JP3999823B2 - Cross-linked polysaccharide, process for producing the same and composite material thereby - Google Patents
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【０００１】
【産業上の利用分野】
本発明は、特に医療用素材として適用される架橋された多糖類、およびその製造法、並びにこれによる複合材料の提供に関する。
【０００２】
【従来の技術】
ヒアルロン酸、アルギン酸、ペクチン、デンプン（アミロース、アミロペクチン）等の多糖類は天然に数多く存在し、生体内にも多数存在している。
例えば、生体内においてはヒアルロン酸のように保湿性、柔軟性、潤滑性などの役割を担っているものや、ヘパリンのように抗血栓性を示すものが存在し、また、近年注目されている成長因子（growth factor ）と特異的に吸着したり結合する多糖類も知られている。
このような特徴を有する多糖類を癒着防止材、神経再生用基材、人工皮膚、創傷被覆材等の医療用素材として用いることは大変有用であるが、多くの多糖類は水溶性であるため一定の形態を保つことが困難であり、前記のような医療用素材への適用は不適切であった。
かかる点、化学修飾や架橋反応を行うことで水不溶性とすることは可能であり、例えば、U.S.P 4,605,691(1986) でE.A.Balzs らはジビニルスルホン(DVS) を用いて、また、PCT WO 86/00079 (1986)でMalson T. はブタンジオールジグリシジルエーテル(BDDE)を用いて、さらにN.Yui らはJ.Cont.Release, 25, 133-143 (1993)などで、ポリグリシジルエーテルを用いてそれぞれヒアルロン酸の架橋反応が可能であることを示しているが、これら何れの方法においても高含水率で強度が極端に弱く、また、分解も極めて速い欠点を解消できず、その結果単独で医療用材料として用いることはできなかった。
【０００３】
【発明が解決しようとする課題】
本発明は、かかる従来法における強度不足と早期分解性の課題を解消し、医療用素材として十分に実用に耐え得る新規な素材、及び、その製造法を提供するもので、併せて、生体内における分解吸収速度の調整も可能としたものである。
【０００４】
【課題を解決するための手段】
即ち、本発明は２つ以上のアルデヒド基を有する有機化合物によってヘミアセタール結合、若しくは、アセタール結合されていることを特徴とする架橋多糖類。及び、２つ以上のアルデヒド基を有する有機化合物と未架橋の多糖類水溶液を混合し、次いでこれを乾燥処理してシート状の固形物とすることを特徴とする架橋多糖類の製造法。並びに、未架橋の多糖類水溶液を乾燥処理してシート状とし、次いでこれを２つ以上のアルデヒド基を有する有機化合物を含有した水と有機溶媒の混合液中に浸漬することを特徴とする架橋多糖類の製造法。更には、架橋された多糖類と生体内分解吸収性材料を組み合わせ、或は、架橋された多糖類と、生理活性物質あるいは医薬品を組み合わせて複合化したことに特徴を有する架橋糖類の複合材料に関する。
【０００５】
【作用】
本発明は、２つ以上のアルデヒド基を有する有機化合物、即ち、グルタルアルデヒド、グリオキザールの内、より好ましくは、医用材料に使用されてるグルタルアルデヒドを用い、これによるヘミアセタール結合、若しくは、アセタール結合によって架橋度を高めて強度、分解性の機能を高めたことに特徴を有する。
即ち、従来よりグルタルアルデヒドは、タンパク質のアミノ基同士を結合させることにより架橋反応を行う架橋試薬として用いられてきたが、多糖類の中には遊離のアミノ基を有するものが存在する反面、多くのものには遊離のアミノ基は存在しない。
