JP2006512462A - 薬物送達媒体としてのマルチアーム(multi−arm)ポリペプチド−ポリ(エチレングリコール)ブロックコポリマー - Google Patents
薬物送達媒体としてのマルチアーム(multi−arm)ポリペプチド−ポリ(エチレングリコール)ブロックコポリマー Download PDFInfo
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- JP2006512462A JP2006512462A JP2004565733A JP2004565733A JP2006512462A JP 2006512462 A JP2006512462 A JP 2006512462A JP 2004565733 A JP2004565733 A JP 2004565733A JP 2004565733 A JP2004565733 A JP 2004565733A JP 2006512462 A JP2006512462 A JP 2006512462A
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Abstract
Description
本発明は、共有結合的付着に利用可能な少なくとも3つの付着部位、及び中心コア分子のそれぞれの付着部位と共有結合的に付着するコポリマーアームを供する中心コア分子を含んで成る単分子マルチアームブロックコポリマーを供する。各コポリマーアームは、中心コア分子と共有結合的に付着する内側のポリペプチドセグメント、及びポリペプチドセグメントと共有結合的に付着する外側の親水性ポリマーセグメントを含んで成る。当該コア分子及び当該ポリペプチドセグメントは一緒に内側コア領域を規定し、そして親水性ポリマーセグメントは親水性外側領域を規定する。生理活性剤は、コポリマー構造中に、好ましくは、ブロックコポリマーの内側コア領域中に封入されることができる。生理活性剤及びブロックコポリマーの構造及び特性に依存して、当該封入は多様な結合又は誘引力によりもたらすことができる。
本発明を一般的な語句で説明してきたがこれらより図面を参照しながら説明する。
本発明はこの度より完全に説明されるだろう。本発明は、しかしながら、多くの異なる形態において実施することができ、そして本明細書における態様に制限すべきではなく;これらの態様は、徹底的に及び完全になるように、そして、当業者に本発明の範囲を完全に伝えるように供される。
本明細書及び請求の範囲において使用される、単一形態は、文中において明らかに他に指示しない限り、複数の指示物を含む。従って、例えば、「薬物」は、単一の薬物、並びに、2又はそれ以上の同一又は異なる薬物を含み、「単分子マルチアームブロックコポリマー」は、単一の単分子マルチアームブロックコポリマー、並びに2又はそれ以上の同一又は異なる単分子マルチアームブロックコポリマーを含み、「賦形剤」は、単一の賦形剤、並びに2又はそれ以上の同一又は異なる賦形剤を含む。
本発明は、共有結合的に付着されるポリペプチドセグメントを有する中心コア分子により規定される内側コア領域、及び、各ポリペプチドポリマーセグメントと共有結合的に付着する親水性ポリマーセグメントにより規定される外側親水性領域を有するマルチアームブロックコポリマーを供する。従って、マルチアーム構造の各アームは内側(即ち、中心コア分子のより近く又は基部)ポリペプチドモノマーセグメント、及び外側(即ち、中心コア分子のより遠く又は末端)親水性ポリマーセグメントを含んで成るブロックコポリマーである。
ポリペプチドは、疎水性の広範な範囲を示すことができる。疎水性ポリペプチドが利用される場合、上記マルチアームブロックポリマーは水溶液中の単分子ミセルとして作用すると考えられ、当該ミセル構造は親水性外側領域により結合される中心疎水性コア領域を含んで成る。結果として、当該態様において、本発明のマルチアームブロックコポリマーは、当該マルチアームブロックコポリマー構造の疎水性コア領域中に被包又は物理的に封入することにより、疎水性生理活性剤の水性溶解度を増大することができる。ポリペプチドの厳密な構造、及び結果的なその疎水性は、特定の薬物分子に対する親和性を最大にするために必要的に調整することができる。
