TW201325610A - 用美洛明穩定化之依那西普調配物 - Google Patents
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- TW201325610A TW201325610A TW101138566A TW101138566A TW201325610A TW 201325610 A TW201325610 A TW 201325610A TW 101138566 A TW101138566 A TW 101138566A TW 101138566 A TW101138566 A TW 101138566A TW 201325610 A TW201325610 A TW 201325610A
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Abstract
本發明提供適用於長期儲存依那西普(etanercept)之穩定化依那西普水性醫藥組合物、製造此等組合物之方法、投藥方法及含其之套組。
Description
本發明係關於用美洛明(meglumine)穩定化以便長期儲存依那西普(etanercept)之水性醫藥組合物、製造該等組合物之方法、其投藥方法及含其之套組。本發明包括不需要精胺酸來穩定之依那西普調配物。
多肽在其使用之前經常必須儲存。當長期儲存時，多肽在溶液中常為不穩定的(Manning等人，1989,Pharm.Res.6：903-918)。為延長其保存期限，已開發出其他處理步驟，諸如乾燥，例如凍乾。然而，凍乾之醫藥組合物不太便於使用。
改良多肽穩定性之典型實踐可藉由改變調配物之元素濃度或藉由添加賦形劑以改質調配物來解決(參見例如美國專利第5,580,856號及第6,171,586號)。然而，使用添加劑仍可產生無活性多肽。另外，在凍乾情況下，再水合步驟可藉由例如聚集或變性而使多肽不活化(Hora等人，1992,Pharm.Res.,9：33-36；Liu等人，1991,Biotechnol.Bioeng.,37：177-184)。多肽聚集因可引起免疫原性而為不合需要的(Cleland等人，1993,Crit.Rev.Therapeutic Drug Carrier Systems,10：307-377；及Robbins等人，1987,Diabetes,36：838-845)。
改良多肽穩定性之另一方式為使用特定濃度之L-精胺
酸(美國專利第7,648,702號)。
一種在使用前儲存多達兩年之多肽為依那西普(Enbrel®,Immunex公司)，其為由人類75千道耳頓(p75)腫瘤壞死因子受體(TNFR)之細胞外配位體結合部分連接至人類IgG1之Fc組件組成的二聚融合多肽。其由934個胺基酸組成且表觀分子量為約150千道耳頓(Physicians Desk Reference,2002,Medical Economics Company公司)。依那西普之Fc組件含有人類IgG1之恆定重鏈2(CH2)域、恆定重鏈3(CH3)域及鉸鏈區，但不含人類IgG1之恆定重鏈1(CH1)域。Fc域可含有一個或所有上述域。依那西普通常藉由重組DNA技術在中國倉鼠卵巢(Chinese hamster ovary；CHO)哺乳動物細胞表現系統中製得。
本發明提供允許依那西普長期儲存的依那西普之新穎穩定液體調配物。
本發明為一種依那西普之水性穩定化調配物，其包含：依那西普；及阻滯該調配物中依那西普之不穩定性、聚集及/或破碎的穩定化成分，該等穩定化成分包含以下至少一者：(a)美洛明；或(b)與蔗糖組合之美洛明；或(c)與氯化鈉組合之美洛明；或(d)與氯化鈉及蔗糖組合之美洛明。
以下討論中所用之各種技術術語係定義於下文標題為
「定義」之章節及說明書整個其餘部分中。
本發明之穩定化依那西普調配物引出特徵在於以下至少一者之長期儲存穩定性：(1)在M3或T2或T4之以下之SEC分析：大於約90%之單體含量；小於約3重量%之聚集體含量；及小於約5重量%之片段3含量：及(2)在M3或T2或T4之HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約3重量%；由HIC層析圖之峰2表示的組成之量大於80重量%；且由HIC層析圖之峰3表示的組成之量小於約20重量%。
在穩定化調配物之較佳態樣中，調配物引出特徵在於以下之長期儲存穩定性：在M3或T2或T4之HIC分析，其中由HIC層析圖之峰2表示的組成之量大於或等於約95重量%；且其中，若在HIC層析圖上存在峰3，則由峰3表示之組合物之量小於或等於約3重量%。
如上概述之穩定化依那西普調配物視情況及較佳不含精胺酸，或基本上無精胺酸。
如藉由在5℃下儲存一個月、二個月或三個月後進行之SEC(尺寸排阻層析法)及HIC(疏水交互作用層析法)分析測定，本發明之調配物具有優良穩定性。此等調配物係與精胺酸為所需組分之市售依那西普調配物相當或比其更佳。因此，本發明進一步係關於如上概述之不含精胺酸或基本上無精胺酸之穩定化依那西普調配物，且其中該組合物在M3或T2或T4下評估時引出符合一或兩個以下準則之長期儲存穩定性：(A)如藉由以下量測：(i)組
合物中聚集體、單體及片段3之量的SEC分析(如本說明書中所定義)及(ii)對應於HIC層析圖之峰1、峰2及峰3之組合物中物質之量的HIC分析(如本說明書中所定義)，穩定性與以商標Enbrel®銷售之市售依那西普相當或比其更佳；及(B)HIC層析圖，其中(i)峰3不存在或基本上不存在且(ii)峰2佔組合物之約95重量%以上；基本上不含對應於聚集體之峰的SEC層析圖；及單體含量佔組合物之至少約95重量%的SEC層析圖。
在一較佳態樣中，本發明之調配物包含約約25 mg/ml至約75 mg/ml依那西普、至多約150 mM之量的氯化鈉、約1 mM至約30 mM磷酸鈉；及約0至5重量%蔗糖或海藻糖或其組合；其中該組合物之pH值為約6.0至約6.6；且其中該組合物之特徵在於，在M3或T2或T4之以下之SEC分析，其中：單體含量大於約85重量%；聚集體含量小於約3重量%，及片段3含量小於約8重量%。符合此等分析準則之調配物不需要精胺酸來穩定。
