JP4754823B2 - Fgf18の投与方法 - Google Patents
Fgf18の投与方法 Download PDFInfo
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- JP4754823B2 JP4754823B2 JP2004543362A JP2004543362A JP4754823B2 JP 4754823 B2 JP4754823 B2 JP 4754823B2 JP 2004543362 A JP2004543362 A JP 2004543362A JP 2004543362 A JP2004543362 A JP 2004543362A JP 4754823 B2 JP4754823 B2 JP 4754823B2
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- fgf18
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- cartilage
- hyaluronic acid
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Description
線維芽細胞成長因子(FGF)ファミリーは、一般的に広範囲の細胞型のためのマイトジェンとして作用する、少なくとも23種の明確なメンバーからなる(Basilico など. , Adv. Cancer Res. 59: 115-165,1992 及び Fernig など., Prog. Growth Factor Res. 5 (4) : 353-377,1994)。FGF18は、FGF8及びFGF17に最も密接して関連するFGFファミリーのメンバーとして同定された。FGF18に関連する活性は、間葉系細胞、特に心筋細胞、骨芽細胞及び軟骨細胞の刺激を包含した(アメリカ特許第6,352,971号)。FGF18は、FGFR4、及びFGFR3及びFGFR2の“III c”スプライス変異体を結合し、そして活性化する。FGFR3は骨成長において役割を演じる。
本発明を詳細に記載する前、次の用語を定義することで本発明の理解を助けることができる:
“親和性標識”とは、第2ポリペプチドの精製又は検出を提供し、又は基質への第2ポリペプチドの結合のための部位を供給するために、第2ポリペプチドに結合され得るポリペプチドセグメントを示すために本明細書において使用される。主に、抗体又は、他の特異的結合剤が利用できるいずれかのペプチド又はタンパク質が親和性標識として使用され得る。
用語“プロモーター”とは、RNA ポリメラーゼの結合及び転写の開始を提供するDNA配列を含む遺伝子の部分を示すために本明細書において使用される。プロモーター配列は通常、遺伝子の5’ 非コード領域に見出されるが、しかし必ずしもそうではない。
不正確な分析方法(例えば、ゲル電気泳動)により決定されるポリマーの分子量及び長さは、おおよその値であることが理解されるであろう。そのような値が“約”X又は“おおよそ”Xとして表される場合、その言及されたXの値は、正確には±10%であることが理解されるであろう。
本発明は、FGF18ポリペプチド又はタンパク質、及び負に荷電されたキャリヤー、例えばヒアルロン酸の組成物が滑膜関節に投与される場合、FGF18の刺激効果が増強される発見に一部、基づかれている。従って、本発明は、間葉細胞、特に軟骨細胞の増殖を刺激するための、FGF18ポリペプチド又はタンパク質、及び負に荷電されたキャリヤー、特にヒアルロン酸の組成物に向けられる。前記組成物は、滑液を含む関節に関節内投与される。
アメリカ特許第4,851,521号及びヨーロッパ特許出願第0.265,116号は両者とも、HA画分及びHAの架橋されたエステルを記載する。アメリカ特許第4,851,521号は、局部使用のための眼科用医薬のための、及び例えば坐剤において経皮的吸収の効果のために全身性効果のための坐剤において、活性成分として及びビークルとして医薬製剤中に組み込まれるHAのエステルを記載する。
例1:FGF18関節内注入:
FGF18を、凍結乾燥し、そしてPBS又は0.5%ヒアルロンナン(0.2μmの無菌濾過された)のいずれかにおいて適切な濃度で再構成した。5μlの最終体積で含まれる、PBS又は0.5%ヒアルロンナンのいずれかに溶解された、FGF18、ビークル(PBS)、ヒアルロナン又はFGF18の適切な組み合わせの単一用量を、生後10週の雌のc57/B16マウスの左後膝関節(膝)の関節内空間中に注入した。グループ当たり7匹の動物が存在した。すべての投与は、イソフルラン麻酔下で行われ、そして100μlのブプレノルフィンが無痛法のために、回収に基づいて投与された。動物を、投与後2週間で殺害し、そして組織を通常の組織学のために採取した。
グループ 処理:
1 処理なし
2 PBS
3 PBS中、5μgのFGF18
4 PBS中、0.5μgのFGF18
5 PBS中、0.05μgのFGF18
6 ヒアルロナン0.5%
7 ヒアルロナン0.5%+5.0μgのFGF18
8 ヒアルロナン0.5%+0.5μgのFGF18
9 ヒアルロナン0.5%+0.05μgのFGF18
