JP5981538B2 - Fgf−18の凍結乾燥製剤 - Google Patents
Fgf−18の凍結乾燥製剤 Download PDFInfo
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- JP5981538B2 JP5981538B2 JP2014515216A JP2014515216A JP5981538B2 JP 5981538 B2 JP5981538 B2 JP 5981538B2 JP 2014515216 A JP2014515216 A JP 2014515216A JP 2014515216 A JP2014515216 A JP 2014515216A JP 5981538 B2 JP5981538 B2 JP 5981538B2
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Description
1)緩衝液、界面活性物質及び安定化剤と共に、FGF-18の混合物を形成する工程、並びに
2)斯かる混合物を凍結乾燥(lyophilisation){凍結乾燥(freeze-drying)}に供する工程、
を含んでなり、緩衝液がリン酸緩衝液であり、安定化剤が糖、例えば、スクロース等であり、界面活性物質がポロクサマー界面活性物質、例えば、ポロクサマー188等である。好ましい実施形態において、緩衝液はpHをちょうど又は約6〜8に維持し、好ましくは、ちょうど又は約7.2に維持する。
1)安定な凍結乾燥製剤であって、凍結乾燥製剤がFGF-18、緩衝液、界面活性物質及び安定化剤、を含んでなる第一の容器、並びに
2)再構成のための溶剤を含んでなる第二の容器、
を含んでなる医薬又は獣医的使用の製品であって、
緩衝液がリン酸緩衝液であり、安定化剤が糖、例えば、スクロース等であり、界面活性物質がポロクサマー界面活性物質、例えば、ポロクサマー188等であり、再構成用溶剤が水又は生理食塩水(例えば、注射用の0.9% w/v塩化ナトリウム)である、製品を供する。
本明細書中の用語「FGF-18タンパク質」又は「FGF-18」は、少なくとも1つのヒトFGF-18タンパク質の生物学的活性を維持するタンパク質であることを意図する。FGF-18は、天然の、その成熟形態、又は切断型とすることができる。ヒトFGF-18タンパク質の生物学的活性には、特に骨芽細胞活性の増加(国際公開第98/16644号)又は軟骨形成の増大(国際公開第2008/023063号)が含まれる。
本発明の主な目的は、FGF-18タンパク質、緩衝液、ポロクサマー界面活性物質及び安定化剤としての糖を含んでなる又はから成る安定な凍結乾燥製剤である。好ましい実施形態において、緩衝液はリン酸緩衝液であり、ポロクサマー界面活性物質はポロクサマー188であり、安定化剤はスクロースである。好ましくは、FGF-18タンパク質は、1)配列番号1の残基28(Glu)〜残基207(Ala)を含んでなる又はから成る配列に相当する、ヒトFGF-18の成熟形態を含んでなる又はから成るポリペプチド、2)配列番号1の残基28(Glu)〜残基196(Lys)を含んでなる又はから成るヒトFGF-18の切断型を含んでなる又はから成るポリペプチド、及び3)配列番号2を含んでなる又はから成るポリペプチド、から成る群から選択される。より好ましくは、FGF-18は、trFGF-18である。
1)濃度比1:95000〜1:6000又は約1:95000〜約1:6000、好ましくは、ちょうど又は約1:92000、1:61000、1:31000、1:18450、1:9200又は1:6100のFGF-18:スクロース、
2)濃度比1:25〜6:10又は約1:25〜6:10、好ましくは、ちょうど又は約1:25、5:83、5:42、1:5、2:5又は6:10のFGF-18:ポロクサマー188、
3)モル比1:10500〜1:700又は約1:10500〜約〜1:700、好ましくは、ちょうど又は約1:10500、1:7000、1:3500、1:2100、1:1050又は1:700、のpH 7.2のFGF-18:リン酸緩衝液、を含んでなる安定な凍結乾燥製剤を目的とし、
FGF-18タンパク質は好ましくは、
1)配列番号1のアミノ酸残基28(Glu)〜207(Ala)を含んでなる又はから成るポリペプチド、2)配列番号1のアミノ酸残基28(Glu)〜196(Lys)を含んでなる又はから成るポリペプチド、又は3)配列番号2を含んでなる又はから成るポリペプチド、から成る群から選択される。より好ましくは、FGF-18タンパク質は、配列番号1のアミノ酸残基28(Glu)〜207(AIa)を含んでなる又はから成る。
1)モル比1:90000〜1:5000又は約1:90000〜1:5000、好ましくは、ちょうど又は約1:87000、1:58000、1:29000、1:17400、1:8700又は1:5800のFGF-18:スクロース、
2)モル比5:120〜5:8又は約5:120〜5:8、好ましくは、ちょうど又は約5:118、5:79、10:79、10:47、5:12又は5:8のFGF-18:ポロクサマー188、
