WO2006016600A1 - Dérivé de l'acide tartarique et matière réticulée de haut poids moléculaire synthétisée en utilisant ce dérivé - Google Patents

Dérivé de l'acide tartarique et matière réticulée de haut poids moléculaire synthétisée en utilisant ce dérivé Download PDF

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Publication number
WO2006016600A1
WO2006016600A1 PCT/JP2005/014636 JP2005014636W WO2006016600A1 WO 2006016600 A1 WO2006016600 A1 WO 2006016600A1 JP 2005014636 W JP2005014636 W JP 2005014636W WO 2006016600 A1 WO2006016600 A1 WO 2006016600A1
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WO
WIPO (PCT)
Prior art keywords
tartaric acid
acid derivative
water
soluble
derivative
Prior art date
Application number
PCT/JP2005/014636
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English (en)
Japanese (ja)
Inventor
Tetsushi Taguchi
Hisatoshi Kobayashi
Junzo Tanaka
Hirofumi Saito
Hirokatsu Aoki
Original Assignee
National Institute For Materials Science
Furuuchi Chemical Corporation
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Publication date
Application filed by National Institute For Materials Science, Furuuchi Chemical Corporation filed Critical National Institute For Materials Science
Priority to JP2006531678A priority Critical patent/JPWO2006016600A1/ja
Publication of WO2006016600A1 publication Critical patent/WO2006016600A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