本発明においては、多糖類の水酸基を利用し、アルデヒド基をもつ有機化合物との間でのヘミアセタール結合、若しくは、アセタール結合により、強度、分解性の改善を可能としたものである。
尚、かかるヘミアセタール結合、若しくは、アセタール結合に到る反応については化学式１に示した。
【０００６】
【化１】
本発明の対象となる多糖類は、ヒアルロン酸、アルギン酸、ペクチン、デンプン（アミロース、アミロペクチン）等の中から選択されるが、とりわけ、医療素材という観点より、保湿性、柔軟性、潤滑性に優れるヒアルロン酸が好ましい。また、得られる架橋物は、ブロック状、棒状等、任意の固形状を呈するが、より好ましくは、キャスティング等の方法によってフィルム状のシートとしたものが癒着防止材、神経再生用基材、人工皮膚、創傷被覆材等の医療用素材として好ましい。
かかる、シート体の形成については、２つ以上のアルデヒド基を有する有機化合物と未架橋の多糖類水溶液を混合し、次いでこれをキャスティングして乾燥処理する方法、或は、未架橋の多糖類水溶液状をキャスティングした後、乾燥処理し、次いでこれを２つ以上のアルデヒド基を有する有機化合物を含有した水と有機溶媒の混合液中に浸漬して得る２つの方法が例示できる。
かかる何れの方法においても、浴中の酸濃度を０．０００１Ｎ（規定）以上、好ましくは、０．００８〜０．２Ｎ（規定）の範囲に調整して処理することが望ましい。即ち、酸濃度が高過ぎても、低過ぎても反応が進まないことがその理由として挙げられる。
かかる酸濃度の調整は例えば、塩酸を用いて行い、前者の方法にあっては、その反応温度を約１５〜３０℃としたとき反応がゆっくりと進み、およそ２４時間後に反応が完結する。
一方、後者の方法においては、未架橋の多糖類フィルムを出発材料として架橋反応を行うもので、２つ以上のアルデヒド基を有する有機化合物を含有した水と有機溶媒の混合液中に浸漬して処理することにより液中での反応を行う。尚、かかる方法による反応温度は約４〜４０℃、好ましくは２０〜３０℃、反応時間は１５〜３０時間の範囲で行うが、温度の高いほど短時間で反応する。
かかる水と有機溶媒の混合比率は、有機溶媒の割合を６０〜９９．９重量％、より好ましくは７５〜８０重量％の範囲とする。即ち、この範囲を外れると、架橋対象物が溶解してしまったり、固形物として取り扱うことが困難な高含水率となるため好ましくない。
かかる有機溶媒は、アセトン、クロロホルム、ヘキサン、メチルエチルケトン、ジオキサン、酢酸エチル、メタノール、エタノールの中から選択できるが、酸性条件下においてグルタルアルデヒドのアルデヒド基がアルコール類の水酸基と反応し、多糖類の水酸基との反応効率が低下し、結果的に架橋が効率的に導入されていない材料しか得られなくなってしまう欠点を解消するためにメタノール、エタノール以外の有機溶媒を選択することが望ましい。特に、取り扱い易さを考慮するとアセトンを用いるのが好適である。
【０００８】
本発明を構成する多糖類の分子量は特に限定されるものではないが、概ね104 〜２×１０6 の範囲にあるものを用い、これを遊離の酸の形態、或は、ナトリウム、カリウムなどのアルカリ金属塩、あるいはカルシウム、マグネシウムなどのアルカリ土類金属塩などとして用いる。
架橋反応における水溶液濃度は、０．１〜５重量％の範囲とし、固形化のための乾燥条件は、１５〜４０℃の範囲において、水分率が５〜２０％となるまで行う。
尚、以上のような諸条件、即ち、架橋剤の量、反応温度、時間、或いは、有機溶媒と水の混合比率、さらには反応を行う際の酸の濃度、多糖類の種類、濃度、乾燥条件などを変化させることによって含水率が４５〜９９. ９％と広い範囲の任意の架橋多糖類材料を得ることが可能であり、これは、従来法による９５〜９９％という狭い範囲の架橋材料しか得られなかったことと比較し大きな特徴である。
【０００９】
本発明はさらに、架橋多糖類と生体内分解吸収性材料からなる補強材料とを複合化することを特徴とする架橋多糖類材料をも提供する。