3)モル比1:10000〜1:700又は約1:10000〜1:700、好ましくは、ちょうど又は約1:10000、1:6600、1:3300、1:2000、1:1000又は1:700のpH 7.2のFGF-18:リン酸緩衝液、
を含んでなる安定な凍結乾燥製剤を目的とし、FGF-18タンパク質は、好ましくは、
1)配列番号1のアミノ酸残基28(Glu)-207(Ala)を含んでなる又はから成るポリペプチド、2)配列番号1のアミノ酸残基28(Glu)-196(Lys)を含んでなる又はから成るポリペプチド、又は3)配列番号2を含んでなる又はから成るポリペプチド、から成る群から選択される。より好ましくは、FGF-18タンパク質は、配列番号1のアミノ酸残基28(Glu)-196(Lys)を含んでなる又はから成る。さらに好ましくは、FGF-18タンパク質は、配列番号2を含んでなる又はから成る。特に実施形態において、FGF-18タンパク質はtrFGF-18である。
1)緩衝液、ポロクサマー界面活性物質及び安定化剤としての糖と、FGF-18の混合物を形成する工程、及び
2)混合物を凍結乾燥へ供する工程、
を含んでなる。
1)上記の安定な凍結乾燥製剤のいずれかを含んでなる第一の容器であって、製剤がFGF-18、緩衝液、ポロクサマー界面活性物質、安定化剤としての糖を含んでなる又はから成る、第一の容器、及び
2)再構成のための溶剤を含んでなる第二の容器、
を含んでなる製品を供する。
配列番号1: 天然のヒトFGF-18のアミノ酸配列。
配列番号2: 組み換え切断FGF-18(trFGF-18)のアミノ酸配列。
本実施例の組み換え切断FGF-18(trFGF-18)は、国際出願第2006/063362号に記載される技術に従って、大腸菌における発現によって調製した。以下の実施例において、trFGF-18及びFGF-18は、互換的に使用する。
- スクロース(1.07653、Merck; 分子量: 342.30 g/Mol)
-リン酸二水素ナトリウム一水和物(1.06345、Merck)
- リン酸二水和物二ナトリウム水素(1.06586、Merck)
- ポロクサマー188(Lutrol F 68 DAC、USP/NF、Basf; 分子量: 8400 g/Mol)
- 注射用の水、
- 生理食塩水(注射用0.9% w/v 塩化ナトリウム)
- タンパク質含有量のためのモノクローナル抗体抗FGF-18クローン#F5A2(RBMから供給)
- BAF3-FGFR3c細胞(ワシントン大学)
- Roswell Park Memorial Institute(RPMI)1640ベースの選択培地(Invitrogen)
- ATPlite 1 step 発光アッセイシステム(Perkin Elmer)
- ヘパリンH3149(Sigma)
- AMICON ULTRA-4 10,000カットオフ(UFC 8012024、Amicon)
- ビアコア 2000(ビアコア)
- CO2 インキュベーター(Heraeus)
- カラムTSK2000SWxI、7.8 x 300 mm、5μ(TosoHaas、code 08540)
- Guard column TSKG2000(Hichrom、code 8543)
- HPLCシステム(水)
- ルミノメーター(Perkin Elmer)
- メンブランフィルター0.22 pm(Durapore type GWVP、Millipore)
- Stabileoソフトウェア(ver. 1.1; Microsoft(登録商標)Excel Visual Basic(登録商標)のパッケージ)
- GraphPadソフトウェア(Prism)
- ステンレス鋼ホルダー22 mL及び220 mLの容量(Sartorius)
- Zorbax 300SB-C18(150X4.6cm)カラム
- DIN2R(3 ml)ガラスバイアル(Nuova OMPI)
- コーティングゴム製ストッパー(S2F452、D777-1、B2-40、West Pharmaceutical)
- ゴム製ストッパー(コード1779、W1816 grey、Pharma-Gummi)
製剤への異なるアッセイ
標準方法を、以下に関して使用した。
- SE-HPLC、
- RP-HPLC、
- 残留水分、
- pH、
- 浸透圧(時間0、のみ)、
- SDS-PAGE/SS、及び
- ペプチドマッピング/UPLC(酸化型)。
異なる製剤中のタンパク質、すなわち、trFGF-18の定量化を、ビアコアによって行った。trFGF-18を含む試料(25pL)を(10 mg/mLのBSAの存在下で適切に希釈)、続いて25℃、5pL/minで、予めモノクローナル抗体抗FGF-18クローンF5A2でコーティングしたセンサー表面上で、続いて再生緩衝液としての5pLの10mMグリシンpH 2.0で試験した。125〜2,000 ng/mLの範囲の標準試料(IRS FGF-18 No. 051230)を、各分析セッションに流した。結果を共鳴単位(RU)として収集し、対数変換後のデータで、二次アルゴリズムを使用してあてはめた標準曲線から、各試料のFGF-18レベルを推定した。
