JP2008201801A - アルブミンを含有していない新規の第viii因子処方物 - Google Patents
アルブミンを含有していない新規の第viii因子処方物 Download PDFInfo
- Publication number
- JP2008201801A JP2008201801A JP2008120035A JP2008120035A JP2008201801A JP 2008201801 A JP2008201801 A JP 2008201801A JP 2008120035 A JP2008120035 A JP 2008120035A JP 2008120035 A JP2008120035 A JP 2008120035A JP 2008201801 A JP2008201801 A JP 2008201801A
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- factor viii
- nacl
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- present
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Classifications
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- A—HUMAN NECESSITIES
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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Abstract
【解決手段】第VIII因子に加えて以下の処方賦形剤:
マンニトール、グリシン、およびアラニンからなる群より選択される4%から10%の充填剤;
スクロース、トレハロース、ラフィノース、およびアルギニンからなる群より選択される1%から4%の安定化剤;
1mM〜5mMのカルシウム塩;
100mM〜300mMのNaCl;ならびに
約6〜8のpHを維持するための緩衝剤;
を含有する、アルブミンを添加することなく処方された第VIII因子組成物。
【選択図】なし
Description
第VIII因子は、血液の凝固を導く反応のカスケードにおいて補因子として作用する、血漿中に見出されるタンパク質である。血液中の第VIII因子活性の量の欠乏は、主に男性が罹患する遺伝状態である、血友病Aとして公知の凝固障害を生じる。血友病Aは、ヒトの血漿に由来するかまたは組換えDNA技術を使用して製造された第VIII因子の治療用調製物で現在処置されている。このような調製物は、放血のエピソードに応答して(要求があり次第治療)、または制御されていない放血を予防するために頻繁に一定の間隔で(予防)のいずれかで、投与される。
Holdings Cambridge Limitedに譲渡)は、糖トレハロースを含有する処方物を記載している。これらの処方物は、以下を含有する:(1)0.1MのNaCl、15mMの塩化カルシウム、15mMのヒスチジン、および1.27M(48%)のトレハロース;または(2)0.011%の塩化カルシウム、0.12%のヒスチジン、0.002%のTris、0.002%のTween 80、0.004%のPEG 3350、7.5%のトレハロース、および0.13%または1.03%のいずれかのNaCl。
本発明は、アルブミンの非存在下で安定である治療用の第VIII因子組成物に関する。詳細には、本発明は、第VIII因子に加えて以下を含有する第VIII因子組成物を含む:マンニトール、グリシン、およびアラニンからなる群より選択される4%から10%の充填剤;スクロース、トレハロース、ラフィノース、アルギニンからなる群より選択される1%から4%の安定化剤;1mMから5mMのカルシウム塩;100mMから300mMのNaCl;ならびに約6から8の間のpHを維持するための緩衝剤。この組成物はさらに、ポリソルベート20、ポリソルベート80、Pluronic F68、またはBrij 35のような界面活性剤を含む。界面活性剤がポリソルベート80である場合は、これは、0.1%未満の量で存在する。
