JP3845716B2 - Bioabsorbable composite molded article, bioabsorbable material, and production method thereof - Google Patents

Description

（式中、Ｒ₁はアルキル基又はアルコキシル基、Ｒ₂はアルキル基又はアルコキシル基又はヒドロキシル基を示す。）
【００５３】
具体的には、酸性リン酸エステルとしては、リン酸モノメチル、リン酸ジメチル、リン酸モノエチル、リン酸ジエチル、リン酸モノプロピル、リン酸ジプロピル、リン酸モノイソプロピル、リン酸ジイソプロピル、リン酸モノブチル、リン酸ジブチル、リン酸モノペンチル、リン酸ジペンチル、リン酸モノヘキシル、リン酸ジヘキシル、リン酸モノオクチル、リン酸ジオクチル、リン酸モノ２−エチルヘキシル、リン酸ジ２−エチルヘキシル、リン酸モノデシル、
【００５４】
リン酸ジデシル、リン酸モノイソデシル、リン酸ジイソデシル、リン酸モノウンデシル、リン酸ジウンデシル、リン酸モノドデシル、リン酸ジドデシル、リン酸モノテトラデシル、リン酸ジテトラデシル、リン酸モノヘキサデシル、リン酸ジヘキサデシル、リン酸モノオクタデシル、リン酸ジオクタデシル、リン酸モノフェニル、リン酸ジフェニル、リン酸モノベンジル、リン酸ジベンジルなどが挙げられる。
【００５５】
ホスホン酸エステルとしては、ホスホン酸モノメチル、ホスホン酸モノエチル、ホスホン酸モノプロピル、ホスホン酸モノイソプロピル、ホスホン酸モノブチル、ホスホン酸モノペンチル、ホスホン酸モノヘキシル、ホスホン酸モノオクチル、ホスホン酸モノエチルヘキシル、ホスホン酸モノデシル、ホスホン酸モノイソデシル、ホスホン酸モノウンデシル、ホスホン酸モノドデシル、ホスホン酸モノテトラデシル、ホスホン酸モノヘキサデシル、ホスホン酸モノオクタデシル、ホスホン酸モノフェニル、ホスホン酸モノベンジルなどが挙げられる。
【００５６】
アルキルホスホン酸としては、モノメチルホスホン酸、ジメチルホスホン酸、モノエチルホスホン酸、ジエチルホスホン酸、モノプロピルホスホン酸、ジプロピルホスホン酸、モノイソプロピルホスホン酸、ジイソプロピルホスホン酸、モノブチルホスホン酸、ジブチルホスホン酸、モノペンチルホスホン酸、ジペンチルホスホン酸、モノヘキシルホスホン酸、ジヘキシルホスホン酸、イソオクチルホスホン酸、ジオクチルホスホン酸、モノエチルヘキシルホスホン酸、ジエチルヘキシルホスホン酸、モノデシルホスホン酸、ジデシルホスホン酸、
【００５７】
モノイソデシルホスホン酸、ジイソデシルホスホン酸、モノウンデシルホスホン酸、ジウンデシルホスホン酸、モノドデシルホスホン酸、ジドデシルホスホン酸、モノテトラデシルホスホン酸、ジテトラデシルホスホン酸、モノヘキサデシルホスホン酸、ジヘキサデシルホスホン酸、モノオクタデシルホスホン酸、ジオクタデシルホスホン酸などや、モノフェニルホスホン酸、ジフェニルホスホン酸、モノベンジルホスホン酸、ジベンジルホスホン酸など、及びそれらの混合物を挙げることができる。
【００５８】
酸性リン酸エステル類成分は有機溶剤との溶解性がよいため作業性に優れ、乳酸系ポリエステルとの反応性に優れる。なかでも酸性リン酸エステルは触媒の失活に大きな効果を示す。
【００５９】
更に、重合触媒の失活処理に用いるキレート剤及び／又は酸性リン酸エステル類の添加量は、その種類、乳酸系ポリエステル中に含まれる触媒の種類、量によって異なるが、乳酸系ポリエステル１００重量部に対して、０.００１〜５重量部を添加することが好ましい。いずれのキレート剤、酸性リン酸エステル類もポリマー鎖の切断を最小に抑えることができ、また、有機系キレート剤、無機系キレート剤、酸性リン酸エステル類を混合して使用しても差し支えない。
【００６０】
しかしキレート剤や酸性リン酸エステル類を過剰に添加すると、貯蔵中に乳酸系ポリエステル鎖が切断され、低分子量化、低粘度化して、本発明の性能が得られないことがあるため、適正量を添加する必要がある。
【００６１】
重合触媒の失活処理後の乳酸系ポリエステル中のラクチド、乳酸、そのオリゴマーなどの酸成分の低減方法としては、重合触媒の失活処理後に取り付けられた脱揮槽、フィルムエバポレーター、ベント付押出機などの脱揮装置を用いて除去するとか、良溶媒に溶解後、貧溶剤中に析出させることによって除去するとか、アルコール、ケトン、炭化水素などの溶剤を用いて、溶解させずに、浸漬或いは分散後抽出して除去することができる。
【００６２】
また、乳酸系ポリエステルの生体内での安全性の向上化方法としては、乳酸系ポリエステルに含有されている触媒を除くことが効果的である。その方法としては、公知の方法、例えば特開平８−３４８４４号公報、特開平８−１０９２５０号公報などに開示されているように、乳酸系ポリエステルを有機溶剤に溶解後、酸性物質及び水と接触させ、有機層を分離して触媒を除去することもできる。
【００６３】
次に、本発明に使用される水溶性ポリマー繊維について説明する。
本発明に使用される水溶性ポリマー繊維としては、特に限定されるものでないが、生体への悪影響がなく、生体内、或いは水や温水で、比較的容易に溶解、分解されるものが好ましい。具体的には、ポリビニルアルコール、プルラン（林原生物研究所製のマントトリオースがα−１,６グルコシド結合したポリマー）、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、メチルセルロース、ポリエチレンオキサイド、アミローズ、ポリペプチドなどの繊維が挙げられ、これらの１種以上を使用することができる。
【００６４】
また、水溶性ポリマー繊維としては、弱酸性液体、弱塩基性液体などに溶解するものも使用することができる。具体的にはセルロース、レーヨン、アセテートなどの繊維が挙げられる。また、上記の水溶性繊維として、分子量、構造の異なるものも使用することができ、例えばポリビニルアルコールのケン化度の異なるものが該当する。さらに、生分解性ポリマーとしては高融点のものが多いため、水溶性ポリマー繊維としては耐熱性が高い方が好ましい。その点ではポリビニルアルコール系繊維が特に好ましい。
【００６５】
また、それらの繊維の太さは、特に限定されるものでなく、使用される生体内の部位によって太さが選ばれる。通常、１μｍ〜１０００μｍが好ましい。
さらに、それらの繊維をモノフィラメント或いはマルチフィラメントとして使用でき、更に、それらの繊維を延伸させ、強度を高めたものも使用することができる。
【００６６】
次に、本発明の生体吸収性複合成形物の製造方法について説明する。
本発明の生体吸収性複合成形物の製造方法は、生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体中に水溶性ポリマー繊維（Ｂ）を含む成形物を成形する際に、１本以上の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の２面間以上を貫通するように、水溶性ポリマー繊維（Ｂ）を生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の中に配置して成形することを特徴とする生体吸収性複合成形物の製造方法である。
【００６７】
本発明の生体吸収性複合成形物は、具体的には、生分解性ポリマーとリン酸カルシウム系化合物を、生分解性ポリマーの融点以上の温度で混練して作製したフィルム間に、１本以上の水溶性ポリマー繊維を挟み、生分解性ポリマーの融点以上の温度で圧着して得る方法や、生分解性ポリマーとリン酸カルシウム系化合物を、生分解性ポリマーの融点以上の温度で混練して作製したのフィルムの間に、水溶性ポリマー繊維を配向させて挟み、生分解性ポリマーの融点以上の温度で圧着して得られる方法などによって製造される。
【００６８】
また、本発明の生体吸収性複合成形物は、生分解性ポリマーとリン酸カルシウム系化合物を、生分解性ポリマーの融点以上の温度で混練して作製したのフィルムの間に、水溶性ポリマー繊維を挟み、生分解性ポリマーの融点以上の温度で圧着して得られた成形物を積層する方法や、生分解性ポリマーとリン酸カルシウム系化合物のフィルムの間に、水溶性ポリマー繊維から成る不織布を挟み、生分解性ポリマーの融点以上の温度で圧着して得る方法、更に得られた成形物を積層する方法により製造される。
【００６９】
さらに、使用される生分解性ポリマーとしては、乳酸系ポリエステルが好ましく、とりわけ、乳酸系ポリエステルが乳酸成分とジカルボン酸成分とジオール成分を必須成分として成るものが好ましい。また、乳酸系ポリエステルとして、触媒を失活処理した乳酸系ポリエステルが好ましい。
【００７０】
また、この生分解性ポリマーとリン酸カルシウム系化合物との複合体のフィルムは、プレス成形機、押出機、射出成形機などにより作製することができる。さらに、この生体吸収性複合成形物は、一般的にはプレス成形機で作製され、成形温度は生分解性ポリマーの融点以上の温度で行われる。
【００７１】
本発明の生体吸収性複合成形物、又は生体吸収性材料は、生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体中に含まれる、少なくとも１本以上の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）の少なくとも２面間以上を貫通し、生分解性ポリマー（Ａ）の外面まで達していることが必須であり、その方向は縦、横、斜め、いずれの方向でも構わない。
【００７２】
多数の水溶性ポリマー繊維が生分解性ポリマー中に含まれる場合は、その水溶性ポリマー繊維の多くが生分解性ポリマーとリン酸カルシウム系化合物との複合体の２面間を貫通している方が、貫通孔が生成される際に水溶液が生分解性ポリマー内部を流通する為、生分解性向上の点から好ましいが、製造上の問題から、必ずしも全ての水溶性ポリマー繊維が生分解性ポリマーとリン酸カルシウム系化合物との複合体の２面間を貫通していなくとも良く、水溶性ポリマー繊維のいくつ本かが生分解性ポリマーとリン酸カルシウム系化合物との複合体の２面間以上を貫通しているものでも良い。また、２面間以上とは、生分解性ポリマーとリン酸カルシウム系化合物との複合体の内部で水溶性ポリマー繊維同士がクロスし、水溶性ポリマー繊維が２面間以上、例えば３面間、又は４面間を貫通したものも含む。
【００７３】
多数の水溶性ポリマー繊維を生分解性ポリマーとリン酸カルシウム系化合物との複合体中に含ませ、成形後に、この成形物を切断することにより、少なくとも１本以上の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の少なくとも２面間以上を貫通し、生分解性ポリマーとリン酸カルシウム系化合物（Ｃ）との複合体（Ａ）の外面まで達している生体吸収性複合成形物を作成することも本発明に含まれる。これらは、水溶性ポリマー繊維の不織布を用いる際に、特に有用である。
【００７４】
また、少なくとも１本以上の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の外面まで達しており、水溶性ポリマー繊維（Ｂ）の一方の端が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の中央部分まである成形物を作成し、次いでこれを中央部分で切断し、少なくとも１本以上の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の少なくとも２面間以上を貫通し、生分解性ポリマー（Ａ）の外面まで達している生体吸収性複合成形物を作成する方法も本発明に含まれる。
【００７５】
本発明の生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の中に水溶性ポリマー繊維（Ｂ）が含まれ、且つ、該水溶性ポリマー繊維（Ｂ）の１本以上が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の２面間を貫通している生体吸収性複合成形物、又は生体吸収性材料の具体的な例を模式図として図１〜図５に示す。
【００７６】
図１は最も簡単な生体吸収性複合成形物、生体吸収性材料の例であり、１本の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）の２面間を貫通している図である。
図１〜図５中の点線部分は水溶性ポリマー繊維（Ｂ）、もしくは該水溶性ポリマー繊維（Ｂ）を溶出除去した孔を示す。
