JP4391750B2 - 複数の官能基を有するセグメントに結合した生物分解性のコポリマー - Google Patents
複数の官能基を有するセグメントに結合した生物分解性のコポリマー Download PDFInfo
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- JP4391750B2 JP4391750B2 JP2002587491A JP2002587491A JP4391750B2 JP 4391750 B2 JP4391750 B2 JP 4391750B2 JP 2002587491 A JP2002587491 A JP 2002587491A JP 2002587491 A JP2002587491 A JP 2002587491A JP 4391750 B2 JP4391750 B2 JP 4391750B2
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Description
本出願は2001年5月7日に登録された米国特許仮出願60/288,806の権益を請求し、それのすべては引用に包含される。
本発明は、複数の官能基、およびいくつかまたは各々の官能基が反応してできた生成物に結合しており、アミノオキシル含有基を含む部分を固着するか、または他の薬物分子残基もしくは他の生物活性物残基を含む部分を固着する、生体適合性で生物分解性のポリマーまたはコポリマーの提供を指向している。
脂肪族ポリエステルは、生物分解性および生体適合性のゆえに、商業的に成功した適用例のある、一群の生体適合材料である。このポリマーは縫合材料、移植材料および薬物担体として広範に使われてきたが、人体の修復に積極的に関与する、なんら固有の生物学的機能を有してはいない。
固着したアミノオキシル基、固着した薬物残基または固着した生物活性物残基を利用可能な濃度で自由に変更し得る、生体適合性で生物分解性のポリマーまたはコポリマーが、共有結合的またはイオン結合的にアミノオキシル含有部分、他の薬物分子残基または他の生物活性物残基を含有する複数の部分の形成よって提供されることをここに発明した。
本発明の第1実施態様に戻って説明する。該実施態様は、加水分解性のエステルまたは窒素−リン結合を含有するポリマーまたはポリマーのセグメントを含んでおり、一端で封止され、他端でそこに付着した複数の官能基を持つポリマーまたはポリマーのセグメントに結合し、そのいくつかまたは各々の官能基は反応してアミノオキシル含有基を含む部分に固着するか、または他の薬物分子残基もしくは他の生物活性物残基を含む部分固着する、生体適合性で生物分解性のコポリマーを指向している。
およびnは例えば30ないし70のように10ないし100、mは例えば3ないし10、好ましくは3ないし7、xは例えば1ないし10、好ましくは1または2、およびyは例えば5ないし50、好ましくは10ないし20の各範囲で変わり得る。反応式中、(1)はベンジルアルコールを表わし、(2)はラクチドを表わし、(3)はε−カプロラクトンを表わし、(4)はベンジルアルコールで末端が封止された、ラクチドとε−カプロラクトンとの不揃いコポリマーであるPBLC−OHを表わし、(5)は無水マレイン酸を表わし、(6)はPBLC−Maを表わし、(7)はアクリル酸を表わし、(8)はPBLCAを表わし、(9)はTEMPAMINを表わし、また(10)はTAM−PBLCAを表わす。
実施2で得たPBLC−OH中の−CH(CH3)−OH末端基に対する−CH2OHのモル比は1/19.62であった。実施2で得たα−オキシプロピオニル・ユニット(Lユニット)に対するε−オキシカプロイル・ユニット(Cユニット)の組成比は1/4.53であったが、使用したモル比は1/5であった。これはε−カプロラクトン・モノマーの重合率がラクチド・モノマーのそれよりも高かったこと示している。実施2で得た生成物では、PBLC−OHコポリマーの95%がα−オキシプロピオニル末端基をもっていた。95%でα−オキシプロピオニル末端基の量が得られたのは、表1の実施2での使用モル比によること、および適用した重合条件でε−カプロラクトン・モノマーの重合率がラクチド・モノマーのそれよりも高かったことのふたつに起因している。もしも使用モル比が代わって、Cユニットが35モルおよびLユニットが7モルであったなら、ラクチド末端基を含むPBLC−OH分子の百分率は増加するが、前述の相対的な重合率のゆえに増加のレベルは限定されるであろう。
上記の多くのバリエーションは、この技術分野に精通した者には明らかであろう。よって本発明は特許請求の範囲にて定義する。
Claims (14)
- 一端で不飽和基含有の化合物との反応を防ぐために封止され、そして、他端で複数のカルボキシ基を有する第2のポリマーまたはコポリマーのセグメントに結合している、第1のポリマーまたはコポリマーのセグメントを含む生体適合性で生物分解性のコポリマーであって、ここで、該第1のポリマーまたはコポリマーのセグメントが直鎖の脂肪族ポリエステルを含み、該第2のポリマーまたはコポリマーのセグメントが不飽和カルボン酸のポリマーまたはコポリマーであって、カルボキシ基のいくつかまたは各々が反応して、アミノオキシル含有基、またはシロリムスおよびパクリタキセルからなる群から選択される薬剤、またはタンパク質、サイトカイン、オリゴヌクレオチド、遺伝子、炭水化物およびホルモンからなる群から選択される生物活性物に結合した、生体適合性で生物分解性のコポリマー。
- いくつかまたは各々のカルボキシル基が反応して、アミド、エステルまたはオキシカルボニルの結合を介して、アミノオキシル含有基を含む部分に結合するか、または他の薬物分子残基もしくは他の生物活性物残基を含む部分に結合する、請求項1の生体適合性で生物分解性のコポリマー。
- 第1のポリマーまたはコポリマーのセグメントの他端で不飽和基を組み込み、そして、二重結合官能性のポリマーまたはコポリマーの存在下で、不飽和基含有のモノマーを重合することによって製造される、請求項2の生体適合性で生物分解性のコポリマー。
- 加水分解性のエステルまたは窒素−リン結合を含んでいて、一端で不飽和基含有の化合物との反応を防ぐために封止され他端に遊離水酸基をもっている出発物質のポリマーまたはコポリマーから生成し、遊離水酸基の水素を、末端部分に不飽和基を含むカルボニルに変換し、末端部分の不飽和基と不飽和カルボキシル基含有の化合物またはそのポリマーとの反応によって複数のカルボキシル基をもつ末端セグメントを与え、いくつかまたは各々のカルボキシル基の修飾によって、カルボキシル基の水酸基に代わって、アミノオキシル含有基を含む部分、または他の薬物分子残基を含む部分もしくは他の生物活性物残基を含む部分を与える、請求項2の生体適合性で生物分解性のコポリマー。
