JP7614599B2 - Resin material and medical molded product made from same - Google Patents

Description

The present invention relates to a resin material and a medical molded article made from the same. More specifically, the present invention relates to a resin material that contains a specific structure in the end group and, in particular, has a reduced amount of residual phenol, and a medical molded article made from the same.

Currently, synthetic polymer materials are widely used as materials for medical devices. It is known that when polymer materials are applied to the body, they are recognized as foreign bodies, triggering a biological defense reaction such as the formation of blood clots. For this reason, high blood compatibility is required for applications that come into direct contact with blood, such as artificial blood vessels, heart-lung machines, catheters, and blood filters.

In light of this background, research has been conducted in recent years to improve the blood compatibility of polymeric materials. For example, it has been reported that high blood compatibility can be imparted by coating the polymer surface with 2-methacryloyloxyethyl phosphorylcholine polymer (PMPC) or poly(2-methoxyethyl acrylate) (PMEA) (Patent Documents 1 and 2). On the other hand, there have also been reports of cases in which the polymer itself has been made blood compatible (Patent Document 3).

On the other hand, polycarbonate (PC) has excellent properties such as high impact resistance, heat resistance, and transparency, and is therefore used in a variety of applications, including automobiles and electrical and electronic applications. However, ordinary PC has low blood compatibility, and has not been actively used in applications that come into contact with blood. For example, blood-compatible PCs that have been introduced with specific substituents to improve blood compatibility have been reported, but they require special monomers and polymerization reactions, making them difficult to use industrially (Patent Document 4). Various types of PCs made from polyethylene glycol have also been reported, but they are not intended to improve blood compatibility and are produced by methods that leave a lot of residual impurities (Patent Documents 5 and 6). Medical materials are used in direct contact with living organisms, so they are required to be safer than in other applications. In particular, the conditions for use in medical applications, that is, contact with body fluids such as blood, cause the decomposition products, unreacted monomers, by-products, and oligomers of the materials to elute, which is a serious drawback for medical materials, making them difficult to use as medical materials. In addition, when used as medical materials, sterilization processes such as autoclaving may be required, and excellent heat resistance is required.

Japanese Unexamined Patent Publication No. 7-268038 JP 2014-161675 A JP 2018-149070 A WO 14/133102 JP 2011-241277 A Special Publication No. 2002-522584

The object of the present invention is to provide a resin material that is excellent in antithrombotic and heat resistance, and in particular, reduces elution.

The inventors discovered that a resin material containing a specific structure in its terminal group has excellent antithrombogenicity and heat resistance, and further reduces the amount of elution into water by reducing the amount of residual phenol, and thus completed the present invention. According to the present invention, the above problems are solved by the following invention.

（式（１）において、Ｒ_１およびＲ_２はそれぞれ独立に水素原子または炭素数１～４の脂肪族炭化水素を表し、Ｒ_３は炭素原子数１～３０のアルキル基を表し、ｍは１～４であり、ｎは２～１５０である。） 1. A resin material containing a terminal group structure represented by the following formula (1) at a polymer chain end, the resin material being characterized in that the terminal group structure represented by the following formula (1) is contained in a proportion of 0.1 to 17% by weight relative to 100% by weight of all repeating constitutional units of the main chain.

(In formula (1), _R1 and _R2 each independently represent a hydrogen atom or an aliphatic hydrocarbon having 1 to 4 carbon atoms, _R3 represents an alkyl group having 1 to 30 carbon atoms, m is 1 to 4, and n is 2 to 150.)

2. The resin material according to the preceding paragraph 1, which is for a device that comes into contact with biological tissue.
3. The resin material according to item 1 or 2 above, having a phenol content of 1000 ppm or less.
4. The resin material according to any one of items 1 to 3 above, which contains in its main chain a repeating structural unit derived from a diol compound selected from the group consisting of an aliphatic diol compound, an alicyclic diol compound, a heterocyclic diol compound, and polyoxyethylene glycol.
5. The resin material according to item 4 above, which contains repeating units derived from the diol compound in a proportion of 50% by weight or more and 100% by weight or less, based on 100% by weight of all repeating units in the main chain.

6. The resin material according to item 4 or 5 above, which contains a repeating structural unit represented by the following formula (2) as the repeating structural unit:

7. The resin material according to item 6 above, which contains the repeating structural unit represented by formula (2) in a proportion of 10% by weight or more and 100% by weight or less, based on 100% by weight of all repeating structural units derived from the diol compound.
8. The resin material according to any one of items 1 to 7 above, which has a glass transition temperature of 80° C. or higher and 160° C. or lower.
9. The resin material according to any one of items 1 to 8 above, which has a water contact angle of 60° or less.
10. The resin material according to any one of items 1 to 9 above, which has a saturated water absorption rate of 1.0% by weight or more.
11. The resin material according to any one of items 1 to 10, having a specific viscosity measured in a methylene chloride solution at 20° C. of 0.15 to 1.5.

（式（３）において、Ｒ_４は水素原子またはメチル基を表し、Ｒ_５は炭素原子数１～３０のアルキル基を表し、ｎは２～１５０である。） 12. The resin material according to any one of items 1 to 11 above, wherein the terminal group structure represented by formula (1) is a terminal group structure represented by formula (3) below:

(In formula (3), R ₄ represents a hydrogen atom or a methyl group, R ₅ represents an alkyl group having 1 to 30 carbon atoms, and n is an integer of 2 to 150.)

13. A medical molded product produced using the resin material according to any one of items 1 to 12 above.
14. A medical molded article that is surface-treated with the resin material according to any one of items 1 to 12 above.

The resin material of the present invention contains a specific structure in the end group, has excellent antithrombogenicity and heat resistance, and furthermore, because the amount of residual phenol is reduced, there is little elution into water. Therefore, it can be widely used in various medical applications including devices that come into contact with biological tissue, such as implantable devices such as artificial organs and catheters, and the industrial effects it provides are exceptional.