即ち、かかる補強材による複合化は、その強度を高め、分解性を調整するために行うもので、かかる補強材料となる生体内分解吸収性材料としてはポリグリコール酸、ポリ乳酸、ポリカプロラクトン、ポリジオキサノン、キチン、キトサン、などの単一重合体、あるいはこれらの共重合体などが挙げられる。これらの補強材料は、編物、織物あるいは不織布の形態で架橋多糖類中に埋入するか、貼り合わせることにより架橋多糖類を複合化する。かかる複合化の際の架橋多糖類と生体内分解吸収性補強材料の配合比率は、架橋多糖類の特性を阻害せず、また、補強効果を付与するために架橋多糖類１〜１０重量部に対して生体内分解吸収性補強材料を０. １〜１０重量部とするのが好ましい。
【００１０】
また、本発明は本発明に係る架橋多糖類に生理活性物質や医薬品を含有させた構成をも提供する。
即ち、多糖類の架橋反応を行う際に生理活性物質や医薬品を共存させることにより、架橋多糖類内部に閉じこめたり、或いは、共有結合により架橋多糖類に固定させる。或いは、架橋多糖類に生理活性物質や医薬品を含浸させることによりかかる複合化架橋多糖類材料が得られる。
架橋多糖類に複合させることのできる生理活性物質としては、ヘパリン、細胞増殖因子（bFGFなど）、また医薬品として、種々の抗生物質や抗菌剤を例示することができる。これらの物質を複合化させることにより抗血栓性の付与、癒着防止能の増加、創傷治癒の促進、感染症の予防などの機能が付与される。
架橋多糖類と生理活性物質や医薬品の配合比率は、架橋多糖類１０〜１００重量部に対して生理活性物質や医薬品０. ５〜５重量部とするのが好ましい。
【００１１】
以下、本発明実施例を用いてより詳細に説明するが、本発明がこれら実施例に限定されないことはいうまでもない。
【実施例１】
分子量が１．８×１０6 である０．０３ｇのヒアルロン酸ナトリウム塩粉末を９ミリリットルの蒸留水に溶解させ、さらに０．１Ｎの塩酸を１ミリリットル加えて酸濃度０．０２Ｎのヒアルロン酸水溶液を調製した。一方、これに酸を加えない水溶液も調製した。
この両区の水溶液に０．２モルとなるようにグルタルアルデヒド水溶液を加え、２５℃で十分に撹拌した後にガラスシャーレにキャストし、風乾させて厚さ０．３ｍｍのフィルムを作製した。
得られたフィルムを蒸留水に浸漬させたところ、酸を加えて反応させたフィルムは２４時間後も形態をしっかりと保った。一方、酸を加えない水溶液より作製したフィルムは２０分以内にゆっくりと溶解した。即ち、その処理条件によって性質の異なる２つの架橋物が得られた。
【００１２】
【実施例２】
分子量が実施例１と同じであるヒアルロン酸ナトリウム塩粉末を１重量％濃度となるように蒸留水中に溶解させ、この溶液をガラス板上に流延して風乾し、厚さ０．３ｍｍの未架橋のヒアルロン酸フィルムを得た。
一方、これとは別にエタノール濃度が８０重量％であるエタノール−水混合水溶液を作製し、この中に０．２モルとなるようにグルタルアルデヒドを加え、架橋浴を調整したものと、かかる架橋浴に更に塩酸溶液を加えて酸濃度０．１Ｎにしたものと２種類の架橋浴を作製し、かかる２種類の架橋浴に前記の未架橋ヒアルロン酸フィルムをそれぞれ浸漬し、２５℃で２４時間反応させた。反応終了後それぞれのフィルムを蒸留水中に浸漬させたところ、酸を加えない架橋浴中で反応したフィルムは直ちに溶解したのに対し、酸を加えた架橋浴中で反応したフィルムはゆっくりと約２０分間で溶解した。
【００１３】
【実施例３】
分子量が実施例１と同じであるヒアルロン酸ナトリウム塩粉末を１重量％濃度となるように蒸留水中に溶解させ、この溶液をガラス板上に流延して風乾し、未架橋のヒアルロン酸フィルムを得た。