在另一較佳實施例中，穩定化依那西普調配物之其他特徵在於：(a)在M3或T2或T4之以下之SEC分析：大於約90重量%單體含量；及小於約3重量%聚集體含量；及(b)在M3或T2或T4之HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約4重量%；由HIC層析圖之峰2表示的組成之量大於約80重量%；且由HIC層析圖之峰3表示的組成之量小於約20重量%；且其中該調配物無或基本上無精胺酸。
本發明之依那西普組合物進一步得到提供含有可接受含量之亞可視微粒(subvisible particle)之調配物的能力。因此，本發明進一步係關於穩定化依那西普調配物，其在M3或T2或T4具有每毫升不超過平均約10,000個尺寸大於5 μm之亞可視微粒。
本發明之穩定化依那西普組合物之其他特徵在於：(a)在M3或T2或T4之以下之SEC分析：大於約90重量%單體含量；及小於約3重量%聚集體含量；及(b)在M3或T2或T4之HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約3重量%；由HIC層析圖之峰2表示的組成之量大於80重量%；且由HIC層析圖之峰3表示的組成之量小於約20重量%，且其中調配物無精胺酸或基本上無精胺酸。
調配物穩定性之其他特徵可在於視情況無或基本上無精胺酸之組合物在M3或T2或T4顯示HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約1%；由HIC層析圖之峰2表示的組成之量大於約95重量%；且由HIC層析圖之峰3表示的組成之量小於約1重量%。符合此等分析準則之調配物不需要精胺酸來穩定。
本發明之視情況無或基本上無精胺酸之較佳穩定化組合物顯示在M3或T2或T4之HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約2%或較佳小於約1%；由HIC層析圖之峰2表示的組成之量大於約95重量%且較佳大於約97%；且由HIC層析圖之峰3表示的組成之
量小於約1重量%，且較佳為0至1%。
如區別於以含有精胺酸之調配物形式提供之市售依那西普，吾人發現令人驚訝的是，根據美國專利第7,648,702號，本文所述及例示之依那西普之調配物實施例不需要精胺酸以便長期穩定，但必要時仍可添加精胺酸。提供未經精胺酸穩定化之依那西普調配物之能力代表對健保系統之可能顯著益處，其藉由向患者及健保提供者提供與需要精胺酸來穩定之目前商業依那西普調配物(亦即Enbrel®)相比可變得以較低成本可得的依那西普之替代調配物來達成。
如本文所用，術語「不穩定性」或類似術語表示依那西普單體在儲存期間經受多種不良轉化之趨勢。此等轉化包括形成寡聚物及高分子量聚集體(下文稱為「聚集體」)，其中基本上完整之依那西普單體的多個複本經由多種非共價吸引(例如靜電交互作用)變得不可逆地彼此締合。儲存期間之不良轉化亦可包括依那西普單體降解為較小片段及/或剪斷物質。理想地，依那西普之調配物應以最大可能程度將調配物在儲存期間導致形成依那西普之聚集體、折疊異常蛋白質、寡聚物及/或片段之趨勢減到最小。由減小形成不期望之聚集體或片段之能力產生的重要益處為藥物之可能毒性及/或免疫原性減小。
本發明之依那西普調配物視情況及較佳無精胺酸或基本上無精胺酸。術語「基本上無精胺酸」意欲意謂精胺酸即使存在亦不有助於調配物中達熟習此項技術者自穩
定觀點來看將其存在判斷為有利或必需的程度之依那西普單體穩定。
此等及其他態樣將據以下描述變得顯而易知，但在不脫離本發明之新穎概念之精神及範疇的情況下可實現其變化及修改。
應瞭解，前述一般說明與以下【實施方式】均僅為例示性及說明性的且不限制如主張之本發明。
現詳細描述本發明之各個實施例。如在說明書及整個申請專利範圍中所用，除非上下文另外明顯規定，否則「一(a/an)」及「該(the)」之含義包括複數個參考物。又，如在說明書及整個申請專利範圍中所用，除非上下文另外明顯規定，否則「在...中(in)」之含義包括「在...中(in)」及「在...上(on)」。另外，本說明書中所用之一些術語在下文得到較特定定義。
本說明書中所用之術語一般具有其在此項技術中、在本發明上下文內及在使用各術語之特定情形中之平常含義。在下文或說明書中別處討論用以所述本發明之某些術語，以向從業者關於實施方式提供其他指導。提供某些術語之同義詞。敘述一或多個同義詞不排除使用其他同義詞。在本說明書任何地方使用實例(包括本文討論之任何術語的實例)僅具有說明性，且決不限制本發明或任
何例示術語之範疇及含義。本發明不限於本說明書中給出之各個實施例。
除非另外定義，否則本文所用之所有技術術語及科學術語均具有與一般技藝人士通常所理解相同之含義。在抵觸之情況下，將以本文件(包括定義)為準。
「約(around)」、「約(about)」或「大約(approximately)」一般意謂在既定值或既定範圍之20%內、10%內、5%、4%、3%、2%或1%內。給出之數值量為近似的，意謂若未清楚規定，則術語「約(around)」、「約(about)」或「大約(approximately)」可經推斷。
術語「依那西普」或「依那西普單體」或「單體」與Enbrel®為同義詞。其係指一種多肽，其為由人類75千道耳頓(p75)腫瘤壞死因子受體(TNFR)之細胞外配位體結合部分連接至人類IgG1之Fc部分組成的二聚融合多肽。其由934個胺基酸組成且表觀分子量為大約150千道耳頓。出於本申請案之目的，術語「依那西普」亦涵蓋胺基酸結構具有不會顯著影響依那西普之功能、效能或親合力之較小修改(包括缺失、添加及/或取代胺基酸)的依那西普。術語「依那西普」涵蓋Enbrel®之所有形式及調配物，包括(但不限於)濃縮調配物、可注射即用調配物；用水、醇及/或其他成分復原之調配物，及其他。
術語「糖」係指單醣、二醣及多醣。糖之實例包括(但不限於)蔗糖、海藻糖、右旋糖及其他。
術語「美洛明」係指具有化學式H3NHCH2(CHOH)4CH2OH
之化合物，其亦稱為1-去氧-1-甲基胺基山梨糖醇；N-甲基-d-還原葡糖胺；及1-去氧-1-甲基胺基-D-葡萄糖醇。
