JP5216002B2 - 硝子体内投与に適したvegfアンタゴニスト製剤 - Google Patents
硝子体内投与に適したvegfアンタゴニスト製剤 Download PDFInfo
- Publication number
- JP5216002B2 JP5216002B2 JP2009515517A JP2009515517A JP5216002B2 JP 5216002 B2 JP5216002 B2 JP 5216002B2 JP 2009515517 A JP2009515517 A JP 2009515517A JP 2009515517 A JP2009515517 A JP 2009515517A JP 5216002 B2 JP5216002 B2 JP 5216002B2
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- JP
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- Prior art keywords
- formulation
- vegf
- polysorbate
- antagonist
- vegf antagonist
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- C07—ORGANIC CHEMISTRY
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- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Description
本発明は血管内皮増殖因子(vascular endothelial growth factor, VEGF)を阻害することができる薬剤を含む、硝子体内投与に適した薬学的製剤、ならびにそのような製剤を作成および使用するための方法に関する。本発明は、安定性が向上した薬学的液体製剤、ならびに硝子体内投与のために凍結乾燥および再構成され得る製剤を含む。
血管内皮増殖因子(VEGF)の発現はヒトの癌においてほぼ遍在的であり、これは腫瘍血管新生の主要な媒介物としてのその役割と矛盾しない。VEGF分子またはそのVEGFR-2受容体への結合によってVEGF機能をブロックすると、移植された腫瘍細胞の増殖は複数の異なる異種移植モデルにおいて阻害される(例えば、Gerber et al.(2000)Cancer Res. 60:6253-6258(非特許文献1)参照)。「VEGFトラップ(VEGF trap)」と呼ばれる、可溶性のVEGF特異的な融合タンパク質アンタゴニストが記載されている(Kim et al. (2002) Proc. Natl. Acad. Sci. USA 99:11399-404(非特許文献2); Holash et al. (2002) Proc. Natl. Acad. Sci. USA 99:11393-8(非特許文献3))。
VEGF特異的な融合タンパク質アンタゴニストの安定な製剤を提供する。VEGF「トラップ」アンタゴニストと薬学的に許容される担体を含む、薬学的に許容される製剤を提供する。特定の態様においては、液体製剤および凍結乾燥された製剤を提供する。
[本発明101]
(a)配列番号:4のアミノ酸配列を含む、1〜100 mg/mlのVEGFアンタゴニスト;
(b)ポリソルベート、ポリエチレングリコール(PEG)、およびプロピレングリコールの内の1つまたは複数である、0.01〜5%の1つまたは複数の有機共溶媒;
(c)塩化ナトリウムまたは塩化カリウムから選択される、30〜150 mMの等張化剤;および
(d)5〜40 mMのリン酸ナトリウム緩衝液
を含み;ならびに
スクロース、ソルビトール、グリセロール、トレハロース、またはマンニトールからなる群より選択される1.0〜7.5%の安定剤を任意でさらに含み、
pHが約5.8〜7.0の間である、
血管内皮増殖因子(vascular endothelial growth factor, VEGF)アンタゴニストの眼科用製剤。
[本発明102]