  • the present invention comprises a tartaric acid derivative in which the carboxyl group of tartaric acid or a derivative thereof is modified with an electron-withdrawing group, a polymer crosslinked product synthesized from the tartaric acid derivative, the tartaric acid derivative and a biodegradable polymer.
  • the present invention relates to a two-component biodegradable and absorbable adhesive medical material.
  • Patent Documents 1 and 2 have developed a low-molecular-weight biological derivative in which at least one carboxyl group of citrate, which is a tricarboxylic acid existing in the citrate circuit, is modified with an electron-withdrawing group (Patent Document 3, Non-Patent Document 3). References 1-3).
  • Patent Document 4 a method for producing an intermolecular cross-linked protein using al force nicnic acid disuccinimide is known (Patent Document 4).
  • Patent Document 1 Japanese Patent Laid-Open No. 9103479
  • Patent Document 2 JP-A-11 239610
  • Patent Document 3 Japanese Patent Laid-Open No. 2004-99562
  • Patent Document 4 JP-A-61-69759
  • Non-Patent Document 1 Polymer Preprints, Japan 2002, Vol.51, No.14,3728
  • Non-Patent Document 2 Polymer Preprints, Japan 2003, Vol.52, No.14,4147
  • Non-Patent Document 3 Polymer Preprints, Japan 2003, Vol.52, No.14,4140
  • Cross-linking agents and condensing agents that have been used so far for medical devices are mainly artificially synthesized non-natural products that are not metabolized in vivo and show toxicity to the living body. thing Has been pointed out. For this reason, the usage and usage are limited when used in the medical field. Furthermore, until now, there has been no biotissue adhesive that has strong tissue adhesion and low residual toxicity of the crosslinking agent or degradation product. In addition, conventional hemostatic agents, vascular embolizers, sealants, or aneurysm sealants are sufficient to easily remove the applied partial force against vascular occlusion, hemostasis, air leak, aneurysm sealing, etc. There was no one with adhesive strength.
  • a water-soluble tartaric acid derivative obtained by modifying tartaric acid, which is a dicarboxylic acid having a hydroxyl group, with an electron-attracting group, and a biodegradable polymer by using the tartaric acid derivative are used.
  • a cross-linked polymer synthesized by cross-linking, a two-component biodegradable absorbable adhesive medical material composed of the tartaric acid derivative and a biodegradable polymer are used.
  • the present invention crosslinks a biodegradable polymer using a dicarboxylic acid derivative obtained by modifying two carboxyl groups of tartaric acid, which is a dicarboxylic acid, with an electron-attracting group, and the obtained tartaric acid derivative.
  • the present invention provides an organic solvent solution or aqueous solution of a biodegradable polymer, a buffer solution, or a water organic solvent mixed solution as an adhesive component, and two carboxyl groups of tartaric acid that is a dicarboxylic acid are electron-withdrawing.
  • the electron-withdrawing group to be used includes one or a combination of two or more of succinimidyl, sulfosuccinimidyl, maleimidyl, phthalimidyl, imidazolyl, nitrophenol, Outlookyl, and derivatives thereof. It is done.
  • biodegradable polymer used in the crosslinked polymer or biodegradable absorbable adhesive medical material can be a protein, glycosaminodarlican, chitosan, polyamino acid, polyalcohol, or a combination of two or more thereof.
  • glycosaminodarlicans include chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparan sulfate, heparin, keratan sulfate, or one or a combination of two or more of these derivatives. These glycosaminodaricans do not depend on the molecular weight and the organism from which they are derived.
  • Proteins include collagen (depending on several tens of types), atelocollagen (not depending on several tens of types), alkali-treated collagen (not depending on several tens of types), gelatin Selected from the group consisting of macromolecules having amino groups such as keratin, hemoglobin, casein, globulin, fibrinogen, albumin derived from human blood, recombinant albumin, albumin fragment, and chemically modified albumin. A combination of one or more of the qualities can be mentioned.
  • biodegradable polymers used in the preparation of biodegradable bioabsorbable adhesive medical materials composed of a crosslinked polymer, a water-soluble tartaric acid derivative and a biodegradable polymer.
  • examples include chitosan (deacetylation degree, regardless of molecular weight), polyamino acid (amino acid type, regardless of molecular weight), and polyalcohol (type, regardless of molecular weight).
  • the biodegradable polymer Solvents for dissolving include buffers prepared by one or a combination of two or more of hydrochloride, sulfate, nitrate, phosphate, carbonate and borate.
  • the tartaric acid derivative in which the carboxyl group of tartaric acid or its derivative is modified with an electron-withdrawing group is more water-soluble than the low molecular weight biological derivatives and alkanedioic acid disuccinimide previously developed by the present inventors.
  • Biodegradable under the condition of aqueous solution using a buffer solution when obtaining a biodegradable bioadhesive adhesive medical material composed of a crosslinked polymer and the tartaric acid derivative and a biodegradable polymer molecule. The reaction proceeds uniformly with the aqueous polymer solution and the reaction time is shortened.