・本発明はさらに、以下を提供し得る:
・(項目1) 第VIII因子に加えて以下の処方賦形剤:
マンニトール、グリシン、およびアラニンからなる群より選択される4%から10%の充填剤;
スクロース、トレハロース、ラフィノース、およびアルギニンからなる群より選択される1%から4%の安定化剤;
1mM〜5mMのカルシウム塩;
100mM〜300mMのNaCl;ならびに
約6〜8のpHを維持するための緩衝剤;
を含有する、アルブミンを添加することなく処方された第VIII因子組成物。
・(項目2) 界面活性剤をさらに含有する、項目1に記載の第VIII因子組成物。
・(項目3) 上記界面活性剤が、ポリソルベート20、ポリソルベート80、Pluronic F68、およびBrij35からなる群より選択される、項目2に記載の第VIII因子組成物。
・(項目4) 上記界面活性剤がポリソルベート80であり、そしてここで、上記ポリソルベート80が0.1%未満の量で存在する、項目3に記載の第VIII因子組成物。
・(項目5) 上記界面活性剤が約0.03%の量で存在する、項目1〜4に記載の第VIII因子組成物。
・(項目6) 上記緩衝剤が、Tris、BIS−Tris Propane、ヒスチジン、PIPES、MOPS、HEPES、MES、およびACESからなる群より選択される、項目1〜5に記載の第VIII因子組成物。
・(項目7) 上記緩衝剤がTrisを含む、項目6に記載の第VIII因子組成物。
・(項目8) 上記Trisが約20mMの量で存在する、項目7に記載の第VIII因子組成物。
・(項目9) 上記緩衝剤が約10mMと約50mMの間のヒスチジンを含む、項目6に記載の第VIII因子組成物。
・(項目10) 上記ヒスチジンが約25mMの量で存在する、項目9に記載の第VIII因子組成物。
・(項目11) 抗酸化剤をさらに含有する、項目1〜10に記載の第VIII因子組成物。
・(項目12) 上記抗酸化剤がグルタチオンである、項目11に記載の第VIII因子組成物。
・(項目13) 上記グルタチオンが約0.05mg/ml〜約1.0mg/mlの量で存在する、項目12に記載の第VIII因子組成物。
・(項目14) 上記充填剤が約8%の量で存在する、項目1〜13に記載の第VIII因子組成物。
・(項目15) 上記充填剤がマンニトールである、項目1〜14に記載の第VIII因子組成物。
・(項目16) 上記充填剤がグリシンである、項目1〜14に記載の第VIII因子組成物。
・(項目17) 上記安定化剤が約2%の量で存在する、項目1〜16に記載の第VIII因子組成物。
・(項目18) 上記安定化剤がスクロースである、項目1〜17に記載の第VIII因子組成物。
・(項目19) 上記安定化剤がアルギニンである、項目1〜17に記載の第VIII因子組成物。
・(項目20) 上記安定化剤がトレハロースである、項目1〜17に記載の第VIII因子組成物。
・(項目21) 上記NaClが約200mM〜約250mMの量で存在する、項目1〜20に記載の第VIII因子組成物。
・(項目22) 上記NaClが約225mMの量で存在する、項目21に記載の第VIII因子組成物。
・(項目23) 上記カルシウム塩が塩化カルシウムである、項目1〜22に記載の第VIII因子組成物。
・(項目24) 上記組成物が凍結乾燥された形態である、項目1〜23に記載の第VIII因子組成物。
・(項目25) 第VIII因子に加えて以下の処方賦形剤:
2%〜6%のヒドロキシエチル澱粉;
スクロース、トレハロース、ラフィノース、およびアルギニンからなる群より選択される1%〜4%の安定化剤;
1mM〜5mMのカルシウム塩;
100mM〜300mMのNaCl;ならびに
約6〜8のpHを維持するための緩衝剤;
を含有する、アルブミンを添加することなく処方された第VIII因子組成物。
・(項目26) 約4%のヒドロキシエチル澱粉を含有する、項目25に記載の第VIII因子組成物。
・(項目27) 約200mMのNaClを含有する、項目25〜26に記載の第VIII因子組成物。
・(項目28) 上記安定化剤が約2%の量で存在する、項目25〜27に記載の第VIII因子組成物。
・(項目29) 上記安定化剤がスクロースである、項目25〜28に記載の第VIII因子組成物。
