JP5377431B2 - タンパク質含有安定化製剤 - Google Patents
タンパク質含有安定化製剤 Download PDFInfo
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- JP5377431B2 JP5377431B2 JP2010153113A JP2010153113A JP5377431B2 JP 5377431 B2 JP5377431 B2 JP 5377431B2 JP 2010153113 A JP2010153113 A JP 2010153113A JP 2010153113 A JP2010153113 A JP 2010153113A JP 5377431 B2 JP5377431 B2 JP 5377431B2
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- antibody
- protein
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- poloxamer
- solution
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- C—CHEMISTRY; METALLURGY
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- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Description
例えば、免疫グロブリン、モノクローナル抗体、ヒト化抗体等の抗体は不安定なタンパク質であり、精製及び調剤行程において実施する濾過ストレス、濃縮ストレス、熱ストレス、さらには原液、製剤保存中の熱、光、輸送ストレスなどによって会合、凝集などの物理的、化学的変化を生じやすい。
(1)界面活性剤としてポロクサマーを含むタンパク質製剤。
(2)ポロクサマーがポロクサマー188である前記(1)記載のタンパク質製剤。
(3)溶液製剤である前記(1)又は(2)に記載のタンパク質製剤。
(4)タンパク質が免疫グロブリンである前記(1)〜(3)のいずれかに記載のタンパク質製剤。
(5)免疫グロブリンがヒト化抗体である前記(4)記載のタンパク質製剤。
(6)免疫グロブリンが抗組織因子抗体である前記(4)記載のタンパク質製剤。
(7)抗組織因子抗体がヒト化抗組織因子抗体である前記(6)記載のタンパク質製剤。
(8)添加剤として抗酸化剤を含まない前記(1)〜(9)のいずれかに記載のタンパク質製剤。
(9)界面活性剤としてポロクサマーを添加することにより、抗酸化剤の添加をすることなくタンパク質製剤中の生物活性を保持し、かつ不溶性異物の生成を抑制する方法。
(10)タンパク質が顆粒球コロニー刺激因子である前記(1)〜(3)のいずれかに記載のタンパク質製剤。
(11)タンパク質が副甲状腺ホルモンである前記(1)〜(3)のいずれかに記載のタンパク質製剤。
本発明では、抗体含有溶液とは、生体由来抗体であるか、あるいは組換え抗体であるかを問わず、いかなる抗体を含む溶液であってもよく、好ましくは、培養して得られた抗体を含むCHO細胞などの哺乳動物細胞の培養培地、あるいはこれに部分的精製などの一定の処理を施したもの(バルク溶液)、あるいは上記のヒト等の動物に投与できるように調製された溶液製剤である。
本発明のタンパク質含有製剤では、界面活性剤としてポロクサマーを添加することにより、抗酸化剤を添加しなくてもタンパク質を酸化することなく高い生物活性を保持し、かつタンパク質含有製剤の不溶性異物の生成を抑制できる。
HO(C2H4O)a(C3H6O)b(C2H4O)aH
ポロクサマーにはポロクサマー124,188,237,338,407がUSP(米国薬局方)に収載されており、本発明では特にポロクサマー188が好ましい。USP記載のポロクサマー188は上記式におけるaが80、bが27、平均分子量が7680−9510であり、BP(英国薬局方)記載のポロクサマー188は上記式におけるaが約75、bが約30、平均分子量が8350である。さらに、EP(欧州薬局方)にはこれ以外に、ポロクサマー182,184,331が記載されている。また、Pluronic (ポロクサマーのBASF社の商標) としては、Pluronic L35,L43,L44,L61,L62,L64,F68,L81,P84,P85,F87,F88,L92,F98,L101,P103,P104,P105,F108,L121,P123,F127があり、これらのものも本発明におけるポロクサマーに含まれる。
