JP4058676B2 - Functional polyurethane and / or polyurethane urea and method for producing the same - Google Patents

Description

【化７】

［上記化学式（２）および化学式（３）において、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁶は炭素数１〜１０のアルキレン基、炭素数６〜１２のアリーレン基、または炭素数７〜１５のアラルキレン基であり、それぞれ同じでも異なっていてもよく、水素原子は他の原子や官能基で置換されていてもよい。Ｒ⁴、Ｒ⁵、Ｒ⁸は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、それぞれ同じでもよく、異なっていてもよく、各基の水素原子は他の原子や官能基で置換されていてもよい。Ｒ⁷は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、炭素数７〜１５のアラルキル基、または下記化学式（４）の構造を有する基である。ＸはＮ、Ｈ−Ｃもしくは下記の化学式（５）の構造を有する基である。］
【化８】

【化９】

[式中、Ａは炭素数２〜１０のオキシアルキレン基であり、１種または２種以上のオキシアルキレン基が混在してもよく、それらの結合順はブロックでもランダムでもよい。また、ｎは１〜３０の整数である。Ｒ⁹、Ｒ¹⁰は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、各基の水素原子は他の原子や官能基で置換されていてもよい。]
【００２９】
本発明においては、機能性ポリオールが脂肪族系ジイソシアネートと専ら付加してドメイン構造を形成していることが重要な要件である。
【００３０】
本発明のポリウレタンおよび／又はポリウレタンウレアの製造方法は特に制限されないが、段階的に反応を行うことが特に好ましい。例えば、次のような方法が例示される：機能性ジオールと脂肪族系ジイソシアネートを適当な溶媒中で混合して反応させ、これに芳香族系ジイソシアネート、続いてマクロポリオールを添加しプレポリマーを調製後、鎖延長剤を添加して高分子量のポリウレタンおよび／又はポリウレタンウレアを得る。この際、マクロポリオールと脂肪族系ジイソシアネートの反応と、それに続き芳香族系ジイソシアネートを添加してプレポリマーを得る反応とでは、一般に芳香族系ジイソシアネートは脂肪族系ジイソシアネートよりも活性が高いので、後者の反応温度を前者の反応温度よりも低く設定することが好ましい。脂肪族系ジイソシアネートの反応に好適な温度のままで芳香族系ジイソシアネートを添加するとゲル化を招く恐れがあり、芳香族系ジイソシアネートの反応に好適な温度で脂肪族系ジイソシアネートの反応を行うと反応が十分に進行せず、得られるポリウレタン類が材料として利用し難いものになってしまう可能性がある。
【００３１】
ポリウレタンおよび／又はポリウレタンウレアの製造方法を更に具体的に示す。以下の製造条件は本発明を制限するものではない。
脂肪族系ジイソシアネートと芳香族系ジイソシアネートの使用比率は、モル比で脂肪族系ジイソシアネート／芳香族系ジイソシアネート＝１／９〜９／１、好ましくは２／８〜７／３さらに好ましくは２／８〜６／４である。これよりも脂肪族系ジイソシアネートが多いと反応が進行しにくく、これよりも芳香族系ジイソシアネートが多いと得られるポリウレタンおよび／又はポリウレタンウレアが着色する恐れがある。脂肪族系ジイソシアネートを反応させる時の反応温度は５０℃〜１２０℃、好ましくは６０℃〜１００℃、芳香族ジイソシアネートを反応させる時の反応温度は３０℃〜１００℃、好ましくは４０℃〜８０℃で、脂肪族系ジイソシアネートを反応させるときの温度よりも低いことが好ましい。反応に使用される溶媒も特に制限されないが、原料に対して不活性であり、原料の溶解性に優れる溶媒が好ましい。具体的には、例えば、Ｎ−メチルホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドン、ヘキサメチルリン酸トリアミド、テトラヒドロフラン、ジオキサン、ジメチルスルホキシド、トルエンなどが例示され、中でもＮ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドンが好ましい。溶媒は単独で使用しても、２種以上を混合して使用してもよい。また、無溶媒で反応を行う方法も適用できる。
【００３２】
本発明のポリウレタンおよび／又はポリウレタンウレアを製造する際には、重合を効率的に行うため、重合触媒を添加してもよい。重合触媒としては、例えば、ジブチルジラウリン酸スズなどのスズ系触媒、テトラブトキシチタンなどのチタン系触媒などが例示される。
【００３３】
本発明のポリウレタンおよび／又はポリウレタンウレアは単独で使用してもよく、また、ブレンド、コーティング、グラフト化、共重合などの方法で他の素材に添加することも可能である。また、本発明のポリウレタンおよび／又はポリウレタンウレアを元にしてブレンド、コーティング、グラフト化、共重合などの方法により改質することも可能である。
【００３４】
ポリウレタン類は、ＰＶＣなどと異なり、特に添加剤を加えることなく望む機械的特性を実現できるのが大きな特長のひとつであるが、本発明においては、添加剤を加えても構わない。例えば、材料に抗菌性を付与する目的で、抗菌剤を練り込むことも可能である。
【００３５】
本発明のポリウレタンおよび／又はポリウレタンウレアは、機械的特性、易加工性などのポリウレタン類が本来有する特性の他、詳細な機構は明らかで無いものの、機能性ポリオールが、比較的分子鎖の自由度が高い脂肪族系ジイソシアネートと付加してドメイン構造を形成していることによると考えられる効果によって、機能性ポリオール由来の機能が十分に発揮されると同時に、脂肪族系ジイソシアネートと芳香族系ジイソシアネートの相補的、および相乗的な効果と考えられる影響によって、より優れた安定性、安全性を実現することが可能である。
【００３６】
このような利点を活かして、本発明のポリウレタンおよび／又はポリウレタンウレアは、従来ポリウレタン類が応用されていたあらゆる用途はもちろんのこと、特に医療用材料として広く利用され得る。具体的には、例えば、血液透析膜や血漿分離膜、血液中老廃物の吸着材、人工肺用膜、血管内バルーン、血液バッグ、カテーテル、カニューレ、シャント、血液回路などの医療用具の主基材、改質用添加剤、積層材、コーティング材などが例示される。
【００３７】
【実施例】
以下、実施例によって本発明を説明するが、本発明はこれらの実施例によって制限されるものではない。
【００３８】
〈実施例１〉
（ポリウレタンの調製）
下記化学式（６）に示す化合物（以下コリンジオールと略記する）：１０．００ｇをセパラブルフラスコに秤取し、Ｎ−メチルピロリドン（ＮＭＰ）：１０６ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を７５℃まで加熱し、ヘキサメチレンジイソシアネート（ＨＤＩ）：２４．２５ｇを加え１時間撹拌した。反応温度を５５℃にまで下げて３０分撹拌し、ＭＤＩ：８４．２０ｇを加え、５５℃で１時間撹拌後、数平均分子量２０００のポリテトラメチレングリコール（ＰＴＭＧ）：２６．６５ｇをＮＭＰ：５３ｍｌに溶解して添加した。５５℃で１時間撹拌しプレポリマーを調製した。この反応混合液に１，４−ブタンジオール（ＢＤ）：３２．６０ｇを２回に分けて添加し５５℃で１時間撹拌した。ＮＭＰ１０６ｍｌを加えて反応混合液を希釈し、５５℃で１２時間撹拌して反応させた。ＢＤ３ｇを加えて末端停止を行い、５５℃から徐々に室温になるまで撹拌を継続した。反応混合液を１０ｌの水に落とし込んで生成物を回収し、７０℃の温水で２時間洗浄後減圧乾燥してポリマーＡを得た。
【化１０】

