WO2013002021A1 - ポリマー及びその製造方法 - Google Patents
ポリマー及びその製造方法 Download PDFInfo
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- WO2013002021A1 WO2013002021A1 PCT/JP2012/065040 JP2012065040W WO2013002021A1 WO 2013002021 A1 WO2013002021 A1 WO 2013002021A1 JP 2012065040 W JP2012065040 W JP 2012065040W WO 2013002021 A1 WO2013002021 A1 WO 2013002021A1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F230/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F230/02—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing phosphorus
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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
- 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
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—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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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F130/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F130/02—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing phosphorus
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
- C08F220/36—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate containing oxygen in addition to the carboxy oxygen, e.g. 2-N-morpholinoethyl (meth)acrylate or 2-isocyanatoethyl (meth)acrylate
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/38—Esters containing sulfur
- C08F220/387—Esters containing sulfur and containing nitrogen and oxygen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/32—Esters containing oxygen in addition to the carboxy oxygen containing epoxy radicals
- C08F220/325—Esters containing oxygen in addition to the carboxy oxygen containing epoxy radicals containing glycidyl radical, e.g. glycidyl (meth)acrylate
Definitions
- the present invention relates to a novel polymer useful for making a medical device in contact with a biological tissue biocompatible, a production method thereof, and a surface treatment agent for a medical device using the polymer.
- Patent Document 1 A technique for imparting lubricity by coating the surface of a medical device has been conventionally known (Patent Document 1, etc.).
- Patent Document 2 in order to enhance biocompatibility, 2-methacryloyloxyethyl-2-trimethylammonioethyl phosphate (hereinafter abbreviated as MPC) and allylamine (hereinafter abbreviated as AAM) are provided on the surface of a medical device.
- MPC 2-methacryloyloxyethyl-2-trimethylammonioethyl phosphate
- AAM allylamine
- Patent Document 3 proposes a method in which a primary amino group-containing MPC copolymer obtained by copolymerizing MPC and 2-aminoethyl methacrylate (hereinafter abbreviated as AEMA) is reacted with the surface of a reactive medical device.
- AEMA 2-aminoethyl methacrylate
- This method has a highly reactive amino group and is chemically bonded to the surface of the medical device, so that a highly durable surface can be obtained by increasing the amino group introduction rate.
- the unreacted residual functional group cationicity may cause protein adsorption, immune cell activation, and cell adsorption, which may reduce its biocompatibility.
- An object of the present invention is to provide a polymer having low cytotoxicity and a method for producing the same that can impart surface hydrophilicity and biocompatibility to a surface of a medical device or the like by a simple treatment.
- Another object of the present invention is to provide a surface treatment agent for medical devices with low cytotoxicity that can impart surface hydrophilicity and biocompatibility to a surface of a medical device or the like by a simple treatment.
- the present inventors are excellent in improving the hydrophilicity of the surface of a medical device by reacting a specific phosphorylcholine-like group-containing polymer with 2-aminoethanethiol. Even when the surface reactivity is low, the inventors have found that a polymer having high biocompatibility and low cytotoxicity can be obtained, and the present invention has been completed.
- a polymer having a weight average molecular weight of 10,000 to 5,000,000 having structural units represented by the formulas (1a) and (1b).
- MPC represented by the formula (2a) and glycidyl methacrylate (hereinafter abbreviated as GMA) represented by the formula (2b) are mixed in a molar ratio of GMA with respect to the total amount of MPC and GMA.
- GMA glycidyl methacrylate
- AET 2-aminoethanethiol
- the polymer of the present invention has the above structure and is a low cytotoxic polymer that can impart surface hydrophilicity and biocompatibility to a surface of a medical device or the like by a simple treatment. It is useful as a surface treatment agent for medical devices such as guide wires, catheters, artificial blood vessels, heart-lung machines, contact lenses, and intraocular lenses.
- FIG. 2 is an IR measurement chart of the polymer prepared in Example 1.
- FIG. 2 is a measurement chart of 1 H NMR of the polymer prepared in Example 1.
- FIG. 2 is a measurement chart of 1 H NMR of the polymer prepared in Example 1.
- the polymer of the present invention is a polymer having a structural unit represented by the above formulas (1a) and (1b) and having a weight average molecular weight of 10,000 to 5,000,000, preferably 100,000 to 1,500,000. It is also possible to have other structural units other than the structural units represented by the formulas (1a) and (1b). If the weight average molecular weight is less than 10,000, the adhesion to the surface of the medical device is not sufficient and the durability may be inferior. If it exceeds 5,000,000, the viscosity at the time of manufacture will be too high and handle it. May become difficult.
- X represents a group represented by the following formula.
- b / (a + b) is less than 5
- adhesion to the surface of a medical device or the like becomes insufficient, and there is a possibility that durability is deteriorated and hydrophilicity of the surface is not improved.