The following describes in detail the embodiments of the present invention. Note that the present invention is not limited to the following embodiments, and can be modified in various ways within the scope of the present invention.

（式（１）において、Ｒ_１およびＲ_２はそれぞれ独立に水素原子または炭素数１～４の脂肪族炭化水素を表し、Ｒ_３は炭素原子数１～３０のアルキル基を表し、ｍは１～４であり、ｎは２～１５０である。） <Resin material>
The resin material of the present invention is a resin material containing a terminal group structure represented by the following formula (1) at a polymer chain end, and is characterized in that the resin material contains the terminal group structure represented by the following formula (1) in a ratio of 0.1 wt % to 17 wt % based on 100 wt % of all repeating structural units of the main chain.

(In formula (1), _R1 and _R2 each independently represent a hydrogen atom or an aliphatic hydrocarbon having 1 to 4 carbon atoms, _R3 represents an alkyl group having 1 to 30 carbon atoms, m is 1 to 4, and n is 2 to 150.)

Polycarbonate, which has excellent properties such as high impact resistance, is used in a variety of applications, but due to its poor blood compatibility it cannot be used in devices that come into contact with biological tissue. However, it has been found that by including repeating units derived from ethylene glycol in the terminal groups, hydrophilicity and flexibility can be increased, biocompatibility can be improved, and antithrombogenicity can be achieved.

The resin material of the present invention contains a terminal group structure represented by the above formula (1) at a specified ratio at the polymer chain end, and thus exhibits appropriate flexibility as well as biocompatibility and heat resistance, and can be used not only as a coating for devices that come into contact with biological tissue, but also as a molded article that constitutes the device.

Below, we will explain in detail each component of the resin material of the present invention, their mixing ratios, preparation methods, etc.

The resin material of the present invention contains a terminal group structure represented by the following formula (1) at the polymer chain end.

In formula (1), _R1 and _R2 each independently represent a hydrogen atom or an aliphatic hydrocarbon having 1 to 4 carbon atoms. Of these, a hydrogen atom or an aliphatic hydrocarbon having 1 to 2 carbon atoms is preferred. A hydrogen atom or a methyl group is particularly preferred.

_R3 represents an alkyl group having 1 to 30 carbon atoms. Among them, an alkyl group having 1 to 20 carbon atoms is preferable, an alkyl group having 1 to 10 carbon atoms is more preferable, an alkyl group having 1 to 6 carbon atoms is further preferable, and an alkyl group having 1 to 4 carbon atoms is particularly preferable. A methyl group is most preferable.

m is an integer of 1 to 4, preferably 2 to 4, and particularly preferably 2.
n is 2 to 150, preferably 2 to 100, more preferably 2 to 50, and particularly preferably 2 to 35.

The repeating units in formula (1) are usually derived by reacting the alcohol portion of a polyoxyalkylene glycol monoether. The number average molecular weight of the polyoxyalkylene glycol monoether used is preferably 100 to 20,000, more preferably 150 to 5,000, and particularly preferably 200 to 2,000. Within this range, an excellent balance of flexibility, heat resistance, and antithrombogenicity is achieved, and outside this range, transparency may not be achieved or the material may become water-soluble and may not be usable as a medical molded product.

Specific examples of polyoxyalkylene glycol monoethers include polyethylene glycol monomethyl ether, polytrimethylene glycol monomethyl ether, polytetramethylene glycol monomethyl ether, and polypropylene glycol monomethyl ether.

In particular, polyoxyalkylene glycol monoethers that give a terminal group structure represented by the following formula (3), that is, polyethylene glycol monoethers or polypropylene glycol monoethers, are preferably used.

In formula (3), R ₄ represents a hydrogen atom or a methyl group. R ₅ represents an alkyl group having 1 to 30 carbon atoms. Among them, an alkyl group having 1 to 20 carbon atoms is preferred, an alkyl group having 1 to 10 carbon atoms is more preferred, an alkyl group having 1 to 6 carbon atoms is even more preferred, and an alkyl group having 1 to 4 carbon atoms is particularly preferred. A methyl group is most preferred. n is 2 to 150, preferably 2 to 100, more preferably 2 to 50, and particularly preferably 2 to 35.

The content of the terminal group represented by the above formula (1) or (3) in the resin material of the present invention is 0.1% by weight or more, preferably 0.5% by weight or more, more preferably 1% by weight or more, even more preferably 2% by weight or more, and particularly preferably 3% by weight or more, based on 100% by weight of all repeating units of the main chain. The upper limit of the content is 17% by weight or less, preferably 15% by weight or less, more preferably 13% by weight or less, even more preferably 12% by weight or less, and particularly preferably 11% by weight or less. By setting the content of the terminal group in this manner, the balance of antithrombotic properties, heat resistance, water solubility, and moldability is excellent, which is preferable. In addition, the phenol content after polymerization can be further reduced, which is preferable when used for medical purposes. The weight ratio can be measured and calculated using a proton NMR of JNM-AL400 manufactured by JEOL Ltd. When two or more types of alcohol components are mixed, a polyoxyalkylene glycol monoether and another hydroxy compound may be used in combination.

The resin material of the present invention preferably contains in its main chain a repeating structural unit derived from a diol compound selected from the group consisting of an aliphatic diol compound, an alicyclic diol compound, a heterocyclic diol compound, and polyoxyethylene glycol. By using a repeating structural unit derived from such a diol compound as a repeating structural unit of the main chain, it is preferable because it has an excellent balance of antithrombogenicity, heat resistance, water solubility, and moldability.

The repeating units derived from the diol compound are preferably contained in a proportion of 50% by weight to 100% by weight, more preferably 70% by weight to 100% by weight, even more preferably 80% by weight to 100% by weight, particularly preferably 90% by weight to 100% by weight, and most preferably 95% by weight to 100% by weight.