【００３９】
（分子量）
臭化リチウムを０．１ｗｔ％添加したＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ）にポリマーＡを加えて溶解し、ゲルパーミエーションクロマトグラフィー（ＧＰＣ）により分子量を測定した。ゲルカラムはShodex AD−803／S、AD−804／S、AD−806／S、AD−802／Sを直列に連結して使用し、ポリエチレングリコールで作成した検量線により、温度は５０℃、移動相は臭化リチウムを０．１ｗｔ％添加したＤＭＦで測定した。結果は表１に示した。
【００４０】
（溶出物）
ＡＳＴＭ Ｆ７５０（材料抽出液のマウス全身毒性試験）の方法に引用された抽出条件である、ＡＳＴＭ Ｆ６１９（メディカル・プラスティックの抽出方法）に記載された抽出条件に準拠し、ポリマーＡ：４．０ｇを生理食塩水：２０ｍｌにより抽出し、抽出液中の総有機炭素量（ＴＯＣ）を測定した。結果は表１に示した。
【００４１】
（細胞毒性）
薬機第９９号（平成７年６月２７日）厚生省薬務局医療機器開発課長通知に記載された、医療用具又は材料の抽出液を用いた細胞毒性試験の方法に準拠して、Ｖ７９細胞を使用し、ポリマーＡのＩＣ５０（％）を求めた。結果は表１に示した。
【００４２】
【表１】

【００４３】
（フィルムの作製）
ポリマーＡを２ｗｔ％の濃度になるようＮＭＰに溶解した。この溶液を水平に保ったスライドガラス上に乗せ、窒素雰囲気下８０℃で１２時間かけてＮＭＰを蒸発させた。その後さらに６０℃で減圧乾燥を１２時間行い、フィルムＡを得た。フィルムＡはスライドガラスから剥離せず、そのまま次の評価に使用した。
【００４４】
（抗血漿凝固性）
上記の操作で得たフィルムＡの乗ったスライドガラスを、３７℃の水浴上に置いたシャーレに乗せた。このフィルム上にクエン酸加牛血漿１００μｌを滴下し、０．０２５ｍｏｌ／ｌの塩化カルシウム水溶液を加えて穏やかに混和した。塩化カルシウム水溶液を添加した時点から血漿が凝固するまでの経過時間を測定し、同様の操作をガラス上で行った場合の血漿凝固に要した時間で割り、相対凝固時間として表した。結果は表１に示した。
【００４５】
（機能性ポリウレタンを含有した中空糸の作製）
高分子体としてポリエーテルスルホン（住友化学工業社製スミカエクセル４８００Ｐ）：５．００ｋｇ、親水化剤としてポリビニルピロリドン（ＢＡＳＦ社製コリドンＫ９０）：２５０ｇ、ポリマーＡ：１５０ｇを溶媒ＮＭＰ：１４．０４ｋｇ、非溶媒トリエチレングリコール：９．４５ｋｇに添加し、１００℃で４時間撹拌して溶解後、１時間静置脱泡した。この溶液を焼結フィルターで濾過して未溶解物を除去し、紡糸原液を得た。スリット外径３００μｍ、スリット内径２００μｍ、内液吐出孔径１００μｍのチューブインオリフィス型のノズルの外側からこの紡糸原液を、内液吐出孔からＮＭＰ２０ｗｔ％のＮＭＰと水の混合溶液の内液を吐出した。ノズルから吐出した紡糸原液は３０ｃｍの空中走行を経て、ノズル直下の凝固浴に導いた。凝固液はＮＭＰ２０ｗｔ％のＮＭＰと水の混合溶液で温度は７０℃とした。紡糸した中空糸は水洗後、巻き取り速度４５ｍ／分でワインダーで巻き取り、中空糸Ａを得た。中空糸Ａの内径は１９０μｍ、外径は２５０μｍで、膜厚は３０μｍであった。
【００４６】
（抗凝血性）
上記の操作で得られた中空糸Ａを１０本束ねて両末端をシリコンチューブに挿入し、シリコン接着剤で固めてマイクロモジュールＡを得た。このマイクロモジュールＡにクエン酸加牛全血を封入し、透析液中に沈めて一定時間経過後、封入血をシャーレに満たした生理食塩水に滴下して状態を観察した。結果は表２に示した。
【００４７】
【表２】