- b / (a + b) exceeds 30, cytotoxicity may increase.
- the polymer of the present invention is, for example, MPC represented by the above formula (2a) and GMA represented by the above formula (2b) at a molar ratio of 5-30% with respect to the total amount of MPC and GMA.
- MPC represented by the above formula (2a)
- GMA represented by the above formula (2b)
- the polymerization reaction of the monomer composition is, for example, replaced with an inert gas such as nitrogen, carbon dioxide, argon or helium in the presence of a radical polymerization initiator or radical polymerization in an atmosphere, for example, bulk polymerization or suspension polymerization. It can be carried out by a known method such as emulsion polymerization or solution polymerization. From the viewpoint of purification of the resulting polymer, solution polymerization is preferred.
- a polymer having a structural unit represented by the formula (2) is obtained.
- the polymer can be purified by a general purification method such as a reprecipitation method, a dialysis method, or an ultrafiltration method.
- radical polymerization initiator examples include 2,2-azobis (2-amidinopropyl) dihydrochloride, 2,2-azobis (2- (5-methyl-2-imidazolin-2-yl) propane) 2 Hydrochloride, 4,4-azobis (4-cyanovaleric acid), 2,2-azobisisobutyramide dihydrate, 2,2-azobis (2,4-dimethylvaleronitrile), 2,2-azobis Isobutyronitrile (AIBN), dimethyl-2,2′-azobisisobutyrate, 1-((1-cyano-1-methylethyl) azo) formamide, 2,2′-azobis (2-methyl-N -Phenylpropionamidin) dihydrochloride, 2,2'-azobis (2-methyl-N- (2-hydroxyethyl) -propionamide), 2,2'-azobis (2-methylpropionamide) And azo radical polymerization initiators such as 4,4′-azobis (4-cyanopentanoic acid) and 2,2′-azobis (2-
- persulfate oxides such as ammonium persulfate, potassium persulfate, and sodium persulfate.
- radical polymerization initiators may be used alone or in a mixture.
- the amount of the polymerization initiator used is usually 0.001 to 10 parts by mass, preferably 0.01 to 5.0 parts by mass with respect to 100 parts by mass of the monomer composition.
- the polymerization reaction of the monomer composition can be performed in the presence of a solvent.
- a solvent those which dissolve the monomer composition and do not react can be used, for example, alcohol solvents such as water, methanol, ethanol, n-propanol and isopropanol; ketone systems such as acetone, methyl ethyl ketone and diethyl ketone.
- the solvent include ester solvents such as ethyl acetate; linear or cyclic ether solvents such as ethyl cellosolve, tetrahydrofuran, and N-methylpyrrolidone; nitrogen-containing solvents such as acetonitrile and nitromethane.
- water, alcohol, or a mixed solvent thereof is used.
- the obtained polymer represented by the formula (2) When the obtained polymer represented by the formula (2) is used for the next reaction, it may be used after purification, or may be diluted with a polymerization solvent and used as it is.
- the reaction of the polymer represented by the formula (2) obtained by the polymerization reaction of the monomer composition and the AET represented by the formula (3) can be performed by heating in a solvent.
- Purification of the polymer represented by the formula (1) obtained can be performed by a general purification method such as a reprecipitation method, a dialysis method, or an ultrafiltration method.
- solvent those which dissolve the polymer represented by the formula (2) and AET and do not react can be used, and examples thereof include protic solvents such as methanol, ethanol, n-propanol and isopropanol. N-propanol is preferred from the viewpoint of reactivity.
- the solution concentration of the polymer represented by the formula (2) during the reaction is preferably 4 to 30% by mass. If it exceeds 30% by mass, the viscosity of the reaction solution increases, and the reaction may not proceed sufficiently. On the other hand, if the amount is less than 4% by mass, the amount of the reaction solvent increases, which may reduce the production efficiency.
- the charged amount of the polymer represented by the formula (2) and AET is preferably such that the molar ratio of the epoxy group to the AET in the polymer represented by the formula (2) is 1: 3 to 100.
- the molar ratio of the AET exceeds 100, it is not economical, and when it is less than 3, a side reaction may occur and a desired water-soluble polymer may not be obtained.
- the above reaction includes a method of adding AET to the polymer represented by the formula (2) and a method of adding the polymer represented by the formula (2) to the AET.
- AET may be added after being dissolved in a solvent in advance, or may be added as it is, but if it is gradually added, side reaction may occur and the desired water-soluble polymer may not be obtained. Therefore, it is preferable to add all at once.
- the reaction temperature is preferably 40 to 100 ° C. If the temperature is lower than 40 ° C, the reaction does not proceed sufficiently. If the temperature exceeds 100 ° C, the resulting polymer may be decomposed.