本発明の抗体製剤のpHは、好ましくはpH4〜8であり、さらに好ましくはpH5〜7.5である。しかしながら、pHは含まれる抗体により異なり、これらに限定されるものではない。
1.抗体試料
抗ヒト組織因子抗体として、WO99/51743に記載のヒト化H鎖バージョンi及びヒト化L鎖バージョンb2とを組み合わせたヒト化抗ヒト組織因子抗体を用いた。本実施例で用いた抗ヒト組織因子抗体は、CHO細胞によって産生される組み換え型抗体であり、IgG4クラスの抗体である。
2.顆粒球コロニー刺激因子(G−CSF)
顆粒球コロニー刺激因子は、遺伝子工学的手法により、チャイニーズハムスター卵巣(CHO)細胞によって遺伝子組換え法を用いて産生し、抽出して分離精製したものを用いた。
3.副甲状腺ホルモン(PTH)
1〜84残基を有する副甲状腺ホルモンは、WO9014415に記載される方法にて製造した。
試験方法
(1)TF中和活性試験
組織因子(TF)は、細胞表面に発現される血液凝固第VII因子受容体であり、血液凝固反応の実質的な開始因子と位置付けられている。組織因子は血液凝固第VII因子との複合体形成を通じて、血液凝固第IX因子及びX因子を活性化させる。従って、ヒト化抗ヒト組織因子抗体の生物活性は以下に記載する方法で、血液凝固第 VIIa因子溶液及び血液凝固第 X因子溶液を用いて測定することができる。
1. 以下の溶液を調製した。
1) A.B.(Assay Buffer):5 mmol/L CaCl2, 0.1% BSAを含むTBS (pH 7.6)。
2) Factor VIIa& Thromborel S混合溶液:Factor VIIaは0.1 PEU/mL、Thromborel Sは0.42 mg/mLとなるようにA.B.で希釈した。
3) Factor X 溶液:A.B.でFactor Xを0.25 PEU/mLに希釈した。
4) テストチーム発色基質 S-2222混合液:1.5 mg/mL発色基質 S-2222溶液1に対し水を1およびポリブレン水溶液を2の割合で混合した。
2. Factor VIIa& Thromborel S混合溶液を60 mL /wellでプレートに分注し室温で60分間静置した。
3. Factor X溶液で希釈した抗ヒト組織因子抗体原液(標準溶液)および試料溶液を40 mL /wellで上記プレートに分注し室温で30分間静置した。
4. 0.5 mol/L EDTA溶液を10 mL /well加え反応を止めた後、テストチーム発色基質 S-2222混合液を50 mL /wellでプレートに分注し室温で30分間静置した。
5. 405 nm - 655 nmの吸光度を測定した。
6. 検量線解析を行い、標準溶液を100%としたときの被験試料の生物活性を算出した。
略号
TBS : Tris Buffered Saline
BSA : Bovine Serum Albumin
EDTA : Ethylenediamine Tetraacetic Acid
(2)イオン交換クロマトグラフィー(IEC)
下記の条件にて試験を行った。
日本薬局方・一般試験法・注射剤の不溶性異物検査法に定めるように、容器に入れた溶液製剤を白色光源の直下、約1000ルクスの明るさの位置で肉眼にて観察する。
実施例1:界面活性剤添加の生物活性に及ぼす効果
様々な界面活性剤を添加した抗ヒト組織因子抗体溶液製剤の生物活性の経時変化を試験した。2.3mg/mLの抗ヒト組織因子抗体を酢酸緩衝液中に含む試料(pH6.0)に界面活性剤としてポリソルベート20,80(いずれもA社製)、ポロクサマー188(B社製)をそれぞれ0.5mg/mL添加して5℃で14日及び40℃で14日保存した後の生物活性(TF−中和活性)を試験した。別途、界面活性剤無添加の群も同様に試験して比較した。得られた結果を図1に示す。
実施例2:界面活性剤の生物活性及び純度に及ぼす効果