術語「甘露糖基甘油酸酯」、「甘露糖基乳酸酯」、「甘露糖基甘醇酸酯」及「二甘油磷酸酯」為此項技術中所熟知且具有其普遍所接受之含義。以下參考文獻在某種程度上詳細地描述此等化合物：Faria等人，Carbohydrate Res.2008,343：3025-3033；Borges等人，Extremophiles 2002,6：209-216；Faria等人，ChemBioChem 2003,4：734-741；Sawangwan等人，Biotechnol.J.2010,5：187-191；及Pais等人，J.Mol.Biol.2009,394：237-250。本申請以引用之方式併入此等參考文獻中所含的此等化合物之描述。
術語「多元醇」係指含有多個羥基之醇。多元醇之實例包括但不限於甘露糖醇、山梨糖醇及其他。
將術語「長期儲存」理解為意謂醫藥組合物可儲存三個月或三個月以上、六個月或六個月以上，且較佳可儲存一年或一年以上。亦將長期儲存理解為意謂醫藥組合物以液體形式在2-8℃下儲存，或例如在-20℃或-20℃以下冷凍。亦涵蓋組合物可冷凍及解凍一次以上。
關於長期儲存，將術語「穩定」或「穩定化」理解為意謂相對於開始儲存時之組合物活性，醫藥組合物中所含之依那西普不會損失大於20%、或更佳15%、或甚至更佳10%，及最佳5%其活性。
術語「哺乳動物」包括但不限於人類。
術語「醫藥學上可接受之載劑」係指任何習知類型之無毒固體、半固體或液體填充劑、稀釋劑、囊封材料、調配輔助劑或賦形劑。醫藥學上可接受之載劑在所用劑量及濃度下對接受者無毒且與調配物之其他成分相容。
術語「組合物」係指通常含有載劑(諸如醫藥學上可接受之載劑)或賦形劑的混合物，該載劑或賦形劑為此項技術中習知且適用於投與受試者以達成治療、診斷或預防目的。其可包括細胞培養物，其中多肽或聚核苷酸存在於細胞中或培養基中。舉例而言，經口投與之組合物可形成溶液、懸浮液、錠劑、丸劑、膠囊、持續釋放調配物、漱口水或散劑。
術語「醫藥組合物」與「調配物」可互換使用。
術語「治療」係指針對哺乳動物之疾病的藥品之任何投與或應用且包括抑制疾病、阻止其發展、減輕該疾病(例如藉由使其消退)，或復原或修復損失的、失去的或有缺陷的功能；或刺激非有效過程。該術語包括獲得所需藥理學作用及/或生理學作用，涵蓋哺乳動物中病理學病狀或病症之任何治療。該作用就完全或部分預防病症或其症狀而言可具有預防性及/或就部分或完全治癒病症及/或該病症所致之不利影響而言可具有治療性。其包括(1)在可能易患病症但尚無症狀之受試者中預防病症出現或復發；(2)抑制病症，諸如阻止其發展；(3)停止或終止該病症或至少其相關症狀，以使宿主不再罹患該病症或其症狀，諸如使得病症或其症狀消退，例如藉由復原
或修復損失的、失去的或有缺陷的功能，或刺激非有效過程來達成；或(4)減輕、緩和或改善病症，或與此相關之症狀，其中改善係以廣義使用以指參數(諸如炎症、疼痛及/或腫瘤尺寸)量值至少減小。
術語「疾病」係指需要醫學介入或因此需要醫學介入之任何病狀、感染、病症或症候群。此醫學介入可包括治療、診斷及/或預防。
術語「治療有效劑量」係指當投與活受試者時對活受試者達成所需作用之量。舉例而言，投與活受試者之本發明多肽之有效量為預防及/或治療整合素αvβ3介導疾病之量。確切量將視治療目的而定，且將由熟習此項技術者使用已知技術可確定。如此項技術中已知，可能必需針對全身性傳遞相對於局部傳遞、年齡、體重、一般健康情況、性別、膳食、投藥時間、藥物交互作用及病狀嚴重度進行調整，且將由熟習此項技術者用常規實驗可確定。
術語「T1」係指依那西普調配物已於40℃下儲存約一週之時間點。
術語「T2」係指依那西普調配物已於40℃下儲存約兩週之時間點。
術語「T4」係指依那西普調配物已於40℃下儲存約四週之時間點。
術語「M3」總體係指三個時間點，且特定言之係指對於在5℃儲存溫度下儲存約一個月、約兩個月或約三個
月之持續時間後的依那西普調配物所觀察到之分析結果。舉例而言，應將在本文中提及在M3進行之分析理解為意謂此分析係在依那西普調配物已儲存選自約一個月、約二個月或約三個月之持續時間的時間點進行。因此，若在對應於至少一個以下儲存持續時間之時間點觀察到所需值：在5℃下儲存大約一個月、大約兩個月或大約三個月，則在本文中依那西普調配物在M3引出某一分析值或量測值之要求得到滿足。
術語「峰1」、「峰2」及「峰3」當在本文中與HIC層析結果之討論關聯使用時係指美國專利7,294,481中所討論之相同峰1、峰2及峰3。
當包括依那西普之水性及凍乾調配物的含有依那西普(Enbrel®)之醫藥組合物長期儲存時，依那西普活性可因依那西普單體經由聚集及/或化學降解(包括形成片段)之不穩定性而損失或減小。因此，本發明提供依那西普水性調配物之若干實施例，其允許依那西普穩定長期儲存，以使依那西普在儲存過程中以液體狀態或冷凍狀態穩定。所提供之調配物包括(但不限於)不含有精胺酸且不需任何額外步驟(諸如再水合)之調配物。
下文較詳細解釋此等實施例。
所有本發明之組合物均包含依那西普(Enbrel®)。如本申請案之背景章節中所解釋，依那西普為由人類75千道
耳頓(p75)腫瘤壞死因子受體(TNFR)之細胞外配位體結合部分連接至人類IgG1之Fc部分組成的二聚融合多肽。依那西普由934個胺基酸組成。依那西普之Fc組件含有人類IgG1之恆定重鏈2(CH2)域、恆定重鏈3(CH3)域及鉸鏈區。Fc域可含有一個或所有上述域。
適用於儲存於本發明之醫藥組合物中之依那西普可由表現依那西普之活宿主細胞(在抗體情況下，諸如為融合瘤)，或已基因工程改造以產生多肽之宿主細胞(在融合多肽或抗體之情況下)產生。此項技術中熟知基因工程改造細胞以產生多肽之方法。參見例如Ausubel等人編，(1990),Current Protocols in Molecular Biology(Wiley,New York)。此等方法包括將編碼多肽及允許多肽表現之核酸引入活宿主細胞中。此等宿主細胞可為細菌細胞、真菌細胞，或較佳為在培養物中生長之動物細胞。細菌宿主細胞包括(但不限於)大腸桿菌細胞(Escherichia coli cell)。適合大腸桿菌菌株之實例包括：HB101、DH5.α、GM2929、JM109、KW251、NM538、NM539及不能裂解外來DNA之任何大腸桿菌菌株。可使用之真菌宿主細胞包括(但不限於)啤酒酵母菌(Saccharomyces cerevisiae)、甲醇酵母(Pichia pastoris)及麴菌細胞(Aspergillus cell)。可使用之動物細胞株之幾個實例為CHO、VERO、BHK、HeLa、Cos、MDCK、293、3T3及W138。新穎動物細胞株可使用熟習此項技術者熟知之方法(例如藉由轉型、病毒感染及/或選擇)建立。依那西普視情況可由宿主細胞