- the reaction time is preferably 3 hours or more and 48 hours or less. If it is less than 3 hours, it becomes difficult to control the reaction. Moreover, when it exceeds 48 hours, a side reaction will arise and the purity of the polymer obtained may fall. Further, during the reaction, it is preferable to carry out the reaction while substituting the inside of the reaction vessel with an inert gas such as nitrogen or argon to prevent the thiol group of AET from being oxidized to disulfide. After completion of the reaction, the desired polymer represented by the formula (1) can be obtained by using a general purification method such as reprecipitation method, dialysis method, and ultrafiltration method.
- the surface treatment agent for medical devices of the present invention comprises an aqueous solution containing 0.1 to 20% by mass of the polymer of the present invention.
- concentration of the polymer in the aqueous solution is less than 0.1% by mass, the reactivity with the surface of the medical device is lowered, and when it exceeds 20% by mass, the viscosity of the aqueous solution increases and handling may be deteriorated.
- the surface treatment agent for medical devices of the present invention can be used by, for example, a method of immobilizing the polymer of the present invention by applying to the surface of the medical device or immersing the medical device in the surface treatment agent for medical devices. it can.
- the immobilization include a method of covalently bonding the polymer of the present invention to the surface of a medical device, a method of ionic bonding, and a method of coordinate bonding. From the viewpoint of durability, covalent bonding is preferable.
- the method for covalent bonding include a method in which a functional group having reactivity with an amino group present in the polymer of the present invention is present on the surface of a medical device and these are covalently bonded.
- the functional group examples include a carboxyl group, a carboxylic anhydride group, an epoxy group, and an isocyanate group.
- the surface of the medical device is used with a polyfunctional reagent such as diisocyanate or diepoxy. By converting it into a functional group, the surface can be made reactive with an amino group.
- the medical device has no functional group such as polyethylene
- the surface of the medical device is treated with plasma treatment, corona treatment, ozone treatment, etc., for example, by adding a carboxyl group or the like to the surface to form an amino group.
- the surface can be reactive with respect to.
- the covalent bonding method can be appropriately selected from known conditions depending on the type and amount of the functional group, the material of the medical device, and the like.
- Examples of medical devices to which the surface treatment agent of the present invention is applied include medical devices that come into contact with body fluids or blood, such as guide wires, catheters, artificial blood vessels, artificial heart lungs, contact lenses, and intraocular lenses.
- Cytotoxicity tests were performed with reference to ISO 10993-5: 2009 and N. Tani et al. Toxicology in vitro 13 (1999) 175-187, and evaluated by cell viability.
- DMEM Dulbecco's Modified Eagle
- 5 mL of an antibiotic / antimycotic solution 100 ⁇ was added through a sterile filter (0.22 ⁇ m) made of polyvinylidene fluoride (PVDF).
- PVDF polyvinylidene fluoride
- FBS sterilized fetal bovine serum
- Cell Culture 9 mL of cell culture medium and 1 mL of cell suspension were added to a sterile petri dish, and the cells were grown in a CO 2 incubator for 48 hours or more to proliferate. The cells in the petri dish were observed with a microscope, and it was confirmed that the number of cells increased and the state of the cells (whether they were dead or floated without being attached). Cell seeding The cell suspension was adjusted to a concentration of 1 ⁇ 10 5 cells / mL using a cell culture medium. The cell suspension 100 ⁇ L / well whose concentration was adjusted to 96 well plate was dispensed with a micropipette and cultured in a CO 2 incubator for 24 hours.
- NR stock solution was dissolved in ion-exchanged water so that the NR was 5 mg / mL.
- the NR stock solution was diluted 100 times with a cell culture medium to obtain an NR medium.
- the 96-well plate exposed to the test substance was taken out, the medium was thrown into a washbasin, and the remaining medium was removed by tapping on a Kim towel.
- the cells were cultured in a CO 2 incubator for 3 hours to incorporate NR into the cells.
- the 96 well plate was removed from the CO 2 incubator and the NR medium was removed.
- MAA Methacrylic Acid
- PE Grafted Polyethylene
- MAA Methacrylic Acid
- PE Grafted Polyethylene
- a polyethylene film cut to 1 ⁇ 4 cm was placed between electrodes of a corona discharge treatment apparatus with an interelectrode distance of 3 cm and an interelectrode voltage of 15 kilovolts, and was subjected to a discharge treatment. . Subsequently, it was immersed in a 10% by mass aqueous methacrylic acid solution, and after deaeration treatment, graft polymerization was performed under vacuum conditions. After polymerization, the film was sufficiently washed with water to obtain a MAA grafted PE film.
