WO2017094691A1 - リン酸残基を有するニトロキシラジカル含有共重合体及びその使用 - Google Patents
リン酸残基を有するニトロキシラジカル含有共重合体及びその使用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
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- 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
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
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- 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
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/064—Use of macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
- C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
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- C08F8/00—Chemical modification by after-treatment
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
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- C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
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- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
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- C08L25/00—Compositions of, homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Compositions of derivatives of such polymers
- C08L25/18—Homopolymers or copolymers of aromatic monomers containing elements other than carbon and hydrogen
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D125/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Coating compositions based on derivatives of such polymers
- C09D125/02—Homopolymers or copolymers of hydrocarbons
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- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D153/00—Coating compositions based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
- C09D153/005—Modified block copolymers
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- C09D171/00—Coating compositions based on polyethers obtained by reactions forming an ether link in the main chain; Coating compositions based on derivatives of such polymers
- C09D171/02—Polyalkylene oxides
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- C08F12/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
- C08F12/02—Monomers containing only one unsaturated aliphatic radical
- C08F12/04—Monomers containing only one unsaturated aliphatic radical containing one ring
- C08F12/14—Monomers containing only one unsaturated aliphatic radical containing one ring substituted by hetero atoms or groups containing heteroatoms
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- C08F2438/00—Living radical polymerisation
- C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
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- C08L2203/16—Applications used for films
Definitions
- the present invention relates to a nitroxy radical-containing copolymer having a phosphate residue, and more specifically, a poly (ethylene glycol) segment (hereinafter sometimes abbreviated as PEG), and a phosphate residue and a cyclic nitroxide radical.
- PEG poly (ethylene glycol) segment
- the copolymer comprising a segment.
- the present invention relates to the use of the copolymer for modifying the metal surface, specifically for making the metal material into a biocompatible material such as an antithrombotic material.
- Metal materials are now widely used in the medical field. For example, stainless steel is used for the stent, and titanium particles are used for the joint portion of the artificial heart. These metal materials have high mechanical strength and are easy to use, but have the great disadvantage that when they come into contact with blood, the blood is activated and blood clots are generated. Therefore, serious side effects such as cerebral infarction may occur.
- the development of medical technologies that process the surface of these metal materials, suppress the coagulation reaction that occurs when the blood is activated, and impart antithrombotic properties has been studied in various ways. Solution has not been reached.
- the present inventors have focused on the fact that active oxygen has played an important role in the activation of blood so far, and applied a polymer having a nitroxy radical that eliminates active oxygen to the living body to treat various inflammations.
- Patent document 1 and also reported that the biocompatibility of the surface in contact with the substance derived from the living body can be modified by the polymer
- Patent document 2 the present inventors have found and reported that activation of blood is suppressed when a similar polymer is coated on polystyrene beads (Non-patent Document 1).
- the present inventors have also developed a technique for coating a metal surface using a polymer having a phosphate residue (Non-patent Document 2).
- a certain cyclic nitroxide radical in a repeating unit in the latter segment is randomly changed to a phosphate residue (-PO ( It has been found that a copolymer having a form replaced with —OH) 2 ) can be used as a surface modifier capable of solving the above-mentioned problems.
- A represents a hydrogen atom, unsubstituted or substituted C 1 -C 12 alkyl, and when substituted, the substituent represents a formyl group, a formula R 1 R 2 CH— group, where R 1 and R 2 is independently C 1 -C 4 alkoxy or R 1 and R 2 are -OCH 2 CH 2 O together -, - O (CH 2) 3 O- or -O (CH 2) 4 O- and Represent, L is a bond or an expression
- X 1 is a compound covalently bonded via — (CH 2 ) a —NH— (CH 2 ) a — or — (CH 2 ) a —O— (CH 2 ) a —.
- X 2 represents PO (—OH) 2
- Y represents H, SH or S—C ( ⁇ S) —Ph
- Ph represents phenyl optionally substituted by 1 or 2 methyl or methoxy
- a is each independently an integer of 0 to 5
- b is an integer from 2 to 6
- c is an integer from 1 to 5
- m is an integer from 2 to 10,000
- n is an integer from 1 to 360
- k is an integer from 1 to 480,
- Up to 50% of n X 1 preferably up to 20%, more preferably up to 10%, or up to 50%, preferably up to 20%, more preferably 10 out of k X 2.
- % Can each be H, halogen or hydroxy, but most preferably X 1 and X 2 are 100% as defined above and Each unit in the n corresponding repeating units and each unit in the k corresponding repeating units exist at random.
- n + k is an integer of 5 to 600
- n / n + k is 0.2 to 0.8, preferably 0.4 to 0.7
- k / n + k is 0. .2 to 0.8, preferably 0.4 to 0.6
- the n and k repeating units are each 100% radicals as defined in principle for X 1 and X 2 above
- a metal material surface carrying the copolymer is provided.
- an apparatus for holding a coating film derived from the copolymer on the surface wherein the surface is a stent, an artificial auxiliary heart, an artificial joint, a cell culture device, a cell analysis device, and a cell separation.
- Devices are provided that are selected from the metal material surfaces of the devices or their parts.
- the copolymer according to the present invention is particularly stably held as a film on the surface of a metal material of a product that comes into direct or indirect contact with human body fluids, tissues or organs, and suppresses, for example, blood activation. Therefore, for example, it has a function of imparting biocompatibility to the metal material surface of a stent, an artificial auxiliary heart, an artificial joint, a cell culture device, a cell analysis device, a cell separation device, or a component thereof.
- the C 1 -C 12 alkyl referred to in the present invention is an alkyl having 1 to 12 carbon atoms which may be linear or branched, and is not limited thereto. Methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl and the like.
- the linking group L is bonded with the stated orientation unless otherwise defined.