分泌至培養基中。
經表現依那西普之純化可藉由任何標準方法進行。當依那西普在細胞內產生時，例如藉由離心或超濾來移除微粒碎片。當依那西普分泌至培養基中時，首先可使用標準多肽濃縮過濾器來濃縮此等表現系統之上清液。亦可添加蛋白酶抑制劑以抑制蛋白水解且可包括抗生素以防止微生物生長。
依那西普可使用例如以下來純化：羥磷灰石層析法、凝膠電泳、透析及親和力層析法，及已知或有待發現之純化技術的任何組合，包括(但不限於)蛋白質A層析法、離子交換柱分餾、乙醇沈澱、逆相HPLC、二氧化矽層析法、肝素SEPHAROSET®層析法、陰離子或陽離子交換樹脂層析法(諸如聚天冬胺酸管柱)、層析聚焦、SDS-PAGE及硫酸銨沈澱。
本發明提供一種穩定水性調配物，其包含依那西普及離子型多元醇衍生物賦形劑，其中該賦形劑選自由以下組成之群：美洛明(N-甲基-D-還原葡糖胺)、甘露糖基甘油酸酯、葡苷基甘油酸酯、甘露糖基乳酸酯、甘露糖基甘醇酸酯及二甘油磷酸酯。
較佳地，在該實施例或態樣中，本發明為一種依那西普之水性穩定化調配物，其包含：依那西普；及阻滯該調配物中依那西普之不穩定性、聚集及破碎的穩定化成分，該穩定化成分包含：(a)美洛明；或(b)與蔗糖組合之
美洛明；或(c)與氯化鈉組合之美洛明；或(d)與氯化鈉及蔗糖組合之美洛明。
美洛明通常用作小分子賦形劑。吾人現已令人驚訝地發現，美洛明亦能夠穩定化含有大蛋白質(諸如依那西普)之水性醫藥組合物。
咸信美洛明減小依那西普以非所欲三級或四級錯合物形式締合之傾向，且因此減小依那西普之聚集。咸信聚集減小持續一長段時間，例如兩年或兩年以上。不意欲受特定理論約束，咸信包括美洛明之離子型多元醇衍生物能夠藉由三種不同機制之組合穩定化含有依那西普之水性醫藥組合物。首先，其可以與甘露糖醇、蔗糖及山梨糖醇相同之方式充當排除溶解物，進而增加構形穩定性。其次，帶電溶質可改變膠態穩定性，進而減小自身締合之傾向，進而減慢聚集。再次，此等離子型多元醇衍生物帶電時接近中性pH值，其可如精胺酸一般充當鹽溶劑(salting-in agent)，進而可能再溶解聚集體。美洛明之穩定化效應不限於減少聚集體，還可涉及穩定化含有依那西普單體之調配物中的該單體之其他態樣。
本發明之醫藥組合物可藉由組合純化之依那西普與離子型多元醇衍生物(較佳為美洛明)製備。此外，需要時可添加緩衝劑、張力修飾劑及另一賦形劑及其他常用無活性成分。為簡單起見，其稍後在說明書中較完整地討論。一般技藝人士應瞭解，包括於組合物中之各種組分之組合可以任何適當順序進行。舉例而言，緩衝劑可首先、
在中間或最後添加，且張力修飾劑亦可首先、在中間或最後添加。一般技藝人士亦應瞭解，一些化學物質可能在某些組合中不相容，因此，輕易經具有類似性質但在相關混合物中相容之不同化學物質取代。
在一較佳實施例中，所提供調配物中美洛明之濃度較佳在約0.1%(w/v)至40%(w/v)之間，更佳約1%至約20%，更佳約2%至約10%，甚至更佳約2%至約5%。
美洛明可獲自商業供應商。
一較佳實施例包含約25 mg/ml至約75 mg/ml依那西普、約1-30 mM磷酸鈉；至多約10%美洛明；視情況選用之至多約5重量%蔗糖；及視情況選用之至多約100 mM氯化鈉，其中該組合物之pH值為約6.0至7.0，及較佳約6.0至約6.6，且最佳約6.3至約6.5。
美洛明穩定化依那西普組合物的特徵較佳在於，在T2之SEC分析，其中：單體含量大於約85重量%；聚集體含量小於約3重量%；及片段3含量小於約8重量%。
其中存在諸如美洛明之離子型多元醇衍生物來穩定之更佳依那西普調配物為特徵在於以下之調配物：(a)在T4之大於約90重量%、91重量%、92重量%、93重量%、94重量%、95重量%、96重量%或97重量%單體含量；及小於約3重量%、2重量%或1重量%聚集體含量之SEC分析；及(b)在T2之HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約4重量%、3重量%、2重量%或1重量
%；由HIC層析圖之峰2表示的組成之量大於80重量%、81重量%、82重量%、83重量%、84重量%或85重量%；且由HIC層析圖之峰3表示的組成之量小於約20重量%、19重量%、18重量%、17重量%、16重量%、15重量%、14重量%或13重量%；及(c)在T4之HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約3重量%、2重量%或1重量%；由HIC層析圖之峰2表示的組成之量大於80重量%、81重量%、82重量%、83重量%、84重量%或85重量%；且由HIC層析圖之峰3表示的組成之量小於20重量%、19重量%、18重量%、17重量%、16重量%、15重量%、14重量%或13重量%。
用美洛明穩定化之尤其較佳依那西普調配物的特徵更佳在於在T4或T2具有以下HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約1%；由HIC層析圖之峰2表示的組成之量大於約99重量%；且由HIC層析圖之峰3表示的組成之量小於約1重量%。
下文實例中定義術語「SEC」、「T2」、「T4」、「HIC」、「單體含量」、「聚集體」及「片段3」、「峰1」、「峰2」及「峰3」。
在其他實施例中，調配物中之美洛明可經以下者之另一離子型多元醇衍生物置換：山梨糖醇、甘油或甘露糖醇，諸如甘露糖基甘油酸酯、葡苷基甘油酸酯、甘露糖基乳酸酯、甘露糖基甘醇酸酯及二甘油磷酸酯(約0.1%
至約40%)。