・(項目30) 上記安定化剤がアルギニンである、項目25〜28に記載の第VIII因子組成物。
・(項目31) 上記安定化剤がトレハロースである、項目25〜28に記載の第VIII因子組成物。
・(項目32) 第VIII因子に加えて以下の処方賦形剤:
300mM〜500mMのNaCl;
スクロース、トレハロース、ラフィノース、およびアルギニンからなる群より選択される1%〜4%の安定化剤;
1mM〜5mMのカルシウム塩;ならびに
約6〜約8のpHを維持するための緩衝剤;
を含有する、アルブミンを添加することなく処方された第VIII因子組成物。
・(項目33) 上記NaClが約400mMの量で存在する、項目32に記載の組成物。
・(項目34) 血友病の処置のための医薬品の調製のための、項目1〜33のいずれかに記載の第VIII因子組成物の使用。
・(項目35) 結晶化が可能な充填剤およびNaClを含有する水性の薬学的処方物を凍結乾燥させる、改善された方法であって、ここで上記方法が、以下の工程:
(a)約−35℃未満の温度で水性の上記薬学的処方物を凍結する工程;
(b)約−30℃〜約−19℃で上記薬学的処方物をアニーリングする工程;
(c)約−50℃未満に上記薬学的処方物の温度を下げる工程;
(d)約−30℃〜−39℃で上記薬学的処方物をアニーリングする工程;次いで、
(e)上記薬学的処方物を凍結乾燥させる工程、
を包含する、改善された方法。
(定義)
本明細書中で使用される場合は、以下の用語およびそのバリエーションは、他に特に示されない限りは、以下のように定義されるはずである:
第VIII因子:第VIII因子分子は、天然に存在し、そして単一の遺伝子産物から生じるポリペプチドの不均質な生体内分布として、治療用調製物中に存在する(例えば、Anderssonら、Proc.Natl.Acad.Sci.USA,83,2979−2983、1986年5月を参照のこと)。用語「第VIII因子」は、本明細書中で使用される場合は、血漿に由来するかまたは組換えDNA技術の使用を通じて産生されたかにはかかわらず、全てのこのようなポリペプチドをいう。第VIII因子を含有する治療用調製物の商業的に入手可能な例として、HEMOFIL MおよびRECOMBINATEの登録商標のもとで販売されているもの(Baxter Healthcare Corporation,Deerfield,Illinois,U.S.A.から入手可能である)が挙げられる。他の現在開発されている調製物は、主に第VIII因子分子の単一のサブ集団を含み、これは、分子のBドメイン部分を欠失している。
一段階アッセイ。Lee、Martin Lら、An Effect of Predilution on Potency Assays of Factor VIII Concentrates,Thrombosis Research(Pergamon Press Ltd.)30、511−519(1983)に記載されているような一段階アッセイが、当該分野で公知である。
本発明の第VIII因子組成物は、充填剤、安定化剤、緩衝剤、塩化ナトリウム、カルシウム塩、および有利には他の賦形剤を含有する。これらの賦形剤は、凍結乾燥された調製物中での第VIII因子の安定性を最大にするために選択されている。しかし、本発明の第VIII因子組成物は、液体の状態でもまた安定性を示す。
Prod.No.D9533)から入手可能である。アルミニウムおよび鉄(II)キレート化剤は、イオンを+3の酸化状態のみならず+2の酸化状態にもキレート化し(1:1のキレート複合体)、そしてマンガンイオンおよび他の金属にも結合し得る。デフェロキサミンは、0.25mg/lの量で有利に使用され得る。
最大の安定性を達成するために、本発明の第VIII因子組成物は、好ましくは、凍結乾燥される。凍結乾燥の間には、第VIII因子は、水性の相から非結晶性の固相に転換され、これは、化学的および/または立体構造的な不安定性からタンパク質を保護する。凍結乾燥された調製物は、非結晶相を含むのみならず、凍結乾燥の間に結晶化する成分をもまた含む。これは、第VIII因子組成物の迅速な凍結乾燥、およびより洗練された形態の塊(すなわち、その中でそれが凍結乾燥された容器の側部から最少の収縮を有する塊)の形成を可能にすると考えられる。本発明の処方物においては、安定化剤は、凍結乾燥させた生成物の非結晶相中に主に存在するように選択され、一方、充填剤(HESを除く)は、凍結の間に結晶化するように選択されている。