- a repeating unit in which a carbon atom of a methylene group is bonded to an oxygen atom of ethyleneoxy and a sulfur atom has X 1 as n pendant groups
- each unit in the n corresponding repeating units and each unit in the k corresponding repeating units exist at random.
- n corresponding repeating units or at least one unit of k corresponding repeating units is combined with L, and each unit in the other repeating units is One or more of each unit bonded to L can be bonded at random.
- Reference to a bond in the context of the present invention means a covalent bond unless otherwise defined.
- Such a linking group L is preferably paraxylylene or metaxylylene in consideration of the production advantages and stability of the copolymer.
- X 2 is a phosphate residue (—PO (—OH) 2 ). It is assumed that the copolymer represented by the formula (I) is fixed to the surface of the metal material via these phosphate residues.
- Y is H, SH or S—C ( ⁇ S) —Ph, where Ph is phenyl optionally substituted by 1 or 2 methyl or methoxy, but Ph may be unsubstituted preferable.
- n and k are preferably plural, more preferably 4 and 3 or more, respectively.
- n + k is an integer of 5 to 600, preferably 10 to 500, more preferably 20 to 300
- n / n + k is 0.2 to 0.8
- k / n + k is 0.2.
- 0.8 more preferably n / n + k is 0.4 to 0.7
- k / n + k is 0.4 to 0.6
- it is preferred that 100% of each group is the group defined for X 1 and X 2 above (that is, other than H, halogen and hydroxy as defined herein).
- n is preferably at least 6, preferably at least 8, in order to impart high affinity for metals while maintaining the ability to suppress blood activation, which is the intended purpose of the present invention.
- k is at least 3, preferably at least 6, more preferably at least 8.
- M is not limited in terms of a theoretically optimal range, but can generally be an integer of 2 to 10,000, preferably 20 to 5,000, more preferably 20 to 3,000.
- the copolymer of the formula (I) is not limited, but the following formula (P)
- X is halogen (chloro, bromo, iodo)
- q corresponds to the integer of n + k
- the X group can be prepared by a process for converting the X 1 and X 2 groups in the precursor block copolymer represented.
- a part of the block copolymer represented by the formula (P) is described in Patent Document 1, or can be manufactured by the manufacturing method described, or can be manufactured based on the manufacturing examples described later.
- the order of conversion of the X 1 and X 2 groups does not matter, but the conversion to the X 2 group precedes the desired proportion of phosphate residues.
- a copolymer is preferable because it can be easily provided.
- a metal material is not limited as long as the objective of this invention is met, Preferably, it can be a medical product, the product used for various other tests and research, or material for components.
- a medical product means a product used in a medical practice such as diagnosis, examination, treatment, etc., or a product or a member or part thereof used in a test or research premised on use in such an act. It may be used either in vitro or in vivo.
- products that come into direct or indirect contact with human body fluids, tissues or organs examples include, but are not limited to, stents, artificial auxiliary hearts, artificial joints, cell culture devices, cell separation devices, cell analysis devices, and the like.
- those whose contact surface is a metal such as stainless steel, titanium, titanium alloy, etc., are intended as main application objects.
- Such a method of supporting or holding the copolymer on the surface can be carried out by preparing a copolymer solution and coating itself by a known coating method. According to the present invention, by removing a solvent and drying a coated or coated film coated by any method, it can be fixed on a metal surface with a certain peeling resistance, and can be supported or held. Thus, on the surface of the metal material carrying or holding the copolymer according to the present invention, the coating film derived from the copolymer is stably fixed to the surface, and the coating film has a metal surface that is biologically or biocompatible. Make it sex.
- Production Example 1 Synthesis of PEG-Cl (2) PEG-OH (1) (50 g, molecular weight 5000, 0.01 mol) was added to a 500 ml eggplant flask and dried under reduced pressure at 110 ° C. for 24 hours. After cooling to 65 ° C., distilled tetrahydrofuran (THF) solvent (200 ml), n-butyllithium (16 mmol, 10 ml), ⁇ , ⁇ -dichloro-p-xylene (DCPX) (25 g, 0.14 mol) while purging with nitrogen And stirred at 65 ° C. for 48 hours. After the reaction, reprecipitation was performed with 2-propanol (IPA) cooled in a freezer.
- THF tetrahydrofuran
- DCPX ⁇ , ⁇ -dichloro-p-xylene
- Production Example 3 Synthesis of PEG-b-PCMS (4) (13-18) To a 100 ml eggplant flask, the compound (3) obtained in Production Example 2 (4 g, 0.8 mmol) and azobisisobutyronitrile (24 mg, 0.14 mmol) were added, and a three-way stopcock was attached. Distilled toluene (40 ml) and p-chloromethylstyrene (16.4 ml, 0.12 mol) were added while purging with nitrogen, and a polymerization reaction was carried out at 60 ° C. for 24 hours. After the reaction, reprecipitation was performed with 600 ml of diethyl ether. The product was separated by suction filtration and the filtrate was discarded.
- Production Example 4 Synthesis of PEG-b-PCMS-r-PDEVBPBP (5) (13-18)
- the compound (4) (1.1 g, 0.1 mmol) obtained in Production Example 3 was added to a 100 ml eggplant flask, a three-way stopcock was attached, and 10 ml of distilled THF solvent was added to the eggplant flask. 55% sodium hydride (144 mg, 3.3 mmol) and a small amount of sodium iodide were added to the other 100 ml eggplant flask, and a three-way stopcock was attached. While purging with nitrogen, 16 ml of distilled THF solvent was added, followed by diethyl phosphite (0.43 ml, 3.3 mmol).
- this solution was added dropwise to Compound 4 in an ice bath and allowed to react at room temperature for 15 hours. After the reaction, the solvent was removed with an evaporator. The product was dissolved in methanol and purified by dialysis with methanol using a MWCO3500 dialysis membrane for 48 hours. After dialysis, the solvent was removed with an evaporator. The product was dissolved in 5 ml of benzene and lyophilized. After lyophilization, the title compound (5) was obtained in 96% yield.