無精胺酸且顯示如上所述之分析性質的較佳美洛明穩定化依那西普調配物包含約25 mg/ml至約75 mg/ml依那西普；約0.5重量%美洛明；約25 mM磷酸鹽；約1%蔗糖；及約100 mM氯化鈉。
無精胺酸且顯示如上所述之分析性質的另一較佳美洛明穩定化依那西普調配物包含約50 mg/ml依那西普；約5重量%美洛明；約25 mM磷酸鹽。
儘管本發明不排除使用精胺酸，但根據本發明之包含諸如美洛明之離子型多元醇衍生物來穩定之依那西普調配物較佳無或基本上無精胺酸。
本發明之調配物亦可包括醫藥組合物之緩衝劑、張力修飾劑、賦形劑、醫藥學上可接受之載劑及其他常用之無活性成分。為簡單起見，其稍後在申請案中較完整地討論。
緩衝劑將pH值維持在所需範圍內。適合緩衝劑包括組胺酸、磷酸鉀、檸檬酸鈉或檸檬酸鉀、順丁烯二酸、乙酸銨、參-(羥甲基)-胺基甲烷(參)、各種形式之乙酸鹽及二乙醇胺。調配物中緩衝劑之濃度較佳在約1 mM至約1M之間，且更佳為約10 mM至約200 mM。此項技術中熟知緩衝劑且其藉由已知方法製造且可獲自商業供應商。
適合緩衝劑之實例為磷酸鹽、組胺酸、檸檬酸鹽、順
丁烯二酸鹽、酒石酸鹽、丁二酸鹽、乙酸鹽、參-(羥甲基)-胺基甲烷(參)、碳酸氫鹽。
在一較佳實施例中，緩衝劑為磷酸鈉。
在一較佳實施例中，醫藥組合物之pH值處於或接近於生理程度。因此，所提供之組合物的pH值較佳在約5.8與約8.4之間；且甚至更佳在約6.2與約7.4之間。一般技藝人士應瞭解，必要時可調節pH值以最大化特定調配物中依那西普之穩定性及溶解性。因此，處於生理範圍外、但患者可耐受之pH值的依那西普調配物亦在本發明之範疇內。
張力修飾劑為有助於溶液滲透壓之分子。較佳調節醫藥組合物之滲透壓以最大化活性成分之穩定性及/或最小化投藥時之患者不適性。一般較佳的是，醫藥組合物與血清等張，亦即具有相同或類似滲透壓，其藉由添加張力修飾劑來達成。
在一較佳實施例中，所提供之調配物的滲透壓為約180 mOsM至約420 mOsM。然而，應瞭解，據特定條件需要，滲透壓可較高或較低。
適用於修飾滲透壓之張力修飾劑之實例包括(但不限於)胺基酸(不包括精胺酸)(例如半胱胺酸、組胺酸及甘胺酸)、鹽(例如氯化鈉、氯化鉀及檸檬酸鈉)及/或醣(例如蔗糖、葡萄糖及甘露糖醇)。
較佳張力修飾劑為甘胺酸、丙胺酸、氯化鈉、氯化鉀及硫酸鈉。
在一較佳實施例中，調配物中張力修飾劑之濃度較佳在約1 mM至約1M之間，且更佳為約10 mM至約200 mM。此項技術中熟知張力修飾劑且其藉由已知方法製造且可獲自商業供應商。
亦可將在呈溶液形式(亦呈乾燥形式或冷凍形式)之同時穩定化多肽之亦稱作化學添加劑、共溶質或共溶劑之賦形劑添加至醫藥組合物中。此項技術中熟知賦形劑且其藉由已知方法製造且可獲自商業供應商。
適合賦形劑之實例包括但不限於糖/多元醇，諸如：蔗糖、乳糖、甘油、木糖醇、山梨糖醇、甘露糖醇、麥芽糖、肌醇、海藻糖、葡萄糖；聚合物，諸如：血清白蛋白(牛血清白蛋白(BSA)、人類SA或重組HA)、右旋糖酐、聚(乙烯醇)PVA、羥丙基甲基纖維素(HPMC)、聚(伸乙基亞胺)、明膠、聚乙烯吡咯啶酮(PVP)、羥乙基纖維素(HEC)；非水性溶劑，諸如：多元醇(例如PEG及甘油)及二甲基甲醯胺(DMF)；胺基酸，諸如：脯胺酸、L-絲胺酸、麩胺酸鈉、丙胺酸、甘胺酸、鹽酸離胺酸、肌胺酸及γ-胺基丁酸；界面活性劑，諸如：Tween®-80(聚山梨醇酯80)、Tween®-20(聚山梨醇酯20)、SDS、聚山梨醇酯、泊洛沙姆(poloxamer)；及雜項賦形劑，諸如：磷酸鉀、乙酸鈉、硫酸銨、硫酸鎂、硫酸鈉、三甲胺N-氧化物、甜菜鹼、金屬離子(例如鋅、鈣及鎂)、CHAPS、單月桂酸鹽、2-O-β-甘露甘油酸酯或上述各者之任何組合。
較佳賦形劑為蔗糖、乳糖、甘油、木糖醇、山梨糖醇、
甘露糖醇、麥芽糖、肌醇、海藻糖、葡萄糖、牛血清白蛋白(BSA)、人類血清白蛋白(HSA)、重組白蛋白、右旋糖酐、PVA、羥丙基甲基纖維素(HPMC)、聚(伸乙基亞胺)、明膠、聚乙烯吡咯啶酮(PVP)、羥乙基纖維素(HEC)、聚乙二醇、乙二醇、甘油、丙胺酸、甘胺酸、鹽酸離胺酸、肌胺酸、SDS、聚山梨醇酯20、聚山梨醇酯80、泊洛沙姆188、三甲胺N-氧化物、甜菜鹼、鋅離子、鈣離子、鎂離子、CHAPS、單月桂酸蔗糖及2-O-β-甘露甘油酸酯。
本發明之調配物中一或多種賦形劑之濃度較佳在約0.001重量%至5重量%之間，更佳為約0.1重量%至2重量%。
在另一實施例中，本發明提供一種治療哺乳動物之方法，其包含向哺乳動物投與治療有效量之本發明之醫藥組合物，其中該哺乳動物患有可用依那西普有利治療之疾病或病症。
在一較佳實施例中，依那西普源自與用該組合物治療之哺乳動物物種相同之哺乳動物物種。
在一較佳實施例中，哺乳動物為人類。
可用所提供之組合物治療的疾病或病症包括(但不限於)類風濕性關節炎、牛皮癬性關節炎、強直性脊椎炎、韋格納病(Wegener's disease)(肉芽腫病)、克隆氏病(Crohn's disease)(或發炎性腸疾病)、慢性阻塞性肺病(COPD)、C型肝炎、子宮內膜異位、哮喘、惡病質、牛
皮癬及異位性皮膚炎。可用本發明之組合物治療的其他疾病或病症包括WO 00/62790、WO 01/62272、美國專利申請案第2001/0021380號及美國專利7,648,702 B2中所述之疾病或病症，該等案之相關部分係以引用的方式併入本文中。
所提供之醫藥組合物可投與需要藉由全身注射(諸如藉由靜脈注射)；或藉由注射或施用於相關部位(當該部位在手術中暴露時，諸如藉由直接注射，或直接施用於該部位)；或藉由局部施用來治療之受試者。
在一個實施例中，本發明提供一種治療及/或預防類風濕性關節炎之方法，其包含向有需要之哺乳動物投與治療有效量之一種所提供之依那西普組合物。
所提供之組合物中依那西普之治療有效劑量將視待治療之病狀、病狀嚴重度、先前療法及患者之臨床史及對治療劑之反應而定。可根據主治醫師之判斷來調整適當劑量以使其可一次性或歷經一系列投藥來投與患者。
在一個實施例中，成人之每劑有效依那西普量為約1-500 mg/m2，或約1-200 mg/m2，或約1-40 mg/m2或約5-25 mg/m2。
或者，可投與均一劑量，其量可介於2-500毫克/劑、2-100毫克/劑或約10-80毫克/劑之範圍內。
