油、棉花糖、可可、可樂、冷櫻桃、冷柑橘、甜精(cyclamate)、右旋糖、尤加利(eucalyptus)、丁香油酚、果糖、水果酒、薑、甘草酸鹽、甘草(洋甘草)糖漿、葡萄、葡萄柚、蜂蜜、異麥芽酮糖醇(isomalt)、檸檬、萊姆、檸檬奶油、甘草酸單銨鹽、麥芽酚、甘露糖醇、楓糖、棉花軟糖、薄荷醇、薄荷奶油、混合莓果、新橙皮苷二氫查耳酮(neohesperidine
DC)、紐甜(neotame)、柳橙、梨、桃、辣薄荷、辣薄荷奶油、覆盆子、麥根沙士、蘭姆酒、糖精、黃樟素(safrole)、山梨糖醇、荷蘭薄荷、荷蘭薄荷奶油、草莓、草莓奶油、甜菊、蔗糖素(sucralose)、蔗糖、糖精鈉、糖精、阿斯巴甜(aspartame)、紐甜(neotame)、乙醯磺胺酸鉀、甘露糖醇、塔林糖(talin)、木糖醇、蔗糖素(sucralose)、山梨糖醇、瑞士奶油、塔格糖(tagatose)、橘子、非洲竹芋甜索(thaumatin)、圖圖果霜(tutti fruitti)、香草、胡桃、西瓜、野生櫻桃、冬青、木糖醇、或此等調味成份之任何組合,例如:茴香-薄荷醇、櫻桃-茴香、肉桂-柳橙、櫻桃-肉桂、巧克力-薄荷、蜂蜜-檸檬、檸檬-萊姆、檸檬-薄荷、薄荷醇-尤加利、柳橙奶油、香草-薄荷、與其混合物。其他具體實施例中,可添加氯化鈉至醫藥製劑中。
習知此相關技藝者可依據胺基酸與賦形劑或添加劑來決定最佳香料組合,以提供最適合消費者需求與適應性之調味產品。參見例如:Roy等人Modifying Bitterness:Mechanism,Ingredients,and Applications(1997)。
胺基酸可採用習知此相關技藝者已知之方法經微囊封。此等已知方法包括例如:噴霧乾燥法、轉盤式法、熱融法、噴霧冷卻法、流化床、靜電沉積法、離心擠出法、旋轉懸浮分離法、在液體-氣體或固體-氣體界面下聚合、加壓擠出法、或噴霧溶劑萃取槽。除了此等方法外,亦可採用數種化學技術,例如:複合凝聚法、溶劑蒸發法、
聚合物-聚合物不相容性、在液體介質中之界面聚合法、原位聚合法、液中乾燥法、及於液體介質中之脫溶劑法。此外,亦可使用其他方法,如:乾式造粒法(亦即輥壓法與乾製粒)、擠出/搓圓法、或奈米粒子包覆法。
當微囊封時,胺基酸之粒度可在1微米至1000微米、5微米至200微米、或10微米至100微米之範圍內。
噴霧乾燥法通常更常用於放大至商業規模時。各種不同具體實施例中,用於噴霧乾燥囊封法之材料係乳化或勻散成濃縮型(例如:10-60%固形物)之核心材料。本發明若干具體實施例中,固形物承載量為約10-20%之間、或約10-40%之間、或約40-60%之間。在一項具體實施例中,微囊封材料係乳化至得到約1至3μm液滴為止。其他具體實施例中,微囊封材料係乳化至得到約1至200μm液滴為止,或乳化至得到約1至100μm液滴為止。一旦得到胺基酸與囊封材料之勻散液時,乳液即呈液滴送入噴霧乾燥加熱室中。若干具體實施例中,液滴係噴霧至加熱室中或從旋轉盤中離心送出。微粒隨後再於加熱室中乾燥,並落入噴霧乾燥室的底部,並在此收集。
凝聚法涉及材料(如:活性醫藥成份)之微囊封,並涉及粒子或液滴形成、聚滴壁形成、及膠囊單離等三階段。此方法可產生極小粒度之微膠囊(10-70微米)。
擠出/搓圓法為另一種方法,其涉及由活性醫藥成份形成濕團塊後,濕團塊擠出通過多孔盤,產生短的圓柱形桿。此等短桿隨後置入快速旋轉之搓圓機中,使圓
柱形桿形成均勻球粒。該等球粒隨後採用流化床乾燥機乾燥,然後採用裝備Wurster插套與噴嘴之流化床包覆功能性包衣。此方法產生平滑、均勻球粒,很適合接收功能性包衣。藥物承載量可能高達80%(依藥物特性而定)。
除了微囊封法外,本發明所使用胺基酸之安定性或釋放時間可採用其他替代方法提高,如:乾式包覆與奈米粒子包覆。乾式包覆涉及形成已包覆之胺基酸之顆粒,其等再與其他組份混合。乾式造粒法係形成密實壓縮塊,隨後研磨成所需粒度,再與醫藥組成物中其他組份混合。乾式造粒法與奈米粒子包覆法可藉由讓此等組份於可加強胺基酸產品貨架壽命及可遮蔽苦味(若包衣材料中使用甜味劑或香料)之可相容成份之造粒基質中稀釋及單離,為活性醫藥提供加強之安定性與遮蔽口味特性。
乾式造粒之典型技術為採用乾製粒或輥壓法。在乾製粒過程期間,乾粉使用常見之壓錠機壓縮,更經常採用重負荷大型輪轉壓縮機。所得壓縮塊或「乾粒(slug)」再研磨成所需粒度。輥壓法為另一種較輕柔的方法;由粉末混合物在兩個輥輪之間擠出形成壓縮片。薄片通常脆弱,會立即破裂成碎片。此等碎片需要輕柔處理以破裂成顆粒,此舉通常只要採用過篩法即可達成。Parikh,D.M.,Handbook of Pharmaceutical Granulation Technology,(Marcel Dekker ed.1997)。