- いくつかまたは各々のカルボキシル基が反応して、アミド、エステルまたはオキシカルボニルの結合を介して、アミノオキシル含有基を含む部分、または他の薬物分子残基もしくは他の生物活性物残基を含む部分を固着する、請求項4の生体適合性で生物分解性のコポリマー。
- 薬物を制御放出する特性を有する生体適合性で生物分解性のポリマーを構成する、請求項5の生体適合性で生物分解性のコポリマー。
- 薬物を制御放出する特性を有する生体適合性で生物分解性のポリマーを構成する、請求項1の生体適合性で生物分解性のコポリマー。
- ポリマーまたはコポリマーのセグメントが、ポリラクチド、ポリカプロラクトン、ポリグリコリド、ポリ(3−ヒドロキシブチラート)およびそれらのコポリマーよりなるグループから選ばれ、ポリマーまたはコポリマーのセグメントは一端で不飽和基含有の化合物との反応を防ぐために封止され、他端で、修飾されたいくつかまたは各々のカルボキシル基含有のポリアクリル酸を含むセグメントに結合しており、カルボキシル基の水酸基に代わって、アミノオキシル含有基を含む部分、または他の薬物分子残基もしくは他の生物活性物残基を含む部分を与える、請求項2の生体適合性で生物分解性のコポリマー。
- 二重結合官能性のポリ(ラクチド−コ−ε−カプロラクトン)を提供するために無水マレイン酸、塩化アクリロイルおよびアリルイソシアナートよりなるグループから選ばれた結合剤と、一端で不飽和基含有の化合物との反応を防ぐために封止され他端において水酸基で終わるポリ(ラクチド−コ−ε−カプロラクトン)の水酸基を反応させること、そして、二重結合官能性のポリ(ラクチド−コ−ε−カプロラクトン)の存在下に、アクリル酸を遊離ラジカル重合することにより結合を形成する、請求項8の生体適合性で生物分解性のコポリマー。
- 一端で不飽和基含有の化合物との反応を防ぐために封止され、他端で、カルボキシル官能基をもつポリアクリル酸および/またはポリメタクリル酸を含むセグメントに結合しており、反応してカルボキシル基の水酸基に代わってアミノオキシル含有基を含む部分、またはシロリムスおよびパクリタキセルからなる群から選択される薬剤、またはタンパク質、サイトカイン、オリゴヌクレオチド、遺伝子、炭水化物およびホルモンからなる群から選択される生物活性物に結合する、ポリ(ラクチド−コ−ε−カプロラクトン)。
- 請求項1のコポリマー、およびスピンラベルおよび/またはシロリムス、パクリタキセルおよびオリゴヌクレオチドからなる群から選択される他の薬物を、スピンラベルおよび/または他の薬物とコポリマーの重量比が1:99ないし99:1で含む、組成物。
- 請求項1のコポリマーを含む、生物医学的適用のための薬物放出組成物。
- 請求項11の組成物を含む、生物医学的適用のための薬物放出組成物。
- 請求項12の薬物放出組成物を含む、薬物溶出システムを有するステント。
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US20050163821A1 (en) * | 2002-08-02 | 2005-07-28 | Hsing-Wen Sung | Drug-eluting Biodegradable Stent and Delivery Means |
US20040170685A1 (en) * | 2003-02-26 | 2004-09-02 | Medivas, Llc | Bioactive stents and methods for use thereof |
US8668926B1 (en) | 2003-09-15 | 2014-03-11 | Shaker A. Mousa | Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists, and formulations thereof |
CA2539288C (en) | 2003-09-15 | 2015-05-12 | Shaker A. Mousa | Thyroid hormone analogs and methods of use |
US9198887B2 (en) | 2003-09-15 | 2015-12-01 | Nanopharmaceuticals Llc | Thyroid hormone analogs and methods of use |
US20060188486A1 (en) * | 2003-10-14 | 2006-08-24 | Medivas, Llc | Wound care polymer compositions and methods for use thereof |
CN101426530B (zh) * | 2004-05-12 | 2012-03-07 | 梅迪沃什有限公司 | 创伤愈合聚合物组合物及其使用方法 |
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AU2002248535B2 (en) | 2006-06-08 |
JP2004526043A (ja) | 2004-08-26 |
CA2440394A1 (en) | 2002-11-14 |
ATE366270T1 (de) | 2007-07-15 |
EP1392751A4 (en) | 2005-01-26 |
ES2220247T3 (es) | 2007-11-16 |
WO2002090417A1 (en) | 2002-11-14 |
EP1392751B1 (en) | 2007-07-04 |
DE60221009D1 (de) | 2007-08-16 |
US20030027940A1 (en) | 2003-02-06 |
US6830747B2 (en) | 2004-12-14 |
EP1392751A1 (en) | 2004-03-03 |
DE02717541T1 (de) | 2004-08-26 |
CA2440394C (en) | 2011-10-04 |
ES2220247T1 (es) | 2004-12-16 |
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