【００４８】
〈比較例１〉
（ポリウレタンの調製）
コリンジオール：１０．００ｇをセパラブルフラスコに秤取し、ＮＭＰ：１０６ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を５５℃まで加熱し、ＭＤＩ：８４．２０ｇを加え、５５℃で１時間撹拌した。反応温度を７５℃にまで上げて３０分撹拌しＨＤＩ：２４．２５ｇを加え１時間撹拌後、数平均分子量２０００のＰＴＭＧ：２６．６５ｇをＮＭＰ：５３ｍｌに溶解して添加した。反応温度を７５℃から６０℃に徐々に下げながら１時間撹拌しプレポリマーを調製した。この反応混合液にＢＤ：３２．６０ｇを２回に分けて添加し６０℃で１時間撹拌した。ＮＭＰ：１０６ｍｌを加えて反応混合液を希釈し、６０℃で１２時間撹拌して反応させた。ＢＤ：３ｇを加えて末端停止を行い、６０℃から徐々に室温になるまで撹拌を継続した。反応混合液を１０ｌの水に落とし込んで生成物を回収し、７０℃の温水で２時間洗浄後減圧乾燥してポリマーＢを得た。
【００４９】
（分子量）（溶出物）（細胞毒性）
実施例１と同様の方法でポリマーＢの分子量、溶出物、細胞毒性を分析した。結果は表１に示した。
【００５０】
（フィルムの作製）（抗血漿凝固性）
実施例１と同様の方法でフィルムＢを作製し、実施例１と同様の方法で抗血漿凝固性を調べた。結果は表１に示した。
【００５１】
（機能性ポリウレタンブレンド中空糸の作製）（抗凝血性）
実施例１と同様の方法で中空糸Ｂを作製し、実施例１と同様の方法で抗凝血性を調べた。結果は表２に示した。
【００５２】
〈比較例２〉
（ポリウレタンの調製）
コリンジオール：１０．００ｇをセパラブルフラスコに秤取し、ＮＭＰ：１０６ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を６０℃まで加熱し、ＭＤＩ：８４．２０ｇとＨＤＩ：２４．２５ｇの混合物を加え、６０℃で２時間撹拌した。その後、数平均分子量２０００のＰＴＭＧ：２６．６５ｇをＮＭＰ：５３ｍｌに溶解して添加した。６０℃で１時間撹拌しプレポリマーを調製した。この反応混合液にＢＤ：３２．６０ｇを２回に分けて添加し６０℃で１時間撹拌した。ＮＭＰ：１０６ｍｌを加えて反応混合液を希釈し、６０℃で１２時間撹拌して反応させた。ＢＤ：３ｇを加えて末端停止を行い、６０℃から徐々に室温になるまで撹拌を継続した。反応混合液を１０ｌの水に落とし込んで生成物を回収し、７０℃の温水で２時間洗浄後減圧乾燥してポリマーＣを得た。
【００５３】
（分子量）（溶出物）（細胞毒性）
実施例１と同様の方法でポリマーＣの分子量、溶出物、細胞毒性を分析した。結果は表１に示した。
【００５４】
（フィルムの作製）（抗血漿凝固性）
実施例１と同様の方法でフィルムＣを作製し、実施例１と同様の方法で抗血漿凝固性を調べた。結果は表１に示した。
【００５５】
（機能性ポリウレタンブレンド中空糸の作製）（抗凝血性）
実施例１と同様の方法で中空糸Ｃを作製し、実施例１と同様の方法で抗凝血性を調べた。結果は表２に示した。
【００５６】
〈比較例３〉
（ポリウレタンの調製）
コリンジオール：１０．００ｇ、数平均分子量１３２０のＰＴＭＧ：１２．７７ｇをセパラブルフラスコに秤取し、Ｎ，Ｎ−ジメチルアセトアミド（ＤＭＡｃ）：３００ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を１００℃まで加熱し、４，４’−メチレンビス（シクロヘキシルイソシアネート）（ＨＭＤＩ）：５２．７１ｇをゆっくり加え、添加後５時間撹拌した。ＨＤＩ：１４．４８ｇをゆっくり加え、添加後１００℃で１０時間撹拌した。ＢＤ：１８．２８ｇをゆっくり添加し、さらに１００℃で５時間撹拌した。反応後、この反応混合液を１０ｌの水に落とし込んだ。得られた沈澱物を濾別し、ＴＨＦに溶解して再びメタノールに注ぎ込み、生じた沈澱物を回収、減圧乾燥してポリマーＤを得た。
【００５７】
（分子量）（溶出物）（細胞毒性）
実施例１と同様の方法でポリマーＤの分子量、溶出物、細胞毒性を分析した。結果は表１に示した。
【００５８】
（フィルムの作製）（抗血漿凝固性）
実施例１と同様の方法でフィルムＤを作製し、実施例１と同様の方法で抗血漿凝固性を調べた。結果は表１に示した。
【００５９】
（機能性ポリウレタンブレンド中空糸の作製）（抗凝血性）
実施例１と同様の方法で中空糸Ｄを作製し、実施例１と同様の方法で抗凝血性を調べた。結果は表２に示した。
【００６０】
〈比較例４〉
（中空糸の作製）（抗凝血性）
ポリマーＡを添加せず、他の条件は実施例１と同様の方法でポリエーテルスルホン製の中空糸Ｅを作製し、実施例１と同様の方法で抗凝血性を調べた。結果は表２に示した。
【００６１】
【発明の効果】
実施例と比較例の比較より明らかなように、本発明のポリウレタンは、溶出物、細胞毒性が低いと同時に、機能性ポリオール由来と考えられる機能性が十分に発揮されることがわかった（実施例、比較例においてはリン脂質類似構造含有ジオールによる抗凝血性の機能）。
詳細な機構は明らかで無いものの、脂肪族系ジイソシアネートと芳香族系ジイソシアネートの相補的、相乗的効果と考えられる影響によって、より優れた安定性、安全性が実現されると同時に、機能性ポリオールが、比較的分子鎖の自由度が高い脂肪族系ジイソシアネートと付加してドメイン構造を形成していることによる効果であると考えられる。
このような利点を活かして、本発明のポリウレタンおよび／又はポリウレタンウレアは従来ポリウレタンおよびポリウレタンウレアが応用されていたあらゆる用途はもちろんのこと、特に医療用材料として広く利用され得る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a functional polyurethane and / or polyurethane urea composed of specific constituent components and a method for producing the same. The polyurethane and / or polyurethane urea of the present invention is particularly suitable for application to medical materials.
[0002]
[Prior art]
Materials used for various applications are required to have characteristics according to the applications. In general, materials having excellent mechanical characteristics, that is, strength and durability are preferable. Materials researched and developed to obtain excellent mechanical properties are also applied to medical materials because of their excellent properties.
[0003]
At the same time, since the medical material is used in direct contact with a living body having a complicated defense system, it is necessary to satisfy biocompatibility, which is a characteristic not normally required for other applications. Examples of a method for imparting biocompatibility to a material include (1) a method using a material that is originally inert to a living body, and (2) a negative charge or hydrophilicity by modifying the material surface, a biological component imitation structure, etc. And (3) a method of immobilizing a bioactive substance capable of improving biocompatibility such as mucopolysaccharides such as heparin and urokinase on the material surface. Among these, the method (3) further includes (A) a method of coating a physiologically active substance, (B) a method of immobilizing the physiologically active substance by ionic bond, and (C) a method of immobilizing the physiologically active substance by covalent bond. It is divided into.
[0004]
Among these, the method (1) is to examine the biocompatibility of the existing material and use a preferable material, but it is effective for obtaining the better biocompatibility required in the present or the future. It's hard to say. Even if a new material is developed, this method is not efficient because it is necessary to start studying from a very basic point and build up the material. Therefore, in order to realize further improvement in biocompatibility using the excellent characteristics of the conventional material, the method (2) or (3) is adopted, but the existing material is modified. For this purpose, it is effective to introduce a functional group into the material as a starting point of the modification. Polyurethane and / or polyurethane urea and / or polyurea (hereinafter abbreviated as polyurethane) is a material having a preferred functional group, for example, an amino group-containing material can be prepared by using an amino group-containing diol as one of the raw materials. It is relatively easy to prepare.
[0005]
In addition, since medical materials are used in direct contact with living bodies, sufficient safety is an important requirement, but biological characteristics including safety of medical materials have been considered sufficiently until recently. There was a tendency for lack of consideration. In particular, the use conditions for medical applications, that is, the decomposition products, unreacted monomers, by-products, and oligomers contained in the material when it comes into contact with bodily fluids such as blood, is a serious drawback for medical materials. It is.
[0006]
For example, polyvinyl chloride (PVC) is very widely used as a medical material because its hardness can be freely changed depending on the amount of plasticizer added, it is relatively stable under general use conditions, and it is inexpensive. Yes. However, PVC is a problem in terms of safety because plasticizers such as phthalates may elute during use, and phthalates are toxic by many studies. is there.
[0007]
Silicone is also used as various types of catheters and tubes as a medical elastomer, and it is also used as a membrane material for artificial lungs due to its gas permeation properties. There are concerns about toxicity.
[0008]
Polyurethanes can be prepared with a suitable hardness without using additives by appropriately setting the blending ratio of the macropolyol serving as the soft segment and the diisocyanate serving as the hard segment and the chain extender. . It is also known that segmented polyurethane forms a microphase-separated structure and thereby exhibits excellent blood compatibility. Moreover, as described above, the functional group can be introduced relatively easily. Due to these advantages, polyurethanes are one of polymer materials that are favorably used as medical materials.
[0009]
There have already been many reports on the technology for obtaining functional polyurethanes. For example, as polyurethanes containing a phospholipid-like structure, JP-A-61-207395, JP-A-08-134085, JP-A-08-259654, JP-A-09-235342, JP-A-09-09 No. 241330, JP-A-10-287687, etc., JP-A-11-071391 as a polyurethane containing a sugar chain residue, and JP-A-11-315126 as a polyurethane containing an unsaturated bond. And JP-A-2000-256426, 2001-172338, and the like.