約1〜100 mg/ml、好ましくは10〜80 mg/mlのVEGFアンタゴニスト、10 mMリン酸ナトリウム緩衝液、40 mM NaCl、0.03%ポリソルベート、および5%スクロースを含み、pHが約6.2〜6.3である、本発明101の眼科用製剤。
[本発明103]
10 mg/ml、20 mg/ml、40 mg/ml、および80 mg/mlからなる群より選択される濃度のVEGFアンタゴニストを含む、本発明102の眼科用製剤。
[本発明104]
10〜80 mg/mlのVEGFアンタゴニスト、10 mMのリン酸ナトリウム、0.03%のポリソルベート、および135 mMの塩化ナトリウムを含み、pHが約6.2〜6.3である、前記本発明のいずれかの眼科用製剤。
[本発明105]
(a)配列番号:4のアミノ酸配列を含む、5〜50 mg/ml、好ましくは5 mg/ml、10 mg/ml、20 mg/ml、または40 mg/mlのVEGFアンタゴニスト;
(b)pHが約5.8〜7.0である、5〜25 mMのリン酸ナトリウム緩衝液;
(c)ポリソルベート、ポリエチレングリコール(PEG)、プロピレングリコール、およびこれらの組み合わせからなる群より選択される、0.01〜0.15%の有機共溶媒;ならびに任意で
(d)スクロース、ソルビトール、グリセロール、トレハロース、およびマンニトールからなる群より選択される1〜10%の安定剤;もしくは20〜150 mMの等張化剤、好ましくは塩化ナトリウム;または1〜10%の安定剤および20〜150 mMの等張化剤
を含む、
血管内皮増殖因子(VEGF)アンタゴニストの凍結乾燥可能な製剤。
[本発明106]
約20 mg/mlのVEGFアンタゴニスト、約10 mMのリン酸ナトリウム緩衝液、約0.03%のポリソルベート、約0.1%のPEG、および約2.5%のスクロースを含み、pHが約6.2〜6.3である、本発明105の凍結乾燥可能な製剤。
[本発明107]
約20 mg/mlのVEGFアンタゴニスト、約5 mMのリン酸ナトリウム緩衝液、約0.015%のポリソルベート、約2.5%のスクロースを含み、および約20mMの塩化ナトリウムをさらに含み、pHが約6.2〜6.3である、本発明105の凍結乾燥可能な製剤。
[本発明108]
約20 mg/mlのVEGFアンタゴニスト、約5 mMのリン酸ナトリウム緩衝液、約0.015%のポリソルベートを含み、および約67.5mMの塩化ナトリウムをさらに含み、pHが約6.2〜6.3である、本発明106の凍結乾燥可能な製剤。
[本発明109]
本発明105〜108のいずれかの凍結乾燥前製剤を凍結乾燥に供し、凍結乾燥製剤を生成する工程を含む、VEGFアンタゴニストの凍結乾燥製剤を製造する方法。
[本発明110]
本発明101の製剤を含む、硝子体内投与に適した予め充填されたシリンジ。
本発明は、記載された特定の方法および実験条件に限定されず、方法および条件は多様であり得る。本明細書中で用いられる用語は特定の態様を説明するためだけのものであり、本発明の範囲は添付の請求の範囲によってのみ限定されるため、特に示さない限り、本明細書中で用いられる用語は限定を意図するものではないことも理解される。
タンパク質を含む製剤の安全な操作および投与は、薬剤を製剤化する者にとって重要な課題である。タンパク質は、安定性の問題をもたらす特有の化学的および物理的特性を有する:タンパク質には様々な分解経路が存在し、このことは化学的および物理的不安定性の両方に関与する。化学的不安定性には、脱アミノ化、凝集、ペプチド骨格の切断、およびメチオニン残基の酸化が含まれる。物理的不安定性には多くの現象が包含され、例えば凝集および/または沈殿が含まれる。
「担体」との用語には、組成物と一緒に投与される、希釈剤、アジュバント、賦形剤、またはビヒクルが含まれる。担体には、滅菌液、例えば水、および石油、動物、植物、または合成物質起源の油を含む油、例えばピーナツオイル、大豆油、鉱油、胡麻油等が含まれてよい。