他の態様において、水性媒体中で電荷を有している親水性生理活性剤は、逆の電荷を有するポリペプチドセグメントを選択することにより、本発明の単分子マルチアームブロックコポリマーの内側コア領域中に封入させることができる。当該逆の電荷は、マルチアーム構造のコア領域と薬物との間の誘引力をもたらす。例えば、正電荷を伴う内側コア領域が、負電荷の活性剤を封入するために必要とされる場合、ポリペプチドセグメントは、好ましくは生理的pHで、又はその付近において(即ち、約7.4のpH)、正に帯電したアミノ酸残基から形成することができる。リジン(約10.0のpKを有する)及びアルギニン(約12.0のpKを有する)は生理的なpHで、又はその付近で正に帯電する。また他のアミノ酸も、環境のpHに依存して正に帯電することができる。例えば、ヒスチジンのイミダゾール環は、正に帯電することができる。
更なる他の態様において、上記生理活性剤がポリペプチド鎖中に存在する懸垂官能基と共有結合的に付着することにより、当該生理活性剤は本発明のマルチアームブロックコポリマーの内側コア領域と共有結合的に付着することができる。例えば、いくつかの異なるアミノ酸、例えば、アスパラギン酸及びグルタミン酸から形成されたポリペプチドは、その側鎖上に懸垂カルボン酸基を含む。これらの酸基は、例えば、アミン基を有する生理活性剤と容易に反応することができ、これにより、生理活性剤はアミド結合を介してポリペプチド鎖と結合する。追加的には、アミン含有リジン残基を含んで成るポリペプチドセグメントは、カルボン酸基を有する生理活性剤反応することができ、これによりアミド結合を形成する。本発明のブロックコポリマーに対する薬物分子の共有結合的付着は図3において示される。
中心コア分子は、所望するコポリマーアームの数と同数のいくつかのポリマー付着部位を供する分子に由来する。「付着部位」は、共有結合を形成するために、他の分子、例えば、アミノ酸と反応できる官能基を意味する。好ましくは、中心コア分子は、アミン基を有する少なくとも3つの末端を有するポリアミン残基である。「ポリアミン」は、コア分子にコポリマーアームを付着させるための付着部位として利用できる複数の末端アミン基を含む分岐型分子を意味する。コアのアミン基は、アミド結合を形成するためにアミノ酸のカルボン酸基と容易に反応するので、ポリアミンコアの使用は好ましい。しかしながら、コポリマーアームとの付着のために利用できる他の官能基を有するコア分子もまた使用することができる。
A’は、ポリオール、例えば、グリセロール、ソルビトール、ペンタエリスリトール、グリセロールオリゴマー、又はポリオール含有シクロデキストリン、例えば、ヒドロキシプロピル−β−シクロデキストリンの残基であり;
PEG0は、約100Daから約1,000Daの分子量を有するPEGオリゴマーであり;そして、
(n)は3から約25であり、そして、中心コア分子に付着する(−O−PEG0−NH2)部分の数を表すために使用される。
当該ポリペプチドは一般的に、無毒及び生体適合性であるべきであり、生物組織に関連する提案された使用(例えば、患者に対する投与)に由来する利点は、臨床家、例えば、医師により評価されるように、如何なる有害な効果に勝ることを意味する。好ましい態様において、当該ポリペプチドセグメントは、アミノ酸、例えば、グリシン、アラニン、バリン、ロイシン、イソロイシン、メチオニン、プロリン、フェニルアラニン、トリプトファン、セリン、スレオニン、アスパラギン、グルタミン、チロシン、システイン、リジン、アルギニン、ヒスチジン、アスパラギン酸、グルタミン酸、又はこれらの組み合わせの残基を含んで成る。ポリペプチドセグメントの疎水的性質を増強する特に好ましいアミノ酸は、バリン、ロイシン、イソロイシン、フェニルアラニン、トリプトファン、チロシン、メチオニン、及びシステインから成る群から選択される。帯電した内側コア領域が所望される場合、当該ポリペプチドは、好ましくは、帯電性又は帯電可能なアミノ酸、例えば、アルギニン、リジン、ヒスチジン、グルタミン酸、アスパラギン酸、又はこれらの組み合わせの残基を含んで成る。
Rは水素、アルキル(例えば、C1-6アルキル)(ここでアルキル鎖の1又は複数の炭素原子はヘテロ原子(例えば、O、S又はN)で任意的に置換されていてよい)、又は置換されたアルキルであり;そして、
(m)は約3から約100であり、好ましくは約3から約50であり、そしてより好ましくは約3から約30である。
当該親水性ポリマーセグメントは、如何なる親水性ポリマーも含んで成ってよく、そして、本発明はこの点に関して制限されない。ポリペプチドを伴う場合、当該親水性ポリマーは、一般的に無毒性且つ生体適合性であるべきである。好ましくは、当該親水性ポリマーセグメントとして、ポリ(エチレングリコール)(「PEG」)が使用される。当該PEGの語は、直鎖状、分岐鎖状、又はマルチ−アーム形態のいずれかにおけるポリエチレングリコールを含み、アルコキシPEG、二機能性PEG、フォーク型PEG、分岐型PEG、懸垂PEG、又は分解可能な結合を伴うPEGを含み、以下により完全に説明される。
