WO2018174111A1 - スルホベタイン基含有反応性化合物、その重合体、及び重合体の製造方法 - Google Patents
スルホベタイン基含有反応性化合物、その重合体、及び重合体の製造方法 Download PDFInfo
- Publication number
- WO2018174111A1 WO2018174111A1 PCT/JP2018/011230 JP2018011230W WO2018174111A1 WO 2018174111 A1 WO2018174111 A1 WO 2018174111A1 JP 2018011230 W JP2018011230 W JP 2018011230W WO 2018174111 A1 WO2018174111 A1 WO 2018174111A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- formula
- polymer
- bond
- Prior art date
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/24—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/30—Low-molecular-weight compounds
- C08G18/38—Low-molecular-weight compounds having heteroatoms other than oxygen
- C08G18/3855—Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur
- C08G18/3857—Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur having nitrogen in addition to sulfur
-
- 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
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/08—Processes
- C08G18/0804—Manufacture of polymers containing ionic or ionogenic groups
- C08G18/0819—Manufacture of polymers containing ionic or ionogenic groups containing anionic or anionogenic groups
- C08G18/0828—Manufacture of polymers containing ionic or ionogenic groups containing anionic or anionogenic groups containing sulfonate groups or groups forming them
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/08—Processes
- C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
- C08G18/44—Polycarbonates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/48—Polyethers
- C08G18/487—Polyethers containing cyclic groups
- C08G18/4879—Polyethers containing cyclic groups containing aromatic groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/48—Polyethers
- C08G18/50—Polyethers having heteroatoms other than oxygen
- C08G18/5021—Polyethers having heteroatoms other than oxygen having nitrogen
- C08G18/5036—Polyethers having heteroatoms other than oxygen having nitrogen containing -N-C=O groups
- C08G18/5045—Polyethers having heteroatoms other than oxygen having nitrogen containing -N-C=O groups containing urethane groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
- C08G18/6505—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen the low-molecular compounds being compounds of group C08G18/32 or polyamines of C08G18/38
- C08G18/6523—Compounds of group C08G18/3225 or C08G18/3271 or polyamines of C08G18/38
- C08G18/6529—Compounds of group C08G18/3225 or polyamines of C08G18/38
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
- C08G18/72—Polyisocyanates or polyisothiocyanates
- C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
- C08G18/76—Polyisocyanates or polyisothiocyanates cyclic aromatic
- C08G18/7657—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings
- C08G18/7664—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups
- C08G18/7671—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups containing only one alkylene bisphenyl group
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L75/00—Compositions of polyureas or polyurethanes; Compositions of derivatives of such polymers
- C08L75/04—Polyurethanes
- C08L75/06—Polyurethanes from polyesters
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2375/00—Characterised by the use of polyureas or polyurethanes; Derivatives of such polymers
- C08J2375/04—Polyurethanes
Definitions
- the present invention relates to a biocompatible polymer mainly used in the medical field, a production method thereof, and a monomer compound constituting the polymer.
- a prosthetic organ, artificial tissue, medical device, or the like When a prosthetic organ, artificial tissue, medical device, or the like is embedded in the body or used in contact with a living body, a protective reaction against these artificial foreign substances occurs.
- plasma protein adsorption occurs, and the cell adheres to the surface of the artificial material through the adsorbed protein.
- a thrombus is formed in the blood and adheres to the surface of the artificial material, or the artificial material is covered with a collagen fiber capsule in the connective tissue. For this reason, the natural substitute function of the artificial material cannot be exhibited.
- complement in plasma is activated, which triggers a series of immune reactions and kills own cells.
- PEG polyethylene glycol
- materials to which PEG is added are widely used because of their high biocompatibility and hydrophilic properties.
- PEG loses its resilience to proteins at 35 ° C. or higher, and there is a problem that proteins are easily adsorbed.
- the biomembrane lipid has a phosphorylcholine (PC) group which is a phospholipid polar group
- a polymer of 2-methacryloyloxyethyl phosphorylcholine (MPC) carrying a PC group has been developed (Non-patent Document 1).
- the MPC polymer has a methacryloyl group having excellent polymerizability, it can be freely designed in accordance with the application by copolymerizing with various vinyl monomers.
- a homopolymer of MPC is water-soluble and therefore not suitable as a medical material used in vivo, but can be rendered water-insoluble by selecting a vinyl monomer to be copolymerized.
- Patent Documents 1 and 2 A polymer obtained by polymerizing a monomer having a PC group and a polyurethane prepolymer has also been developed (Patent Documents 1 and 2).
- the monomer having a PC group is highly hygroscopic, its synthesis and handling are not easy unless it is in a non-aqueous environment. Accordingly, there is a need for the development of a biocompatible material having various characteristics suitable for use in contact with a living body and which can be easily manufactured.
- An object of the present invention is to provide a material that is a biocompatible material having various characteristics suitable for use in contact with a living body and can be easily manufactured.
- R 1 s are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
- X is a single bond, an oxygen atom, or —COO—, —OOC—, -CONH-, -NH-, -NHCO-, -NR 3- , or -CH 2 O- represents any group
- Y represents a single bond or an oligooxyalkylene group
- two R 2 Are the same or different and each represents an alkyl group having 1 to 6 carbon atoms
- R 3 represents an alkyl group having 1 to 6 carbon atoms
- m represents an integer of 1 to 10
- n represents an integer of 2 to 10 To express.
- a polymer containing at least 1 mol% of the structural unit represented by the formula (1) and having a number average molecular weight of 5,000 or more has high biocompatibility and has practically sufficient heat resistance
- Any one of the groups represented by O—, Y represents a single bond or an oligooxyalkylene group, two R 2 s are the same or different and each represents an alkyl group having 1 to 6 carbon atoms, and R 3 represents C represents an alkyl group having 1 to 6 carbon atoms, m represents an integer of 1 to 10, and n represents an integer of 2 to 10.)
- a compound represented by [2] The compound according to [1], wherein two As are both a substituent containing an amino group. [3] The compound according to [1] or [2], wherein n is an integer of 3 to 5.
- a polymer having a sulfobetaine group has been considered to be less biocompatible than a polymer having a phosphorylcholine group.
- the polymer of the present invention having a sulfobetaine group has sufficient biocompatibility and has excellent heat resistance and mechanical strength.
- a medical material that is embedded in a living body or used in contact with a living body is required to withstand autoclave sterilization (120 ° C., 1 atm), which is a general-purpose sterilization method. It can withstand
- medical materials that are embedded in a living body or used in contact with a living body are often required to have appropriate stretchability in order not to give mechanical stress to the living body. Moreover, it needs to be strong enough not to break even when stretched.
- a material used as a coating material is required to have high breaking strength and elongation.
- the polymer of the present invention has sufficient breaking strength and elongation rate, and therefore can be used for a wide range of applications.
- a monomer having high hygroscopicity is difficult to be charged at the time of the polymerization reaction unless it is in a non-aqueous environment, or the amount of charge is likely to vary, but the monomer compound of the present invention used for the production of the polymer of the present invention is Since the hygroscopic property is lower than that of the monomer having a phosphorylcholine group, the handling is easy. Further, the monomer compound of the present invention can be synthesized in a shorter process than the monomer having a phosphorylcholine group. Furthermore, since a reaction in a heat-sealed system that is necessary for the synthesis of a monomer having a phosphorylcholine group is not required, it can be produced at low cost. Therefore, the polymer of the present invention can also be produced easily and inexpensively as compared with the polymer having a phosphorylcholine group.
- the compound of the present invention has the following formula (1) (In formula (1), two R 1 s are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and A is the same or different and is an amino group, a hydroxyl group, an epoxy group, or X represents a single bond, an oxygen atom, or —COO—, —OOC—, —CONH—, —NH—, —NHCO—, —NR 3 —, or —CH 2.
- formula (1) two R 1 s are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and A is the same or different and is an amino group, a hydroxyl group, an epoxy group, or X represents a single bond, an oxygen atom, or —COO—, —OOC—, —CONH—, —NH—, —NHCO—, —NR 3 —, or —CH 2.
- Any one of the groups represented by O—, Y represents a single bond or an oligooxyalkylene group, two R 2 s are the same or different and each represents an alkyl group having 1 to 6 carbon atoms, and R 3 represents C represents an alkyl group having 1 to 6 carbon atoms, m represents an integer of 1 to 10, and n represents an integer of 2 to 10.) And a reactive compound having a sulfobetaine group.
- Examples of the alkyl group having 1 to 6 carbon atoms represented by R 1 include methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like. It is done.
- Two R 1 are the same and are preferably a hydrogen atom.
- the reactive group contained in the substituent A is preferably a hydroxyl group or an amino group.
- a hydroxyl group can form a urethane bond with an isocyanate group, and an amino group can form a urea bond with an isocyanate group, whereby a polymer having high mechanical strength can be obtained.
- the reactive group contained in the substituent A is an amino group, a polymer having particularly high mechanical strength can be obtained.
- the functional groups contained in the two substituents A are preferably the same. Specifically, it is preferable that the two substituents A each have an amino group, a hydroxyl group, an epoxy group, or a (meth) acryloyl group. More preferably, the two substituents A are the same.
- X is preferably —COO— or —CONH—, and more preferably —COO—.
- X is —COO—
- the compound of the formula (1) can be easily synthesized, and a highly biodegradable polymer can be obtained.
- X is —CONH—
- the compound of formula (1) and the resulting polymer have high resistance to acid and alkali.
- Examples of the alkyl group having 1 to 6 carbon atoms represented by R 3 when X is —NR 3 — include methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl Group, pentyl group, hexyl group and the like.
- R 3 is preferably an alkyl group having 1 to 3 carbon atoms, more preferably a methyl group, from the viewpoint of small steric hindrance.