【００７７】
図２は複数の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の内部で交差して生分解性ポリマー（Ａ）の４面間を貫通している図である。
図３及び図４は複数の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の内部で交差して生分解性ポリマー（Ａ）の４面間を貫通している図である。
【００７８】
図５は複数の水溶性ポリマー繊維（Ｂ）が生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）との複合体の内部で交差して生分解性ポリマー（Ａ）の多数の面間を貫通している図である。
本発明の生分解性成形物から水溶性ポリマー繊維（Ｂ）を溶出除去し、水溶性ポリマー繊維の形状の孔を生じさせた本発明の生体吸収性材料は、図１〜図５に示す模式図で同様に示される。
【００７９】
生分解性ポリマーとリン酸カルシウム系化合物との複合体を貫通している水溶性ポリマー繊維を、水溶液、更に詳しくは、水、温水、弱酸性液、弱塩基性液、あるいは体液を含む水溶液など、水溶性ポリマー繊維を溶解、分解するものに、生分解性ポリマーとリン酸カルシウム系化合物との複合体を浸漬し、生分解性ポリマーとリン酸カルシウム系化合物との複合体から溶出、除去することにより、生分解性ポリマーとリン酸カルシウム系化合物との複合体内部に２面間以上を貫通する孔が生成し、生体内等の水溶液の存在下において、水溶液が該孔を自由に流通することにより、生分解性ポリマーとリン酸カルシウム系化合物との複合体自体の構造は保ちながら、その内部から徐々に生分解性ポリマーが分解される特性を有することになる。
【００８０】
生分解性ポリマーとリン酸カルシウム系化合物との複合体中の水溶性ポリマー繊維を水溶液、即ち、水、温水、弱酸性液、弱塩基性液、あるいは体液を含む水溶液などに浸漬し、水溶性ポリマー繊維を溶解、除去して、連通孔を作る際に、その浸漬温度は生分解性ポリマーが溶解或いは分解されない範囲での高い温度が好ましい。浸漬温度が高い方が水溶性ポリマー繊維の除去速度が速いからである。
【００８１】
水溶性ポリマー繊維（Ｂ）中に、薬剤を予め含有させ、生分解性ポリマーとリン酸カルシウム系化合物との複合体中に含ませることにより、生分解性ポリマーとリン酸カルシウム系化合物との複合体中から、水溶性ポリマー繊維が水溶液中に溶出するにつれて、徐々に、これらの薬剤を放出させる除法性機能を持たせることも可能である。この際に、生分解性ポリマー（Ａ）にも、これらの薬剤を含ませ、更に水溶性ポリマー繊維（Ｂ）中に同種又は異種の薬剤を含ませることにより、異なる除法速度で同種の薬剤の放出を制御することも可能であるし、又、異種の薬剤を異なる放出速度で放出することも可能である。
【００８２】
本発明の生分解性ポリマー（Ａ）と水溶性ポリマー繊維（Ｂ）とリン酸カルシウム系化合物（Ｃ）から成る生体吸収性複合成形物は、使用目的により、その弾性率、生体内での分解、分解速度、硬・軟組織の誘導及びそれらの再生速度などの要求性能が異なるため、生分解性ポリマー（Ａ）と水溶性ポリマー繊維（Ｂ）とリン酸カルシウム系化合物（Ｃ）との重量比は一概に特定できないが、通常は、（Ａ＋Ｃ）／（Ｂ）が９９／１〜２０／８０、好ましくは９８／２〜３０／７０、更に好ましくは９５／５〜４０／６０である。（Ａ）／（Ｃ）は８０／２０〜５／９５、好ましくは７０／３０〜１０／９０、更に好ましくは６０／４０〜１５／８５である。
【００８３】
また、本発明の内、生分解性ポリマー（Ａ）と水溶性ポリマー繊維（Ｂ）とリン酸カルシウム系化合物（Ｃ）から成る生体吸収性複合成形物は、熱処理して結晶化させてもよい。結晶化させることにより、耐熱性を大幅に高めることができ、硬くなり、剛性も高くなる傾向がある。
【００８４】
結晶化させる温度は、生分解性ポリマーのガラス転移点以上、融点以下の温度で行われる。また、結晶化を促進させるため、タルク、カオリン、二酸化ケイ素、窒化ホウ素などの核剤や結晶性ポリマー或いはそれらの混合物を、生分解性ポリマーに対して０.１〜１０重量％、好ましくは０.２〜５重量％添加することができる。核剤の形状は、特に限定されないが、０.１〜０.５μｍが好ましい。
【００８５】
また、本発明の生分解性ポリマー（Ａ）と水溶性ポリマー繊維（Ｂ）とリン酸カルシウム系化合物（Ｃ）から成る生体吸収性複合成形物を製造する前の、生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）を混練するときに、ポリエチレングリコールなどの水溶性ポリマー、生理学的に許容される塩化ナトリウム、塩化カリウムなどの塩類などを、本発明の生体吸収性複合成形物としての機械特性を低下せしめない範囲で混合して使用することができる。
【００８６】
また、本発明の生分解性ポリマーに、生理活性物質、薬剤を配合することができる。さらに機械的特性を損なわない範囲で、ポリ乳酸、ポリグリコール酸、それらの共重合体なども組合せ取り入れることもできる。
【００８７】
更に、粘度調節剤としてステアリルアルコール、トリメチロールエタン、トリメチロールプロパン、ペンタエリスリトール、グリセリンなどのアルコール成分を本発明の作用効果を損なわない範囲で添加することができる。
【００８８】
生分解性ポリマー（Ａ）とリン酸カルシウム系化合物（Ｃ）と上記の素材との混練は生分解性ポリマー（Ａ）の融点以上の温度、具体的には、通常、温度５０〜２５０℃、好ましくは６０〜２００℃で混練する。また、乳酸系ポリエステルの場合には、その中の残留揮発成分、とりわけ、残留ラクチドを除去するため混練しながら、脱揮することが好ましく、或いは混練後、減圧度０.０１〜５０torrで脱揮することが好ましい。さらに、乳酸系ポリエステルは水分により加水分解を生じやすいので、減圧下もしくは不活性ガス雰囲気下で外気に触れることなく混練することが好ましい。混練は、押出機、リアクター、ニーダー、ロールやそれらの組合せで行うことができる。
【００８９】
押出機としては、単軸押出機或いは二軸押出機を使用できるが、混練状態から二軸押出機が好ましい。更に、混練後、引き続いて残留揮発成分などを減圧下で除去するためにはベント口が付いているものが好ましい。リアクターとしては、通常の反応釜を使用できるが、混練物質は粘度が高く、攪拌剪断応力により生ずる攪拌熱による分子量低下や着色などから、剪断応力が小さく、しかも均一に混合できるスタテック・ミキサーの使用が好ましい。
【００９０】
本発明の生体吸収性複合成形物は、成形加工性や機械的物性に優れ、生体内で分解し、炎症性反応が少ないため、生体吸収性材料として広範な用途が期待できる。その用途は、特に制限されないが、具体的には、本発明の生体吸収性複合成形物は生体骨に近い強度や弾性率を有し、しかも生体骨との接合や置換が速やかに起こるため、骨置換材、骨接合材や骨充填材に、また、本複合成形物は機械的強度や柔軟性の他、高い組織親和性が有るため、カテーテルや人工心臓・ペースメーカーなどの皮膚端子に、さらに本複合成形物に使用の生分解性ポリマーは熱安定性に優れるため、その溶融状態での薬剤の含浸や混練が可能で、しかも水溶性ポリマー繊維の種類、太さ、本数などにより、徐放性を木目細かく制御できるため、薬剤徐放性基材に使用することができる。薬剤徐放性基材に使用される薬剤としては、例えば、種々の消炎剤や抗ガン剤、あるいは腸におけるカルシウムの吸収や骨におけるカルシウム沈着を促進する活性ビタミンＤなどを使用することができる。また、歯槽骨再生用遮断膜、硬・軟組織再生促進膜などにも使用できる。
【００９１】
【実施例】
以下に実施例及び比較例により、本発明をさらに具体的に説明する。なお、例中の部は特に記載のない限り全て重量基準である。
得られた生体吸収性複合成形物の性能評価は、貯蔵安定性、成形加工性、骨組織の誘導・再生度、炎症性反応などについて行った。
【００９２】
また、分子量は、ＧＰＣにより測定し、ポリスチレン換算値として示した。
融点はセイコー社製示差走査型熱量計ＤＳＣ−２００型を用い、昇温速度１０℃／分の条件で測定した融解吸熱曲線から求めた。
【００９３】
貯蔵安定性については、生体吸収性複合成形物を、３５℃、８０％湿度中に１ヶ月放置し、分子量の保持率の程度で下記の４段階で評価した。
◎：分子量の保持率が９０％以上。
○：分子量の保持率が８０〜９０％。
△：分子量の保持率が６０〜８０％。
×：分子量の保持率が６０％以下。
【００９４】
成形加工性については、生体吸収性複合成形物を、８０℃〜１００℃の温水に入れ、力を加えて変形の程度で下記の４段階で評価した。
◎：極めて容易に変形した。
○：容易に変形した。
△：変形し難い。
×：変形せず。
【００９５】
骨組織の誘導・再生度は、犬の長管骨に開けた穴に生体吸収性複合成形物を埋入し、１ヶ月後に顕微鏡観察を行い、下記の４段階で評価した。
◎：骨組織の誘導・再生が著しく進んでいた。
○：骨組織の誘導・再生が相当程度進んでいた。
△：骨組織の誘導・再生が痕跡程度進んでいた。
×：骨組織の誘導・再生が全く進んでいなかった。
【００９６】
炎症性反応は、犬の長管骨に開けた穴に、生体吸収性複合成形物を埋入し、４週間後に顕微鏡観察を行い、下記の４段階で評価した。
◎：炎症性の反応が全く見られなかった。
○：炎症性の反応が痕跡程度見られた。
△：炎症性の反応が相当程度見られた。
×：炎症性の反応が著しく見られた。
【００９７】
（参考例１）
脂肪族ポリエステル（コハク酸成分５０モル％、１,４−ブタンジオール成分５０モル％、重量平均分子量３９,０００）１０部と、Ｌ−ラクチド８７部と、ＤＬ−ラクチド３部と溶媒としてトルエン１５部とを反応釜に仕込み、不活性ガス雰囲気下で、１７５℃で１時間それらを溶融混合し、触媒としてオクタン酸錫を０.０３部加えて、同温度で６時間反応させた。
【００９８】
反応終了後、得られた乳酸系ポリマー１０部をｍ−クレゾール９０部に溶解した。この溶液に２％塩酸水溶液１００部を添加し、３０分間撹拌後、放置し、水層と有機層とを分離した。有機層に１００部の水を混合、撹拌、放置、有機層分離の操作を２回繰り返した。この有機層を１３０℃、５torrの減圧下で脱揮した。その重量平均分子量は１８３,０００、融点は１６２℃であった。
【００９９】
（参考例２）
脂肪族ポリエステル（セバシン酸成分５０モル％、エチレングリコール成分５０モル％、重量平均分子量３６,０００）３０部と、Ｌ−ラクチド７０部と溶媒としてトルエン１５部とを反応釜に仕込み、不活性ガス雰囲気下で、１７５℃で１時間それらを溶融混合し、触媒としてオクタン酸錫を０.０３部加えて、同温度で６時間反応させた後、リン酸モノドデシルとリン酸ジドデシルとの混合物を０.１部を加え、さらに３０分間反応させ、次いで２００℃に昇温し、５torrの減圧下で脱揮し、ペレット化した。得られたペレットの重量平均分子量は１６２,０００、融点は１６７℃であった。
【０１００】
（参考例３）
脂肪族ポリエステル（セバシン酸成分５０モル％、１,６−ヘキサンジオール成分２５モル％、エチレングリコール２５モル％、重量平均分子量３６,０００）５０部と、Ｌ−ラクチド５０部と溶媒としてトルエン１５部とを反応釜に仕込み、不活性ガス雰囲気下で、１７５℃で１時間それらを溶融混合し、触媒としてオクタン酸錫を０.０３部加えて、同温度で６時間反応させた後、エチレンジアミン四酢酸を０.２部を加え、さらに３０分間反応させ、次いで２００℃に昇温し、５torrの減圧下で脱揮し、ペレット化した。得られたペレットの重量平均分子量は１４７,０００、融点は１６５℃であった。
【０１０１】
（参考例４）
Ｌ−ラクチド９８部と、Ｄ−ラクチド２部と溶媒としてトルエン１５部とを反応釜に仕込み、不活性ガス雰囲気下で、１７５℃で１時間それらを溶融混合し、触媒としてオクタン酸錫を０.０３部加えて、同温度で６時間反応させた後、酒石酸を０.２部を加え、さらに３０分間反応させ、次いで２００℃に昇温し、５torrの減圧下で脱揮し、ペレット化した。得られたペレットの重量平均分子量は１８４,０００、融点は１６６℃であった。
【０１０２】
（参考例５）
激しく撹拌した水酸化カルシウム懸濁液にリン酸水溶液を徐々にｐＨが９になるまで滴下し生成した沈殿を、８００℃で３時間焼成して得たヒドロキシアパタイトを更に乳鉢で粉砕し、篩に通した。（平均粒径３９μｍ）
【０１０３】
（参考例６）
激しく撹拌した水酸化カルシウム懸濁液にリン酸水溶液を徐々にｐＨが７になるまで滴下し生成した沈殿を、８００℃で３時間焼成して得たリン酸三カルシウムを更に乳鉢で粉砕し、篩に通した。（平均粒径４５μｍ）