Examples of such diol compounds (diol monomers) include the diol compounds described in WO 2004/111106 and WO 2011/021720. These may be used alone or in combination of two or more. Representative examples of diol components are shown below, but the present invention is not limited thereto.

The aliphatic diol compounds include 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, 1.9-nonanediol, 1,10-decanediol, 1,12-dodecanediol, 2-methyl-1,3-propanediol, neopentyl glycol, 3-methyl-1,5-pentanediol, 2-n-butyl-2-ethyl-1 ,3-propanediol, 2,2-diethyl-1,3-propanediol, 2,4-diethyl-1,5-pentanediol, 1,2-hexane glycol, 1,2-octyl glycol, 2-ethyl-1,3-hexanediol, 2,3-diisobutyl-1,3-propanediol, 2,2-diisoamyl-1,3-propanediol, 2-methyl-2-propyl-1,3-propanediol, etc.

Examples of the alicyclic diol compounds include cyclohexane dimethanol, tricyclodecane dimethanol, adamantane diol, pentacyclopentadecane dimethanol, 3,9-bis(2-hydroxy-1,1-dimethylethyl)-2,4,8,10-tetraoxaspiro[5.5]undecane, 2,2,4,4-tetramethylcyclobutanediol, 1,1'-spirobiindane-6,6'-diol, decalin-2,6-dimethanol, norbornane dimethanol, and cyclopentane-1,3-dimethanol.

Examples of the heterocycle-containing diol compound include 3,9-bis(2-hydroxy-1,1-dimethylethyl)-2,4,8,10-tetraoxaspiro[5.5]undecane, 2,2',1,1'-,1,1'-spirobiindane-6,6'-diol, isosorbide, isomannide, and isoidide.

Examples of the polyoxyethylene glycol include polyethylene glycol, polytrimethylene glycol, polytetramethylene glycol, and polypropylene glycol.

Among these diol compounds, isosorbide, isomannide, and isoidide are preferably used. These compounds are ether diols derived from carbohydrates, and are also obtained from biomass in nature, and are one of the so-called renewable resources. The repeating units derived from these compounds are represented by the following formula (2).

The above formula (2) is exemplified by repeating units (2-1), (2-2) and (2-3) represented by the following formulae, which are stereoisomers.

The repeating units (2-1), (2-2) and (2-3) are called isosorbide, isomannide and isoidide, respectively. Isosorbide is obtained by hydrogenating D-glucose obtained from starch and then dehydrating it. Other ether diols can be obtained by the same reaction, except for the starting material.

Among isosorbide, isomannide, and isoidide, the repeating structural unit derived from isosorbide (1,4;3,6-dianhydro-D-sorbitol) is particularly preferred due to its ease of production and excellent heat resistance.

In the resin material of the present invention, the content ratio of the repeating structural unit represented by the above formula (2) in the main chain is preferably 10% by weight or more, 20% by weight or more, 30% by weight or more, 40% by weight or more, 50% by weight or more, 60% by weight or more, 70% by weight or more, 80% by weight or more, 90% by weight or more, and 100% by weight or less, based on 100% by weight of the repeating structural units derived from all diol compounds. By setting such a weight ratio, an excellent balance of antithrombotic properties and heat resistance is achieved, which is preferable. The weight ratio can be measured and calculated using a proton NMR of JNM-AL400 manufactured by JEOL Ltd.

Furthermore, as the repeating structural units constituting the other main chain, repeating structural units derived from aromatic dihydroxy compounds are preferred.

The aromatic dihydroxy compounds include α,α'-bis(4-hydroxyphenyl)-m-diisopropylbenzene (bisphenol M), 1,1-bis(4-hydroxyphenyl)cyclohexane, 1,1-bis(4-hydroxyphenyl)-3,3,5-trimethylcyclohexane, 4,4'-dihydroxy-3,3'-dimethyldiphenyl sulfide, bisphenol A, 2,2-bis(4-hydroxy-3-methylphenyl)propane (bisphenol C), 2,2-bis(4-hydroxyphenyl)-1,1,1,3,3,3-hexafluoropropane (bisphenol AF), biphenol, 1,1-bis(4-hydroxyphenyl)-m-diisopropylbenzene ... 9,9-bis(4-(2-hydroxyethoxy)phenyl)-1,8-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-3-methylphenyl)-1,8-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-3-phenylphenyl)-1,8-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-1-naphthyl)-1,8-diphenylfluorene, 9,9-bis(6-(2-hydroxyethoxy)-2-naphthyl)-1,8-diphenylfluorene, 9,9-bis(4-hydroxyphenyl)-1,8-diphenylfluorene fluorene, 9,9-bis(4-hydroxy-3-methylphenyl)-1,8-diphenylfluorene, 9,9-bis(4-hydroxy-3-phenylphenyl)-1,8-diphenylfluorene, 9,9-bis(4-hydroxy-1-naphthyl)-1,8-diphenylfluorene, 9,9-bis(6-hydroxy-2-naphthyl)-1,8-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)phenyl)-2,7-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-3-methylphenyl)-2,7-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-3-phenylphenyl) fluorene, 9,9-bis(4-(2-hydroxyethoxy)-1-naphthyl)-2,7-diphenylfluorene, 9,9-bis(6-(2-hydroxyethoxy)-2-naphthyl)-2,7-diphenylfluorene, 9,9-bis(4-hydroxyphenyl)-2,7-diphenylfluorene, 9,9-bis(4-hydroxy-3-methylphenyl)-2,7-diphenylfluorene, 9,9-bis(4-hydroxy-3-phenylphenyl)-2,7-diphenylfluorene, 9,9-bis(4-hydroxy-1-naphthyl)-2,7-diphenylfluorene, 9,9-bis(6-hydroxy-2-naphthyl)-2 ,7-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)phenyl)-3,6-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-3-methylphenyl)-3,6-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-3-phenylphenyl)-3,6-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-1-naphthyl)-3,6-diphenylfluorene, 9,9-bis(6-(2-hydroxyethoxy)-2-naphthyl)-3,6-diphenylfluorene, 9,9-bis(4-hydroxyphenyl)-3,6-diphenylfluorene, 9,9-bis( 4-hydroxy-3-methylphenyl)-3,6-diphenylfluorene, 9,9-bis(4-hydroxy-3-phenylphenyl)-3,6-diphenylfluorene, 9,9-bis(4-hydroxy-1-naphthyl)-3,6-diphenylfluorene, 9,9-bis(6-hydroxy-2-naphthyl)-3,6-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)phenyl)-4,5-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-3-methylphenyl)-4,5-diphenylfluorene, 9,9-bis(4-(2-hydroxyethoxy)-3-phenylphenyl)-4,5-diphenylfluorene fluorene, 9,9-bis(4-(2-hydroxyethoxy)-1-naphthyl)-4,5-diphenylfluorene, 9,9-bis(6-(2-hydroxyethoxy)-2-naphthyl)-4,5-diphenylfluorene, 9,9-bis(4-hydroxyphenyl)-4,5-diphenylfluorene, 9,9-bis(4-hydroxy-3-methylphenyl)-4,5-diphenylfluorene, 9,9-bis(4-hydroxy-3-phenylphenyl)-4,5-diphenylfluorene, 9,9-bis(4-hydroxy-1-naphthyl)-4,5-diphenylfluorene, 9,9-bis(6-hydroxy-2-naphthyl)-4,5-diphenylfluorene, Examples include 2,2'-bis(2-hydroxyethoxy)-3,3'-diphenyl-1,1'-binaphthyl, 2,2'-bis(2-hydroxyethoxy)-6,6'-diphenyl-1,1'-binaphthyl, 2,2'-bis(2-hydroxyethoxy)-7,7'-diphenyl-1,1'-binaphthyl, 2,2'-bis(2-hydroxyethoxy)-3,3'-dimethyl-1,1'-binaphthyl, 2,2'-bis(2-hydroxyethoxy)-6,6'-dimethyl-1,1'-binaphthyl, 2,2'-bis(2-hydroxyethoxy)-7,7'-dimethyl-1,1'-binaphthyl, 1,1'-bi-2-naphthol, and dihydroxynaphthalene.