polya及びpolybは、PEG主鎖、例えば、メトキシポリ(エチレングリコール)であり;
R”は非反応性部分、例えば、H、メチル、又はPEG主鎖であり;そして、
P及びQは非反応性結合である。好ましい態様において、当該分岐型PEGポリマーは、メトキシポリ(エチレングリコール)二置換性リジンである。
本発明のブロックコポリマーのより特異的な構造の態様を説明する。以下に示される特異的な構造は、典型的な構造として提示されるだけであり、本発明の範囲を制限することを意図するものではない。
Aは、ポリオール、例えば、グリセロール、ソルビトール、ペンタエリスリトール、グリセロールオリゴマー、又はポリオール−含有シクロデキストリン、例えば、ヒドロキシプロピル−β−シクロデキストリンの残基を含んで成る中心コア分子であり;
Oは酸素であり;
Bは親水性オリゴマー、例えば、PEGオリゴマーであり;
Cはポリペプチドセグメントであり;
Dは親水性ポリマーセグメント、例えば、PEGポリマーであり;
Eはキャッピング基(例えば、アルコキシ)又は官能基(例えば、ヒドロキシ、活性エステル等)であり;
L1及びL2は結合、例えば、アミド結合であり;
(m’)は3から約25であり、中心コア分子に付着する(−O−B−L1−C)部分の数を表すために使用され;
(n’)は2から約25であり、(m’)個の(−O−B−L1−C)部分に付着する(L2−D−E)部分の数を表すために使用され、各(−O−B−L1−C)部分は単一の(L2−D−E)部分を有し;そして、
(n’)<(m’)である。
各A,O,B,C,D,E,L1及びL2は、独立に、化学式VII に関して上述した通りであり、
Tは標的化部分であり;
(p)は少なくとも1又はそれ以上の正の整数であり、中心コア分子に付着する(T−D−L2−C−L−B−O−)部分の数を表し;
(k)は少なくとも1又はそれ以上の正の整数であり、中心コア分子に付着する(−O−B−L−C−L2−D−E)部分を表し;そして、
(k)及び(p)の合計は3から約25である。ある態様において、(p)は1から約5であり、好ましくは1から約3であり、そして、(k)及び(p)の合計は約6から約21であり、好ましくは約8から約15である。
各POLYPEPTIDEは、ポリペプチドセグメント、好ましくはアスパラギン酸、グルタミン酸、又はリジンから形成されるポリペプチドであり;そして、
各PEGはポリ(エチレングリコール)であり、好ましくは上述のような末端キャッピング又は官能基を含む。
本発明の単分子マルチアームブロックコポリマー中に輸送される生理活性分子又は薬物は、当該ブロックコポリマー構造中に物理的に封入されることができる如何なる生理活性剤でもよい。封入又は被包された当該薬物はそれ自体又は医薬的に受容可能な塩の形態において利用することができる。使用される場合、当該薬物化合物の塩は、薬理的且つ医薬的に受容可能であるが、非医薬的に受容可能な塩は遊離活性化合物を調製するために慣習的に使用することができ、本発明の範囲から除外されるものではない。薬理的且つ医薬的に受容可能な塩は、文献中に詳しく説明される標準的な方法を使用して当該薬物と有機又は無機酸との反応により調製することができる。有用な塩の例は、制限されることなく、以下の酸から調製される:塩化水素、臭化水素、硫酸、硝酸、リン酸、マレイン酸、酢酸、サリチル酸、p−トルエンスルホン酸、酒石酸、クエン酸、メタンスルホン酸、ギ酸、マロン酸、コハク酸、ナフタレン−2−スルホン酸、及びベンゼンスルホン酸等。また、医薬的に受容可能な塩はアルカリ金属又はアルカリ土類塩、例えば、カルボン酸基のナトリウム、カリウム、又はカルシウム塩として調製することができる。
他の観点において、本発明は、ヒトの医学的な使用のための、上述のマルチアームブロックコポリマー、並びに、少なくとも1つのマルチアームブロックコポリマー中に、好ましくはコア分子及びポリペプチドセグメントにより規定される内側コア領域中に封入される生理活性剤医薬製剤及び組成物を供する。前述で示した通り、疎水性製剤の疎水性コアを有するブロックコポリマー構造への取り込みは、疎水性薬物に溶解能を供し、そして患者に対する投与後の循環している薬物の滞留時間を増強することができる。