【０１０４】
（実施例１）
参考例１で得られた乳酸系ポリエステル３０部と、参考例５で得られたヒドロキシアパタイト７０部とを１８０℃に設定の混練機で１０分間混練、冷却後、粉砕し、１８０℃の熱プレスで、縦１０ｃｍ、横１０ｃｍ、厚さ１５０μｍのシートを作製した。次いで、そのシートの間に、太さ１５０μｍのポリビニルアルコールの繊維を２００μｍの間隔で挟み、１８０℃の熱プレスで圧着した。得られた成形物を、ポリビニルアルコールの繊維が同方向になるよう１８０℃の熱プレスで積層後、冷却した。この積層操作を繰り返し、厚み１０ｍｍの積層成形物を得た。
【０１０５】
次いで、この積層成形物を、切断機で縦５ｍｍ、横５ｍｍ、長さ８ｍｍに切り取り、角柱試料を作製した。そのとき、ポリビニルアルコールの繊維方向と角柱試料の横方向が垂直に成るようにした。得られた角柱試料について、貯蔵安定性、成形加工性の評価を行った。また、その角柱試料を犬の長管骨に埋植し、４週間後に取り出したものについて、骨組織の誘導・置換度、炎症性反応の評価を行った。結果を表１に示す。
【０１０６】
（実施例２）
参考例２で得られた乳酸系ポリエステル２５部と、参考例６で得られたリン酸三カルシウム７５部とを１８０℃に設定の混練機で１０分間混練、冷却後、粉砕し、１８０℃の熱プレスで、縦１０ｃｍ、横１０ｃｍ、厚さ１５０μｍのシートを作製した。次いで、そのシートの間に、太さ１５０μｍのポリビニルアルコールの繊維を２００μｍの間隔で挟み、１８０℃の熱プレスで圧着した。得られた成形物を、ポリビニルアルコールの繊維が縦、横交互になるよう１８０℃の熱プレスで積層後、冷却した。この積層操作を繰り返し、厚み１０ｍｍの積層成形物を得た。次いで、この積層成形物を切断機で縦５ｍｍ、横５ｍｍ、長さ８ｍｍに切り取り、角柱試料を作製した。そのとき、ポリビニルアルコールの繊維方向と角柱試料の長さ方向が垂直に成るようにした。得られた角柱試料及び、その試料を犬の長管骨に埋植し、４週間後に取り出したものについて、実施例１同様の評価を行った。結果を表１に示す。
【０１０７】
（実施例３）
参考例３で得られた乳酸系ポリエステル３０部と、参考例６で得られたリン酸三カルシウム７０部とを１８０℃に設定の混練機で１０分間混練、冷却後、粉砕し、１８０℃の熱プレスで、縦１０ｃｍ、横１０ｃｍ、厚さ１５０μｍのシートを作製した。次いで、そのシートの間に、太さ２００μｍのヒドロキシプロピルセルロースの繊維を２００μｍの間隔で挟み、１８０℃の熱プレスで圧着した。得られた成形物を、ヒドロキシプロピルセルロースの繊維が同方向になるよう１８０℃の熱プレスで積層後、冷却した。この積層操作を繰り返し、厚み１０ｍｍの積層成形物を得た。
【０１０８】
次いで、この積層成形物を切断機で縦５ｍｍ、横５ｍｍ、長さ８ｍｍに切り取り、角柱試料を作製した。そのとき、ヒドロキシプロピルセルロースの繊維方向と角柱試料の長さ方向が垂直に成るようにした。得られた角柱試料を４０℃の温水中に１時間放置し、ヒドロキシプロピルセルロースの繊維を除去、乾燥後、貯蔵安定性、成形加工性の評価を行った。また、その試料を犬の長管骨に埋植し、４週間後に取り出したものについて、骨組織の誘導・再生、炎症性反応の評価を行った。結果を表１に示す。
【０１０９】
（実施例４）
参考例４で得られたポリ乳酸３０部と、参考例６で得られたリン酸三カルシウム７０部とを１８０℃に設定の混練機で１０分間混練、冷却後、粉砕し、１８０℃の熱プレスで、縦１０ｃｍ、横１０ｃｍ、厚さ１５０μｍのシートを作製した。次いで、そのシートの間に、太さ１５０μｍのポリビニルアルコールの繊維を２００μｍの間隔で挟み、１８０℃の熱プレスで圧着した。得られた成形物を、ポリビニルアルコールの繊維が縦、横交互になるよう１８０℃の熱プレスで積層後、冷却した。この積層操作を繰り返し、厚み１０ｍｍの積層成形物を得た。次いで、この積層成形物を切断機で縦５ｍｍ、横５ｍｍ、長さ８ｍｍに切り取り、角柱試料を作製した。そのとき、ポリビニルアルコールの繊維方向と角柱試料の横方向が垂直に成るようにした。得られた角柱試料及び、その試料を犬の長管骨に埋植し、４週間後に取り出したものについて、実施例１同様の評価を行った。結果を表１に示す。
【０１１０】
（実施例５）
参考例１に使用の脂肪族ポリエステル（コハク酸５０モル％、１,４ブタンジオール５０モル％、重量平均分子量３９,０００）２５部と、参考例６で得られたリン酸三カルシウム７５部とを１５０℃に設定の混練機で１０分間混練、冷却後、粉砕し、１５０℃の熱プレスで、縦１０ｃｍ、横１０ｃｍ、厚さ１５０μｍのシートを作製した。次いで、そのシートの間に、太さ１８０μｍのプルランの繊維を２００μｍの間隔で挟み、１５０℃の熱プレスで圧着した。得られた成形物を、プルランの繊維が縦、横交互になるよう１５０℃の熱プレスで積層後、冷却した。
【０１１１】
この積層操作を繰り返し、厚み１０ｍｍの積層成形物を得た。次いで、この積層成形物を切断機で縦５ｍｍ、横５ｍｍ、長さ８ｍｍに切り取り、角柱試料を作製した。そのとき、プルランの繊維方向と角柱試料の横方向が垂直に成るようにした。得られた角柱試料及び、その試料を犬の長管骨に埋植し、４週間後に取り出したものについて、実施例１同様の評価を行った。結果を表１に示す。
【０１１２】
（比較参考例１）
Ｌ−ラクチド９５部と、ＤＬ−ラクチド５部と溶媒としてトルエン１５部とを反応釜に仕込み、不活性ガス雰囲気下で、１７５℃で１時間それらを溶融混合し、触媒としてオクタン酸錫を０.０３部加えて、同温度で６時間反応させ、次いで２００℃に昇温後、５torrの減圧下で脱揮し、ペレット化した。その重量平均分子量は１４３,０００、融点は１６２℃であった。
【０１１３】
（比較参考例２）
Ｌ−ラクチド９６部と、Ｄ−ラクチド２部と、グリコリド２部と、溶媒としてトルエン１５部とを反応釜に仕込み、不活性ガス雰囲気下で、１７５℃で１時間それらを溶融混合し、触媒としてオクタン酸錫を０.０３部加えて、同温度で６時間反応させ、次いで２００℃に昇温後、５torrの減圧下で脱揮し、ペレット化した。その重量平均分子量は１３８,０００、融点は１６１℃であった。
【０１１４】
（比較参考例３）
脂肪族ポリエステル（セバシン酸成分５０モル％、エチレングリコール成分５０モル％、重量平均分子量３６,０００）３０部と、Ｌ−ラクチド７０部と溶媒としてトルエン１５部とを反応釜に仕込み、不活性ガス雰囲気下で、１７５℃で１時間それらを溶融混合し、触媒としてオクタン酸錫を０.０３部加えて、同温度で６時間反応させ、次いで２００℃に昇温し、５torrの減圧下で脱揮し、ペレット化した。得られたペレットの重量平均分子量は１３２,０００、融点は１６０℃であった。
【０１１５】
（比較例１）
比較参考例１で得られたポリ乳酸３５部と、参考例５で得られたヒドロキシアパタイト６５部とを１８０℃に設定の混練機で１０分間混練、冷却後、粉砕し、１８０℃に設定の熱プレスで５ｍｍ厚のシートを得た後、切断機で縦５ｍｍ、横５ｍｍ、長さ８ｍｍに切り取り、角柱試料を作製した。得られた角柱試料及び、その試料を犬の長管骨に埋植し、４週間後に取り出したものについて、実施例１同様の評価を行った。結果を表２に示す。
【０１１６】
（比較例２）
比較参考例２で得られた乳酸系ポリエステル２５部と、参考例６で得られたリン酸三カルシウム７５部とを１８０℃に設定の混練機で１０分間混練、冷却後、粉砕し、１８０℃の熱プレスで５ｍｍ厚のシートを成形した後、切断機で縦５ｍｍ、横５ｍｍ、長さ８ｍｍに切り取り、角柱試料を作製した。得られた角柱試料及び、その試料を犬の長管骨に埋植し、４週間後に取り出したものについて、実施例１同様の評価を行った。結果を表２に示す。
【０１１７】
（比較例３）
比較参考例２で得られた乳酸系ポリエステル３０部と、参考例５で得られたヒドロキシアパタイト７０部とを１８０℃に設定の混練機で１０分間混練、冷却後、粉砕し、１８０℃の熱プレスで２５０μｍ厚のシートを成形した後、切断機で縦５ｍｍ、横５ｍｍ、長さ８ｍｍに切り取り、角柱試料を作製した。得られた角柱試料及び、その試料を犬の長管骨に埋植し、４週間後に取り出したものについて、実施例１同様の評価を行った。結果を表２に示す。
【０１１８】
【表１】

【０１１９】
【表２】

【０１２０】
【発明の効果】
本発明は、骨の置換材、接合材、修復材などの生体材料、皮膚端子、カテーテルなどの医療器具、歯槽骨及びその周辺組織の再生膜関連の歯科材料、薬剤徐放性基材等に有用な、生体での炎症性反応が起こらず、良好な分解吸収性を示すことにより、生体組織の再生を促進でき、しかも、良好な成形性、貯蔵安定性を有する生体吸収性複合成形物、生体吸収性材料及びその製造方法を提供できる。
【図面の簡単な説明】
【図１】 本発明の生体吸収性複合成形物、又は生体吸収性材料の例を示す模式図である。
【図２】 本発明の生体吸収性複合成形物、又は生体吸収性材料の例を示す模式図である。
【図３】 本発明の生体吸収性複合成形物、又は生体吸収性材料の例を示す模式図である。
【図４】 本発明の生体吸収性複合成形物、又は生体吸収性材料の例を示す模式図である。
【図５】 本発明の生体吸収性複合成形物、又は生体吸収性材料の例を示す模式図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to biomaterials such as bone replacement materials, bonding materials, and repair materials, medical device materials such as skin terminals and catheters, bioabsorbable composite molded articles useful as drug sustained-release substrates, bioabsorbable materials, and It relates to the manufacturing method.
[0002]
[Prior art]
JP-A-63-181756 discloses a porous calcium phosphate sintered body or a porous calcium phosphate reinforced with polylactic acid or the like as a repair material in the case where a living bone is lost or a joint material when fractured. JP-A-7-148243 discloses a calcium phosphate fiber, a calcium phosphate fiber reinforced with polylactic acid or the like, and a knitted product of these fibers disclosed in JP-A 63-89166. A compound in which hydroxyapatite, tricalcium phosphate or the like is combined in a molten state with lactic acid is disclosed.
[0003]
However, materials composed solely of calcium phosphate, such as calcium phosphate sintered bodies and calcium phosphate fibers, are brittle, and porous calcium phosphates are reinforced with polylactic acid, and calcium phosphate fibers are reinforced with polylactic acid. In addition, those obtained by compounding polylactic acid with hydroxyapatite, tricalcium phosphate or the like in a molten state have drawbacks that bone tissue is difficult to be induced and regenerated.