- the oligooxyalkylene group represented by Y is an oxyalkylene group having 2 to 12 carbon atoms and 1 to 3 oxygen atoms, specifically, — (CH 2 CH 2 O) q —, — (CH 2 CH 2 CH 2 O) q — or — (CH 2 CH 2 CH 2 CH 2 O) q — (q is an integer of 1 to 3).
- Y is preferably a single bond.
- the two R 2 are the same and are preferably an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group.
- M is preferably an integer of 2 to 6, more preferably 2.
- n is preferably an integer of 2 to 6, more preferably an integer of 3 to 5, and most preferably 4.
- the compound of formula (1) can be produced, for example, by the method described below.
- A is a substituent containing an amino group
- A is an amino group.
- the following formula (3) And a dinitro compound represented by the following formula (4): And a compound represented by the following formula (5): Is synthesized.
- the compound represented by the formula (5) and the following formula (6) Is reacted with a sultone compound represented by the following formula (7):
- a compound having a sulfobetaine group represented by is synthesized.
- the compound represented by the formula (3) can be synthesized from a commercially available compound using a known reaction in accordance with the method described in Examples described later.
- the above synthesis method is a method for synthesizing the compound of the formula (1) when X is —COO— and Y is a single bond.
- HCl is eliminated between —COOH of the compound of the formula (3) and —Cl of the compound of the formula (4).
- the formula (3) has a substituent capable of eliminating HCl with —Cl of the compound of the formula (4). What is necessary is just to change the compound of these.
- the reaction between the compound of formula (3) and the compound of formula (4) is carried out so that the compound of formula (3): the compound of formula (4) is charged in a ratio of 1: 1 to 1: 5 mol, and hydrogen chloride is generated. It is preferable to carry out the reaction in the presence of a tertiary amine such as triethylamine, or to remove hydrogen chloride out of the system by blowing an inert gas into the reaction system.
- a tertiary amine such as triethylamine
- the compound of formula (5) is reacted with a 1,3-dihalogenated alkane (2 to 10 carbon atoms) to form a quaternary compound.
- the compound of formula (7) can also be obtained by converting to an ammonium salt and then reacting with a sulfite. Details of this reaction are described, for example, in JP-A-10-87601.
- the reduction reaction of the nitro group of the compound of formula (7) can be performed by catalytic reduction using a metal such as nickel, platinum, palladium, rhodium as a catalyst in a hydrogen gas atmosphere.
- the reaction is performed by reacting a reducing agent such as diborane, lithium borohydride, sodium borohydride, sodium aluminum hydride, dialkoxyaluminum sodium hydride, diethylaluminum sodium hydride and the compound of formula (7).
- a catalyst such as tin chloride.
- Any of the above reactions for synthesizing the compound of formula (8) from the compound of formula (3) is preferably carried out in a solvent.
- Any solvent may be used as long as it does not participate in the reaction.
- alcohols such as methanol, ethanol and isopropyl alcohol
- glycols such as ethylene glycol and propylene glycol
- ketones such as acetone and methyl ethyl ketone
- diethyl ether and tetrahydrofuran Alkyl ethers such as dimethoxyethane
- aromatic compounds such as benzene, toluene and xylene
- aliphatic hydrocarbon compounds such as n-hexane
- alicyclic hydrocarbon compounds such as cyclohexane; methyl acetate and ethyl acetate
- the reaction temperature is preferably about ⁇ 100 to
- the polymer of the present invention has the following formula (2) (In formula (2), two R 1 s are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and X is a single bond, an oxygen atom, or —COO—, —OOC—, -CONH-, -NH-, -NHCO-, -NR 3- , or -CH 2 O- represents any group, Y represents a single bond or an oligooxyalkylene group, and two R 2 Are the same or different and each represents an alkyl group having 1 to 6 carbon atoms, R 3 represents an alkyl group having 1 to 6 carbon atoms, m represents an integer of 1 to 10, and n represents an integer of 2 to 10 To express.) Is a polymer having a number average molecular weight of 5,000 or more. Illustrative and preferred examples of R 1 , R 2 , R 3 ,
- the number average molecular weight of the polymer of the present invention is usually 5,000 or more, but may be 10,000 or more, 30,000 or more, or 50,000 or more. If it is this range, it will become a polymer which has sufficient heat resistance, mechanical strength, and solvent resistance.
- the number average molecular weight can be 5,000,000 or less, 1,000,000 or less, 500,000 or less, or 100,000 or less. In general, polymers with low solubility are easily gelled and have disadvantages such as a roughened coating surface when the polymer is coated. However, if the number average molecular weight is within this range, the polymer is stable without gelation. It becomes a polymer.
- the number average molecular weight of the polymer of the present invention is 5,000 to 5,000,000, 5,000 to 1,000,000, 5,000 to 500,000, 5,000 to 100,000, 10,000, 000 to 5,000,000, 10,000 to 1,000,000, 10,000 to 500,000, 10,000 to 100,000, 30,000 to 5,000,000, 30,000 to 1, 000,000, 30,000-500,000, 30,000-100,000, 50,000-5,000,000, 50,000-1,000,000, 50,000-500,000, and 50 , 100,000 to 100,000.
- the weight average molecular weight of the polymer of this invention can be 5,000 or more, 10,000 or more, or 50,000 or more. If it is this range, it will become a polymer which has sufficient heat resistance, mechanical strength, and solvent resistance.
- the weight average molecular weight can be 2,000,000 or less, 1,000,000 or less, or 500,000 or less. If it is this range, it will become a stable polymer, without gelatinizing.
- the weight average molecular weight of the polymer of the present invention is 5,000 to 2,000,000, 5,000 to 1,000,000, 5,000 to 500,000, 10,000 to 2,000,000, 10,000 to 1,000,000, 10,000 to 500,000, 50,000 to 2,000,000, 50,000 to 1,000,000, and 50,000 to 500,000.
- the number average molecular weight and the weight average molecular weight are values measured by gel permeation chromatography (GPC) using polystyrene as a standard substance.
- the polymer of the present invention has biocompatibility sufficient for practical use by containing at least 1 mol% of the structural unit represented by the formula (2).
- the biocompatibility is improved as the content of the structural unit represented by the formula (2) is higher.
- the content of the structural unit represented by the formula (2) is preferably 5 mol% or more, more preferably 10 mol% or more, and even more preferably 30 mol% or more. If it is this range, it can be used for a wide range of medical uses.
- the upper limit of the content of the structural unit represented by the formula (2) is usually about 70 mol%. Examples of the content of the structural unit represented by the formula (2) in the polymer of the present invention include 5 to 70 mol%, 10 to 70 mol%, and 30 to 70 mol%.
- the content of the structural unit represented by the formula (2) is adjusted by adjusting the ratio of the compound represented by the formula (1) in the raw material compounds (including monomers and / or prepolymers) subjected to polymerization. Can be a value.
- the polymer of the present invention exhibits sufficient biocompatibility even when the content of the structural unit represented by the formula (2) is low. Therefore, it can be manufactured at a low cost by increasing the ratio of inexpensive monomers and prepolymers.
- a polymer having a structural unit represented by formula (2) comprises a compound represented by formula (1) and another polymerizable monomer or a prepolymer having a reactive functional group. It can be produced by polymerization.
- the other polymerizable monomer one having a functional group capable of forming a bond with the functional group contained in the substituent A of the compound of the formula (1) by polycondensation reaction, polyaddition reaction, or radical polymerization reaction can be used. .
- the number of this functional group in the other polymerizable monomer may be two or more when the substituent A of the formula (1) includes an amino group, a hydroxyl group, or an epoxy group, and the substitution of the formula (1) When group A contains a (meth) acryloyl group, it may be one or more. Further, in addition to such other polymerizable monomers, a monomer having a phosphocholine group or a monomer having a sulfobetaine group other than the compound of the formula (1) as long as the effects of the present invention are not impaired. Monomers may be used.
- the prepolymer having a reactive functional group has a reactive functional group at the terminal which can form a bond with the functional group A of the compound of formula (1) by polycondensation reaction, polyaddition reaction, or radical polymerization reaction. It only has to be.
- the terminal may be either the main chain terminal or the side chain terminal.
- the number of reactive functional groups in the prepolymer may be two or more when the substituent A in the formula (1) contains an amino group, a hydroxyl group, or an epoxy group.
- group A contains a (meth) acryloyl group, it may be one or more.
- a monomer having a phosphocholine group or a monomer having a sulfobetaine group other than the compound of formula (1) is used as long as the effects of the present invention are not impaired. May be.
- dicarboxylic acid or a derivative thereof is used as the other polymerizable monomer, a polyamide having an amide bond in the main chain skeleton can be obtained.
- dicarboxylic acid or derivative thereof used as another polymerizable monomer include, for example, the following formula (16) (In the formula, Y 1 represents a divalent organic group, preferably a divalent organic group that is a dicarboxylic acid residue, and X 1 represents a hydroxyl group, a halogen atom, or an alkoxy group.) The compound shown by can be used.
- the polyamide repeating unit obtained has the following formula (17): (Wherein Y 1 represents a divalent organic group, preferably a divalent organic group that is a dicarboxylic acid residue, A ′ represents a residue obtained by removing an amino group from A in Formula (1), and R 1 , R 2 , R 3 , X, Y, m, and n are the same as those in Formula (2).) Is a repeating unit.
- dicarboxylic acid represented by the formula (16) or a derivative thereof examples include phthalic acid, terephthalic acid, isophthalic acid, 2,6-naphthalenedicarboxylic acid, 1,6-naphthalenedicarboxylic acid, and 2,6-anthracene dicarboxylic acid.
