JP5655179B2 - [4−(メチルチオ)フェニルチオ]メタンビスホスホン酸又は薬学的に許容され得るその塩を有効成分とする骨形成促進剤 - Google Patents
[4−(メチルチオ)フェニルチオ]メタンビスホスホン酸又は薬学的に許容され得るその塩を有効成分とする骨形成促進剤 Download PDFInfo
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- JP5655179B2 JP5655179B2 JP2010527665A JP2010527665A JP5655179B2 JP 5655179 B2 JP5655179 B2 JP 5655179B2 JP 2010527665 A JP2010527665 A JP 2010527665A JP 2010527665 A JP2010527665 A JP 2010527665A JP 5655179 B2 JP5655179 B2 JP 5655179B2
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- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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Description
[態様1][(4−メチルチオ)フェニルチオ]メタンビスホスホン酸又は薬学的に許容され得るその塩を有効成分とする骨形成促進剤。
[態様2][(4−メチルチオ)フェニルチオ]メタンビスホスホン酸のナトリウム塩を有効成分とする骨形成促進剤。
[態様3][4−(メチルチオ)フェニルチオ]−メタンビスホスホン酸・2ナトリウム塩を有効成分とする骨形成促進剤。
[態様4]有効成分がリン酸カルシウムから成る徐放剤に吸着されてなる、態様1〜3のいずれか一項に記載の骨形成促進剤。
[態様5]リン酸カルシウムがα−トリカルシウムホスフェート、β−トリカルシウムホスフェート、オクタカルシウムホスフェート及びハイドロキシアパタイトから成る群から選択される、態様4記載の骨形成促進剤。
[態様6]態様1〜5のいずれか一項に記載の骨形成促進剤を含み、骨形成促進作用を有する医薬組成物。
[態様7]水溶液の形態である、態様6記載の医薬組成物。
[態様8]注射液の形態を有する、態様7に記載の医薬組成物。
[態様9]態様1〜5のいずれか一項に記載の骨形成促進剤、又は、態様6〜8のいずれか一項に記載の医薬組成物を投与することから成る、骨形成促進方法。
[態様10]態様1〜5のいずれか一項に記載の骨形成促進剤、又は、態様6〜8のいずれか一項に記載の医薬組成物を部位に局所投与することから成る、骨形成促進方法。
[態様11]態様1〜5のいずれか一項に記載の骨形成促進剤、又は、態様6〜8のいずれか一項に記載の医薬組成物を部位に局所投与することから成る、該部位における骨形成促進方法。
[態様12]歯槽骨部に局所投与することから成る、態様11記載の方法。
平均体重2.2kgの雄性日本家兎9羽を用い、それらを3羽づつ3群に分けた。各群の家兎の左側(実験側)上顎第1大臼歯と第2大臼歯の口蓋側歯間歯槽骨の骨膜下に、生理的浸透圧と生理的なpHに調整した0.1、1.0、ないし10 mMのMPMBP溶液50μlを4日おきに6回注射した(いずれもネンブタール麻酔下で実施)。反対側(右側)の同部位には、50μl の生理的食塩水(0.9%NaCl溶液)を同様に注射し、対照とした。最後の注射後4日目に、ネンブタール過剰投与により動物を屠殺し、上顎骨を摘出、10%中性ホルマリン溶液(pH 7.4)で固定した。薬物投与部位附近の歯槽骨および口蓋骨を関心領域として、pQCT(peripheral Quantitative Computerized Tomography;図2) およびμCT (microfocus Computerized Tomography;図3) による3次元解析を行った。その結果、10 mM及び1.0 mMのMPMBP投与群の家兎において、図2に示すような歯槽骨口蓋側への骨添加(「exp」で示した矢印の部分)、また、図3に示すような歯槽部から口蓋正中部にかけての口蓋骨が厚みを増す像が観察された(「exp」で示した矢印の部分)。これらの変化は、1.0mM投与群に比べて10mM投与群の方が強く、0.1mM投与群での効果は不明であった。MPMBPの生体内におけるこのような骨形成促進効果は、既存のビスホスフォネート化合物においては報告されていない。