[0004]
Moreover, since polylactic acid used in the calcium phosphate reinforcement generally contains a large amount of residual lactide, the ring-opening becomes a chain dimer of lactic acid or lactic acid, and decomposes polylactic acid. There are problems such as rapid degradation and absorption in vivo, inferior stability during storage and thermal stability during molding, and the amount of residual lactide is large due to lot fluctuation. There were variations in the degradation and absorption in the body, and there was a shortcoming of poor reproducibility.
[0005]
Conventionally, attempts have been made to improve the bioapplicability by making holes in these biodegradable polymer moldings, but these are mechanically formed in the biodegradable polymer moldings. For example, a method using a drill or a laser, and it was difficult to open a large number of fine holes in the biodegradable polymer.
[0006]
[Problems to be solved by the invention]
The problems to be solved by the present invention are excellent biocompatibility, bioresorbability, storage stability, and biomaterials such as bone replacement materials, bonding materials, bone filling materials, dental materials, and biorepair materials. Another object of the present invention is to provide a bioabsorbable composite molded article, a bioabsorbable material useful for medical device materials such as a skin terminal and a catheter, a drug sustained-release base material, and a method for producing them.
[0007]
[Means for Solving the Problems]
The present inventors have made the composite of biodegradable polymer and calcium phosphate penetrate the water-soluble polymer fiber, or after that, remove the water-soluble polymer fiber with water or hot water to create a communication hole. , Preferably using lactic acid-based polyester as biodegradable polymer, especially by reducing the residual lactide in lactic acid-based polyester, there is no inflammatory reaction in vivo, it shows good degradability, fibrous It has been found that the induction of tissue and bone tissue and the regeneration thereof can be promoted, and that it has good moldability and storage stability, and the present invention has been completed.
[0008]
That is, the present invention
(1) The water-soluble polymer fiber (B) is contained in the composite of the biodegradable polymer (A) and the calcium phosphate compound (C), and at least one of the water-soluble polymer fibers (B) is alive. A bioabsorbable composite molded article penetrating two or more surfaces of the composite of the degradable polymer (A) and the calcium phosphate compound (C),
(2) The bioabsorbable composite molded article according to (1), wherein the water-soluble polymer fiber (B) has a thickness of 1 μm to 1000 μm,
(3) The bioabsorbable composite molded article according to (1) or (2), wherein the water-soluble polymer fiber (B) is a polyvinyl alcohol fiber,
[0009]
(4) The bioabsorbable composite molded article according to any one of (1) to (3), wherein the biodegradable polymer (A) is a lactic acid-based polyester,
(5) The bioabsorbable composite molded article according to (4), wherein the lactic acid-based polyester includes a lactic acid component, a dicarboxylic acid component, and a diol component as essential components, and (6) the lactic acid-based polyester is The bioabsorbable composite molded article according to (4) or (5), characterized in that the catalyst is a lactic acid-based polyester obtained by deactivating the catalyst,
[0010]
(7) When molding a molded product containing the water-soluble polymer fiber (B) in the composite of the biodegradable polymer (A) and the calcium phosphate compound (C), one or more water-soluble polymer fibers (B ) Penetrates between two or more surfaces of the composite of the biodegradable polymer (A) and the calcium phosphate compound (C) so that the water-soluble polymer fiber (B) is transformed into the biodegradable polymer (A) and the calcium phosphate compound. (C) a method for producing a bioabsorbable composite molded article, characterized by being placed in a composite with the molded article,
(8) At least one water-soluble polymer fiber (B) is sandwiched between films of the biodegradable polymer (A) and the calcium phosphate compound (C), and at a temperature equal to or higher than the melting point of the biodegradable polymer (A). The method for producing a bioabsorbable composite molded article according to (7), wherein the film and the water-soluble polymer fiber (B) are pressure-bonded,
(9) The method for producing a bioabsorbable composite molded article according to (7) or (8), wherein the water-soluble polymer fiber (B) has a thickness of 1 μm to 1000 μm,
[0011]
(10) The method for producing a bioabsorbable composite molded article according to (9), wherein the water-soluble polymer fiber (B) is a polyvinyl alcohol fiber,
(11) The method for producing a bioabsorbable composite molded article according to any one of (7) to (10), wherein the biodegradable polymer (A) is a lactic acid-based polyester,
(12) The method for producing a bioabsorbable composite molded article according to (11), wherein the lactic acid-based polyester includes a lactic acid component, a dicarboxylic acid component, and a diol component as essential components,
(13) The method for producing a bioabsorbable composite molded article according to (11) or (12), wherein the lactic acid-based polyester is a lactic acid-based polyester obtained by deactivating the catalyst.
[0012]
(14) The water-soluble polymer fiber (B) in the bioabsorbable composite molded product produced by any one of the methods described in (7) to (13) above is removed with an aqueous solution. A method for producing a bioabsorbable material, and
(15) One or more pores having a pore diameter of 1 μm to 1000 μm produced by the production method described in (14) above are two sides of a complex of a biodegradable polymer (A) and a calcium phosphate compound (C) It is a bioabsorbable material that penetrates more than the gap.
[0013]
DETAILED DESCRIPTION OF THE INVENTION
The components constituting the bioabsorbable composite molded article of the present invention will be described below.
The calcium phosphate-based compound used in the present invention is a compound containing a portion derived from phosphoric acid and a total of 50% by weight or more, specifically, tricalcium phosphate, hydroxyapatite, carbonate apatite, magnesium-containing apatite. And fluorine apatite. Further, the crystal structure thereof may be any and may be amorphous. In particular, by using tricalcium phosphate as a calcium phosphate compound, it is easily replaced with living bone in vivo.
[0014]
In addition, the calcium phosphate compound used in the present invention refers to a spherical, porous, or amorphous material composed of aggregates having an average particle size of 0.1 μm to 300 μm. When the average particle size is less than 0.1 μm, it becomes difficult to knead with a biodegradable polymer, particularly lactic acid-based polyester, and when it is more than 300 μm, joining and replacement with living bones in vivo are difficult to occur. Further, fibers having an average cross-sectional diameter of 0.01 mm to 5 mm may be used. When fibers are used, the mechanical strength tends to increase.
[0015]
In addition, the production method of hydroxyapatite used in the present invention is not particularly specified, but specifically, there are a dry method, a hydrothermal method, a wet method, and an alkoxide method, and heat treatment may be performed. Further, although the production method of tricalcium phosphate is not particularly specified, there are specifically a dry method, a hydrothermal method, and a wet method, and heat treatment may be performed.
[0016]
The biodegradable polymer used in the present invention is not particularly limited, but a biodegradable plastic handbook such as aliphatic polyester, starch-based natural polymer, chitosan-based natural polymer, etc. (Biodegradable Plastics Research Group, 1995 edition). Polymers, aliphatic polyester amides, cellulose acetates, etc., described on page 28 of May 26, 2010), and lactic acid polyesters, which are one of aliphatic polyesters, are particularly preferred as biodegradable polymers.
[0017]
The lactic acid-based polyester varies depending on the required mechanical properties in vivo, degradation rate, kneadability with other materials, and the like, but usually has a weight average molecular weight of 3,000 to 400,000 and a melting point of 50. What is -200 degreeC is suitable. When high mechanical properties are required, the weight average molecular weight is preferably 20,000 or more, and if it is less than 3,000, the mechanical properties of the lactic acid polyester obtained therefrom are insufficient, exceeding 400,000. And formability is inferior, which is not preferable.
[0018]
Moreover, the lactic acid-type polyester used by this invention means what contains 30 weight% or more of lactic acid components in lactic acid-type polyester. Specifically, the lactic acid polyester refers to a homopolymer of a lactic acid component, a copolymer of a lactic acid component and another monomer component and / or a polymer component, a blend of a lactic acid polyester and a biodegradable polymer, and the like. Specific examples of a copolymer of a lactic acid component and other monomer component and / or polymer component include a lactic acid component, a hydroxycarboxylic acid component, a cyclic ester component of hydroxycarboxylic acid, a polyester, a polyether, a polycarbonate, and a cellulose derivative. And a copolymer thereof.
[0019]
Examples of the lactic acid component include lactic acid and lactide which is a cyclic dimer of lactic acid. Lactic acid is a monomer having optical activity, and L-lactic acid and D-lactic acid exist. Lactide includes isomers of L-lactide, D-lactide, and MESO-lactide. Therefore, lactic acid-based polyester can realize preferable polymer characteristics by combining these two kinds of lactic acid and three kinds of lactide.
[0020]
In particular, in order to achieve high heat resistance with the lactic acid-based polyester of the present invention, it is preferable that lactic acid has a higher optical activity. Specifically, the lactic acid preferably contains 70% by weight or more of L-form or D-form in the total lactic acid. In order to obtain further excellent heat resistance, it is preferable that 85% by weight or more of L-form or D-form is contained as lactic acid. Moreover, also about lactide, it is preferable to contain 70 weight% or more of L-lactide or D-lactide in total lactide. In order to obtain further excellent heat resistance, the content of L-lactide or D-lactide is 85% by weight or more in the total lactide.
[0021]
As the hydroxycarboxylic acid component of the monomer component copolymerized with the lactic acid component, glycolic acid, dimethyl glycolic acid, β-hydroxypropanoic acid, α-hydroxybutyric acid, β-hydroxybutyric acid, γ-hydroxybutyric acid, α-hydroxyvaleric acid, β-hydroxyvaleric acid, γ-hydroxyvaleric acid, δ-hydroxyvaleric acid, δ-hydroxymethylvaleric acid, α-hydroxycaproic acid, β-hydroxycaproic acid, γ-hydroxycaproic acid, δ-hydroxycaproic acid, δ -Hydroxymethyl caproic acid, (epsilon) -hydroxycaproic acid, (epsilon) -hydroxymethyl caproic acid, etc. are mentioned.
[0022]
Examples of the cyclic ester component of hydroxycarboxylic acid include glycolide, β-methyl-δ-valerolactone, γ-valerolactone, γ-undecalactone, ε-caprolactone, and paradioxanone.
[0023]
Next, the manufacturing method of lactic acid-type polyester is demonstrated.
When the lactic acid-based polyester referred to in the present invention is a homopolymer of a lactic acid component, as seen in Polymer, 20, 1459 (1979), lactide is subjected to ring-opening polymerization in the presence of a catalyst, Alternatively, as disclosed in JP-A-6-172502, it is produced by directly polycondensing lactic acid in the presence of a solvent and then removing residual volatile components, particularly residual lactide.
[0024]
In the case of a copolymer of a lactic acid component and another hydroxycarboxylic acid component or a cyclic ester component of hydroxycarboxylic acid, the lactic acid-based polyester referred to in the present invention directly combines lactic acid and another hydroxycarboxylic acid component. It is preferably produced by condensation or by ring-opening polymerization of a cyclic ester component of lactide and hydroxycarboxylic acid in the presence of a catalyst to subsequently remove residual volatile components, especially residual lactide.
[0025]
In particular, when the lactic acid-based polyester of the present invention is a copolymer of a lactic acid component and another hydroxycarboxylic acid component or a cyclic ester component of hydroxycarboxylic acid, the lactic acid component in the copolymer is 30% by weight or more. When it is, the obtained lactic acid-type polyester becomes high in mechanical strength.
[0026]
As the biodegradable polymer used in the present invention, a lactic acid-based polymer is preferable. In particular, when the lactic acid-based polyester is a copolymer having a lactic acid component, a dicarboxylic acid component, and a diol component as essential components, it was obtained. It is preferable because the molded product has high flexibility. Flexibility improves as the dicarboxylic acid component and diol component increase. Moreover, as the lactic acid-based polyester, a lactic acid-based polyester obtained by deactivating the catalyst is preferable.
[0027]
Specifically, the lactic acid-based polyester comprising the lactic acid component, the dicarboxylic acid component, and the diol component as essential components contains 30% by weight or more of the lactic acid component in the copolymer, and the dicarboxylic acid component and the diol component are 70%. A copolymer containing less than% by weight is exemplified. More specifically, the total amount of the dicarboxylic acid component and the diol component is 2% to 70% by weight, more preferably 4% to 60% by weight, based on the lactic acid component. If it is less than 2% by weight, the flexibility is not sufficient, and finely controlled in vivo degradability and suppression of inflammatory reaction cannot be achieved. On the other hand, when it is more than 70% by weight, preferred mechanical properties cannot be obtained.
[0028]
The production method is not limited, but after polyester or lactide comprising a dicarboxylic acid component and a diol component is copolymerized or transesterified in the presence of a ring-opening polymerization catalyst, or disclosed in JP-A-7-172425. As disclosed, lactic acid, dicarboxylic acid component and diol component are depolymerized by dehydration and deglycolization in the presence of catalyst and solvent, and then the residual volatile component, especially residual lactide is removed. .
