JP2005187670A - Activated polymalic acid derivative and polymer crosslinked product - Google Patents
Activated polymalic acid derivative and polymer crosslinked product Download PDFInfo
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- JP2005187670A JP2005187670A JP2003431703A JP2003431703A JP2005187670A JP 2005187670 A JP2005187670 A JP 2005187670A JP 2003431703 A JP2003431703 A JP 2003431703A JP 2003431703 A JP2003431703 A JP 2003431703A JP 2005187670 A JP2005187670 A JP 2005187670A
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- 239000002253 acid Substances 0.000 title claims abstract description 45
- 229920000642 polymer Polymers 0.000 title claims abstract description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 14
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical group OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 10
- 238000004132 cross linking Methods 0.000 claims abstract 2
- -1 succinimidyl Chemical group 0.000 claims description 12
- 108010035532 Collagen Proteins 0.000 claims description 11
- 102000008186 Collagen Human genes 0.000 claims description 11
- 229920001436 collagen Polymers 0.000 claims description 11
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 8
- 235000011090 malic acid Nutrition 0.000 claims description 8
- 239000001630 malic acid Substances 0.000 claims description 8
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 6
- 229920006037 cross link polymer Polymers 0.000 claims description 6
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 6
- 235000018102 proteins Nutrition 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- 108090000623 proteins and genes Proteins 0.000 claims description 6
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- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 3
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims description 3
- 108010076119 Caseins Proteins 0.000 claims description 3
- 102000011632 Caseins Human genes 0.000 claims description 3
- 229920001661 Chitosan Polymers 0.000 claims description 3
- 229920001287 Chondroitin sulfate Polymers 0.000 claims description 3
- 229920000045 Dermatan sulfate Polymers 0.000 claims description 3
- 102000008946 Fibrinogen Human genes 0.000 claims description 3
- 108010049003 Fibrinogen Proteins 0.000 claims description 3
- 102000006395 Globulins Human genes 0.000 claims description 3
- 108010044091 Globulins Proteins 0.000 claims description 3
- 102000001554 Hemoglobins Human genes 0.000 claims description 3
- 108010054147 Hemoglobins Proteins 0.000 claims description 3
- 229920002971 Heparan sulfate Polymers 0.000 claims description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 3
- 229920000288 Keratan sulfate Polymers 0.000 claims description 3
- 108010076876 Keratins Proteins 0.000 claims description 3
- 102000011782 Keratins Human genes 0.000 claims description 3
- 108010058846 Ovalbumin Proteins 0.000 claims description 3
- 108010071390 Serum Albumin Proteins 0.000 claims description 3
- 102000007562 Serum Albumin Human genes 0.000 claims description 3
- 108010045569 atelocollagen Proteins 0.000 claims description 3
- 239000005018 casein Substances 0.000 claims description 3
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 claims description 3
- 235000021240 caseins Nutrition 0.000 claims description 3
- 229940059329 chondroitin sulfate Drugs 0.000 claims description 3
- AVJBPWGFOQAPRH-FWMKGIEWSA-L dermatan sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 claims description 3
- 229940051593 dermatan sulfate Drugs 0.000 claims description 3
- 229940012952 fibrinogen Drugs 0.000 claims description 3
- 229920000669 heparin Polymers 0.000 claims description 3
- 229960002897 heparin Drugs 0.000 claims description 3
- 229920002674 hyaluronan Polymers 0.000 claims description 3
- 229960003160 hyaluronic acid Drugs 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 claims description 3
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims description 3
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 3
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- 150000005846 sugar alcohols Polymers 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 6
- 239000012567 medical material Substances 0.000 abstract description 5
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- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 239000000853 adhesive Substances 0.000 abstract 1
- 230000001070 adhesive effect Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 10
- 150000001718 carbodiimides Chemical class 0.000 description 10
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000227 bioadhesive Substances 0.000 description 5
- 239000000512 collagen gel Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003431 cross linking reagent Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000010102 embolization Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
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- 230000002439 hemostatic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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- Materials For Medical Uses (AREA)
- Polyesters Or Polycarbonates (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
Abstract
Description
この出願の発明は、生体接着剤等の生体適合医用材料への応用において有用な、活性化ポリリンゴ酸誘導体とこれを用いた高分子架橋体に関するものである。 The invention of this application relates to an activated polymalic acid derivative useful for application to biocompatible medical materials such as a bioadhesive, and a polymer crosslinked product using the same.