VEGFアンタゴニストとは血管内皮増殖因子(VEGF)の生物学的作用をブロックまたは阻害することができる化合物であり、VEGFをトラップすることができる融合タンパク質を含む。好ましい態様においては、VEGFアンタゴニストは配列番号:2または4、より好ましくは配列番号:4の融合タンパク質である。特定の態様においては、VEGFアンタゴニストはCHO細胞等の哺乳動物細胞株において発現し、翻訳後に修飾されてもよい。特定の態様においては、融合タンパク質は配列番号:4の27〜457位のアミノ酸を含み、62、94、149、222、および308位のAsn残基においてグリコシル化されている。好ましくは、VEGFアンタゴニストは配列番号:4の融合タンパク質2つから構成される二量体である。
1つの局面において、本発明はVEGFアンタゴニストを含む安定な薬学的に許容される製剤を提供し、ここで該製剤は眼科用途に適した液体製剤である。好ましくは、液体製剤は薬学的に有効な量のVEGFアンタゴニストを含む。製剤は1つまたは複数の薬学的に許容される担体、緩衝液、等張化剤、安定剤、および/または賦形剤を含んでいてもよい。一例として、薬学的に許容される液体製剤は、薬学的に有効な量のVEGFアンタゴニスト、緩衝液、有機共溶媒、例えばポリソルベート、等張化剤、例えばNaCl、および任意に安定剤、例えばスクロースもしくはトレハロースを含む。
本発明の1つの局面においては、VEGFアンタゴニストを含む眼科用に許容される製剤が提供され、ここで該製剤は凍結乾燥可能な製剤である。凍結乾燥可能な製剤は、溶液、懸濁液、エマルジョン、または投与もしくは使用に適したその他の任意の形態に再構成することができる。凍結乾燥可能な製剤は、典型的には、最初に液体として調製され、その後凍結および凍結乾燥される。凍結乾燥前の総液体容量は、凍結乾燥製剤の最終的に再構成された容量に対して少なくても、同等でも、多くてもよい。凍結乾燥のプロセスは当業者に周知であり、典型的には、制御された条件下で、凍結製剤から水を昇華することを含む。
本方法を説明する前に、本発明は特定の方法および記載された実験条件に限定されず、方法および条件は多様であり得ることを理解するべきである。本明細書に用いられる用語は特定の態様を説明するためだけのものであり、本発明の範囲は添付の請求の範囲によってのみ限定されるため、本明細書に用いられる用語は限定を意図するものではないことも理解される。
50 mg/ml VEGFトラップ(配列番号:4)、10 mMリン酸塩、50 mM NaCl、0.1%ポリソルベート20、5%スクロースを含み、pHが6.25である眼科用液体製剤を3 mlガラスバイアル中で5℃で保存し、3、6、9、12、18、および24ヶ月の時点でサンプルをテストした。安定性はSE-HPLCで決定した。結果を表1に示す。濁度はOD405 nmで測定し、回収されたタンパク質の割合(%)および純度はサイズ排除HPLCで測定した。
50 mg/ml VEGFトラップ(配列番号:4)、10 mMリン酸塩、50 mM NaCl、3%ポリエチレングリコール3350、5%スクロースを含み、pHが6.25である液体製剤を3 mlガラスバイアル中で5℃で保存し、3、6、9、12、18、および24ヶ月の時点でサンプルをテストした。安定性の結果を表2に示す。濁度、回収されたタンパク質の割合(%)、および純度は上記の通りに決定した。
40 mg/ml VEGFトラップ(配列番号:4)、10 mMリン酸塩、40 mM NaCl、0.03%ポリソルベート20、5%スクロースを含み、pHが6.3である液体製剤を3 mlガラスバイアル中で5℃で保存し、0.5、1、2、3、および4ヶ月の時点でサンプルをテストした。安定性の結果を表3に示す。濁度、回収されたタンパク質の割合(%)、および純度は上記の通りに決定した。
40 mg/ml VEGFトラップ(配列番号:4)、10 mMリン酸塩、40 mM NaCl、0.03%ポリソルベート20、5%スクロースを含み、pHが6.3である液体製剤を、4023/50 FluroTecコーティングされたプランジャー付きの予め充填された1 mlルアー(luer)ガラスシリンジ中で5℃で保存し、0.5、1、2、3、および4ヶ月の時点でサンプルをテストした。安定性の結果を表4に示す。濁度、回収されたタンパク質の割合(%)および純度は上記の通りに決定した。
