JP5027157B2 - 自己集合性の両親媒性ポリマーを有する薬物の可溶化および標的化導入 - Google Patents
自己集合性の両親媒性ポリマーを有する薬物の可溶化および標的化導入 Download PDFInfo
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- JP5027157B2 JP5027157B2 JP2008551234A JP2008551234A JP5027157B2 JP 5027157 B2 JP5027157 B2 JP 5027157B2 JP 2008551234 A JP2008551234 A JP 2008551234A JP 2008551234 A JP2008551234 A JP 2008551234A JP 5027157 B2 JP5027157 B2 JP 5027157B2
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Landscapes
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Description
好ましい実施形態において、ジチオールのヒドロキシルまたはアミノ基は、反応基Xであり、官能基YおよびY′は、C部分の結合点としての役割を果たすと同時に、標的または薬物部分の結合点としての役割を果たす。あるいは、基YおよびY′は、C部分を結合するためにヒドロキシルまたはアミノ基を使用すると同時に、結合点としての役割を果たす。
本発明はまた、本発明のくし形ポリマーの調製のための工程を提供する。これらのポリマーの合成は、下記に記載の手順に従い、当業者による有機合成について、容易に実施される。主要な出発物質はポリエチレングリコールであり、好ましくは、使用前に乾燥させる。これは、気泡の形成が停止するまで、高温で、融解されたPEGを真空下で撹拌することにより、便宜的に実施される。これは、PEGの質により異なるが、8〜12時間かかる場合がある。乾燥した時点で、PEGは、アルゴン下で永久保存することができる。例えば、1430〜1570の分子量分布を有する商用の多分散系の「PEG1500」など、市販のPEGの産業用および研究用の等級を本発明のポリマーの生成において使用することができる。当該の物質は、PEG鎖の中央で第2ヒドロキシル基を導入する、ビスフェノールAジグリシジルエーテルに組み込むことができる。本発明のポリマーが最も再生可能で均一な品質を有することを確証するために、PEGは、好ましくは、ビスフェノールAがなく、低分散性がないことである。アラバマ州ハンツビルから市販されているNektar Therapeutics(以前は、Shearwater Polymers)、およびノルウェーオスロから市販されているPolypure ASなど、95%より多い単分散であるPEGポリマーが最も好ましい。特に好ましいPEGの例は、95%より多いHO(CH2CH2O)28H、分子量1252である「PEG-28」である。
実施例1:PEG-ジ(アルキルアミドスクシニル)ジチオエーテル中間分子量ポリマー(C16-π-ポリマーA)
実施例1a:ウンデシルアミン
実施例1b:オクタデシルアミン
実施例1c:4-ノニルベンジルアミン
実施例1d:3-[(4-フェノキシ)フェニル]プロピルアミン
無水マレイン酸の1モルあたりの0.55モルのDTTおよび0.55モルのTEMEDを使用することを除いては、実施例1を参照にした手順に従った。粘度が急速に蓄積される場合、活発な撹拌を必要とした。反応物のほとんどは、5〜10分以内に完了し、温度が55℃から80℃に上昇する場合、さらに4時間にわたって、ゆっくりと完了したことを示した。
ポリマーにおいて、カルボキシル酸基の1モルあたりの1.5モルのドデシルアミンを使用することを除いては、実施例1を参照にした手順に従った。N-ヒドロキシスクシンイミド(NHS、カルボキシル酸基の1モルあたりの1.0モル)および1,1′-カルボニルジイミダゾール(CDI、カルボキシル酸基の1モルあたりの3.0モル)を添加し、反応物を80℃で4時間撹拌し、上記のように処理した。
実施例3a:ウンデシルアミン
実施例3b:テトラデシルアミン
実施例3c:オクタデシルアミン
実施例3d:デヒドロアビエチルアミン