亦可將其他成份併入本發明製劑中,包括維生素、礦物質、脂肪、脂肪酸(如:DHA、EPA與ARA(花生四烯酸))、碳水化合物、與其他化合物,較佳呈醫療有效量。合適之礦物質包括例如:氯化鈣、鉻、銅、氟化物、碘、鐵、鎂、錳、鉬、磷、鉀、硒、硫、鈉、與鋅。合適之維生素實例包括維生素A(視黃醇、視黃醇乙酸酯與棕櫚酸酯、β-胡蘿蔔素)、硫胺素(維生素B1)、核黃素(維生素B2)、菸鹼酸(維生素B3、菸酸)、泛酸(維生素B5)、維生素B6(吡哆辛)、維生素B12(鈷胺素)、生物素、維生素C(抗壞血酸)、維生素D(鈣化醇)、維生素E(α-生育酚)、葉酸(葉酸鹽)、與維生素K(葉綠醌、甲萘醌(menaquinone))。
一項具體實施例中,除了製劑中所含之胺基酸外,該製劑亦包含醫療有效量之一種或更多種、五種或更多種、10種或更多種、或所有下列營養素:膽鹼、肌醇、維生素A、維生素D、維生素E、維生素K、維生素C、硫胺素、核黃素、菸鹼酸、維生素B6、葉酸鹽、維生素B12、生物素、泛酸、鉀、鈣、鎂、鐵、鋅、銅、錳、硒、鉻、鉬、碘、鈉、磷、氯化物、十二碳六烯酸、花生四烯酸與葉黃素。
當然咸了解,任何上述營養素均可呈習知此相關技藝者習知可提供類似營養價值之形式,如:上述營養素之鹽類與螯合物與酯類及其他衍生物。表H說明各種不同營養素實例、有效營養劑量、及可併入本發明製劑中之營養素衍生物。製劑可包括任何一種此等營養素或其組
合。
該製劑之特別佳具體實施例包括經一種或多種釋放修飾性之賦形劑包覆之胺基酸顆粒,本文中亦稱為
「延遲胺基酸釋放速率之包覆方式」,或「達成所示釋放速率之包覆方式」。該等顆粒可採用如上述濕式或乾式造粒技術製造,但其等較佳係採用濕式造粒法製造。其等亦較佳係限制在特定粒度範圍內,如:0.1-3mm、0.5-2.0mm、0.5-1.0mm、0.5-2.0mm、或1.0-2.0mm。各胺基酸可含在其自己的顆粒內,但經修飾釋放之胺基酸較佳係在顆粒內混合。
經修飾釋放之性質較佳係利用合適之修飾釋放性之包衣施加在顆粒上來達成,其施加量佔胺基酸重量之1wt%至30wt%、或5wt%至25wt%。適合包衣之延遲釋放之賦形劑說明於本文中,但較佳組成物包括包覆佔胺基酸重量之1wt%至15wt%、2wt%至10wt%、或5wt%至7.5wt%之乙基纖維素。另一種較佳組成物包含第一層乙基纖維素包衣(如上述)與佔胺基酸重量之5%至15%或約10wt%之二山嵛酸甘油酯之第二層包衣。
提供下列實例以供彼等習知此相關技藝者更完整揭示內容及說明如何製造及評估本文所主張之方法,並希望僅供舉例說明本發明,且無意限制本發明者有關其發明之範圍。已試圖在數值(例如:數量、溫度,等等)上確保準確性,但仍應考量有一些誤差與偏差。
表1列出用於苯酮尿症之膳食管理之四種不同的代表
性胺基酸混合物,以百分比計。
下表說明使用聚乙烯吡咯烷酮K26/32(Plasdone K26/32)作為結合劑與遮味劑(產品2、3、4、與5)之含18種胺基酸(不包括甲硫胺酸)之五種不同產品。參考製劑(產品1)不使用聚乙烯吡咯烷酮K26/32且不使用香料。
各製劑係依據下列一般方法製造。
- 各種不同型態天平
- 高剪切混合器:Diosna Laboratory混合器P1/6
- 篩網
- 靜態烤箱
- 混合機器
精確稱取胺基酸,並採用混合機器混合20分鐘。
精確稱取胺基酸,及採用混合機器混合20分鐘。取混合物移至Diosna,於葉片速度250rpm混合1分鐘。混合物使用聚乙烯吡咯烷酮K26/32之醇溶液(10%乙醇溶液-10g含於100g乙醇中)濕化。經過1分30秒後,添加溶液與顆粒,於葉片速度250rpm與切斬速度500rpm混合3分鐘。排出顆粒,通過寬0.8mm之篩網。於靜態烤箱中,於40℃乾燥約4小時。排出,再度通過寬0.8mm之篩網。
精確稱取胺基酸,並採用混合機器混合20分鐘。取混合物轉移至Diosna,並在葉片速度250rpm混合1分30秒。混合物使用聚乙烯吡咯烷酮K26/32之醇溶液(於乙醇溶液中之含量為10% -10g含於100g AA中)與香料。加至聚乙烯吡咯烷酮K26/32之醇溶液中之香料用量如下:
-1.13g焦糖含量58%之乙醇溶液(用於產品3)
-1.13g香草含量60%之乙醇溶液(用於產品4)
-1.46g香蕉含量14%之乙醇溶液(用於產品5)
1分30秒後,於葉片速度250rpm與切斬速度500rpm混合該溶液與顆粒3分鐘。排出顆粒,通過寬0.8mm之篩網。於靜態烤箱中,在40℃乾燥約4小時。排出混合物,通過寬0.8mm之篩網。
甲硫胺酸製法係採用聚乙烯吡咯烷酮K26/32作為結合劑與遮味劑,加上極少量焦糖香料,採用類似步驟1中產品3、4與5所採用之方法製造。
最終製劑製法為依下所報導用量混合步驟1粉末/顆粒加上步驟2顆粒。
所有上述產品製法均為由產品2、3、4與5之粉末或顆粒與產品6之顆粒混合。
下列試驗係採用實例2(產品8、9、10與11)所報導之最終製劑,於6位健康成人中進行。結果係以平均值報導:
如上述數據所示,在勻散性與口味方面,本發明製劑優於市售參考產品,且優於不使用聚乙烯吡咯烷酮K26/32之製劑。
以類似實例2所報導之彼等顆粒產品為起始物(稍微改變香料用量),製備數種餅型製劑。
透過簡單混合過程,在上述產品中添加蔗糖、二氧化矽與二山嵛酸甘油酯。最終製劑如下:
採取單孔壓錠機製備錠劑,平均重量在5.5與6.2g之間。為了校正打錠機中有些沾黏問題,以產品1為起始物製備新製劑:
由6位健康成人測試實例4所示之產品4、5與6之氣味與口味。結果係以平均值表示。
取各個別胺基酸、稀釋劑(若使用時)與HPMC分別稱重與過篩,於適當混合機中與混合20分鐘。
取混合物移至Diosna混合機中,採用葉片速度250rpm混合1分鐘。使用EC(含量15%)之醇溶液濕化混合物。
1分30秒後,添加溶液與顆粒,在葉片速度250rpm與斬切速度500rpm3分鐘。排出顆粒,通過寬0.63mm之篩網。
於45℃靜態烤箱中乾燥約4小時。排出,通過寬0.8mm之篩網。
亦可能一次同時加工處理4至5種胺基酸成為顆粒,並共同混合所有胺基酸顆粒,製成最終產品。有些有潛力製劑之實例報導於實例1之表1。
製備下列配方,以測定溶解試驗中修飾色胺酸釋放時之羥丙基-甲基纖維素(HPMC)與乙基纖維素(EC)之需要量。
取單一胺基酸、甘露糖醇與HPMC稱重及過篩,於適當容器中,採用混合機混合20分鐘。
取混合物移至Diosna混合機中,採用葉片速度250rpm混合1分鐘。使用EC(含量15%)之醇溶液濕化混合物。1分30秒後,添加溶液與顆粒,在葉片速度250rpm與斬切速度500rpm3分鐘。排出顆粒,通過寬0.63mm之篩網。於45℃靜態烤箱中乾燥約4小時。排出,通過寬0.8mm之篩網。
於下文說明之溶解條件下分析製劑,以測定製劑(pH 1.2 2小時,2小時後提高至pH 6.8)於50與100rpm之籃子條件下之色胺酸釋放速率,與無包衣AA之單純混合物比較。溶解試驗結果報導於第3圖。採用HPLC進行分析。
裝置:攪拌槳
溫度:37℃±5℃
介質:0.1N鹽酸
pH調整:0.2M磷酸鈉十二水合物溶液。介質體積:450ml 0.1N HCl。20分鐘後,調整溶解介質至pH 6.8±0.05(依據歐洲藥典(European Pharmacopoeia 2.9.3)延緩釋放固體劑型方法A)。
速度:50rpm或100rpm
取樣時間:無包衣製劑為5與15分鐘
有包衣製劑為5、15、30、60、120、125、135、150、180分鐘(120分鐘後,介質之pH改為pH 6.8)
容器濃度:約90μg/ml(有一部份延緩製劑之粉末在溶解試驗期間保留成為界面活性劑)
下列製劑係依據實例7所示製程製備,並於下文報導之條件下進行溶解試驗。製劑中之色胺酸釋放速率示於第4圖。採用HPLC進行分析。
裝置:攪拌槳
溫度:37℃±5℃
介質:0.1N鹽酸
介質體積:450ml
速度:50rpm
取樣時間:5’、15’、30’、60’、120’、180’
容器濃度:約90μg/ml(有一部份延遲製劑之粉末在
溶解試驗期間保留成為界面活性劑)
下列製劑係依據實例7所示製程製備,並於下文說明之條件下進行溶解試驗。製劑中之色胺酸釋放速率示於第5圖。採用HPLC進行分析。
取單一胺基酸經過稱重及過篩,於適當容器中,使用混合機器混合20分鐘。
取混合物移至Diosna混合機中,使用葉片速度250rpm混合1分鐘。使用EC(乙基纖維素)(含量15%)之醇溶液濕化混合物。經過1分30秒後,添加溶液與顆粒,在葉片速度500rpm與斬切速度1500rpm 3分鐘。排出顆粒,通過
寬0.8mm之篩網。於45℃靜態烤箱中乾燥約5小時30分鐘。排出,通過寬1.4mm之篩網。
在下文說明之溶解條件下分析製劑,以測定製劑(pH 1.2)在籃子條件下,於50rpm下之色胺酸之釋放速率。溶解試驗結果報導於第5圖。
裝置:籃子
溫度:37℃±5℃
介質:0.1N鹽酸
介質體積:450ml
速度:50rpm
取樣時間:5’、15’、30’、60’、120’、180’、240’、300’、與360’
容器濃度:約90μg/ml(有一部份延遲製劑之粉末在溶解試驗期間保留成為界面活性劑)
下列製劑係依據下述製程製備。
- 各種不同型態之天平
- ProCepT Mipro 900ml設定
- 篩網
- 靜態烤箱
- ProCepT流化床由下而上包覆法(熔融噴嘴)(或任何其他適合顆粒熱融包覆法之裝置)
於合適裝置中混合所有胺基酸。
取胺基酸混合物移至ProCepT Mipro,添加由2%藻酸鈉水溶液組成之造粒溶液與顆粒。造粒後,顆粒過篩;採用0.5mm<PSD<1mm之部份進行下一個步驟。
取過篩之顆粒部份移至流化床裝置,使用15%(w/w)乙基纖維素之甲醇溶液噴塗。聚合物之添加總量應等於顆
粒重量之約5.00%。
取包覆乙基纖維素之顆粒移至流化床裝置,使用熔融之二山嵛酸甘油酯噴塗。聚合物之添加總量應等於顆粒重量之約15.00%。
溶解介質:介質pH 1.2±0.1(0.1N鹽酸)
裝置:攪拌槳裝置(裝置2,USP<711>經修正);50rpm
時間:30-60-120-180分鐘
溫度:37±0.5℃
介質體積:500mL
樣本:2.0g胺基酸混合物
龐德羅溶解試驗:30-60-120-180分鐘
龐德羅溶解試驗結果考量乙基纖維素與二山嵛酸甘油酯不可溶於HCl溶液。在30-60-120-180分鐘,溶解介質通過濾紙真空過濾。過濾後之粉末與濾紙於50℃真空烘箱中乾燥±4小時,直到達到恆定重量為止,並取樣稱重。若有差異時,則計算胺基酸釋放量,示於第6圖。