本発明のマルチアームブロックコポリマーは、前もって形成したポリペプチドセグメントをコア分子に共有結合的に付着させること、続いて、前もって形成した親水性ポリマーセグメントを当該ポリペプチドセグメントの末端に付着させることにより調製することができる。2つのポリマーセグメント間、及び当該ポリペプチドセグメントとコア分子間の結合は、利用される官能基に依存するであろう。典型的には、当該結合は、アミド結合である。しかしながら、他の結合のタイプ、例えば、カルバメート、エステル、カルボネート、及びアセタールもまた、本発明と離れることなく使用できる。
生理活性剤又は薬物を本発明のブロックコポリマーのコア領域中に封入させるために、いくつかの方法が存在する。上述の通り明らかに、当該薬物はポリペプチド又はPEG鎖に対する薬物の共有結合的付着により封入されることができる。
上に示したように、本発明のマルチアームブロックコポリマーは、疎水性薬物分子を水溶液中に可溶化するために、又は、帯電性薬物分子若しくはポリペプチド又はPEG鎖に共有結合的に付着できる如何なる薬物分子を封入し、そして保護するために使用することができる。結果として、本発明のコポリマー構造は、コポリマー構造中に、特にコポリマーの内側コア領域中に多様な薬物を封入することにより、そして治療的有効量のその中に封入された生理活性剤を伴うマルチアームブロックコポリマーを哺乳類に投与することにより、薬物送達媒体として使用することができる。
本発明を説明するために以下の実施例を与えるが、本発明を制限するものとして考えるべきではない。実施例1−3は、ベンジル保護カルボン酸基を有するアミノ酸のN−カルボキシ無水物の形成方法を説明する。実施例4−5は、ポリペプチド鎖をポリアミドコア分子に付着させるための開環重合技術を説明する。実施例6は、中心ポリアミンコア分子に付着したブロックコポリマーアームを形成するために、PEGポリマーセグメントを各ポリペプチド鎖に付着させる方法を説明する。実施例7は、ブロックコポリマーアームのポリペプチドセグメントに沿って位置する懸垂カルボン酸基の脱保護のための技術を説明する。実施例8は、生理活性剤をブロックコポリマーアームのポリペプチドセグメントの当該懸垂カルボン酸基に抱合する方法を説明する。実施例9は、金属含有製剤、シスプラチンとポリ(アスパラギン酸)セグメントのカルボン酸基の複合体を形成する方法を説明する。実施例10は、実施例8において形成された抱合体からの活性剤の放出速度を説明する。
シス−ジアミノジクロロ白金(0.012g、Aldrich )を20mlの水に溶解させた。8−アームポリ(アスパラギン酸)−PEG5000(0.056g、実施例7に由来)を20mlの水に溶解させた。当該溶液を、アスパラギン酸基の最終濃度が10mMとなるように希釈した。アスパラギン酸に対する白金の異なる濃度比の3つの製剤を形成するように当該シス−ジアミノジクロロ白金溶液を加えた。当該3つの調製製剤は、1:1(図4において「1:1」とされる)、1:1.5(図4において「1:1.5」とされる)、及び1:2(図4において「1:2」とされる)のアスパラギン酸に対する白金比を有する。時間に対する249nmでのUV吸収の変化は、各製剤についてプロットし、図4において示す。図4において示されるように、249nmにおける吸光度は、室温でのインキュベーションタイムで増加し、シス−ジアミノジクロロ白金が、8−アームポリ(アスパラギン酸)−PEG5000中のポリ(アスパラギン酸)セグメントと複合体を形成したことを示している。
5−フルオロウラシル(「5−FU」)と8−アームポリ(アスパラギン酸)−PEG5000の抱合体(実施例8に由来)をリン酸バッファー溶液(0.1M、pH7.4)中に溶解させた。当該溶液を室温及び37℃で保管した。時間間隔において、当該溶液をHPLC(ウルトラハイドロゲル250、水)で分析した。50%の5−FUが放出された時間(t1/2)は室温において58時間であり、そして37℃において13時間であった。
Claims (44)
- 薬物送達媒体として有用な単分子マルチアームブロックコポリマーであって:
コポリマーアームへの共有結合的な付着のために利用できる少なくとも3つの付着部位を供する中心コア分子;及び、
上記の中心コア分子の上記の少なくとも3つの付着部位のそれぞれに共有結合的に付着するコポリマーアームであって、各コポリマーアームが上記中心コア分子の上記付着部位と共有結合的に付着する内側ポリペプチドセグメント、及び上記ポリペプチドセグメントと共有結合的に付着する外側親水性ポリマーセグメントを含んで成るコポリマーアーム、