- Production Example 5 Synthesis of PEG-b-PCMS-r-PVBP (6) (13-18) To a 100 ml two-necked eggplant flask, the compound (5) obtained in Production Example 4 (1 g, 0.08 mmol) was added, and a three-way stopcock and a reflux tube were attached. Dichloromethane (12 ml) and trimethylsilyl bromide (1.07 ml, 8.2 mmol) were added while purging with nitrogen, and reacted at 45 ° C. for 3 hours while refluxing. After the reaction, the solvent was removed with an evaporator. The reactant was dissolved in excess methanol and reacted at room temperature for 24 hours. After the reaction, the solvent was removed with an evaporator.
- the reaction product was dissolved in methanol and purified by dialysis with methanol using a MWCO3500 dialysis membrane for 48 hours. After dialysis, the solvent was removed with an evaporator. The reaction product was dissolved in 5 ml of benzene and freeze-dried. After lyophilization, the title compound (6) was obtained in 93% yield.
- Production Example 6 Synthesis of PEG-b-PMNT-r-PVBP (7) (13-18)
- the compound (6) obtained in Production Example 5 (490 mg, 0.04 mmol) was added to a 50 ml eggplant flask, a three-way stopcock was attached, and 5 ml of dimethyl sulfoxide was added.
- 4-amino-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (4-aminoTEMPO) (445 mg, 2.6 mmol) was added to the other 50 ml eggplant flask, and a three-way stopcock was attached. While replacing, 5 ml of dimethyl sulfoxide was added.
- a 4-aminoTEMPO solution was added dropwise to Compound 6 and reacted at room temperature for 24 hours. After the reaction, purification was performed by performing methanol dialysis for 48 hours using a MWCO3500 dialysis membrane. After purification, the solvent was removed with an evaporator. The product was dissolved in benzene and lyophilized. After lyophilization, the title compound (7) was obtained in 98% yield. From the results of 1 HNMR and electron spin resonance (ESR) measurement, the number of 4-aminoTEMPO-ized units and phosphorylated units (corresponding to n and k in the above formula) in compound 7 were 13 and 18, respectively.
- ESR electron spin resonance
- Production Example 7 Synthesis of PEG-b-PCMS (4) (12-6)
- the compound (3) (4.5 g) obtained in Production Example 2 and azobisisobutyronitrile (40 mg) were added to a 100 ml eggplant flask, and a three-way stopcock was attached.
- Distilled toluene (100 ml) and p-chloromethylstyrene (10 ml) were added while purging with nitrogen, and a polymerization reaction was carried out at 60 ° C. for 24 hours. After the reaction, reprecipitation was performed with 600 ml of diethyl ether.
- the product was separated by suction filtration and the filtrate was discarded.
- the product was dissolved in acetone and reprecipitated again with isopropanol and then ethyl ether. After lyophilization, the title compound (4) (6.25 g) was obtained.
- Production Example 8 Synthesis of PEG-b-PCMS-r-PDEVBPBP (5) (12-6) Compound (4) (830 mg) obtained in Production Example 7 was added to a 100 ml eggplant flask, a three-way stopcock was attached, and distilled THF was added. 8 ml of the solvent was added to the eggplant flask. 55% sodium hydride (43 mg) and a small amount of sodium iodide were added to the other 100 ml eggplant flask, and a three-way stopcock was attached. While purging with nitrogen, 3 ml of distilled THF solvent was added, followed by diethyl phosphite (0.13 ml).
- this solution was added dropwise to Compound 4 in an ice bath and allowed to react at room temperature for 15 hours. After the reaction, the solvent was removed with an evaporator. The product was dissolved in methanol and purified by dialysis with methanol using a MWCO3500 dialysis membrane for 48 hours. After dialysis, the solvent was removed with an evaporator. The product was dissolved in 5 ml of benzene and lyophilized. After lyophilization, the title compound (5) was obtained in 86% yield.
- Production Example 9 Synthesis of PEG-b-PCMS-r-PVBP (6) (12-6)
- the compound (5) (0.086 mmol) obtained in Production Example 8 was added to a 100 ml two-necked eggplant flask, and a three-way stopcock and a reflux tube were attached.
- Dichloromethane (10 ml) and trimethylsilyl bromide (300 ⁇ l, 2.3 mmol) were added while purging with nitrogen, and the mixture was reacted at 45 ° C. for 3 hours while refluxing.
- the solvent was removed with an evaporator.
- the reactant was dissolved in excess methanol and reacted at room temperature for 24 hours. After the reaction, the solvent was removed with an evaporator.
- the reaction product was dissolved in methanol and purified by dialysis with methanol using a MWCO3500 dialysis membrane for 48 hours. After dialysis, the solvent was removed with an evaporator. The reaction product was dissolved in 5 ml of benzene and freeze-dried. After lyophilization, the title compound (6) was obtained in 65% yield.
- Production Example 10 Synthesis of PEG-b-PMNT-r-PVBP (7) (12-6)
- the compound (6) (500 mg) obtained in Production Example 9 was added to a 50 ml eggplant flask, a three-way stopcock was attached, and 5 ml of dimethyl sulfoxide was added.
- 4-amino-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (4-aminoTEMPO) (616 mg) was added to the other 50 ml eggplant flask, and a three-way stopcock was attached. 5 ml of dimethyl sulfoxide was added.
- a 4-aminoTEMPO solution was added dropwise to Compound 6 and reacted at room temperature for 24 hours.
- Production Example 11 Synthesis of PEG-b-PCMS (4) (41-23)
- the compound (3) (4.5 g) obtained in Production Example 2 and azobisisobutyronitrile (40 mg) were added to a 100 ml eggplant flask, and a three-way stopcock was attached.