表10a報導代表性胺基酸製劑AA混合物(bkT037/71)
之定性與定量性組成物。
- 各種不同型態之天平
- 篩網
- 靜態烤箱
- 混合機器
所有胺基酸過篩及在合適裝置中混合。
胺基酸經機械方式通過350μm不銹鋼篩網,於混合機中混合30分鐘。
溶解介質:介質pH 1.2±0.1(0.1N鹽酸)
裝置:攪拌槳裝置(裝置2,USP<711>經修正)50rpm
時間:30-60分鐘
溫度:37±0.5℃
介質體積:500mL
樣本:2.0g胺基酸混合物
龐德羅溶解試驗:30-60-120-180分鐘
每個時間點有其個別溶解容器。在30-60-120-180分鐘,溶解介質通過濾紙真空過濾。過濾後之粉末與濾紙於50℃真空烘箱中乾燥±4小時,直到達到恆定重量為止,並取樣稱重。若有差異時,則計算胺基酸釋放量。
龐德羅溶解試驗結果報導於表10b與第7圖。
分析條件:
‧HPLC:Agilent系列1200
‧檢測器:螢光計Agilent系列1200
‧層析管柱:YMC-Triart C18 12nm S(250 x 4.6mm-5μm)
在萃取(採用不同方式)及使用FMOC(氯甲酸9-芴基甲酯)衍化後,分析胺基酸。註:肉鹼係採用LC/MS分析。
AA混合物(bkT037/71)之溶解試驗結果報導於表10c與第8圖。
表10d報導四批包覆乙基纖維素之不同胺基酸顆粒之定量性與定性製劑。
- 各種不同型態之天平
- ProCepT Mipro 900ml設定
- 篩網
- 靜態烤箱
- ProCepT流化床由下而上包覆法(熔融物噴嘴)(或任何其他適合顆粒熱熔包覆法之裝置)
於合適裝置中混合所有胺基酸。
取胺基酸混合物移至ProCepT Mipro。添加由2%藻酸鈉水溶液組成之造粒溶液與顆粒。造粒後,顆粒過篩;採用0.5mm<PSD<1mm與0.5mm<PSD<1.5mm之部份用於下一個步驟。
取過篩之顆粒部分移至流化床裝置,使用15%(w/w)乙基纖維素之乙醇溶液噴塗。聚合物之添加總量應等於顆
粒重量之約5.00%與7.50%。
產品之溶解試驗
溶解條件:
溶解介質:介質pH 1.2±0.1(0.1N鹽酸)
裝置:攪拌槳裝置(裝置2,USP<711>經修正);50rpm
時間:30-60-120-180-240分鐘
溫度:37±0.5℃
介質體積:500mL
樣本:2.0g胺基酸混合物
龐德羅溶解試驗:取樣時間:30-60-120-180分鐘
每個時間點有其個別溶解容器。
在30-60-120-180分鐘,溶解介質通過濾紙真空過濾。過濾後之粉末與濾紙於50℃真空烘箱中乾燥±4小時,直到達到恆定重量為止,並取樣稱重。若有差異時,則計算胺基酸釋放量。
龐德羅溶解試驗結果示於表10e與第9圖。
單一胺基酸之釋放分析僅於原型APR批次2與APR批次4中進行。
分析條件:
‧HPLC:Agilent系列1200
‧檢測器:螢光計Agilent系列1200
‧層析管柱:YMC-Triart C18 12nm S(250 x 4.6mm-5μm)
在萃取(採用不同方式)及使用FMOC(氯甲酸9-芴基甲酯)衍化後,分析胺基酸。註:肉鹼係採用LC/MS分析。
APR批次2(bkT037/72-2)之溶解試驗結果報導於表10f與第10圖。
APR批次4(bkT037/72-4)之溶解試驗結果報導於表10g與第11圖。
表11a報導4種包覆乙基纖維素與二山嵛酸甘油酯作為釋放速率修飾劑之不同胺基酸製劑之定性與定量性組成物。
- 各種不同型態之天平
- ProCepT Mipro 900ml設定
- 篩網
- 靜態烤箱
- ProCepT流化床由下而上包覆法(熔融物噴嘴)(或任何其他適合顆粒熱熔包覆法之裝置)
於合適裝置中混合所有胺基酸。
取胺基酸混合物移至ProCepT Mipro,添加由2%藻酸鈉水溶液組成之造粒溶液與顆粒。造粒後,顆粒過篩;採用0.5mm<PSD<1mm或0.5mm<PSD<1.6mm之部份進行下一個步驟。
取過篩之顆粒部份移至流化床裝置,使用15%(w/w)乙基纖維素之甲醇溶液噴塗。聚合物之添加總量應等於顆粒重量之約5.00%與7.50%。
取包覆乙基纖維素之顆粒移至流化床裝置,使用熔融之二山嵛酸甘油酯噴塗。聚合物之添加總量應等於顆粒重量之約10.00%。
分析條件:
產品之溶解試驗
溶解介質:介質pH 1.2±0.1(0.1N鹽酸)
裝置:攪拌槳裝置(裝置2,USP<711>經修正);50rpm
時間:30-60-120-180-240分鐘
溫度:37±0.5℃
介質體積:500mL
樣本:2.0g胺基酸混合物
龐德羅溶解試驗:取樣時間:30-60-120-180分鐘
在30-60-120-180分鐘,溶解介質通過濾紙真空過濾。
過濾後之粉末與濾紙於50℃真空烘箱中乾燥±4小時,直到達到恆定重量為止,並取樣稱重。若有差異時,則計算胺基酸釋放量。
龐德羅溶解試驗結果報導於表11b與第12圖。
該等分析已於原型APR批次5與APR批次7上進行。
分析條件:
‧HPLC:Agilent系列1200
‧檢測器:螢光計Agilent系列1200