- 1,6-anthracene dicarboxylic acid 4,4′-biphenyl dicarboxylic acid, 4,4′-diphenylmethane dicarboxylic acid, 4,4′-diphenyl ether dicarboxylic acid, 2,2-bis (4-carboxylphenyl) propane, , 2-bis [4- (4-carboxyphenylphenoxy) phenyl] propane aromatic dicarboxylic acid; 2,5-furandicarboxylic dicarboxylic acid; oxalic acid, malonic acid, succinic acid , Glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, tartaric acid Saturated aliphatic dicarboxylic acids; unsaturated aliphatic dicarboxylic acids such as fumaric acid and itaconic maleic acid; cycloalkanedicarboxylic acids such as 1,9-nonanedicarboxylic acid and 1,
- aromatic dicarboxylic acids are preferable, and 2,2-bis [4- (4-chlorocarbonylphenyloxy) phenyl] propane is more preferable.
- Dicarboxylic acid or its derivative can be used individually by 1 type or in combination of 2 or more types.
- the main clavicle can be obtained by performing an imidization reaction by heat treatment or dehydration and cyclization using a catalyst such as an amine catalyst.
- a catalyst such as an amine catalyst.
- a polyimide having an imide bond is obtained.
- tetracarboxylic dianhydrides used as other polymerizable monomers include, for example, the following formula (18) (In the formula, Y 2 represents a tetravalent organic group, preferably a tetravalent organic group which is a tetracarboxylic acid residue.) The compound shown by can be used.
- the repeating unit of the obtained polyimide is represented by the following formula (19).
- Y 2 represents a tetravalent organic group, preferably a tetravalent organic group which is a tetracarboxylic acid residue
- a ′ represents a residue obtained by removing an amino group from A in formula (1)
- R 1 , R 2 , R 3 , X, Y, m, and n are the same as in formula (2).
- tetracarboxylic dianhydride represented by the formula (18) examples include pyromellitic dianhydride, 2,3,6,7-naphthalenetetracarboxylic dianhydride, 1,2,5,6- Naphthalenetetracarboxylic dianhydride, 1,4,5,8-naphthalenetetracarboxylic dianhydride, 2,3,6,7-anthracenetetracarboxylic dianhydride, 1,2,5,6-anthracenetetra Carboxylic dianhydride, 3,3 ′, 4,4′-diphenyltetracarboxylic dianhydride, bis (3,4-dicarboxyphenyl) ether dianhydride, 3,3 ′, 4,4′-benzophenone Tetracarboxylic dianhydride, bis (3,4-dicarboxyphenyl) sulfone dianhydride, bis (3,4-dicarboxyphenyl) methane dianhydride, 2,2-bis (3,4
- a diisocyanate compound is used as another polymerizable monomer, a polyurea having a urea bond in the main chain skeleton can be obtained.
- a diisocyanate compound used as another polymerizable monomer for example, the following formula (20) (In the formula, Y 3 represents a divalent organic group, preferably a divalent organic group which is a diisocyanate compound residue.) The compound shown by can be used.
- the polyurea repeating unit obtained has the following formula (21): (Wherein Y 3 represents a divalent organic group, preferably a divalent organic group which is a diisocyanate compound residue, A ′ represents a residue obtained by removing an amino group from A in formula (1), and R 1 , R 2 , R 3 , X, Y, m, and n are the same as those in Formula (2).) Is a repeating unit.
- diisocyanate compound represented by the formula (20) examples include 1,4-phenylene diisocyanate, 1,3-phenylene diisocyanate, 1,4-xylylene diisocyanate, 1,3-xylylene diisocyanate, 2,4-toluene.
- Diisocyanate 2,5-toluylene diisocyanate, 4,4′-biphenylene diisocyanate, 4,4′-diphenyl ether diisocyanate, 4,4′-diphenylmethane diisocyanate, 4,4 ′-(2,2-diphenylpropane) diisocyanate
- Examples include tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate, and octamethylene diisocyanate.
- 4,4′-diphenylmethane diisocyanate and hexamethylene diisocyanate are preferable, and 4,4′-diphenylmethane diisocyanate is more preferable.
- a diisocyanate compound can be used individually by 1 type or in combination of 2 or more types.
- A is a substituent containing a hydroxyl group
- a diisocyanate compound, dicarboxylic acid or a derivative thereof is used as another polymerizable monomer. Can do. If a diisocyanate compound is used as another polymerizable monomer, a polyurethane having a urethane bond in the main chain skeleton can be obtained.
- the structural formula, specific examples, and preferred ones of the diisocyanate compound are the same as in the case where the functional group A is a substituent containing an amino group.
- the repeating unit of the obtained polyurethane has the following formula (22) (Wherein Y 3 represents a divalent organic group, preferably a divalent organic group that is a diisocyanate compound residue, A ′ represents a residue obtained by removing a hydroxyl group from A in formula (1), and R 1 , R 2 , R 3 , X, Y, m, and n are the same as those in Formula (2).) Is a repeating unit.
- a diisocyanate compound can be used individually by 1 type or in combination of 2 or more types.
- dicarboxylic acid or a derivative thereof is used as the other polymerizable monomer, a polyester having an ester bond in the main chain skeleton can be obtained.
- the structural formula, specific examples, and preferred ones of the dicarboxylic acid or its derivative are the same as in the case where the functional group A is a substituent containing an amino group.
- the repeating unit of the obtained polyurethane has the following formula (23): (Wherein Y 1 represents a divalent organic group, preferably a divalent organic group that is a dicarboxylic acid residue, A ′ represents a residue obtained by removing the hydroxyl group from A in formula (1), and R 1 , R 2 , R 3 , X, Y, m, and n are the same as those in formula (2). Dicarboxylic acid or its derivative can be used individually by 1 type or in combination of 2 or more types.
- A is a substituent containing an epoxy group
- an epoxy compound other than the compound of formula (1) is used as another polymerizable monomer.
- Dicarboxylic acids or derivatives thereof, polyol compounds, diisocyanate compounds, and the like can be used.
- a polyester type epoxy polymer can be obtained. If a polyol compound is used as another polymerizable monomer, a polyether type epoxy polymer can be obtained. If a diisocyanate compound is used as another polymerizable monomer, a polyurethane type epoxy polymer can be obtained.
- epoxy compound other than the compound of the formula (1) examples include isosorbide diglycidyl ether, isomannide diglycidyl ether, isoid diglycidyl ether, spiroglycol diglycidyl ether, 2,4: 3,5-di-O.
- -Diglycidyl ethers having a heterocyclic ring such as methylene-mannitol diglycidyl ether and having a condensed ring structure or a spiro ring structure in the molecule; 1,4-dioxane-2,5-diglycidyl ether, 2,3: Examples include diglycidyl ethers having a heterocyclic ring such as 4,5-di-O-methylene-galactose diglycidyl ether; glycidyl ethers such as ethylene glycol, glycol, and polyethylene glycol. Epoxy compounds other than the compound of formula (1) can be used singly or in combination of two or more.
- dicarboxylic acid or derivative thereof are the same as those in the case where the substituent A is a substituent containing an amino group.
- Dicarboxylic acid or its derivative can be used individually by 1 type or in combination of 2 or more types.
- polyol compound examples include bisphenol F, bisphenol C, bisphenol K, bisphenol Z, bisphenol S, tetramethylbisphenol A, tetramethylbisphenol F, tetramethylbisphenol S, tetramethylbisphenol Z, dihydroxydiphenyl sulfide, 4,4 Non-endocrine disrupting bisphenols such as' -thiobis (3-methyl-6-tert-butylphenol); catechol, resorcin, methylresorcin, hydroquinone, monomethylhydroquinone, dimethylhydroquinone, trimethylhydroquinone, mono-tert-butylhydroquinone, di- dihydroxybenzenes such as tert-butylhydroquinone; dihydroxynaphthalene, dihydroxymethylnaphthalene Dihydroxynaphthalenes such as dihydroxydimethylnaphthalene; dihydroxyanthracenes such as dihydroxyanthracene, dihydroxymethylanthracene
- diisocyanate compound examples are the same as when the substituent A is a substituent containing an amino group.
- a diisocyanate compound can be used individually by 1 type or in combination of 2 or more types.
- the (meth) acrylic compound for example, the following formula (24) (In the formula, R 4 represents a hydrogen atom or a methyl group, and R 5 represents an organic group.)
- the compound shown by can be used.
- the repeating unit of the obtained polymer has the following formula (25) (In the formula, R 4 represents a hydrogen atom or a methyl group, R 5 represents an organic group, A ′ represents a residue obtained by removing (meth) acryloyl group from A in formula (1), R 1 , R 2 , R 3 , X, Y, m, and n are the same as in formula (2).) Is a repeating unit.
- the (meth) acrylic compound represented by the formula (24) include methyl (meth) acrylate, ethyl (meth) acrylate, n-butyl (meth) acrylate, isobutyl (meth) acrylate, ( T-butyl (meth) acrylate, neopentyl (meth) acrylate, cyclohexyl (meth) acrylate, benzyl (meth) acrylate, octyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, Cetyl (meth) acrylate, ethyl carbitol (meth) acrylate, hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, hydroxybutyl (meth) acrylate, methoxyethyl (meth) acrylate, (meth ) Methoxybutyl
- Examples of the prepolymer having a reactive functional group at the terminal include an isocyanate group terminal-containing urethane prepolymer obtained by reacting an excess amount of a diisocyanate compound and a diol compound by a known method.
- a urea bond is formed by reacting an isocyanate group-containing urethane prepolymer with a compound of the formula (1) in which the functional group A is a substituent containing an amino group, and a urethane bond and a urea bond are formed on the main chain skeleton. It is possible to produce poly (urethane-urea).
