JP2009510197A - ビス−(α−アミノ)−ジオール−ジエステル含有ポリ(エステルアミド)およびポリ(エステルウレタン)組成物および使用の方法 - Google Patents
ビス−(α−アミノ)−ジオール−ジエステル含有ポリ(エステルアミド)およびポリ(エステルウレタン)組成物および使用の方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
- C08L77/12—Polyester-amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/041—Mixtures of macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/44—Polyester-amides
Abstract
Description
本発明は一般に、薬物送達系および特に脂肪族系アミノ酸を生分解性ポリマーバックボーンに組み入れるポリマー送達組成物に関する。
1970年代に最初に導入された最も初期の薬物送達系は乳酸およびグリコール酸から形成されるポリマーをベースとした。今日、ポリマー材料は、主としてそれらが加工しやすく研究者らは分子合成を介してそれらの化学的および物理的特性を容易に制御できることから、依然として研究のための最も重要な方法を提供する。基本的に、それらのサイズおよび形状から双方とも「ミクロスフェア」として公知であるポリマーの系の2つの大きなカテゴリーが研究されている:貯蔵系およびマトリックス系。前者はポリマーシェル内への薬学的製剤の内包を伴い、後者は薬物がポリマーネットワーク内に物理的に捕捉またはマトリックス化される系を示す。
本発明は、機械的特性において顕著な改善を伴う2つのビス-(α-アミノ酸)をベースとするビルディングブロックを含む新規のビス-(α-アミノ酸)-ジオール-ジエステルをベースとするPEAおよびPEURコポリマー組成物に基づく。ビス-(α-アミノ酸)-ジオール-ジエステルは活性型重縮合(APC)に有用なジアミンモノマーの一種であり、これは本来、2つの脂肪性エステル結合を含む。このようなエステル基は様々なエステラーゼ によって酵素的に認識されることができる。例えば、活性化二塩基酸エステルを用いたジアミンモノマーの縮合により、エステルおよびアミド結合を持つPEA巨大分子が生じる。本発明のポリマーにおける2つのビス(α-アミノ酸)をベースとするビルディングブロックの少なくとも1つにおけるジオール残基としての1,4:3,6-ジアンヒドロヘキシトールの二環性フラグメントの組み入れは、ポリマーに高いガラス転移温度(Tg)を付与する。2つのビス-(αアミノ酸)をベースとする(例えば、PEAのビス-(α-アミノ酸)-ジオール-ジエステルコモノマー)への少なくとも2つの直線性飽和または不飽和脂肪性ジオール残基の組み入れは形成されるポリマーの伸び特性を高める。類似して、コポリマー内の二塩基酸残基の少なくとも1つが不飽和二塩基酸である場合、ポリマーそのものが架橋結合するためにTgの上昇が起こる。同様に、本発明のPEURコポリマーは、ポリマーに対して亢進された機械的特性を提供するためにPEUR EUに適したビス-(α-アミノ酸)ジエステルビルディングブロックとの重縮合に用いられるジオール残基の適切な選択に基づく。さらに、本発明のPEAおよびPEURコポリマー組成物は、任意で、ポリマーにさらなる柔軟性を導入して、所望ならば、生物活性物質の共有結合に適したペンダント基を与えるために、C保護された無指向性アミノ酸モノマーに基づく第三のモノマーを含むことができる。
下記の一般的構造式(I)によって記載される化学構造を持つPEA:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、式中、nは約5〜約100である。
式中、R1は(C2-C20)アルキレン、(C2-C20)アルケニレン、およびその組み合わせからなる群より独立して選択される;それぞれ、単一のコモノマーのmまたはpにおけるR3およびR4は水素、(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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択される;R5は下記構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択される;かつ
R6は(C2-C20)アルキレン、(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択される;
または、下記の一般的構造式(III)によって記載される化学構造を持つPEA:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、式中、nは約5〜約100である。
式中、R1は(C2-C20)アルキレン、(C2-C20)アルケニレン、およびそれらの組み合わせからなる群より独立して選択される;単一のコモノマーmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択される;R5は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択される;R6は(C2-C20)アルキレン、(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択される;R7は水素、(C6-C10)アリール(C1-C6)アルキルまたは保護基である;R8は独立して(C1-C20)アルキルまたは(C2-C20)アルケニルである;