- Phosphate Buffer Solution 0.900 g of sodium chloride and 0.104 g of sodium dihydrogen phosphate were weighed into a 100 cc volumetric flask, and ion exchanged water was added to make 100 mL. What was adjusted to pH 7.4 vicinity by adding 1N sodium hydroxide aqueous solution to this was made into the phosphate buffer solution. Preparation of protein soil solution 0.388 g of albumin, 0.161 g of ⁇ -globulin, 0.120 g of lysozyme, and 0.100 g of mucin were weighed, and 100 mL of phosphate buffer was added and dispersed.
- a 1M calcium chloride aqueous solution was added and mixed uniformly to obtain a protein soil solution.
- Preparation of Extract 50 mL of ion-exchanged water was placed in a 100 cc volumetric flask, 148 ⁇ L of trifluoroacetic acid was added thereto, and the volume was increased to 100 mL with ion-exchanged water.
- the liquid prepared above and 100 mL of acetonitrile were mixed and used as an extract.
- Protein adsorption test Two 1 ⁇ 4 cm polymer-grafted films were immersed in 32 mL of the protein soil solution and allowed to stand at 37 ° C. for 4 hours. Thereafter, the film was rinsed with physiological saline, and immersed in 32 mL of the extract to extract for 1 hour. 200 ⁇ L of the extracted liquid was collected, 800 ⁇ L of the extracted liquid was added for dilution, 1 mL of Micro BCA reagent was added and heated at 60 ° C. for 1 hour, and then the absorbance at 562 nm was measured to calculate the amount of protein attached.
- Evaluation criteria A; (sample protein adsorption amount / blank protein adsorption amount) ⁇ 0.2, B; 0.2 ⁇ (sample protein adsorption amount / blank protein adsorption amount) ⁇ 0.8, C; 0.8 ⁇ ( Sample protein adsorption / blank protein adsorption).
- a PE film was used for the blank.
- Example 1-1 Dissolved in 68.3 g of MPC (manufactured by NOF Corporation), 1.7 g of GMA (manufactured by NOF Corporation) and 210.0 g of n-propanol (NPA, manufactured by Kishida Chemical Co., Ltd.), a thermometer and a cooling tube were attached. Nitrogen was blown for 30 minutes in a 500 mL four-necked flask. Thereafter, 0.27 g of t-butyl peroxyneodecanoate (PB-ND, manufactured by NOF Corporation) was added at 60 ° C., and a polymerization reaction was carried out for 8 hours. The chemical structure of the obtained polymer was confirmed by IR and 1 H NMR.
- PB-ND t-butyl peroxyneodecanoate
- the polymer is a polymer having a ratio of 95 mol% based on MPC represented by the formula (1a), a ratio of 5 mol% based on units having an amino group represented by the formula (1b), and a weight average molecular weight of 650000. all right.
- Example 1-2 MPC 66.4 g, GMA 3.6 g, and NPA 163.3 g were placed in a 500 mL four-necked flask equipped with a thermometer and a condenser, and nitrogen was blown in for 30 minutes. Thereafter, 0.23 g of PB-ND was added at 60 ° C., and the polymerization reaction was carried out for 8 hours. The chemical structure of the obtained polymer was confirmed by IR and 1 H NMR. Subsequently, 204.2 g of NPA was added to 233.3 g of this polymerization solution (polymer solution represented by the formula (2)) and mixed uniformly.
- polymer solution represented by the formula (2) polymer solution represented by the formula (2)
- the polymer is a polymer having a ratio based on MPC represented by the formula (1a) of 90 mol%, a ratio based on units having an amino group represented by the formula (1b) of 10 mol%, and a weight average molecular weight of 880000. all right.
- Example 1-3 62.5 g of MPC, 7.5 g of GMA, and 210.0 g of NPA were placed in a 500 mL four-necked flask equipped with a thermometer and a condenser tube, and nitrogen was blown for 30 minutes. Thereafter, 0.27 g of PB-ND was added at 60 ° C., and the polymerization reaction was carried out for 8 hours. The chemical structure of the obtained polymer was confirmed by IR and 1 H NMR. Subsequently, 157.5 g of NPA was added to 280.0 g of this polymerization solution (polymer solution represented by formula (2)) and mixed uniformly.
- polymer solution represented by formula (2) polymer solution represented by formula (2)
- Example 1-4 MPC 58.0 g, GMA 12.0 g, and NPA 163.3 g were placed in a 500 mL four-necked flask equipped with a thermometer and a condenser, and nitrogen was blown for 30 minutes. Thereafter, 0.23 g of PB-ND was added at 60 ° C., and the polymerization reaction was carried out for 8 hours. The chemical structure of the obtained polymer was confirmed by IR and 1 H NMR. Subsequently, 204.2 g of NPA was added to 233.3 g of this polymerization solution (polymer solution represented by the formula (2)) and mixed uniformly.