抗ヒト組織因子抗体溶液製剤の生物活性及び純度に及ぼす界面活性剤の添加効果を試験した。10mg/mLの抗ヒト組織因子抗体を酢酸緩衝液中に含む試料(pH5.5)に界面活性剤としてポリソルベート80(C社製)、ポロクサマー188(D社製)をそれぞれ0.5mg/mL添加して25℃で6ヶ月保存する加速試験後、生物活性をTF−中和活性により、また純度試験をイオン交換クロマトグラフィー(IEC)により試験した。別途、加速試験を行わない抗ヒト組織因子抗体原液(bulk)を同様に試験して比較した。得られた結果を図2に示す。
イオン交換クロマトグラフィーでは、ポリソルベート80を添加した抗ヒト組織因子抗体溶液製剤ではメインピークが減少し、メインピークの直前に新しいピーク(図2中の矢印)が出現していた。このメインピークの直前に出現したピーク画分では、一部のアミノ酸残基が酸化されたものが確認されている。しかしポロクサマー188を添加した製剤は、抗ヒト組織因子抗体原液に近いクロマトグラムを保持していた。
実施例3:ポリソルベート80による抗ヒト組織因子抗体の活性低下に対するL-メチオニンの添加効果、及び前記添加効果とポロクサマー添加効果との比較
ポリソルベート80添加による抗ヒト組織因子抗体溶液製剤の活性低下に対するL-メチオニンの添加効果を試験し、これをポロクサマー188添加の製剤と比較した。10mg/mLの抗ヒト組織因子抗体を酢酸緩衝液中に含む試料(pH5.5)に以下の物質を添加した試料を調製した:
1)ポリソルベート80を0.5mg/mL
2)ポリソルベート80を0.5mg/mL+L-メチオニンを5mg/mL
3)ポロクサマー188を0.5mg/mL
各試料を25℃で6ヶ月保存する加速試験後、生物活性をTF−中和活性により試験し、抗ヒト組織因子抗体原液 (bulk)の生物活性と比較した。
実施例4:界面活性剤の不溶性異物に及ぼす効果
抗ヒト組織因子抗体溶液製剤の不溶性異物の生成に及ぼす界面活性剤の添加効果を試験した。10mg/mLの抗ヒト組織因子抗体を酢酸緩衝液中に含む試料(pH6.0)に界面活性剤としてポリソルベート80(C社製)、ポロクサマー188(D社製)をそれぞれ0.5mg/mL添加して調製直後及び5℃で24ヶ月保存した後の不溶性異物を試験した。別途、界面活性剤無添加の群も同様に試験して比較した。得られた結果を表1に示す。試料5バイアル中、不溶性異物が確認されたバイアルの本数を示した。界面活性剤無添加では製造直後から不溶物が目視された。しかし、ポロクサマー188及びポリソルベート80ではいずれも不溶性異物の生成は認められなかった。
上述の顆粒球コロニー刺激因子溶液製剤及び副甲状腺ホルモン溶液製剤に、種々の界面活性剤を添加して、顆粒球コロニー刺激因子及び副甲状腺ホルモンの酸化に対する効果を検証した。
実施例5:界面活性剤の顆粒球コロニー刺激因子の酸化に及ぼす影響
顆粒球コロニー刺激因子溶液製剤に対して界面活性剤がどのような影響を及ぼすかを試験した。0.25mg/mLのコロニー刺激因子をリン酸緩衝液中に含む試料(pH6.5)に界面活性剤としてポリソルベート80(A社製)、ポリソルベート20(A社製)、ポロクサマー188(B社製)をそれぞれ0.05%添加して25℃で5週間保存する加速試験後、顆粒球コロニー刺激因子の酸化体の量を逆相クロマトグラフィー(RPC)により測定した。
逆相クロマトグラフィーからわかるとおり、各種界面活性剤を添加した顆粒球コロニー刺激因子溶液製剤のメインピークの直前に、酸化体(図4中の矢印)が出現していた。これらのピーク画分からは、顆粒球コロニー刺激因子の一部のアミノ酸残基が酸化されたものが確認されている。
実施例6:界面活性剤の副甲状腺ホルモンの酸化に及ぼす影響
副甲状腺ホルモン刺激因子溶液製剤に対して界面活性剤がどのような影響を及ぼすかを試験した。0.25mg/mLの副甲状腺ホルモンをクエン酸緩衝液中に含む試料(pH5.0)に界面活性剤としてポリソルベート80(A社製)、ポリソルベート20(A社製)、ポロクサマー188(B社製)をそれぞれ0.05%添加して、40℃で2週間保存する加速試験後、副甲状腺ホルモンの酸化体の量を逆相クロマトグラフィー(RPC)により測定した。
逆相クロマトグラフィーからわかるとおり、各種界面活性剤を添加した副甲状腺ホルモン溶液製剤のメインピークの直前に、酸化体(図5中の矢印)が出現していた。これらのピーク画分からは、副甲状腺ホルモンの一部のアミノ酸残基が酸化されたものが確認されている。