[0029]
Furthermore, polylactic acid obtained using lactide as a raw material, polylactic acid obtained by polycondensation of lactic acid in the presence or absence of a solvent, and polyester comprising a dicarboxylic acid component and a diol component, together with a transesterification catalyst After transesterification below, it is produced by removing residual volatile components, especially residual lactide.
[0030]
Furthermore, the polyester comprising a dicarboxylic acid component and a diol component used when producing the lactic acid-based polyester is dehydrated and deglycolized under reduced pressure conditions in the presence of an esterification catalyst. A method of polycondensation, a method of polycondensation of a dicarboxylic acid component and a diol component as disclosed in JP-A-7-172425 by dehydration and deglycolization under the use of a dehydrating agent in the presence of a catalyst, etc. Can be manufactured.
[0031]
There are no particular restrictions on the dicarboxylic acid component and diol component copolymerized with the lactic acid component, but specific examples of the dicarboxylic acid component include malonic acid, succinic acid, glutaric acid, adipic acid, 2-methyladipic acid, Pimelic acid, corkic acid, azelaic acid, sebacic acid, nonanedicarboxylic acid, decanedicarboxylic acid, undecanedicarboxylic acid, dodecanedicarboxylic acid, maleic anhydride, fumaric acid, citraconic acid, diglycolic acid, cyclohexa-3,5-diene- 1,2-carboxylic acid, malic acid, citric acid, trans-hexahydroterephthalic acid, cis-hexahydroterephthalic acid, dimer acid, and the like, and mixtures thereof. In particular, when an aliphatic dicarboxylic acid component having 4 to 20 carbon atoms is used, the flexibility is excellent.
[0032]
Also, the diol component is not particularly limited, but a diol component that does not contain an aromatic ring is preferable because of its degradability in vivo. Specifically, ethylene glycol, propylene glycol, trimethylene glycol, butane-1,2-diol, butane-1,3-diol, butane-1,4-diol, butane-2,3-diol, 2,2 -Dimethylpropane-1,3-diol, cis-2-butene-1,4-diol, trans-2-butene-1,4-diol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, heptamethylene glycol, Octamethylene glycol, nonamethylene glycol,
[0033]
Decamethylene glycol, undecamethylene glycol, dodecamethylene glycol, tridecamethylene glycol, eicosamethylene glycol, trans-1,4-cyclohexanedimethanol, 2,2,4-trimethylpentane-1,3-diol, hydrogenated Bisphenol A, p-xylylene glycol, diethylene glycol, triethylene glycol, dipropylene glycol, tripropylene glycol, and the like, and mixtures thereof.
[0034]
Furthermore, when a polyoxyalkylene having many ether-bonded oxygen atoms is used as the diol component, the flexibility is excellent. Examples thereof include polyethylene glycol, polypropylene glycol, polybutylene glycol, polypentanediol, polytetramethylene glycol, and a block copolymer of polyethylene glycol and polypropylene glycol.
[0035]
In order to improve the thermal stability and storage stability during melt-kneading and melt-molding of lactic acid-based polyesters, especially reduce the acid components such as residual lactide, lactic acid and oligomers thereof in lactic acid-based polyester (A). Is effective. As its reduction method, it can be removed using a devolatilizer such as a devolatilization tank, a film evaporator, a vented extruder attached after the production process of lactic acid polyester, or it can be removed by a solvent precipitation method, alcohol, Extraction and removal can be performed after immersion or dispersion without using a solvent such as ketone or hydrocarbon, without dissolving the solvent.
[0036]
The polymerization catalyst used in the production of the lactic acid-based polyester of the present invention is a known polymerization catalyst such as a ring-opening polymerization catalyst, an esterification catalyst, or a transesterification catalyst. Tin, zinc, lead, titanium, bismuth, zirconium , And metals such as germanium and cobalt, and compounds thereof. Among the metal compounds, metal organic compounds, carbonates, and halides are particularly preferable.
[0037]
Specifically, tin octoate, tin chloride, zinc chloride, zinc acetate, lead oxide, lead carbonate, titanium chloride, diacetacetoxyoxy titanium, tetraethoxy titanium, tetrapropoxy titanium, tetrabutoxy titanium, germanium oxide, zirconium oxide, etc. Is suitable. The addition amount is 0.001 to 2 parts by weight with respect to 100 parts by weight of the reaction component, and the addition amount is more preferably 0.002 to 0.5 parts by weight from the viewpoint of reaction rate, coloring and the like.
[0038]
In addition, as the esterification catalyst used in the production of the polyester comprising the dicarboxylic acid component and the diol component, the same catalyst as that described above is used, and it may be added from the beginning of the esterification or immediately before the deglycolization reaction. preferable.
[0039]
The reaction temperature when producing the lactic acid-based polyester of the present invention varies depending on the type, amount, combination and the like of the lactic acid component, dicarboxylic acid component and diol component, but is usually 125 ° C to 250 ° C, preferably 140 ° C to 230 ° C. More preferably, it is 150 to 200 ° C.
[0040]
Next, the lactic acid polyester obtained by deactivating the catalyst will be described. By deactivating the polymerization catalyst used in the production of the lactic acid-based polyester, acid components such as lactide, lactic acid and oligomers thereof in the lactic acid-based polyester can be reduced. As a result, the storage stability and stability at high heat during molding are greatly improved. The deactivation treatment of the polymerization catalyst can be achieved by reacting with the catalyst in the polyester by adding or contacting the catalyst deactivator at the end of the production process or after the production of the lactic acid-based polyester. As the polymerization catalyst deactivator, acidic phosphates and chelating agents are particularly preferred.
[0041]
Chelating agents used as a polymerization catalyst deactivator include organic chelating agents and inorganic chelating agents. Organic chelating agents have low hygroscopicity and excellent thermal stability. The organic chelate that can be used is not particularly limited, but amino acids, phenols, hydroxycarboxylic acids, diketones, amines, oximes, phenanthrolines, pyridine compounds, dithio compounds, N-containing phenols as coordination atoms, coordination Examples of atoms include N-containing carboxylic acids, diazo compounds, thiols, porphyrins, and the like.
[0042]
Specifically, glycine, leucine, alanine, serine, α-aminobutyric acid, acetylaminoacetic acid, glycylglycine, glutamic acid and the like as amino acids, alizarin, t-butylcatechol, 4-isopropyltropolone, chromotrope as phenols Examples of hydroxycarboxylic acids such as acid, tyrone, oxine, propyl gallate and the like include tartaric acid, succinic acid, citric acid, monooctyl citrate, dibenzoyl-D-tartaric acid, diparatoluyl-D-tartaric acid and the like.
[0043]
Diketones include acetylacetone, hexafluoroacetylacetone, benzoylacetone, thenoyltrifluoroacetone, trifluoroacetylacetone, and amines include ethylenediamine, diethylenetriamine, 1,2,3-triaminopropane, thiodiethylamine, triethylenetetramine, triethanol Examples of oximes such as amine, tetraethylenepentamine, and pentaethylenehexamine include dimethylglyoxime, α, α-furyldioxime, salicylaldoxime, and the like.
[0044]
Examples of phenanthrolines include neocuproine and 1,10-phenanthroline, examples of pyridine compounds include 2,2-bipyridine, 2,2 ', 2 "-terpyridyl, and examples of dithio compounds include xanthogenic acid, diethyldithiocarbamic acid, and toluene-3,4. Examples of the coordination atom N-containing phenol such as -dithiol include o-aminophenol, oxine, nitroso R salt, 2-nitroso-5-dimethylaminophenol, 1-nitroso-2-naphthol, 8-selenoquinoline and the like.
[0045]
Coordinating atom N-containing carboxylic acids include quinaldic acid, nitrilotriacetic acid, ethylenediaminediacetic acid, hydroxyethylethylenediaminetriacetic acid, ethylenediaminetetraacetic acid, trans-cyclohexanediaminetetraacetic acid, diethylenetriaminepentaacetic acid, triethylenetetraminehexaacetic acid, anilinediacetic acid 2-sulfoaniline diacetic acid, 3-sulfoaniline diacetic acid, 4-sulfoaniline diacetic acid, 2-aminobenzoic acid-N, N-diacetic acid, 3-aminobenzoic acid-N, N-diacetic acid, 4- Aminobenzoic acid-N, N-diacetic acid, methylamine diacetic acid, β-alanine-N, N-diacetic acid,
[0046]
Examples of diazo compounds such as β-aminoethylsulfonic acid-N, N-diacetic acid and β-aminoethylphosphonic acid-N, N-diacetic acid include diphenylcarbazone, magneson, dithizone, Eriochrome Black T, 4- (2 -Thiazolylazo) resorcin, 1- (2-pyridylazo) -2-naphthol and the like as thiols, thiooxine, thionalide, 1,1,1-trifluoro-4- (2-thienyl) -4-mercapto-3-butene 2-one, 3-mercapto-p-cresol and the like.
[0047]
Examples of porphyrins include tetraphenylporphine and tetrakis (4-N-methylpyridyl) porphine, and other examples include cuperone, murexide, polyethyleneimine, polymethylacryloylacetone, polyacrylic acid, and the like, and mixtures thereof.
[0048]
Among them, organic chelating agents that efficiently coordinate with the metal ions of the catalyst contained in the lactic acid polyester and suppress the cleavage of the polymer terminal include nitrilotriacetic acid, ethylenediaminediacetic acid, tetraethylenepentamine, hydroxy Coordinating atom N-containing carboxylic acid such as ethylethylenediaminetriacetic acid, ethylenediaminetetraacetic acid, trans-cyclohexanediaminetetraacetic acid, diethylenetriaminepentaacetic acid, triethylenetetraminehexaacetic acid,
[0049]
Examples thereof include hydroxycarboxylic acids such as tartaric acid, dibenzoyl-D-tartaric acid, diparatoluoyl-D-tartaric acid, citric acid, and monooctyl citrate. In particular, the above-mentioned coordination atom N-containing carboxylic acid is excellent in thermal stability and storage stability, and hydroxycarboxylic acid is characterized by little coloring.
[0050]
Inorganic chelating agents have high hygroscopicity, and their effects are lost when they absorb moisture. Specific examples include phosphoric acids such as phosphoric acid, phosphorous acid, pyrophosphoric acid, and polyphosphoric acid.
[0051]
Moreover, acidic phosphate ester forms the complex with the metal ion of the catalyst contained in lactic acid-type polyester, loses catalytic activity, and shows the effect which suppresses the cutting | disconnection of a polymer chain. The acidic phosphoric acid esters refer to acidic phosphoric acid esters, phosphonic acid esters, alkylphosphonic acid, and the like, and mixtures thereof, and the general formula thereof is shown below.
[0052]
[Chemical 1]

(Wherein R ₁ Is an alkyl group or an alkoxyl group, R ₂ Represents an alkyl group, an alkoxyl group or a hydroxyl group. )
[0053]
Specifically, as the acidic phosphate ester, monomethyl phosphate, dimethyl phosphate, monoethyl phosphate, diethyl phosphate, monopropyl phosphate, dipropyl phosphate, monoisopropyl phosphate, diisopropyl phosphate, monobutyl phosphate, Dibutyl phosphate, monopentyl phosphate, dipentyl phosphate, monohexyl phosphate, dihexyl phosphate, monooctyl phosphate, dioctyl phosphate, mono 2-ethylhexyl phosphate, di-2-ethylhexyl phosphate, monodecyl phosphate,
[0054]
Didecyl phosphate, monoisodecyl phosphate, diisodecyl phosphate, monoundecyl phosphate, diundecyl phosphate, monododecyl phosphate, didodecyl phosphate, monotetradecyl phosphate, ditetradecyl phosphate, monohexadecyl phosphate, dihexadecyl phosphate, phosphorus Examples thereof include monooctadecyl acid, dioctadecyl phosphate, monophenyl phosphate, diphenyl phosphate, monobenzyl phosphate, and dibenzyl phosphate.
[0055]
Phosphonate esters include monomethyl phosphonate, monoethyl phosphonate, monopropyl phosphonate, monoisopropyl phosphonate, monobutyl phosphonate, monopentyl phosphonate, monohexyl phosphonate, monooctyl phosphonate, monoethylhexyl phosphonate, monodecyl phosphonate Monoisodecyl phosphonate, monoundecyl phosphonate, monododecyl phosphonate, monotetradecyl phosphonate, monohexadecyl phosphonate, monooctadecyl phosphonate, monophenyl phosphonate, monobenzyl phosphonate, and the like.
