JP5242769B2 - 骨集積および殺腫瘍部分を有する修飾ヒドロキシポリマー複合体 - Google Patents
骨集積および殺腫瘍部分を有する修飾ヒドロキシポリマー複合体 Download PDFInfo
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- JP5242769B2 JP5242769B2 JP2011503339A JP2011503339A JP5242769B2 JP 5242769 B2 JP5242769 B2 JP 5242769B2 JP 2011503339 A JP2011503339 A JP 2011503339A JP 2011503339 A JP2011503339 A JP 2011503339A JP 5242769 B2 JP5242769 B2 JP 5242769B2
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- hydroxypolymer
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- guanidine
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- biphosphonate
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
- A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Description
[活性化]
医薬品グレードのデキストランPM40(150mg)を水5mlに溶解させた。過ヨウ素酸ナトリウム120mgを加え、次いで、濃硫酸25μlを加えた。この混合溶液を45分間撹拌した。酸化を停止させるため、エチレングリコール25μlを加え、さらに15分間反応させることによって過剰な過ヨウ素酸塩を破壊した。次に、pHを0.2M酢酸ナトリウムで6.5に調整した。
上記の手順によって得られた溶液2mlをアレンドロネート20mgおよびシアノ水素化ホウ素ナトリウム5mgと混合した。この溶液を室温で撹拌し、1.5時間インキュベートさせた。1時間後、アミノグアニジン80mgを加えた。この溶液を室温でさらに4時間撹拌し、次に、溶離剤としてPBSを用いるPD10カラム上において低分子量成分から分離した。精製した複合体溶液4mLを得た。通常、この合成では、デキストラン1mol当りグアニジン20〜30molおよびアレンドロネート10〜20molとなる。
LarssonおよびNygren(Larsonら、 Anticancer Res, 1989年、第9版:1111〜1119頁)に記載されるように蛍光細胞毒性アッセイを行った。
[活性化]
医薬品グレードのデキストランPM70(150mg)を水6mlに溶解させた。過ヨウ素酸ナトリウム120mgを加え、次いで、濃硫酸25μl加えた。この混合溶液を30分間撹拌した。酸化を停止させるため、エチレングリコール75μlを加え、さらに15分間反応させることによって過剰な過ヨウ素酸塩を破壊した。溶離剤として0.1M酢酸塩(pH6.5)を用いるPD10カラム上においてゲル濾過により低分子量成分から1mLずつ活性化デキストランを精製した。各分離において、活性化デキストラン溶液2mLを得た。
上記の手順によって得られた溶出液1mlをアレンドロネート10mgおよび過ヨウ素酸ナトリウム5mgと混合した。この溶液を室温で撹拌し、2時間インキュベートさせた。2時間後、アミノグアニジン65mg2を加えた。この溶液を室温で一晩撹拌し、次に、溶離剤としてPBSを用いるPD10カラム上において低分子量成分から分離した。精製した複合体溶液2mLを得た。
上記の手順によって得られた溶出液1mlをアミノグアニジン65mgおよび過ヨウ素酸ナトリウム5mgと混合した。この溶液を室温で撹拌し、2時間インキュベートさせた。2時間後、アレンドロネート10mgを加えた。この溶液を室温で一晩撹拌し、次に、溶離剤としてPBSを用いるPD10カラム上において低分子量成分から分離した。精製した複合体溶液2mLを得た。