マウス頭蓋骨由来の骨芽細胞様株化細胞MC3T3-E1細胞(RIKEN Bio Resource Center, CELL BANK:RCB1126)を用い、骨形成の指標の一つとされ、また骨芽細胞前駆細胞の骨芽細胞への分化の指標とされるアルカリホスファターゼ(ALP)活性に対して、MPMBPがどのような効果を持つかについて検討した。MC3T3-E1細胞をα-MEM(10%牛血清添加)で培養し、コンフルエントに達した後、MPMBPの存在(1,10,および100μM)ないし非存在下で、6、10、ないし20日間、48 well のculture plate 中で培養した。培養終了後、細胞ホモジネートを作製し、Lowry et al の方法(J Biochem 1954;207:19-37)によりALP活性(per well)を測定した。その結果、MPMBPは、用量依存的、かつ経時的にALP活性を上昇させた(図4、左)。同様な実験を、他のビスホスフォネート化合物(クロドクロネート、パミドロネート、インカドロネート、ゾレドロネート)についても行った結果、クロドロネートは公知の様に(Felix and Fleisch, Biochem J 1979; 183:73-81; Igarashi et al, Prostaglandins, Leukotriens, and Essential Fatty Acids 1997; 56: 121-125)ALP活性を上昇させた(図4、右)が、パミドロネートには有意な変化は見られず(図5、左上)、インカドロネートやゾレドロネートは、高濃度でALP活性を著明に低下させた(図5、左下および右下)。これらの事実は、ALP活性に及ぼすビスホスフォネート化合物の効果は一様ではなく、P-C-P結合の炭素原子にどのような側鎖が付加されるかによって異なることを示すと同時に、MPMBPにおいては、[4-メチルチオ(フェニルチオ)]側鎖が、ALP活性の上昇に重要な役割を果たしていることを示している。
骨器官培養系を用いてMPMBPが、骨基質の産生にどのような効果を及ぼすかについて検討した。生後3-6日後のマウスより、無菌的にカルバリア(頭蓋冠)を採取した。これらをStern and Krieger の方法(Calcif Tissue Int 1983; 35:172-17)によりDMEM(10%牛血清添加、ヘパリン無添加、LPS 10μg/ml 添加あるいは無添加)で48時間培養した。培養終了後、Suzuki, Takeyama et al により記載された方法(J Histochem Cytochem 2005; 53:1525-1537)により、タイプIコラーゲンとアルカリホスファターゼの二重染色(図6及び8)、タイプIコラーゲンとアリザリンレッドの二重染色(図7)、あるいはタイプIコラーゲンのみ(図9)の免疫組織化学染色を行い、共焦点レーザー顕微鏡により観察した。
上段パネルは骨表面のノマルスキー微分干渉像。中段パネルは、タイプIコラーゲンとアルカリホスファターゼの二重染色を行った後の骨表面像、下段パネルは、タイプIコラーゲンとアルカリホスファターゼの二重染色を行ったあとの骨断面像を夫々示す。タイプIコラーゲンはロダミンにより赤色、アルカリホスファターゼ(骨芽細胞を染色)は脱リン酸化されると蛍光を発する基質(ELF-97)を用いることにより、その酵素活性が緑色に観察できる。培養液中へのMPMBPの添加により、LPS(10μg/ml)(リポポリサッカライド:骨吸収促進因子の一つ)の存在、非存在に関わらず対照骨に比べて著明に骨基質(タイプIコラーゲン:赤色の部分)の産生が増加している。骨芽細胞は、MPMBPの存在下でコラーゲン線維の産生が増すため、自身が産生するコラーゲン線維により被覆され、対照骨のように明瞭に観察できない。また、ノマルスキー微分干渉像の観察から、MPMBPの存在下では、LPSによる骨吸収が抑制され、LPSによって形成される吸収窩の大きさが、対照骨に比べて著しく小さいことが観察できる。
MPMBPの骨形成促進作用のメカニズムを解明するための実験として、骨芽細胞様株化細胞MC3T3-E1細胞を用い、骨形成関連遺伝子の発現に及ぼす効果を、リアルタイムRT-PCR法により検討した。また、その効果をゾレドロネートの作用と比較した。
実験には、α-MEM(10%牛血清添加)で培養後、コンフルエントに達した骨芽細胞様株化細胞MC3T3-E1細胞を用いた。3日間MPMBP(1, 10, ないし100μM)ないしはゾレドロネート(0.1, 0.5 ないしは 2.0μM)の存在下で培養した(60mm径dishを使用)。培養終了後、細胞をscrapeし, トリゾール によりRNA を抽出した。5μgのRNAからcDNAを合成し、アルカリホスファターゼ、タイプI−αコラーゲン、オステオカルシン、骨シアロタンパク遺伝子に対する特異的プライマーを設定し、サーマルサイクラー中でPCR増幅を行い、上記遺伝子の発現量を測定した。
その結果、MPMBPは100μMの濃度において、骨形成促進の指標とされる上記遺伝子の発現をいずれも有意に上昇させた(図10)。これに対してゾレドロネートは、用いた濃度範囲(細胞増殖が抑制されない濃度範囲)では、これら遺伝子の発現量に有意の変化を及ぼさなかった。(図11)。
