JP2017075320A - 薬物送達のための新規な生分解性ポリエステルアミドコポリマー - Google Patents
薬物送達のための新規な生分解性ポリエステルアミドコポリマー Download PDFInfo
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- JP2017075320A JP2017075320A JP2016223372A JP2016223372A JP2017075320A JP 2017075320 A JP2017075320 A JP 2017075320A JP 2016223372 A JP2016223372 A JP 2016223372A JP 2016223372 A JP2016223372 A JP 2016223372A JP 2017075320 A JP2017075320 A JP 2017075320A
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- polyesteramide copolymer
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- 229920006216 polyvinyl aromatic Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 229920001290 polyvinyl ester Polymers 0.000 description 1
- 229920001289 polyvinyl ether Polymers 0.000 description 1
- 229920006215 polyvinyl ketone Polymers 0.000 description 1
- 229920000131 polyvinylidene Polymers 0.000 description 1
- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical group [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940117265 prinzide Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 239000002089 prostaglandin antagonist Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
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- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 150000008163 sugars Chemical class 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
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- 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
- 150000004579 taxol derivatives Chemical class 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
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- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
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- YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[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 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
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- 230000003442 weekly effect Effects 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/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)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
Images
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
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Abstract
Description
のα−アミノ酸−ジオール−ジエステルをベースとするポリエステルアミド(PEA)コポリマーが言及されており、
式中、
− mは0.1〜0.9であり;pは0.9〜0.1であり;nは50〜150であり;
− R1はそれぞれ独立して、(C1〜C20)アルキレンであり;
− R2はそれぞれ独立して、水素または(C6〜C10)アリール(C1〜C6)アルキルであり;