- a urethane bond is formed by making the isocyanate group terminal containing urethane prepolymer and the compound of Formula (1) whose functional group A is a substituent containing a hydroxyl group, and a polyurethane can be manufactured.
- diol compound examples include hydroquinone, 1,3-phenylenediol, 1,4-xylylene diol, 1,3-xylylene diol, 2,4-toluylene diol, 2,5-toluylene diol, 4,4′-biphenylenediol, 4,4′-diphenyletherdiol, 4,4′-diphenylmethanediol, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, heptamethylene glycol, octamethylene glycol, Polyethylene glycol, polypropylene glycol, polytetraethylene oxide, ⁇ , ⁇ -bis (hydroxypropyl) polydimethylsiloxane, ⁇ , ⁇ -bis (hydroxyethoxypropyl) polydimethylsiloxane Polytetramethylene ether glycol, and polycarbonate dio
- Examples of the diisocyanate compound that can be used for the synthesis of the isocyanate group-terminated urethane prepolymer include those exemplified as the polymerizable monomer copolymerized with the compound of the formula (1). Among these, 4,4′-diphenylmethane diisocyanate and hexamethylene diisocyanate are preferable, and 4,4′-diphenylmethane diisocyanate is more preferable.
- a diisocyanate compound can be used individually by 1 type or in combination of 2 or more types.
- the diol compound used for the synthesis of the urethane prepolymer becomes a soft segment in the polymer of the present invention obtained after polymerization with the compound of the formula (1). Therefore, the number average molecular weight of the diol compound is preferably 800 or more, and more preferably 1,000 or more. If it is this range, the polymer of this invention will have sufficient softness
- Examples of the number average molecular weight of the diol compound used for the synthesis of the urethane prepolymer include 800 to 3,000, 800 to 2,000, 1,000 to 3,000, and 1,000 to 2,000.
- the ratio of the diol compound used in the synthesis of the urethane prepolymer and the compound of formula (1) should be about 4: 6 to 8: 2 in terms of the molar ratio of the diol compound and the compound of formula (1). In particular, about 5: 5 to 7: 3 is preferable.
- the compound represented by the formula (1) Since the compound represented by the formula (1) is a rigid compound, depending on the type of the prepolymer having other polymerizable monomer or reactive functional group, the resulting polymer is likely to be rigid. It may be desirable that the medical material is flexible to some extent so as not to apply mechanical stress to the living body. In such applications, when the compound represented by the formula (1) is polymerized, the formula (1) It is desirable to adjust the flexibility of the polymer by coexisting a polymerizable monomer having two or more functional groups identical to the functional group contained in the substituent A of the compound (1).
- the use ratio of the compound of the formula (1) is preferably 1 mol% or more, more preferably 5 mol% or more with respect to the total amount of the polymerizable monomer coexisting with the compound of the formula (1). Within this range, sufficient heat resistance and mechanical strength can be obtained. The upper limit of this ratio may be about 50 mol%. If it is this range, the polymer which has moderate softness
- the polymerizable monomer having two or more functional groups identical to the functional group contained in the substituent A of the compound of formula (1) is a diamine if the functional group contained in A of the compound of formula (1) is an amino group.
- a compound or the like may be used. If the functional group contained in A of the compound of formula (1) is a hydroxyl group, a diol compound or the like may be used, and the functional group contained in A of the compound of formula (1) is an epoxy group. If necessary, a diepoxy compound or the like may be used. If the functional group contained in A of the compound of the formula (1) is a (meth) acryloyl group, the (meth) acryloyl group is bonded to both ends (main chain end, side chain end).
- (Meth) acrylic compound possessed by any) may be used. These co-polymerizable monomers can be used singly or in combination of two or more. In order to improve the flexibility of the polymer of the present invention, it is desirable to use a co-polymerizable monomer having a glass transition point of 0 ° C. or lower.
- Examples of the diamine compound that coexists with the compound represented by the formula (1) include 1,4-phenylenediamine, 1,3-phenylenediamine, 2,5-diaminotoluene, 2,6-diaminotoluene, and 4,4′-diamino.
- the polymer of the present invention can be used as an artificial blood vessel, an artificial heart valve, an artificial joint, an artificial skin, a scaffold for cell proliferation of an artificial tissue or an artificial bone, a dental material, a tissue adhesive, a cardiac pacemaker, a stent, and a surgical suture.
- the polymer of the present invention may be used alone, or may be used by mixing with other polymers as long as the effects of the present invention are not impaired. Since the polymer of the present invention has both high breaking strength and elongation, it is particularly suitable for forming into a shape such as a film, sheet, fiber, or coating.
- a sulfobetaine group-containing diamine (d) (1.7 g, 3.3 mmol) dissolved in dimethyl sulfoxide (10 ml) was added dropwise at room temperature. After completion of the dropwise addition, the mixture was reacted at 70 ° C. for 24 hours. After completion of the reaction, the reaction solution was poured into excess methanol, and the generated precipitate was suction filtered. The obtained solid was vacuum-dried at 40 ° C. to obtain 6.2 g of a sulfobetaine group-containing segmented polyurethane urea (SPUUSB) as a brown solid (yield 91.8%).
- SPUUSB sulfobetaine group-containing segmented polyurethane urea
- Example 2 In Example 1, except that the amount of polycarbonate diol used was 4.66 g (4.66 mmol) and the amount of sulfobetaine group-containing diamine (d) was 1.06 g (2.0 mmol), the same as in Example 1, 6.5 g of a sulfobetaine group-containing segmented polyurethane urea (SPUUSB30) was obtained as a brown solid (yield 88.8%).
- SPUUSB30 a sulfobetaine group-containing segmented polyurethane urea
- Example 3 In Example 1, except that the sulfobetaine group-containing diamine synthesized using butane sultone instead of propane sultone to be reacted with compound (b) was used in the same monomer ratio as in Example 1, the same as in Example 1. Then, 2.48 g of sulfobetaine group-containing segmented polyurethane urea (SPUUSBB) was obtained as a brown solid (yield 86.1%).
- SPUUSBB sulfobetaine group-containing segmented polyurethane urea
- Example 4 In Example 3, the amount of polycarbonate diol used was 3.7 g (3.7 mmol), and the amount of sulfobetaine group-containing diamine (d) was 0.87 g (1.6 mmol). As a brown solid, 5.32 g of segmented polyurethane urea (SPUUSBB30) containing sulfobetaine group was obtained (yield 89.3%).
- SPUUSBB30 segmented polyurethane urea
- Example 5 In Example 3, instead of polycarbonate diol having a number average molecular weight of 1,000, a polycarbonate diol having a number average molecular weight of 2,000 was used in the same manner as in Example 3 except that a sulfobetaine group-containing compound was used. 8.6 g of segmented polyurethane urea (SPUUSBBR) was obtained as a brown solid (yield 84.8%).
- SPUUSBBR segmented polyurethane urea
- Example 6 In Example 3, a sulfobetaine group-containing diamine synthesized using 2- (dimethylamino) hexyl chloride hydrochloride instead of 2- (dimethylamino) ethyl chloride hydrochloride to be reacted with compound (a) was used. Except that the monomer ratio was the same as in Example 3, 2.74 g of sulfobetaine group-containing segmented polyurethaneurea (SPUUSBB6) was obtained as a brown solid (yield 51.6%).
- SPUUSBB6 sulfobetaine group-containing segmented polyurethaneurea
- thermophysical properties of polymer (5% weight loss temperature)
- the decomposition start temperatures of the segmented polyurethane urea resins obtained in Examples 1 to 6 and Comparative Example 1 were measured under the following conditions.
- ⁇ Device Thermogravimetric analyzer TG / DTA (manufactured by Seiko Electronics Co., Ltd.)
- Measurement range 40 °C to 550 °C
- Rise rate 10 °C / min
- Atmosphere Nitrogen
- Glass-transition temperature The glass transition temperatures of the segmented polyurethane urea resins obtained in Examples 1 to 6 and Comparative Example 1 were measured under the following conditions.
- ⁇ Device Differential scanning calorimeter DSC-6200 (Seiko Electronics Co., Ltd.) ⁇ Measurement range: -100 °C to 200 °C ⁇ Temperature increase rate: 10 °C / min
- Thermo Fisher Scientific company make processed with the BCA protein assay kit (Thermo Fisher Scientific company make), and measured the light absorbency of 562 nm with the microplate reader. The absorbance at 562 nm is proportional to the amount of bovine plasma albumin adsorbed on the test piece.
- the phosphate buffered saline was extracted and further immersed in human platelet-rich plasma collected from human blood at 37 ° C for 2 hours. did. Thereafter, the polymer thin film surface of the test piece was washed three times with phosphate buffered saline. Next, 25% glutaraldehyde diluted with phosphate buffered saline was added, and left for 2 hours to fix platelets. The surface of the prepared sample was observed with a scanning electron microscope (SEM). Evaluated as ⁇ when there is no or almost no platelet adsorption, ⁇ when slightly adsorbed platelets, ⁇ when many platelet adsorption was observed, and x when platelet adsorption was very much and aggregated did.
- SEM scanning electron microscope
- Table 1 shows the structural characteristics and evaluation results of each segmented polyurethane urea resin.
- the segmented polyurethane urea resin of Comparative Example 1 having no sulfobetaine group has a remarkably high protein adsorption amount and cannot be applied to a living body. Further, the breaking strength was insufficient.
- the polymers of Examples 1 to 6 had practically sufficient heat resistance, mechanical strength, and biocompatibility. In particular, regarding the mechanical strength, it had practically sufficient breaking strength and elongation rate.
- the polymers of Examples 3 to 5 in which n is 4 in the formula (1) had particularly high mechanical strength and excellent biocompatibility with little platelet adsorption.