または、下記の一般的構造式(IV)によって記載される化学構造を持つPEUR:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、nは約5〜約100である。
また、式中、R2は(C2-C20)アルキレン、(C2-C20)アルケニレン、および構造式(III)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片からなる群より選択される;単一のコモノマーのmまたはpにおけるR3およびR4はそれぞれ、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、および-(CH2)2S(CH3)からなる群より独立して選択される;R5は(C2-C20)アルキレンおよび(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択される;R6は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片より選択される;
または、下記の一般的構造式(V)によって記載される化学構造を持つPEUR:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、nは約5〜約100である。
式中、R2は(C2-C20)アルキレン、(C2-C20)アルケニレン、および構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片からなる群より選択される;単一のコモノマーのmまたはpにおけるR3およびR4はそれぞれ、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、および-(CH2)2S(CH3)からなる群より独立して選択される;R5は(C2-C20)アルキレンおよび(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択される;R6は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片より選択される;R7は水素、(C6-C10)アリール(C1-C6)アルキルまたは保護基である;R8は独立して(C1-C20)アルキルまたは(C2-C20)アルケニルである。
本発明は、機械的特性の顕著な改善を伴う2つのビス-(α-アミノ酸)-ジオール-ジエステル(ジエステル-ジアミン)含有コポリマーにそれぞれ基づくPEAおよびPEURコポリマーについて記載する。ビルディングブロックの各々は任意の所与のPEAまたはPEURコポリマーの特性に寄与するが、本発明では、コポリマーの機械的特性を制御するために3つの可能なモノマー単位(無指向性アミノ酸をベースとするモノマーを含む)の各々におけるジオール残基の選択が利用される。2つのジエステル-ジアミンをベースとするコモノマーの内の少なくとも1つにおけるジオール残基としての1,4:3,6-ジアンヒドロヘキシトールの二環性断片の組み入れはコポリマーに比較的高いガラス転移温度(Tg)を与えると同時に、このような各コモノマーにおける飽和または不飽和アルキルの残基の導入は形成されるコポリマーの高い伸び特性を提供する(表1)。
式中、R1は、(C2-C20)アルキレン、(C2-C20)アルケニレン、およびそれらの組み合わせからなる群より独立して選択され;単一のコモノマーmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択され;R5は下記の構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択され;
R6は(C2-C20)アルキレン、(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択される;
または、下記の一般的構造式(III)によって記載される化学構造を持つPEA:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、式中、nは約5〜約100であり;
式中、R1は(C2-C20)アルキレン、(C2-C20)アルケニレン、およびそれらの組み合わせからなる群より独立して選択され;単一のコモノマーmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択され;R5は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択され;R6は(C2-C20)アルキレン、(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択され;R7は水素、(C6-C10)アリール(C1-C6)アルキルまたは保護基であり;R8は独立して(C1-C20)アルキルまたは(C2-C20)アルケニルであって、例えば、R8は独立して(C3-C6)アルキルまたは(C3-C6)アルケニルである;
または、下記の一般的構造式(IV)によって記載される化学構造を持つPEURコポリマー:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、nは約5〜約100であり;