(Method of manufacturing resin material)
The resin material of the present invention is produced by a reaction means known per se for producing a normal polycarbonate resin, for example, a method of reacting a diol component with a carbonate precursor such as a carbonic acid diester. Next, the basic means for these production methods will be briefly described.

The transesterification reaction using a carbonic acid diester as a carbonate precursor is carried out by heating and stirring a specified ratio of diol components with a carbonic acid diester under an inert gas atmosphere, and distilling off the resulting alcohol or phenols. In this case, a structure derived from the alcohol component can be introduced into the terminal portion by adding an alcohol component in advance as an end terminator. The reaction temperature varies depending on the boiling point of the alcohol or phenols produced, but is usually in the range of 120 to 300°C. The reaction is completed by reducing the pressure from the beginning and distilling off the resulting alcohol or phenols.

The carbonic acid diester used in the transesterification reaction may be an ester of an aryl group or an aralkyl group having 6 to 12 carbon atoms, which may be substituted. Specific examples include diphenyl carbonate, ditolyl carbonate, bis(chlorophenyl) carbonate, and m-cresyl carbonate. Of these, diphenyl carbonate is particularly preferred. The amount of diphenyl carbonate used is preferably 0.97 to 1.10 moles, more preferably 1.00 to 1.06 moles, per mole of the total of the dihydroxy compounds.

In addition, in the melt polymerization method, a polymerization catalyst can be used to increase the polymerization rate. Examples of such polymerization catalysts include alkali metal compounds, alkaline earth metal compounds, nitrogen-containing compounds, and metal compounds.

As such compounds, organic acid salts, inorganic salts, oxides, hydroxides, hydrides, alkoxides, quaternary ammonium hydroxides, etc. of alkali metals or alkaline earth metals are preferably used, and these compounds can be used alone or in combination.

Examples of alkali metal compounds include sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, potassium acetate, cesium acetate, lithium acetate, sodium stearate, potassium stearate, cesium stearate, lithium stearate, sodium borohydride, sodium benzoate, potassium benzoate, cesium benzoate, lithium benzoate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, dilithium hydrogen phosphate, disodium phenylphosphate, disodium, dipotassium, dicesium, and dilithium salts of bisphenol A, and sodium, potassium, cesium, and lithium salts of phenol.

Examples of alkaline earth metal compounds include magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, magnesium diacetate, calcium diacetate, strontium diacetate, barium diacetate, barium stearate, etc.

Examples of nitrogen-containing compounds include quaternary ammonium hydroxides having alkyl or aryl groups, such as tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, and trimethylbenzylammonium hydroxide. Other examples include tertiary amines, such as triethylamine, dimethylbenzylamine, and triphenylamine, and imidazoles, such as 2-methylimidazole, 2-phenylimidazole, and benzimidazole. Other examples include bases or basic salts, such as ammonia, tetramethylammonium borohydride, tetrabutylammonium borohydride, tetrabutylammonium tetraphenylborate, and tetraphenylammonium tetraphenylborate.

Examples of metal compounds include zinc aluminum compounds, germanium compounds, organotin compounds, antimony compounds, manganese compounds, titanium compounds, zirconium compounds, etc. These compounds may be used alone or in combination of two or more.

The amount of these polymerization catalysts used is selected from the range of preferably 1×10 ⁻⁹ to 1×10 ⁻² equivalents, preferably 1×10 ⁻⁸ to 1×10 ⁻⁵ equivalents, more preferably 1×10 ⁻⁷ to 1×10 ⁻³ equivalents per mole of the diol component.