従来より、生体接着剤、止血材、血管塞栓材、医用封止材等として高分子系の架橋剤や縮合剤の各種のものが検討されてきており、たとえば、ポリグルタル酸のカルボキシル基を修飾して活性化し、このものをゼラチン等と反応させたものを架橋剤等として用いることが提案されている（特許文献１−２、非特許文献１）。 Conventionally, various types of polymeric crosslinking agents and condensing agents have been studied as bioadhesives, hemostatic materials, vascular embolization materials, medical sealants, etc., for example, by modifying the carboxyl group of polyglutaric acid. It has been proposed to use a product obtained by reacting this with gelatin or the like as a crosslinking agent (Patent Document 1-2, Non-Patent Document 1).
しかしながら、従来、生体接着剤等の医用材料として開発されてきた架橋剤や縮合剤はいずれも人工的に化学合成された非天然物系のものであって、その実際的応用においては生体内での毒性が懸念されているものである。
そこで、この出願の発明は、以上のとおりの背景から、生体への医用材料としての適用においても毒性への懸念のほとんどない天然物系の材料として、生体接着剤等への応用において有用な新しい技術手段を提供することを課題としている。 Therefore, the invention of this application is a new material useful in application to bioadhesives, etc., as a natural product-based material with little concern about toxicity even when applied as a medical material to a living body. The challenge is to provide technical means.
この出願の発明は、上記の課題を解決するものとして、第１には、 分子構造中に２以上のリンゴ酸構造単位を有するポリリンゴ酸において、リンゴ酸構造単位のカルボキシル基の１以上が電子吸引性基により反応修飾されていることを特徴とする活性化ポリリンゴ酸誘導体を提供し、第２には、電子吸引性基がスクシンイミジル、スルホスクシンイミジル、マレイミジル、イミダゾールイル、ニトロフェニル、およびトレジル基のうちの少くとも１種あることを特徴とする活性化ポリリンゴ酸誘導体を提供する。 The invention of this application is to solve the above-mentioned problems. First, in polymalic acid having two or more malic acid structural units in the molecular structure, one or more of the carboxyl groups of the malic acid structural unit are electron-attracted. An activated polymalic acid derivative characterized in that it is modified with a reactive group, and second, the electron-withdrawing group is succinimidyl, sulfosuccinimidyl, maleimidyl, imidazolyl, nitrophenyl, and trezil Provided is an activated polymalic acid derivative characterized in that there is at least one of the groups.
また、この出願の発明は、第３には、上記第１または第２の発明の活性化ポリリンゴ酸誘導体の反応修飾された活性化カルボキシル基部分が他の高分子に反応架橋されていることを特徴とする高分子架橋体を提供し、第４には、他の高分子がタンパク質、グリコサミノグリカン、キトサン、ポリアミノ酸、ポリアルコール、またはこれらの２以上組み合わせであることを特徴とする高分子架橋体を、第５には、他の高分子がコンドロイチン硫酸、デルマタン硫酸、ヒアルロン酸、ヘパラン硫酸、ヘパリン、ケラタン硫酸、またはこれらの誘導体からなるグリコサミノグリカンであることを特徴とする高分子架橋体を、第６には、他の高分子がコラーゲン、アテロコラーゲン、アルカリ可溶化コラーゲン、ゼラチン、ケラチン、血清アルブミン、卵白アルブミン、ヘモグロビン、カゼインおよびグロブリン、フィブリノーゲン、またはこれらの誘導体からなるタンパク質であることを特徴とする高分子架橋体を提供する。 The third aspect of the invention of this application is that the activated carboxyl group moiety of the activated polymalic acid derivative of the first or second invention is reactively crosslinked to another polymer. A polymer crosslinked product is provided, and fourthly, the other polymer is a protein, glycosaminoglycan, chitosan, polyamino acid, polyalcohol, or a combination of two or more thereof. The molecular cross-linked product, fifthly, the other polymer is a glycosaminoglycan composed of chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparan sulfate, heparin, keratan sulfate, or a derivative thereof. The molecular cross-linked product, and sixthly, other polymers are collagen, atelocollagen, alkali-solubilized collagen, gelatin, keratin, serum albumin Providing ovalbumin, hemoglobin, casein and globulin, fibrinogen, or a crosslinked polymer, which is a protein consisting of their derivatives.