- Distilled toluene (100 ml) and p-chloromethylstyrene (25 ml) were added while purging with nitrogen, and a polymerization reaction was carried out at 60 ° C. for 24 hours. After the reaction, reprecipitation was performed with 600 ml of diethyl ether.
- the product was separated by suction filtration and the filtrate was discarded.
- the product was dissolved in acetone and reprecipitated again with isopropanol and then ethyl ether. After lyophilization, the title compound (4) was obtained in 20% yield.
- Production Example 12 Synthesis of PEG-b-PCMS-r-PDEVBPBP (5) (41-23) To a 100 ml eggplant flask, the compound (4) (710 mg) obtained in Production Example 11 was added, and a three-way cock was attached, and distilled THF was added. 10 ml of the solvent was added to the eggplant flask. To the other 100 ml eggplant flask, 55% sodium hydride (144 mg) and a small amount of sodium iodide were added, and a three-way stopcock was attached. While purging with nitrogen, 16 ml of distilled THF solvent was added, followed by diethyl phosphite (0.43 ml).
- this solution was added dropwise to the compound (4) in an ice bath and allowed to react at room temperature for 15 hours. After the reaction, the solvent was removed with an evaporator. The product was dissolved in methanol and purified by dialysis with methanol using a MWCO3500 dialysis membrane for 48 hours. After dialysis, the solvent was removed with an evaporator. The product was dissolved in 5 ml of benzene and lyophilized. After lyophilization, the title compound (5) was obtained in 98% yield.
- Production Example 13 Synthesis of PEG-b-PCMS-r-PVBP (6) (41-23)
- the compound (5) (0.042 mmol) obtained in Production Example 12 was added to a 100 ml two-necked eggplant flask, and a three-way stopcock and a reflux tube were attached.
- Dichloromethane (5 ml) and trimethylsilyl bromide (650 ⁇ l, 5.1 mmol) were added while purging with nitrogen, and reacted at 45 ° C. for 3 hours while refluxing. After the reaction, the solvent was removed with an evaporator.
- the reactant was dissolved in excess methanol and reacted at room temperature for 24 hours. After the reaction, the solvent was removed with an evaporator.
- the reaction product was dissolved in methanol and purified by dialysis with methanol using a MWCO3500 dialysis membrane for 48 hours. After dialysis, the solvent was removed with an evaporator. The reaction product was dissolved in 5 ml of benzene and freeze-dried. After lyophilization, the title compound (6) was obtained in 90% yield.
- Production Example 14 Synthesis of PEG-b-PMNT-r-PVBP (7) (41-23)
- the compound (6) (0.02 mmol) obtained in Production Example 13 was added to a 50 ml eggplant flask, a three-way stopcock was attached, and 5 ml of dimethyl sulfoxide was added.
- 4-amino-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (4-aminoTEMPO) 4 g
- the 4-aminoTEMPO solution was added dropwise to the compound (6) and reacted at room temperature for 24 hours.
- SUS430 stainless steel having a thickness of 1 mm was cut into 1 cm square, and ultrasonically washed with distilled water, methanol, and acetone for 15 minutes. After cleaning, the surface was cleaned and hydroxylated by immersing
- the stainless steel surface was fixed by infiltrating overnight with 2% glutaraldehyde, and finally dehydrated with ethanol (50%, 70%, 100%) and dried by nitrogen flow to prepare the SEM sample. went.
- the sample was previously sputtered with a sputtering apparatus (JEOL JFC-1600 auto fine coater). As a result, adhesion of blood clots and blood components was observed on the stainless steel surface before the polymer coating.
- Example 2 and 3 Coating In Example 1 (1), instead of compound (7) (13-18), compound (7) (12-6) obtained in Production Example 10 or obtained in Production Example 14 The compound (7) (41-23) was used for coating under the conditions described therein, and then elemental analysis (C / Cr) by XPS was performed on each coating surface as described in (2). It was. The result is shown in FIG. From the figure, it can be confirmed that the copolymer according to the present invention is stably supported or held on the stainless steel surface in a wide range of phosphorylated units (k).