一方、これとは別にアセトン濃度が８０重量％であるアセトン−水混合水溶液を作製し、この中に０．２５Ｍとなるようにグルタルアルデヒドを加え、これを２区に分けて、その架橋浴に塩酸溶液を加えて酸濃度０．１Ｎにしたものと、酸を加えない２種類の架橋浴を調整した。かかる２種類の架橋浴に前記の未架橋ヒアルロン酸フィルムをそれぞれ浸漬し、２５℃で２４時間反応させた。反応終了後それぞれのフィルムを蒸留水中に浸漬させたところ、酸を加えない架橋浴中で反応したフィルムは２４時間のうちにゆっくりと溶解したのに対して、酸を加えた架橋浴中で反応したフィルムは２４時間後でも全く形態に変化は見られなかった。また、このフィルムの含水率を３７℃の生理食塩水中に浸漬し、２４時間後に測定したところ５５％であった。
【００１４】
【実施例４】
分子量が実施例１と同じであるヒアルロン酸ナトリウム塩粉末を１重量％濃度となるように蒸留水中に溶解させ、この溶液をガラス板上に流延して風乾し、未架橋のヒアルロン酸フィルムを得た。
一方、これとは別にアセトン濃度が８０重量％であるアセトン−水混合水溶液を作製し、これに各、１０ｍＭ、５０ｍＭ、１００ｍＭ、２５０ｍＭのグルタルアルデヒド（ＧＡ）を加えた区をつくり、更に、これを各５区に分けた後、各区に塩酸溶液を加えて０．１Ｎ、０．０５Ｎ、０．０１Ｎ、０．００５Ｎの酸濃度に調整した区を作製して架橋浴とした。ついで、かかる浴に前記の未架橋ヒアルロン酸フィルムを浸漬し、２５℃で２４時間反応させた。
反応終了後それぞれのフィルムを蒸留水中に浸漬し、その含水率を測定した結果を図１に示した。なお、含水率が低いことは、分解が遅く、強度が高いことを示す。
【００１５】
【図１】
【００１６】
【実施例５】
アルギン酸ナトリウム塩、ペクチン、アミロペクチン粉末をそれぞれ１重量％濃度となるように蒸留水中に溶解させ、それぞれの水溶液をガラス板上に流延して風乾し、未架橋のそれぞれのフィルムを得た。
一方、これとは別にアセトン濃度が８０重量％であるアセトン−水混合水溶液を作製し、この中に０．２５Ｍとなるようにグルタルアルデヒドを加え、架橋浴を調整した。また、その架橋浴に塩酸溶液を加えて酸濃度０．１Ｎにしたものと、酸を加えない２種類の架橋浴を作製した。かかる２種類の架橋浴に前記の未架橋のそれぞれのフィルムを、それぞれ浸漬し、２５℃で２４時間反応させた。反応終了後それぞれのフィルムを蒸留水中に浸漬させたところ、酸を加えない架橋浴中で反応したフィルムはいずれも２４時間のうちにゆっくりと溶解したのに対して、酸を加えた架橋浴中で反応したフィルムは２４時間後でも全く形態に変化は見られなかった。さらに、７日後においても形態に変化は見られなかった。
【００１７】
【実施例６】
分子量が１．８×１０6 である０．０６ｇのヒアルロン酸ナトリウム塩粉末を２０ミリリットルの蒸留水に溶解させ、さらに０．２Ｎの塩酸を１ミリリットル加えて酸濃度０．０２Ｎのヒアルロン酸水溶液を調製し、次いで、これに０．２モルとなるようグルタルアルデヒド水溶液を加え、よく撹拌した後、ポリグリコール酸糸にて平編組織に編成した編地を浸漬して風乾させ、複合化した架物を構成した。
【００１８】
【発明の効果】
本発明は、従来の強度不足と早期分解性の課題を解消し、医療用素材として十分に実用に耐え得る新規な素材、及び、その製造法を提供するもので、併せて、生体内における分解吸収速度の調整も可能としたものである。
このような特徴を有する多糖類を癒着防止材、神経再生用基材、人工皮膚、創傷被覆材等の医療用素材として用いることは大変有用である。
【図面の簡単な説明】
【図１】実施例４の結果を図表化した図[0001]
[Industrial application fields]
The present invention relates to a cross-linked polysaccharide applied particularly as a medical material, a method for producing the same, and a composite material provided thereby.