この出願の発明によれば、生体への医用材料としての適用においても毒性への懸念のほとんどない天然物系の材料として、生体接着剤等への応用において有用な新しい技術手段が実現されることになる。 According to the invention of this application, new technical means useful in application to bioadhesives and the like can be realized as a natural product-based material with little concern about toxicity even when applied as a medical material to a living body. become.
この出願の発明は上記のとおりの特徴をもつものであるが、以下にその実施の形態について説明する。 The invention of this application has the features as described above, and an embodiment thereof will be described below.
この出願の発明においては、前記のとおり、活性化ポリリンゴ酸誘導体は、分子構造中に２以上のリンゴ酸構造単位を有するポリリンゴ酸において、リンゴ酸構造単位のカルボキシル基の１以上が電子吸引性基により反応修飾されている。 In the invention of this application, as described above, in the activated polymalic acid derivative, in the polymalic acid having two or more malic acid structural units in the molecular structure, one or more of the carboxyl groups of the malic acid structural unit are electron withdrawing groups. Is modified by the reaction.
この場合のポリリンゴ酸は、２以上のリンゴ酸構造単位を有するオリゴマーあるいはポリマーの各種のものであってよく、他の重合性モノマー、特に生分解性の他のヒドロキシカルボン酸との共重合ポリマーであってもよい。このようなポリリンゴ酸の重量平均分子量としては、一般的には、１，０００〜数万程度が好適に考慮されるが、後述するような最終的な高分子架橋体ゲルの所要の物性や用途に応じて定めることができる。 The polymalic acid in this case may be a variety of oligomers or polymers having two or more malic acid structural units, and may be a copolymerized polymer with other polymerizable monomers, particularly biodegradable other hydroxycarboxylic acids. There may be. As the weight average molecular weight of such polymalic acid, generally about 1,000 to several tens of thousands is preferably considered, but the required physical properties and applications of the final polymer crosslinked gel as described later are used. Can be determined according to
また、電子吸引性基については、活性化ポリリンゴ酸誘導体の性質や用途に応じて各種のものであってよいが、なかでもスクシンイミジル、スルホスクシンイミジル、マレイミジル、イミダゾールイル、ニトロフェニル、およびトレジル基のうちの少くとも１種であることが好ましい。 In addition, the electron-withdrawing group may be various depending on the nature and use of the activated polymalic acid derivative. Among them, succinimidyl, sulfosuccinimidyl, maleimidyl, imidazolyl, nitrophenyl, and tresyl Preferably at least one of the groups.
たとえば以上のような、この出願の発明に係る活性化ポリリンゴ酸誘導体は、ポリリンゴ酸と、電子吸引性基を有する反応剤、たとえば、Ｎ−ヒドロキシアミン系活性エステル誘導性化合物とを反応させて得ることができる。Ｎ−ヒドロキシアミン系活性エステル誘導性化合物との反応によって、ポリリンゴ酸はそのカルボキシル基において−ＣＯ−Ｏ−Ｎ結合を形成することになる。 For example, the activated polymalic acid derivative according to the invention of this application as described above is obtained by reacting polymalic acid with a reagent having an electron-withdrawing group, for example, an N-hydroxyamine-based active ester-derived compound. be able to. By reaction with an N-hydroxyamine-based active ester-derived compound, polymalic acid will form a —CO—O—N bond at its carboxyl group.
ポリリンゴ酸は先行技術である活性化ポリグルタミン酸とちがい酵素加水分解ではなく
、自然加水分解によりリンゴ酸にまで速やかに加水分解される。そして、生体内のクエン酸サイクルによって代謝され、人体に対して無害であることはいうまでもない。また、使用するポリリンゴ酸の分子量およびスクシンイミジル基等の導入率を変えることで様々な反応性、溶解性が期待される新規多官能性架橋剤である。
Polymalic acid is rapidly hydrolyzed to malic acid by natural hydrolysis rather than enzymatic hydrolysis unlike activated polyglutamic acid, which is the prior art. Needless to say, it is metabolized by the in vivo citrate cycle and is harmless to the human body. Further, it is a novel multifunctional crosslinking agent that is expected to have various reactivity and solubility by changing the molecular weight of polymalic acid used and the introduction rate of succinimidyl group and the like.