[0010]
Among these, JP-A-61-207395 discloses polyurethanes having a phospholipid-like structure obtained from a diol having a phospholipid-like structure and diphenylmethane diisocyanate. It has been pointed out by the inventor himself in Japanese Patent Laid-Open No. 08-134085 that this is insufficient. The polyurethanes disclosed in JP-A-08-134085 are phospholipid-like structure-containing polyurethanes obtained from diol having a phospholipid-like structure and hexamethylene diisocyanate or tolylene diisocyanate. In this technology, There is no idea of improving functionality, safety and stability by using two or more diisocyanates, which is one of the points of the present invention. The same applies to the techniques disclosed in Japanese Patent Laid-Open Nos. 08-259654, 09-235342, and 10-287687. Japanese Patent Application Laid-Open No. 09-241330 discloses a prepolymer comprising a copolymer of a phosphorylcholine group-containing (meth) acrylic acid ester and a (meth) acrylic acid derivative, and a polyurethane obtained from a diisocyanate compound. Since the polymer becomes a polyhydric alcohol, the resulting polyurethane has a cross-linked structure, the mobility of the polymer chain conformation is remarkably limited, and a sufficient function is hardly exhibited.
[0011]
Although the prior arts exemplified as polyurethanes containing phospholipid-like structures were individually considered as described above, all of the existing functional polyurethanes including these were loosely mixed with functional polyol as one of the raw materials. However, the consideration of the existence state in the polymer chain is insufficient. In polyurethanes prepared using functional polyol as one of the raw materials, it must be carefully considered whether it is in a polymer chain and the functional polyol-derived part is in an environment where it can fully function. . It is pointed out that the polyurethanes obtained by the existing technology may be buried in the material depending on the use environment, and may not function sufficiently.
[0012]
In addition, although there are some deviations from the viewpoint of functional polyurethanes, polyurethanes that use aliphatic diisocyanates and aromatic diisocyanates in combination with a clear intention are disclosed in, for example, 295063, JP 07-026096, JP 07-097560, JP 07-166052, JP 08-052939, JP 08-067814, JP 09-255866 And JP-A-11-349805 and 2000-034439.
[0013]
Of these, in JP-A No. 05-295063, JP-A No. 07-026096, JP-A No. 09-255866, JP-A No. 11-349805, and JP-A No. 2000-034439, diisocyanate forms an isocyanurate group. Discloses a crosslinkable polyurethane prepared by using the polyisocyanate. In these techniques, a raw material for imparting a special function to polyurethanes is not particularly used, and it is difficult to obtain a functional polyurethane and / or polyurethane urea intended for the present application. In addition, since these polyurethanes have a crosslinked structure, even if a functional structure is introduced, the mobility of conformation of the polymer chain is remarkably limited, and a sufficient function is hardly exhibited. In addition, since these patents are supposed to be used as paints and adhesives, no consideration is given to stability and safety against heat and hydrolysis, which are one of the purposes of the present application.
[0014]
Japanese Patent Laid-Open No. 08-052939 discloses a polyisocyanate containing an allophanate group, and there is a description that the polyisocyanate is derived from an aromatic diisocyanate and an aliphatic diisocyanate. This means that a crosslinked structure is introduced into the obtained material, and, as in the case of using a polyisocyanate by isocyanurate group formation, even if a functional structure is introduced, the conformation of the polymer chain Mobility is remarkably limited, and sufficient functions are difficult to be exhibited.
[0015]
Further, JP 07-097560 A and JP 07-166052 A disclose a polyurethane in which an aromatic diisocyanate and an aliphatic diisocyanate are used in combination assuming use as an adhesive and charging member, respectively. However, no consideration has been given to safety.
[0016]
Japanese Patent Application Laid-Open No. 08-067814 discloses a resin composition comprising a polyurethane resin using as a raw material an aliphatic diisocyanate and / or a mixed diisocyanate of an alicyclic diisocyanate and an aromatic diisocyanate. These are polyurethanes with improved yellowing resistance, chemical resistance, solvent solubility, and scratch resistance, and are not intended to improve safety (cytotoxicity, acute toxicity, etc.), especially hydrolysates There is a problem in the safety of the material in that polycaprolactone polyol, which is easily generated, is an essential component.
[0017]
The present inventors have already described functional polyurethanes in JP-A Nos. 04-153211, 04-235724, 04-248826, 04-250168, and 04-298523. No. 4, JP-A-04-325161, etc. have been filed. These are all technologies relating to polyurethanes containing tertiary amino groups or quaternary ammonio groups. In the techniques disclosed in these, amino groups or ammonio groups are contained in polyester polyols or polyether polyols, and are introduced into polyurethanes by polymerizing them as one of raw materials. Although the amino group or ammonio group is contained in the soft segment, the mobility in the polymer chain is relatively large, but an amino polyester polyol or amino polyether polyol is prepared for introduction of the amino group or ammonio group. It must be a simple method.
[0018]
In addition, the present inventors have applied for WO98 / 46659, JP 2000-128950 A, JP 2000-126566 A, etc. as biocompatible and antithrombotic materials. In these technologies, polyurethane or polyurethane urea obtained by using a diol having a phosphorylcholine structure as at least a part of the diol component is disclosed for the purpose of improving biocompatibility and antithrombogenicity. JP-A-2000-128950 and JP-A-2000-126566 promote the segmentation of materials by using two or more diisocyanates, particularly two or more aliphatic diisocyanates (including alicyclics). It is disclosed that the antithrombogenicity is remarkably improved by forming a microphase separation structure. However, these materials have the disadvantage that the amount of eluate is still large, while the main purpose is to use them for medical purposes.
[0019]
[Problems to be solved by the invention]
Functional polyurethanes may cause problems such as degradation of strength due to hydrolysis reaction or generation of eluate during sterilization or in vivo use, but mechanical properties, ease of processing, and hardness adjustment From the standpoints of ease of use and good biocompatibility, it is a preferred material. The present invention maintains these desirable characteristics and has a structure that is advantageous for further function at the same time, and at the same time, the stability to heat during processing and the stability to hydrolysis during use, which are problematic in the prior art, are improved. An object of the present invention is to provide functional polyurethanes with high safety.
[0020]
[Means for Solving the Problems]
