JP2009503187A - ナノ粒子を用いたドラッグデリバリーのためのトリブロック共重合体 - Google Patents
ナノ粒子を用いたドラッグデリバリーのためのトリブロック共重合体 Download PDFInfo
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- JP2009503187A JP2009503187A JP2008523856A JP2008523856A JP2009503187A JP 2009503187 A JP2009503187 A JP 2009503187A JP 2008523856 A JP2008523856 A JP 2008523856A JP 2008523856 A JP2008523856 A JP 2008523856A JP 2009503187 A JP2009503187 A JP 2009503187A
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- triblock copolymer
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Abstract
Description
製薬およびバイオテクノロジー産業が抱える重要な問題点は、疎水性の治療用化合物のための効果的で無毒なデリバリーシステムの利用可能性が限られていることである。例えば、胸部および卵巣の腫瘍の治療に選択されるパクリタキセルは、疎水性である。したがって、パクリタキセルの臨床的な投与には、望ましくない副作用につながる油またはエタノールの賦形剤に分散させる必要がある。
本発明者らのアプローチによって、幅広い疎水性の治療薬をデリバリーできる、ナノ粒子のための多用途の共重合体アーキテクチャが開発されてきた。本発明者らは、本明細書中に、ナノ粒子は、抗腫瘍剤であるパクリタキセルなどの疎水性分子と強く複合体化し、これをインビトロで腫瘍細胞に効果的にデリバリーすることをさらに示す。
1.一群のトリブロック共重合体は、患者に導入された後、完全に再吸収可能である。前記組成物は、無毒のビルディングブロックのみから誘導されるため、前記トリブロック共重合体はそれ自体、予想されるインビボの分解産物と同様、無毒であって生体適合性である。
図1は、PEG−b−オリゴ(DTR−SA)−b−PEGトリブロック共重合体の典型的な構造を示す図面である。
図5Aは、遊離フルオレセイン分画後のナノ粒子(▲)、およびフルオレセイン存在下で調製したナノ粒子(●)の検出を示す;
図5Bは、遊離DAF分画後のナノ粒子(▲)およびDAF存在下19で調製したナノ粒子(●)の検出を示す;
図5Cは、遊離フルオレセイン分画後のナノ粒子(▲)およびフルオレセイン存在下で調製したナノ粒子(●)の検出を示す;
図5Dは、遊離DAF分画後のナノ粒子(▲)およびDAF存在下で調製したナノ粒子(●)の検出を示す。
本発明の共重合体は、A−B−A型のトリブロックである。A末端ブロックは水溶性、親水性、および無毒であり、好ましくはポリ(アルキレンオキサイド)から選択され、疎水性の中央のBブロックはポリアリーレートまたはポリカーボネートである。好ましいポリアリーレートの実施形態においては、中央ブロックは、チロシン誘導ジフェノールのフェノール性ヒドロキシル基と二酸のカルボン酸基との間のエステル結合によって互いに結合する、チロシン誘導ジフェノールおよび二酸から共重合される。他の好ましい実施形態においては、前記ポリカーボネート中央ブロックは、同一のジヒドロキシモノマーから共重合される。
実施例1−2:ポリ(エチレングリコール)−ブロック−オリゴ−(DTRスベレート)−ブロック−ポリ(エチレングリコール)自己組織化ナノ粒子の調製
命名:一群のABAトリブロック共重合体であるポリ(エチレングリコール)−ブロック−オリゴ−(DTRスベレート)−ブロック−ポリ(エチレングリコール)を以下のように略す:対称PEGのA−ブロックを、2000または5000g/molの分子量を有する意味で、それぞれ2Kまたは5Kと略す;オリゴB−ブロック(デサミノチロシル−チロシンアルキルエステル(DTR)のスベリン酸エステル(SA))は、そのペンダントエステルのR基で区別され、この際、RはE=エチル、B=n−ブチル、O=n−オクチル、またはBn=ベンジルである(図1)。例えば、トリブロックオリゴマーであるPEG5K−b−オリゴ(デサミノチロシル−チロシンエチルエステルスベレート)−b−PEG5Kは、5K/DTE−SAと略す。
モデル化合物と複合体化したナノ粒子を、20mgのトリブロック共重合体を、200μLのDMF中の100μgのフルオレセイン色素または1%のDMSOを含む200μLのDMF中の200μgのパクリタキセルと結合させることによって調製した。これらの溶液を、4.8mLの脱イオン水に撹拌しながら滴下して添加し、得られたナノ粒子−溶質複合体をろ過(孔径0.22μm)し、使用前にガラスまたはポリプロピレンの容器に室温で保存した。特定の用途には、この手順を3倍にスケールアップした。トリブロック共重合体を入れないこと以外は上記と同様にして遊離の溶質の溶液を調製した。
試薬:デサミノチロシルチロシンオクチルエステル(DTO)は既知の手法を用いて調製した。塩化メチレン(DCM)(HPLCグレード)およびピリジン(認証ACS)は、Fisher Scientific社(ペンシルバニア州ピッツバーグ)から購入した。トリホスゲン(TP)はAldrich Chemical社(ウィスコンシン州ミルウォーキー)から購入した。ポリ(エチレングリコール)(PEG)(Mw=5000)はFluka社(スイス)から購入した。これらの試薬は、さらなる精製をせずに用いた。
Claims (24)
- A−B−A構造を有し、各A末端ブロックは水溶性、親水性、および無毒であり;B中央ブロックは式(I)で表される構造を有する、同一または異なった繰り返し単位を有するポリカーボネートである、トリブロック共重合体:
- 前記末端ブロックが、以下の構造を有するポリ(アルキレンオキサイド)である、請求項1に記載のトリブロック共重合体:
- 前記末端ブロックが、CH3O−[CH2−CH2−O−]mの構造を有する、請求項1に記載のトリブロック共重合体。
- Zが約10である、請求項1に記載のトリブロック共重合体。
- R1およびR2の1以上がエーテル結合を含む、請求項1に記載のトリブロック共重合体。
- R1が−CH2−CH2−である、請求項1に記載のトリブロック共重合体。
- R2が、エチル基、ブチル基、ヘキシル基、オクチル基、デシル基、ドデシル基、およびベンジル基からなる群から選択される、請求項1に記載のトリブロック共重合体。
- 請求項1に記載のトリブロック共重合体から形成されるナノ粒子。
- (a)A−B−A構造を有し、各A末端ブロックは水溶性、親水性、および無毒であり;B中央ブロックは式IIで表される構造を有する、同一または異なった繰り返し単位を有し、疎水性である、トリブロック共重合体のナノ粒子:
(b)前記ナノ粒子によって複合体化される疎水性化合物;
を含む組成物。 - 前記末端ブロックが、以下の構造を有するポリ(アルキレンオキサイド)である、請求項9に記載の組成物:
- 前記末端ブロックが、CH3O−[CH2−CH2−O−]mの構造を有する、請求項9に記載の組成物。
- Zが約10である、請求項9に記載の組成物。
- R、R1およびR2の1以上がエーテル結合を含む、請求項9に記載の組成物。
- R1が−CH2−CH2−である、請求項9に記載の組成物。
- R2が、エチル基、ブチル基、ヘキシル基、オクチル基、デシル基、ドデシル基、およびベンジル基からなる群から選択される、請求項9に記載の組成物。
- Rが、12までの炭素原子を含む、請求項9に記載の組成物。
- Rが、−CH2−CH2−C(=O)−、−CH=CH−、−CH2−CH(−OH)−、−CH2−C(=O)−および(−CH2−)zからなる群から選択され、この際、zは0〜12である、請求項16に記載の組成物。
- 前記複合体化された疎水性化合物は、生物活性化合物または薬剤活性化合物である、請求項9に記載の組成物。
- 製薬上許容される担体および有効量の請求項9に記載の組成物を含む、疎水性化合物を必要とする患者にデリバリーするための組成物。
- 前記ナノ粒子がドラッグデリバリーオリゴマーマトリックスに組み込まれる、または分散される、請求項19に記載の組成物。
- 前記活性な疎水性化合物は、抗腫瘍剤、抗生物質、抗菌剤、スタチン、ペプチド、タンパク質、ホルモン、およびワクチンからなる群から選択される、請求項18、19、または20に記載の組成物。
- 前記活性な疎水性化合物は、パクリタキセル、カンプトテシン、9−ニトロカンプトテシン、シスプラチン、カルボプラチン、シプロフロキサシン、ドキソルビシン、ロリプラム、シンバスタチン、メトトレキサート、インドメタシン、プロビプロフェン、ケトプロフェン、イロキシカム、ジクロフェナク、シクロスポリン、エトラコナゾール、ラパマイシン、ノコダゾール、コルヒチン、ケトコナゾール、テトラサイクリン、ミノサイクリン、ドキシサイクリン、オフロキサシン、ゲンタマイシン、オクトレオチド、カルシトニン、インターフェロン、テストステロン、プロゲステロン、エストラジオール、エストロゲン、およびインスリンからなる群から選択される、請求項21に記載の組成物。
- 前記複合体化された化合物は、造影剤である、請求項19に記載の組成物。
- 請求項19または20に記載の組成物を必要とする患者に投与することを含む、部位特異的な、または全身の、ドラッグデリバリーの方法。
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US11/191,181 US8591951B2 (en) | 2002-05-15 | 2005-07-27 | Tri-block copolymers for nanosphere-based drug delivery |
PCT/US2005/028572 WO2007018544A2 (en) | 2005-07-27 | 2005-08-12 | Tri-block copolymers for nanosphere-based drug delivery |
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EP (1) | EP1922019A4 (ja) |
JP (1) | JP4913810B2 (ja) |
KR (1) | KR20080059150A (ja) |
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Also Published As
Publication number | Publication date |
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US20060013882A1 (en) | 2006-01-19 |
AU2005335197A1 (en) | 2007-02-15 |
WO2007018544A3 (en) | 2007-07-12 |
KR20080059150A (ko) | 2008-06-26 |
EP1922019A2 (en) | 2008-05-21 |
CA2616810A1 (en) | 2007-02-15 |
US8591951B2 (en) | 2013-11-26 |
WO2007018544A2 (en) | 2007-02-15 |
EP1922019A4 (en) | 2009-09-02 |
JP4913810B2 (ja) | 2012-04-11 |
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