以上の活性化ポリリンゴ酸誘導体は、反応修飾された活性化カルボキシル基部分が他の高分子に反応架橋されていることを特徴とする高分子架橋体を提供する。たとえば上記の活性化ポリリンゴ酸の−ＣＯ−Ｏ−Ｎ結合との反応によって、高分子架橋体は−ＣＯ−Ｎのアミド結合を形成することになる。 The activated polymalic acid derivative described above provides a polymer crosslinked product in which an activated carboxyl group moiety modified by reaction is reactively crosslinked with another polymer. For example, the polymer crosslinked product forms an amide bond of —CO—N by the reaction of the activated polymalic acid with the —CO—O—N bond.
この場合の他の高分子としては各種のものであってよいが、好適なものとしては、タンパク質、グリコサミノグリカン、キトサン、ポリアミノ酸、ポリアルコール、またはこれらの２以上組み合わせが例示される。たとえば、具体的には、他の高分子として、コンドロイチン硫酸、デルマタン硫酸、ヒアルロン酸、ヘパラン硫酸、ヘパリン、ケラタン硫酸、またはこれらの誘導体からなるグリコサミノグリカンがあるいは、他の高分子として、コラーゲン、アテロコラーゲン、アルカリ可溶化コラーゲン、ゼラチン、ケラチン、血清アルブミン、卵白アルブミン、ヘモグロビン、カゼインおよびグロブリン、フィブリノーゲン、またはこれらの誘導体からなるタンパク質が例示される。 Various other polymers may be used in this case, but preferred examples include protein, glycosaminoglycan, chitosan, polyamino acid, polyalcohol, or a combination of two or more thereof. For example, specifically, the other polymer is chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparan sulfate, heparin, keratan sulfate, or a glycosaminoglycan composed of these derivatives, or the other polymer is collagen. And proteins consisting of atelocollagen, alkali solubilized collagen, gelatin, keratin, serum albumin, ovalbumin, hemoglobin, casein and globulin, fibrinogen, or derivatives thereof.
上記のとおりの活性化ポリリンゴ酸誘導体、そしてこれを用いての高分子架橋体の製造のための方法については、後述の実施例に沿って、当業者において適宜な態様が採用されてよく、またその変更がなされてもよい。 As for the activated polymalic acid derivative as described above, and the method for producing a crosslinked polymer using the same, appropriate modes may be adopted by those skilled in the art according to the examples described below. That change may be made.
そこで以下に実施例を示し、さらに詳しく説明する。 Therefore, an example will be shown below and will be described in more detail.
もちろん、以下の例によって発明が限定されることはない。 Of course, the invention is not limited by the following examples.
（実施例１−１） 重量平均分子量が１８００であるポリリンゴ酸２．１２ｇのジメチルホルムアミド（ＤＭＦ）溶液中に室温にてＮ−ヒドロキシスクシンイミド０．４６ｇと塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）０．７７ｇとモレキュラーシーブス（３Ａ）６ｇを加え、２０時間攪拌した。その後、過剰の酢酸エチル、アセト−ヘキサンを用いて精製し、ポリリンゴ酸の側鎖カルボキシル基の３８．３％がＮ−ヒドロキシスクシンイミドに修飾された誘導体０．８６ｇを得た。
（実施例１−２）３０％アルカリ可溶化コラーゲンのジメチルスルホキシド（ＤＭＳＯ）溶液２００μＬ中に合成したポリリンゴ酸誘導体５０ｍｇを加え、攪拌した。３７℃にて２４時間静置し、コラーゲンゲルを合成した。
（実施例２−１） 重量平均分子量が１８００であるポリリンゴ酸１．２ｇのジメチルホルムアミド（ＤＭＦ）溶液中に室温にてＮ−ヒドロキシスクシンイミド０．２６ｇと塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）０．４４ｇとモレキュラーシーブス（３Ａ）４ｇを加え、窒素下で２０時間攪拌した。その後、過剰の酢酸エチル、アセト−ヘキサンを用いて精製し、ポリリンゴ酸の側鎖カルボキシル基の３８．３％がＮ−ヒドロキシスクシンイミドに修飾された誘導体０．２１ｇを得た。