The present inventors have already patented many functional polyurethanes and polyurethanes or polyurethane ureas having improved antithrombogenicity obtained by using two or more aliphatic (including alicyclic) diisocyanates in combination. As described above, the application was filed, but as a result of further intensive studies, the present invention was achieved. That is, the present invention relates to a functional polyurethane and / or polyurethane urea obtained by using a functional polyol, a macropolyol, a chain extender, an aliphatic diisocyanate, and an aromatic diisocyanate as at least a part of the raw material. Relates to polyurethane and / or polyurethane urea which is exclusively added with an aliphatic diisocyanate to form a domain structure, and a medical material comprising the same.
[0021]
Polyurethanes are generally prepared from three types of raw materials: diisocyanate, macropolyol as a soft segment, and chain extender. Of these, diisocyanates are roughly classified into aromatic diisocyanates and aliphatic diisocyanates. Aromatic diisocyanates have a relatively high reactivity, and therefore, when polyurethane and polyurethane urea are prepared, the molecular weight of the obtained polyurethane and polyurethane urea is preferably improved. However, coloring due to oxidative degradation and aromatic amines that can be carcinogenic may occur due to hydrolysis. Aliphatic diisocyanates are less likely to be colored and are less likely to produce carcinogens when hydrolyzed. However, the reactivity is slightly inferior to that of aromatic diisocyanate, and more severe conditions and addition of a catalyst are required for polymer preparation.
The present invention is a functional polyurethane and / or polyurethane urea obtained by using all of functional polyol, macropolyol, chain extender, aliphatic diisocyanate, and aromatic diisocyanate as a part of the raw material.
[0022]
The aliphatic diisocyanate referred to in the present invention includes alicyclic diisocyanates. For example, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, dodecamethylene diisocyanate, 3,3′-diisocyanatopropyl ether, cyclopentane diisocyanate, cyclohexane Examples include, but are not limited to, diisocyanate and 4,4′-methylenebis (cyclohexyl isocyanate). Moreover, the hydrogen atom of the hydrocarbon skeleton forming the diisocyanate may be substituted with another atom or a functional group.
[0023]
The aliphatic diisocyanate of the present invention is preferably a linear hydrocarbon diisocyanate having an isocyanato group at both ends. Specific examples include, but are not limited to, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, dodecamethylene diisocyanate. The hydrogen atom of the hydrocarbon skeleton forming the diisocyanate may be substituted with another atom or a functional group. Of these, tetramethylene diisocyanate, hexamethylene diisocyanate, and octamethylene diisocyanate are preferable, and hexamethylene diisocyanate is particularly preferable.
[0024]
Examples of the aromatic diisocyanate referred to in the present invention include tolylene diisocyanate, xylylene diisocyanate, phenylene diisocyanate, naphthalene diisocyanate, isocyanatobenzyl isocyanate, 4,4′-methylenebis (phenyl isocyanate). It is not limited to. Moreover, the hydrogen atom of the hydrocarbon skeleton forming the diisocyanate may be substituted with another atom or a functional group. Of these, 4,4′-methylenebis (phenylisocyanate) (hereinafter abbreviated as MDI) is particularly preferable. As the aliphatic diisocyanate and aromatic diisocyanate used in the present invention, one kind of diisocyanate may be used, or two or more kinds may be mixed and used.
[0025]
As the macropolyol referred to in the present invention, macropolyols serving as soft segment components used in general polyurethanes can be widely used. Among these, a macropolyol that does not substantially contain a carboxylic acid ester bond is preferable because of its high hydrolysis resistance. Specifically, for example, a low molecular weight diol (for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol, 2,2-dimethyltrimethylene glycol, 1, 4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, etc.) and dicarboxylic acid or ester-forming derivatives thereof (eg oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, dodecanedicarboxylic acid, terephthalic acid Polyphthalate obtained by ring-opening polymerization of polycarboxylic acid ester diol, ε-caprolactone, etc. obtained by reacting isophthalic acid or these acid halides, active esters, amides, etc.) Diols (also included in the broad definition of polycarboxylic acid ester diols), polyether diols such as polyethylene glycol, polypropylene glycol and polytetramethylene glycol, polyalkylene diols such as polybutadiene diol, polyisoprene diol and hydrogenated polyisoprene diol And various polycarbonate diols. Of these, polyether diol is particularly preferred. Macropolyols may be used alone or in combination of two or more.
[0026]
As the chain extender of the present invention, a chain extender used for general polyurethanes and a chain extender that will be developed in the future can be widely used, and are not particularly limited. Specifically, for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol, 2,2-dimethyltrimethylene glycol, 1,4-dihydroxycyclohexane, 1 Diols such as 1,4-dihydroxymethylcyclohexane, diethylene glycol, and triethylene glycol; diamines such as ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, xylylenediamine, phenylenediamine, and 4,4′-methylenebis (phenylamine); -Amino alcohols such as aminoethanol, 3-aminopropanol, 4-aminobutanol, as well as dihydrazides (e.g. Examples include diamines in a broad sense such as oxalic acid dihydrazide, malonic acid dihydrazide, succinic acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, and isophthalic acid dihydrazide. Not limited to these, low molecular weight diols, diamines, and amino alcohols can all be applied regardless of the presence or absence of known, novel, or application examples to polyurethanes. These chain extenders may be used alone or in combination of two or more.
[0027]
In the present invention, a functional polyol is further used as a component other than diisocyanate, macropolyol, and chain extender. Examples of functional polyols include tertiary amino group-containing polyols for immobilizing heparin, polyols having a phosphorylcholine-like structure that is a cell membrane component, and a negative charge is introduced into the material surface to cause adhesion by electrostatic repulsion with platelets. Examples include organic acid group-containing polyols for the purpose of suppression, polyols containing reactive carbon-carbon unsaturated bonds, and polydimethylsiloxane diols with application to gas permeable materials in mind. In the case of macropolyols containing reactive carbon-carbon unsaturated bonds and polyurethanes obtained by using polydimethylsiloxane diol as a soft segment, functional polyols are simultaneously used as raw materials for macropolyols. Accordingly, “functional polyurethane and / or polyurethane urea obtained by using at least a part of a functional macropolyol, a chain extender, an aliphatic diisocyanate and an aromatic diisocyanate as a raw material” are also included in the present invention.
[0028]
As the functional polyol, in particular, the phosphorylcholine-like structure-containing diol represented by the following chemical formula (2) or the following chemical formula (3) is effective in improving the blood compatibility of the resulting material.
[Chemical 6]