0.2M 酢酸ナトリウム緩衝液(pH6)300μl中のグアニジン−デキストラン−ビホスホネート複合体3mgを過テクネチウム酸塩300μl(約700MBq)と混合し、次いで、塩化第一スズ10μl(エタノール中約50μg)を加え、この溶液をゆるやかに混合し、15分間インキュベートさせた。インキュベーション後、この溶液を使い捨てセファデックスG25カラム(PD10)上で精製した。最後に、この精製した溶液を滅菌フィルタ(0.22μ)で濾過し、得られた標識収率を測定した。
骨病変と診断された二人のホルモン抵抗性前立腺癌患者に、約500MBqのテクネチウム99mで標識されたデキストラン−グアニジン−ビホスホネート約3mgを注射した。注射してから2、4、6、24時間後に、ガンマ画像を回収した。
明確な摂取は、右膝(図7)および右肩(図8)において示される。これらの画像は、診断の際に実施された従来の骨のスキャンの結果と一致している。この結果は、デキストラン−グアニジン−ビホスホネートの実現可能性および前立腺癌の骨転移を治療するためのその潜在力を示している。デキストラン−グアニジン−ビホスホネートは、骨粗鬆症の治療に対して潜在力を有する。
Claims (12)
- 修飾ヒドロキシポリマー複合体であって、前記修飾ヒドロキシポリマー複合体は、ビホスホネート基および少なくとも1つの遊離アミノ基を有するグアニジン基であるアグマチンまたはアミノグアニジンによって置換されたヒドロキシポリマーデキストランであり、前記ビホスホネート基および前記グアニジン基は、前記ヒドロキシポリマーの活性化ヒドロキシル基に共有結合したことを特徴とする修飾ヒドロキシポリマー複合体。
- 前記ビホスホネート基は、ネリドロネートまたはアレンドロネートであることを特徴とする請求項1に記載の修飾ヒドロキシポリマー複合体。
- 前記ヒドロキシポリマーデキストランは、分子量が103〜106ダルトンであることを特徴とする請求項1または2に記載の修飾ヒドロキシポリマー複合体。
- 前記修飾ヒドロキシポリマー複合体は、ヒドロキシポリマーデキストラン1mol当り、グアニジン基であるアグマチンまたはアミノグアニジンを少なくとも25mol含むことを特徴とする請求項1〜3のいずれかに記載の修飾ヒドロキシポリマー複合体。
- 前記修飾ヒドロキシポリマー複合体は、少なくとも1つのさらなる共有結合した官能基を含むことを特徴とする請求項1〜4のいずれかに記載の修飾ヒドロキシポリマー複合体。
- 前記官能基は、放射性核種、治療性化合物、抗癌剤、または標的剤であることを特徴とする請求項5に記載の修飾ヒドロキシポリマー複合体。
- 骨腫瘍もしくは骨転移または骨粗鬆症を治療するための、請求項1〜6のいずれかに記載の修飾ヒドロキシポリマー複合体を含む組成物。
- 治療される前記骨腫瘍または骨転移は、ホルモン抵抗性前立腺癌または乳癌に関連する請求項7に記載の組成物。
- 前記組成物は、局所、膀胱内、部位局所、腹膜内、腫瘍内、全身、または静脈内投与可能であることを特徴とする請求項7または8に記載の組成物。
- 少なくとも1つの薬学的に許容可能なアジュバントをさらに含むことを特徴とする腫瘍細胞死滅効果を有する請求項7〜9のいずれかに記載の組成物。
- 少なくとも1つの遊離アミノ基を有するグアニジン化合物であるアグマチンまたはアミノグアニジンおよびビホスホネート化合物は、精製した活性化ヒドロキシポリマーデキストランを含む溶液に順次加えられることを特徴とする請求項1〜6のいずれかに記載の修飾ヒドロキシポリマー複合体を製造する方法。
- 前記活性化ヒドロキシポリマーは、過ヨウ素酸塩がヒドロキシポリマーを含む水溶液に加えられ、次いで濃硫酸が加えられる酸化反応によって得られ、前記酸化反応は、エチレングリコールを加えることによって停止し、次いで、ゲル濾過によって精製が行われることを特徴とする請求項11に記載の方法。
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BRPI0822415B8 (pt) | 2021-05-25 |
US20110118207A1 (en) | 2011-05-19 |
CN101990442A (zh) | 2011-03-23 |
WO2009124580A1 (en) | 2009-10-15 |
IL208424A (en) | 2015-03-31 |
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