  • the low molecule used as a starting material of the water-soluble tartaric acid derivative of the present invention is tartaric acid or a derivative thereof, for example, a hydroxyl group (-OH) in tartaric acid is converted to a sulfate group (-OSO Na) or a carboxylic acid.
  • Soluble tartaric acid derivatives have two carboxyl groups in tartaric acid or its derivatives, e.g., electron-withdrawing groups such as succinimidyl, sulfosuccinimidyl, maleimidyl, phthalimidyl, imidazolyl, nitrophenol, toresyl or their derivatives.
  • a synthetic reaction is carried out with one or a combination of two or more, and an active ester is introduced.
  • the water-soluble tartaric acid derivative of the present invention can be obtained by the following synthesis reaction.
  • Tartaric acid or a derivative thereof is added to about 0.001 to 10% by weight, more preferably about 1 to 3% by weight with respect to 100% by weight of the organic solvent, and a condensing agent such as 1-ethyl 3- (3- Dimethylaminopropyl) carbodiimide (EDC) or dicyclohexylcarbodiimide (DCC) is added in an amount of about 0.001 to 20% by weight, more preferably about 5 to 15% by weight, based on 100% by weight of the solvent.
  • a condensing agent such as 1-ethyl 3- (3- Dimethylaminopropyl) carbodiimide (EDC) or dicyclohexylcarbodiimide (DCC)
  • reaction temperature 0 to: L00 ° C., more preferably 10 to 30 ° C., reaction time 1 to 48 hours, more preferably 1 to 3 hours.
  • the acid derivative and reaction by-product DCC urea precipitate is added in an amount of about 0.001 to about LO weight%, more preferably about 3 to 8 weight% with respect to 100 weight% of the solvent.
  • reaction temperature 0 to: L00 ° C., more preferably 10 to 30 ° C., reaction time 1 to 48 hours, more preferably 1 to 3 hours.
  • the tartaric acid derivative is isolated by filtering DCC urea as a reaction by-product through a glass filter. After the filtrate is distilled off under reduced pressure, the resulting residue is purified by washing with an organic solvent such as n-hexane and filtering.
  • Exceeding the above reaction conditions is inappropriate because the carboxyl group in tartaric acid cannot be modified with N-hydroxysuccinimide, which is an electron-absorbing I-group.
  • a water-soluble tartaric acid derivative represented by the following structural formula is obtained.
  • This water-soluble tartaric acid derivative is useful as a crosslinking agent, a curing agent for medical adhesives, and a fixing agent such as a pig valve (Carpentier-Edowards valve: CE valve).
  • the cross-linking reaction between the water-soluble tartaric acid derivative of the present invention and the biodegradable polymer has a concentration of the tartaric acid derivative of about 0.1 to 50% by weight of the biodegradable polymer in the solvent.
  • the reaction is carried out at about 01% to 50% by weight, preferably about 10 to 50 ° C.
  • Exceeding the above reaction conditions is unsuitable because the reaction rate becomes slow, the crosslinking density of the resulting crosslinked product becomes low, and a crosslinked product may not be obtained. It is preferable to dissolve the tartaric acid derivative in the above-mentioned solvent and mix them as a solution having an appropriate concentration so that the concentration is within the above-mentioned concentration range in order to cause a uniform reaction.
  • a dimethyl sulfoxide solution or a buffer solution having a combination force of one or more of hydrochloride, sulfate, nitrate, phosphate, carbonate and borate, or the buffer solution-dimethyl sulfoxide A mixed solution or the like can be used.
  • crosslinked product having a structure as shown in FIG. 1 is obtained.
  • This crosslinked product is a hyde mouth gel having a water content of about 80 to 99% by weight.
  • This crosslinked product can be used for medical adhesives, hemostatic agents, vascular embolization agents, aneurysm sealing agents, and the like.
  • the polymer crosslinked product produced as described above is applied to any one of a bioadhesive, a hemostatic agent, a vascular embolization agent, and an aneurysm sealant, the crosslinking reaction is directly performed on the affected part. .
  • a crosslinking reaction it is suitably used as an anti-adhesion agent, a scaffold material for tissue regeneration, and a drug carrier.
  • the cross-linking reaction between the water-soluble tartaric acid derivative of the present invention and the biodegradable polymer used in the biodegradable and absorbable adhesive medical material is performed by the concentration of the biodegradable polymer in the solvent of 0.1 to 50% by weight.
  • the concentration of the tartaric acid derivative is about 0.01% to 50% by weight, preferably 10%. React at about 50 ° C. If the reaction conditions are not met, the adhesion time becomes longer and the adhesion strength also becomes weaker. It is preferable that the tartaric acid derivative is also dissolved in the solvent and mixed as a solution having an appropriate concentration so that the concentration is within the above-mentioned concentration range in order to allow the two components to react uniformly.
  • Examples of the solvent include a dimethyl sulfoxide solution or a buffer solution having a combination force of one or more of hydrochloride, sulfate, nitrate, phosphate, carbonate and borate, or the buffer solution-dimethylsulfoxide.