‧層析管柱:YMC-Triart C18 12nm S(250 x 4.6mm-5μm)
在使用FMOC(氯甲酸9-芴基甲酯)衍化後,分析胺基酸。註:肉鹼係採用LC/MS分析。
APR批次5(bkT037/73-5)之單一胺基酸溶解試驗結果報導於表11c與第13圖。
APR批次7(bkT037/72-7)之單一胺基酸溶解試驗之結果報導於表11d與第14圖。
表11e與第15圖報導四種試驗製劑分別在各種不同時間點釋放之總胺基酸(龐德羅溶解試驗),並與立即釋放型胺基酸製劑比較。
表11f-11j報導四種不同試驗製劑在各獨立時間點之個別胺基酸釋放量。
針對苯酮尿症之胺基酸混合物之定量性組成物已依據營養學家建議最優化;單一胺基酸之百分比報導於表12a。
於豬中進行活體內生體可用率試驗,以建立預測本發明製劑藥物動力學及代謝之模式,與具有類似胺基酸比例與總量之相當之游離胺基酸混合物、及市售奶蛋白質(酪蛋白)製劑商品比較。測試下列製劑:
‧APR-04(bkT037/72-4)
‧APR-07(bkT037/73-7)
‧游離胺基酸(bkT037/71)
‧酪蛋白
‧個體:8隻豬
‧設計:4種製劑交叉
‧投藥途徑與方法:利用胃管經口投藥。要投予每隻動物之產品劑量係與少量水(300ml)混合,以確保快速(5分鐘)食入。利用針筒投予產品總量。動物在接受處理前先禁食13.5±0.5小時,在處理前一小時及處理後一小時才懸掛飲水。
‧投藥劑量、頻率與持續時間:產品用量係依據體重投予,且各試驗產品等於0.8g胺基酸/kg體重。該產品係
在每個處理日早上投予一次。
‧洗清:48-72小時
‧血液取樣:處理(T)前0.75h、T前0.5h、T前0.25h、T後0.25h、T後0.5h、T後0.75h、T後1h、T後1.25h、T後1.5h、T後2h、T後2.5h、T後3h、T後4h、T後5h
‧分析:測定及分析14種胺基酸(丙胺酸、精胺酸、麩醯胺、甘胺酸、組胺酸、異白胺酸、白胺酸、離胺酸、脯胺酸、絲胺酸、蘇胺酸、色胺酸、酪胺酸、纈胺酸)之血漿濃度。甲硫胺酸與天冬胺酸因安定性問題而不包括在分析中。評估下列參數:濃度/時間曲線下面積(AUC0-終點)、高峰濃度(Cmax)、到達高峰濃度之時間(Tmax)與C終點。由兩種APR製劑與游離胺基酸及酪蛋白之製劑進行比較。
胺基酸(AA)之血漿濃度係其在血漿中出現(Ra)與消失(Rd)之速率之結果。控制Ra之因素包括蛋白質攝取與組織釋放。控制Rd之因素包括組織吸收及透過尿液、汗液等等之身體流失。激素亦有助於調節血漿AA濃度,特別是胰島素與升糖素(此二者均會誘發低胺基酸血症,但原因完全不同),與皮質醇(其誘發高胺基酸血症)。此外,在病理狀態下,兒茶酚胺、甲狀腺激素、與細胞素可調控血漿AA濃度。攝入蛋白質後之AA之周邊可利用度係受到肝臟控制,在攝取過高蛋白質時會活化尿素生成,在低蛋白質膳食期間則壓制尿素生成(Cynober 2002)。所有此等因素均會
影響血漿中本文所報導之胺基酸濃度。
14種胺基酸之平均血漿濃度隨時間之變化(以集合物計)報導於第16圖與表14a。進行計算之前未先扣除基線值。
進行下列觀察:
‧當與游離胺基酸製劑比較時,APR製劑顯示胺基酸集合物之較低血漿高峰值(Cmax)。
‧若吾人考量單一胺基酸曲線時,由Ln換算數據採用重覆測定ANOVA(Repeated Measures ANOVA),由APR-04相對於游離胺基酸,比較精胺酸、異白胺酸、白胺酸、酪胺酸與纈胺酸時,在Cmax上顯示顯著差異(p<0.05)。
‧若吾人考量單一胺基酸曲線時,由Ln換算數據採用重覆測定ANOVA,由APR-07相對於游離胺基酸,比較異白胺酸、白胺酸、酪胺酸與纈胺酸時,在Cmax上顯示顯著差異(p<0.05)。
‧若吾人考量BC數據時,Cmax差異可能甚至更顯著,
其中扣除胺基酸基線值(如下表14b所示),但整體胺基酸集合物之平均值則沒有統計上顯著差異:
‧在游離胺基酸製劑中觀察到胺基酸之較高初始血漿高峰濃度(Cmax)快速下降,由「C終點」參數可證。「C終點」為取樣終點(5h)時之胺基酸血漿濃度。
‧若吾人比較單一胺基酸曲線時,在丙胺酸、精胺酸、麩醯胺、甘胺酸、組胺酸、異白胺酸、白胺酸、離胺酸、脯胺酸、絲胺酸、蘇胺酸、色胺酸與纈胺酸(14種胺基酸中之13種)上,APR-04處理組之C終點高於游離胺基酸組(但除了纈胺酸外,其餘均沒有統計顯著性)。
‧若吾人比較單一胺基酸曲線時,在精胺酸、組胺酸、異白胺酸、白胺酸、離胺酸、脯胺酸、色胺酸、與纈胺酸(14種胺基酸中之8種)上,APR-07處理組之C終點高於游離胺基酸組(但除了纈胺酸、異白胺酸與白胺酸外,其餘均沒有統計顯著性)。
‧若吾人考量必需胺基酸小組與BCAA(分支鏈胺基酸)小組(參見點2與3)時,在胺基酸集合物之血漿濃度曲線中
觀察到之Cmax與C終點趨勢則出現統計顯著性。
經測試之必需胺基酸之平均血漿濃度(以集合物計)報導於第17圖與表14c。集合在一起分析之胺基酸為精胺酸、組胺酸、異白胺酸、白胺酸、蘇胺酸、離胺酸、色胺酸與纈胺酸。選擇此小組進行分析的原因為此等胺基酸無法內源性合成。因此,其等在從頸靜脈所取得血漿樣本中之濃度可能比可分別獨立由生物體產生而出現在血液中之非必需胺基酸更能代表該試驗製劑之腸部吸收性。