− R3はそれぞれ独立して、水素、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、または(C6〜C10)アリール(C1〜C6)アルキルであり;
− R4はそれぞれ独立して、(C2〜C20)アルキレンである。
の1,4:3,6−ジアンヒドロへキシトール二環式断片であり、
R7は、Hまたはベンジル基から選択されてもよく、R8は−(CH2)4−である。R7がHである場合には、このポリマーはさらに、PEA−III−Hとして示され、R7がベンジルである場合には、このポリマーはさらに、PEA−III−Bzとして示される。
による生分解性ポリ(エステルアミド)ランダムコポリマー(PEA)を提供することによって達成され、
式中、
− m+pは0.9〜0.1であり、qは0.1〜0.9であり
− m+p+q=1であり、ただしmまたはpは0であることができ、
− nは5〜300であり;
− R1は独立して、(C2−C20)アルキレン、(C2−C20)アルケニレン、−(R9−CO−O−R10−O−CO−R9)−、−CHR11−O−CO−R12−COOCR11−およびその組み合わせからなる群から選択され;
− 単一主鎖単位mまたはpにおけるR3およびR4はそれぞれ独立して、水素、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C6〜C10)アリール、(C1〜C6)アルキル、−(CH2)SH、−(CH2)2S(CH3)、−CH2OH、−CH(OH)CH3、−(CH2)4NH3+、−−(CH2)3NHC(=NH2+)NH2、−CH2COOH、−(CH2)COOH、−CH2−CO−NH2、−CH2CH2−CO−NH2、−CH2CH2COOH、CH3−CH2−CH(CH3)−、(CH3)2−CH−CH2−、H2N−(CH2)4−、Ph−CH2−、CH=C−CH2−、HO−p−Ph−CH2−、(CH3)2−CH−、Ph−NH−、
からなる群から選択され;
− R5は、(C2〜C20)アルキレン、(C2〜C20)アルケニレン、アルキルオキシまたはオリゴエチレングリコールからなる群から選択され、
− R6は、構造式(III);
の1,4:3,6−ジアンヒドロへキシトールの二環式断片から選択され、
− R7は、(C6〜C10)アリール(C1〜C6)アルキルからなる群から選択され、
− R8は−(CH2)4−であり;
− R9またはR10は独立して、C2〜C12アルキレンまたはC2〜C12アルケニレンから選択され、
− R11またはR12は独立して、H、メチル、C2〜C12アルキレンまたはC2〜C12アルケニレンから選択され、ただしaは少なくとも0.05であり、bは少なくとも0.05であり、a+b=1である。
要するに、PEA H/Bzポリマーは、持続性の薬物送達のための優れた溶液を提供し、先行技術のPEA Bzポリマーとは異なり加水分解的に分解する。PLGAまたはPLLAなどの他の先行技術ポリマーもまた、主にバルク侵食メカニズムを介して分解すると思われる。これは図8で確認される。
PEA−I−Bz、PEA−I−H/Bz25%H、PEA−I−H/Bz50%HおよびPEA−I−100%Hをステンレス鋼フィルム上にコーティングし、αキモトリプシン(ウシ)8.5U/mLおよびNaN30.05%を含有する緩衝液に浸漬し、緩衝液を1週間に2回新しくした。微量天秤を使用して、時間の経過に伴う乾燥試料の重量減少を決定した。結果を図1に示す。PEA−I−Bz、PEA−I−H/Bz25%HおよびPEA−I−H/Bz50%Hは同等な分解速度で分解し、および試験期間35日間にわたって初期質量の40〜60%を失うことが確認された。これと対照的に、PEA−I−100%Hはかなり速く分解し、10日以内に完全に分解した。
PEA−I−Bz、PEA−I−H/Bz25%HおよびPEA−I−H/Bz50%Hをステンレス鋼フィルム上にコーティングし、αキモトリプシン(ウシ)8.5U/mLおよびNaN30.05%を含有する緩衝液に浸漬し、緩衝液を1週間に2回新しくした。乾燥試料に関して、THFを移動相として使用してGPCシステムで相対分子量を評価した。分子量は、ポリスチレン標準物質を基準とする。結果を図2に示す。
PEA−I−Bz、PEA−I−H/Bz25%HおよびPEA−I−H/Bz50%Hをステンレス鋼フィルム上にコーティングし、NaN30.05%を含有するPBS緩衝液に浸漬し、その緩衝液を1週間に2回新しくした。乾燥試料に関して、THFを溶媒として使用してGPCシステムで相対分子量を評価した。分子量は、ポリスチレン標準物質を基準とする。結果を図3に示す。
それぞれのPEA−I−H/Bzコポリマー(5%、25%、50%、100%H)から、直径10mmのディスク5枚をフィルムから打ち抜き、計量し、37℃のリン酸緩衝生理食塩水(PBS)5.0mlに入れた。いくつかの時間間隔にて、ディスクを計量し、水の吸収による質量増加を決定した。それぞれ2日後に、PBS溶液を新しくした。結果を図4および5に示す。
ローディング率10%のPEA−I−Bz、PEA−I−H/Bz25%H、PEA−I−H/Bz50%Hの薬物ローディングディスクを作製した。直径7mmの個々のディスク3枚を37℃のPBS緩衝液に入れた。様々な時点で、吸い込み条件を確実にするためにPBS溶液全体を新たにし、続いて薬物濃度を測定した。一般に、最初の週には試料を毎日測定し、後の時点では毎週測定した。結果を図6に示す。クロラムフェニコールの放出は、278nmでの検出を用いて、C18カラム上でRP−HPLCによって測定された。PEA−I−H/Bz25%Hの10%ローディングディスクからのクロラムフェニコールの溶出は、PEA−I−Bzと比べて速かった。