  • a mixed solution or the like can be used.
  • the structure of the interface between the biological tissue and the adhesive obtained by the above reaction is such that the tartaric acid derivative undergoes a crosslinking reaction with the biopolymer in the biological tissue and the biodegradable polymer in the adhesive. Adhere by.
  • DCC Dicyclohexylcarbodiimide
  • THF tetrahydrofuran
  • succinimide was added to 100% by weight of the solvent, and the mixture was stirred for 1 hour, and then stirred at room temperature for 2 hours.
  • a mixed solution of DCC urea and a tartaric acid derivative was obtained.
  • TAD synthesized in Example 1 a polymer bridge of alkali-treated collagen (A 3 ⁇ 41) A bridge body was synthesized. 0. Dissolve TAD100 1 in 1M phosphate buffer solution (pH 7.0). 1 concentration 2.5 wZv% phosphate buffer solution (0.1 ⁇ , ⁇ ⁇ 7.0) was added in 4 ⁇ / ⁇ 1 and stirred. The final concentration of TAD was added to 20, 50, 100, and 150 mM. Thereafter, the mixture was allowed to stand at 37 ° C for 30 minutes, and the presence or absence of collagen cross-linked body formation was confirmed. The results are shown in Table 1.
  • TAD human serum albumin
  • a crosslinked polymer of human serum albumin (HSA) was synthesized.
  • 0.1. TAD 100 1 was dissolved in 1M phosphate buffer solution (pH 7.0), and added to phosphate buffer solution (0.1M, pH 7.0) 4OO ⁇ with HSA concentration of 45w Zv% and stirred.
  • the final concentration of TAD was 100, 150, 200 mM.
  • the mixture was allowed to stand at 37 ° C for 30 minutes, and the presence or absence of HSA crosslinked product formation was confirmed.
  • Table 2 From the results in Table 2, it was confirmed that 0.1M phosphate buffer solution, that is, gelation of biopolymers under aqueous solution conditions.
  • a biological tissue adhesive was prepared as follows. Albumin derived from human serum (A1653 manufactured by Sigma Aldrich Japan Co., Ltd.) was dissolved in 0.1 M sodium phosphate buffer (pH 7.0) to a concentration of 45% by weight. To this albumin solution 4001, 100 M / l of a 0.1 M phosphate buffer solution (pH 7.0) of TAD as a curing component was added and stirred for several seconds at 25 ° C. The TAD concentration with respect to the final volume (500 ul) was adjusted to lOOmM, 150mM, 200mM, and 250mM.
  • Collagen casing (made by Nitta Gelatin Co., Ltd., composition: collagen 44%, cellulose 18%, glycerin 15%, vegetable oil 3%, carboxymethylcellulose 2%) as an adherend for measuring the adhesive strength to living tissue Used to measure the adhesive strength. Apply 50 folds of the mixed solution before hardening to a 10 mm x 10 mm area of a collagen casing (width 10 mm x length 25 mm), and place an equal-sized collagen casing on the bonding surface. Superimposed. Further, a 50 g weight was placed on the adhesive surface and allowed to stand at 37 ° C for 1 hour. The adhesive strength was measured with a tensile tester (TA-XT2i manufactured by Eihiro Seiki Co., Ltd.). Measurement conditions were 25 ° C and a measurement speed of 2 mm / s. The results are shown in Table 3. From the results in Table 3, it was confirmed that the adhesive strength became stronger depending on the TAD concentration.
  • TAD concentration a tensile tester
  • the water-soluble tartaric acid derivative of the present invention is useful as a cross-linking agent for medical materials such as bioadhesives, hemostatic agents, vascular embolic agents, and aneurysm sealants.
  • medical materials such as bioadhesives, hemostatic agents, vascular embolic agents, and aneurysm sealants.
  • a biodegradable polymer once used after cross-linking reaction with a biodegradable polymer, it can also be used as an anti-adhesive agent, a scaffold material for tissue regeneration, and a drug carrier.
  • FIG. 1 is a schematic view showing the structure of a crosslinked product of the present invention.
  • FIG. 2 is a schematic diagram showing a structure of an interface between a biological tissue and an adhesive when the biological tissue adhesive of the present invention is used.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Biological Depolymerization Polymers (AREA)
  • Pyrrole Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Étant donné qu'elles ne sont pas des substances naturelles mais synthétisées artificiellement, les adhésifs à usage biologique et les agents réticulés et des agents de condensation qui ont été employés dans le traitement des dispositifs médicaux comme des valves cardiaques démontrent une toxicité sans être métabolisés in vivo. Pour les dissoudre, il faut avoir recours aux solvants organiques. Il est donc devenu nécessaire de développer un agent de réticulation soluble dans l'eau qui possède une grande biocompatibilité. Un dérivé de l'acide tartarique soluble dans l'eau obtenu en modifiant un groupement carboxylique de l'acide tartarique et son dérivé contenant un groupement hydroxyle dans la molécule avec un groupement accepteur d'électron tel que le succinimidyle, le sulfosuccinimidyle, le maléimidyle, le phthalimidyle, l'imidazolyle, le nitrophényle ou le trésyle ou une combinaison de deux ou plus de ceux-ci, et une matière réticulée de haut poids moléculaire obtenue en utilisant ce dérivé de l'acide tartarique.
PCT/JP2005/014636 2004-08-10 2005-08-10 Dérivé de l'acide tartarique et matière réticulée de haut poids moléculaire synthétisée en utilisant ce dérivé WO2006016600A1 (fr)

