JP2012025768A - 高分子−第ix因子部分の抱合体 - Google Patents
高分子−第ix因子部分の抱合体 Download PDFInfo
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- JP2012025768A JP2012025768A JP2011221316A JP2011221316A JP2012025768A JP 2012025768 A JP2012025768 A JP 2012025768A JP 2011221316 A JP2011221316 A JP 2011221316A JP 2011221316 A JP2011221316 A JP 2011221316A JP 2012025768 A JP2012025768 A JP 2012025768A
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
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- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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Abstract
【解決手段】IX因子部分および1つ以上の水溶性高分子の抱合体を提供することによる。一般に、水溶性高分子は、ポリエチレングリコールまたはその誘導体である。また、(とりわけ)抱合体を含む組成物、抱合体の生成方法、および抱合体を含む組成物の患者への投与方法も提供する。
【選択図】図1
Description
フェニルアラニンは、PheまたはF;ロイシンは、LeuまたはL;イソロイシンは、IleまたはI;メチオニンは、MetまたはM;バリンは、ValまたはV;セリンは、SerまたはS;プロリンは、ProまたはP;スレオニンは、ThrまたはT;アラニンは、AlaまたはA;チロシンは、TyrまたはY;ヒスチジンは、HisまたはH;グルタミン(Glutarnine)は、GlnまたはQ;アスパラギンは、AsnまたはN;リシンは、LysまたはK;アスパラギン酸は、AspまたはD;グルタミン酸は、GluまたはE;システインは、CysまたはC;トリプトファンは、TrpまたはW;アルギニンは、ArgまたはR;グリシンは、GlyまたはG。
polyaおよびpolybは、メトキシポリ(エチレングリコール)のような、(同一の、または異なる)PEG骨格である;
R”は、H、メチル、またはPEG骨格のような非反応性部分である:且つ
PおよびQは、非反応性結合である}。1つ以上の実施態様では、分岐PEG高分子は、メトキシポリ(エチレングリコール)二置換リシンである。使用される特定の第IX因子に依存して、二置換リシンの反応性エステル官能基は、第IX因子部分内のターゲットグループとの反応に好適な官能基を形成するように、さらに改変することが可能である。
(n)は、2乃至3400の値を有する整数である;
Xは、スペーサ部分であり、メチレン(「−CH2−」)、エチレン(「−CH2CH2−」)、およびプロピレン(「−CH2CH2CH2−」)のうちの1つのであることが好ましい;
R1は、有機ラジカルであり、Hまたはメチル(「−CH3」)であることが好ましい;且つ
F9は、第IX因子部分である}。
各(n)は、それぞれ2乃至3400の値を有する整数である;
Xは、スペーサ部分である;
(b)は、2乃至6の値を有する整数である;
(c)は、2乃至6の値を有する整数である;
各発生におけるR2は、それぞれHまたは低級アルキルである;
F9は、第IX因子部分である}。
各(n)は、それぞれ2乃至3400の値を有する整数である;
(a)は、ゼロでまたは1である;
Xは、存在する場合、1つ以上の原子を含むスペーサ部分である;
(b’)は、ゼロまたは1乃至10の値を有する整数である;
(c)は、1乃至10の値を有する整数である;
各発生におけるR2は、それぞれHまたは有機ラジカルである;