実施例3e:コレステロール2-アミノエチルエーテル
実施例3f:10-フェノキシデシルアミン
実施例3g:セバシン酸ヒドラジド
実施例3h:オレイン酸ヒドラジド
実施例3i:デヒドロアビエチン酸ヒドラジド
実施例3j:コール酸ヒドラジド
実施例3k:パルミチン酸ヒドラジド
乾燥ジエチルエーテル(10ml)のPEG(6.66mmol)およびトリエチルアミン(2.32ml、16.65mmol)の溶液をアルゴン下で0℃で冷却し、塩化メタンスルホニル(1.03ml、13.32mmol)で滴下処理した。1時間、0℃で撹拌を継続し、その後、室温で2時間撹拌した。エーテルを蒸発させ、溶液からろ過したトリエチルアミン塩酸塩を沈殿させるために、乾燥アセトン(15ml)を残留物に添加した。ろ液を臭化リチウム(2.31g、26.64mmol)で処置し、20時間、還流加熱した。その後、混合物をヘキサンで希釈し、CeliteTM(0.5cm)で覆われたシリカ(3cm)の短カラムでろ過し、ヘキサンで溶離した。ろ液を乾燥し、ろ過し、α,ω-ジブロモ-PEGを油に放置するために蒸発させる。
実施例1に記載の方法で、乾燥PEGをエチレンジアミンテトラ酢酸2無水物と反応させ、その後、実施例1に記載のドデシルアミンと、または実施例3に記載のヘキサデシルと、または実施例3a〜3kに記載のアミンとアミンアミド化する。
実施例5a:ナフタレンテトラカルボン酸2無水物
実施例5b:ペリレンテトラカルボン酸2無水物
実施例5c:ベンゾフェノンテトラカルボン酸2無水物
実施例5d:4,4′-(ヘキサフルオロイソプロピリデン)ジフタル酸無水物
実施例5e:ブタンテトラカルボキシル酸2無水物
実施例5f:ビシクロ(2,2,2)オクト-7-エン-2,3,5,6-テトラカルボキシル酸2無水物
実施例5g:ジエチレンテトラアミン5酢酸2無水物
実施例5h:3,4,3′,4′-ジフェニルスルホンテトラカルボキシル酸2無水物
実施例5i:3,4,3′,4′-ジフェニルエーテルテトラカルボキシル酸2無水物
実施例5j:ピロメリット二無水物
実施例1に記載のように調製されたPEGジマレイン酸エステルを実施例1のDTT2使用される同様の手順を使用して、ドデカンチオール(PEGジマレイン酸エステルの1当量あたり2当量)と反応させる。重合が行われない場合、希釈する必要はなく、反応を溶解PEG-ジマレイン酸エステルにおいて行う。TEMED触媒を添加してから、チオールを添加する。TLCを使用して、出発物質の消失後、反応を行った。蒸発によるアルキルチオールの消失が有意になる時点までの温度を使用することができる(約100℃まで)。わずかな過剰アルキルチオールをマレイン基を完全飽和するために使用してもよい。臭気またはTLCでなにも検出されなくなるまで、過剰アルキルチオールを窒素またはアルゴンで散布および/または真空下で加熱することにより反応の終わりで除去する。
実施例6Aa:メルカプトコハク酸ジ-t-ブチルエステル
実施例6Ab:テトラデカンチオール
実施例6Ac:ヘキサデカンチオール
実施例6Ad:2-メルカプトエタンスルホン酸
実施例6Ae:3-メルカプトプロパンスルホン酸
実施例6Af:6-メルカプトヘキサン酸t-ブチルエステル
実施例6Ag:4-メルカプト安息香酸t-ブチルエステル
実施例6Ah:メルカプト酢酸t-ブチルエステル
実施例6Ai:4-(t-ブトキシカルボニルアミノ)ブタンチオール
実施例6Aj:3-(t-ブトキシカルボニルアミノ)ベンジルメルカプタン
実施例6Ak:4-デシルベンジルメルカプタン
実施例6Ba:2-(O-BOC)-1,3-ジアミノ-2-プロパノール
実施例6Bb:N′,N′′-ジ(BOC)ヘキサエチレンテトラアミン
実施例6Bc:N′,N′′-ジ(BOC)スペルミン
実施例6Bd:N′-BOCスペルミジン
実施例6Be:N′,N′′,N′′′-トリ(BOC)ペンタエチレンヘキサミン
実施例6Bf:アグマチン
実施例6Bg:リシンt-ブチルエステル
実施例6Bh:1,6-ジアミノヘキサン
実施例6Bi:1,4-フェニレンジアミン
実施例6Bj:1,3-フェニレンジアミン
実施例6Bk:1,4-ジアミノブタン-2,3-ジオールアセトニド
実施例7a:meso-2,3-ビス(n-ブトキシ)ブタン-1,4-ジチオール
実施例7b:meso-2,3-ビス(4-ノニルフェニルメトキシ)ブタン-l,4-ジチオール