若每週投與劑量一次以上，則例示性劑量範圍係與前述劑量範圍相同或低於前述劑量範圍，且較佳以25-100毫克/劑之每劑範圍每週投與兩次或兩次以上。
在另一實施例中，容許之注射投藥劑量含有80-100毫克/劑，或者含有80毫克/劑。
劑量可每週、每兩週或間隔若干週(例如2至8週)來投與。
在一個實施例中，藉由單次皮下(SC)注射來投與25 mg/ml至75 mg/ml依那西普。
在一些情況下，將於至少三週之期間每週一至三次藉由投與至多約100 mg醫藥組合物之劑量來獲得患者病狀改良。可能必需治療較長期間以誘導所需改良程度。
對於不可治癒之慢性病狀，可無限繼續該方案。對於兒科患者(4歲至17歲)，適合方案可包括投與0.4 mg/kg至5 mg/kg依那西普之劑量，每週一或多次。
在另一實施例中，本發明之醫藥調配物可以散裝調配物形式製備，因此將醫藥組合物之組分調節為高於投藥所需之組分且在投藥之前適當稀釋。
醫藥組合物可以單一的治療劑形式投與或需要時與其他療法組合投與。因此，在一個實施例中，所提供之治療及/或預防方法係與投與治療有效量之另一活性劑組合使用。其他活性劑可在投與本發明之醫藥組合物之前、期間或之後投與。另一活性劑可作為所提供之組合物之一部分或者作為個別調配物來投與。
投與所提供之醫藥組合物可以各種方式達成，包括非經腸、經口、經頰、舌下、經鼻、經直腸、腹膜內、皮內、經皮、皮下、靜脈內、動脈內、心內、室內
(intraventricular)、顱內、氣管內、鞘內投藥、肌肉內注射、玻璃體內注射及局部施用。
本發明之醫藥組合物尤其適用於非經腸投與，亦即皮下、肌肉內、靜脈內、腹膜內、腦脊髓內、關節內、滑膜內、玻璃體內及/或鞘內投與。非經腸投與可藉由快速注射或連續輸注來達成。用於注射之醫藥組合物可以單位劑型呈現，例如在安瓿中或在多劑量容器中，添加有防腐劑。另外，已開發出許多最新藥物傳遞方法且本發明之醫藥組合物適用於使用此等新穎方法來投與，例如Inject-ease®、Genject®、注射筆(諸如GenPen®)，及無針裝置(諸如MediJector®及BioJector®)。本發明之醫藥組合物亦可適於有待發現之投藥方法。亦參見Langer,1990,Science,249：1527-1533。
所提供之醫藥組合物亦可調配為儲存式製劑。此等長時間作用調配物可藉由植入(例如皮下或肌肉內)或藉由肌肉內注射來投與。因此，舉例而言，調配物可用以下修飾：適合之聚合或疏水性物質(例如呈可接受之油中乳液之形式)或離子交換樹脂，或呈微溶衍生物形式，例如呈微溶鹽形式。
醫藥組合物必要時可在可含有一或多個含有活性成分之單位劑型的小瓶、包裝或分配裝置中呈現。在一個實施例中，分配裝置可包含具有即用於注射之單次劑量液體調配物之注射器。注射器可附有投藥說明書。
在另一實施例中，本發明係關於套組或容器，其含有
本發明之水性醫藥組合物。水性醫藥組合物中多肽之濃度可在寬範圍改變，但一般在約0.05微克/毫升至約20,000微克/毫升(μg/ml)水性調配物之範圍內。套組亦可附有使用說明書。
本發明更詳細地描述於以下實例中，因為其許多修改及變化將對熟習此項技術者顯而易知，所以該等實例意欲僅具有說明性。
用美洛明穩定化之依那西普調配物可通常使用下文描述之程序來製備及測試。
稱重各固體調配物組分至既定體積調配物緩衝液所需之量。將此等組分合併於能夠裝載及量測調配物緩衝液之既定體積的燒杯或容器中。將體積等於大約¾目標既定調配物緩衝液之去離子水添加至燒杯中，接著溶解該等組分。使用1 M氫氧化鈉及/或1 M氯化氫將緩衝液pH值調節至目標調配物pH值。接著經由添加去離子水使最終調配物緩衝液體積上升至目標體積。將依那西普蛋白溶液置於透析材料外殼(諸如Thermo Scientific Slide-A-Lyzer MINI透析單元10,000 MWCO)中，接著將其置為在4℃下與所需調配物緩衝液接觸12小時。調配物緩衝液體積與蛋白質溶液體積之比應不小於1000：1。接
著將透析外殼及其所含之蛋白質溶液置於第二個等體積調配物緩衝液中在4℃下持續另外12小時。自透析材料外殼中移除所得蛋白質溶液，且使用紫外線光譜法測定蛋白質濃度。使用離心(諸如Amicon Ultra 10,000 MWCO離心深縮機)及/或用調配物緩衝液稀釋將蛋白質濃度調節至所需程度。
可在各個時間點藉由尺寸排阻層析法(SEC)、變性SEC(dSEC)、疏水相交互作用層析法(HIC)、十二烷基磺酸鈉聚丙烯醯胺凝膠電泳(SDS-PAGE)測試組合物之長期穩定性，且測試其結合及生物活性。生物活性可藉由許多熟知分析來量測。
舉例而言，尺寸排阻層析法之技術描述於Hawe等人，Pharm.Res.2011,28：2302及/或van Marrschalkerweerd等人，Eur.J.Pharm.Biopharm.2011,78：213中。類似地，一般技藝人士亦熟知變性尺寸排阻層析法、疏水交互作用層析法及十二烷基磺酸鈉-聚丙烯醯胺凝膠電泳之技術。
咸信組合物將穩定兩年或兩年以上之期間。
步驟1 . 細胞擴增。以一種在此項技術已知之方式，產生足夠數目細胞以便接種生產生物反應器所必需之細胞擴增係使用表現依那西普融合蛋白之CHO細胞的純系來進行。此表現過程之產物(收集之細胞培養液)產生正確折疊之依那西普以及不正確折疊及/或聚集之依那西普以及其他雜質之混合物。對包含此蛋白質混合物之收集之細胞培養液進行清潔劑病毒不活化。
步驟2 . 親和力層析法。以熟知方式使用習知蛋白質A親和管柱對上述步驟1中獲得的收集之細胞細胞培養物進行親和力層析。產物回收率係大約85%。所得產物為包含正確折疊之依那西普、不正確折疊之依那西普，及/或正確及/或不正確折疊之依那西普之聚集體，或蛋白質片段的複雜蛋白質混合物。將獲自此蛋白質A親和管柱
純化步驟之產物調節至pH 3.5，接著進行病毒不活化步驟。在病毒不活化之後，將產物調節至pH 5.5，接著以已知方式使用市售膠囊過濾器進一步淨化。