A catalyst deactivator can also be added in the later stages of the reaction. Known catalyst deactivators are effectively used as catalyst deactivators, and among these, ammonium salts and phosphonium salts of sulfonic acid are preferred. Furthermore, salts of dodecylbenzenesulfonic acid such as tetrabutylphosphonium salt of dodecylbenzenesulfonic acid, and salts of paratoluenesulfonic acid such as tetrabutylammonium salt of paratoluenesulfonic acid are preferred.

As sulfonic acid esters, methyl benzenesulfonate, ethyl benzenesulfonate, butyl benzenesulfonate, octyl benzenesulfonate, phenyl benzenesulfonate, methyl paratoluenesulfonate, ethyl paratoluenesulfonate, butyl paratoluenesulfonate, octyl paratoluenesulfonate, phenyl paratoluenesulfonate, etc. are preferably used. Among these, tetrabutylphosphonium dodecylbenzenesulfonate is most preferably used.

When at least one polymerization catalyst selected from alkali metal compounds and/or alkaline earth metal compounds is used, the amount of these catalyst deactivators used is preferably 0.5 to 50 moles per mole of the catalyst, more preferably 0.5 to 10 moles, and even more preferably 0.8 to 5 moles.

(Method of refining resin material)
The resin material of the present invention is preferably purified to reduce the phenol content. The method of purifying the resin material is not particularly limited, but includes poor solvent precipitation, washing with water under alkaline conditions, treatment with ion exchange resin, freeze purification, and other techniques. The amount of phenol contained after purification is preferably 1000 ppm or less. More preferably, it is 500 ppm or less, even more preferably, it is 300 ppm or less, particularly preferably, it is 200 ppm or less, and most preferably, it is 100 ppm or less. If the amount of phenol exceeds 1000 ppm, the phenol elution into water becomes a problem, and it may be unsuitable for medical use. In addition, the total amount of metals of Groups 1 and 2 contained after purification is preferably 20 ppm or less. More preferably, it is 15 ppm or less, and even more preferably, it is 10 ppm or less. If the total amount of metals of Groups 1 and 2 exceeds 20 ppm, the elution of metal components into water becomes a problem, and it may be unsuitable for medical use.

(Specific viscosity: η _SP )
The specific viscosity (η _SP ) of the resin material of the present invention is preferably 0.15 to 1.5, more preferably 0.2 to 1.3, even more preferably 0.25 to 1.2, particularly preferably 0.3 to 1.0, and most preferably 0.3 to 0.6. When the specific viscosity is in the above range, the strength and moldability of the molded product are good.

The specific viscosity in the present invention was determined by dissolving 0.7 g of the resin material in 100 ml of methylene chloride at 20° C. using an Ostwald viscometer.
Specific viscosity (η _SP )=(t−t ₀ )/t ₀
[ _t0 is the number of seconds that methylene chloride falls, and t is the number of seconds that the sample solution falls]

Specific viscosity can be measured, for example, as follows: First, the resin material is dissolved in methylene chloride of 20 to 30 times its weight, and the soluble portion is collected by celite filtration. The solution is then removed and the material is thoroughly dried to obtain a solid that is soluble in methylene chloride. 0.7 g of this solid is dissolved in 100 ml of methylene chloride, and the specific viscosity at 20°C is determined using an Ostwald viscometer.

(Glass transition temperature: Tg)
The upper limit of the glass transition temperature (Tg) of the resin material of the present invention is preferably 160° C. or less, more preferably 150° C. or less, and even more preferably 1400° C. or less. The lower limit is preferably 80° C. or more, more preferably 90° C. or more, and even more preferably 100° C. or more. When the Tg is within the above range, the moldability is good, which is preferable, and furthermore, the material has resistance to sterilization treatment, making it more suitable, for example, as a material for implantation in the body.

The glass transition temperature (Tg) is measured using a 2910 DSC manufactured by TA Instruments Japan Ltd. at a heating rate of 20°C/min.

(5% weight loss temperature: Td)
The lower limit of the 5% weight loss temperature of the resin material of the present invention is preferably 280° C., more preferably 300° C. The upper limit of the 5% weight loss temperature is preferably 400° C., more preferably 390° C., and even more preferably 400° C. Preferably, it is 380° C. Therefore, the 5% weight loss temperature (Td) of the resin material of the present invention is preferably 280 to 400° C. When the 5% weight loss temperature is within the above range, This is preferable because the resin material hardly decomposes when it is molded using the material. The 5% weight loss temperature is measured using a TGA (model TGA2950) manufactured by TA Instruments.

(Water Absorption Rate)
The saturated water absorption of the resin material of the present invention is preferably 1.0% by weight or more, more preferably 2.0% by weight or more. If the water absorption is 1.0% by weight or more, the surface becomes sufficiently hydrophilic, which is preferable for the expression of antithrombotic properties. In addition, the resin material of the present invention is preferably water-insoluble. If the resin material is water-soluble, the polymer chains will diffuse in the biological environment, making it unsuitable for medical molded products. In addition, water-insoluble means that there is no weight loss in the water absorption measurement.

(Water Contact Angle)
The water contact angle of the resin material of the present invention is preferably 60° or less, more preferably 58° or less, and even more preferably 56° or less. When the water contact angle is 60° or less, the surface is sufficiently hydrophilic, which is favorable for the expression of antithrombotic properties.

(Composition)
The resin material of the present invention may contain polymers other than the resin material of the present invention, heat stabilizers, plasticizers, light stabilizers, polymerized metal deactivators, flame retardants, lubricants, antistatic agents, surfactants, antibacterial agents, ultraviolet absorbers, release agents, and the like, as long as the antithrombotic properties are not impaired.