[Chemical 7]

[In the above chemical formulas (2) and (3), R ¹ , R ² , R ^Three , R ⁶ Are an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an aralkylene group having 7 to 15 carbon atoms, which may be the same or different, and the hydrogen atom is another atom or functional group. May be substituted. R ^Four , R ^Five , R ⁸ Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, which may be the same or different from each other, It may be substituted with an atom or a functional group. R ⁷ Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure represented by the following chemical formula (4). X is N, HC or a group having the structure of the following chemical formula (5). ]
[Chemical 8]

[Chemical 9]

[In the formula, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more oxyalkylene groups may be mixed, and their bonding order may be block or random. Moreover, n is an integer of 1-30. R ⁹ , R ^Ten Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group may be substituted with another atom or a functional group. . ]
[0029]
In the present invention, it is an important requirement that the functional polyol is exclusively added to the aliphatic diisocyanate to form a domain structure.
[0030]
The method for producing the polyurethane and / or polyurethane urea of the present invention is not particularly limited, but it is particularly preferable to carry out the reaction stepwise. For example, the following method is exemplified: A functional diol and an aliphatic diisocyanate are mixed and reacted in an appropriate solvent, and an aromatic diisocyanate and then a macropolyol are added thereto to prepare a prepolymer. Thereafter, a chain extender is added to obtain a high molecular weight polyurethane and / or polyurethane urea. At this time, in the reaction of the macropolyol and the aliphatic diisocyanate and the subsequent reaction to obtain the prepolymer by adding the aromatic diisocyanate, the aromatic diisocyanate is generally more active than the aliphatic diisocyanate. The reaction temperature is preferably set lower than the former reaction temperature. Addition of an aromatic diisocyanate at a temperature suitable for the reaction of the aliphatic diisocyanate may cause gelation, and if the reaction of the aliphatic diisocyanate is performed at a temperature suitable for the reaction of the aromatic diisocyanate, the reaction will occur. There is a possibility that the resulting polyurethanes will not be sufficiently used as a material because of insufficient progress.
[0031]
The method for producing polyurethane and / or polyurethane urea will be described more specifically. The following production conditions do not limit the present invention.
The use ratio of the aliphatic diisocyanate to the aromatic diisocyanate is, as a molar ratio, aliphatic diisocyanate / aromatic diisocyanate = 1/9 to 9/1, preferably 2/8 to 7/3, more preferably 2/8. ~ 6/4. If the amount of aliphatic diisocyanate is larger than this, the reaction hardly proceeds, and if the amount of aromatic diisocyanate is larger than this, the resulting polyurethane and / or polyurethane urea may be colored. The reaction temperature when the aliphatic diisocyanate is reacted is 50 ° C to 120 ° C, preferably 60 ° C to 100 ° C, and the reaction temperature when the aromatic diisocyanate is reacted is 30 ° C to 100 ° C, preferably 40 ° C to 80 ° C. Thus, the temperature is preferably lower than the temperature at which the aliphatic diisocyanate is reacted. The solvent used in the reaction is not particularly limited, but a solvent that is inert to the raw material and excellent in solubility of the raw material is preferable. Specific examples include N-methylformamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, dimethyl sulfoxide, toluene and the like. Of these, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone are preferable. A solvent may be used individually or may be used in mixture of 2 or more types. Moreover, the method of reacting without a solvent is also applicable.
[0032]
In producing the polyurethane and / or polyurethane urea of the present invention, a polymerization catalyst may be added in order to carry out the polymerization efficiently. Examples of the polymerization catalyst include a tin-based catalyst such as tin dibutyldilaurate and a titanium-based catalyst such as tetrabutoxy titanium.
[0033]
The polyurethane and / or polyurethane urea of the present invention may be used alone, or may be added to other materials by a method such as blending, coating, grafting or copolymerization. Further, it can be modified by a method such as blending, coating, grafting or copolymerization based on the polyurethane and / or polyurethane urea of the present invention.
[0034]
Polyurethanes, unlike PVC, are one of the major features that can achieve the desired mechanical properties without adding any additives, but in the present invention, additives may be added. For example, an antibacterial agent can be kneaded for the purpose of imparting antibacterial properties to the material.
[0035]
The polyurethane and / or polyurethane urea of the present invention has a relatively high degree of freedom of molecular chain, although the functional polyol is not clear in addition to the properties inherent in polyurethanes such as mechanical properties and easy processability. Due to the effect considered to be due to the addition of a high aliphatic diisocyanate to form a domain structure, the function derived from the functional polyol is sufficiently exerted, and at the same time, the aliphatic diisocyanate and the aromatic diisocyanate Greater stability and safety can be achieved by the effects considered to be complementary and synergistic effects.
[0036]
Taking advantage of such advantages, the polyurethane and / or polyurethane urea of the present invention can be widely used as a medical material, in addition to all uses where polyurethanes have been conventionally applied. Specifically, the main base of medical devices such as hemodialysis membranes, plasma separation membranes, blood waste adsorbents, artificial lung membranes, intravascular balloons, blood bags, catheters, cannulas, shunts, blood circuits, etc. Examples thereof include materials, modifying additives, laminate materials, coating materials, and the like.
[0037]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not restrict | limited by these Examples.
[0038]
<Example 1>
(Preparation of polyurethane)
A compound represented by the following chemical formula (6) (hereinafter abbreviated as choline diol): 10.00 g was weighed into a separable flask, and N-methylpyrrolidone (NMP): 106 ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 24.25 g of hexamethylene diisocyanate (HDI) was added, and the mixture was stirred for 1 hour. The reaction temperature was lowered to 55 ° C. and the mixture was stirred for 30 minutes, MDI: 84.20 g was added, and after stirring at 55 ° C. for 1 hour, polytetramethylene glycol (PTMG) with a number average molecular weight of 2000: 26.65 g was added to NMP: 53 ml. It was dissolved and added. A prepolymer was prepared by stirring at 55 ° C. for 1 hour. To this reaction mixture, 1,4-butanediol (BD): 32.60 g was added in two portions, and the mixture was stirred at 55 ° C. for 1 hour. 106 ml of NMP was added to dilute the reaction mixture, and the mixture was stirred at 55 ° C. for 12 hours for reaction. 3 g of BD was added to terminate the end, and stirring was continued from 55 ° C. until the temperature gradually reached room temperature. The reaction mixture was dropped into 10 l of water to recover the product, washed with warm water at 70 ° C. for 2 hours, and then dried under reduced pressure to obtain polymer A.
Embedded image