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Abstract
Description
Aは、水素原子、非置換または置換C1-C12アルキルを表し、置換されている場合の置換基は、ホルミル基、式R1R2CH-基を表し、ここで、R1およびR2は独立してC1-C4アルコキシまたはR1とR2は一緒になって-OCH2CH2O-、-O(CH2)3O-もしくは-O(CH2)4O-を表し、
Lは、結合であるか、あるいは式
X1は-(CH2)a-NH-(CH2)a-または-(CH2)a-O-(CH2)a-を介して共有結合した式
X2はPO(-OH)2を表し、
YはH、SHまたはS-C(=S)-Phを表し、Phは1または2個のメチルまたはメトキシで置換されていてもよいフェニルを表し、
aは、各独立して0~5の整数であり、
bは2~6の整数であり、
cは1~5の整数であり、
mは2~10,000の整数であり、
nは1~360の整数であり、
kは1~480の整数であり、
但し、
n個のX1の中の50%まで、好ましくは20%まで、よりこのましくは10%まで、またはk個のX2の中の50%まで、好ましくは20%まで、より好ましくは10%まで、がそれぞれ、H、ハロゲンまたはヒドロキシであることができるが、最も好ましくはX1及びX2は100%上記の定義のとおりでありかつ、
n個の該当する反復単位中の各単位とk個の該当する反復単位中の各単位は、それぞれランダムに存在する。
別の態様の本発明として、前記共重合体を担持する金属材料表面が提供される。
さらに別の態様の本発明として、前記共重合体に由来する塗膜を表面に保持する装置であって、前記表面がステント、人工補助心臓、人工関節、細胞培養装置、細胞解析装置および細胞分離装置またはそれらの部品の金属材料表面から選ばれる、装置が提供される。
本発明に関していうC1-C12アルキルは、直鎖または分岐していてもよい炭素原子1~12のアルキルであって、限定するものでないが、メチル、エチル、プロピル、イソプロピル、n-ブチル、tert-ブチル、ヘキシル、ヘプチル、オクチル、ノニル、ウンデシル、ドデシル等を含む。
本発明に関して結合という場合、別に定義しない限り、共有結合を意味する。かような連結基Lは、前記共重合体の製造上の利点および安定性等を考慮すると、パラキシリレンまたはメタキシリレンであることが好ましい。
A、L、Y、mは上記の定義と同義であり、Xはハロゲン(クロロ、ブロモ、ヨード)であり、qは上記n+kの整数に相当する、
で表される前駆ブロック共重合体からX基をX1およびX2基に転化する方法によって製造できる。
金属材料は本発明の目的に沿う限り限定されるものでないが、好ましくは、医療用製品、その他の各種試験、研究に用いられる製品または部品用材料であることができる。たとえば、医療用製品とは、診断、検査、治療等の医療行為で用いる製品またはかような行為に使用することを前提とした試験もしくは研究で用いる製品またはそれらの部材もしくは部品を意味し、in vitroまたはin vivoのいずれで用いられるものであってもよい。特に、ヒトの体液、組織または器官と直接もしくは間接的に接触する製品を挙げることができる。このような製品としては、限定されるものでないが、ステント、人工補助心臓、人工関節、細胞培養装置、細胞分離装置、細胞解析装置等を挙げることができる。これらの製品および部品の中、前記接触する表面が金属、例えば、ステンレス、チタン、チタン合金、等であるものを主たる適用対象として意図している。
こうして、本発明に従う共重合体を担持または保持した金属材料表面は、前記共重合体に由来する塗膜が安定に前記表面に固定されており、当該塗膜は、金属表面を生物または生体適合性にする。
500mlナスフラスコにPEG-OH(1)(50g,分子量5000,0.01mol)を加え、110℃の減圧下で24時間乾燥させた。65℃まで冷却した後、窒素置換しながら蒸留テトラヒドロフラン(THF)溶媒(200ml)、n-ブチルリチウム(16mmol,10ml)、α,α-ジクロロ-p-キシレン(DCPX)(25g,0.14mol)を加え、65℃で48時間撹拌した。反応後、冷凍庫で冷やした2-プロパノール(IPA)により再沈殿を行った。遠心分離により反応物を分離させ、上澄み液を除いた。反応物をメタノールに溶かし、再び再沈殿を行った。再沈殿は9回行った。9回目の遠心分離及び上澄み液の除去の後、反応物をデシケータ内で36時間減圧乾燥を行った。減圧乾燥後、標題の化合物(2)を収率80%で得た。
1HNMR(CDCl3,400MHz)
7.35-7.34ppm(q,4H),4.58ppm(s,2H),4.56ppm(s,2H),3.83-3.45ppm(s,474H),3.38ppm(s,3H)
500mlナスフラスコに前記化合物(2)(40g,0.08mol)を加え、110℃の減圧下で一晩乾燥させた。また、もう一方で100mlナスフラスコに窒素置換しながら蒸留THF溶媒(50ml)、二硫化炭素(4ml,0.07mol)、フェニルマグネシウムブロミド(6.7ml,3M,0.02mol)を氷浴下で加え、20分間撹拌させた。そのまま室温で2時間反応させることでグリニャール試薬を調製した。化合物2を40℃まで冷却した後、窒素置換しながら蒸留THF溶媒(200ml)、グリニャール試薬を加え、40℃で48時間反応させた。反応後、冷凍庫で冷やした2-プロパノール(IPA)により再沈殿を行った。遠心分離により反応物を分離させ、上澄み液を除いた。反応物をメタノールに溶かし、再び再沈殿を行った。再沈殿は5回行った。5回目の遠心分離及び上澄み液の除去の後、反応物をデシケータ内で36時間減圧乾燥を行った。減圧乾燥後、標題の化合物(3)を収率95%で得た。
1HNMR(CDCl3,400MHz)
8.00ppm(d,1H),7.98ppm(d,1H),7.54-7.50ppm(t,1H),7.40-7.30ppm(m,6H),4.58ppm(s,2H),4.55ppm(s,2H),3.83-3.45ppm(s,500H),3.38ppm(s,3H)
GPC Mw:5213 Mw/Mn=1.21