Priority Applications (1)

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JP2006531678A JPWO2006016600A1 (ja) 2004-08-10 2005-08-10 酒石酸誘導体及び該誘導体により合成された高分子架橋体

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JP2004-233869 2004-08-10
JP2004233869 2004-08-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009060621A1 (fr) * 2007-11-08 2009-05-14 Fujifilm Corporation Composition médicale pour prévenir une adhérence post-chirurgicale
WO2012077776A1 (fr) * 2010-12-09 2012-06-14 東レ株式会社 Particules biodégradables, matière d'occlusion vasculaire et procédé de production de particules biodégradables
CN103442742A (zh) * 2011-03-30 2013-12-11 东丽株式会社 生物降解性粒子、血管栓塞材料及生物降解性粒子的制造方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4101380A (en) * 1975-06-12 1978-07-18 Research Products Rehovot Ltd. Process for the cross-linking of proteins
JPH02180903A (ja) * 1988-12-29 1990-07-13 Nippon Oil & Fats Co Ltd 架橋キトサン
JP2004099562A (ja) * 2002-09-11 2004-04-02 National Institute For Materials Science 生体低分子誘導体
JP2004261222A (ja) * 2003-02-13 2004-09-24 National Institute For Materials Science 生体内分解吸収性粘着性医用材料
JP2005168949A (ja) * 2003-12-15 2005-06-30 National Institute For Materials Science 生体内分解吸収性粘着性医用材料

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4101380A (en) * 1975-06-12 1978-07-18 Research Products Rehovot Ltd. Process for the cross-linking of proteins
JPH02180903A (ja) * 1988-12-29 1990-07-13 Nippon Oil & Fats Co Ltd 架橋キトサン
JP2004099562A (ja) * 2002-09-11 2004-04-02 National Institute For Materials Science 生体低分子誘導体
JP2004261222A (ja) * 2003-02-13 2004-09-24 National Institute For Materials Science 生体内分解吸収性粘着性医用材料
JP2005168949A (ja) * 2003-12-15 2005-06-30 National Institute For Materials Science 生体内分解吸収性粘着性医用材料

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009060621A1 (fr) * 2007-11-08 2009-05-14 Fujifilm Corporation Composition médicale pour prévenir une adhérence post-chirurgicale
WO2012077776A1 (fr) * 2010-12-09 2012-06-14 東レ株式会社 Particules biodégradables, matière d'occlusion vasculaire et procédé de production de particules biodégradables
US9353217B2 (en) 2010-12-09 2016-05-31 Toray Industries, Inc. Biodegradable particles, vascular occlusion material, and method for producing biodegradable particles
CN103442742A (zh) * 2011-03-30 2013-12-11 东丽株式会社 生物降解性粒子、血管栓塞材料及生物降解性粒子的制造方法

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