[0039]
(Molecular weight)
Polymer A was added and dissolved in N, N-dimethylformamide (DMF) to which 0.1 wt% of lithium bromide was added, and the molecular weight was measured by gel permeation chromatography (GPC). The gel column uses Shodex AD-803 / S, AD-804 / S, AD-806 / S, and AD-802 / S connected in series. The phase was measured with DMF to which 0.1 wt% of lithium bromide was added. The results are shown in Table 1.
[0040]
(Eluate)
Based on the extraction conditions described in ASTM F619 (medical plastic extraction method), which is the extraction conditions cited in the method of ASTM F750 (mouse systemic toxicity test of material extract), polymer A: 4.0 g Saline: Extracted with 20 ml, and the total organic carbon content (TOC) in the extract was measured. The results are shown in Table 1.
[0041]
(Cytotoxicity)
In accordance with the method of cytotoxicity test using extract of medical device or material described in Drug Machine No.99 (June 27, 1995), Notification of Director of Medical Device Development, Ministry of Health and Welfare, V79 cells Was used to determine the IC50 (%) of polymer A. The results are shown in Table 1.
[0042]
[Table 1]

[0043]
(Production of film)
Polymer A was dissolved in NMP to a concentration of 2 wt%. This solution was placed on a glass slide kept horizontal, and NMP was evaporated over 12 hours at 80 ° C. in a nitrogen atmosphere. Thereafter, vacuum drying was further performed at 60 ° C. for 12 hours to obtain a film A. The film A was not peeled off from the slide glass and used as it was for the next evaluation.
[0044]
(Anti-plasma coagulability)
The slide glass with the film A obtained by the above operation was placed on a petri dish placed on a 37 ° C. water bath. On this film, 100 μl of citrated cow plasma was dropped, 0.025 mol / l calcium chloride aqueous solution was added and gently mixed. The elapsed time from when the calcium chloride aqueous solution was added until the plasma coagulated was measured and divided by the time required for plasma coagulation when the same operation was performed on glass, and expressed as a relative coagulation time. The results are shown in Table 1.
[0045]
(Production of hollow fiber containing functional polyurethane)
Polyethersulfone (Sumitomo Chemical Co., Ltd., Sumika Excel 4800P): 5.00 kg as the polymer, Polyvinylpyrrolidone (Collidon K90, manufactured by BASF): 250 g, Polymer A: 150 g as solvent NMP: 14.04 kg, Non-solvent triethylene glycol: Added to 9.45 kg, dissolved by stirring at 100 ° C. for 4 hours, and then allowed to stand and degas for 1 hour. This solution was filtered through a sintered filter to remove undissolved substances, and a spinning dope was obtained. This spinning stock solution was discharged from the outside of a tube-in-orifice type nozzle having a slit outer diameter of 300 μm, a slit inner diameter of 200 μm, and an inner liquid discharge hole diameter of 100 μm, and an inner liquid of a mixed solution of NMP of 20 wt% NMP and water was discharged from the inner liquid discharge hole. The spinning dope discharged from the nozzle passed through 30 cm in air and led to a coagulation bath directly under the nozzle. The coagulation liquid was a mixed solution of NMP 20 wt% NMP and water, and the temperature was 70 ° C. The spun hollow fiber was washed with water and wound with a winder at a winding speed of 45 m / min. The hollow fiber A had an inner diameter of 190 μm, an outer diameter of 250 μm, and a film thickness of 30 μm.
[0046]
(Anticoagulant)
Ten hollow fibers A obtained by the above operation were bundled, both ends were inserted into a silicon tube, and solidified with a silicon adhesive to obtain a micromodule A. The micromodule A was encapsulated with citrated whole blood, submerged in dialysate, and after a certain period of time, the encapsulated blood was dropped into physiological saline filled in a petri dish and the state was observed. The results are shown in Table 2.
[0047]
[Table 2]

