JP2003082054A - Polymer excellent in safety - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polymer improved in stability and safety which had trouble in a conventional technique and capable of simultaneously realizing preferable characteristics such as good mechanical properties, ready processability, ready control of hardness, properties capable of readily imparting functionality by selection of a raw material and good biocompatibility. SOLUTION: This linear polymer has urethane bond and/or urea bond in the molecule. In the polymer, the whole organic carbon concentration in an extracted solution obtained by carrying out extraction operation of the polymer with physiological saline at 50 deg.C for 72 hr at a bath ratio of 20 ml physiological saline to 4.0 g polymer is <=400 ppm.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has a small amount of eluate,
The present invention relates to a polymer having excellent stability and safety.
The highly safe polymer of the present invention is particularly suitable for medical applications.

[0002]

2. Description of the Related Art Materials are required to have characteristics according to their uses, but generally have mechanical characteristics such as strength and durability. Materials with excellent mechanical properties are also applied to medical materials.

At the same time, since medical materials are used in direct contact with the living body, higher safety is required more than other applications. However, biological properties including safety of medical materials tend to lack sufficient consideration and consideration until recent years. In particular, the usage conditions for medical applications,
That is, it is a serious drawback as a medical material that the decomposition products, unreacted monomers, by-products, and oligomers contained in the material elute upon contact with body fluids such as blood.

For example, polyvinyl chloride (PVC) is very widely used as a medical material because its hardness can be freely changed by the amount of plasticizer added, it is relatively stable under general use conditions, and it is inexpensive. It's being used. However, PVC has a possibility that a plasticizer such as a phthalate ester may be eluted at the time of use, and many studies have shown that the phthalate ester is toxic, which is a safety issue. .

Silicone is also used as a medical elastomer for various catheters and tubes, and is also used as a membrane material for artificial lungs due to its gas permeability, but when it is left in the body for a long time, it is released as an eluate. There is concern about the toxicity of silicone.

Polyurethane can be prepared into a material having a desired hardness without using any additive by appropriately setting the compounding ratio of the macropolyol which becomes the soft segment and the diisocyanate or the chain extender which becomes the hard segment. Is. In addition, segmented polyurethanes are known to form microphase separated structures, thereby exhibiting excellent blood compatibility. In addition, it is relatively easy to prepare a material having a preferable functional group, for example, an amino group-containing polyurethane can be prepared by using an amino group-containing diol as one of the raw materials. Due to these advantages, polyurethane is one of the polymer materials favorably used as a medical material. However, on the other hand, it has been reported that the strength is reduced and the eluate is generated due to a hydrolysis reaction during sterilization or in-vivo use, which may cause a problem in safety.

A technique utilizing polyurethane and / or polyurethane urea and / or polyurea (hereinafter abbreviated as polyurethanes) in which an aliphatic diisocyanate and an aromatic diisocyanate are used in combination for the purpose of improving various physical properties required as materials. Has already been reported. As a disclosure of polyurethanes in which an aliphatic diisocyanate and an aromatic diisocyanate are used in combination with a clear intention, for example, JP-A-05-05
-295063, JP-A-07-026096, JP-A-0
7-097560, JP-A-07-166052, JP-A-08-052939, JP-A-08-067814, JP-A-09-255866, JP-A-11-349805, JP-A-2000-034439 and the like.