上記の結果から、タンパク質溶液製剤の酸化を抑制する効果は、ポロクサマー188がポリソルベート類よりも優れていることが判明した。
Claims (3)
- 界面活性剤としてポロクサマーを0.5mg/mL含み、添加剤として抗酸化剤を含まず、タンパク質が造血因子、副甲状腺ホルモンまたは抗体である、容器に密封・滅菌されているタンパク質溶液製剤。
- ポロクサマーがポロクサマー188である請求項1に記載の溶液製剤。
- タンパク質が造血因子である、請求項1または2に記載の溶液製剤。
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EP (1) | EP1598074B1 (ja) |
JP (2) | JP4607010B2 (ja) |
KR (1) | KR101235507B1 (ja) |
CN (1) | CN100353997C (ja) |
AU (1) | AU2004216298B2 (ja) |
CA (1) | CA2517310C (ja) |
HK (1) | HK1084340A1 (ja) |
WO (1) | WO2004075913A1 (ja) |
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- 2004-02-27 CN CNB2004800030798A patent/CN100353997C/zh not_active Expired - Lifetime
- 2004-02-27 US US10/547,366 patent/US8765124B2/en not_active Expired - Lifetime
- 2004-02-27 WO PCT/JP2004/002429 patent/WO2004075913A1/ja active Application Filing
- 2004-02-27 EP EP04715529.6A patent/EP1598074B1/en not_active Expired - Lifetime
- 2004-02-27 CA CA2517310A patent/CA2517310C/en not_active Expired - Lifetime
- 2004-02-27 KR KR1020057015821A patent/KR101235507B1/ko active IP Right Grant
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Also Published As
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JPWO2004075913A1 (ja) | 2006-06-01 |
EP1598074A4 (en) | 2011-10-26 |
JP2010215664A (ja) | 2010-09-30 |
CN1744912A (zh) | 2006-03-08 |
KR101235507B1 (ko) | 2013-02-20 |
EP1598074A1 (en) | 2005-11-23 |
US8765124B2 (en) | 2014-07-01 |
US20090264629A1 (en) | 2009-10-22 |
WO2004075913A1 (ja) | 2004-09-10 |
CN100353997C (zh) | 2007-12-12 |
CA2517310A1 (en) | 2004-09-10 |
JP4607010B2 (ja) | 2011-01-05 |
CA2517310C (en) | 2015-11-24 |
KR20050113199A (ko) | 2005-12-01 |
AU2004216298A1 (en) | 2004-09-10 |
AU2004216298B2 (en) | 2009-04-23 |
US20060159653A1 (en) | 2006-07-20 |
EP1598074B1 (en) | 2019-01-02 |
US9968677B2 (en) | 2018-05-15 |
HK1084340A1 (en) | 2006-07-28 |
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