式中、R2は(C2-C20)アルキレン、(C2-C20)アルケニレン、構造式(III)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片からなる群より選択され;単一のコモノマーのmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択され;R5は(C2-C20)アルキレン、および(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択され;R6は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択される;
または、下記の一般的構造式(V)によって記載される化学構造を持つPEUR:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、nは約5〜約100であり;
式中、R2は(C2-C20)アルキレン、(C2-C20)アルケニレン、構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片からなる群より選択され;単一のコモノマーのmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択され;R5は(C2-C20)アルキレン、および(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択され;R6は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択され;R7は水素、(C6-C10)アリール(C1-C6)アルキルまたは保護基であり;R8は独立して(C1-C20)アルキルまたは(C2-C20)アルケニルである。
式中、
であり、例えば、および/または(b)R3またはR4は-CH2-CH=CH-CH2-である。(a)が存在して(b)が存在しない場合、R3またはR4は-C4H8-または-C6H12-である。(a)が存在しないで(b)が存在する場合は、R1または は-C4H8-または-C8H16-である。
式中、それぞれのR9は独立して(C6-C10)アリールであって、一つまたは複数のニトロ、シアノ、ハロ、トリフルオロメチル、またはトリフルオロメトキシで置換されてもよい;R6は独立して(C2-C20)アルキレンまたは(C2-C20)アルキルオキシ、(C2-C20)アルケニレンまたは構造式(II)を持つその他のジオール残基である。
1.約22℃〜約120℃の範囲、例えば、約37℃〜約80℃の範囲のガラス転移温度;
2.平均厚 約0.125mmのコポリマーのフィルムは約25Mpa〜約90Mpa、例えば、約30Mpa〜約60Mpaの引張り降伏応力を持つ;
3.平均厚 約0.125mmのコポリマーのフィルムは約2%〜約400%、例えば、約65%〜約300%の伸び率を持つ;さらに
4.平均厚 約0.125mmのコポリマーのフィルムは約400Mpa〜約3000Mpa、例えば、約1000Mpa〜約2500Mpaの範囲のヤング率を持つ;
従って、3つのビルディングブロック単位の内容および相対的割合を適切に選択することによって、当業者は、生分解性および生体適合性であり、幅広い機械的特性を持つ本発明のビス-(α-アミノ酸)含有PEAまたはPEURコポリマーを得ることができる。
式中、
はコポリマーを表し;
Rは生物活性物質であってもよく;かつ
nは1〜200、好ましくは1〜50の範囲であり得る。
一つの態様において、本明細書に記載される通りPEAおよびPEURコポリマー組成物はコポリマーに直接連結した一つまたは複数の生物活性物質を持つ。コポリマーの残基は1つまたは複数の生物活性物質の残基に連結することができる。例えば、コポリマーの1つの残基は生物活性物質の1つの残基に直接連結することができる。コポリマーおよび生物活性物質はそれぞれ1つのオープンバレンスを持つことができる。または、異なる治療的または対症的活性を持つ1つよりも多い生物活性物質、多数の生物活性物質、または生物活性物質の混合物をコポリマーに直接連結することができる。しかし、各生物活性物質の残基はコポリマーの対応する残基に連結させることができるので、1つまたは複数の生物活性物質の残基の数はコポリマーの残基上のオープンバランスの数に一致する。
本発明のPEAおよびPEURコポリマー組成物において用いられるコポリマー内での分散について意図される生物活性物質には、抗増殖剤、ラパマイシンおよび任意のその類似体または誘導体、パクリタキセルまたは任意のそのタキセン類似体もしくは誘導体、エベロリウムス、シロリムス、タクロリムス、または-リムス名を持つ任意の薬物ファミリー、ならびにシンバスタチン、アトロバスタチン、フルバスタチン、プラバスタチン、ロバスタチン、ロスバスタチンのようなスタチン類、17AAG(17-アリルアミノ-17-デメトキシゲルダナマイシン)のようなゲルダナマイシン類;エポチロンDおよびその他のエポチロン類、17-ジメチルアミノエチルアミノ-17-デメトキシ-ゲルダナマイシン、ならびに熱ショックタンパク質90(Hsp90)、シロスタゾールなどのその他のポリケチド阻害剤が含まれる。
実施例1