以上、上記4つの実施例のいずれにおいてもMPMBPは、骨形成に対して促進的な効果をもつことが新たに確認された。
Claims (8)
- [(4−メチルチオ)フェニルチオ]メタンビスホスホン酸又は薬学的に許容され得るその塩を有効成分とする、抜歯窩、のう胞若しくは腫瘍摘出後の骨欠損部;歯周病により吸収された歯槽骨欠損部;先天性異常による顎裂部;骨折部位及び/又はインプラント周囲骨の修復、再生又は補填に用いるための骨形成促進剤。
- [(4−メチルチオ)フェニルチオ]メタンビスホスホン酸のナトリウム塩を有効成分とする、請求項1記載の骨形成促進剤。
- [4−(メチルチオ)フェニルチオ]−メタンビスホスホン酸・2ナトリウム塩を有効成分とする、請求項1記載の骨形成促進剤。
- 有効成分がリン酸カルシウムから成る徐放剤に吸着されてなる、請求項1〜3のいずれか一項に記載の骨形成促進剤。
- リン酸カルシウムがα−トリカルシウムホスフェート、β−トリカルシウムホスフェート、オクタカルシウムホスフェート及びハイドロキシアパタイトから成る群から選択される、請求項4記載の骨形成促進剤。
- 請求項1〜5のいずれか一項に記載の骨形成促進剤を含み、抜歯窩、のう胞若しくは腫瘍摘出後の骨欠損部;歯周病により吸収された歯槽骨欠損部;先天性異常による顎裂部;骨折部位及び/又はインプラント周囲骨の修復、再生又は補填に用いるための医薬組成物。
- 水溶液の形態である、請求項6記載の医薬組成物。
- 注射液の形態を有する局所投与用である、請求項7に記載の医薬組成物。
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JP3566984B2 (ja) | 1994-06-02 | 2004-09-15 | 帝人株式会社 | 骨形成促進剤 |
CA2182886A1 (en) | 1994-12-22 | 1996-06-27 | Hiromi Uchiro | Process for producing bis(4-alkylthiophenyl) disulfide |
CA2321864A1 (en) * | 1998-12-25 | 2000-07-06 | Toray Industries, Inc. | Interleukin-6 production inhibitor |
ES2337545T3 (es) | 1999-07-19 | 2010-04-27 | Toray Industries, Inc. | Farmacos para enfermedades periodontales. |
WO2001008690A1 (fr) * | 1999-08-02 | 2001-02-08 | Toray Industries, Inc. | Stabilisateurs d'insertion pour implants |
WO2001017562A1 (en) * | 1999-09-02 | 2001-03-15 | Yamanouchi Pharmaceutical Co., Ltd. | Osteogenesis promoting agents |
-
2009
- 2009-08-05 WO PCT/JP2009/003758 patent/WO2010026701A1/ja active Application Filing
- 2009-08-05 US US13/059,969 patent/US20110230447A1/en not_active Abandoned
- 2009-08-05 JP JP2010527665A patent/JP5655179B2/ja active Active
- 2009-08-05 EP EP09811231.1A patent/EP2340841B1/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993005052A1 (fr) * | 1991-09-05 | 1993-03-18 | Toray Industries, Inc. | Derive d'acide methanediphosphonique, sa production et son utilisation comme remede |
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EP2340841B1 (en) | 2016-11-09 |
EP2340841A4 (en) | 2012-03-28 |
US20110230447A1 (en) | 2011-09-22 |
EP2340841A1 (en) | 2011-07-06 |
WO2010026701A1 (ja) | 2010-03-11 |
JPWO2010026701A1 (ja) | 2012-01-26 |
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