- FIG. 1 shows a scanning electron micrograph of a sample obtained by subjecting each test piece of PET film, Comparative Example 1, Example 4 and Example 6 to a blood compatibility test. The adsorption of platelets to each test piece of Example 4 and Example 6 was very small compared to the test piece of Comparative Example 1.
- the polymer of the present invention has sufficient biocompatibility and has excellent heat resistance and mechanical strength. Therefore, it can be used for a wide range of applications as a medical material that is embedded in a living body or used in contact with a living body or a biological separation material.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Manufacturing & Machinery (AREA)
- Engineering & Computer Science (AREA)
- Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Materials Engineering (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Polyurethanes Or Polyureas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
しかし、このような非水溶性のMPC共重合体であっても、医療現場で多用されるアルコール類によりポリマーが欠落したり、溶出するなどの問題があった。また、柔軟な主鎖構造の影響により、オートクレーブ滅菌に耐え得る耐熱性がなく、また、耐加水分解性、機械的強度も不十分であった。
従って、生体と接触させて用いるのに適した諸特性を有する生体適合性材料であり、かつ容易に製造できる材料の開発が求められている。
で示される構造単位を少なくとも1モル%含有し、数平均分子量が5,000以上である重合体は、高い生体適合性を有し、かつ実用上十分な耐熱性及び機械的強度を備えることを見出した。
〔1〕 下記式(1)
で示される化合物。
〔2〕 2つのAが共にアミノ基を含む置換基である、〔1〕に記載の化合物。
〔3〕 nが3~5の整数である、〔1〕又は〔2〕に記載の化合物。
〔4〕 下記式(2)
で示される構造単位を少なくとも1モル%含有し、数平均分子量が5,000以上である重合体。
〔5〕 主鎖骨格に、アミド結合、ウレタン結合、ウレア結合、及びイミド結合からなる群より選ばれる結合を有する、〔4〕に記載の重合体。
〔6〕 上記式(2)で示される構造単位を少なくとも1モル%と、ジイソシアネート化合物とジオール化合物とを反応させて得られるイソシアネート基末端含有ウレタン予備重合体からなる構造単位とを含有し、数平均分子量が5,000以上である、〔4〕に記載の重合体。
〔7〕 主鎖骨格に、ウレタン結合、及びウレア結合を有する、〔6〕に記載の重合体。
〔8〕 nが3~5の整数である、〔4〕~〔7〕の何れかに記載の重合体。
〔9〕 〔4〕~〔8〕の何れかに記載の重合体を含むフィルム、シート、繊維、又は皮膜。
〔10〕 〔4〕~〔8〕の何れかに記載の重合体を含む医療用品。
〔11〕 上記式(1)で示される化合物と、他の重合性モノマーとを、重縮合反応、重付加反応、若しくはラジカル重合反応させるか、又は上記式(1)で示される化合物を含む重合性モノマーと、これと反応し得る官能基末端含有予備重合体とを反応させる工程を含む、〔4〕に記載の重合体の製造方法。
〔12〕 製造される重合体が、主鎖骨格に、アミド結合、ウレタン結合、ウレア結合、及びイミド結合からなる群より選ばれる結合を有するものである、〔11〕に記載の製造方法。
〔13〕 上記式(1)における置換基Aがアミノ基又は水酸基を含み、式(1)で示される化合物と反応し得る官能基末端含有予備重合体が、ジイソシアネート化合物とジオール化合物とを反応させて得られるイソシアネート基末端含有ウレタン予備重合体である、〔11〕に記載の製造方法。
生体内に埋設したり生体と接触させて用いられる医療用材料は、汎用の滅菌方法であるオートクレーブ滅菌(120℃・1気圧)に耐えることが求められるが、本発明の重合体は、オートクレーブ滅菌に耐えるものである。
また、生体内に埋設したり生体と接触させて用いられる医療用材料は、生体に力学的なストレスを与えないために、適度な伸縮性が求められる場合が多い。しかも、伸ばしても破断しないだけの強度が必要である。特に、被覆材として用いる材料は、高い破断強度と伸長率が求められる。この点、本発明の重合体は、十分な破断強度と伸長率を兼ね備えるため、広い用途に用いることができる。
(1)スルホベタイン基を有する反応性化合物
本発明の化合物
本発明の化合物は、下記式(1)
で示される、スルホベタイン基を有する反応性化合物である。
2つの置換基Aに含まれる官能基は同一であるのが好ましい。具体的には、2つの置換基Aが、共にアミノ基、水酸基、エポキシ基、又は(メタ)アクリロイル基を有することが好ましい。2つの置換基Aは、同一であるのがより好ましい。
Xが-NR3-である場合のR3で表される炭素数1~6のアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、sec-ブチル基、tert-ブチル基、ペンチル基、ヘキシル基などが挙げられる。R3は、立体障害が小さい点で、炭素数1~3のアルキル基であるのが好ましく、メチル基であるのがより好ましい。
式(1)の化合物は、例えば、以下に述べる方法により製造することができる。
(a)Aがアミノ基を含む置換基である場合
Aがアミノ基を含む置換基であるとき、Aがアミノ基である場合を例にとって説明すると、例えば、先ず、下記式(3)
また、反応温度は、約-100~150℃が好ましく、約-50~100℃がより好ましく、約0~50℃がさらにより好ましい。
Aが水酸基を含む置換基であるとき、Aが水酸基である場合を例にとって説明すると、例えば、まず、下記式(9)
また、式(9)の化合物から式(12)で示される化合物に至るまでの全ての反応は、式(3)で示される化合物から式(8)で示される化合物を合成する条件を適用することができる。
Aがエポキシ基を含む置換基であるとき、Aがエポキシ基である場合を例にとって説明すると、例えば、上記式(12)で示される化合物に対し、エピクロロヒドリンを作用させることで、下記式(13)
また、例えば、上記式(8)で示される化合物に対し、エピクロロヒドリンを作用させることで、下記式(14)で示される化合物が得られる。
Aが(メタ)アクリロイル基を含む置換基であるとき、Aが(メタ)アクリロイル基である場合を例にとって説明すると、例えば、上記式(12)で示される化合物に対し、塩化(メタ)アクリロイルを作用させることで、下記式(15)で示される化合物が得られる。
本発明の重合体
本発明の重合体は、下記式(2)
で示される構造単位を少なくとも1モル%含有し、数平均分子量が5,000以上である重合体である。
R1、R2、R3、X、Y、m、及びnの例示と好ましいものは、式(1)の化合物について説明した通りである。
本発明の重合体の数平均分子量としては、5,000~5,000,000、5,000~1,000,000、5,000~500,000、5,000~100,000、10,000~5,000,000、10,000~1,000,000、10,000~500,000、10,000~100,000、30,000~5,000,000、30,000~1,000,000、30,000~500,000、30,000~100,000、50,000~5,000,000、50,000~1,000,000、50,000~500,000、及び50,000~100,000が挙げられる。
また、本発明の重合体の重量平均分子量は、5,000以上、10,000以上、又は50,000以上とすることができる。この範囲であれば、十分な耐熱性、機械的強度、及び耐溶剤性を有する重合体となる。また、重量平均分子量は、2,000,000以下、1,000,000以下、又は500,000以下とすることができる。この範囲であれば、ゲル化することなく、安定な重合体となる。
本発明の重合体の重量平均分子量としては、5,000~2,000,000、5,000~1,000,000、5,000~500,000、10,000~2,000,000、10,000~1,000,000、10,000~500,000、50,000~2,000,000、50,000~1,000,000、及び50,000~500,000が挙げられる。
数平均分子量、及び重量平均分子量は、ポリスチレンを標準物質とした、ゲルパーミエーションクロマトグラフィー(GPC)により測定した値である。
本発明の重合体における式(2)で示される構造単位の含有率としては、5~70モル%、10~70モル%、及び30~70モル%が挙げられる。
式(2)で示される構造単位の含有率は、重合に供する原料化合物(モノマー及び/又は予備重合体を含む)の中の式(1)で示される化合物の比率を調節することで所望の値にすることができる。
式(2)で示される構造単位を有する重合体は、式(1)で示される化合物と他の重合性モノマー、又は反応性官能基を有する予備重合体とを重合させることにより製造することができる。
他の重合性モノマーは、式(1)の化合物の置換基Aに含まれる官能基と重縮合反応、重付加反応、又はラジカル重合反応により結合を生じ得る官能基を有するものを用いることができる。他の重合性モノマー中のこの官能基の数は、式(1)の置換基Aがアミノ基、水酸基、又はエポキシ基を含む場合は、2つ以上であればよく、式(1)の置換基Aが(メタ)アクリロイル基を含む場合は、1つ以上であればよい。
また、このような他の重合性モノマーに加えて、さらに、本発明の効果を損なわない範囲で、ホスホコリン基を有するモノマーや、スルホベタイン基を有するモノマーであって式(1)の化合物以外のモノマーを用いてもよい。
また、予備重合体と反応させる場合も、さらに、本発明の効果を損なわない範囲で、ホスホコリン基を有するモノマーや、スルホベタイン基を有するモノマーであって式(1)の化合物以外のモノマーを用いてもよい。
(a)Aがアミノ基を含む置換基である場合
式(1)の化合物においてAがアミノ基を含む置換基である場合、他の重合性モノマーとして、ジカルボン酸又はその誘導体、テトラカルボン酸二無水物、ジイソシアネートなどを用いることができる。
他の重合性モノマーは、1種を単独で、又は2種以上を組み合わせて使用できる。
他の重合性モノマーとして用いられるジカルボン酸又はその誘導体としては、例えば、下記式(16)
で示される化合物を用いることができる。
この場合、得られるポリアミドの繰り返し単位は、下記式(17)
で示される繰り返し単位となる。
中でも、芳香族ジカルボン酸が好ましく、2,2-ビス[4-(4-クロロカルボニルフェニルオキシ)フェニル]プロパンがより好ましい。
ジカルボン酸又はその誘導体は、1種を単独で、又は2種以上を組み合わせて使用できる。