を含んで成る単分子マルチアームブロックコポリマー。 - 上記中心コア分子が、アミン基を有する少なくとも3つの末端を有するポリアミン残基である、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記中心コア分子が、ヒドロキシル基を有する少なくとも3つの末端を有するポリオール残基を含んで成る、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記ポリオールがグリセロール、ソルビトール、ペンタエリスリトール、及びグリセロールオリゴマーから成る群から選択される、請求項3に記載の単分子マルチアームブロックコポリマー。
- 上記ポリオールがヘキサグリセロールである、請求項3に記載の単分子マルチアームブロックコポリマー。
- 上記ポリオールがヒドロキシプロピル−β−シクロデキストリンである、請求項3に記載の単分子マルチアームブロックコポリマー。
- 上記中心コア分子が、更に、上記ポリオールの残基の各末端に付着した親水性オリゴマー鎖を含んで成る、請求項3に記載の単分子マルチアームブロックコポリマー。
- 上記親水性オリゴマー鎖が、約100Daから約5,000Daの分子量を有するエチレングリコールオリゴマー鎖である、請求項7に記載の単分子マルチアームブロックコポリマー。
- 各親水性オリゴマー鎖が、上記ポリペプチドセグメントとアミド結合を介して共有結合的に付着する、請求項7に記載の単分子マルチアームブロックコポリマー。
- 上記ポリペプチドセグメントが、グリシン、アラニン、バリン、ロイシン、イソロイシン、メチオニン、プロリン、フェニルアラニン、トリプトファン、セリン、スレオニン、アスパラギン、グルタミン、チロシン、システイン、リジン、アルギニン、ヒスチジン、アスパラギン酸、グルタミン酸、及びこれらの組み合わせから成る群から選択されるアミノ酸残基を含んで成る、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記ポリペプチドが、帯電性アミノ酸残基を含んで成る、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記帯電性アミノ酸が、アルギニン、リジン、ヒスチジン、グルタミン酸、アスパラギン酸、及びこれらの組み合わせから成る群から選択される、請求項11に記載の単分子マルチアームブロックコポリマー。
- 上記ポリペプチドセグメントが、官能基を有する、少なくとも1つのアミノ酸残基を含んで成る、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記官能基が、ヒドロキシル、活性エステル、活性カルボネート、アセタール、アルデヒド、アルデヒド水和物、スルホン酸アルキル若しくはアリール、ハライド、ジスルフィド、アルケニル、アクリレート、メタクリレート、アクリルアミド、活性スルホン、アミン、ヒドラジン、チオール、カルボン酸、イソシアネート、イソチオシアネート、マレイミド、ビニルスルホン、ジチオピリジン、ビニルピリジン、ヨードアセトアミド、エポキシド、グリオキサル、ジオン、メシレート、トシレート、又はトレシレートから成る群から選択される、請求項13に記載の単分子マルチアームブロックコポリマー。
- 上記外側親水性ポリマーセグメントが、ポリ(エチレングリコール)を含んで成る、請求項1に記載の単分子マルチアームブロックコポリマー。
- 各ポリペプチドセグメントが約100Daから約20,000Daの分子量を有する、請求項1に記載の単分子マルチアームブロックコポリマー。
- 各ポリペプチドセグメントが、約500Daから約10,000Daの分子量を有する、請求項16に記載の単分子マルチアームブロックコポリマー。
- 上記外側親水性ポリマーセグメントが、約100Daから約20,000Daの分子量を有する、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記外側親水性ポリマーセグメントが、約500Daから約10,000Daの分子量を有する、請求項18に記載の単分子マルチアームブロックコポリマー。
- 上記単分子マルチアームブロックコポリマーが、約10,000Daから約200,000Daの総分子量を有する、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記単分子マルチアームブロックコポリマーが、約20,000Daから約80,000Daの総分子量を有する、請求項20に記載の単分子マルチアームブロックコポリマー。