実施例7c:meso-2,3-ビス(ビフェニル-4-メトキシ)ブタン-1,4-ジチオール
実施例7d:4,6-ビス(デシロキシ)ベンゼン-1,3-ジメタンチオール
実施例7e:4,5-ビス(デシロキシ)ベンゼン-1,2-ジメタンチオール
実施例7f:3,4-ビス(デシロキシ)チオフェン-2,5-ジメタンチオール
2-ドデセン-1-イル無水コハク酸を無水マレイン酸の代わりに使用することを除いては、実施例1の方法に従う。ドデセニル置換基は、最終ポリマーにおいてペンダントC鎖を提供する。
実施例8Aa:イソブテニル無水コハク酸
実施例8Ab:2-オクテン-1-イル無水コハク酸
実施例8Ac:オクタデセニル無水コハク酸
実施例8Ad:3-オキサビシクロ-ヘキサン-2,4-ジオン
実施例8Ae:シクロヘキサンジカルボン酸無水物
実施例8Af:フタル酸無水物
実施例8Ag:4-デシル無水フタル酸
実施例8Ah:ヘキサヒドロメチルフタル酸無水物
実施例8Ai:テトラヒドロフタル酸無水物
実施例8Aj:ノルボルネンジカルボン酸無水物
実施例8Ak:カンタリジン
実施例8Al:ビシクロオクテンジカルボン酸無水物
実施例8Am:exo-3,6-エポキシ-1,2,3,6-テトラヒドロフタル酸無水物
実施例8An:S-アセチルメルカプト無水コハク酸
実施例1の方法により、実施例8Aおよび8Aaから8Anに記載されるように取得した置換PEGコハク酸エステルをDTTと反応させる。
実施例8Ba:エタン-1,2-ジチオール
実施例8Bb:プロパン-1,3-ジチオール
実施例8Bc:ブタン-1,4-ジチオール
実施例8Bd:ペンタン-1,5-ジチオール
実施例8Be:ヘキサン-1,6-ジチオール
実施例8Bf:1,4-ベンゼンジチオール
実施例8Bg:1,3-ベンゼンジチオール
実施例8Bh:1,4-ベンゼンジメタンチオール
実施例8Bi:1,3-ベンゼンジメタンチオール
実施例8Bj:1,2-ベンゼンジメタンチオール
実施例6Bの方法により、実施例8Aに記載されるように取得した置換PEGコハク酸エステルを1,4-ジアミノブタンと共重合させる。
実施例8Ca:2O-BOC1,3-ジアミノ-2-プロパノール
実施例8Cb:N′,N′′-ジ(BOC)ヘキサエチレンテトラアミン
実施例8Cc:N′,N′′-ジ(BOC)スペルミン
実施例8Cd:N′-BOCスペルミジン
実施例8Ce:N′,N′′,N′′′-トリ(BOC)ペンタエチレンヘキサミン
実施例8Cf:アグマチン
実施例8Cg:リシンt-ブチルエステル
実施例8Ch:1,6-ジアミノヘキサン
実施例8Ci:1,4-フェニレンジアミン
実施例8Cj:1,3-フェニレンジアミン
実施例8Ck:1,4-ジアミノブタン-2,3-ジオールアセトニド
PEGトシル酸:1モルのPEG(DMFに溶解された、またはそのまま溶解した)に、アルゴン下で撹拌すると同時に、2.1モルのトシルクロリド(5%過剰モル)を添加した。本反応混合物に、2.2モルのテトラメチルエチレンジアミン(TEMED)を添加した。その後、反応物を45℃で2時間培養した。TLCを使用して、TLC溶媒として、エチルアセテート、トルエン、またはエタノールに生成物を分解した。PEGトシル酸をトルエンを有する反応混合物から抽出することができる。トルンスルホニルクロリドの代わりに、メシルクロリド(実施例4を参照)、トリフリック酸無水物、またはトレシルクロリドなどのその他のスルホニル剤をまた使用することもできる(米国特許出願第10/397332号、米国特許第20040006051号を参照)。
実施例10a:オレイン酸
実施例10b:コレステリルコハク酸エステル
実施例10c:ビフェニル-4-カルボキシル酸
実施例10d:4-オクチルフェニル酢酸
実施例10e:ヘキサデカ-6-イン酸
ポリマーAジマレイン酸エステルを無水マレイン酸をポリマーAヒドロキシル基と反応させることにより調製する。導入した活性2重結合をチオール含有のリガンドをポリマーに添加するために使用することができる。ポリマーと無水マレイン酸の割合は、0〜100%の完全化学量論のエステル化と異なる置換を取得するために変更することが可能である。