<Medical Molded Products>
The resin molded article of the present invention can be obtained by molding the resin material of the present invention. Here, the term "medical molded article" includes devices that come into contact with biological tissues in a living body, such as implantable devices such as artificial organs and catheters, devices that handle biological materials taken from a living body outside the body, such as artificial dialysis machines, heart-lung machines, storage containers for blood for transfusion, and blood processing devices, as well as devices that handle biological tissues for a specific purpose, such as substrates for cell culture and devices that selectively adhere and separate specific cells from body fluids. The resin material of the present invention has high affinity with biological components and biological tissues, and has excellent antithrombotic properties that make it difficult to cause thrombus even when it comes into contact with blood, so it can be suitably used for the above medical molded article.

(shape)
In the present invention, the material and shape of the members constituting the medical molded article are not particularly limited, and may be, for example, any of porous bodies, fibers, nonwoven fabrics, particles, films, sheets, tubes, hollow fibers, powders, and the like.

(Molding method)
The molded article made of the resin material of the present invention can be molded by any method, such as injection molding, compression molding, extrusion molding, solution casting, electrospinning, etc. The resin material of the present invention has excellent moldability and heat resistance, and can be used as various molded articles.

The resin material of the present invention can also be extruded to produce various profile extrusion products, sheets, and films. Sheets and films can also be produced by inflation, calendaring, casting, and other methods. It can also be molded into heat shrinkable tubes by a specific stretching operation. The resin material of the present invention can also be molded into molded products by rotational molding, blow molding, and other methods.

(Surface Treatment)
The resin material of the present invention may be coated on at least a part of the surface of a substrate constituting a medical device, etc. Methods for retaining the resin material of the present invention on the surface of a medical device, etc. include a coating method, a spraying method, a dipping method, etc., and any of these methods can be used without particular limitation. The film thickness is preferably 0.1 μm to 1 mm.

The present invention will be further explained below with reference to examples. However, the present invention is in no way limited to these examples. In the examples, parts are parts by weight, and percentages are percentages by weight. Evaluations were performed according to the following methods.

(Evaluation of resin materials)
(1) Polymer composition ratio (NMR)
The polymer composition ratio (molar ratio) was calculated by measuring with a proton NMR spectrometer, JNM-AL400, manufactured by JEOL Ltd.

(2) Specific viscosity (η _sp )
The pellets were dissolved in methylene chloride to a concentration of about 0.7 g/dL, and the viscosity was measured at 20° C. using an Ostwald viscometer (apparatus name: RIGO AUTO VISCOSIMETER TYPE VMR-0525・PC). The viscosity η _sp was calculated from the following formula.
η _sp =t/t _o −1
t: flow time of the sample solution
t _o : Flow time of solvent only

(3) Glass transition temperature (Tg)
The measurement was carried out using a TA Instruments DSC (model: DSC2910) by heating about 10 mg of the pellet at a temperature increase rate of 20° C./min.

(4) 5% Weight Loss Temperature: This was measured using a TGA (Model TGA2950) manufactured by TA Instruments, by heating about 10 mg of the pellet at a temperature increase rate of 20° C./min.

(5) Phenol Content 1.5 g of resin pellets were dissolved in 15 ml of methylene chloride, and then 135 ml of acetonitrile was added and stirred. The mixture was concentrated using an evaporator and then filtered through a 0.2 μm filter. 10 μl of this measurement solution was subjected to HPLC analysis using a mixture of acetonitrile/0.2% aqueous acetic acid and acetonitrile as an eluent in a Develosil ODS-7 column manufactured by Nomura Chemical Co., Ltd. at a column temperature of 30° C. and a detector at 277 nm using a gradient program.

(Film Evaluation)
(1) Saturated Water Absorption Resin pellets were dissolved in methylene chloride, and the methylene chloride was evaporated to obtain a cast film having a thickness of about 100 μm. The cast film was dried at 100° C. for 12 hours and then immersed in water at 25° C. for 72 hours. The weight increase after this was measured, and the water absorption was calculated by the following formula.
Water absorption rate (%) = resin weight after water absorption × 100 / resin weight before water absorption

(2) Water Contact Angle The film obtained by the method (1) above was measured using a DM-501Hi manufactured by Kyowa Interface Science.

[Example 1]
<Production of resin material>
511.5 parts of isosorbide (hereinafter abbreviated as ISS), 70.0 parts of polyethylene glycol monomethyl ether (terminal terminator, molecular weight 1000, hereinafter abbreviated as PEG1000-ME), 757.3 parts of diphenyl carbonate (hereinafter abbreviated as DPC), and 3.7×10 ⁻³ parts of barium stearate as a catalyst were heated to 180° C. under a nitrogen atmosphere and melted. After confirming that the mixture had melted, the EI reaction process was started. After the start of decompression, the pressure was reduced while adjusting the final degree of vacuum to 8.0 kPa over 40 minutes, and after reaching 8.0 kPa, the degree of vacuum was maintained. At the same time as the start of decompression, the temperature was raised at a rate of 30° C./hr until the final resin temperature reached 220° C. After reaching 220° C., the pressure was reduced to 1.0 kPa and the resin temperature was 220° C. for 10 minutes until 80% of the theoretical amount of phenol was distilled off. After confirming that 80% had been distilled off, the PA reaction process (early stage) was started. The temperature was raised at a rate of 0.5 ° C./min so that the final resin temperature was 230 ° C. In addition, in parallel with the temperature rise, the pressure was reduced over 60 minutes so that the final reduced pressure degree was 1 kPa. Subsequently, the PA reaction process (late stage) was started. In the late stage, the temperature was raised at a rate of 1 ° C./min so that the final resin temperature was 240 ° C. In addition, in parallel with the temperature rise, the pressure was reduced over 20 minutes until the final reduced pressure degree was 134 Pa. The reaction was terminated when a predetermined stirring power value was reached, and the mixture was discharged from the bottom of the reaction tank under nitrogen pressure, and cut with a pelletizer while cooling in a water tank to obtain pellets. The amount of phenol in the pellets after polymerization was about 200 ppm. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