他の重合性モノマーとして用いられるテトラカルボン酸二無水物としては、例えば、下記式(18)
で示される化合物を用いることができる。
この場合、一旦ポリアミド酸を得、このポリアミド酸のイミド化によりポリイミドを得ることができるが、得られるポリイミドの繰り返し単位は、下記式(19)
で示される繰り返し単位となる。
テトラカルボン酸二無水物は、1種を単独で、又は2種以上を組み合わせて使用できる。
他の重合性モノマーとして用いられるジイソシアネート化合物としては、例えば、下記式(20)
で示される化合物を用いることができる。
この場合、得られるポリウレアの繰り返し単位は、下記式(21)
で示される繰り返し単位となる。
中でも、4,4’-ジフェニルメタンジイソシアネート、ヘキサメチレンジイソシアネートが好ましく、4,4’-ジフェニルメタンジイソシアネートがより好ましい。
ジイソシアネート化合物は、1種を単独で、又は2種以上を組み合わせて使用できる。
式(1)の化合物においてAが水酸基を含む置換基である場合、他の重合性モノマーとして、ジイソシアネート化合物、ジカルボン酸又はその誘導体などを用いることができる。
他の重合性モノマーとして、ジイソシアネート化合物を用いれば、主鎖骨格にウレタン結合を有するポリウレタンが得られる。ジイソシアネート化合物の構造式、具体例、及び好ましいものは、官能基Aがアミノ基を含む置換基である場合と同じである。
また、得られるポリウレタンの繰り返し単位は、下記式(22)
で示される繰り返し単位となる。
ジイソシアネート化合物は、1種を単独で、又は2種以上を組み合わせて使用できる。
また、得られるポリウレタンの繰り返し単位は、下記式(23)
ジカルボン酸又はその誘導体は、1種を単独で、又は2種以上を組み合わせて使用できる。
式(1)の化合物においてAがエポキシ基を含む置換基である場合、他の重合性モノマーとして、式(1)の化合物以外のエポキシ化合物、ジカルボン酸又はその誘導体、ポリオール化合物、ジイソシアネート化合物などを用いることができる。
式(1)の化合物以外のエポキシ化合物は、1種を単独で、又は2種以上を組み合わせて使用できる。
ポリオール化合物は、1種を単独で、又は2種以上を組み合わせて使用できる。
式(1)の化合物においてAが(メタ)アクリロイル基を含む置換基である場合、他の重合性モノマーとして、(メタ)アクリル系化合物((メタ)アクリル酸又は(メタ)アクリレート)などを用いることができる。
で示される化合物を用いることができる。
この場合、得られる重合体の繰り返し単位は、下記式(25)
で示される繰り返し単位となる。
1,4-ブタンジオールジ(メタ)アクリレート、1,6-ヘキサンジオールジ(メタ)アクリレート、1,9-ノナンジオールジ(メタ)アクリレート、2-n-ブチル-2-エチル-1,3-プロパンジオールジ(メタ)アクリレート、トリプロピレングリコールジ(メタ)アクリレート、テトラエチレングリコールジ(メタ)アクリレート、メチレンビスアクリルアミド、トリメチロールプロパントリ(メタ)アクリレート、ペンタエリスリトールトリ(メタ)アクリレートなどの多官能モノマーなどが挙げられる。
(メタ)アクリル系化合物は、1種を単独で、又は2種以上を組み合わせて使用できる。
反応性官能基を末端に有する予備重合体としては、過剰量のジイソシアネート化合物と、ジオール化合物とを公知の方法で反応させて得られる、イソシアネート基末端含有ウレタン予備重合体が挙げられる。
イソシアネート基末端含有ウレタン予備重合体と、官能基Aがアミノ基を含む置換基である式(1)の化合物を反応させることによりウレア結合が形成され、主鎖骨格にウレタン結合とウレア結合とを有するポリ(ウレタン-ウレア)を製造することができる。
また、イソシアネート基末端含有ウレタン予備重合体と、官能基Aが水酸基を含む置換基である式(1)の化合物を反応させることによりウレタン結合が形成され、ポリウレタンを製造することができる。
中でも、ポリカーボネートジオール、ポリテトラメチレンエーテルグリコールが好ましく、ポリカーボネートジオールがより好ましい。
ジオール化合物は、1種を単独で、又は2種以上を組み合わせて使用できる。
中でも、4,4’-ジフェニルメタンジイソシアネート、ヘキサメチレンジイソシアネートが好ましく、4,4’-ジフェニルメタンジイソシアネートがより好ましい。
ジイソシアネート化合物は、1種を単独で、又は2種以上を組み合わせて使用できる。
また、ウレタン予備重合体の合成に用いるジオール化合物と式(1)の化合物との使用比率は、モル比で、ジオール化合物と式(1)の化合物が4:6~8:2程度とすることができ、中でも5:5~7:3程度が好ましい。
式(1)で示される化合物は剛直な化合物であるため、他の重合性モノマー又は反応性官能基を有する予備重合体の種類によっては、得られる重合体も剛直なものになり易い。医療材料は、生体に力学的ストレスを与えないために、ある程度柔軟であることが望ましい場合があり、そのような用途においては、式(1)で示される化合物を重合させる際に、式(1)の化合物の置換基Aに含まれる官能基と同じ官能基を2つ以上有する重合性モノマーを共存させて重合体の柔軟性を調節することが望ましい。
本発明の重合体の柔軟性を向上させるために、共存重合性モノマーは、ガラス転移点が0℃以下であるものを用いることが望ましい。
本発明の重合体は、人工血管、人工心臓弁、人工関節、人工皮膚、人工組織又は人工骨の細胞増殖用の足場、歯科材料、組織接着材、心臓ペースメーカー、ステント、手術用縫合糸のような生体に埋設して用いられる医療用品、カテーテル、コンタクトレンズ、薬物徐放送達用基材、内視鏡のような生体に接触して用いられる医療用品、血液透析膜、血液保存パックのような生体分離材料と接触して用いられる医療用品、これらの医療用品の被覆材などの材料として使用できる。
本発明の重合体は、単独で用いてもよく、本発明の効果を損なわない範囲で他の重合体と混合して用いてもよい。
本発明の重合体は、高い破断強度と伸長率を兼ね備えるため、特に、フィルム、シート、繊維、又は被膜のような形状に成形することに適している。
ナスフラスコ中で3,5-ジヒドロキシ安息香酸メチル(30.0g,148.5mmol)をジメチルアセトアミド(300ml)に攪拌、溶解し、得られた溶液に4-フルオロニトロベンゼン(50.3g,357mmol)と炭酸カリウム(49.3g,357mmol)を加え、85℃で16時間反応させた。反応終了後、反応混合物を蒸留水に注ぎ、得られた沈殿物を吸引濾過した。固体を40℃で真空乾燥することで、化合物(a)において、カルボキシル基がメチル化された化合物を白色固体として61.1g得た(収率100%)。
ナスフラスコ中で化合物(a)(41g,103.5mmol)、2-(ジメチルアミノ)エチルクロリド塩酸塩(17.9g,124.2mmol)、炭酸カリウム(28.6g,207mmol)をジメチルアセトアミド(400ml)に攪拌、溶解し、110℃で24時間反応させた。反応終了後、ジメチルアセトアミドを減圧下で留去し、クロロホルムで抽出し、0.5N塩酸、炭酸水素ナトリウム水溶液で洗浄した後、有機相を硫酸ナトリウムで脱水、ろ過後、溶媒を減圧下で留去し、化合物(b)を黄色固体として46g得た(収率95%)。
この化合物の構造は、下記のLC-MSスペクトルから確認した。
LC-MS(ES): Calcd. for C23H22N3O8 468.1 [M+H]+, Found.: 468.3
ナスフラスコ中で化合物(b)(6.0g,12.8mmol)をクロロホルム(75ml)に攪拌、溶解し、1,3プロパンスルトン(9.4g,76.8mmol)を加え、45℃で13時間反応させた。反応終了後、析出した白色固体を吸引濾過した。固体を40℃で真空乾燥することで、化合物(c)を白色固体として7.2g得た(収率95%)。
この化合物の構造は下記のLC-MSスペクトルから確認した。
LC-MS(ES): Calcd. for C26H28N3O11S 590.1 [M+H]+, Found.: 590.5
ナスフラスコ中で化合物(c)(300mg,0.51mmol)をメタノール(15ml)に分散し、5%パラジウム‐カーボン粉末(30mg)を加え、系内を水素置換し25℃で16時間反応させた。反応終了後、メタノールを減圧下で体積比10分の1程度まで濃縮し、ジエチルエーテル中に沈殿させ、吸引濾過した。固体を40℃で真空乾燥することで、スルホベタイン基含有ジアミン (d)を茶色固体として240mg得た(収率89%)。
この化合物の構造は下記のLC-MSスペクトルから確認した。
LC-MS(ES): Calcd. for C26H32N3O7S 530.2 [M+H]+, Found.: 530.6
実施例1
窒素雰囲気下、三口フラスコ中にポリカーボネートジオール(数平均分子量1,000)(3.3g,3.3mmol)とジメチルスルホキシド(1ml)を加え、70℃に昇温し、溶解させた。その溶液に4,4’‐ジフェニルメタンジイソシアネート(1.6g,6.6mmol)をジメチルスルホキシド(2ml)に溶解させたものを室温で滴下した。滴下終了後、70℃で1時間反応させた。反応終了後、スルホベタイン基含有ジアミン(d)(1.7g,3.3 mmol)をジメチルスルホキシド(10ml)に溶解させたものを室温で滴下した。滴下終了後、70℃で24時間反応させた。反応終了後、過剰のメタノール中に反応溶液を注ぎ込み、生成した沈殿物を吸引濾過した。得られた固体を40℃で真空乾燥することで、スルホベタイン基含有セグメント化ポリウレタンウレア(SPUUSB)を茶色固体として6.2g得た(収率91.8%)。
実施例1において、ポリカーボネートジオールの使用量を4.66g(4.66mmol)とし、スルホベタイン基含有ジアミン(d)の使用量を1.06g(2.0mmol)とした他は、実施例1と同様にして、スルホベタイン基含有セグメント化ポリウレタンウレア(SPUUSB30)を茶色固体として6.5g得た(収率88.8%)。
実施例1において、化合物(b)と反応させるプロパンスルトンに代えてブタンスルトンを用いて合成したスルホベタイン基含有ジアミンを実施例1と同様のモノマー比率で用いた他は、実施例1と同様にして、スルホベタイン基含有セグメント化ポリウレタンウレア(SPUUSBB)を茶色固体として2.48g得た(収率86.1%)。
実施例3において、ポリカーボネートジオールの使用量を3.7g(3.7mmol)とし、スルホベタイン基含有ジアミン(d)の使用量を0.87g(1.6mmol)とした他は、実施例3と同様にして、スルホベタイン基含有セグメント化ポリウレタンウレア(SPUUSBB30)を茶色固体として5.32g得た(収率89.3%)。
実施例3において、数平均分子量1,000のポリカーボネートジオールに代えて、数平均分子量2,000のポリカーボネートジオールを実施例3と同様のモノマー比率で用いた他は、実施例3と同様にして、スルホベタイン基含有セグメント化ポリウレタンウレア(SPUUSBBR)を茶色固体として8.6g得た(収率84.8%)。
実施例3において、化合物(a)と反応させる2-(ジメチルアミノ)エチルクロリド塩酸塩に代えて、2-(ジメチルアミノ)ヘキシルクロリド塩酸塩を用いて合成したスルホベタイン基含有ジアミンを実施例3と同様のモノマー比率で用いた他は、実施例3と同様にして、スルホベタイン基含有セグメント化ポリウレタンウレア(SPUUSBB6)を茶色固体として2.74g得た(収率51.6%)。
比較例1
