JP4619357B2 - pH感受性ブロックコポリマーおよび疎水性薬物を含む医薬品組成物 - Google Patents
pH感受性ブロックコポリマーおよび疎水性薬物を含む医薬品組成物 Download PDFInfo
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- JP4619357B2 JP4619357B2 JP2006515571A JP2006515571A JP4619357B2 JP 4619357 B2 JP4619357 B2 JP 4619357B2 JP 2006515571 A JP2006515571 A JP 2006515571A JP 2006515571 A JP2006515571 A JP 2006515571A JP 4619357 B2 JP4619357 B2 JP 4619357B2
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- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
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Description
(各pHにおけるPEO−b−poly(nBA50−co−MAA50)超分子集成体からの3Hプロゲステロンのin vitro放出)
プロゲステロンは、超分子集成体からの薬物放出に及ぼすpHの影響を評価するためのモデル疎水性薬物として使用した。フィルムキャスティング法により、分子量5300DaのPEO−b−ポリ(nBA50−co−MAA50)の超分子集成体に3H−プロゲステロンを担持した。簡単に述べると、シンチレーションバイアル中で、ポリマー10mg、プロゲステロン1mgおよび3H−プロゲステロン1μCiを、ジクロロメタン、エタノールおよび水の混合物に溶解した。溶液を減圧下で蒸発させ、ガラス面上でポリマーと薬物のフィルムを注型する。フィルムを水で水和させて超分子集成体を得たのち、この溶液を2μmフィルターで濾過して沈殿薬物を除去した。
(超分子集成体に捕捉されたフェノフィブレートをラットに経口投与する際のバイオアベイラビリティ試験)
フェノフィブレート(FNB)は、超分子集成体への薬物の取込みがラットへの経口投与時のバイオアベイラビリティに及ぼす影響を評価するための、水に溶けにくい疎水性薬物のモデルとして使用した。一連の実験では、乳化およびフィルムキャスティング法により各PEO−b−ポリ(EA−co−MAA)およびPEO−b−ポリ(nBA50−co−MAA50)ポリマーにおいてFNBの取込みを試験した。FNB担持はFEO−b−ポリ(nBA50−co−MAA50)ポリマーの方が高かった。従って、これらのポリマーを用いて、スプレーグ−ドーリーラットにおける超分子集成体に担持したFNBの相対的バイオアベイラビリティを評価した。
(PEO−b−P(nBA50−co−MAA50)とポリ−l−リジンのポリイオン複合体ミセルの形成)
分子量16,100のポリ−l−リジン(PLL)を、分子量がそれぞれ5100および5700DaであるPEO−b−P(EA50−co−MAA50)とPEO−b−P(nBA50−co−MAA50)のコポリマーによるポリイオンミセル形成のためのモデル陽イオン化合物として用いた。1:1および2:1のポリマー:PLL(−/+)電荷比(モル:モル)を複合体形成に用いた。リン酸緩衝液(pH7.4)中で濃度2.5mg/mLのポリマー保存液とPLL(分子量16,100)保存液を調製し、室温で混合して最終ポリマー濃度1mg/mLを得た。溶液を0.2μmフィルターで濾過し、動的光散乱法(DLS)を用いて25℃でサイズ測定を実施した。その結果を表1に示す。
(PEO−b−P(nBA50−co−MAA50)と塩酸ベラパミルとの複合体形成)
塩酸ベラパミルはモデル陽イオン薬物として使用した。PEO−b−P(nBA50−co−MAA50)および塩酸ベラパミルのユニバーサル緩衝液溶液を混合し、最終ポリマー濃度0.5mg/mLおよび塩酸ベラパミル濃度0.8mg/mLを得た。溶液のpHを6.1に調節し、DLS法を用いてサイズを測定した。38±10.3nmのポリイオン複合体ミセルを得た。
MAA−メタクリル酸、
EA−アクリル酸エチル、
PEO−ポリ(エチレンオキシド)
Claims (23)
- ポリ(エチレンオキシド)とポリ(アクリル酸ブチル(アルキル)−co−(アルキル)アクリル酸)のジブロックコポリマーおよび少なくとも1つの生物学的活性物質を含む医薬組成物。
- 請求項1に記載のポリマーであって、前記ポリ(エチレンオキシド)部分が200〜80,000Daの範囲の分子量を有するポリマー。
- 請求項1に記載のポリマーであって、前記ポリ(アクリル酸ブチル(アルキル)−co−(アルキル)アクリル酸)部分が200〜80,000Daの範囲の分子量を有するポリマー。
- 請求項1に記載のポリマーであって、前記アルキルが0から10の炭素原子を有するアルキル鎖であるポリマー。
- 請求項1に記載のポリマーであって、アクリル酸ブチル(アルキル)の前記ブチル部分が直鎖または分岐鎖であるポリマー。
- 請求項1に記載のポリマーであって、前記アクリル酸ブチル(アルキル):(アルキル)アクリル酸が5:95〜95:5の範囲のモル比にあるポリマー。
- 請求項1に記載の医薬組成物であって、前記ジブロックポリマーが50:50のアクリル酸n―ブチル:メタクリル酸モル比を有するポリ(エチレンオキシド)−ブロック−ポリ(アクリル酸n−ブチル−co−メタクリル酸)である医薬組成物。
- 請求項1に記載の医薬組成物であって、超分子集成体あるいはミセルの形態にある医薬組成物。
- 請求項8に記載の医薬組成物であって、前記超分子集成体あるいはミセルが5から1000ナノメートルのサイズ範囲にある医薬組成物。
- 請求項8に記載の医薬組成物であって、前記超分子集成体が環境pHの変化に反応して可逆的に会合あるいは解離する医薬組成物。
- 請求項1に記載の医薬組成物であって、前記生物学的活性物質の放出速度がpHの上昇と共に上昇する医薬組成物。
- 請求項8に記載の医薬組成物であって、前記生物学的活性物質が物理的あるいは化学的方法により前記超分子集成体に組込まれた疎水性薬物である医薬組成物。
- 請求項12に記載の医薬組成物であって、前記疎水性薬物がフェノフィブレートである医薬組成物。
- 請求項8に記載の医薬組成物であって、前記生物学的活性物質が陽イオンあるいはポリ陽イオンである医薬組成物。