表14c報導數據之統計分析(AUC、Cmax、與C終點:採用經過邦弗朗尼校正(Bonferroni adjustment)之事後比較(post hoc)分析之單向重覆測定ANOVA;Tmax:弗里德曼(Friedman)試驗後進行多重項目試驗以供捉對比較)報導於表14d。
經測試之分支鏈胺基酸試驗之平均血漿濃度(以集合物計)報導於第18圖與表14e。集合在一起分析之胺基酸為纈胺酸、異白胺酸與白胺酸。選擇此小組進行分析的原因為此等必需胺基酸在胺基酸中之獨特性為其第一個分解代謝步驟不會在肝臟中發生。因此,其等大多避過第一道內臟代謝作用(Brosnan等人)。
表14e報導數據之統計分析(AUC、Cmax、與C終點:採用經過邦弗朗尼校正之事後比較分析之單向重覆測定
ANOVA;Tmax:弗里德曼試驗後進行多重項目試驗以供捉對比較)示於表14f。
經測試之大型中性胺基酸之血漿濃度(以集合物計)報導於第19圖與表14g。集合在一起分析之胺基酸為色胺酸、蘇胺酸、纈胺酸、異白胺酸、白胺酸、組胺酸。酪胺酸因為在溶解試驗及活體內試驗中之行為反常,而甲硫胺酸因為在樣本中不安定而被排除在外。苯基丙胺酸因為沒有存在於試驗製劑中而沒有分析。選擇此必需胺基酸小組進行分析係因為LNAA與苯基丙胺酸有進入腦內之共通轉運系統。LNAA血漿濃度高會降低腦部吸收(Van Spronsen等人),可能因此產生臨床優點。特定言之,若該小組之分析顯示APR製劑之C終點比游離胺基酸製劑提高,則可推斷該患者可能對苯基丙胺酸有些許「延長保護/耐受」。
表14g報導數據統計分析(AUC、Cmax與C終點:採用經過邦弗朗尼校正之事後比較分析之單向重覆測定ANOVA;Tmax:弗里德曼試驗後進行多重項目試驗以供捉對比較)報導於表14h。
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本申請書全文提及各種不同公開文獻。此等公開文獻之揭示內容已以參考方式併入本文中,以便更詳細說明與本發明有關之技藝態樣。習知此相關技藝者咸了解可在不偏離本發明範圍或本質下進行各種不同修飾與變化。習知
此相關技藝者可由本文所揭示之說明書與操作法了解本發明其他具體實施例。該說明書與與實例僅供舉例說明,本發明之真正範圍與本質將由下列申請專利範圍指明。
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由於本案的圖為實驗數據圖,並非本案的代表圖。故本案無指定代表圖。
Claims (40)
- 一種口服投予之胺基酸製劑,其包含一或多種經修飾釋放之胺基酸,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中x%為90%、80%、70%、60%、50%、或甚至40%。
- 一種口服投予之胺基酸製劑,其包含一或多種選自:異白胺酸、白胺酸、酪胺酸、纈胺酸、與其組合之經修飾釋放之胺基酸,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中x%為90%、80%、70%、60%、50%、或甚至40%。
- 一種口服投予之胺基酸製劑,其包含一或多種經修飾釋放之分支鏈胺基酸,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中x%為90%、80%、70%、60%、50%、或甚至40%。
- 如申請專利範圍第3項所述之製劑,其中該製劑包含經 修飾釋放之纈胺酸、異白胺酸與白胺酸。
- 一種口服投予之胺基酸製劑,其包含經修飾釋放之必需胺基酸之組合,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中x%為90%、80%、70%、60%、50%、或甚至40%。
- 如申請專利範圍第5項所述之製劑,其中該製劑包含經修飾釋放之精胺酸、組胺酸、異白胺酸、白胺酸、蘇胺酸、離胺酸與色胺酸。
- 一種口服投予之胺基酸製劑,其包含經修飾釋放之大型中性胺基酸,其中該包含2g經修飾釋放之大型中性胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃,在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中x%為90%、80%、70%、60%、50%、或甚至40%。
- 如申請專利範圍第7項所述之製劑,其中該製劑包含經修飾釋放之色胺酸、蘇胺酸、纈胺酸、異白胺酸、白胺酸、與組胺酸。
- 一種口服投予之胺基酸製劑,其包含經修飾釋放之非必需胺基酸之組合,其中該包含2g經修飾釋放之胺基酸之製劑於<711>USP 39 NF 34,攪拌槳裝置中,於37℃, 在450或500mL之0.1N鹽酸(pH 1.2)中,槳板速度50rpm進行之溶解試驗中,於30分鐘內釋放之經修飾釋放之胺基酸不超過x%,其中x%為90%、80%、70%、60%、50%、或甚至40%。