[0056]
Alkylphosphonic acids include monomethylphosphonic acid, dimethylphosphonic acid, monoethylphosphonic acid, diethylphosphonic acid, monopropylphosphonic acid, dipropylphosphonic acid, monoisopropylphosphonic acid, diisopropylphosphonic acid, monobutylphosphonic acid, dibutylphosphonic acid Monopentylphosphonic acid, dipentylphosphonic acid, monohexylphosphonic acid, dihexylphosphonic acid, isooctylphosphonic acid, dioctylphosphonic acid, monoethylhexylphosphonic acid, diethylhexylphosphonic acid, monodecylphosphonic acid, didecylphosphonic acid,
[0057]
Monoisodecylphosphonic acid, diisodecylphosphonic acid, monoundecylphosphonic acid, diundecylphosphonic acid, monododecylphosphonic acid, didodecylphosphonic acid, monotetradecylphosphonic acid, ditetradecylphosphonic acid, monohexadecylphosphonic acid, di Examples include hexadecylphosphonic acid, monooctadecylphosphonic acid, dioctadecylphosphonic acid, monophenylphosphonic acid, diphenylphosphonic acid, monobenzylphosphonic acid, dibenzylphosphonic acid, and the like, and mixtures thereof.
[0058]
The acidic phosphoric acid ester component is excellent in workability because of its good solubility in an organic solvent, and excellent in reactivity with lactic acid-based polyester. Of these, acidic phosphates have a great effect on the deactivation of the catalyst.
[0059]
Furthermore, although the addition amount of the chelating agent and / or acidic phosphoric acid ester used for the deactivation treatment of the polymerization catalyst varies depending on the type and the type and amount of the catalyst contained in the lactic acid polyester, 100 parts by weight of the lactic acid polyester It is preferable to add 0.001-5 weight part with respect to this. Any chelating agent or acidic phosphate ester can minimize polymer chain scission, and organic chelating agents, inorganic chelating agents, and acidic phosphate esters may be used in combination. .
[0060]
However, if an excessive amount of chelating agent or acidic phosphate ester is added, the lactic acid-based polyester chain is cleaved during storage, resulting in lower molecular weight and lower viscosity, and the performance of the present invention may not be obtained. Need to be added.
[0061]
As a method for reducing acid components such as lactide, lactic acid and oligomers thereof in the lactic acid-based polyester after the deactivation treatment of the polymerization catalyst, there are a devolatilization tank, a film evaporator, and a vented extruder attached after the deactivation treatment of the polymerization catalyst. It can be removed by using a devolatilizer, etc., dissolved in a good solvent and then precipitated by depositing in a poor solvent, or by using a solvent such as alcohol, ketone, hydrocarbon, etc. It can be extracted and removed after dispersion.
[0062]
As a method for improving the safety of lactic acid-based polyester in vivo, it is effective to remove the catalyst contained in lactic acid-based polyester. As the method, as disclosed in known methods such as JP-A-8-34844 and JP-A-8-109250, a lactic acid polyester is dissolved in an organic solvent, and then contacted with an acidic substance and water. The catalyst can be removed by separating the organic layer.
[0063]
Next, the water-soluble polymer fiber used in the present invention will be described.
The water-soluble polymer fiber used in the present invention is not particularly limited, but is preferably one that does not adversely affect the living body and can be dissolved and decomposed relatively easily in the living body or with water or warm water. Specifically, fibers such as polyvinyl alcohol, pullulan (manufactured by Hayashibara Biotechnology Laboratories Mantotriose, α-1,6-glucoside-bonded polymer), hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyethylene oxide, amylose, polypeptide, etc. And one or more of these can be used.
[0064]
Moreover, as a water-soluble polymer fiber, what melt | dissolves in a weak acidic liquid, a weak basic liquid, etc. can be used. Specific examples include fibers such as cellulose, rayon, and acetate. Moreover, as said water-soluble fiber, the thing from which molecular weight and a structure differ can be used, for example, the thing from which the saponification degree of polyvinyl alcohol differs is applicable. Furthermore, since many biodegradable polymers have high melting points, it is preferable that the water-soluble polymer fiber has high heat resistance. In that respect, polyvinyl alcohol fiber is particularly preferable.
[0065]
Moreover, the thickness of those fibers is not particularly limited, and the thickness is selected depending on the in-vivo site to be used. Usually, 1 μm to 1000 μm is preferable.
Furthermore, those fibers can be used as monofilaments or multifilaments, and furthermore, those fibers can be stretched to increase the strength.
[0066]
Next, the manufacturing method of the bioabsorbable composite molded article of the present invention will be described.
The method for producing a bioabsorbable composite molded product of the present invention is performed when a molded product containing a water-soluble polymer fiber (B) in a composite of a biodegradable polymer (A) and a calcium phosphate compound (C) is molded. The water-soluble polymer fiber (B) is passed so that one or more water-soluble polymer fibers (B) penetrate between two or more surfaces of the composite of the biodegradable polymer (A) and the calcium phosphate compound (C). It is a method for producing a bioabsorbable composite molded article characterized by being placed in a composite of a biodegradable polymer (A) and a calcium phosphate compound (C).
[0067]
Specifically, the bioabsorbable composite molded article of the present invention has one or more water-soluble materials between films prepared by kneading a biodegradable polymer and a calcium phosphate compound at a temperature equal to or higher than the melting point of the biodegradable polymer. A film obtained by sandwiching a biodegradable polymer fiber and crimping at a temperature higher than the melting point of the biodegradable polymer, or by kneading the biodegradable polymer and a calcium phosphate compound at a temperature higher than the melting point of the biodegradable polymer The water-soluble polymer fiber is oriented and sandwiched between them, and is manufactured by a method obtained by pressure bonding at a temperature equal to or higher than the melting point of the biodegradable polymer.
[0068]
In addition, the bioabsorbable composite molded article of the present invention has a water-soluble polymer fiber sandwiched between films prepared by kneading a biodegradable polymer and a calcium phosphate compound at a temperature equal to or higher than the melting point of the biodegradable polymer. , A method of laminating a molded product obtained by pressure bonding at a temperature equal to or higher than the melting point of the biodegradable polymer, or sandwiching a non-woven fabric made of water-soluble polymer fibers between the biodegradable polymer and the calcium phosphate compound film. It is manufactured by a method obtained by pressure bonding at a temperature equal to or higher than the melting point of the degradable polymer and a method of laminating the obtained molded product.
[0069]
Furthermore, the biodegradable polymer used is preferably a lactic acid-based polyester, and particularly preferably a lactic acid-based polyester comprising a lactic acid component, a dicarboxylic acid component, and a diol component as essential components. Moreover, as the lactic acid-based polyester, a lactic acid-based polyester obtained by deactivating the catalyst is preferable.
[0070]
In addition, the composite film of the biodegradable polymer and the calcium phosphate compound can be produced by a press molding machine, an extruder, an injection molding machine, or the like. Furthermore, this bioabsorbable composite molded article is generally produced by a press molding machine, and the molding temperature is performed at a temperature equal to or higher than the melting point of the biodegradable polymer.
[0071]
The bioabsorbable composite molded article or bioabsorbable material of the present invention comprises at least one or more water-soluble polymer fibers (included in a composite of a biodegradable polymer (A) and a calcium phosphate compound (C) ( It is essential that B) penetrates between at least two surfaces of the biodegradable polymer (A) and reaches the outer surface of the biodegradable polymer (A). It doesn't matter which direction.
[0072]
When a large number of water-soluble polymer fibers are included in the biodegradable polymer, it is more likely that most of the water-soluble polymer fibers penetrate between the two surfaces of the composite of the biodegradable polymer and the calcium phosphate compound. The aqueous solution circulates inside the biodegradable polymer when the through-hole is generated, which is preferable from the viewpoint of improving biodegradability. However, due to manufacturing problems, all water-soluble polymer fibers are not necessarily composed of biodegradable polymer and calcium phosphate. It does not need to penetrate between two surfaces of the complex with the compound, and some of the water-soluble polymer fibers penetrate between two or more surfaces of the complex of the biodegradable polymer and the calcium phosphate compound. But it ’s okay. Further, the term “between two surfaces or more” means that the water-soluble polymer fibers cross within the composite of the biodegradable polymer and the calcium phosphate compound, and the water-soluble polymer fibers are between two or more surfaces, for example, between three surfaces, or 4 Including those that penetrate between surfaces.
[0073]
A large number of water-soluble polymer fibers (B) are produced by including a large number of water-soluble polymer fibers in a composite of a biodegradable polymer and a calcium phosphate compound, and cutting the molded product after molding. Penetrates at least two surfaces of the complex of the degradable polymer (A) and the calcium phosphate compound (C) and reaches the outer surface of the complex (A) of the biodegradable polymer and the calcium phosphate compound (C). It is also included in the present invention to produce a bioabsorbable composite molded article. These are particularly useful when using a nonwoven fabric of water-soluble polymer fibers.
[0074]
Further, at least one or more water-soluble polymer fibers (B) reach the outer surface of the composite of the biodegradable polymer (A) and the calcium phosphate compound (C), and one of the water-soluble polymer fibers (B) A molded product having an end up to the central portion of the composite of the biodegradable polymer (A) and the calcium phosphate compound (C) is formed, and then cut at the central portion, so that at least one water-soluble polymer fiber ( A bioabsorbable composite molded article in which B) penetrates at least two surfaces of the composite of the biodegradable polymer (A) and the calcium phosphate compound (C) and reaches the outer surface of the biodegradable polymer (A). The method of creating is also included in the present invention.
[0075]
The composite of the biodegradable polymer (A) and the calcium phosphate compound (C) of the present invention contains a water-soluble polymer fiber (B), and at least one of the water-soluble polymer fibers (B) A specific example of a bioabsorbable composite molded article or a bioabsorbable material penetrating between two surfaces of the composite of the biodegradable polymer (A) and the calcium phosphate compound (C) is shown in FIG. To FIG.
[0076]
FIG. 1 is an example of the simplest bioabsorbable composite molded article and bioabsorbable material, in which one water-soluble polymer fiber (B) penetrates between two surfaces of the biodegradable polymer (A). It is.
1 to 5 indicate the water-soluble polymer fibers (B) or the holes from which the water-soluble polymer fibers (B) have been eluted and removed.
[0077]
FIG. 2 shows that a plurality of water-soluble polymer fibers (B) cross inside the composite of biodegradable polymer (A) and calcium phosphate compound (C) and penetrate between four surfaces of biodegradable polymer (A). FIG.
3 and 4 show four surfaces of the biodegradable polymer (A) by crossing a plurality of water-soluble polymer fibers (B) inside the composite of the biodegradable polymer (A) and the calcium phosphate compound (C). It is the figure which has penetrated between.
[0078]
FIG. 5 shows that a plurality of water-soluble polymer fibers (B) cross each other inside the composite of the biodegradable polymer (A) and the calcium phosphate compound (C), so that a large number of surfaces of the biodegradable polymer (A) are crossed. It is the figure which has penetrated.
The bioabsorbable material of the present invention in which the water-soluble polymer fiber (B) is eluted and removed from the biodegradable molded product of the present invention to form pores in the shape of the water-soluble polymer fiber is shown schematically in FIGS. The same is shown in the figure.
[0079]
A water-soluble polymer fiber penetrating a complex of a biodegradable polymer and a calcium phosphate compound is an aqueous solution, more specifically, water, warm water, weakly acidic liquid, weakly basic liquid, or aqueous solution containing body fluid. Biodegradability is achieved by immersing a complex of a biodegradable polymer and a calcium phosphate compound into one that dissolves and decomposes the biodegradable polymer fiber, and eluting and removing the complex from the biodegradable polymer and the calcium phosphate compound. A pore penetrating between two or more surfaces is generated inside the complex of the polymer and the calcium phosphate compound, and the aqueous solution freely circulates through the pore in the presence of the aqueous solution in a living body or the like. While maintaining the structure of the complex itself with the calcium phosphate compound, the biodegradable polymer is gradually degraded from the inside.
[0080]
A water-soluble polymer fiber in a complex of a biodegradable polymer and a calcium phosphate compound is immersed in an aqueous solution, that is, an aqueous solution containing water, warm water, a weakly acidic solution, a weakly basic solution, or a body fluid. When the communicating hole is formed by dissolving and removing the polymer, the immersion temperature is preferably a high temperature within a range where the biodegradable polymer is not dissolved or decomposed. This is because the higher the immersion temperature, the faster the removal rate of the water-soluble polymer fiber.