（実施例２−２） ３０％アルカリ可溶化コラーゲンのＤＭＳＯ溶液２００μＬ中に合成したポリリンゴ酸誘導体５０ｍｇを加え、攪拌した。３７℃にて２４時間静置し、コラーゲンゲルを合成した。
（実施例３−１） 重量平均分子量が１７００であるポリリンゴ酸５．０６ｇのジメチルホルムアミド（ＤＭＦ）溶液中に室温にてＮ−ヒドロキシスクシンイミド１．００ｇと塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）１．６７ｇとモレキュラーシーブス（３Ａ）１０ｇを加え、窒素下で２０時間攪拌した。その後、過剰の酢酸エチル、アセト−ヘキサンを用いて精製し、ポリリンゴ酸の側鎖カルボキシル基の３８．３％がＮ−ヒドロキシスクシンイミドに修飾された誘導体２．３ｇを得た。
（実施例３−２） ３０％アルカリ可溶化コラーゲンのＤＭＳＯ溶液２００μＬ中に合成したポリリンゴ酸誘導体５０ｍｇを加え、攪拌した。３７℃にて２４時間静置し、コラーゲンゲルを合成した。
（実施例４−１） 重量平均分子量が１７００であるポリリンゴ酸５．１２ｇのジメチルホルムアミド（ＤＭＦ）溶液中に室温にてＮ−ヒドロキシスクシンイミド２．５４ｇと塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）４．２３ｇとモレキュラーシーブス（３Ａ）１５ｇを加え、窒素下で２０時間攪拌した。その後、過剰の酢酸エチル、アセト−ヘキサンを用いて精製し、ポリリンゴ酸の側鎖カルボキシル基の３８．３％がＮ−ヒドロキシスクシンイミドに修飾された誘導体２．９ｇを得た。
（実施例４−２） ３０％アルカリ可溶化コラーゲンのＤＭＳＯ溶液２００μＬ中に合成したポリリンゴ酸誘導体５０ｍｇを加え、攪拌した。３７℃にて２４時間静置し、コラーゲンゲルを合成した。
（実施例５−１） 重量平均分子量が１７００であるポリリンゴ酸５．０３ｇのジメチルホルムアミド（ＤＭＦ）溶液中に室温にてＮ−ヒドロキシスクシンイミド３．９９ｇと塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）６．６４ｇとモレキュラーシーブス（３Ａ）２６ｇを加え、窒素下で２０時間攪拌した。その後、過剰の酢酸エチル、アセト−ヘキサンを用いて精製し、ポリリンゴ酸の側鎖カルボキシル基の３８．３％がＮ−ヒドロキシスクシンイミドに修飾された誘導体２．７ｇを得た。
（実施例５−２） ３０％アルカリ可溶化コラーゲンのＤＭＳＯ溶液２００μＬ中に合成したポリリンゴ酸誘導体５０ｍｇを加え、攪拌した。３７℃にて２４時間静置し、コラーゲンゲルを合成した。
(Example 1-1) In a dimethylformamide (DMF) solution of 2.12 g of polymalic acid having a weight average molecular weight of 1800, 0.46 g of N-hydroxysuccinimide and 1-ethyl-3- (3-dimethyl hydrochloride) at room temperature. Aminopropyl) carbodiimide (EDC) 0.77 g and molecular sieves (3A) 6 g were added and stirred for 20 hours. Then, it refine | purified using excess ethyl acetate and aceto-hexane, and obtained 0.86g of derivatives by which 38.3% of the side chain carboxyl group of polymalic acid was modified by N-hydroxysuccinimide.
(Example 1-2) 50 mg of a synthesized polymalic acid derivative was added to 200 μL of a 30% alkali-solubilized collagen solution in dimethyl sulfoxide (DMSO) and stirred. The collagen gel was synthesize | combined by leaving still at 37 degreeC for 24 hours.
(Example 2-1) In a dimethylformamide (DMF) solution of 1.2 g of polymalic acid having a weight average molecular weight of 1800, 0.26 g of N-hydroxysuccinimide and 1-ethyl-3- (3-dimethyl hydrochloride) at room temperature. Aminopropyl) carbodiimide (EDC) 0.44 g and molecular sieves (3A) 4 g were added and stirred for 20 hours under nitrogen. Then, it refine | purified using excess ethyl acetate and aceto-hexane, and obtained 0.21g of derivatives which 38.3% of the side chain carboxyl group of polymalic acid was modified by N-hydroxysuccinimide.