100mlナスフラスコに製造例2で得られる化合物(3)(4g,0.8mmol)、アゾビスイソブチロニトリル(24mg,0.14mmol)を加え、三方活栓を取り付けた。窒素置換しながら蒸留トルエン(40ml)、p-クロロメチルスチレン(16.4ml,0.12mol)を加え、60℃で24時間重合反応させた。反応後、ジエチルエーテル600mlで再沈殿を行った。吸引濾過により生成物を分離させ、濾液を捨てた。生成物をアセトンに溶かし、再び再沈殿を行った。再沈殿は3回行った。3回目の濾過の後、ベンゼン15mlに反応物を溶解させ、凍結乾燥を行った。凍結乾燥後、標題の化合物(4)を収率78%で得た。1HNMR(CDCl3,400MHz)
7.24-6.16ppm(m,152H),4.67-4.27ppm(m,74H),3.83-3.45ppm(s,470H),3.38ppm(s,3H),2.40-1.06ppm(m,126H)
GPC Mw=12465 Mw/Mn=1.35
100mlナスフラスコに製造例3で得られる化合物(4)(1.1g,0.1mmol)を加え、三方活栓を取り付け、蒸留THF溶媒をナスフラスコに10ml加えた。もう一方の100mlナスフラスコに55%水素化ナトリウム(144mg,3.3mmol)、少量のヨウ化ナトリウムを加え、三方活栓を取り付けた。窒素置換しながら、蒸留THF溶媒を16ml加え、続いて亜リン酸ジエチル(0.43ml,3.3mmol)を加えた。さらに、この溶液を化合物4に氷浴下で滴下し、室温で15時間反応させた。反応後、エバポレーターにて溶媒を除去した。生成物をメタノールに溶解させ、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。透析後、エバポレーターにて溶媒を除去した。生成物をベンゼン5mlに溶解させ凍結乾燥を行った。凍結乾燥後、標題の化合物(5)を収率96%で得た。
1HNMR(CDCl3,400MHz)
7.24-6.16ppm(m,137H),4.67-4.24ppm(m,26H), 4.21-3.79ppm(m,80H),3.78-3.45ppm(s,423H), 3.38ppm(s,3H),3.23-2.86ppm(s,36H),2.37-0.94ppm(m,232H)
31PNMR(MeOD,600MHz,standard:85% phosphoric acid)26.84ppm
100mlの2口ナスフラスコに製造例4で得られる化合物(5)(1g,0.08mmol)加え、三方活栓と還流管を取り付けた。窒素置換しながらジクロロメタン(12ml)、トリメチルシリルブロミド(1.07ml,8.2mmol)を加え、還流させながら45℃で3時間反応させた。反応後、エバポレーターで溶媒を除去した。過剰のメタノールに反応物を溶解させ、室温で24時間反応させた。反応後、エバポレーターで溶媒を除去した。反応物をメタノールに溶解させ、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。透析後、エバポレーターにて溶媒を除去した。反応物をベンゼン5mlに溶解させ凍結乾燥を行った。凍結乾燥後、標題の化合物(6)を収率93%で得た。
1HNMR(D2O,400MHz)
7.52-5.63ppm(br,160H),4.52p-4.01ppm(br, 22H),3.73-3.27ppm(m,594H),3.83-3.20ppm(s,3H),2.90-2.34ppm(br,36H),2.26-0.54ppm(br,104H)
31PNMR(MeOD,600MHz,standard:85% phosphoric acid)23.99ppm
50mlナスフラスコに製造例5で得られる化合物(6)(490mg,0.04mmol)を加え、三方活栓を取り付け、ジメチルスルホキシドを5ml加えた。また、もう一方の50mlナスフラスコに4-アミノ-2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル(4-aminoTEMPO)(445mg,2.6mmol)を加え、三方活栓を取り付け、窒素置換しながら、ジメチルスルホキシドを5ml加えた。4-aminoTEMPO溶液を化合物6に滴下し、室温で24時間反応させた。反応後、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。精製後、エバポレーターで溶媒を除去した。生成物をベンゼンに溶解させ、凍結乾燥を行った。凍結乾燥後、標題の化合物(7)を収率98%で得た。
1HNMR及び電子スピン共鳴(ESR)測定結果より化合物7における、4-aminoTEMPO化単位とリン酸化単位の数(上式中のn及びkに該当する)はそれぞれ13及び18であった。
1HNMR(D2O,phenylhydrazine,400MHz)
3.69-3.23ppm(m,530H),3.18ppm(s,3H),2.99-2.40ppm(br,34H),1.78-1.59ppm(s,37H),1.09-0.86ppm(s,114H)
100mlナスフラスコに製造例2で得られる化合物(3)(4.5g)、アゾビスイソブチロニトリル(40mg)を加え、三方活栓を取り付けた。窒素置換しながら蒸留トルエン(100ml)、p-クロロメチルスチレン(10ml)を加え、60℃で24時間重合反応させた。反応後、ジエチルエーテル600mlで再沈殿を行った。吸引濾過により生成物を分離させ、濾液を捨てた。生成物をアセトンに溶かし、再びイソプロパノール及び次エチルエーテルで再沈殿を行った。凍結乾燥後、標題の化合物(4)(6.25g)を得た。
100mlナスフラスコに製造例7で得られる化合物(4)(830mg)を加え、三方活栓を取り付け、蒸留THF溶媒をナスフラスコに8ml加えた。もう一方の100mlナスフラスコに55%水素化ナトリウム(43mg)、少量のヨウ化ナトリウムを加え、三方活栓を取り付けた。窒素置換しながら、蒸留THF溶媒を3ml加え、続いて亜リン酸ジエチル(0.13ml)を加えた。さらに、この溶液を化合物4に氷浴下で滴下し、室温で15時間反応させた。反応後、エバポレーターにて溶媒を除去した。生成物をメタノールに溶解させ、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。透析後、エバポレーターにて溶媒を除去した。生成物をベンゼン5mlに溶解させ凍結乾燥を行った。凍結乾燥後、標題の化合物(5)を収率86%で得た。