- polymer solution represented by the formula (2) polymer solution represented by the formula (2)
- Comparative Examples 1-1 and 1-2 The reaction was performed in the same manner as in Example 1-1 except that each monomer, solvent, and initiator shown in Table 1 were used. Each measurement was performed on the obtained polymer in the same manner as in Example 1-1. The results are shown in Table 1.
- Comparative Example 1-3 18.8 g of MPC and 1.2 g of AEMA (manufactured by Aldrich) were dissolved in 80.0 g of ion-exchanged water, placed in a 200 mL four-necked flask equipped with a thermometer and a condenser tube, and nitrogen was blown for 30 minutes. Thereafter, 0.1492 g of 2,2′-azobis (2-methylpropionamidine) dihydrochloride (V-50, manufactured by Wako Pure Chemical Industries, Ltd.) was added at 60 ° C., and the polymerization reaction was carried out for 8 hours. The chemical structure of the obtained polymer was confirmed by IR and 1 H NMR.
- Comparative Examples 1-4 and 1-5 Polymerization was carried out in the same manner as Comparative Example 1-3 except that each monomer, solvent, and initiator shown in Table 1 were used. The chemical structure of the obtained polymer was confirmed by IR and 1 H NMR.
- the cell viability of the polymers of Examples 1-1 to 1-4 was higher than that of Comparative Examples 1-2 to 1-4, and was found to be safe.
- the films surface is hydrophilized and the protein adsorption is suppressed.
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Abstract
Description
しかし、AAMは毒性が高く取り扱いが不便であり、AAMの共重合組成比を高くすることは好ましくない。
特許文献3には、MPCと2-アミノエチルメタクリレート(以下、AEMAと略す)とを共重合することにより得られる1級アミノ基含有MPCコポリマーを、反応性の医療機器表面と反応させる方法が提案されている。この方法は、反応性の高いアミノ基を有し、医療機器表面に対して化学結合させるために、アミノ基の導入率を高くすることで高耐久性の表面が得られる。
しかし、未反応で残存する官能基のカチオン性によって、たんぱく質の吸着や免疫細胞の活性化、細胞への吸着が生じ、その生体適合性が低減するおそれがある。
本発明の別の課題は、医療機器等の表面に簡便な処理で表面親水性と生体適合性とを付与しうる、細胞毒性の低い医療機器用表面処理剤を提供することにある。
本発明のポリマーは、上記式(1a)及び(1b)で表される構成単位を有する重量平均分子量10,000~5,000,000、好ましくは、100,000~1,500,000のポリマーであり、式(1a)及び(1b)で表される構成単位以外の他の構成単位を有することも可能である。重量平均分子量が10,000未満の場合は、医療機器表面への付着性が十分でないため耐久性が劣るおそれがあり、5,000,000を超える場合は、製造時の粘性が高くなりすぎ取り扱いが困難となるおそれがある。
反応時間は、3時間以上48時間以内が好ましい。3時間未満であると、反応を制御することが難しくなる。また、48時間を超えると、副反応が生じ、得られるポリマーの純度が低下する可能性がある。
また、反応時は、反応容器内を窒素やアルゴンなどの不活性ガスに置換することにより、AETのチオール基が酸化してジスルフィドとなることを防ぎながら反応させることが好ましい。