この実施例は、構造式(I)によって記載されるコ-ポリ-4-[Leu(DAS)0.75-Leu(6)0.25](表1の化合物#2)の調製を示し、式中、m=0.75、p=0.25、R1=R2=(CH2)4、R3=R4=イソ-ブチル、R5=(CH2)6、およびR6=式(III)である。
この実施例は、構造式(I)によって記載されるポリ-4-[L-Leu(DAS)0.45-L-Leu(6)0.55](表1の化合物#3)の調製を示し、式中、m=0.45、q=0.55、R1=R2=(CH2)4、R3=R4=イソ-ブチル、R5=(CH2)6、およびR6=式(III)である。
この実施例は、構造式(I)によって記載されるポリ-4-[L-Leu(DAS)0.20-L-Leu(6)0.80](表1の化合物#4)の調製を示し、式中、m=0.20、q=0.80、R1=R2=(CH2)4、R3=R4=イソ-ブチル、R5=(CH2)6、およびR6=式(III)である。
この実施例は、構造式(I)によって記載されるポリ-4-[L-Phe(DAS)0.75-L-Phe(4)0.25](表2の化合物#2)の調製を示し、式中、m=0.20、q=0.80、R1=R2=(CH2)4、R3=R4=CH2(C6H5)、R5=(CH2)4、およびR6=式(III)である。
実施例5
この実施例は、構造式(V)によって記載されるポリ-3-[L-Leu(DAS)0.15-L-Leu(6)0.60-(L-Lys(Bn)0.25](表2の化合物#3)の調製を示し、式中、p=0.6、m=0.15、q=0.25、R8=R9=(CH2)3、R3=R4=イソ-ブチル、R8=(CH2)6、R9=式III、およびR7=CH2(C6H5)である。(下記のスキーム2を参照されたい)。
実施例6
式(I)によって記載されるコポリ-[(8)0.75-(Fum)0.25]-「L-Leu(6)0.50-L-Leu(DAS)0.50](化合物#4、表1)の調製、式中、m=0.50、q=0.50、R1=(CH2)8、R2=(CH2)8-25%および(-CH=CH-)-25%。R3=R4=イソブチル、R5=(CH2)6、R6=式(III))。
次の実施例は、DAS含有コモノマーの異なる送り量に基づくPEAおよびPEURの機械的および物理化学的特性を示す。コポリマーの製造における相対的送り量および得られる特性は以下の表2に示す通りである。
Claims (41)
- 次のコポリマーの少なくとも1つまたは混合物を含むコポリマー組成物:
下記の一般的構造式(I)によって記載される化学構造を持つPEA:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、式中、nは約5〜約100であり;
式中、R1は、(C2-C20)アルキレン、(C2-C20)アルケニレン、およびそれらの組み合わせからなる群より独立して選択されて;単一のコモノマーmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択されて;R5は下記構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択されて;
R6は(C2-C20)アルキレン、(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択されて;
または、下記の一般的構造式(III)によって記載される化学構造を持つPEA:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、式中、nは約5〜約100であり;
式中、R1は(C2-C20)アルキレン、(C2-C20)アルケニレン、およびそれらの組み合わせからなる群より独立して選択されて;単一のコモノマーmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択されて;R5は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択されて;R6は(C2-C20)アルキレン、(C2-C20)アルケニレンもしくはアルキルオキシからなる群より選択されて;R7は水素、(C6-C10)アリール(C1-C6)アルキルもしくは保護基であり;R8は独立して(C1-C20)アルキルもしくは(C2-C20)アルケニルであり;
または、下記の一般的構造式(IV)によって記載される化学構造を持つPEURコポリマー:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、nは約5〜約100であり;
かつ、式中、R2は(C2-C20)アルキレン、(C2-C20)アルケニレン、および構造式(III)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片からなる群より選択されて;単一のコモノマーのmまたはpにおけるR3およびR4はそれぞれ、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、および-(CH2)2S(CH3)からなる群より独立して選択されて;R5は(C2-C20)アルキレンおよび(C2-C20)アルケニレンもしくはアルキルオキシからなる群より選択されて;R6は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片より選択されて;