步驟3A . 混合模式陽離子交換層析法。使用31.8 L(45 cm直徑×20 cm床高)填充床GE Healthcare Capto MMC層析管柱以純化上文步驟2中所得之產物。在使用之前，管柱係與2 CV 25 mM乙酸鹽(pH 5.5)平衡且用2 CV 0.1 N NaOH、1 M NaCl消毒且以2 CV 25 mM乙酸鹽、0.7 M NaCl(pH 5.5)中和。接著使管柱與8-10 CV 25 mM乙酸鹽(pH 5.5)平衡直至流出液為pH 5.5及3.5 mS/cm為止。用WFI將上文步驟2之蛋白質A池稀釋至6 mS/cm，且在各循環塗覆於負載至多15 g/L培養基之管柱。在200 cm/h之線速度下操作管柱以得到6分鐘滯留時間。負載之後，以2 CV 25 mM乙酸鹽(pH 5.5)洗滌管柱。接著用8.5 CV 15%至85%梯度之25 mM乙酸鹽(pH 5.5)至25 mM乙酸鹽、0.7 M NaCl(pH 5.5)溶離產物。在0.15 OD(A280，1.0 cm路徑長度)開始收集產物，且在50%峰最大值時結束收集。溶離液體積為大約5 CV。用2 CV 10 mM Tris、1 M NaCl(pH 8.0)自管柱汽提殘餘產物及污染物且棄置。使用Millipore Opticap XL10,0.22 μm Durapore膠囊過濾器(0.69 m2)過濾獲自混合模式管柱之產物。獲自此步驟之產物呈現在步驟2獲得之蛋白質A物質約70%之回收率
步驟3B . 混合模式陰離子交換層析法。使用27.0 L(45 cm直徑×17 cm床高)填充床GE Healthcare Capto Adhere
層析管柱以進一步純化上文步驟3A中所得之產物。在使用之前，管柱係與2 CV 25 mM Tris(pH 8.0)平衡且用2 CV 0.1 N NaOH、1 M NaCl消毒，且以2 CV 25 mM Tris(pH 8.0)中和及平衡。在產物負載之前，管柱與3 CV 10 mM Tris(pH 8.0)平衡。每公斤池用約0.045 kg 1 M Tris(pH 8.3)將上文步驟3A之Capto MMC池調節至pH 8.1。用WFI，以1：3.8線內稀釋上文步驟3A之產物以將傳導率調節為12.0 mS/cm及pH 8.0。接著將所得物質塗覆於負載至多15 g/L培養基之管柱。在170 cm/h之線速度下操作管柱以得到6分鐘滯留時間。負載之後，以2 CV 25 mM Tris(pH 8.0)洗滌管柱。接著用10 CV梯度(20%至90%)25 mM Tris(pH 8.0)至10 mM Tris、1 M NaCl(pH 8.0)溶離產物。在0.15 OD(A280，1.0 cm路徑長度)開始收集產物，且在25%峰最大值時結束收集。溶離液體積為4-6 CV。使用市售膠囊過濾器過濾溶離產物，接著以已知方式進行病毒過濾及切向流過濾步驟。自步驟3B(包括最終病毒及切向流過濾步驟)之總產物回收率為大約68%。在過濾步驟之前量測之產物回收率為約75%。
分析：發現此實例中所得之最終過濾產物如藉由HIC測定具有大於約90重量%正確折疊之依那西普；如藉由HIC測定具有小於5重量%不正確折疊之依那西普物質；藉由HIC分析具有小於約3重量%剪斷物質(咸信為依那西普片段，其中其TNFR部分已截斷)，及如藉由尺寸排阻層析法測定具有大於95重量%之正確與不正確折疊之
依那西普的組合量。
在透析及濃縮之後，在生物安全櫃(bio safety cabinet)中無菌過濾上文例示之依那西普調配物之樣本。使用經滅菌吸管及高壓處理過的吸管尖，將依那西普調配物之樣本轉移至預標記及高壓處理過的1 mL凍乾小瓶中。將小瓶塞上無菌丁基塞子且用鋁蓋捲邊。接著將所有小瓶均轉移至熱穩定爐中。對樣本進行兩個熱穩定性方案：(1)在40℃下兩週及(2)在25℃下四週。在整個本說明書中，此兩個溫度方案分別指定為「T2」及「T4」。
使用尺寸排阻層析法(SEC)、高效液相層析法(其中分析物按尺寸分離)之熟知技術分析本文揭示之依那西普調配物(參見Rogner,M.(2000).Size Exclusion Chromatography.Protein Liquid Chromatography.M.Kastner.Amsterdam,Elsevier.61：89-145.)。為評估上述依那西普樣本之熱穩定性，依據以下文獻藉由SEC方法檢查該等樣本：(van Maarschalkerweerd,A.,G.J.Wolbink等人，(2011).「Comparison of analytical methods to detect instability of etanercept during thermal stress testing.」European Journal of Pharmaceutics and Biopharmaceutics 78(2)：213-221)。將移動相緩衝液製備
為含有50 mM單水合磷酸二氫鈉及150 mM精胺酸。使用1 M HCl將pH值調節至6.5。所有分離均使用Tosoh TSK-Gel SWxl 6 mm×4 cm guard管柱(目錄號8543)線性連接於Tosoh TSK-Gel G4000 SWxl 7.8 mm×30 cm(目錄號8542)進行。為進行分離，將管柱調為室溫(23℃)且與流動速率為0.5 mL/min之移動相平衡。使用自動取樣器將5微升50 mg/mL依那西普調配物注射於管柱上。歷經30分鐘在0.5毫升/分鐘之流動速率下實現分離。在此期間在280 nm之波長下監測管柱溶離劑。
所有積分均使用Chromeleon軟體(Dionex)進行。在積分之前，自所有層析圖均減去不含依那西普之緩衝液之SEC層析圖。所有積分均在12分鐘與26分鐘滯留時間之間進行。將若干參數用以定義峰。所偵測到之峰的最小面積設為0.05 mAu*min。用於峰偵測之二維敏感性設定0.01 mAu及75秒。使用手動積分工具手動添加峰肩。兩步手動調節所有偵測到之峰。第一，將峰基線(峰之底部邊界)調節為水平。第二，將峰基線之垂直位置調節為層析圖基線之垂直位置。層析圖基線值係定義為不存在分析物時之信號。不存在分析物時之信號係定義為在12分鐘滯留時間時之吸光率(mAu)。
在上述依那西普調配物之SEC分析中，識別出三種SEC層析溶離份且加以研究。所分析溶離份按自SEC管柱溶