窒素雰囲気下、三口フラスコ中にポリカーボネートジオール(1.1g,1.11mmol)とジメチルスルホキシド(1ml)を加え、70℃に昇温し、溶解させた。その溶液に4,4’‐ジフェニルメタンジイソシアネート(0.5g,2.2mmol)をジメチルスルホキシド(2ml)に溶解させたものを室温で滴下した。滴下終了後、70℃で1時間反応させた。反応終了後、1,3-ビス(4-アミノフェノキシ)ベンゼン(0.33g,1.1mmol)をジメチルスルホキシド(10ml)に溶解させたものを室温で滴下した。滴下終了後、70℃で24時間反応させた。反応終了後、過剰のメタノール中に反応溶液を注ぎ込み、生成した沈殿物を吸引濾過した。得られた固体を40℃で真空乾燥することで、セグメント化ポリウレタンウレア(SPUU)を茶色固体として1.69g得た(収率87.3%)。
実施例1~6及び比較例1で得た各セグメント化ポリウレタンウレア樹脂の重量平均分子量、及び数平均分子量を、下記条件のゲルパーミエーションクロマトグラフィーにより標準ポリスチレン換算で求めた。(GPC条件)
・装置:Shodex GPC-104システム(昭和電工株式会社製)
・カラム:Shodex GPC KD-806M(昭和電工株式会社製)
・ガードカラム:KF-G(昭和電工株式会社製)
・サンプル濃度:1重量%になるようにTHFで希釈した。
・移動相溶媒:テトラヒドロフラン (THF)
・流量:1.0ml/分
・カラム温度:40℃
(5%重量減少温度)
実施例1~6及び比較例1で得た各セグメント化ポリウレタンウレア樹脂の分解開始温度を以下の条件で測定した。
・装置:熱重量分析装置TG/DTA(セイコー電子工業株式会社製)
・測定範囲:40℃から550℃
・昇温速度:10℃/分
・雰囲気:窒素
実施例1~6及び比較例1で得た各セグメント化ポリウレタンウレア樹脂のガラス転移温度を以下の条件で測定した。
・装置:示差走査熱量計DSC-6200(セイコー電子工業株式会社製)
・測定範囲:-100℃から200℃
・昇温速度:10℃/分
実施例1~6及び比較例1で得た各セグメント化ポリウレタンウレア樹脂を、10wt%のDMF溶液として調製し、溶媒キャスト法によって膜を形成した。
得られた膜の破断強度と最大伸長率を、引張試験機を用いて以下の条件で測定した。
・装置:ストログラフ VG20E(株式会社東洋精機製作所製)
・引っ張り速度:12mm/分
・試験片の形状:ポリマーフィルムを長方形(長さ:40mm、幅:10mm、厚さ:0.2mm)に加工し、試験片とした。
(タンパク質吸着性)
実施例1~6及び比較例1で得た各セグメント化ポリウレタンウレア樹脂を、2.0重量%となるようにN,N-ジメチルホルムアミドに溶解させて、各ポリマー溶液を得た。各溶液から溶媒キャスト法により膜を形成させ、これを円形(直径:14mm、厚さ:0.2 mm)に切り抜き、各ポリマー膜による試験片を得た。
試験片をリン酸緩衝液に浸漬し、37℃で24時間振盪させた。次いで、試験片を取り出し、1mg/ml ウシ血漿アルブミン(BSA)水溶液に浸漬し、37℃で24時間振盪させた。次いで、水に浸漬、37℃で5分間、3回洗浄した。1%SDS水溶液に浸漬し、37℃で24時間振盪させ、試験片表面に吸着したタンパク質を溶離させ、回収した。さらに、BCAタンパク質アッセイキット(Thermo Fisher Scientific社製)で処理し、マイクロプレートリーダーで562nmの吸光度を測定した。
562nmにおける吸光度は試験片に吸着したウシ血漿アルブミンの量に比例する。
実施例1~6及び比較例1で得た各セグメント化ポリウレタンウレア樹脂を、2.0重量%となるようにN,N-ジメチルホルムアミドに溶解させて、各ポリマー溶液を得た。各溶液から溶媒キャスト法により膜を形成させ、これを正方形(8 mm x 8mm、厚さ:0.2 mm)に切り抜き、各ポリマー膜による試験片を得た。
また、正方形(8 mm x 8mm、厚さ:0.2 mm)に切り抜いたPETフィルムも参考例の試験片とした。
次いで、これらの試験片を、リン酸緩衝生理食塩水に室温で24時間浸漬した後、リン酸緩衝生理食塩水を抜き取り、さらにヒトの血液より採取したヒト血小板多血漿に37℃で2時間浸漬した。その後、その試験片のポリマー薄膜表面を、リン酸緩衝生理食塩水にて3回洗浄した。次いで、25% グルタルアルデヒドをリン酸緩衝生理食塩水で希釈したものを加え、2時間放置し血小板を固定した。走査型電子顕微鏡(SEM)により、作製したサンプルの表面観察を行った。
血小板吸着がない又はほとんど認められない場合を◎、わずかに血小板吸着が認められる場合を〇、血小板吸着が多く認められる場合を△、血小板吸着が非常に多く、凝集している場合を×と評価した。
これに対して、表1が示す通り、実施例1~6の重合体は、実用上十分な耐熱性、機械的強度、及び生体適合性を兼ね備えていた。特に、機械的強度については、実用上十分な破断強度と伸長率を兼ね備えていた。また、式(1)においてnが4である実施例3~5の重合体は、特に、機械的強度が高く、また、血小板の吸着が少なく優れた生体適合性を有していた。
Claims (13)
- 2つのAが共にアミノ基を含む置換基である、請求項1に記載の化合物。
- nが3~5の整数である、請求項1又は2に記載の化合物。
- 主鎖骨格に、アミド結合、ウレタン結合、ウレア結合、及びイミド結合からなる群より選ばれる結合を有する、請求項4に記載の重合体。
- 上記式(2)で示される構造単位を少なくとも1モル%と、ジイソシアネート化合物とジオール化合物とを反応させて得られるイソシアネート基末端含有ウレタン予備重合体からなる構造単位とを含有し、数平均分子量が5,000以上である、請求項4に記載の重合体。
- 主鎖骨格に、ウレタン結合、及びウレア結合を有する、請求項6に記載の重合体。
- nが3~5の整数である、請求項4~7の何れかに記載の重合体。
- 請求項4~8の何れかに記載の重合体を含むフィルム、シート、繊維、又は皮膜。
- 請求項4~8の何れかに記載の重合体を含む医療用品。
- 上記式(1)で示される化合物と、他の重合性モノマーとを、重縮合反応、重付加反応、若しくはラジカル重合反応させるか、又は上記式(1)で示される化合物を含む重合性モノマーと、これと反応し得る官能基末端含有予備重合体とを反応させる工程を含む、請求項4に記載の重合体の製造方法。
- 製造される重合体が、主鎖骨格に、アミド結合、ウレタン結合、ウレア結合、及びイミド結合からなる群より選ばれる結合を有するものである、請求項11に記載の製造方法。
- 上記式(1)における置換基Aがアミノ基又は水酸基を含み、式(1)で示される化合物と反応し得る官能基末端含有予備重合体が、ジイソシアネート化合物とジオール化合物とを反応させて得られるイソシアネート基末端含有ウレタン予備重合体である、請求項11に記載の製造方法。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/493,426 US11434322B2 (en) | 2017-03-24 | 2018-03-21 | Sulfobetaine group-comprising reactive compound, polymer thereof, and method of producing the polymer |
CA3056363A CA3056363A1 (en) | 2017-03-24 | 2018-03-21 | Sulfobetaine group-containing reactive compound, polymer thereof, and method for producing polymer |
KR1020197028614A KR20190133684A (ko) | 2017-03-24 | 2018-03-21 | 술포베타인기 함유 반응성 화합물, 그 중합체, 및 중합체의 제조 방법 |
EP18772000.8A EP3604275B1 (en) | 2017-03-24 | 2018-03-21 | Sulfobetaine-group-containing reactive compound, polymer thereof, and method for producing polymer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017059084A JP6916644B2 (ja) | 2017-03-24 | 2017-03-24 | スルホベタイン基含有反応性化合物、その重合体、及び重合体の製造方法 |
JP2017-059084 | 2017-03-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018174111A1 true WO2018174111A1 (ja) | 2018-09-27 |
Family
ID=63584529
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2018/011230 WO2018174111A1 (ja) | 2017-03-24 | 2018-03-21 | スルホベタイン基含有反応性化合物、その重合体、及び重合体の製造方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US11434322B2 (ja) |
EP (1) | EP3604275B1 (ja) |
JP (1) | JP6916644B2 (ja) |
KR (1) | KR20190133684A (ja) |
CA (1) | CA3056363A1 (ja) |
WO (1) | WO2018174111A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109894050A (zh) * | 2019-04-04 | 2019-06-18 | 中国石油大学(北京) | 一种芳基醚磺基甜菜碱表面活性剂及其制备方法 |
WO2021074857A1 (en) * | 2019-10-17 | 2021-04-22 | 3M Innovative Properties Company | Sulfobetaine-modified polyurethane or polyurea foam |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH1087601A (ja) | 1996-09-13 | 1998-04-07 | Nagase Kasei Kogyo Kk | 3−スルホプロピルベタイン類の製造方法 |
WO2004074298A1 (ja) | 2003-02-18 | 2004-09-02 | Tokai University | ホスホリルコリン基を有する化合物、その重合体ならびにその製造方法 |
WO2008029744A1 (fr) | 2006-09-01 | 2008-03-13 | Tokai University Educational System | Composé diamine ayant un groupe phosphorylcholine, polymère de celui-ci et procédé servant à produire celui-ci |
CN101429287A (zh) * | 2008-11-28 | 2009-05-13 | 南京大学 | 一种高抗凝血纤维素膜材料及其制备方法 |
JP2015061901A (ja) * | 2013-08-21 | 2015-04-02 | 学校法人東海大学 | ホスホリルコリン基を有する重合体からなるナノシート分散液 |
WO2016132993A1 (ja) * | 2015-02-17 | 2016-08-25 | 富士フイルム株式会社 | 重合用組成物およびその製造方法、これを含むコーティング用組成物、これらを用いたコーティング用組成物の製造方法ならびにコーティングの製造方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4151346B2 (ja) | 2002-08-09 | 2008-09-17 | 日立工機株式会社 | 燃焼式打込み工具 |