または、下記の一般的構造式(V)によって記載される化学構造を持つPEUR:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、nは約5〜約100であり;
かつ、式中、R2は(C2-C20)アルキレン、(C2-C20)アルケニレン、および構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片からなる群より選択されて;単一のコモノマーのmまたはpにおけるR3およびR4はそれぞれ、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、および-(CH2)2S(CH3)からなる群より独立して選択されて;R5は(C2-C20)アルキレンおよび(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択されて;R6は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片より選択されて;R7は水素、(C6-C10)アリール(C1-C6)アルキルまたは保護基であり;R8は独立して(C1-C20)アルキルまたは(C2-C20)アルケニルである。 - コポリマー分子中のR3またはR4の少なくとも1つがCH2Phである、請求項1記載の組成物。
- R3またはR4が水素、CH2-CH(CH3)2、CH3)、CH(CH3)2)、CH(CH3)-CH2-CH3)、CH2-C6H5、(CH2)4-NH2)または(CH2)2SCH3)から選択される、請求項1記載の組成物。
- R3およびR4のすべてが水素、CH2-CH(CH3)2、CH3)、CH(CH3)2)、CH(CH3)-CH2-CH3)、CH2-C6H5、(CH2)4-NH2)または(CH2)2SCH3)から選択される、請求項1記載の組成物。
- R1およびR2の少なくとも1つが-CH2-CH=CH-CH2-、-(CH2)4-、-(CH2)6-および-(CH2)8-から選択される、請求項1記載の組成物。
- R5およびR6の少なくとも1つが-CH2-CH=CH-C2-である、請求項1記載の組成物。
- 1,4;3,6-ジアンヒドロヘキシトールがD-グルシトール、D-マンニトールまたはL-イジトールから誘導される、請求項1記載の組成物。
- 1,4;3,6-ジアンヒドロヘキシトールが1,4:3,6-ジアンヒドロソルビトール(DAS)である、請求項1記載の組成物。
- R8が独立して(C3-C6)アルキルまたは(C3-C6)アルケニルである、請求項1記載の組成物。
- R8が-(CH2)4-である、請求項1記載の組成物。
- 約2日から約6年の期間に渡って生分解する、請求項1記載の組成物。
- 2つから多数の異なるアミノ酸から形成されるよう生分解する、請求項1記載の組成物。
- コポリマーが約15,000から約300,000Daの範囲の分子量を持つ、請求項1記載の組成物。
- コポリマーが約22℃から約120℃の範囲のガラス転移温度(Tg)を持つ、請求項1記載の組成物。
- コポリマーのフィルムが約25Mpaから約90Mpaの引張り降伏応力を持つ、請求項1記載の組成物。
- コポリマーのフィルムが降伏点において約2%から約400%の伸び率を持つ、請求項1記載の組成物。
- コポリマーのフィルムが降伏点において約400Mpaから約3000Mpaの範囲のヤング率を持つ、請求項1記載の組成物。
- コポリマー中に分散した少なくとも1つの生物活性物質の有効量をさらに含む、請求項1記載の組成物。
- コポリマー分子鎖当たり約5から約150の分子の生物活性物質を含む、請求項14記載の組成物。
- 少なくとも1つの生物活性物質がコポリマーに共有結合されている、請求項14記載の組成物。
- コポリマーが約15,000Daから約400,000Daの範囲の分子量を持つ、請求項1記載の組成物。
- コポリマーが約15,000Daから約300,000Daの範囲の分子量を持つ、請求項1記載の組成物。
- コポリマーが構造式IまたはIVによって記載される化学式を持ち、かつ、mおよびpがコポリマー内にランダムに分布する、請求項1記載の組成物。
- コポリマーが構造式IIIまたはVによって記載される化学式を持ち、かつ、m、pおよびqがコポリマー内にランダムに分布する、請求項1記載の組成物。
- 生分解性、生体適合性粒子の形で製造される、請求項1記載の組成物。
- 請求項1記載の組成物を含む、生分解性、生体適合性の外科的装置。
- 完全に生分解性である、請求項26記載の装置。
- 組成物がコポリマー内に分散した少なくとも1つの生物活性物質をさらに含む、請求項26記載の装置。
- 生物活性物質が生理学的条件下において外科的装置から制御された様式で放出される、請求項28記載の装置。
- 生物活性物質が約2日から約6年という時間に渡って放出される、請求項28記載の装置。
- 完全に生分解性である、請求項28記載の装置。
- 外科的装置が血管ステントまたは透析用シャントである、請求項28記載の装置。
- 外科的装置が内部固定用装置である、請求項28記載の装置。
- 内部固定用装置が縫合糸である、請求項33記載の装置。
- 内部固定用装置が外科用スクリューである、請求項33記載の装置。
- 内部固定用装置が移植可能プレートである、請求項33記載の装置。
- 内部固定用装置が移植可能ロッドである、請求項33記載の装置。
- 対象の体内部位を固定するための方法であって、体内部位を固定する間に実質的に生体適合性の分解産物を生じるように装置が生分解するよう、対象の体内部位に内部固定用装置を移植する段階を含む方法であって、