[Example 2]
<Refining Resin Materials>
The pellets obtained in Example 1 were dissolved in dichloromethane to a concentration of 5.0 wt%, and the same weight of pure water was added, followed by washing with water using a separatory funnel. After standing, the lower dichloromethane layer was collected. This series of operations was carried out twice in total. The collected dichloromethane solution was then dropped into 10 times the amount (volume equivalent) of ethanol to carry out poor solvent precipitation. The precipitate was collected by filtration under reduced pressure, rinsed with pure water, and then dried under vacuum at 60°C for 24 hours. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

[Example 3]
<Production of resin material>
Except for using 511.5 parts of ISS, 26.3 parts of polyethylene glycol monomethyl ether (terminal terminator, molecular weight 750, hereinafter abbreviated as PEG750-ME), 757.3 parts of DPC, and 3.7×10 ⁻³ parts of barium stearate as a catalyst, the same operation as in Example 1 was carried out. The amount of phenol in the pellets after polymerization was about 300 ppm.

<Refining Resin Materials>
The obtained pellets were subjected to the same operations as in Example 2. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

[Example 4]
<Production of resin material>
Except for using 511.5 parts of ISS, 52.5 parts of PEG750-ME, 757.3 parts of DPC, and 3.7×10 ⁻³ parts of barium stearate as a catalyst, the same operation as in Example 1 was carried out. The amount of phenol in the pellets after polymerization was about 300 ppm.

<Refining Resin Materials>
The obtained pellets were subjected to the same operations as in Example 2. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

[Example 5]
<Production of resin material>
Except for using 506.4 parts of ISS, 35.0 parts of polyethylene glycol (molecular weight 1000, hereinafter abbreviated as PEG1000), 26.3 parts of PEG750-ME, 757.3 parts of DPC, and 3.7×10 ⁻³ parts of barium stearate as a catalyst, the same operation as in Example 1 was carried out. The amount of phenol in the pellets after polymerization was about 300 ppm.

<Refining Resin Materials>
The obtained pellets were subjected to the same operations as in Example 2. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

[Comparative Example 1]
<Production of resin material>
Except for using 511.5 parts of ISS, 757.3 parts of DPC, and 3.7×10 ⁻³ parts of barium stearate as a catalyst, the same operation as in Example 1 was carried out. The amount of phenol in the pellets after polymerization was about 1100 ppm.

<Refining Resin Materials>
The obtained pellets were subjected to the same operation as in Example 2, except that the drying temperature was 100° C. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

[Comparative Example 2]
<Production of resin material>
Except for using 511.5 parts of ISS, 131.3 parts of PEG750-ME, 757.3 parts of DPC, and 3.7×10 ⁻³ parts of barium stearate as a catalyst, the same operation as in Example 1 was carried out. The amount of phenol in the pellets after polymerization was about 200 ppm.

<Refining Resin Materials>
The obtained pellets were subjected to the same operation as in Example 2. The evaluation results of the obtained resin material (pellets) are shown in Table 1. The produced film was brittle and could not be evaluated as a film.

[Comparative Example 3]
<Production of resin material>
799.0 parts of bisphenol A, 757.3 parts of DPC, and 2.0×10 ⁻⁴ parts of sodium hydroxide as a catalyst were heated to 200° C. under a nitrogen atmosphere and melted. After it was confirmed that the mixture had melted, the EI reaction process was started. After the start of the decompression, the pressure was reduced over 20 minutes while adjusting the final degree of vacuum to 8.0 kPa, and after reaching 8.0 kPa, the degree of vacuum was maintained. At the same time as the start of the decompression, the temperature was raised at a rate of 30° C./hr until the final resin temperature reached 240° C. After reaching 240° C., the temperature was maintained for 10 minutes until 80% of the theoretical amount of phenol was distilled off at a degree of vacuum of 1.0 kPa and a resin temperature of 240° C. After it was confirmed that 80% had distilled off, the PA reaction process (pre-stage process) was started. The temperature was raised at a rate of 1.0° C./min so that the final resin temperature was 280° C. In addition, in parallel with the temperature increase, the pressure was reduced over 60 minutes so that the final degree of vacuum was 1 kPa. Subsequently, the PA reaction process (later process) was started. In the later process, the temperature was raised at a rate of 1° C./min so that the final resin temperature was 300° C. In parallel with the temperature rise, the pressure was reduced over 20 minutes until the final reduced pressure reached 134 Pa. When a predetermined stirring power value was reached, the reaction was terminated, and the mixture was discharged from the bottom of the reaction tank under nitrogen pressure, and while cooling in a water tank, it was cut with a pelletizer to obtain pellets. The amount of phenol in the pellets after polymerization was about 200 ppm.

<Refining Resin Materials>
The obtained pellets were subjected to the same operation as in Example 2, except that the drying temperature was 100° C. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

[Reference Example 1]
<Production of resin material>
Except for using 799.0 parts of BPA, 52.5 parts of PEG750-ME, 757.3 parts of DPC, and 3.7×10 ⁻³ parts of barium stearate as a catalyst, the same operation as in Comparative Example 2 was carried out. The amount of phenol in the pellets after polymerization was about 200 ppm.

<Refining Resin Materials>
The obtained pellets were subjected to the same operation as in Comparative Example 3. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

[Reference Example 2]
<Production of resin material>
Except for using 491.0 parts of ISS, 140.0 parts of PEG1000, 757.3 parts of DPC, and 3.7×10 ⁻³ parts of barium stearate as a catalyst, the same operation as in Example 1 was carried out. The amount of phenol in the pellets after polymerization was about 1100 ppm.

<Refining Resin Materials>
The obtained pellets were subjected to the same operations as in Example 2. The evaluation results of the obtained resin material (pellets) are shown in Table 1.