100mlの2口ナスフラスコに製造例8で得られる化合物(5)(0.086mmol)を加え、三方活栓と還流管を取り付けた。窒素置換しながらジクロロメタン(10ml)、トリメチルシリルブロミド(300μl,2.3mmol)を加え、還流させながら45℃で3時間反応させた。反応後、エバポレーターで溶媒を除去した。過剰のメタノールに反応物を溶解させ、室温で24時間反応させた。反応後、エバポレーターで溶媒を除去した。反応物をメタノールに溶解させ、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。透析後、エバポレーターにて溶媒を除去した。反応物をベンゼン5mlに溶解させ凍結乾燥を行った。凍結乾燥後、標題の化合物(6)を収率65%で得た。
50mlナスフラスコに製造例9で得られる化合物(6)(500mg)を加え、三方活栓を取り付け、ジメチルスルホキシドを5ml加えた。また、もう一方の50mlナスフラスコに4-アミノ-2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル(4-aminoTEMPO)(616mg)を加え、三方活栓を取り付け、窒素置換しながら、ジメチルスルホキシドを5ml加えた。4-aminoTEMPO溶液を化合物6に滴下し、室温で24時間反応させた。反応後、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。精製後、エバポレーターで溶媒を除去した。生成物をベンゼンに溶解させ、凍結乾燥を行った。凍結乾燥後、標題の化合物(7)を収率91%で得た。1HNMR及び電子スピン共鳴(ESR)測定結果より化合物(7)における、4-aminoTEMPO化単位とリン酸化単位の数(上式中のn及びkに該当する)は12及び6であった。
100mlナスフラスコに製造例2で得られる化合物(3)(4.5g)、アゾビスイソブチロニトリル(40mg)を加え、三方活栓を取り付けた。窒素置換しながら蒸留トルエン(100ml)、p-クロロメチルスチレン(25ml)を加え、60℃で24時間重合反応させた。反応後、ジエチルエーテル600mlで再沈殿を行った。吸引濾過により生成物を分離させ、濾液を捨てた。生成物をアセトンに溶かし、再びイソプロパノール及び次エチルエーテルで再沈殿を行った。凍結乾燥後、標題の化合物(4)を収率20%で得た。
100mlナスフラスコに製造例11で得られる化合物(4)(710mg)を加え、三方活栓を取り付け、蒸留THF溶媒をナスフラスコに10ml加えた。もう一方の100mlナスフラスコに55%水素化ナトリウム(144mg)、少量のヨウ化ナトリウムを加え、三方活栓を取り付けた。窒素置換しながら、蒸留THF溶媒を16ml加え、続いて亜リン酸ジエチル(0.43ml)を加えた。さらに、この溶液を化合物(4)に氷浴下で滴下し、室温で15時間反応させた。反応後、エバポレーターにて溶媒を除去した。生成物をメタノールに溶解させ、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。透析後、エバポレーターにて溶媒を除去した。生成物をベンゼン5mlに溶解させ凍結乾燥を行った。凍結乾燥後、標題の化合物(5)を収率98%で得た。
100mlの2口ナスフラスコに製造例12で得られる化合物(5)(0.042mmol)を加え、三方活栓と還流管を取り付けた。窒素置換しながらジクロロメタン(5ml)、トリメチルシリルブロミド(650μl,5.1mmol)を加え、還流させながら45℃で3時間反応させた。反応後、エバポレーターで溶媒を除去した。過剰のメタノールに反応物を溶解させ、室温で24時間反応させた。反応後、エバポレーターで溶媒を除去した。反応物をメタノールに溶解させ、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。透析後、エバポレーターにて溶媒を除去した。反応物をベンゼン5mlに溶解させ凍結乾燥を行った。凍結乾燥後、標題の化合物(6)を収率90%で得た。
50mlナスフラスコに製造例13で得られる化合物(6)(0.02mmol)を加え、三方活栓を取り付け、ジメチルスルホキシドを5ml加えた。また、もう一方の50mlナスフラスコに4-アミノ-2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル(4-aminoTEMPO)(1.4g)を加え、三方活栓を取り付け、窒素置換しながら、ジメチルスルホキシドを5ml加えた。4-aminoTEMPO溶液を化合物(6)に滴下し、室温で24時間反応させた。反応後、MWCO3500の透析膜を用いてメタノール透析を48時間行うことで精製した。精製後、エバポレーターで溶媒を除去した。生成物をベンゼンに溶解させ、凍結乾燥を行った。凍結乾燥後、標題の化合物(7)を収率98%で得た。1HNMR及び電子スピン共鳴(ESR)測定結果より化合物(7)における、4-aminoTEMPO化単位とリン酸化単位の数(上式中のn及びkに該当する)は41及び23であった。
(1)ステンレスに対するポリマーコーティング
厚さ1mmのステンレス(SUS430)を1cm角に切り出し、蒸留水、メタノール、アセトンで15分間超音波洗浄を行った。洗浄後、ステンレス片をピラニア溶液(硫酸:過酸化水素=3:1)に60℃で10分間浸すことで、表面の洗浄及びヒドロキシル化を行った。蒸留水で洗浄後、ステンレス片をすぐに化合物(7)(13-18)のメタノール溶液(15mg/ml)に24時間浸し、ポリマーのコーティングを行った。コーティング後、ステンレス片をメタノールで洗浄し、窒素フローで乾燥させ、ポリマーコートステンレスを得た。
この試験は、X線光電子分光分析(XPS)(日本電子 JPS-9010TR)を用いて、上記の方法で得られたポリマーコートステンレス表面の元素分析を行ったものである。
XPSの測定では、アルミニウム(AlKα,hν=1468.6eV)を線源として用い、C・O・Fe・Cr・N・P各元素についてスペクトルを得た。これらのスペックトルから、ポリマーコートステンレス表面の炭素原子の割合(C/Cr)がポリマーコート前と比較して上昇していることが分かった。また、ポリマー固有の元素であるリン元素に関しても同様であった。このことから、ステンレス表面にポリマーがコーティングされたことが分かった。XPSによる表面元素分析結果を、それぞれ図1および2に示す。図から、それぞれ、多量の炭素およびリンがポリマーコートした表面から検出されている。