[0002]
[Prior art]
Many polysaccharides such as hyaluronic acid, alginic acid, pectin, and starch (amylose, amylopectin) exist in nature, and there are also many in vivo.
For example, in vivo there are those that play a role of moisture retention, flexibility, lubricity and the like like hyaluronic acid, and those that show antithrombotic properties like heparin, and have been attracting attention in recent years. Polysaccharides that specifically adsorb or bind to growth factors are also known.
It is very useful to use polysaccharides having such characteristics as medical materials such as anti-adhesion materials, nerve regeneration base materials, artificial skin, and wound dressings, but many polysaccharides are water-soluble. It was difficult to maintain a certain form, and application to the medical material as described above was inappropriate.
In this respect, it is possible to make it water-insoluble by performing chemical modification or a crosslinking reaction. For example, in USP 4,605,691 (1986), EABalzs et al. Used divinyl sulfone (DVS) and PCT WO 86/00079 ( 1986) Malson T. used butanediol diglycidyl ether (BDDE), N. Yui et al., J. Cont. Release, 25, 133-143 (1993) etc. Although it has been shown that an acid crosslinking reaction is possible, none of these methods can solve the drawbacks of high moisture content, extremely weak strength, and extremely rapid degradation, and as a result, it is a medical material alone. It could not be used as.
[0003]
[Problems to be solved by the invention]
The present invention eliminates the problems of insufficient strength and early degradability in the conventional method, and provides a novel material that can sufficiently withstand practical use as a medical material, and a method for producing the same. It is also possible to adjust the rate of decomposition and absorption in.
[0004]
[Means for Solving the Problems]
That is, the present invention is a cross-linked polysaccharide characterized in that hemiacetal bond or acetal bond is formed by an organic compound having two or more aldehyde groups. A method for producing a crosslinked polysaccharide, comprising mixing an organic compound having two or more aldehyde groups and an uncrosslinked polysaccharide aqueous solution, and then drying the mixture to form a sheet-like solid. In addition, the cross-linking is characterized in that an aqueous solution of uncrosslinked polysaccharide is dried to form a sheet and then immersed in a mixture of water and an organic solvent containing an organic compound having two or more aldehyde groups. Production method of polysaccharides. Furthermore, the present invention relates to a composite material of a cross-linked saccharide characterized by combining a cross-linked polysaccharide and a biodegradable absorbent material, or combining a cross-linked polysaccharide and a physiologically active substance or a pharmaceutical product. .
[0005]
[Action]
The present invention uses an organic compound having two or more aldehyde groups, that is, glutaraldehyde or glyoxal, and more preferably glutaraldehyde used for medical materials, thereby forming a hemiacetal bond or an acetal bond. It is characterized in that the degree of cross-linking is increased to enhance the strength and degradability functions.
That is, glutaraldehyde has been used as a cross-linking reagent for performing a cross-linking reaction by bonding amino groups of proteins, but some polysaccharides have a free amino group, but many There is no free amino group.
In the present invention, strength and degradability can be improved by using a hydroxyl group of a polysaccharide and a hemiacetal bond or an acetal bond with an organic compound having an aldehyde group.
Such a hemiacetal bond or a reaction leading to an acetal bond is shown in Chemical Formula 1.
[0006]
[Chemical 1]
The polysaccharide which is the subject of the present invention is selected from hyaluronic acid, alginic acid, pectin, starch (amylose, amylopectin), etc., and is particularly excellent in moisture retention, flexibility and lubricity from the viewpoint of medical materials. Hyaluronic acid is preferred. The obtained cross-linked product exhibits an arbitrary solid shape such as a block shape or a rod shape. More preferably, a film-like sheet obtained by a method such as casting is used as an adhesion preventing material, a nerve regeneration base material, an artificial material. It is preferable as a medical material such as skin and wound dressing.
Regarding the formation of such a sheet body, a method of mixing an organic compound having two or more aldehyde groups and an uncrosslinked polysaccharide aqueous solution and then casting and drying the mixture, or an uncrosslinked polysaccharide aqueous solution Examples of the method include two methods obtained by casting the shape, drying, and then immersing it in a mixture of water and an organic solvent containing an organic compound having two or more aldehyde groups.