FGF-18の生物学的活性を、FGF受容体3c(FGFR3c)を安定に遺伝子導入したBaF3細胞系統を使用して、インビトロ(in-vitro)生物検定によって増殖活性として測定する。BaF3細胞発現FGFR3cは、FGF-18刺激下で増殖する。
FGF-18凍結乾燥製剤の組成を、以下の表1に供する。
表1: FGF-18凍結乾燥製剤に関する組成(*)
実施例2.1: さらに試験する凍結乾燥プレ製剤を特定するために、加速安定性条件(2〜8℃、25℃及び40℃)を使用した(データの提示なし)。
表1の候補凍結乾燥製剤において、2週間〜24月間の安定性データを収集した。
表2: SE-HPLCにより分析した、貯蔵での凍結乾燥プレ製剤(FGF-18の10 mcg/バイアル及びF68の0.2 mg/バイアル)におけるFGF-18モノマーのパーセンテージ(%)。
(b)製剤化前のピークは、77.5%に存在した。
* 1mL WFIでの再構成後、元のバッチは0.5mLであった。
** 回収の%; 製剤BF中のFGF-18タンパク質の量と比較。
1. Ellsworth et al., 2002, Osteoarthritis and Cartilage, 10: 308-320
2. Shimoaka et al., 2002, JBC 277(9)7493-7500
3. 国際公開第2008023063号
4. 国際公開第2004032849号
5. 国際公開第00/21548号
6. 国際公開第2008/121563号
7. 国際公開第92/01442号
8. 国際公開第01/39788号
9. 国際公開第98/16644号
10. 国際公開第2006/063362号
11. Custers et al., 2007, Osteoarthritis and Cartilage, 15:1241-1248
Claims (12)
- FGF-18、pHを7.0〜7.5に維持するリン酸緩衝液、ポロクサマー188、及びスクロースを含んでなる、安定な凍結乾燥製剤。
- 前記リン酸緩衝液が、pHを7.2に維持する、請求項1に記載の安定な凍結乾燥製剤。
- 前記リン酸緩衝液の濃度が、5〜100 mMである、請求項1又は2に記載の安定な凍結乾燥製剤。
- 前記ポロクサマー188の濃度が、0.1〜0.4 mg/バイアルである、請求項1〜3のいずれか1項に記載の安定な凍結乾燥製剤。
- 前記スクロースの濃度が、10〜60 mg/バイアルである、請求項1〜4のいずれか1項に記載の安定な凍結乾燥製剤。
- FGF-18の濃度が、20〜300 mcg/バイアルである、請求項1〜5のいずれか1項に記載の安定な凍結乾燥製剤。
- 前記製剤が、20、30、60、100、200又は300 mcg/バイアルのFGF-18、pHを7.2に維持する10 mMリン酸緩衝液、30 mg/バイアルのスクロース、及び0.2 mg/バイアルのポロクサマー188を含んでなる、請求項1〜6のいずれか1項に記載の安定な凍結乾燥製剤。
- 前記製剤が、FGF-18を5%以上含んでなる、請求項1〜7のいずれか1項に記載の安定な凍結乾燥製剤。
- FGF-18が、
a. 配列番号1のアミノ酸残基28〜207を含んでなる又はから成るポリペプチド、
b. 配列番号1のアミノ酸残基28〜196を含んでなる又はから成るポリペプチド、及び
c. 配列番号2を含んでなる又はから成るポリペプチド、
から成る群から選択される、請求項1〜8のいずれか1項に記載の安定な凍結乾燥製剤。 - 請求項1〜9のいずれか1項に記載の安定な凍結乾燥製剤の製造方法であって、
a. FGF-18と、リン酸緩衝液、ポロクサマー188及びスクロースとの混合物を形成する工程、及び
b. 前記混合物を凍結乾燥に供する工程、
を含んでなる、前記方法。 - 請求項1〜9のいずれか1項に記載の安定な凍結乾燥製剤を含んでなる第一の容器、及び再構成用の溶剤を含んでなる第二の容器、を含んでなる製品。
- 前記安定な凍結乾燥製剤を含んでなる容器及び再構成用の溶剤を含んでなる容器が、デュアルチャンバーシステムの2つのコンパートメントである、請求項11に記載の製品。
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CN109836487B (zh) * | 2019-03-01 | 2022-06-17 | 重庆派金生物科技有限公司 | 一种人成纤维细胞生长因子18及其可溶性重组表达方法、制备方法、制剂和应用 |
CN112121150A (zh) * | 2019-06-24 | 2020-12-25 | 杭州生物医药创新研究中心 | 一种成纤维细胞生长因子10冻干粉 |
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CN118310835A (zh) * | 2024-04-16 | 2024-07-09 | 杭州百凌生物科技有限公司 | 一种质控品冻干粉及其制备方法和应用 |
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