粉末C16-π-ポリマーAジマレイン酸エステル(実施例11)(253mg)を水(5mL)に添加し、混合物を活発に撹拌した。システイン(24mg)およびTEMED(30.5μl)を反応混合物に添加し、混合物をアルゴン雰囲気下で、室温で撹拌した。ニンヒドリンを有する検出とともに、反応の進行をTLC(シリカゲルプレート、n-ブタノール-酢酸-水、3:1:1)で監視した。反応混合物は、ポリマーとともに移動するニンヒドリン陽性スポットを示した。システインはまた、ニンヒドリン陽性スポットを得、一方、出発ポリマーは、ニンヒドリンでいずれの色も得られなかった。
実施例1:染料の可溶化
不溶性物質を除去するように遠心分離にかけられたが精製されていない、PEG1500-コスクシニルDTT-ビス-C16-アミドポリマー(C16-ポリマーA、実施例1)の50mg/ml水溶液の1.0mlアリコートに、別々の容器(FlexExcel透明ポリプロピレン舟形秤、WB2.5サイズ、AllExcel,Inc.,West Haven,CTの製品)中のエオシンY、ジクロロフルオレセイン、およびスーダンIVといった染料の超過量を添加し、成分を一緒に攪拌してペーストを形成したTM。その後、耐水性両面テープを使用して、容器の底を小型宝石超音波洗浄器槽の底に取り付けた。ちょうど十分な量の水を槽に添加し、舟形秤を約3分の1の高さまで浸した。超音波処理を5分ずつ、15分間行った。液体を遠心分離管に移して、卓上遠心分離機中で30分間2度遠心分離にかけ、非溶解染料を沈殿させた。浮遊物をきれいな管に移して再び遠心分離にかけ、同伴固体を除去した。ポリマー溶液の量と同じ量の蒸留水中の同じ量の染料の懸濁液を、対照として同じ方法で処理する。結果として生じた溶液をTLCプレートに染みをつけ(25ul)、液滴から円を形成した。染みの強度をエタノールまたはエタノール/水中で作られた染料溶液の標準から作られた染みと比較して近似濃度を決定した。染みを図1に示す。水中の染料の溶解度は、室温で11以上の脱イオン水(非緩衝化)に適切な量の染料を溶解させ、必要に応じてさらに水を添加して(つまり水で滴定して)飽和溶液を得ることによって、決定した。
プルプリン、アムホテリシンB、カンプトセシン、およびドキソルビシンを、代表的な難溶性活性薬剤成分(API)として選択した。アムホテリシンBは、抗菌薬注射剤としてリポソーム製剤の形で使用される一方で、カンプトセシンおよびドキソルビシンは抗癌剤である。プルプリンは、薬剤実用性の可能性があるDNA挿入染料であり、エオシンYは光線力学療法における利用の可能性がある感光性一重項酸素試薬である。各APIは、C16-π-ポリマーA、C18-π-ポリマーB、および/またはC16-π-ポリマーA-葉酸抱合体とともに、水中で可溶化した(下記参照)。可溶化は、染料について上記に説明したように、可溶化APIおよび非可溶化対照をTLCプレートに染みをつけることによって実証した。
実施例1:局所緩和薬、クリームまたはペーストに対する適合性
実施例1のポリマーの水溶液を、リン酸緩衝生理食塩水中で調製し、その後0.22umフィルタを通して無菌管内へろ過した。
実施例1:アミド結合形成を介したC-16π-ポリマーBへのガラクトサミンの付着
ガラクトサミン(GA)は、肝アシアロ糖タンパク受容体(ASGPR)を標的にし、共有結合したガラクトサミンを有するポリマーは、肝臓に運搬される。L.Seymour et al.,“Hepatic Drug Targeting:Phase I Evaluation of Polymer-Bound Doxorubicin”J.Clin.Oncology,20(6):1668-1676(2002)およびその中の参考文献を参照。
BDDC(2.44g、8.56mmol)を、アルゴンで洗い流した125mLの丸底フラスコ内で検量した(BDDCは蜜様稠度があり非常に粘性が高く、扱いが困難である)。C18-π-ポリマーA(10g、4.28mmol)をフラスコに添加し、混合物を70℃に加熱し、残留物を一緒に30分間攪拌した。葉酸(3g)を添加し、続いて十分なTHFを添加して攪拌を可能にした。残留物を40〜70℃で一晩攪拌し、湿気から保護した。その後THFを蒸発させ、水(80mL)を添加し、混合物をさらに2時間50℃で攪拌した。室温まで冷却した後、混合物をカットオフが3500ダルトンの透析管の一部分に移し、0.1N HCl(2×2000ml)、水(2000ml)、5%炭酸ナトリウム(2×2000ml)および水(4×2000ml)に対して透析し、未反応の試薬および副生成物を除去した。明るい黄色〜オレンジ色の残留物を除去した。一部は恒量まで蒸発して固体濃度を決定し、上記の可溶化実験に使用した。