In any of these methods, it is desirable to adjust the acid concentration in the bath to 0.0001 N (normal) or more, preferably in the range of 0.008 to 0.2 N (normal). That is, the reason is that the reaction does not proceed even if the acid concentration is too high or too low.
For example, the acid concentration is adjusted using hydrochloric acid. In the former method, the reaction proceeds slowly when the reaction temperature is about 15 to 30 ° C., and the reaction is completed after about 24 hours.
On the other hand, in the latter method, a crosslinking reaction is carried out using an uncrosslinked polysaccharide film as a starting material, which is immersed in a mixture of water and an organic solvent containing an organic compound having two or more aldehyde groups. The reaction is carried out in the liquid by treatment. The reaction temperature by this method is about 4 to 40 ° C., preferably 20 to 30 ° C., and the reaction time is 15 to 30 hours. The higher the temperature, the shorter the reaction time.
The mixing ratio of the water and the organic solvent is such that the ratio of the organic solvent is 60 to 99.9% by weight, more preferably 75 to 80% by weight. That is, if it is out of this range, the cross-linking target is dissolved, or the water content becomes difficult to handle as a solid, which is not preferable.
Such an organic solvent can be selected from acetone, chloroform, hexane, methyl ethyl ketone, dioxane, ethyl acetate, methanol, and ethanol. Under acidic conditions, the aldehyde group of glutaraldehyde reacts with the hydroxyl group of the alcohol to form a hydroxyl group of the polysaccharide. It is desirable to select an organic solvent other than methanol and ethanol in order to eliminate the disadvantage that the reaction efficiency of the resin is reduced, and as a result, only materials in which crosslinking is not efficiently introduced can be obtained. In particular, acetone is suitable for ease of handling.
[0008]
The molecular weight of the polysaccharide constituting the present invention is not particularly limited, but is generally in the range of 10 4 to 2 × 10 6 and is used as a free acid form, or sodium, potassium, etc. Or an alkaline earth metal salt such as calcium or magnesium.
The aqueous solution concentration in the cross-linking reaction is in the range of 0.1 to 5% by weight, and the drying conditions for solidification are performed in the range of 15 to 40 ° C. until the moisture content becomes 5 to 20%.
In addition, various conditions as described above, that is, the amount of the crosslinking agent, the reaction temperature, the time, or the mixing ratio of the organic solvent and water, and further the acid concentration at the time of the reaction, the type of polysaccharide, the concentration, the drying By changing conditions and the like, it is possible to obtain an arbitrary cross-linked polysaccharide material having a moisture content of 45 to 99.9% in a wide range, which is a cross-linked material in a narrow range of 95 to 99% according to the conventional method. This is a great feature compared to what was only possible.
[0009]
The present invention further provides a cross-linked polysaccharide material comprising a composite of a cross-linked polysaccharide and a reinforcing material composed of a biodegradable absorbent material.
That is, the compounding with such a reinforcing material is performed in order to increase the strength and adjust the degradability, and as a biodegradable absorbent material as the reinforcing material, polyglycolic acid, polylactic acid, polycaprolactone, polydioxanone , Chitin, chitosan, and the like, or copolymers thereof. These reinforcing materials are embedded in the cross-linked polysaccharide in the form of a knitted fabric, a woven fabric or a non-woven fabric, or are combined to form a composite of the cross-linked polysaccharide. The blending ratio of the cross-linked polysaccharide and the biodegradable absorbable reinforcing material at the time of such complexing does not inhibit the characteristics of the cross-linked polysaccharide, and in order to impart a reinforcing effect, 1 to 10 parts by weight of the cross-linked polysaccharide. On the other hand, the biodegradable absorbable reinforcing material is preferably 0.1 to 10 parts by weight.
[0010]
The present invention also provides a constitution in which a physiologically active substance or a pharmaceutical is contained in the crosslinked polysaccharide according to the present invention.