第VIII因子の濃度の影響、および第VIII因子の回収の際の安定化剤の添加の影響を、いくつかの実験において調べた。これらの実験を、モデル充填剤としてマンニトールを、そしてモデル安定化剤としてスクロースを使用して行った。以下の表3に記載する3つのサンプル処方物を,これらの実験において使用した。これらの実験で使用した全ての処方物は、10mMのTris、200mMのNaCl、8%のマンニトール、4mMのCaCl2、および0.02%のTween−80を含み、そしてpH7.0で行われた。
実施例1に概説される凍結乾燥プロセスの開発の後、このプロセスのさらなる最適化を行った。より高いガラス転移温度を有する(そして、理論的には、より良好の第VIII因子の安定性を有する)凍結乾燥した組成物を、以下によって産生することができる:(1)最初に−45℃以下に凍結温度を低下させる(例えば、約−50℃または−55℃に低下させる);(2)−20℃または−22℃(±5℃)に温度を上昇させる;次いで、(3)再び−45℃以下に温度を低下させる。温度を、可能である場合には、1分間に約0.5℃から約1.0℃の間の速度で、低下または上昇させる。一旦、所望される温度に到達すると、組成物を1から3時間の間その温度で維持する。この改良された凍結サイクルを、以下の表6に示す。
受容可能な塊の出現およびガラス転移温度を有する凍結乾燥させた生成物を産生するために、塩化ナトリウムを含有している凍結乾燥させた薬学的調製物の充填剤(例えば、グリシンまたはマンニトール)が、結晶化のために必要とされ得ると考えられる。従って、結晶化が可能な充填剤についての以下の改良した凍結乾燥プロセスを開発した。
さらなる実験を、充填剤としてグリシンまたはマンニトールを含有している凍結乾燥させた第VIII因子組成物に対するヒスチジンの影響を詳細に試験するために行った。不可逆的な熱の流れ(Madulated DSC,mDSC)を、冷却の間のこれらの充填剤の結晶化を検出するために使用した。結晶化の温度および結晶化の全熱量の両方を、結晶化発熱線を使用して決定した。暖化の間のNaCl共晶融解吸熱の出現を、NaClの結晶化を検出するために使用した。mDSC中で、結晶化の程度を、全熱流シグナルを使用することによって、純粋なNaCl溶液の融解のエンタルピーに対する、処方物の融解のエンタルピーの比として決定した。さらに、X線回折分析を、凍結乾燥させた処方物中での結晶化の程度を決定するために行った。
多数の可能性のある第VIII因子処方物(7個の候補の安定化剤および5個の充填剤を含む)の物理的な特徴を、別の実験において評価した。充填剤および安定化剤に加えて、以下の表8に列挙する全ての処方物(処方物11を除く)は、10mMのTris−HCl、200mMのNaCl、0.02%のTween−80、4mMのCaCl2を含有し、そしてpH7.0であった。処方物11は、10mMのTris−HCl、0.02%のTween−80、および4mMのCaCl2を含有し、そしてこれもまた、pH7.0であった。全てのpH測定を、室温で行った。
上記の表8に記載する第VIII因子組成物を、それらの安定性について評価するために、時間の長さを変化させて、−70℃、25℃、40℃、および50℃での保存中に配置した。第VIII因子の活性レベルを、2週間後、1ヶ月後、2ヶ月後、および3ヶ月後に評価し、そして結果を以下の表10にまとめる。サンプルのうちの2つ(1つは、充填剤としてマンニトールを使用し、そして安定化剤としてソルビトールを使用する、そして他方は、充填剤としてマンニトールを使用し、そして安定化剤としてグリセロールを使用する)は、低い安定性を示した。残りの処方物は全て、第VIII因子を安定化させる能力を示した。
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- 本明細書に記載されるような、組成物。
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