各発生におけるR3は、それぞれHまたは有機ラジカルである;且つ
F9は、第IX因子部分である}。
本発明の実施は、特に明記しない限り、従来技術の範囲内にある、有機合成などの従来の技術を用いる。このような技術は、文献において完全に説明される。試薬および物質は、逆に定められていなければ市販のものである。前掲の、J.March、Organic Chamistry:Reactions Mechanisms and Structure、4th Ed.(New York:Wiley−Interscience、1992)を参照のこと。
実施例1
mPEG−SMB(30kDa)による第IX因子のPEG化
(高分子と第IX因子の比率 1:1;エタノールなし)
実施例2
mPEG−SMB(30kDa)による第IX因子のPEG化
(高分子と第IX因子の比率10:1;エタノールなし)
実施例3
分岐mPEG2−N−ヒドロキシスクシンイミド(40kDa)による第IX因子のPEG化
(高分子と第IX因子の比率1:1;エタノールなし)
実施例4
分岐mPEG2−N−ヒドロキシスクシンイミド(40kDa)による第IX因子のPEG化
(高分子と第IX因子の比率10:1;エタノールなし)
実施例5
mPEG−SMB(30kDa)による第IX因子のPEG化
(高分子と第IX因子の比率10:1;エタノールあり)
実施例6
mPEG−SMB(30kDa)による第IX因子のPEG化
(高分子と第IX因子の比率20:1;エタノールあり)
実施例7
分岐mPEG2−N−ヒドロキシスクシンイミド(40kDa)による第IX因子のPEG化
(高分子と第IX因子の比率10:1;エタノールあり)
実施例8
分岐mPEG2−N−ヒドロキシスクシンイミド(40kDa)による第IX因子のPEG化
(高分子と第IX因子の比率20:1;エタノールあり)
実施例9
mPEG−SMB(30kDa)による第IX因子のPEG化
(高分子と第IX因子の比率20:1;エタノールなし)
実施例10
mPEG−SPA(20kDa)による第IX因子のPEG化
(高分子と第IX因子の比率20:1;エタノールなし)
実施例11
mPEG−SPA(20kDa)による第IX因子のPEG化
(高分子と第IX因子の比率40:1;エタノールなし)
実施例12
分岐mPEG−ブチルアルデヒド(20kDa)による第IX因子のPEG化
(高分子と第IX因子の比率10:1;エタノールなし)
実施例13
分岐mPEG−ブチルアルデヒド(20kDa)による第IX因子のPEG化
(高分子と第IX因子の比率20:1;エタノールなし)
実施例14
mPEG−SPA(20kDa)による第IX因子のPEG化
(高分子と第IX因子の比率53:1;エタノールなし)
実施例15
mPEG−SPA(20kDa)による第IX因子のPEG化
(高分子と第IX因子の比率110:1;エタノールなし)
実施例16
分岐mPEG−ブチルアルデヒド(20kDa)による第IX因子のPEG化
(高分子と第IX因子の比率は20:1;エタノールあり)
実施例17
mPEG−SBAによる第IXa因子のPEG化
実施例19
mPEG−KALによるシステイン挿入第IX因子の抱合、20K
実施例20
典型的な第IX因子−PEG抱合体の生体外活性
Claims (62)
- 直接的にまたは1つ以上の原子を含むスペーサ部分を介して、水溶性高分子に共有結合した第IX因子部分を含み、当該水溶性高分子の分子量が5,000ダルトンより多く、約150,000ダルトンより少ない抱合体。
- 直接的にまたは1つ以上の原子を含むスペーサ部分を介して、水溶性高分子にアミノ酸残基において共有結合した第IX因子部分を含み、当該アミノ酸残基が直接的にまたは当該スペーサ部分を介して、−CH2−C(O)−O−、−N(H)−C(O)CH2−O−、−C(O)−N(H)−、−N(H)−C(O)−CH2−O−、−C(O)−CH2−O−、−C(O)−CH2−CH2−C(O)−O−、ジアゾ、またはトリアジン結合により結合していない抱合体。
- 直接的にまたは1つ以上の原子を含むスペーサ部分を介して、非線形の水溶性高分子に共有結合した第IX因子部分を含む抱合体。