この試験は、接触角計(協和界面科学CA-X)を用いて、上記の方法で得られたポリマーコートステンレス表面の濡れ性を評価したものである。接触角の測定では、液滴量2μlの蒸留水を液滴化後、60秒経過時点における接触角を測定して、水に対する静的接触角とした。測定の結果を図3に示す。図から、ピラニア洗浄したステンレスでは、表面がヒドロキシル化され親水性を得たことで、接触角の低下が見られた。一方、ポリマーコート後では接触角が大きく上昇していた。これはポリマーによって表面のヒドロキシル基が覆われコーティング前と比べて親水性が低下したためであると考えられる。このことからも、ステンレス表面にポリマーがコーティングされたことが示唆された。
この試験は、上記の方法で得られたポリマーコートステンレスをリン酸緩衝生理食塩水に浸漬させることでポリマーの安定性を評価したものである。ポリマーコートステンレスをPBS(150mM,15ml)中に37℃で任意の時間浸漬させた。その後、ポリマーコートステンレスを回収し、蒸留水で洗浄、窒素フローにより乾燥させた後、XPSにより表面元素分析を行った。その結果、図4に示す。図からリン酸残基を有するポリマーPEG-b-PMNT-r-PVBP(7)または化合物(7)(13-18)をコーティングしたステンレス表面(SS-PEG-b-PMNT-r-PVBP)は4週間PBSに浸漬した後でも炭素原子の割合(C/Cr)に変化は見られなかったことから安定にポリマーがコーティングされていることがわかる。一方で、リン酸残基を持たないPEG-b-PMNT(化合物(7)のk=0のポリマーに相当する)及びPEG-b-PCMS(化合物(6)のk=0のポリマーに相当する)は炭素原子の割合(C/Cr)が低いことからコーティングされていないことがわかる。このことから、ポリマーの有するリン酸基とステンレス表面が安定的に化学結合していることが分かる。なお、Pi-SSは、ステンレス片表面をピラニア洗浄した表面についてのデータである。
この試験は、走査型電子顕微鏡(SEM)(日本電子 JSM-5510SEM)を用いて、上記の方法で得られたポリマーコートステンレスの全血接触後の表面を観察したものである。ポリマーコートステンレス片及びコントロールとしてピラニア洗浄したステンレス片を1.5mlチューブへ入れ、予めヘパリンを血液に対し5U/mlとなるよう加えた。Balb/cマウスから全血をチューブに採取し、37℃で3時間インキュベート後、PBSで3回洗浄した。その後、ステンレス表面を2%グルタルアルデヒドに一晩浸潤させることで固定化を行い、最後にエタノール(50%,70%,100%)で脱水、窒素フローにより乾燥させることで、SEMサンプルの調製を行った。SEMの測定では、サンプルを予めスパッタ装置(日本電子 JFC-1600オートファインコーター)にて金をスパッタリングした。その結果、ポリマーコート前のステンレス表面では血塊や血液成分の付着が見られた。
実施例1の(1)において、化合物(7)(13-18)の代わりに、製造例10で得られる化合物(7)(12-6)または製造例14で得られる化合物(7)(41-23)を用いたこと以外そこに記載された条件でコーティング処理し、次いで同(2)に記載に従って、各コーティング表面のXPSによる元素分析(C/Cr)を行った。その結果を図6に示す。
図から、幅広いリン酸化単位の数(k)において、本発明に従う共重合体はステンレス表面に安定に担持または保持されることが確認できる。図中、黒塗りカラムは化合物(7)(12-6)(n=12,k=6に相当)のコーティング表面の、白塗りカラムは化合物(7)(41-23)(n=41,k=23に相当)のコーティング表面のデータに基づき、斜線カラムはポリマーコートなしのピラニア洗浄後のステンレス表面のデータに基づく。
Claims (8)
- 下記式(I)で表される共重合体。
上記式中、
Aは、水素原子、非置換または置換C1-C12アルキルを表し、置換されている場合の置換基は、ホルミル基、式R1R2CH-基を表し、ここで、R1およびR2は独立してC1-C4アルコキシまたはR1とR2は一緒になって-OCH2CH2O-、-O(CH2)3O-もしくは-O(CH2)4O-を表し、
Lは、結合であるか、あるいは式
-(CH2)cS-、-CO(CH2)cS-、-(CH2)cNH-、-(CH2)cCO-、-CO-、-COO-、-CONH-からなる群より選ばれる連結基を表し、
X1は-(CH2)a-NH-(CH2)a-または-(CH2)a-O-(CH2)a-を介して共有結合した式
で表される基から選ばれ、
X2はPO(-OH)2を表し、
YはH、SHまたはS-C(=S)-Phを表し、Phは1または2個のメチルまたはメトキシで置換されていてもよいフェニルを表し、
aは、各独立して0~5の整数であり、
bは2~6の整数であり、
cは1~5の整数であり、
mは2~10,000の整数であり、
nは1~360の整数であり、
kは1~480の整数であり、
但し、
n個のXの中の50%まで、またはk個のYの中の50%までが、それぞれ、H、ハロゲンまたはヒドロキシであることができ、かつ、
n個の該当する反復単位中の各単位とk個の該当する反復単位中の各単位は、それぞれランダムに存在する。 - 請求項1に記載の共重合体であって、nおよびkの定義において、n+kが5~600の整数であり、n/n+kが0.2~0.8であり、k/n+kが0.2~0.8であり、ここで、n及びk個の反復単位は、それぞれ100%が原則として前記X1及びX2について定義した基である、共重合体。
- 請求項2に記載の共重合体であって、kが少なくとも3の整数であり、nが少なくとも3の整数である、共重合体。
- 請求項1~3のいずれかに記載の共重合体であって、Lがパラキシリレンまたはメタキシリレンである共重合体。
- 請求項1~4のいずれかに記載の共重合体を担持する金属材料表面。
- 金属材料がステンレス、チタンまたはチタン合金である、請求項5に記載の金属材料表面。
- 請求項5または6に記載の金属材料表面であって、ステント、人工補助心臓、人工関節、細胞培養装置、細胞解析装置および細胞分離装置またはそれらの部品の表面から選ばれる、金属材料表面。
- 請求項1~4のいずれかに記載の共重合体に由来する塗膜を表面に保持する装置であって、前記表面がステント、人工補助心臓、人工関節、細胞培養装置、細胞解析装置および細胞分離装置またはそれらの部品の金属材料表面から選ばれる、装置。
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