[0081]
In the water-soluble polymer fiber (B), by containing the drug in advance and including it in the complex of the biodegradable polymer and the calcium phosphate compound, from the complex of the biodegradable polymer and the calcium phosphate compound, As the water-soluble polymer fiber elutes into the aqueous solution, it is possible to provide a detrimental function that gradually releases these drugs. At this time, the biodegradable polymer (A) also contains these drugs, and further contains the same or different drugs in the water-soluble polymer fiber (B), so that the same drugs can be removed at different rates. Release can be controlled and different drugs can be released at different release rates.
[0082]
The bioabsorbable composite molded article comprising the biodegradable polymer (A), the water-soluble polymer fiber (B) and the calcium phosphate compound (C) according to the present invention has an elastic modulus, degradation in vivo, and degradation depending on the purpose of use. Because the required performances such as speed, induction of hard and soft tissues and their regeneration speed are different, the weight ratio of biodegradable polymer (A), water-soluble polymer fiber (B) and calcium phosphate compound (C) is generally specified Usually, (A + C) / (B) is 99/1 to 20/80, preferably 98/2 to 30/70, and more preferably 95/5 to 40/60. (A) / (C) is 80/20 to 5/95, preferably 70/30 to 10/90, and more preferably 60/40 to 15/85.
[0083]
In the present invention, the bioabsorbable composite molded article comprising the biodegradable polymer (A), the water-soluble polymer fiber (B) and the calcium phosphate compound (C) may be crystallized by heat treatment. By making it crystallize, the heat resistance can be greatly increased, and it tends to be hard and rigid.
[0084]
The crystallization temperature is a temperature not lower than the glass transition point and not higher than the melting point of the biodegradable polymer. In order to promote crystallization, a nucleating agent such as talc, kaolin, silicon dioxide, boron nitride, a crystalline polymer, or a mixture thereof is 0.1 to 10% by weight, preferably 0, based on the biodegradable polymer. .2 to 5% by weight can be added. The shape of the nucleating agent is not particularly limited, but is preferably 0.1 to 0.5 μm.
[0085]
The biodegradable polymer (A) and calcium phosphate before producing a bioabsorbable composite molded article comprising the biodegradable polymer (A), water-soluble polymer fiber (B) and calcium phosphate compound (C) of the present invention. When kneading the system compound (C), water-soluble polymers such as polyethylene glycol, physiologically acceptable salts such as sodium chloride and potassium chloride are used as the mechanical properties of the bioabsorbable composite molded product of the present invention. They can be mixed and used within a range that does not decrease.
[0086]
In addition, a bioactive substance and a drug can be added to the biodegradable polymer of the present invention. Furthermore, polylactic acid, polyglycolic acid, copolymers thereof, and the like can be incorporated in combination as long as the mechanical properties are not impaired.
[0087]
Furthermore, alcohol components such as stearyl alcohol, trimethylol ethane, trimethylol propane, pentaerythritol, and glycerin can be added as viscosity modifiers within a range that does not impair the effects of the present invention.
[0088]
The kneading of the biodegradable polymer (A), the calcium phosphate compound (C) and the above-mentioned material is performed at a temperature equal to or higher than the melting point of the biodegradable polymer (A), specifically 50 to 250 ° C., preferably Kneading at 60 to 200 ° C. In the case of lactic acid-based polyester, it is preferable to devolatilize while kneading in order to remove residual volatile components, particularly residual lactide, or devolatilization at a reduced pressure of 0.01 to 50 torr after kneading. It is preferable to do. Furthermore, since lactic acid-based polyester tends to be hydrolyzed by moisture, it is preferable to knead without touching the outside air under reduced pressure or in an inert gas atmosphere. Kneading can be performed with an extruder, a reactor, a kneader, a roll, or a combination thereof.
[0089]
As the extruder, a single screw extruder or a twin screw extruder can be used, but a twin screw extruder is preferable from the kneaded state. Furthermore, in order to remove residual volatile components and the like under reduced pressure after kneading, those having a vent port are preferable. As a reactor, a normal reaction kettle can be used, but the kneaded material has a high viscosity, and a static mixer that has low shear stress and can be mixed uniformly due to a decrease in molecular weight and coloring caused by stirring heat generated by stirring shear stress. Is preferred.
[0090]
The bioabsorbable composite molded article of the present invention is excellent in molding processability and mechanical properties, decomposes in vivo, and has little inflammatory reaction. Therefore, it can be expected to be widely used as a bioabsorbable material. Although its use is not particularly limited, specifically, the bioabsorbable composite molded article of the present invention has a strength and elastic modulus close to that of living bones, and furthermore, joining and replacement with living bones occur rapidly, In addition to mechanical strength and flexibility, this composite molded product has high tissue compatibility in addition to bone substitutes, bone cements and bone fillers, so it can be applied to skin terminals such as catheters, artificial hearts and pacemakers. The biodegradable polymer used in this composite molded product is excellent in thermal stability, so that it can be impregnated and kneaded with the drug in its molten state, and it can be released slowly depending on the type, thickness, number of water-soluble polymer fibers, etc. Therefore, it can be used as a drug sustained-release base material. Examples of the drug used for the sustained-release drug base include various anti-inflammatory agents and anticancer agents, or active vitamin D that promotes calcium absorption in the intestine and calcium deposition in bone. It can also be used for alveolar bone regeneration barrier films, hard / soft tissue regeneration promoting films, and the like.
[0091]
【Example】
Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples. All parts in the examples are based on weight unless otherwise specified.
Performance evaluation of the obtained bioabsorbable composite molded article was performed with respect to storage stability, moldability, bone tissue induction / regeneration, inflammatory reaction, and the like.
[0092]
The molecular weight was measured by GPC and indicated as a polystyrene converted value.
The melting point was determined from a melting endothermic curve measured using a differential scanning calorimeter DSC-200 manufactured by Seiko Co., Ltd. under a temperature rising rate of 10 ° C./min.
[0093]
Regarding storage stability, the bioabsorbable composite molded article was left to stand at 35 ° C. and 80% humidity for 1 month, and evaluated according to the following four levels in terms of the degree of molecular weight retention.
A: Retention rate of molecular weight is 90% or more.
A: Retention rate of molecular weight is 80 to 90%.
Δ: Retention rate of molecular weight is 60 to 80%.
X: Retention rate of molecular weight is 60% or less.
[0094]
Regarding the moldability, the bioabsorbable composite molded article was evaluated in the following four stages according to the degree of deformation by applying force to hot water of 80 ° C to 100 ° C.
A: Deformed extremely easily.
○: Deformed easily.
Δ: Not easily deformed.
X: No deformation.
[0095]
The degree of induction / regeneration of bone tissue was evaluated according to the following four steps by embedding a bioabsorbable composite molded article in a hole drilled in the long bone of a dog and observing it with a microscope one month later.
A: Induction and regeneration of bone tissue was remarkably advanced.
○: Bone tissue induction / regeneration progressed considerably.
Δ: Bone tissue induction / regeneration progressed to a trace.
X: Bone tissue induction / regeneration was not progressing at all.
[0096]
Inflammatory reaction was evaluated by the following four steps by placing a bioabsorbable composite molded article in a hole drilled in the long bone of a dog and performing microscopic observation after 4 weeks.
A: No inflammatory reaction was observed.
○: A trace of inflammatory reaction was observed.
Δ: A considerable degree of inflammatory reaction was observed.
X: The inflammatory reaction was remarkably seen.
[0097]
(Reference Example 1)
10 parts of aliphatic polyester (succinic acid component 50 mol%, 1,4-butanediol component 50 mol%, weight average molecular weight 39,000), L-lactide 87 parts, DL-lactide 3 parts and toluene 15 as a solvent In an inert gas atmosphere, they were melt-mixed at 175 ° C. for 1 hour, 0.03 parts of tin octoate was added as a catalyst, and the mixture was reacted at the same temperature for 6 hours.
[0098]
After completion of the reaction, 10 parts of the obtained lactic acid polymer was dissolved in 90 parts of m-cresol. To this solution, 100 parts of a 2% aqueous hydrochloric acid solution was added, stirred for 30 minutes, and allowed to stand to separate the aqueous layer and the organic layer. The operation of mixing 100 parts of water with the organic layer, stirring, allowing to stand, and separating the organic layer was repeated twice. This organic layer was devolatilized at 130 ° C. under reduced pressure of 5 torr. Its weight average molecular weight was 183,000, and its melting point was 162 ° C.
[0099]
(Reference Example 2)
30 parts of aliphatic polyester (sebacic acid component 50 mol%, ethylene glycol component 50 mol%, weight average molecular weight 36,000), 70 parts of L-lactide and 15 parts of toluene as a solvent were charged into a reaction kettle, and an inert gas Under an atmosphere, melt and mix them at 175 ° C. for 1 hour, add 0.03 parts of tin octoate as a catalyst, react at the same temperature for 6 hours, and then add a mixture of monododecyl phosphate and didodecyl phosphate. 0.1 part was added and reacted for another 30 minutes, then heated to 200 ° C., devolatilized under reduced pressure of 5 torr, and pelletized. The obtained pellets had a weight average molecular weight of 162,000 and a melting point of 167 ° C.
[0100]
(Reference Example 3)
50 parts aliphatic polyester (50 mol% sebacic acid component, 25 mol% 1,6-hexanediol component, 25 mol% ethylene glycol, 36,000 weight average molecular weight), 50 parts L-lactide and 15 parts toluene as solvent Were melted and mixed at 175 ° C. for 1 hour under an inert gas atmosphere, 0.03 parts of tin octoate was added as a catalyst and reacted at the same temperature for 6 hours. 0.2 part of acetic acid was added and reacted for another 30 minutes, then heated to 200 ° C., devolatilized under reduced pressure of 5 torr, and pelletized. The obtained pellets had a weight average molecular weight of 147,000 and a melting point of 165 ° C.
[0101]
(Reference Example 4)
98 parts of L-lactide, 2 parts of D-lactide and 15 parts of toluene as a solvent were charged into a reaction kettle and melt-mixed at 175 ° C. for 1 hour under an inert gas atmosphere. Add 0.03 parts and react at the same temperature for 6 hours, then add 0.2 parts of tartaric acid, react for another 30 minutes, then heat to 200 ° C., devolatilize under reduced pressure of 5 torr, and pelletize did. The obtained pellets had a weight average molecular weight of 184,000 and a melting point of 166 ° C.
[0102]
(Reference Example 5)
Hydrophobic aqueous solution was added dropwise to a vigorously stirred calcium hydroxide suspension until the pH reached 9, and the precipitate formed was calcined at 800 ° C. for 3 hours. I passed. (Average particle size 39μm)
[0103]
(Reference Example 6)
A precipitate formed by adding a phosphoric acid aqueous solution dropwise to a vigorously stirred calcium hydroxide suspension until the pH is 7 was further pulverized in a mortar by tricalcium phosphate obtained by baking at 800 ° C. for 3 hours, Passed through sieve. (Average particle size 45μm)
[0104]
Example 1
30 parts of the lactic acid polyester obtained in Reference Example 1 and 70 parts of the hydroxyapatite obtained in Reference Example 5 were kneaded for 10 minutes in a kneader set at 180 ° C., cooled, pulverized, and heated at 180 ° C. Thus, a sheet having a length of 10 cm, a width of 10 cm, and a thickness of 150 μm was produced. Next, polyvinyl alcohol fibers having a thickness of 150 μm were sandwiched between the sheets at intervals of 200 μm, and pressure-bonded by a hot press at 180 ° C. The obtained molded product was laminated by hot pressing at 180 ° C. so that the polyvinyl alcohol fibers were in the same direction, and then cooled. This lamination operation was repeated to obtain a laminated molded product having a thickness of 10 mm.
[0105]
Next, this laminated molded product was cut into a length of 5 mm, a width of 5 mm, and a length of 8 mm with a cutting machine to prepare a prism sample. At that time, the fiber direction of the polyvinyl alcohol and the lateral direction of the prismatic sample were set to be vertical. The obtained prism sample was evaluated for storage stability and moldability. Further, the prism samples were implanted in the long bones of dogs and taken out after 4 weeks, and the induction / replacement degree of bone tissue and inflammatory reaction were evaluated. The results are shown in Table 1.