40 mg/ml VEGFトラップ(配列番号:4)、10 mMリン酸塩、135 mM NaCl、0.03%ポリソルベート20を含み、pHが6.3である液体製剤を3 mlガラスバイアル中で5℃で保存し、0.5、1、2、3、および4ヶ月の時点でサンプルをテストした。安定性の結果を表5に示す。濁度、回収されたタンパク質の割合(%)、および純度は上記の通りに決定した。
40 mg/ml VEGFトラップ(配列番号:4)、10 mMリン酸塩、135 mM NaCl、0.03%ポリソルベート20を含み、pHが6.3である液体製剤を、4023/50 FluroTecコーティングされたプランジャー付きの1 mlの予め充填されたルアーガラスシリンジ中で5℃で保存し、0.5、1、2、3、4および5ヶ月の時点でサンプルをテストした。安定性の結果を表6に示す。濁度、回収されたタンパク質の割合(%)、および純度は上記の通りに決定した。
20 mg/ml VEGFトラップ(配列番号:4)、5 mMリン酸塩、20 mM NaCl、0.015%ポリソルベート20、2.5%スクロースを含み、pHが6.3である液体製剤0.8 mlを、3 mlガラスバイアル中で凍結乾燥した。サンプルを5℃で保存し、1および2ヶ月後にテストした。VEGFトラップは最終濃度40 mg/mlのVEGFトラップに再構成した(最終容量は0.4 ml)。安定性の結果を表7に示す(t =月での時間、* =外観、** =再構成時間)。濁度、回収されたタンパク質の割合(%)、および純度は上記の通りに決定した。
20 mg/ml VEGFトラップ(配列番号:4)、5 mMリン酸塩、67.5 mM NaCl、0.015%ポリソルベート20を含み、pHが6.3である液体製剤0.8 mlを、3 mlガラスバイアル中で凍結乾燥した。サンプルを5℃で保存し、1、2および3ヶ月後にテストした。VEGFトラップは最終濃度40 mg/mlのVEGFトラップに再構成した(最終容量は0.4 ml)。安定性の結果を表8に示す(t =月での時間、* =外観、** =再構成時間)。
Claims (5)
- 配列番号:4のアミノ酸配列の27〜457位のアミノ酸を含む、40 mg/mlのVEGFアンタゴニスト;
0.03%のポリソルベート;
40 mMの塩化ナトリウム;
10 mMのリン酸ナトリウム緩衝液;および
5%のスクロースを含み、
pHが5.8〜7.0の間である、
血管内皮増殖因子(vascular endothelial growth factor, VEGF)アンタゴニストの眼科用製剤。 - 40 mg/mlのVEGFアンタゴニスト、10 mMのリン酸ナトリウム緩衝液、40 mMのNaCl、0.03%のポリソルベート20、および5%のスクロースからなる、pHが6.2〜6.3である、請求項1記載の眼科用製剤。
- 配列番号:4のアミノ酸配列の27〜457位のアミノ酸を含む、20 mg/mlのVEGFアンタゴニスト、5 mMのリン酸ナトリウム緩衝液、0.015%のポリソルベート、2.5%のスクロース、および20mMの塩化ナトリウムを含み、pHが6.2〜6.3である、血管内皮増殖因子(VEGF)アンタゴニストの凍結乾燥可能な製剤。
- 請求項3記載の凍結乾燥可能な製剤を凍結乾燥に供し、凍結乾燥製剤を生成する工程を含む、VEGFアンタゴニストの凍結乾燥製剤を製造する方法。
- 請求項1または2記載の製剤を含む、硝子体内投与に適した予め充填されたシリンジ。
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UA117045C2 (uk) | 2014-01-25 | 2018-06-11 | Ченгду Кангхонг Байотекнолоджиз Ко., Лтд. | Гібридний білок для пригнічення ангіогенезу або судинного росту та його застосування |
US20160144025A1 (en) | 2014-11-25 | 2016-05-26 | Regeneron Pharmaceuticals, Inc. | Methods and formulations for treating vascular eye diseases |
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