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示:
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示:
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示:
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示::
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示:
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示::
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示:
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示:
- 如申請專利範圍第1項之製劑,其包含五種或更多種下列胺基酸作為經修飾釋放之胺基酸,其以重量份數表示:
- 如申請專利範圍第10至18項中任一項所述之製劑, 其包含十種或更多種所示之胺基酸作為經修飾釋放之胺基酸,其係以所示之重量份數表示。
- 如申請專利範圍第10至18項中任一項所述之製劑,其包含十五種或更多種所示之胺基酸作為經修飾釋放之胺基酸,其係以所示之重量份數表示。
- 如申請專利範圍第10至18項中任一項所述之製劑,其包含所有所示之胺基酸,其係以所示之重量份數表示。
- 如申請專利範圍第10至18項中任一項所述之製劑,其包含所示之大型中性胺基酸作為經修飾釋放之胺基酸,其係以所示之重量份數表示。
- 如申請專利範圍第10至18項中任一項所述之製劑,其包含所示之必需胺基酸作為經修飾釋放之胺基酸,其係以所示之重量份數表示。
- 如申請專利範圍第10至18項中任一項所述之製劑,其包含所示之分支鏈胺基酸作為經修飾釋放之胺基酸,其係以所示之重量份數表示。
- 如申請專利範圍第1至24項中任一項所述之製劑,其係呈錠劑、丸劑、軟式或硬式明膠膠囊、粉末、顆粒、微球粒、口含錠、封裝粉末或顆粒或微球粒之藥囊、酏劑、懸浮液、乳液、溶液、或糖漿。
- 如申請專利範圍第1至25項中任一項所述之製劑,其中該製劑包含1至40克胺基酸,其中當對人類患者每天投予3至4次該製劑時,該製劑在醫療上有效符合胺基酸膳食需求。
- 如申請專利範圍第1至26項中任一項所述之製劑,其中該製劑包含呈立即釋放型態之該胺基酸之第一部份與呈經修飾釋放型態之該胺基酸之第二部份。
- 如申請專利範圍第1至27項中任一項所述之製劑,其中該製劑進一步包含選自:維生素、礦物質與碳水化合物所組成群中之一或多種額外成份。
- 如申請專利範圍第1至28項中任一項所述之製劑,其中x%等於70%。
- 如申請專利範圍第1至29項中任一項所述之製劑,其中該經修飾釋放之胺基酸為以胺基酸重量計,經5wt%至25wt%之一或多種釋放修飾性之賦形劑包覆之顆粒。
- 如申請專利範圍第1至30項中任一項所述之製劑,其中該經修飾釋放之胺基酸進一步包含選自:乙基纖維素、二山嵛酸甘油酯、乙酸纖維素、乙酸乙烯酯/乙烯氯共聚物、丙烯酸酯/甲基丙烯酸酯共聚物、聚環氧乙烷、羥丙基甲基纖維素、鹿角菜膠、藻酸與其鹽類、羥乙基纖維素、羥丙基纖維素、刺梧桐樹膠、金合歡膠、黃蓍膠、刺槐豆膠、關華豆膠、羧甲基纖維素鈉、甲基纖維素、蜂蠟、巴西棕櫚蠟、鯨蠟醇、氫化植物油、硬脂醇、丙烯酸共聚物、藻酸鈉、鹿角菜膠、藻酸、果膠、羧甲基纖維素鈉、或其組合所組成群中之一或多種釋放修飾性之賦形劑。
- 如申請專利範圍第1至31項中任一項所述之製劑,其 進一步包含選自:乳糖、蔗糖、右旋糖、山梨糖醇、果糖、與纖維素粉末所組成群中之增積劑。
- 如申請專利範圍第1至32項中任一項所述之製劑,其進一步包含選自:微晶纖維素、澱粉、交聚維酮、甘醇酸澱粉鈉、與交聯羧甲基纖維素鈉之崩解劑。
- 如申請專利範圍第1至33項中任一項所述之製劑,其進一步包含選自:滑石、玉米澱粉、二氧化矽、月桂基硫酸鈉、硬脂酸鎂、硬脂酸鈣、硬脂酸鈉、硬脂酸、硬脂基富馬酸鈉、氫化棉籽油、滑石、蠟類、鯨蠟醇、硬脂酸甘油酯、棕櫚酸甘油酯、山嵛酸甘油酯、氫化植物油、與硬脂醇之助滑劑或潤滑劑。
- 如申請專利範圍第1至34項中任一項所述之製劑,其進一步包含選自:聚乙烯基吡咯烷酮、澱粉、甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素、蔗糖溶液、右旋糖溶液、關華豆膠、黃原膠、金合歡膠、黃蓍膠、刺槐豆膠與藻酸鈉、或藻酸鹽之結合劑。
- 一種為有其需要之哺乳動物個體補充胺基酸之方法,其包括對該個體經口投予如申請專利範圍第1至35項中任一項所定義之製劑。
- 一種為有其需要之患者治療選自下列各者所組成群中之代謝病症之方法:於有其需要之患者中之苯酮尿症、高酪胺酸血症、高白胺酸症、甲基丙二酸血症、高胱胺酸尿症、高甘胺酸血症、異戊酸血症、丙酸血症、與麩胺酸血症,其包括對該患者經口投予如申請專利範圍第 1至35項中任一項所定義之製劑。