[0106]
(Example 2)
25 parts of the lactic acid polyester obtained in Reference Example 2 and 75 parts of tricalcium phosphate obtained in Reference Example 6 were kneaded for 10 minutes with a kneader set at 180 ° C., cooled, pulverized, and 180 ° C. A sheet having a length of 10 cm, a width of 10 cm, and a thickness of 150 μm was produced by hot pressing. Next, polyvinyl alcohol fibers having a thickness of 150 μm were sandwiched between the sheets at intervals of 200 μm, and pressure-bonded by a hot press at 180 ° C. The obtained molded product was cooled after being laminated by a hot press at 180 ° C. so that the fibers of polyvinyl alcohol alternated vertically and horizontally. This lamination operation was repeated to obtain a laminated molded product having a thickness of 10 mm. Next, this laminated molded product was cut into a length of 5 mm, a width of 5 mm, and a length of 8 mm with a cutting machine to prepare a prism sample. At that time, the fiber direction of the polyvinyl alcohol and the length direction of the prismatic sample were made perpendicular to each other. The same evaluation as in Example 1 was performed on the obtained prism sample and the sample that was implanted in the long bone of a dog and taken out after 4 weeks. The results are shown in Table 1.
[0107]
Example 3
30 parts of the lactic acid polyester obtained in Reference Example 3 and 70 parts of tricalcium phosphate obtained in Reference Example 6 were kneaded for 10 minutes with a kneader set at 180 ° C., cooled, pulverized, and 180 ° C. A sheet having a length of 10 cm, a width of 10 cm, and a thickness of 150 μm was produced by hot pressing. Subsequently, hydroxypropylcellulose fibers having a thickness of 200 μm were sandwiched between the sheets at an interval of 200 μm and pressed by a hot press at 180 ° C. The obtained molded product was laminated by hot pressing at 180 ° C. so that the hydroxypropyl cellulose fibers were in the same direction, and then cooled. This lamination operation was repeated to obtain a laminated molded product having a thickness of 10 mm.
[0108]
Next, this laminated molded product was cut into a length of 5 mm, a width of 5 mm, and a length of 8 mm with a cutting machine to prepare a prism sample. At that time, the fiber direction of hydroxypropyl cellulose and the length direction of the prismatic sample were made perpendicular. The obtained prism sample was left in warm water at 40 ° C. for 1 hour to remove the hydroxypropyl cellulose fiber, and after drying, storage stability and molding processability were evaluated. In addition, the sample was implanted in the long bone of a dog and taken out after 4 weeks, and induction / regeneration of bone tissue and inflammatory reaction were evaluated. The results are shown in Table 1.
[0109]
Example 4
30 parts of polylactic acid obtained in Reference Example 4 and 70 parts of tricalcium phosphate obtained in Reference Example 6 were kneaded for 10 minutes in a kneader set at 180 ° C., cooled, pulverized, and heated at 180 ° C. A sheet having a length of 10 cm, a width of 10 cm, and a thickness of 150 μm was produced by pressing. Next, polyvinyl alcohol fibers having a thickness of 150 μm were sandwiched between the sheets at intervals of 200 μm, and pressure-bonded by a hot press at 180 ° C. The obtained molded product was cooled after being laminated by a hot press at 180 ° C. so that the fibers of polyvinyl alcohol alternated vertically and horizontally. This lamination operation was repeated to obtain a laminated molded product having a thickness of 10 mm. Next, this laminated molded product was cut into a length of 5 mm, a width of 5 mm, and a length of 8 mm with a cutting machine to prepare a prism sample. At that time, the fiber direction of the polyvinyl alcohol and the lateral direction of the prismatic sample were set to be vertical. The same evaluation as in Example 1 was performed on the obtained prism sample and the sample that was implanted in the long bone of a dog and taken out after 4 weeks. The results are shown in Table 1.
[0110]
(Example 5)
25 parts of aliphatic polyester (50 mol% succinic acid, 50 mol% of 1,4 butanediol, weight average molecular weight 39,000) used in Reference Example 1, and 75 parts of tricalcium phosphate obtained in Reference Example 6 Was kneaded for 10 minutes with a kneader set at 150 ° C., cooled and pulverized, and a sheet having a length of 10 cm, a width of 10 cm, and a thickness of 150 μm was produced by a hot press at 150 ° C. Next, pullulan fibers having a thickness of 180 μm were sandwiched between the sheets at intervals of 200 μm, and pressure-bonded by hot pressing at 150 ° C. The obtained molded product was cooled after laminating with a hot press at 150 ° C. so that the pullulan fibers alternated vertically and horizontally.
[0111]
This lamination operation was repeated to obtain a laminated molded product having a thickness of 10 mm. Next, this laminated molded product was cut into a length of 5 mm, a width of 5 mm, and a length of 8 mm with a cutting machine to prepare a prism sample. At that time, the fiber direction of pullulan and the lateral direction of the prismatic sample were set to be vertical. The same evaluation as in Example 1 was performed on the obtained prism sample and the sample that was implanted in the long bone of a dog and taken out after 4 weeks. The results are shown in Table 1.
[0112]
(Comparative Reference Example 1)
95 parts of L-lactide, 5 parts of DL-lactide and 15 parts of toluene as a solvent were charged into a reaction kettle and melt-mixed at 175 ° C. for 1 hour under an inert gas atmosphere. 0.03 part was added and reacted at the same temperature for 6 hours, then heated to 200 ° C., devolatilized under reduced pressure of 5 torr, and pelletized. The weight average molecular weight was 143,000, and melting | fusing point was 162 degreeC.
[0113]
(Comparative Reference Example 2)
96 parts of L-lactide, 2 parts of D-lactide, 2 parts of glycolide, and 15 parts of toluene as a solvent are charged into a reaction kettle, and they are melt-mixed at 175 ° C. for 1 hour in an inert gas atmosphere. Then, 0.03 part of tin octoate was added and reacted at the same temperature for 6 hours, then heated to 200 ° C., devolatilized under reduced pressure of 5 torr, and pelletized. Its weight average molecular weight was 138,000, and its melting point was 161 ° C.
[0114]
(Comparative Reference Example 3)
30 parts of aliphatic polyester (sebacic acid component 50 mol%, ethylene glycol component 50 mol%, weight average molecular weight 36,000), 70 parts of L-lactide and 15 parts of toluene as a solvent were charged into a reaction kettle, and an inert gas Under an atmosphere, melt and mix them at 175 ° C. for 1 hour, add 0.03 parts of tin octoate as a catalyst, react at the same temperature for 6 hours, then raise the temperature to 200 ° C. and remove under reduced pressure of 5 torr. Volatilized and pelletized. The obtained pellets had a weight average molecular weight of 132,000 and a melting point of 160 ° C.
[0115]
(Comparative Example 1)
35 parts of polylactic acid obtained in Comparative Reference Example 1 and 65 parts of hydroxyapatite obtained in Reference Example 5 were kneaded for 10 minutes in a kneader set at 180 ° C., cooled, pulverized, and set at 180 ° C. After obtaining a sheet having a thickness of 5 mm by hot pressing, the sheet was cut into a length of 5 mm, a width of 5 mm, and a length of 8 mm by a cutting machine to prepare a prism sample. The same evaluation as in Example 1 was performed on the obtained prism sample and the sample that was implanted in the long bone of a dog and taken out after 4 weeks. The results are shown in Table 2.
[0116]
(Comparative Example 2)
25 parts of lactic acid-based polyester obtained in Comparative Reference Example 2 and 75 parts of tricalcium phosphate obtained in Reference Example 6 were kneaded for 10 minutes in a kneader set at 180 ° C., cooled and pulverized, 180 ° C. A sheet of 5 mm thickness was formed by a hot press, and cut into 5 mm length, 5 mm width, and 8 mm length by a cutting machine to prepare a prism sample. The same evaluation as in Example 1 was performed on the obtained prism sample and the sample that was implanted in the long bone of a dog and taken out after 4 weeks. The results are shown in Table 2.
[0117]
(Comparative Example 3)
30 parts of the lactic acid polyester obtained in Comparative Reference Example 2 and 70 parts of the hydroxyapatite obtained in Reference Example 5 were kneaded for 10 minutes in a kneader set at 180 ° C., cooled, pulverized, and heated at 180 ° C. After forming a sheet having a thickness of 250 μm with a press, the sheet was cut into 5 mm in length, 5 mm in width, and 8 mm in length with a cutting machine to prepare a prism sample. The same evaluation as in Example 1 was performed on the obtained prism sample and the sample that was implanted in the long bone of a dog and taken out after 4 weeks. The results are shown in Table 2.
[0118]
[Table 1]

[0119]
[Table 2]

[0120]
【The invention's effect】
The present invention is applied to biomaterials such as bone replacement materials, bonding materials, and restoration materials, medical devices such as skin terminals and catheters, dental materials related to regeneration membranes of alveolar bone and surrounding tissues, sustained-release drug base materials, etc. A useful bioabsorbable composite molded article that does not cause an inflammatory reaction in the living body and can promote the regeneration of living tissue by exhibiting good decomposition and absorbability, and has good moldability and storage stability, A bioabsorbable material and a method for producing the same can be provided.
[Brief description of the drawings]
FIG. 1 is a schematic view showing an example of a bioabsorbable composite molded article or a bioabsorbable material of the present invention.
FIG. 2 is a schematic view showing an example of a bioabsorbable composite molded article or a bioabsorbable material of the present invention.
FIG. 3 is a schematic view showing an example of a bioabsorbable composite molded article or a bioabsorbable material of the present invention.
FIG. 4 is a schematic view showing an example of a bioabsorbable composite molded article or a bioabsorbable material of the present invention.
FIG. 5 is a schematic view showing an example of a bioabsorbable composite molded article or a bioabsorbable material of the present invention.

Claims (15)

The composite of the biodegradable polymer (A) and the calcium phosphate compound (C) contains a water-soluble polymer fiber (B), and at least one of the water-soluble polymer fibers (B) is a biodegradable polymer. A bioabsorbable composite molded article characterized by penetrating through at least two surfaces of a complex of (A) and a calcium phosphate compound (C). The bioabsorbable composite molded article according to claim 1, wherein the water-soluble polymer fiber (B) has a thickness of 1 µm to 1000 µm. The bioabsorbable composite molded article according to claim 1 or 2, wherein the water-soluble polymer fiber (B) is a polyvinyl alcohol fiber. The bioabsorbable composite molded article according to any one of claims 1 to 3, wherein the biodegradable polymer (A) is a lactic acid-based polyester. The bioabsorbable composite molded article according to claim 4, wherein the lactic acid polyester comprises a lactic acid component, a dicarboxylic acid component, and a diol component as essential components. The bioabsorbable composite molded article according to claim 4 or 5, wherein the lactic acid-based polyester is a lactic acid-based polyester obtained by deactivating the catalyst. When molding a molded product containing the water-soluble polymer fiber (B) in the composite of the biodegradable polymer (A) and the calcium phosphate compound (C), one or more water-soluble polymer fibers (B) are produced. The water-soluble polymer fiber (B) is transformed into the biodegradable polymer (A) and the calcium phosphate compound (C) so as to penetrate between two or more surfaces of the complex of the degradable polymer (A) and the calcium phosphate compound (C). A method for producing a bioabsorbable composite molded article, characterized in that it is placed in a composite with the molded article. One or more water-soluble polymer fibers (B) are sandwiched between the film of the biodegradable polymer (A) and the calcium phosphate compound (C), and the film and water soluble at a temperature equal to or higher than the melting point of the biodegradable polymer (A). The method for producing a bioabsorbable composite molded article according to claim 7, wherein the adhesive polymer fiber (B) is pressure-bonded. The method for producing a bioabsorbable composite molded article according to claim 7 or 8, wherein the water-soluble polymer fiber (B) has a thickness of 1 µm to 1000 µm. The method for producing a bioabsorbable composite molded article according to claim 9, wherein the water-soluble polymer fiber (B) is a polyvinyl alcohol fiber. The method for producing a bioabsorbable composite molded article according to any one of claims 7 to 10, wherein the biodegradable polymer (A) is a lactic acid-based polyester. The method for producing a bioabsorbable composite molded article according to claim 11, wherein the lactic acid polyester comprises a lactic acid component, a dicarboxylic acid component, and a diol component as essential components. The method for producing a bioabsorbable composite molded article according to claim 11 or 12, wherein the lactic acid-based polyester is a lactic acid-based polyester obtained by deactivating the catalyst. Bioabsorbable material soluble polymer fibers bioabsorbable composite molding in (B) is characterized that you have holes is removed by an aqueous solution is formed of any one of claims 1 to 6. The one or more pores having a pore diameter of 1 μm to 1000 μm penetrate through at least two surfaces of the complex of the biodegradable polymer (A) and the calcium phosphate compound (C) . Bioabsorbable material.

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