- 各抱合体中の前記水溶性高分子が、ポリ(酸化アルキレン)、ポリ(ビニルピロリドン)、ポリ(ビニルアルコール)、ポリオキサゾリン、およびポリ(アクリロイルモルホリン)から成る群から選択される、請求項1、2、または3に記載の抱合体。
- 各水溶性高分子が、ポリ(酸化アルキレン)である、請求項4に記載の抱合体。
- 各ポリ(酸化アルキレン)が、ポリ(エチレングリコール)である、請求項5に記載の抱合体。
- 前記ポリ(エチレングリコール)が、ヒドロキシ、アルコキシ、置換アルコキシ、アルケノキシ、置換アルケノキシ、アルキノキシ、置換アルキノキシ、アリールオキシ、および置換アリールオキシから成る群から選択される、エンドキャップ部分で末端がキャップされる、請求項6に記載の抱合体。
- 前記ポリ(エチレングリコール)が、メトキシで末端がキャップされる、請求項6に記載の抱合体。
- 前記水溶性高分子が、5,000ダルトン乃至約150,000ダルトンの範囲の総重量平均分子量を有する、請求項2または3に記載の抱合体。
- 前記ポリ(エチレングリコール)が、約6,000ダルトン乃至約100,000ダルトンの範囲の総重量平均分子量を有する、請求項6に記載の抱合体。
- 前記ポリ(エチレングリコール)が、約10,000ダルトン乃至約85,000ダルトンの範囲の総重量平均分子量を有する、請求項10に記載の抱合体。
- 前記ポリ(エチレングリコール)が、約20,000ダルトン乃至約85,000ダルトンの範囲の総重量平均分子量を有する、請求項11に記載の抱合体。
- 各水溶性高分子が線状である、請求項1または2に記載の抱合体。
- 各水溶性高分子が分岐状である、請求項1または2に記載の抱合体。
- 前記第IX因子部分が、第IX因子、第IXa因子、およびそれらのいずれかの生物活性フラグメント、欠損変異体、置換変異体、または付加変異体から成る群から選択される、請求項1、2、または3に記載の抱合体。
- 前記第IX因子部分が第IX因子である、請求項15に記載の抱合体。
- 前記第IX因子部分が第IXa因子である、請求項16に記載の抱合体。
- 前記第IX因子部分が組み換え的に誘導される、請求項6に記載の抱合体。
- 前記第IX因子部分が血液由来である、請求項6に記載の抱合体。
- 前記第IX因子部分に、3つを超えない水溶性高分子が結合した、請求項6に記載の抱合体。
- 複数の抱合体を含み、当該組成物中の全ての抱合体の少なくとも約80%が、それぞれが1つ、2つ、3つ、または4つの水溶性高分子に共有結合した第IX因子部分を含み、さらに、当該抱合体中の各水溶性高分子に対して、当該第IX因子部分が、直接的にまたは1つ以上の原子を含むスペーサ部分を介して、水溶性高分子に結合した組成物。
- 複数の抱合体を含み、当該組成物中の全ての抱合体の少なくとも約85%が、それぞれ第IX因子部分に共有結合した1つ乃至3つの水溶性高分子を有し、各水溶性高分子が、5,000ダルトン乃至約150,000ダルトンの範囲の重量平均分子量を有する組成物。
- 複数のモノPEG化第IX因子部分の抱合体を含み、当該組成物中の全ての抱合体の少なくとも約85%が、モノPEG化第IX因子部分の抱合体である組成物。
- 各抱合体中の前記水溶性高分子が、ポリ(酸化アルキレン)、ポリ(ビニルピロリドン)、ポリ(ビニルアルコール)、ポリオキサゾリン、およびポリ(アクリロイルモルホリン)から成る群から選択される、請求項21、22、または23に記載の組成物。
- 各水溶性高分子が、ポリ(酸化アルキレン)である、請求項24に記載の組成物。
- 各ポリ(酸化アルキレン)が、ポリ(エチレングリコール)である、請求項25に記載の組成物。
- 前記ポリ(エチレングリコール)が、ヒドロキシ、アルコキシ、置換アルコキシ、アルケノキシ、置換アルケノキシ、アルキノキシ、置換アルキノキシ、アリールオキシ、および置換アリールオキシから成る群から選択される、エンドキャップ部分で末端がキャップされる、請求項26に記載の組成物。
- 前記ポリ(エチレングリコール)が、メトキシで末端がキャップされる、請求項26に記載の組成物。