ポリマーPEA−I−H/Bz25%H、PEA−I−H35%HおよびPEA−I−HとPEA−I−Bzの機械的ブレンドの膨潤挙動を比較した;ブレンド1は、PEA−I−H25重量%およびPEA I Bz75重量%を含み、ブレンド2は、PEA−I−H35重量%およびPEA I Bz65重量%を含み、ブレンド3は、PEA−I−H50重量%およびPEA I Bz50重量%を含む。ポリマー10%(重量)の溶液20gが得られるように、ポリマーを無水エタノールに溶解する。溶解には数時間かかった。その後、溶液をテフロン(Teflon)皿(直径8cmのディスク)に注いだ。これらのディスクをガラスビーカーで覆うか、窒素フロー下のデシケーター内に入れた。表面がもはや粘着性でなくなったら、完全真空下にて65℃でディスクをさらに乾燥させた。気泡の形成を防ぐために、ゆっくりと最大真空度に到達させた。最大真空度に達した後、温度が上昇し始めた。
で計算した。結果を図7に示す。
PEA−I−Bz、PEA−I−H/Bz5%H、PEA−I−H/Bz15%HおよびPEA−I−35%Hの10重量%溶液をエタノール中で調製した。厚さ75μmのステンレス鋼箔上にポリマー溶液をキャストし、65℃で減圧下にて乾燥させた。得られた被覆金属フィルムを表面積約1cm2の片に切断した。ポリマー被覆金属片を用いて、時間の経過に伴うポリマーの分解を評価した。NaN30.05%を含有するPBS緩衝液5mlに、ポリマー被覆ステンレス鋼片を個々に浸漬した。3回繰り返して、試料を採取し、65℃で減圧下にて乾燥させた。質量減少および分子量分析に関して、溶出剤としてTHFを用いたGPCシステムを使用して、乾燥したコーティングを評価した。PEA−I−Bzは、安定な分子量に基づく良好な加水分解安定性を例証し、ごく限られた数のカルボキシル基を導入(PEA−I−H/Bz5%Hと同様)することによって既に、時間の経過に伴って分子量がわずかに低下するが、実現可能なポリマー分解を得るには明らかに遅すぎる。意外なことに、PEA−I−H/Bz15%HおよびPEA−I−H/Bz35%Hは、ポリマーの加水分解に伴う分子量の顕著な低下を示した。結果を図8に示す。
[a.ポリマーと薬物の溶液の調製およびフィルムの作製]
ポリマー中の薬物5重量%の薬物ポリマー配合物を以下のように調製した。フルオレセイン約100mgをTHF10mLに溶解した。完全に溶解した後、溶液を使用して、ポリマー約2.0gを溶解した。透明な溶液が得られたら、超音波によって試料を少なくとも90分間ガス抜きした。その後、溶液をテフロン型(直径=40mm、深さ=4mm)に、限度一杯のレベルまでキャストした。溶液を空気中にて室温で一晩蒸発させた。次いで、テフロン型全体を真空オーブン内に移し、溶媒が完全に蒸発するまで、徐々に下げられた圧力下にて室温で連続的に蒸発させた。
放出の実験のために、乾燥ポリマーコーティングから打ち抜かれたディスクを2つ組で作製した。ガラスバイアル内のPBS9mlにディスクを浸漬し、放出期間中、ガラスバイアルを一定の37℃で穏やかに振盪した。実験の最初には、PBS溶液を毎日2回新しくした。次いで、回数を1日1回に減らし、その後、後期には2日おきに1回に減らした。緩衝液内に放出されるフルオレセインの含有量をHPLCまたはUV分光法のいずれかによって決定した。
Claims (16)
- 構造式(IV)
による生分解性ポリエステルアミドコポリマー(PEA)であって、
式中、
− m+pは0.9〜0.1であり、qは0.1〜0.9であり、
− m+p+q=1であり、ただしmまたはpは0であることができ、
− nは約5〜約300であり;
− R1は独立して、(C2〜C20)アルキレン、(C2〜C20)アルケニレン、−(R9−CO−O−R10−O−CO−R9)−、−CHR11−O−CO−R12−COOCR11−およびその組み合わせからなる群から選択され;
単一主鎖単位mまたはpにおけるR3およびR4はそれぞれ独立して、水素、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C6〜C10)アリール、(C1〜C6)アルキル、−(CH2)SH、−(CH2)2S(CH3)、−CH2OH、−CH(OH)CH3、−(CH2)4NH3+、−(CH2)3NHC(=NH2+)NH2、−CH2COOH、−(CH2)COOH、−CH2−CO−NH2、−CH2CH2−CO−NH2、−CH2CH2COOH、CH3−CH2−CH(CH3)−、(CH3)2−CH−CH2−、H2N−(CH2)4−、Ph−CH2−、CH=C−CH2−、HO−p−Ph−CH2−、(CH3)2−CH−、Ph−NH−、NH−(CH2)3−C−、NH−CH=N−CH=C−CH2−からなる群から選択され;
− R5は、(C2〜C20)アルキレン、(C2〜C20)アルケニレン、アルキルオキシまたはオリゴエチレングリコールからなる群から選択され、
− R6は、構造式(III);
の1,4:3,6−ジアンヒドロへキシトールの二環式断片から選択され、
− R7は、(C6〜C10)アリール(C1〜C6)アルキルからなる群から選択され、
− R8は−(CH2)4−であり;
− R9またはR10は独立して、C2〜C12アルキレンまたはC2〜C12アルケニレンから選択され、
− R11またはR12は独立して、H、メチル、C2〜C12アルキレンまたはC2〜C12アルケニレンから選択され、aは少なくとも0.05であり、bは少なくとも0.05であり、a+b=1であることを特徴とする、生分解性ポリエステルアミドコポリマー(PEA)。 - aが少なくとも0.15である、請求項1に記載のポリエステルアミドコポリマー。