- 如申請專利範圍第38或39項所述之方法,其中當每天投予3或4次該製劑時,該製劑包含醫療有效量之胺基酸。
- 一種製造如申請專利範圍第1至35項中任一項所述之製劑之方法,其包括:a.提供包含複數種胺基酸之第一混合物;b.令該混合物與濕潤劑及結合劑接觸,形成濕混合物;c.視需要令該濕混合物通過篩網,形成均勻濕顆粒;d.乾燥該均勻濕顆粒,形成乾顆粒;e.視需要令該乾顆粒通過篩網,形成均勻乾顆粒;及f.視需要以經修飾釋放之組成物包覆該均勻乾顆粒。
- 如申請專利範圍第41項所述之方法,其進一步包括壓縮該均勻乾顆粒形成可嚼式錠劑。
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KR20200126404A (ko) * | 2018-03-01 | 2020-11-06 | 463아이피 파트너즈, 엘엘씨 | 마이크로캡슐화 제품, 이의 투명한 용액, 및 제조 방법 |
CA3099762A1 (en) * | 2018-06-20 | 2019-12-26 | Axcella Health Inc. | Methods of manufacturing amino acid compositions |
US11701335B2 (en) * | 2018-08-31 | 2023-07-18 | Apr Applied Pharma Research S.A. | Methods of normalizing amino acid metabolism |
IT201900013473A1 (it) * | 2019-07-31 | 2021-01-31 | Vetagro Int S R L | Composizioni comprendenti amminoacidi e un ulteriore componente per l'apporto di amminoacidi ad un animale monogastrico quale uomo o maiale |
US20240148652A1 (en) * | 2019-10-17 | 2024-05-09 | Hercules Llc | A dispersible extended release composition, and a process for preparing the same |
CN110946839A (zh) * | 2019-12-31 | 2020-04-03 | 烟台万润药业有限公司 | 一种补充硒、维生素c的咀嚼片及其制备方法 |
CN111821272A (zh) * | 2020-08-11 | 2020-10-27 | 河北科星药业有限公司 | 犬用复方氨基酸肠溶片及其制备方法 |
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- 2016-09-29 TW TW105131262A patent/TWI729005B/zh active
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2018
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- 2018-03-23 CO CONC2018/0003224A patent/CO2018003224A2/es unknown
- 2018-03-26 SA SA518391206A patent/SA518391206B1/ar unknown
- 2018-03-26 IL IL258349A patent/IL258349B/en unknown
- 2018-03-28 CL CL2018000811A patent/CL2018000811A1/es unknown
- 2018-03-28 US US15/938,837 patent/US10500180B2/en active Active
- 2018-04-27 PH PH12018501072A patent/PH12018501072A1/en unknown
- 2018-10-30 HK HK18113849.6A patent/HK1254555A1/zh unknown
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2022
- 2022-04-27 US US17/660,999 patent/US20220347142A1/en active Pending
- 2022-07-13 AU AU2022205198A patent/AU2022205198A1/en active Pending
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2023
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