- 上記中心コア分子が、コポリマーアームへの共有結合的な付着のために利用可能な少なくとも4つの付着部位を有する、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記中心コア分子が、コポリマーアームへの共有結合的な付着のために利用可能な少なくとも8つの付着部位を有する、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記中心コア分子が、コポリマーアームへの共有結合的な付着のために利用可能な3から約25の付着部位を有する、請求項1に記載の単分子マルチアームブロックコポリマー。
- 少なくとも1つの標的化部分が、少なくとも1つの親水性ポリマーセグメントに共有結合的に付着している、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記標的化部分が、タンパク質、抗体、抗体断片、ペプチド、炭水化物、脂質、オリゴヌクレオチド、DNA、RNA、又は2,000ダルトン以下の分子量を有する小分子から成る群から選択される、請求項25に記載の単分子マルチアームブロックコポリマー。
- 上記標的化部分が、モノ−葉酸、又は抗−EGFr Fabである、請求項25に記載の単分子マルチアームブロックコポリマー。
- 少なくとも1つのキャッピング基又は官能基が、少なくとも1つの親水性ポリマーセグメントに共有結合的に付着する、請求項1に記載の単分子マルチアームブロックコポリマー。
- 上記キャッピング基又は官能基が、アルコキシ、ヒドロキシル、活性エステル、活性カルボネート、アセタール、アルデヒド、アルデヒド水和物、スルホン酸アルキル若しくはアリール、ハライド、ジスルフィド、アルケニル、アクリレート、メタクリレート、アクリルアミド、活性スルホン、アミン、ヒドラジン、チオール、カルボン酸、イソシアネート、イソチオシアネート、マレイミド、ビニルスルホン、ジチオピリジン、ビニルピリジン、ヨードアセトアミド、エポキシド、グリオキサル、ジオン、メシレート、トシレート、及びトレシレートから成る群から選択される、請求項28に記載の単分子マルチアームブロックコポリマー。
- 上記Eがアルコキシである、請求項30に記載の単分子マルチアームブロックコポリマー。
- 上記Eがヒドロキシである、請求項30に記載の単分子マルチアームブロックコポリマー。
- 上記Eが、アルコキシ、ヒドロキシル、活性エステル、活性カルボネート、アセタール、アルデヒド、アルデヒド水和物、スルホン酸アルキル若しくはアリール、ハライド、ジスルフィド、アルケニル、アクリレート、メタクリレート、アクリルアミド、活性スルホン、アミン、ヒドラジン、チオール、カルボン酸、イソシアネート、イソチオシアネート、マレイミド、ビニルスルホン、ジチオピリジン、ビニルピリジン、ヨードアセトアミド、エポキシド、グリオキサル、ジオン、メシレート、トシレート、及びトレシレートから成る群から選択される、請求項30に記載の単分子マルチアームブロックコポリマー。
- 上記Aが、グリセロール、ソルビトール、ペンタエリスリトール、及びヒドロキシプロピル−β−シクロデキストリン、及びグリセロールオリゴマーから成る群から選択されるポリオール残基である、請求項30に記載の単分子マルチアームブロックコポリマー。
- 上記Dが、ポリ(エチレングリコール)を含んで成る、請求項30に記載の単分子マルチアームブロックコポリマー。
- 上記Cが、グリシン、アラニン、バリン、ロイシン、イソロイシン、メチオニン、プロリン、フェニルアラニン、トリプトファン、セリン、スレオニン、アスパラギン、グルタミン、チロシン、システイン、リジン、アルギニン、ヒスチジン、アスパラギン酸、グルタミン酸、及びこれらの組み合わせから成る群から選択されるアミノ酸残基を含んで成る、請求項30に記載の単分子マルチアームブロックコポリマー。
- 少なくとも1つのCのアミノ酸残基が官能基を有する、請求項30に記載の単分子マルチアームブロックコポリマー。
- 上記Bがエチレングリコールオリゴマーである、請求項30に記載の単分子マルチアームブロックコポリマー。
- 医薬組成物であって:
コポリマーアームへの共有結合的な付着に利用可能な少なくとも3つ付着部位を供する中心コア分子、及び上記中心コア分子の上記少なくとも3つの付着部位のそれぞれと共有結合的に付着するコポリマーアームであって、各コポリマーアームが上記中心コア分子の上記付着部位に共有結合的に付着する内側ポリペプチドセグメント、及び上記ポリペプチドセグメントに共有結合的に付着する外側親水性ポリマーセグメントを含んで成るコポリマーアームを含んで成る単分子マルチアームブロックコポリマー、ここで当該中心コア分子及び当該ポリペプチドセグメントが内側コア領域を規定し、そして当該ポリペプチドセグメントが疎水性外側領域を規定する;並びに、
上記単分子マルチアームコポリマーの内側領域中に封入された生理活性剤、
を含んで成る、医薬組成物。 - 上記ポリペプチドセグメントが1又は複数の帯電性アミノ酸残基を含んで成り、そして、上記内側領域中に封入された生理活性剤が、1又は複数の帯電性アミノ酸残基と反対の電荷を有する、請求項40に記載の医薬組成物。
- 上記生理活性剤が、上記ポリペプチドセグメントのアミノ酸残基に共有結合的に付着する、請求項40に記載の医薬組成物。
- 上記内側コア領域と上記生理活性剤が共に疎水性である、請求項40に記載の医薬組成物。
- 更に、医薬的に受容可能な担体を含んで成る、請求項40に記載の医薬組成物。
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JP2015511987A (ja) * | 2012-03-16 | 2015-04-23 | ザ・ジョンズ・ホプキンス・ユニバーシティー | Hif−1阻害剤の送達のための放出制御製剤 |
WO2014038168A1 (ja) * | 2012-09-10 | 2014-03-13 | パナソニック株式会社 | 機能性物質、生体活性用薬剤及び機能性物質の生体内への浸透方法、並びに機能性物質放散装置及び空気清浄装置 |
JP2014051478A (ja) * | 2012-09-10 | 2014-03-20 | Panasonic Corp | 機能性物質、生体活性用薬剤及び機能性物質の生体内への浸透方法、並びに機能性物質放散装置及び空気清浄装置 |
WO2016093352A1 (ja) * | 2014-12-12 | 2016-06-16 | 日本化薬株式会社 | 核酸代謝拮抗剤が結合した多分岐化合物 |
WO2017110669A1 (ja) * | 2015-12-22 | 2017-06-29 | 日本化薬株式会社 | スルホキシド誘導体配位白金(ii)錯体の高分子結合体 |
US10946028B2 (en) | 2015-12-22 | 2021-03-16 | Nippon Kayaku Kabushiki Kaisha | Polymer conjugate of sulfoxide derivative-coordinated platinum(II) complex |
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US7316811B2 (en) | 2008-01-08 |
AU2003300380A1 (en) | 2004-07-29 |
EP1581583A1 (en) | 2005-10-05 |
AU2003300380B2 (en) | 2008-11-06 |
EP1581583B1 (en) | 2010-03-24 |
DE60331860D1 (en) | 2010-05-06 |
US20080069902A1 (en) | 2008-03-20 |
CN100349963C (zh) | 2007-11-21 |
CN1732212A (zh) | 2006-02-08 |
JP4490291B2 (ja) | 2010-06-23 |
ATE461961T1 (de) | 2010-04-15 |
US20110237747A1 (en) | 2011-09-29 |
KR101045504B1 (ko) | 2011-06-30 |
CA2508015A1 (en) | 2004-07-22 |
MXPA05007146A (es) | 2005-09-21 |
US8323632B2 (en) | 2012-12-04 |
US20040161403A1 (en) | 2004-08-19 |
CA2508015C (en) | 2012-04-03 |
US7976834B2 (en) | 2011-07-12 |
WO2004060977A1 (en) | 2004-07-22 |
KR20050091050A (ko) | 2005-09-14 |
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