- aが少なくとも0.5である、請求項1または2に記載のポリエステルアミドコポリマー。
- aが少なくとも0.8である、請求項1〜3のいずれか一項に記載のポリエステルアミドコポリマー。
- − p=0およびm+q=1、m=0.75であり、
− aは0.5であり、a+b=1であり、
− R1は(CH2)8であり、R3は(CH3)2−CH−CH2−であり、R5はヘキシルであり、R7はベンジルであり、R8は−(CH2)4−である、請求項1に記載のポリエステルアミドコポリマー。 - − m+p+q=1、q=0.25、p=0.45およびm=0.3であり、
− aは0.5であり、a+b=1であり、
− R1は−(CH2)8であり;R3およびR4はそれぞれ、(CH3)2−CH−CH2−であり、R5は、(C2〜C20)アルキレンからなる群から選択され、R7はベンジルであり、R8は−(CH2)4−であり;
− R6は、構造式(III)の1,4:3,6−ジアンヒドロへキシトールの二環式断片から選択される、請求項1に記載のポリエステルアミドコポリマー。 - − m+p+q=1、q=0.25、p=0.45およびm=0.3であり、
− a=0.75、a+b=1であり、
− R1は−(CH2)8であり;R4は(CH3)2−CH−CH2−であり、R7はベンジルであり、R8は−(CH2)4であり、
− R6は、構造式(III)の1,4:3,6−ジアンヒドロへキシトールの二環式断片から選択される、請求項1に記載のポリエステルアミドコポリマー。 - − m+p+q=1、q=0.1、p=0.30およびm=0.6であり、
− aは0.5であり、a+b=1であり、
− R1は−(CH2)4であり;R3およびR4はそれぞれ、(CH3)2−CH−CH2−であり;R7はベンジルであり、R8は−(CH2)4−であり;R5は、(C2〜C20)アルキレンからなる群から選択され、
− R6は、構造式(III)の1,4:3,6−ジアンヒドロへキシトールの二環式断片から選択される、請求項1に記載のポリエステルアミドコポリマー。 - 薬物として使用される、請求項1〜8のいずれか一項に記載のポリエステルアミドコポリマー。
- 薬物送達用途における、請求項1〜8のいずれか一項に記載のポリエステルアミドコポリマーの使用。
- 請求項1〜8のいずれか一項に記載のポリエステルアミドコポリマーと、生理活性物質と、を含む組成物。
- 請求項1〜8のいずれか一項に記載のポリエステルアミドコポリマーまたは請求項11に記載の組成物を含む、物品。
- フィルム、コーティングまたはミセルの群から選択される、請求項12に記載の物品。
- 請求項1〜8のいずれか一項に記載のポリエステルアミドコポリマーまたは請求項11に記載の組成物を含む、デバイス。
- 請求項12または13に記載の物品を含む、デバイス。
- 治療学的な心血管分野、獣医学分野、眼科分野、痛みの管理の分野、MSK分野、癌治療分野などの医療分野における、およびワクチン送達組成物における、請求項1〜8のいずれか一項に記載のポリエステルアミドコポリマーまたは請求項11に記載の組成物、請求項12または13に記載の物品または請求項14または15に記載のデバイスの使用。
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Also Published As
Publication number | Publication date |
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JP6048979B2 (ja) | 2016-12-21 |
CA2839526A1 (en) | 2012-12-27 |
EP2723801B1 (en) | 2017-01-18 |
JP2014523937A (ja) | 2014-09-18 |
CA2839841C (en) | 2019-11-05 |
ES2558357T3 (es) | 2016-02-03 |
JP6045575B2 (ja) | 2016-12-14 |
US20140120170A1 (en) | 2014-05-01 |
CA2839841A1 (en) | 2012-12-27 |
JP2014522886A (ja) | 2014-09-08 |
CN103619910B (zh) | 2016-08-31 |
EP2723801A1 (en) | 2014-04-30 |
WO2012175746A1 (en) | 2012-12-27 |
CN103748139A (zh) | 2014-04-23 |
US9896544B2 (en) | 2018-02-20 |
JP6248364B2 (ja) | 2017-12-20 |
CN103619910A (zh) | 2014-03-05 |
CN103748139B (zh) | 2016-08-17 |
EP2723800A1 (en) | 2014-04-30 |
US20140220099A1 (en) | 2014-08-07 |
WO2012175748A1 (en) | 2012-12-27 |
US20160367681A1 (en) | 2016-12-22 |
EP2723800B1 (en) | 2015-10-07 |
US9963549B2 (en) | 2018-05-08 |
EP3159368A1 (en) | 2017-04-26 |
US9873764B2 (en) | 2018-01-23 |
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