ともにシアル酸に結合することが知られている血球凝集素およびノイラミニダーゼ外皮タンパク質のため、ノイラミン酸誘導体はインフルエンザウイルスに対する部分を標的にしていることが予期される。
1mlの水中の43ミクロモルCOOH基準である、C16-π-ポリマーB、および40ミクロモルのノイラミン酸β-メチルグリコシド(Toronto Research Chemicals)を共に混合し、0.1mlの水中の40ミクロモルNHSを添加し、それに続いて0.1mlの水中の40ミクロモルEDC塩酸塩を添加した。反応混合物を周辺温度で48時間振り、イソプロパノール-酢酸エチル-水(4:3:2)を伴うシリカゲル上のTLCによって分析した。130℃の70%硫酸中の0.2%オルシノールによる検出は、開始ポリマーによる呈色反応を生成しないが、反応混合物のTLCは、ポリマーによる紫斑同時移動を生じた。
ザナミビル(GG167)は、ウイルスノイラミニダーゼの強力阻害剤であり、多価リガンドとしてこの分子を有するポリマーは、インフルエンザウイルス複製の阻害剤である。
表面糖タンパク質高分子量メラノーマ関連抗原(HMW-MAA)に向けられる単鎖可変断片抗体(scFv)は、メラノーマ細胞を標的にする。F.Martin et al.,J.Virology,73:6923-6929(1999)を参照。
Claims (25)
- 以下の構造:
- pは平均して、2から4の範囲である、請求項1に記載のポリマー。
- 平均して、1.5≦p≦2である、請求項1に記載のポリマー。
- 前記ポリマーブロックAが、ポリ(エチレングリコール)およびポリ(プロピレングリコール)、ならびにその共重合体からなる群から選択される、請求項1〜4のいずれか一項に記載のポリマー。
- 前記ポリマーブロックAが、ポリ(エチレングリコール)である、請求項5に記載のポリマー。
- 前記ポリマーブロックAが、4〜700のモノマー単位の平均長さを有する、請求項6に記載のポリマー。
- ポリエチレングリコールおよび無水マレイン酸を化学反応させ、無水マレイン酸によって、ポリエチレングリコールの末端ヒドロキシル基に完全なエステル化をもたらし、そして得られた産物をジチオスレイトールと化学反応させて得られる組成物。
- ポリエチレングリコールおよび無水マレイン酸を化学反応させ、無水マレイン酸によって、ポリプロピレングリコールの末端ヒドロキシル基に完全なエステル化をもたらし、そして得られた産物をジチオスレイトールと化学反応させて得られる組成物。
- 以下の構造:
を有するポリマー。 - 以下の構造:
を有するポリマー。 - 請求項1〜9のいずれかに記載のポリマーを含み、有効量の医薬活性剤をさらに含む、医薬組成物。
- 水性溶媒中の物質の溶解度を増加する方法であって、前記物質および前記ポリマーの水溶性複合体を形成するために、請求項1または請求項2に記載のポリマーと前記物質を接触させるステップを含む、前記方法。
- 非水性溶媒中の物質の溶解度を増加する方法であって、前記物質、および非水性溶媒中に可溶である前記ポリマーの複合体を形成するために、請求項1または請求項2に記載のポリマーと前記物質を接触させるステップを含む、前記方法。
- 請求項17または請求項18に記載の方法であって、前記物質が、ビタミン、栄養素、薬物、着色料、核酸複合体、および造影剤からなる群から選択される、前記方法。
- 前記物質が、薬物である、請求項19に記載の方法。
- 前記ポリマー上に存在する前記反応性官能基Xの1つ以上に標的部分を結合するステップを含む、請求項4に記載のポリマーに、生物学的標的に対する結合親和力を誘発する方法。
- 前記生物学的標的は、細胞またはウイルスの表面である、請求項20に記載の方法。
- 請求項21に記載の方法であって、前記標的部分が、受容体に特異的なリガンド、抗体、抗体フラグメント、RGDアミノ酸配列を含むペプチド、YISRGモチーフを含むペプチド、成長因子、シアル酸誘導体、N-アセチルノイラミン酸誘導体、葉酸、メトトレキサート、プテロイン酸、エストラジオール、エストラトリオール、テストステロン、マンノース-6-リン酸、糖類、ビタミン、トリプトファン、アミノアルキルアダマンタン、Fuzeon(登録商標)、PRO-542、BMS-488043、シアル酸、2-デオキシ-2,3-ジデヒドロ-N-アセチルノイラミン酸、4-グアニジノ-Neu5Ac2en(ザナミビル)、オセルタミビル、およびRWJ-270201からなる群から選択される、前記方法。