Next, a platelet adhesion test was performed using the resin materials obtained in Examples 2 to 5, the resin materials obtained in Comparative Examples 1 and 2, the resin material obtained in Reference Example 1, and the biocompatible polymers PMEA (poly(2-methoxyethyl acrylate), manufactured by NOF Corporation; Reference Example 1) and PMPC (phosphocholine-based polymer, product name: Revisure CM5206, manufactured by NOF Corporation; Reference Example 2) used as references, according to the following method. The platelet adhesion test was also performed on the PET substrate alone (blank; Reference Example 3). The results are shown in Table 2.

<Platelet adhesion test>
The antithrombotic properties were evaluated by a platelet adhesion test. Each of the materials to be tested was prepared as a 0.2% dichloromethane solution, which was then applied by spin coating onto a PET film and dried to prepare a sample. 0.2 mL of fresh human platelet-rich plasma anticoagulated with sodium citrate was dropped onto the sample with a pipette and allowed to stand at 37°C for 60 minutes. The sample was then rinsed with a phosphate buffer solution and fixed with glutaraldehyde, after which the substrate was observed under a scanning electron microscope and the number of platelets adhering to an area of 1 x 104 ^μm2 was counted. A relative comparison was made as the ratio (S) of the number of platelets adhering to a blank PET substrate. Compared to PET, a lower number of platelet adhesion indicates better biocompatibility.
S = (number of platelets attached to the test resin)/(number of platelets attached to the PET blank)
A: 0≦S≦0.2
B: 0.2 < S ≦ 0.4
C: 0.4 < S ≦ 0.6
D: 0.6 < S ≦ 0.8
E: 0.8 < S

Furthermore, the resins obtained in Examples 1 to 5 and the resin in Reference Example 2 were used to carry out elution amount tests by the following method. The results are shown in Table 3.

<Phenol elution amount test>
Each copolymer material pellet was dissolved in methylene chloride, and the methylene chloride was evaporated to produce a cast film having a thickness of about 100 μm. 100 ml of pure water was added to 2 g of the obtained film, and the film was immersed at 40° C. for 72 hours. 2.5 ml of the extract was sampled, and the absorbance at a wavelength of 270 nm was measured using a spectrophotometer (U-3310, manufactured by Hitachi, Ltd.). The quantitative value of phenol in the extract was calculated using a calibration curve obtained by similar measurement using a standard sample.

As shown in Table 2, by including a specific terminal structure in the resin material, it is possible to obtain excellent antithrombotic properties and heat resistance. Also, as shown in Table 3, by including a specific terminal structure in the resin material and reducing the amount of phenol contained, it is possible to reduce elution into water. In particular, in Example 1, the amount of phenol elution can be reduced by introducing terminal groups even without a purification process. The resin material of the present invention is particularly suitable for use in devices that come into contact with biological tissues in the body, such as implantable devices such as artificial organs and catheters, devices that handle biological materials extracted from the body outside the body, such as artificial dialysis machines, heart-lung machines, storage containers for blood for transfusion, and blood processing devices, as well as devices that handle biological tissues for a specific purpose, such as substrates for cell culture and devices that selectively adhere and separate specific cells from body fluids.

The resin material of the present invention has excellent antithrombogenicity, heat resistance and low elution properties, and can therefore be widely used in medical molded products, such as implantable devices such as artificial organs and devices that come into contact with biological tissues inside the body, such as catheters.

Claims (13)

A resin material containing repeating units represented by the following formula (2) in a proportion of 50% by weight or more and 100% by weight or less, based on 100% by weight of all repeating units in the main chain, and containing a terminal group structure represented by the following formula (1) at a polymer chain end, wherein the resin material contains the terminal group structure represented by the following formula (1) in a proportion of 0.1 to 17% by weight, based on 100% by weight of all repeating units in the main chain, and the number average molecular weight of the polyoxyalkylene glycol monoether from which the terminal group structure represented by formula (1) is derived is 150 to 5,000 .

(In formula (1), _R1 and _R2 each independently represent a hydrogen atom or an aliphatic hydrocarbon having 1 to 4 carbon atoms, _R3 represents an alkyl group having 1 to 30 carbon atoms, m is 1 to 4, and n is 2 to 150.)
The resin material according to claim 1, which is for a device that comes into contact with biological tissue. The resin material according to claim 1 or 2, having a phenol content of 1000 ppm or less. The resin material according to any one of claims 1 to 3, which contains in its main chain a repeating structural unit derived from a diol compound selected from the group consisting of an aliphatic diol compound, an alicyclic diol compound, a heterocyclic diol compound other than that which induces the formula (2), and polyoxyethylene glycol. The resin material according to claim 4, which contains repeating units derived from the diol compound in a ratio of 0% by weight to 50% by weight, based on 100% by weight of all repeating units in the main chain. The resin material according to any one of claims 1 to 5 , comprising the repeating structural unit represented by formula (2) in a proportion of 70% by weight or more and 100% by weight or less, based on 100% by weight of all repeating structural units derived from the diol compound. The resin material according to any one of claims 1 to 6 , having a glass transition temperature of 80°C or higher and 160°C or lower. The resin material according to any one of claims 1 to 7 , which has a water contact angle of 60° or less. The resin material according to any one of claims 1 to 8 , which has a saturated water absorption rate of 1.0% by weight or more. The resin material according to any one of claims 1 to 9, which has a specific viscosity of 0.15 to 1.5 measured in a methylene chloride solution at 20°C. The resin material according to any one of claims 1 to 10 , wherein the terminal group structure represented by the formula (1) is a terminal group structure represented by the following formula (3):
(In formula (3), R ₄ represents a hydrogen atom or a methyl group, R ₅ represents an alkyl group having 1 to 30 carbon atoms, and n is an integer of 2 to 150.) A medical molded product produced using the resin material according to any one of claims 1 to 11 . A medical molded article obtained by surface treatment using the resin material according to any one of claims 1 to 11 .