内部固定用装置が次のコポリマーの少なくとも1つまたは混合物を含む方法:
下記の一般的構造式(I)によって記載される化学構造を持つPEA:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、式中、nは約5〜約100であり;
式中、R1は(C2-C20)アルキレン、(C2-C20)アルケニレン、およびそれらの組み合わせからなる群より独立して選択されて;単一のコモノマーmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択されて;R5は下記構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択されて;
R6は(C2-C20)アルキレン、(C2-C20)アルケニレンもしくはアルキルオキシからなる群より選択されて;
または、下記の一般的構造式(III)によって記載される化学構造を持つPEA:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、式中、nは約5〜約100であり;
式中、R1は(C2-C20)アルキレン、(C2-C20)アルケニレン、およびそれらの組み合わせからなる群より独立して選択されて;単一のコモノマーmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択されて;R5は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択されて;R6は(C2-C20)アルキレン、(C2-C20)アルケニレンまたはアルキルオキシからなる群より選択されて;R7は水素、(C6-C10)アリール(C1-C6)アルキルもしくは保護基であり;R8は独立して(C1-C20)アルキルもしくは(C2-C20)アルケニルであり;
または、下記の一般的構造式(IV)によって記載される化学構造を持つPEURコポリマー:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、nは約5〜約100であり;
式中、R2は(C2-C20)アルキレン、(C2-C20)アルケニレン、および構造式(III)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片からなる群より選択されて;
単一のコモノマーのmまたはpにおけるR3およびR4はそれぞれ、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)アルキルおよび-(CH2)2S(CH3)からなる群より独立して選択されて;R5は(C2-C20)アルキレン、および(C2-C20)アルケニレンもしくはアルキルオキシからなる群より選択されて;R6は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片から選択されて;
または、下記の一般的構造式(V)によって記載される化学構造を持つPEUR:
式中、mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、nは約5〜約100であり;
また、式中、R2は(C2-C20)アルキレン、(C2-C20)アルケニレン、および構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片からなる群より選択されて;単一のコモノマーのmまたはpにおけるR3およびR4はそれぞれ、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、および-(CH2)2S(CH3)からなる群より独立して選択されて;R5は(C2-C20)アルキレンおよび(C2-C20)アルケニレンもしくはアルキルオキシからなる群より選択されて;R6は構造式(II)の1,4:3,6-ジアンヒドロヘキシトールの二環性断片より選択されて;R7は水素、(C6-C10)アリール(C1-C6)アルキルまたは保護基であり;R8は独立して(C1-C20)アルキルもしくは(C2-C20)アルケニルである。 - 内部固定用装置が約2日から約6年以内に完全に生分解する、請求項38記載の方法。
- 内部固定用装置がコポリマー内に分散した少なくとも1つの生物活性物質をさらに含み、該生物活性物質が内部固定用装置の生分解中に体内部位周辺の組織に放出される、請求項38記載の方法。
- 生分解性内部固定用装置を製造するための方法であって、該装置を製造するために請求項1記載の組成物を用いる段階を含む方法。
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WO2007035938A2 (en) | 2007-03-29 |
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CA2623198C (en) | 2014-08-05 |
WO2007035938A3 (en) | 2007-05-31 |
EP1926780A2 (en) | 2008-06-04 |
CA2623198A1 (en) | 2007-03-29 |
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