- 前記標的部分は、モノクローナル抗体または抗体フラグメントである、請求項22に記載の方法。
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US7897170B2 (en) * | 2006-08-25 | 2011-03-01 | Boston Scientific Scimed, Inc. | Medical devices having improved mechanical performance |
US20100008938A1 (en) | 2007-01-22 | 2010-01-14 | Anil Diwan | Self assembling amphiphilic polymers as antiviral agents |
AP2941A (en) * | 2007-07-19 | 2014-07-31 | Allexcel Inc | Self-assembling amphiphilic polymers as anticanceragents |
EP2344134B1 (en) | 2008-09-23 | 2017-11-08 | The Regents of The University of California | Nanocarriers for drug delivery |
WO2010038747A1 (ja) * | 2008-09-30 | 2010-04-08 | 国立大学法人大阪大学 | 親水性材料、医用材料および薬剤徐放材料 |
KR100987693B1 (ko) | 2008-10-20 | 2010-10-13 | 서울대학교산학협력단 | 폴리(에틸렌 글리콜)-b-[폴리(L-세린)-g-폴리(D,L-락티드)]의 블록공중합체 및 이를 이용한 약물전달체용 나노입자의 제조 방법 |
MX2013005275A (es) | 2010-11-10 | 2014-03-31 | Battelle Memorial Institute | Sistema de liberacion de particulas de polimero auto-ensamble. |
US8496946B2 (en) | 2011-03-10 | 2013-07-30 | International Business Machines Corporation | Antimicrobial hydrogels, methods of preparation thereof, and articles therefrom |
US9642916B2 (en) | 2012-12-12 | 2017-05-09 | The Regents Of The University Of California | Porphyrin modified telodendrimers |
CN103254442B (zh) * | 2013-04-28 | 2015-01-14 | 天津大学 | 二硫键键接的聚酯梳型接枝共聚物及其制备方法和应用 |
WO2016172042A1 (en) * | 2015-04-18 | 2016-10-27 | The Texas A&M University System | Polymer systems and their applications in diagnostics and drug delivery |
WO2017193294A1 (zh) * | 2016-05-10 | 2017-11-16 | 苏州大学张家港工业技术研究院 | 基于聚氨基酸的功能性生物可降解纳米粒子的制备方法 |
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CN110423355B (zh) * | 2019-08-29 | 2021-09-14 | 武汉轻工大学 | 羧甲基化莲藕多糖-曲古霉素a轭合物的制备方法 |
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