(Example 2-2) 50 mg of a synthesized polymalic acid derivative was added to 200 μL of a DMSO solution containing 30% alkali-solubilized collagen, and the mixture was stirred. The collagen gel was synthesize | combined by leaving still at 37 degreeC for 24 hours.
(Example 3-1) In a dimethylformamide (DMF) solution of 5.06 g of polymalic acid having a weight average molecular weight of 1700, 1.00 g of N-hydroxysuccinimide and 1-ethyl-3- (3-dimethylhydrochloride at room temperature 1.67 g of aminopropyl) carbodiimide (EDC) and 10 g of molecular sieves (3A) were added and stirred for 20 hours under nitrogen. Then, it refine | purified using excess ethyl acetate and aceto-hexane, and obtained 2.3 g of derivatives by which 38.3% of the side chain carboxyl group of polymalic acid was modified by N-hydroxysuccinimide.
(Example 3-2) 50 mg of a polymalic acid derivative synthesized in 200 μL of a DMSO solution of 30% alkali-solubilized collagen was added and stirred. The collagen gel was synthesize | combined by leaving still at 37 degreeC for 24 hours.
(Example 4-1) 2.54 g of N-hydroxysuccinimide and 1-ethyl-3- (3-dimethyl hydrochloride) in a dimethylformamide (DMF) solution of 5.12 g of polymalic acid having a weight average molecular weight of 1700 at room temperature Aminopropyl) carbodiimide (EDC) 4.23 g and molecular sieves (3A) 15 g were added, and the mixture was stirred under nitrogen for 20 hours. Then, it refine | purified using excess ethyl acetate and aceto-hexane, and obtained 2.9g of derivatives which 38.3% of the side chain carboxyl group of polymalic acid was modified by N-hydroxysuccinimide.
(Example 4-2) 50 mg of a polymalic acid derivative synthesized in 200 μL of a DMSO solution of 30% alkali-solubilized collagen was added and stirred. The collagen gel was synthesize | combined by leaving still at 37 degreeC for 24 hours.
(Example 5-1) In a dimethylformamide (DMF) solution of 5.03 g of polymalic acid having a weight average molecular weight of 1700, 3.99 g of N-hydroxysuccinimide and 1-ethyl-3- (3-dimethyl hydrochloride at room temperature 6.64 g of aminopropyl) carbodiimide (EDC) and 26 g of molecular sieves (3A) were added and stirred for 20 hours under nitrogen. Then, it refine | purified using excess ethyl acetate and aceto-hexane, and obtained 2.7g of derivatives which 38.3% of the side chain carboxyl group of polymalic acid was modified by N-hydroxysuccinimide.
(Example 5-2) 50 mg of a synthesized polymalic acid derivative was added to 200 μL of a DMSO solution containing 30% alkali-solubilized collagen, followed by stirring. The collagen gel was synthesize | combined by leaving still at 37 degreeC for 24 hours.
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| JP2012232070A (en) * | 2011-05-09 | 2012-11-29 | National Institute For Materials Science | Adhesive substrate and method for manufacturing the same |
| CN105949477A (en) * | 2016-05-24 | 2016-09-21 | 福建农林大学 | Water-soluble unmodified collagen and method for preparing same |
| CN115869471A (en) * | 2022-03-25 | 2023-03-31 | 成都百瑞恒通医疗科技有限公司 | Anticoagulation functional material and preparation method and application thereof |
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| JP2012232070A (en) * | 2011-05-09 | 2012-11-29 | National Institute For Materials Science | Adhesive substrate and method for manufacturing the same |
| CN105949477A (en) * | 2016-05-24 | 2016-09-21 | 福建农林大学 | Water-soluble unmodified collagen and method for preparing same |
| CN115869471A (en) * | 2022-03-25 | 2023-03-31 | 成都百瑞恒通医疗科技有限公司 | Anticoagulation functional material and preparation method and application thereof |
| CN115869471B (en) * | 2022-03-25 | 2024-01-26 | 成都百瑞恒通医疗科技有限公司 | Anticoagulation functional material, preparation method and application thereof |
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