10 擬似注射
最後に、FGF18の有意な全身性効果が、遠隔の軟骨部位又は他の組織でヒアルロナンと共に5μgのFGF18を受けた動物において観察されなかった。しかしながら、骨端のいくらかの集中的閉鎖が、HAのみを受けた1匹の動物、及び5μgのFGFのみを受けた1匹の動物に置いて観察された。それらの観察の有意性は、この時点で明確ではない。
FGF18が変形性関節症(OA)の設定に置いて、軟骨組織を生成するか、又は軟骨変性を逆転するかどうかを評価するために、OAを、ラットの膝関節において半月板裂け目をつけることにより誘発した。このモデルにおいては、半月板への損傷は、自発的変形性関節炎において生じる変化を模倣する進行性軟骨変性及び骨増殖体形成を誘発する。
Claims (16)
- 線維芽細胞成長因子18(FGF18)及び負に荷電されたキャリヤーを含んで成る医薬的に許容できる混合物を含んで成る、軟骨形成ポリペプチドの関節内供給し、軟骨組織の形成及び維持を促進する組成物において、前記負に荷電されたキャリヤーが、ヒアルロン酸(HA)、ヒアルロン酸のエステル、ヒアルロン酸の塩、低分子量ヒアルロナン及び高分子量ヒアルロナンから成る群から選択され、前記HAが架橋されていない、ことを特徴とする前記組成物。
- 前記負に荷電されたキャリヤーがHAである、請求項1に記載の組成物。
- 持効性配合物である請求項1又は2に記載の組成物。
- 前記持効性配合物が、溶液、ゲル、ペースト又はパテから成る群から選択されたマトリックスを含んで成る請求項3に記載の組成物。
- 前記持効性配合物が、レザバーシステムを含んで成る請求項3に記載の組成物。
- 関節内投与の前、FGF18の存在下で培養された軟骨細胞をさらに含んで成る請求項1又は2に記載の組成物。
- 抗−炎症薬剤をさらに含んで成る請求項1又は2に記載の組成物。
- FGF18及び負に荷電されたキャリヤーを含んで成る医薬的に許容できる混合物を含んで成る、哺乳類の関節における軟骨細胞増殖のため、軟骨組織の形成及び維持の促進する滑膜腔内投与用医薬組成物において、前記負に荷電されたキャリヤーが、ヒアルロン酸(HA)、ヒアルロン酸のエステル、ヒアルロン酸の塩、低分子量ヒアルロナン及び高分子量ヒアルロナンから成る群から選択され、前記HAが架橋されていない、ことを特徴とする前記組成物。
- 前記負に荷電されたキャリヤーがHAである、請求項8に記載の組成物。
- 注射用の請求項8又は9に記載の医薬組成物。
- 手術による移植のための請求項8又は9に記載の医薬組成物。
- 前記混合物が、持効性配合物である請求項8又は9に記載の医薬組成物。
- 前記持効性配合物が、溶液、ゲル、ペースト又はパテから成る群から選択されたマトリックスを含んで成る請求項12に記載の医薬組成物。
- 前記持効性配合物が、レザバーシステムを含んで成る請求項12記載の医薬組成物。
- 前記混合物が、抗−炎症薬剤をさらに含んで成る請求項8又は9に記載の医薬組成物。
- 哺乳類の関節炎を治療するために滑膜腔内に投与するための、請求項1〜15のいずれか1項に記載の組成物。
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2003
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000078356A1 (en) * | 1999-06-18 | 2000-12-28 | Orquest, Inc. | Injectable hyaluronate-sulfated polysaccharide conjugates |
Also Published As
Publication number | Publication date |
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CA2500742C (en) | 2014-02-18 |
AU2003279835B2 (en) | 2009-09-10 |
CA2500742A1 (en) | 2004-04-22 |
ES2493840T3 (es) | 2014-09-12 |
EP1551426A4 (en) | 2009-06-24 |
JP2006508078A (ja) | 2006-03-09 |
US20080193425A1 (en) | 2008-08-14 |
IL167748A (en) | 2010-11-30 |
US8507430B2 (en) | 2013-08-13 |
WO2004032849A3 (en) | 2004-09-30 |
US20040136970A1 (en) | 2004-07-15 |
EP1551426A2 (en) | 2005-07-13 |
WO2004032849A2 (en) | 2004-04-22 |
AU2003279835A1 (en) | 2004-05-04 |
JP2011079861A (ja) | 2011-04-21 |
EP1551426B1 (en) | 2014-06-25 |
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