That is, when a polysaccharide cross-linking reaction is performed, a physiologically active substance or a pharmaceutical is allowed to coexist, so that it is confined inside the cross-linked polysaccharide or is fixed to the cross-linked polysaccharide by a covalent bond. Alternatively, such a composite cross-linked polysaccharide material can be obtained by impregnating the cross-linked polysaccharide with a physiologically active substance or a pharmaceutical product.
Examples of the physiologically active substance that can be conjugated to the crosslinked polysaccharide include heparin, cell growth factor (bFGF, etc.), and various antibiotics and antibacterial agents as pharmaceuticals. By compounding these substances, functions such as imparting antithrombogenicity, increasing adhesion preventing ability, promoting wound healing, and preventing infection are imparted.
The blending ratio of the cross-linked polysaccharide and the physiologically active substance or pharmaceutical is preferably 0.5 to 5 parts by weight with respect to 10 to 100 parts by weight of the cross-linked polysaccharide.
[0011]
Hereinafter, although it demonstrates in detail using an Example of this invention, it cannot be overemphasized that this invention is not limited to these Examples.
[Example 1]
0.03 g of hyaluronic acid sodium salt powder having a molecular weight of 1.8 × 10 6 is dissolved in 9 ml of distilled water, and 1 ml of 0.1N hydrochloric acid is further added to prepare an aqueous solution of hyaluronic acid having an acid concentration of 0.02N. Prepared. On the other hand, an aqueous solution to which no acid was added was also prepared.
A glutaraldehyde aqueous solution was added to the aqueous solutions in both sections so as to have a concentration of 0.2 mol, and the mixture was sufficiently stirred at 25 ° C., then cast on a glass petri dish and air-dried to produce a film having a thickness of 0.3 mm.
When the obtained film was immersed in distilled water, the film reacted with the addition of acid kept its form firmly after 24 hours. On the other hand, a film prepared from an aqueous solution to which no acid was added dissolved slowly within 20 minutes. That is, two cross-linked products having different properties depending on the treatment conditions were obtained.
[0012]
[Example 2]
Hyaluronic acid sodium salt powder having the same molecular weight as in Example 1 was dissolved in distilled water to a concentration of 1% by weight, and this solution was cast on a glass plate and air-dried. A crosslinked hyaluronic acid film was obtained.
On the other hand, an ethanol-water mixed aqueous solution having an ethanol concentration of 80% by weight was prepared separately, glutaraldehyde was added so as to be 0.2 mol, and a crosslinking bath was prepared. Further, a hydrochloric acid solution was added to adjust the acid concentration to 0.1 N and two types of crosslinking baths were prepared. The uncrosslinked hyaluronic acid film was immersed in the two types of crosslinking baths and reacted at 25 ° C. for 24 hours. I let you. When each film was immersed in distilled water after completion of the reaction, the film reacted in the crosslinking bath without addition of acid immediately dissolved, whereas the film reacted in the crosslinking bath with addition of acid slowly decreased to about 20 Dissolved in minutes.
[0013]
[Example 3]
Hyaluronic acid sodium salt powder having the same molecular weight as in Example 1 was dissolved in distilled water to a concentration of 1% by weight, and this solution was cast on a glass plate and air-dried to obtain an uncrosslinked hyaluronic acid film. Obtained.
Separately, on the other hand, an acetone-water mixed aqueous solution having an acetone concentration of 80% by weight was prepared, and glutaraldehyde was added thereto so that the concentration was 0.25M. A hydrochloric acid solution was added to adjust the acid concentration to 0.1 N and two crosslinking baths without acid were prepared. The uncrosslinked hyaluronic acid film was immersed in the two types of crosslinking baths and reacted at 25 ° C. for 24 hours. When each film was immersed in distilled water after completion of the reaction, the film reacted in the crosslinking bath without addition of acid slowly dissolved within 24 hours, whereas it reacted in the crosslinking bath with addition of acid. The film did not change in shape at all even after 24 hours. Further, the water content of this film was immersed in physiological saline at 37 ° C. and measured after 24 hours, and it was 55%.
[0014]
[Example 4]
Hyaluronic acid sodium salt powder having the same molecular weight as in Example 1 was dissolved in distilled water to a concentration of 1% by weight, and this solution was cast on a glass plate and air-dried to obtain an uncrosslinked hyaluronic acid film. Obtained.