前記反応終了後、得られた反応液を再沈殿法、透析法、限外濾過法などの一般的な精製方法を用いることで目的の式(1)で示されるポリマーを得ることができる。
該固定化は、例えば、医療機器表面に本発明のポリマーを共有結合させる方法、イオン結合させる方法、配位結合させる方法が挙げられる。耐久性の点からは共有結合させることが好ましい。
前記共有結合させる方法として、例えば、医療機器の表面に、本発明のポリマー中に存在するアミノ基に対して反応性を有する官能基を存在させ、これらを共有結合させる方法が挙げられる。
医療機器が、ポリエチレン等の官能基を全く持たない場合には、医療機器の表面を、プラズマ処理、コロナ処理、オゾン処理等で処理し、例えば、カルボキシル基等を表面に付与することによってアミノ基に対して反応性を有する表面とすることができる。
前記共有結合させる方法は、その官能基の種類や量、医療機器の材質等により、公知の条件から適宜選択して行うことができる。
<化合物中のアミノ基の定量>
アミノ基の定量は、2,4,6-トリニトロベンゼンスルホン酸ナトリウム(以下、TNBSと略す)を用いて行った。具体的には、得られたポリマー0.01gを蒸留水9.99gに溶解させ、これに113mMのホウ酸緩衝液4mL、11.4mMのNa2SO3水溶液1mL、3.8mMのTNBS水溶液1mLを加え、37℃で1時間反応を行った。反応終了後、紫外可視分光光度計(日本分光社製 V-550)を用いて波長420nmで吸光度の測定を行い、ポリマー中のアミノ基の導入率を算出した。
得られたポリマー5mgを、0.1mol/L硫酸ナトリウム水溶液1gへ溶解し、測定した。その他の測定条件は以下の通りである。
カラム:Shodex(GSM-700)、移動相:0.1mol/L硫酸ナトリウム水溶液、標準物質:プルラン、検出:視差屈折率計RI-8020(東ソー社製)、重量平均分子量(Mw)の算出:分子量計算プログラム(SC-8020用GPCプログラム)、流速1.0ml/分、カラム温度:40℃、試料溶液注入量:100μL、測定時間:30分間。
細胞毒性試験は、ISO10993-5:2009及びN.Tani et al. Toxicology in vitro 13(1999)175-187を参考に行い、細胞生存率により評価した。
細胞培養用培地の調製
ダルベッコ改変イーグル(DMEM)培地の500mLのボトルに、抗生物質・抗真菌剤溶液(100x)5mLをポリフッ化ビニリデン(PVDF)製滅菌フィルター(0.22μm)に通して加えた。続いて、滅菌済みウシ胎児血清(FBS)50mLを4℃にて解凍してから加え、細胞培養用培地とした。
細胞の培養
滅菌シャーレに細胞培養用培地9mL、細胞の懸濁液1mLを添加し、CO2インキュベーター内で48時間以上培養して細胞を増殖させた。シャーレ中の細胞を顕微鏡で観察し、細胞数が増えていることと、細胞の状態(死滅したり、接着せずに浮遊したりしていないか)を確認した。
細胞の播種
細胞懸濁液を濃度が1×105cells/mLになるように、細胞培養用培地を用いて濃度調整した。96wellプレートに濃度調整した細胞懸濁液100μL/wellをマイクロピペットで分注し、CO2インキュベーター内で24時間培養した。
サンプルのポリマーと陽性対照の生化学用ラウリル硫酸ナトリウム(SLS)を、細胞培養用培地又はダルベッコリン酸緩衝生理食塩水(10x)(PBS)で溶解し、PVDF製滅菌フィルター(0.22μm)を通して滅菌した。調製したポリマー溶液(被験物質)を96wellプレート上で段階希釈した。
被験物質の暴露
上記で調製した、ポリマー濃度1.0質量%の被験物質を、24時間培養した上記96wellプレートに100μL添加し、CO2インキュベーター内で24時間暴露した。
NRを5mg/mLとなるようにイオン交換水に溶解し、NR保存液とした。NR保存液を細胞培養用培地で100倍希釈し、NR培地とした。被験物質を暴露した96wellプレートを取り出し、培地を洗面器に捨てキムタオル上でたたいて残った培地を取り除いた。続いて、NR培地を100μL/wellずつマイクロピペットで添加した後、CO2インキュベーター内で3時間培養し、細胞にNRを取り込ませた。
CO2インキュベーターから96wellプレートを取り出してNR培地を取り除いた。100μL/wellのPBSを添加し、次いで、PBSを取り除いた後、エタノール50質量%、イオン交換水49質量%、酢酸1質量%の割合で混合したNR抽出液を100μL/wellずつマイクロピペットで添加し、振盪機で5分間攪拌して細胞からNRを抽出し、プレートリーダーで540nmの吸光度を測定した。
下式より細胞生存率50%となるSLSの接触濃度が約0.01質量%であることを確認し、被検物質処理時の細胞生存率を算出した。
1×4cmにカットしたポリエチレンフィルムを電極間距離3cm、電極間電圧15キロボルトのコロナ放電処理装置の電極間に設置し、放電処理を行った。次いで、10質量%メタクリル酸水溶液中に浸漬し、脱気処理後、真空条件化でグラフト重合を行った。重合後、十分に水洗することでMAAグラフト化PEフィルムを得た。
水溶性カルボジイミド0.04gを含む、後述する実施例及び比較例で調製したポリマーの5質量%水溶液4.0g中に、上記で作製した1×4cmのMAAグラフト化PEフィルムを浸漬し、室温で24時間カップリング反応処理を行った。処理後、水洗することで得られたポリマーグラフト化フィルムについて以下の評価を行った。