- 前記水溶性高分子が、5,000ダルトン乃至約150,000ダルトンの範囲の総重量平均分子量を有する、請求項21または23に記載の組成物。
- 前記ポリ(エチレングリコール)が、約6,000ダルトン乃至約100,000ダルトンの範囲の総重量平均分子量を有する、請求項26に記載の組成物。
- 前記ポリ(エチレングリコール)が、約10,000ダルトン乃至約85,000ダルトンの範囲の総重量平均分子量を有する、請求項30に記載の組成物。
- 前記ポリ(エチレングリコール)が、約20,000ダルトン乃至約85,000ダルトンの範囲の総重量平均分子量を有する、請求項31に記載の組成物。
- 各水溶性高分子が線状である、請求項6に記載の組成物。
- 各水溶性高分子が分岐状である、請求項6に記載の組成物。
- 前記第IX因子部分が、第IX因子、第IXa因子、およびそれらのいずれかの生物活性フラグメント、欠損変異体、置換変異体、または付加変異体から成る群から選択される、請求項21、22、または23に記載の組成物。
- 前記第IX因子部分が第IX因子である、請求項35に記載の組成物。
- 前記第IX因子部分が第IXa因子である、請求項35に記載の組成物。
- 前記第IX因子部分が組み換え的に誘導される、請求項26に記載の組成物。
- 前記第IX因子部分が血液由来である、請求項26に記載の組成物。
- 前記第IX因子部分に、3つを超えない水溶性高分子が結合した、請求項21または22に記載の組成物。
- 前記組成物が、実質的にアルブミンを含まない、請求項26に記載の組成物。
- 前記組成物が、第IX因子の活性を有さないタンパク質を実質的に含まない、請求項26に記載の組成物。
- 前記組成物が、非共有結合の水溶性高分子を実質的に含まない、請求項26に記載の組成物。
- 凍結乾燥形態である、請求項26に記載の組成物。
- 液体の形態である、請求項26に記載の組成物。
- 医薬として許容される賦形剤をさらに含む、請求項26に記載の組成物。
- 各モノPEG化第IX因子部分の抱合体が、直接的にまたは1つ以上の原子を含むスペーサ部分を介して、水溶性高分子に共有結合した第IX因子部分を含む、請求項23に記載の組成物。
- 各抱合体が、前記水溶性高分子またはスペーサ部分に、前記第IX因子部分を結合するアミド結合を含む、請求項21、22、または26に記載の組成物。
- 各抱合体が、前記水溶性高分子またはスペーサ部分に、前記第IX因子部分を結合する第2級アミン結合を含む、請求項21、22、または26に記載の組成物。
- 各抱合体が、前記水溶性高分子またはスペーサ部分に、前記第IX因子部分を結合するカルバメート結合を含む、請求項21、22、または26に記載の組成物。
- 各抱合体が、前記水溶性高分子またはスペーサ部分に、前記第IX因子部分を結合するチオエーテル結合を含む、請求項21、22、または26に記載の組成物。
- 各抱合体が、前記水溶性高分子またはスペーサ部分に、前記第IX因子部分を結合するジスルフィド結合を含む、請求項21、22、または26に記載の組成物。
- 抱合条件下で、第IX因子部分を高分子試薬と接触させる段階を含む、抱合体を生成するための方法。
- 更なるアルコールを加えない、請求項53に記載の方法。
- 酸化段階を実施しない、請求項53に記載の方法。
- 直接的にまたは1つ以上の原子を含むスペーサ部分を介して、水溶性高分子に共有結合した第IX因子部分を含む抱合体を得るに十分な条件下で、第IX因子の組成物に、高分子試薬の組成物を添加する段階を含む、抱合体を生成するための方法。
- 更なるアルコールを加えない、請求項56に記載の方法。
- 酸化段階を実施しない、請求項56に記載の方法。
- 患者に請求項46に記載の組成物を投与する段階を含む、抱合体を送達するための方法。
- 皮下注射によって実施される、請求項59に記載の方法。
- 前記患者が血友病Bを罹患している、請求項59に記載の方法。
- 前記患者に、手術前の2日以内に前記組成物を投与する、請求項59に記載の方法。
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