On the other hand, an acetone-water mixed aqueous solution having an acetone concentration of 80% by weight was prepared separately, and 10m, 50mM, 100mM, and 250mM glutaraldehyde (GA) were added to each, and this was further divided. Were divided into 5 sections, and a hydrochloric acid solution was added to each section to prepare sections adjusted to acid concentrations of 0.1 N, 0.05 N, 0.01 N, and 0.005 N, and used as a crosslinking bath. Subsequently, the uncrosslinked hyaluronic acid film was immersed in such a bath and reacted at 25 ° C. for 24 hours.
After completion of the reaction, each film was immersed in distilled water and the water content was measured. The results are shown in FIG. A low moisture content indicates that the decomposition is slow and the strength is high.
[0015]
[Figure 1]
[0016]
[Example 5]
Alginate sodium salt, pectin, and amylopectin powder were each dissolved in distilled water to a concentration of 1% by weight, and each aqueous solution was cast on a glass plate and air-dried to obtain an uncrosslinked film.
On the other hand, an acetone / water mixed aqueous solution having an acetone concentration of 80% by weight was prepared separately, and glutaraldehyde was added thereto so as to have a concentration of 0.25 M to prepare a crosslinking bath. Moreover, a hydrochloric acid solution was added to the cross-linking bath to make an acid concentration of 0.1 N, and two types of cross-linking baths to which no acid was added were prepared. Each of the uncrosslinked films was immersed in the two types of crosslinking baths and reacted at 25 ° C. for 24 hours. When each film was immersed in distilled water after completion of the reaction, all the films reacted in the crosslinking bath without addition of acid dissolved slowly within 24 hours, whereas in the crosslinking bath with addition of acid. The film reacted with no change in shape even after 24 hours. Furthermore, no change was observed in the morphology even after 7 days.
[0017]
[Example 6]
0.06 g of hyaluronic acid sodium salt powder having a molecular weight of 1.8 × 10 6 is dissolved in 20 ml of distilled water, and 1 ml of 0.2N hydrochloric acid is further added to prepare an aqueous solution of hyaluronic acid having an acid concentration of 0.02N. Then, after adding a glutaraldehyde aqueous solution to 0.2 mol and stirring well, the knitted fabric knitted into a flat knitted structure with polyglycolic acid yarn is immersed and air-dried to form a composite frame Made up a thing.
[0018]
【The invention's effect】
The present invention solves the problems of conventional strength deficiency and early degradability, and provides a novel material that can sufficiently withstand practical use as a medical material, and a method for producing the same. The absorption rate can also be adjusted.
It is very useful to use polysaccharides having such characteristics as medical materials such as anti-adhesion materials, nerve regeneration base materials, artificial skin, and wound dressings.
[Brief description of the drawings]
FIG. 1 is a diagram illustrating the results of Example 4
Claims (7)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| JP16690095A JP3999823B2 (en) | 1995-06-07 | 1995-06-07 | Cross-linked polysaccharide, process for producing the same and composite material thereby |
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| JP16690095A JP3999823B2 (en) | 1995-06-07 | 1995-06-07 | Cross-linked polysaccharide, process for producing the same and composite material thereby |
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| AU6459299A (en) * | 1999-10-29 | 2001-05-14 | Min Hu | Surface treatment with polypeptides to improve fibroblast adhesion to hyaluronan |
| JP2004099779A (en) * | 2002-09-10 | 2004-04-02 | Japan Science & Technology Corp | Phenol-based polymer nanotube and method for producing the same |
| US8293890B2 (en) * | 2004-04-30 | 2012-10-23 | Advanced Cardiovascular Systems, Inc. | Hyaluronic acid based copolymers |
| JP4460617B2 (en) * | 2007-09-28 | 2010-05-12 | 株式会社資生堂 | Swellable crosslinked hyaluronic acid powder and method for producing the same |
| WO2018164358A1 (en) * | 2017-03-07 | 2018-09-13 | (주)진우바이오 | Method for manufacturing hyaluronate film and hyaluronate film manufactured thereby |
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