XPSにてフィルム表面の分析を行い、ポリマーの付着量を算出した。
評価基準:A;理論値の90%以上、B;理論値の50%以上90%未満、C;理論値の50%未満。
水中に浸漬させておいたポリマーグラフト化フィルムを、水中から引き上げ、水膜が切れるまでの時間を計測し、表面親水性評価を行った。評価方法は以下に示すように行った。
評価基準:A;水膜が切れるまでの時間が30秒以上、B;水膜が切れるまでの時間が10秒以上30秒未満、C;水膜が切れるまでの時間が10秒未満。
リン酸緩衝液の調製
塩化ナトリウム0.900g、リン酸2水素ナトリウム0.104gを、100ccのメスフラスコに秤量し、イオン交換水を加えて100mLとした。これに1N水酸化ナトリウム水溶液を加えてpH7.4付近に調整したものをリン酸緩衝液とした。
たんぱく質汚れ液の調製
アルブミン0.388g、γ-グロブリン0.161g、リゾチーム0.120g、ムチン0.100gを秤量し、リン酸緩衝液100mLを加え、分散させた。1M塩化カルシウム水溶液を加え、均一に混合したものをたんぱく質汚れ液とした。
抽出液の調製
100ccのメスフラスコにイオン交換水50mLを入れ、これにトリフルオロ酢酸148μL加えた後に、イオン交換水で100mLにメスアップした。
上記で調製した液とアセトニトリル100mLとを混合し、これを抽出液とした。
1×4cmのポリマーグラフト化フィルム2枚を上記たんぱく質汚れ液32mLに浸漬し、37℃で4時間静置した。その後、フィルムを生理食塩水ですすぎ、上記抽出液32mLに浸漬させて1時間抽出を行った。抽出後の液を200μL採取し、抽出液を800μL加えて希釈し、Micro BCA試薬1mLを加えて60℃で1時間加熱した後、562nmの吸光度を測定し、付着したたんぱく質量を算出した。
評価基準:A;(サンプルたんぱく質吸着量/ブランクたんぱく質吸着量)<0.2、B;0.2≦(サンプルたんぱく質吸着量/ブランクたんぱく質吸着量)<0.8、C;0.8≦(サンプルたんぱく質吸着量/ブランクたんぱく質吸着量)。なお、ブランクにはPEフィルムを使用した。
MPC(日油株式会社製)68.3g、GMA(日油株式会社製)1.7g、n-プロパノール(NPA、キシダ化学社製)210.0gに溶解し、温度計と冷却管を付けた500mLの4つ口フラスコに入れて30分間窒素を吹込んだ。その後、60℃でt-ブチルパーオキシネオデカノエイト(PB-ND、日油株式会社製)を0.27g加えて8時間重合反応させた。得られた重合体の化学構造はIR、1H NMRにより確認した。続いて、この重合液(式(2)で表されるポリマー溶液)280.0gにNPA157.5gを加えて均一に混合した。続いてAET(和光純薬工業社製)9.8gを溶解させて昇温し、74℃で12時間攪拌した。反応終了後、透析精製し、凍結乾燥により白色粉体のポリマーを回収した。得られたポリマーについて、IR、1H NMR、元素分析、アミノ基定量、重量平均分子量の測定を行った。結果を以下及び表1に示す。なお、IR、1H NMRの測定チャートを図1及び図2にそれぞれ示す。
1H NMRデータ:0.7-1.2ppm(CH3C-)、1.4-2.3ppm(-CH2C-)、2.7-3.1ppm(-CH2CH(OH)CH2-、-OCH2CHCH2OH-)、3.3ppm(-N(CH3)3)、3.5-4.4ppm(-CH2CH2O-)。
元素分析
実測値:C:44.86%、H:7.56%、N:4.85%、
理論値:C:44.97%、H:7.47%、N:4.83%。
アミノ基導入率(b/(a+b)×100):5mol%。
以上の結果より、式(1a)で示されるMPCに基づく比率が95mol%、式(1b)で示されるアミノ基を有するユニットに基づく比率が5mol%、重量平均分子量が650000のポリマーであることがわかった。
MPC66.4g、GMA3.6g、NPA163.3gを温度計と冷却管を付けた500mLの4つ口フラスコに入れて30分間窒素を吹込んだ。その後、60℃でPB-NDを0.23g加えて8時間重合反応させた。得られた重合体の化学構造はIR、1H NMRにより確認した。続いて、この重合液(式(2)で表されるポリマー溶液)233.3gにNPA204.2gを加えて均一に混合した。続いてAET19.6gを溶解させて昇温し、74℃で12時間攪拌した。反応終了後、透析精製し、凍結乾燥により白色粉体のポリマーを回収した。得られたポリマーについて、実施例1-1と同様に各測定を行った。結果を以下及び表1に示す。
1H NMRデータ:0.7-1.2ppm(CH3C-)、1.4-2.3ppm(-CH2C-)、2.7-3.1ppm(-CH2CH(OH)CH2-、-OCH2CHCH2OH-)、3.3ppm(-N(CH3)3)、3.5-4.4ppm(-CH2CH2O-)。
元素分析
実測値:C:45.11%、H:7.63%、N:4.86%、
理論値:C:45.20%、H:7.49%、N:4.91%。
アミノ基導入率(b/(a+b)×100):10mol%。
以上の結果より、式(1a)で示されるMPCに基づく比率が90mol%、式(1b)で示されるアミノ基を有するユニットに基づく比率が10mol%、重量平均分子量が880000のポリマーであることがわかった。