離之次序為：(1)代表可能經由完整依那西普分子中之非共價靜電吸引組裝之完整依那西普TNFR：FC融合蛋白之聚集體的高分子量溶離份(下文為「聚集體」或聚集體含量)；(2)代表完整依那西普TNFR：Fc融合蛋白之單體含量(下文稱作「單體含量」之「單體」)；(3)可能代表依那西普分子之一個片段或片段群體的溶離份，其中TNFR：分子融合蛋白之一部分已變得自單體裂解；損失在分子鉸鏈區之融合蛋白之Fab部分之一臂。如藉由SEC量測，將最常見之片段或剪斷物質稱為片段3。在進行SEC分析時，將觀察到聚集體首先溶離，接著單體溶離，接著片段3溶離。
以下表展示藉由如上所述之SEC分析測定之聚集體、單體及片段3之相對量。
可以此項技術已知及美國專利7,294,481(以引用的方式併入本文中)中一般描述之方式進行HIC層析。在t0(在5℃下製備24小時內)及又在25℃下儲存兩週後(t2)或在25℃下儲存4週後評估樣本。在本發明之調配物之HIC層析圖中，咸信HIC層析圖中之峰1為「片段3」或包括「片段3」，其係使用如上文在SEC資料之討論中所提及
之SEC來識別及定量；峰2為如上文在SEC資料之討論中提及之依那西普單體；且峰3包括如上文在SEC資料之討論中提及之「聚集體」。應進一步瞭解，如本文中所用，術語「峰1」、「峰2」及「峰3」亦構成對美國專利7,294,481(以引用的方式併入本文中)之第4圖中提及及揭示之HIC峰1、峰2及峰3的提及。
據對說明書之考慮及對本文所揭示之本發明的實踐，熟習此項技術者將顯而易知本發明之其他實施例。意欲將說明書及實例視為僅具有例示性，本發明之正確範疇及精神由以下申請專利範圍指示。
Claims (11)
- 一種依那西普(etanercept)之水性穩定化調配物，其包含：依那西普；及阻滯該調配物中該依那西普之不穩定性、聚集及/或破碎的穩定化成分，該等穩定化成分包含以下至少一者：(a)美洛明(meglumine)；或(b)與蔗糖組合之美洛明；或(c)與氯化鈉組合之美洛明；或(d)與氯化鈉及蔗糖組合之美洛明。
- 如申請專利範圍第2項之組合物，其進一步包含一或多種選自緩衝劑、張力修飾劑及賦形劑之其他組分。
- 如申請專利範圍第3項之組合物，其中該穩定劑基本上由以下至少一者組成：(a)美洛明；或(b)與蔗糖組合之美洛明；或(c)與氯化鈉組合之美洛明；或(d)與氯化鈉及蔗糖組合之美洛明；且其中該調配物視情況無或基本上無精胺酸，且該調配物引出特徵在於以下至少一者之長期儲存穩定性：在M3或T2或T4之以下之SEC分析：大於約90重量%單體含量；小於約3重量%聚集體含量；及小於約5重量%片段3含量：及在M3或T2或T4之HIC分析，其中由HIC層析圖之峰1表示的組成之量小於約3重量%；由該HIC層析圖之峰2表示的該組成之該量大於80重量%；且由該HIC層析圖之峰3表示的該組成之該量小於約20重量%。
- 如申請專利範圍第2項之調配物，其視情況無或基本 上無精胺酸，該調配物包含約25 mg/ml至約75 mg/ml依那西普、約1-30 mM磷酸鈉；至多約10%美洛明；視情況選用之至多約5重量%蔗糖；及視情況選用之至多約100 mM氯化鈉，其中該組合物之pH值為約6.0至6.6；且其中該組合物之特徵在於，在M3或T2或T4之以下之SEC分析，其中：該單體含量大於約85重量%；聚集體含量小於約3重量%；及片段3含量小於約8重量%。
- 如申請專利範圍第4項之組合物，其引出特徵在於以下之長期儲存穩定性：(a)在M3或T2或T4之以下之SEC分析：大於約90重量%單體含量；及小於約3重量%聚集體含量；及(b)在M3或T2或T4之HIC分析，其中由該HIC層析圖之峰1表示的該組成之該量小於約4重量%；由該HIC層析圖之峰2表示的該組成之該量大於約80重量%；且由該HIC層析圖之峰3表示的該組成之該量小於約20重量%；及
- 如申請專利範圍第3項之組合物，其具有在M3或T2或T4之HIC分析，其中由該HIC層析圖之峰1表示的該組成之該量小於約1重量%；由該HIC層析圖之峰2表示的該組成之該量大於約95重量%；且由該HIC層析圖之峰3表示的該組成之該量小於約3重量%。
- 如申請專利範圍第3項之組合物，其包含：約50 mg/ml依那西普；約0.5重量%美洛明；約10 mM至30 mM磷酸鹽；約1%蔗糖；及約100 mM氯化鈉。
- 如申請專利範圍第3項之組合物，其包含：約50 mg/ml依那西普；約5重量%美洛明；約10 mM至30 mM磷酸鹽；且無或基本上無蔗糖及氯化鈉。
- 如申請專利範圍第3項之組合物，其引出特徵在於以下之長期儲存穩定性：在M3或T2或T4之HIC分析，其中由該HIC層析圖之峰2表示的該組成之該量大於或等於約95重量%；且其中若該HIC層析圖上存在峰3，則由峰3表示之該組成之該量小於或等於約1重量%。
- 如申請專利範圍第3項之組合物，其在M3或T2或T4具有每毫升不超過平均約10,000個尺寸大於5 μm之亞可視微粒(subvisible particle)。
- 如申請專利範圍第1項之組合物，其不含精胺酸，或基本上無精胺酸，其中該組合物在M3或T2或T4引出符合一或兩個以下準則之長期儲存穩定性：(A)如藉由以下量測：(i)該組合物中聚集體、單體及片段3之量的SEC分析(如本說明書中所定義)及(ii)該組合物中對應於該HIC層析圖之峰1、峰2及峰3之物質之量的HIC分析(如本說明書中所定義)，穩定性與以商標Enbrel®銷售之市售依那西普相當或比其更佳；及(B)HIC層析圖，其中(i)峰3不存在或基本上不存在，且(ii)峰2佔該組合物之約95重量%以上；基本上不含對應於聚集體之峰的SEC層析圖；及該單體含量佔該組合物之至少約95重量%的SEC層析圖。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI609877B (zh) * | 2012-09-11 | 2018-01-01 | 柯赫勒斯生物科學有限公司 | 高純度及優良產量之正確折疊之恩博（ｅｔａｎｅｒｃｅｐｔ） |
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