[0048]
<Comparative example 1>
(Preparation of polyurethane)
Cholinediol: 10.00 g was weighed into a separable flask, and NMP: 106 ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 55 ° C., 84.20 g of MDI was added, and the mixture was stirred at 55 ° C. for 1 hour. The reaction temperature was raised to 75 ° C. and stirred for 30 minutes. After adding HDI: 24.25 g and stirring for 1 hour, 26.65 g of PTMG having a number average molecular weight of 2000 was dissolved in 53 ml of NMP and added. The reaction temperature was gradually lowered from 75 ° C. to 60 ° C. and stirred for 1 hour to prepare a prepolymer. To this reaction mixture, BD: 32.60 g was added in two portions and stirred at 60 ° C. for 1 hour. NMP: 106 ml was added to dilute the reaction mixture, and the mixture was stirred at 60 ° C. for 12 hours for reaction. BD: 3 g was added to terminate the end, and stirring was continued from 60 ° C. to room temperature gradually. The reaction mixture was dropped into 10 l of water to recover the product, washed with warm water at 70 ° C. for 2 hours, and then dried under reduced pressure to obtain polymer B.
[0049]
(Molecular weight) (Eluate) (Cytotoxicity)
The molecular weight, eluate, and cytotoxicity of polymer B were analyzed in the same manner as in Example 1. The results are shown in Table 1.
[0050]
(Production of film) (Anti-plasma coagulability)
Film B was produced in the same manner as in Example 1, and anti-plasma clotting properties were examined in the same manner as in Example 1. The results are shown in Table 1.
[0051]
(Production of functional polyurethane blend hollow fiber) (anticoagulant)
Hollow fiber B was produced in the same manner as in Example 1, and anticoagulant properties were examined in the same manner as in Example 1. The results are shown in Table 2.
[0052]
<Comparative example 2>
(Preparation of polyurethane)
Cholinediol: 10.00 g was weighed into a separable flask, and NMP: 106 ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 60 ° C., a mixture of MDI: 84.20 g and HDI: 24.25 g was added, and the mixture was stirred at 60 ° C. for 2 hours. Thereafter, 26.65 g of PTMG having a number average molecular weight of 2000 was dissolved in 53 ml of NMP and added. A prepolymer was prepared by stirring at 60 ° C. for 1 hour. To this reaction mixture, BD: 32.60 g was added in two portions and stirred at 60 ° C. for 1 hour. NMP: 106 ml was added to dilute the reaction mixture, and the mixture was stirred at 60 ° C. for 12 hours for reaction. BD: 3 g was added to terminate the end, and stirring was continued from 60 ° C. to room temperature gradually. The reaction mixture was dropped into 10 l of water to recover the product, washed with warm water at 70 ° C. for 2 hours, and then dried under reduced pressure to obtain polymer C.
[0053]
(Molecular weight) (Eluate) (Cytotoxicity)
The molecular weight, eluate, and cytotoxicity of polymer C were analyzed in the same manner as in Example 1. The results are shown in Table 1.
[0054]
(Production of film) (Anti-plasma coagulability)
Film C was produced by the same method as in Example 1, and anti-plasma coagulation property was examined by the same method as in Example 1. The results are shown in Table 1.
[0055]
(Production of functional polyurethane blend hollow fiber) (anticoagulant)
Hollow fiber C was produced in the same manner as in Example 1, and anticoagulant properties were examined in the same manner as in Example 1. The results are shown in Table 2.
[0056]
<Comparative Example 3>
(Preparation of polyurethane)
Cholinediol: 10.00 g and PTMG of number average molecular weight 1320: 12.77 g were weighed into a separable flask, and N, N-dimethylacetamide (DMAc): 300 ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 100 ° C., 4,4′-methylenebis (cyclohexyl isocyanate) (HMDI): 52.71 g was slowly added, and stirred for 5 hours after the addition. HDI: 14.48 g was slowly added, followed by stirring at 100 ° C. for 10 hours. BD: 18.28 g was slowly added, and further stirred at 100 ° C. for 5 hours. After the reaction, the reaction mixture was dropped into 10 l of water. The resulting precipitate was filtered off, dissolved in THF and poured into methanol again, and the resulting precipitate was recovered and dried under reduced pressure to obtain polymer D.
[0057]
(Molecular weight) (Eluate) (Cytotoxicity)
The molecular weight, eluate, and cytotoxicity of polymer D were analyzed in the same manner as in Example 1. The results are shown in Table 1.
[0058]
(Production of film) (Anti-plasma coagulability)
Film D was produced in the same manner as in Example 1, and anti-plasma coagulation was examined in the same manner as in Example 1. The results are shown in Table 1.
[0059]
(Production of functional polyurethane blend hollow fiber) (anticoagulant)
Hollow fiber D was produced in the same manner as in Example 1, and anticoagulant properties were examined in the same manner as in Example 1. The results are shown in Table 2.
[0060]
<Comparative example 4>
(Production of hollow fiber) (anticoagulant)
The polymer A was not added, and under the other conditions, a hollow fiber E made of polyethersulfone was prepared in the same manner as in Example 1. The results are shown in Table 2.
[0061]
【The invention's effect】
As is clear from the comparison between the examples and the comparative examples, it was found that the polyurethane of the present invention has a sufficiently low eluate and cytotoxicity and at the same time sufficiently exhibits the functionality considered to be derived from the functional polyol (implementation). In the examples and comparative examples, the function of anticoagulation by the diol containing a phospholipid-like structure).
Although the detailed mechanism is not clear, superior stability and safety are realized by the effects considered to be complementary and synergistic effects of aliphatic diisocyanate and aromatic diisocyanate, and at the same time, functional polyol It is considered that the effect is due to the addition of an aliphatic diisocyanate having a relatively high degree of molecular chain freedom to form a domain structure.
Taking advantage of such advantages, the polyurethane and / or polyurethane urea of the present invention can be widely used as a medical material, not to mention all uses where polyurethane and polyurethane urea have been conventionally applied.

Claims (7)

A polyurethane and / or polyurethane urea obtained by using at least a part of a polyol, macropolyol, chain extender, aliphatic diisocyanate and aromatic diisocyanate having the structure of chemical formula (1) as a raw material, A polyurethane and / or a polyurethane urea, wherein a component having a polyol having the structure shown added exclusively with an aliphatic diisocyanate forms a domain structure.

[In the above chemical formula (1), R is an ethylene group . ] 2. The compound obtained by adding an aromatic diisocyanate and a macropolyol to a component obtained by reacting a polyol having a structure of the chemical formula (1) with an aliphatic diisocyanate, and further extending the chain with a chain extender. Polyurethane and / or polyurethane urea.

[In the above chemical formula (1), R is an ethylene group . ] The reaction of the polyol having the structure of the chemical formula (1) and the aliphatic diisocyanate is performed at a higher temperature than the reaction of adding the aromatic diisocyanate and the macropolyol to the reaction product of the polyol and the aliphatic diisocyanate. The polyurethane and / or polyurethane urea according to claim 2.

[In the above chemical formula (1), R is an ethylene group . ] The polyurethane and / or polyurethane urea according to claim 3, wherein the polyol having the structure represented by the chemical formula (1) has a structure represented by the following chemical formula (2) or chemical formula (3).

[In the above chemical formula (1), R is an ethylene group . ]

[In the above chemical formulas (2) and (3), R ¹ , R ² and R ³ are each an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an aralkylene group having 7 to 15 carbon atoms. Each may be the same or different, and the hydrogen atom may be substituted with another atom or functional group. R ⁴ , R ⁵ and R ⁸ are each an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, which may be the same or different, The hydrogen atom of each group may be substituted with other atoms or functional groups. R ⁶ is an ethylene group. R ⁷ is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure represented by the following chemical formula (4). X is N, HC or a group having the structure of the following chemical formula (5). ]

[In the formula, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more oxyalkylene groups may be mixed, and their bonding order may be block or random. Moreover, n is an integer of 1-30. R ⁹ and R ¹⁰ are an alkyl group having 1 to ¹⁰ carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group is substituted with another atom or a functional group May be. ]   A medical material containing the polyurethane and / or polyurethane urea according to claim 1.   The medical material which has as a main component the polyurethane and / or polyurethane urea in any one of Claims 1-5. A polyurethane characterized by adding an aromatic diisocyanate and a macropolyol to a component obtained by reacting a polyol having a structure of the chemical formula (1) with an aliphatic diisocyanate, and further extending the chain with a chain extender. Or the manufacturing method of a polyurethane urea.

[In the above chemical formula (1), R is an ethylene group . ]