JP2008029744A (ja) | 2006-07-31 | 2008-02-14 | Samii Kk | 遊技機 |
-
2017
- 2017-03-24 JP JP2017059084A patent/JP6916644B2/ja active Active
-
2018
- 2018-03-21 CA CA3056363A patent/CA3056363A1/en active Pending
- 2018-03-21 KR KR1020197028614A patent/KR20190133684A/ko unknown
- 2018-03-21 WO PCT/JP2018/011230 patent/WO2018174111A1/ja active Application Filing
- 2018-03-21 US US16/493,426 patent/US11434322B2/en active Active
- 2018-03-21 EP EP18772000.8A patent/EP3604275B1/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH1087601A (ja) | 1996-09-13 | 1998-04-07 | Nagase Kasei Kogyo Kk | 3−スルホプロピルベタイン類の製造方法 |
WO2004074298A1 (ja) | 2003-02-18 | 2004-09-02 | Tokai University | ホスホリルコリン基を有する化合物、その重合体ならびにその製造方法 |
JP4628951B2 (ja) | 2003-02-18 | 2011-02-09 | 学校法人東海大学 | ホスホリルコリン基を有する化合物、その重合体ならびにその製造方法 |
WO2008029744A1 (fr) | 2006-09-01 | 2008-03-13 | Tokai University Educational System | Composé diamine ayant un groupe phosphorylcholine, polymère de celui-ci et procédé servant à produire celui-ci |
JP5276443B2 (ja) | 2006-09-01 | 2013-08-28 | 学校法人東海大学 | ホスホリルコリン基を有するジアミン化合物、その重合体ならびに製造方法 |
CN101429287A (zh) * | 2008-11-28 | 2009-05-13 | 南京大学 | 一种高抗凝血纤维素膜材料及其制备方法 |
JP2015061901A (ja) * | 2013-08-21 | 2015-04-02 | 学校法人東海大学 | ホスホリルコリン基を有する重合体からなるナノシート分散液 |
WO2016132993A1 (ja) * | 2015-02-17 | 2016-08-25 | 富士フイルム株式会社 | 重合用組成物およびその製造方法、これを含むコーティング用組成物、これらを用いたコーティング用組成物の製造方法ならびにコーティングの製造方法 |
Non-Patent Citations (2)
Title |
---|
POLYMER JOURNAL, vol. 22, 1990, pages 355 |
See also references of EP3604275A4 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109894050A (zh) * | 2019-04-04 | 2019-06-18 | 中国石油大学(北京) | 一种芳基醚磺基甜菜碱表面活性剂及其制备方法 |
CN109894050B (zh) * | 2019-04-04 | 2020-04-03 | 中国石油大学(北京) | 一种芳基醚磺基甜菜碱表面活性剂及其制备方法 |
WO2021074857A1 (en) * | 2019-10-17 | 2021-04-22 | 3M Innovative Properties Company | Sulfobetaine-modified polyurethane or polyurea foam |
CN114555666A (zh) * | 2019-10-17 | 2022-05-27 | 3M创新有限公司 | 磺基甜菜碱改性的聚氨酯或聚脲泡沫 |
Also Published As
Publication number | Publication date |
---|---|
EP3604275A4 (en) | 2020-03-18 |
US20200131300A1 (en) | 2020-04-30 |
US11434322B2 (en) | 2022-09-06 |
JP6916644B2 (ja) | 2021-08-11 |
KR20190133684A (ko) | 2019-12-03 |
EP3604275B1 (en) | 2022-02-16 |
EP3604275A1 (en) | 2020-02-05 |
JP2018162216A (ja) | 2018-10-18 |
CA3056363A1 (en) | 2018-09-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Fukushima | Poly (trimethylene carbonate)-based polymers engineered for biodegradable functional biomaterials | |
US4623347A (en) | Antithrombogenic elastomer products | |
WO2009137715A2 (en) | Versatile biodegradable elastic polymers featured with dual crosslinking mechanism for biomedical applications | |
Gyawali et al. | Citric-acid-derived photo-cross-linked biodegradable elastomers | |
JP2015061901A (ja) | ホスホリルコリン基を有する重合体からなるナノシート分散液 | |
WO2018174111A1 (ja) | スルホベタイン基含有反応性化合物、その重合体、及び重合体の製造方法 | |
JP5276443B2 (ja) | ホスホリルコリン基を有するジアミン化合物、その重合体ならびに製造方法 | |
Liu et al. | Synthesis of a novel biomedical poly (ester urethane) based on aliphatic uniform-size diisocyanate and the blood compatibility of PEG-grafted surfaces | |
Xu et al. | Synthesis of polycarbonate urethanes with functional poly (ethylene glycol) side chains intended for bioconjugates | |
JP4628951B2 (ja) | ホスホリルコリン基を有する化合物、その重合体ならびにその製造方法 | |
Luo et al. | Novel THTPBA/PEG‐derived highly branched polyurethane scaffolds with improved mechanical property and biocompatibility | |
US9034930B2 (en) | Biodegradable polymeric hydrogel composition | |
Nutan et al. | Library of Derivatizable Multiblock Copolymers by Nucleophilic Substitution Polymerization and Targeting Specific Properties | |
Nan et al. | Synthesis and characterization of novel h‐HTBN/PEG PU copolymers: effect of surface properties on hemocompatibility | |
WO2007036782A1 (en) | A oligomeric lactide macromer based copolymer and a process for the preparation thereof | |
Manzano et al. | Synthesis and applications of carbohydrate-based polyurethanes | |
Yang et al. | Shape memory polyurethane potentially used for vascular stents with water-induced stiffening and improved hemocompatibility | |
Barrett et al. | Developing chemoselective and biodegradable polyester elastomers for bioscaffold application | |
Iwano et al. | Synthesis of biocompatible elastic polyurethane containing phospholipid moiety | |
KR100285238B1 (ko) | 폴리디메틸실록산(pdms)과 폴리에틸렌글리콜(peg)이 결합된 의료용 폴리우레탄 및 그의 제조방법 | |
JP4058676B2 (ja) | 機能性ポリウレタンおよび/又はポリウレタンウレアおよびその製造方法 | |
KR20220118848A (ko) | 형상기억고분자, 이의 제조방법 및 용도 | |
Bizet | Design of Waterborne Isocyanate-free Poly (Hydroxy Urethane) s–Poly (Butyl Methacrylate) Hybrids via Miniemulsion and Properties of the Cast Films | |
JP2004131566A (ja) | 分岐ポリエチレンオキシド−合成高分子ブロック共重合体 | |
Liu et al. | Degradable bioelastomers: synthesis and biodegradation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18772000 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3056363 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20197028614 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2018772000 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2018772000 Country of ref document: EP Effective date: 20191024 |