- 請求項14に記載の医薬組成物であって、前記ポリ陽イオンが陽イオン残基を有するペプチドあるいは蛋白質である医薬組成物。
- 請求項14に記載の医薬組成物であって、前記陽イオンあるいはポリ陽イオンが静電的に前記(アルキル)アクリル酸単位と相互作用する医薬組成物。
- 請求項14に記載の医薬組成物であって、前記陽イオンが塩酸ベラパミルである医薬組成物。
- 請求項8に記載の医薬組成物であって、前記生物学的活性物質が前記(アルキル)アクリル酸単位との金属配位複合体を形成する医薬組成物。
- 請求項18に記載の医薬組成物であって、前記生物学的活性物質がシスプラチンである医薬組成物。
- 請求項18に記載の医薬組成物であって、前記生物学的活性物質がカルボプラチンである医薬組成物。
- 請求項12に記載の医薬組成物であって、前記超分子集成体への疎水性薬物の組込みが前記疎水性薬物の経口投与時のバイオアベイラビリティを高める医薬組成物。
- 請求項8に記載の医薬組成物であって、経口、静脈内、動脈内、皮下、筋肉内、腹腔内、直腸、膣あるいは局所経路で投与される医薬組成物。
- 請求項8に記載の医薬組成物であって、その表面に標的リガンドを有する医薬組成物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US10/607,446 US7094810B2 (en) | 2001-06-08 | 2003-06-25 | pH-sensitive block copolymers for pharmaceutical compositions |
PCT/CA2004/000561 WO2004112757A1 (en) | 2003-06-25 | 2004-04-14 | Pharmaceutical compositions comprising ph-sensitive block copolymers and a hydrophobic drug |
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JP4619357B2 true JP4619357B2 (ja) | 2011-01-26 |
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US (1) | US7094810B2 (ja) |
EP (1) | EP1638539B1 (ja) |
JP (1) | JP4619357B2 (ja) |
AT (1) | ATE418970T1 (ja) |
AU (1) | AU2004248863B2 (ja) |
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CA (1) | CA2530736C (ja) |
CY (1) | CY1110264T1 (ja) |
DE (1) | DE602004018772D1 (ja) |
DK (1) | DK1638539T3 (ja) |
ES (1) | ES2323701T3 (ja) |
MX (1) | MXPA05014017A (ja) |
PL (1) | PL1638539T3 (ja) |
PT (1) | PT1638539E (ja) |
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JP2003523544A (ja) * | 2000-02-17 | 2003-08-05 | レックスマーク・インターナショナル・インコーポレーテツド | 導電性駆動ハブを備えたトナーカートリッジ |
US6939564B2 (en) * | 2001-06-08 | 2005-09-06 | Labopharm, Inc. | Water-soluble stabilized self-assembled polyelectrolytes |
WO2005079856A1 (en) * | 2004-02-23 | 2005-09-01 | The University Of British Columbia | Drug delivery compositions comprising hydrophobic polymers and amphipathic molecules |
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AU2009246321A1 (en) * | 2008-05-13 | 2009-11-19 | Phaserx, Inc. | Polymeric carrier |
WO2009140423A2 (en) * | 2008-05-13 | 2009-11-19 | University Of Washington | Targeted polymer bioconjugates |
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WO2004112757A1 (en) | 2004-12-29 |
PL1638539T3 (pl) | 2009-10-30 |
JP2007505029A (ja) | 2007-03-08 |
DK1638539T3 (da) | 2009-05-04 |
US20040072784A1 (en) | 2004-04-15 |
ES2323701T3 (es) | 2009-07-23 |
CY1110264T1 (el) | 2015-01-14 |
PT1638539E (pt) | 2009-04-09 |
AU2004248863A1 (en) | 2004-12-29 |
SI1638539T1 (sl) | 2009-10-31 |
EP1638539B1 (en) | 2008-12-31 |
DE602004018772D1 (de) | 2009-02-12 |
CA2530736C (en) | 2013-07-02 |
AU2004248863B2 (en) | 2009-03-12 |
CA2530736A1 (en) | 2004-12-29 |
US7094810B2 (en) | 2006-08-22 |
EP1638539A1 (en) | 2006-03-29 |
BRPI0411872A (pt) | 2006-08-08 |
MXPA05014017A (es) | 2007-01-31 |
ATE418970T1 (de) | 2009-01-15 |
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