MPC62.5g、GMA7.5g、NPA210.0gを温度計と冷却管を付けた500mLの4つ口フラスコに入れて30分間窒素を吹込んだ。その後、60℃でPB-NDを0.27g加えて8時間重合反応させた。得られた重合体の化学構造はIR、1H NMRにより確認した。続いて、この重合液(式(2)で表されるポリマー溶液)280.0gにNPA 157.5gを加えて均一に混合した。続いてAET39.3gを溶解させて昇温し、74℃で12時間攪拌した。反応終了後、透析精製し、凍結乾燥により白色粉体のポリマーを回収した。得られたポリマーについて、実施例1-1と同様に各測定を行った。結果を以下及び表1に示す。
1H NMRデータ:0.7-1.2ppm(CH3C-)、1.4-2.3ppm(-CH2C-)、2.7-3.1ppm(-CH2CH(OH)CH2-、-OCH2CHCH2OH-)、3.3ppm(-N(CH3)3)、3.5-4.4ppm(-CH2CH2O-)。
元素分析
実測値:C:45.47%、H:7.69%、N:5.10%、
理論値:C:45.66%、H:7.52%、N:5.08%。
アミノ基導入率(b/(a+b)×100):20mol%。
以上の結果より、式(1a)で示されるMPCに基づく比率が80mol%、式(1b)で示されるアミノ基を有するユニットに基づく比率が20mol%、重量平均分子量が630000のポリマーであることがわかった。
MPC58.0g、GMA12.0g、NPA163.3gを温度計と冷却管を付けた500mLの4つ口フラスコに入れて30分間窒素を吹込んだ。その後、60℃でPB-NDを0.23g加えて8時間重合反応させた。得られた重合体の化学構造はIR、1H NMRにより確認した。続いて、この重合液(式(2)で表されるポリマー溶液)233.3gにNPA204.2gを加えて均一に混合した。続いてAET58.9gを溶解させて昇温し、74℃で12時間攪拌した。反応終了後、透析精製し、凍結乾燥により白色粉体のポリマーを回収した。得られたポリマーについて、実施例1-1と同様に各測定を行った。結果を以下及び表1に示す。
1H NMRデータ:0.7-1.2ppm(CH3C-)、1.4-2.3ppm(-CH2C-)、2.7-3.1ppm(-CH2CH(OH)CH2-、-OCH2CHCH2OH-)、3.3ppm(-N(CH3)3)、3.5-4.4ppm(-CH2CH2O-)。
元素分析
実測値:C:45.47%、H:7.69%、N:5.10%
理論値:C:45.66%、H:7.52%、N:5.08%。
アミノ基導入率(b/(a+b)×100):30mol%
以上の結果より、式(1a)で示されるMPCに基づく比率が70mol%、式(1b)で示されるアミノ基を有するユニットに基づく比率が30mol%、重量平均分子量が850000のポリマーであることがわかった。
表1に示す各単量体、溶媒及び開始剤を用いた以外は、実施例1-1と同様に反応を行った。得られたポリマーについて、実施例1-1と同様に各測定を行った。結果を表1に示す。
MPC18.8g、AEMA(Aldrich社製)1.2gをイオン交換水80.0gに溶解し、温度計と冷却管を付けた200mLの4つ口フラスコに入れて30分間窒素を吹込んだ。その後、60℃で2,2'-アゾビス(2-メチルプロピオンアミジン)二塩酸塩(V-50、和光純薬工業社製)を0.1492g加えて8時間重合反応させた。得られたポリマーの化学構造はIR、1H NMRにより確認した。
表1に示す各単量体、溶媒及び開始剤を用いた以外は、比較例1-3と同様に重合を行った。得られたポリマーの化学構造はIR、1H NMRにより確認した。
Claims (3)
- 請求項1記載のポリマーを0.1~20質量%含む水溶液からなる医療機器用表面処理剤。
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Also Published As
Publication number | Publication date |
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CN103596996B (zh) | 2015-11-25 |
US20140142240A1 (en) | 2014-05-22 |
EP2725042A4 (en) | 2014-11-05 |
KR20140041705A (ko) | 2014-04-04 |
US9127099B2 (en) | 2015-09-08 |
EP2725042B1 (en) | 2018-08-29 |
JP5871000B2 (ja) | 2016-03-01 |
TWI526458B (zh) | 2016-03-21 |
EP2725042A1 (en) | 2014-04-30 |
JPWO2013002021A1 (ja) | 2015-02-23 |
KR101851825B1 (ko) | 2018-04-24 |
CN103596996A (zh) | 2014-02-19 |
TW201302820A (zh) | 2013-01-16 |
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