Among these, Japanese Patent Laid-Open No. 05-29506
3, JP-A-07-026096, JP-A 09-2558
66, JP-A-11-349805, and JP-A-2000-03.
4439 discloses a crosslinkable polyurethane prepared by converting a diisocyanate into a polyisocyanate by forming an isocyanurate group and using the polyisocyanate. Since these polyurethanes have a crosslinked structure, it is difficult to obtain the linear polymer which is the object of the present application. Further, since these are intended for use as paints and adhesives, no consideration is given to the stability and safety against heat and hydrolysis, which are the objects of the present application. In the present invention, the linear polymer means a polymer in which a crosslinked structure or a network structure is not intentionally introduced and which does not substantially contain these structures. Examples of characteristics of the linear polymer include solubility in a solvent and thermoplasticity. Specifically, when considering polyurethanes, for example, a polyfunctional raw material having a functionality of three or more is not used, and a difunctional diisocyanate and a difunctional diol and / or
It also means polyurethanes obtained from difunctional diamines. When a polymer is modified by introducing a graft chain, a cross-linked structure and a network structure are not introduced by grafting, and sufficient solubility as a comb-shaped grafted polymer,
If it is thermoplastic, it can be considered a linear polymer in the present invention. In polyurethanes, even a polymer obtained from a bifunctional raw material may form an allophanate bond and form a crosslinked structure when prepared under severe conditions. The linear polymer of the present invention basically does not include such polyurethanes, but if it has sufficient solubility and thermoplasticity, even if it contains an unintended crosslinked structure, It is considered to be within the tolerance range of the chain polymer.

Japanese Unexamined Patent Publication No. 08-052939 discloses a polyisocyanate containing an allophanate group, and it is described that the polyisocyanate is derived from an aromatic diisocyanate and an aliphatic diisocyanate.
Active introduction of allophanate groups means introduction of a cross-linked structure in the resulting material, and it is difficult to obtain a linear polymer as in the case of using a polyisocyanate by forming an isocyanurate group. .

Further, JP-A-07-097560 and JP-A-07-166052 disclose polyurethanes in which an aromatic diisocyanate and an aliphatic diisocyanate are used in combination for use as an adhesive and as a charging member, respectively. However, no consideration was given to safety.

Japanese Unexamined Patent Publication (Kokai) No. 08-067814 discloses a resin composition containing, as a component, a polyurethane resin prepared from an aliphatic diisocyanate and / or a mixed diisocyanate of an alicyclic diisocyanate and an aromatic diisocyanate as a raw material. These are polyurethanes with improved yellowing resistance, chemical resistance, solvent solubility, and scratch resistance, and are not intended to improve safety (cytotoxicity, acute toxicity, etc.), especially hydrolyzed products. There is a problem in the safety of the material in that the polycaprolactone polyol, which easily produces propylene, is used as an essential component.

Further, the inventors of the present invention have disclosed WO98 / 46659 and JP-A-200 as a biocompatible and antithrombotic material.
Nos. 0-128950 and 2000-126566 are filed. In these technologies, biocompatibility,
For the purpose of improving antithrombogenicity, a polyurethane or polyurethaneurea obtained by using a diol having a phosphorylcholine structure as at least a part of the diol component is disclosed. In JP-A-2000-128950 and JP-A-2000-126566, segmentation of a material is promoted by using two or more kinds of diisocyanates, particularly two or more kinds of aliphatic diisocyanates (including alicyclic groups), and microphase separation is performed. It is disclosed that the formation of the structure significantly improves antithrombotic properties. However, these materials have a drawback that they have a large amount of eluate, although they are mainly used for medical purposes.

Although various indexes for evaluating the stability and safety of polymers have been considered, those that are relatively easy to perform, have good reproducibility, and can be evaluated for overall stability and safety in a comprehensive manner. Surprisingly few. An acute systemic toxicity test, a subacute toxicity test, or cytotoxicity is used to evaluate the safety to the living body. However, since it is necessary to use animals and cultured cells for the experiment, it cannot be said that the experiment can be carried out easily. In addition, manufacturing approval standards for various medical devices are stipulated (eg, “Dialysis-type artificial kidney device approval standards” June 2, 1983).
(0th Ministry of Health, Labor and Welfare Notification, etc.), in which the method and standard value of the eluate test are shown, but it cannot be said that polymers that meet this standard value have sufficient safety. Exists.

[0014]

DISCLOSURE OF THE INVENTION The present invention improves stability and safety, which have been still problematic even though attempts have been made to improve them by various approaches in the prior art, and at the same time, other desirable properties are simultaneously improved. The object is to provide a polymer that can be realized. In particular, it is a preferable material from the viewpoint of mechanical properties, easiness of processing, easiness of hardness adjustment, easiness of imparting functionality by selection of raw materials, good biocompatibility, etc. With regard to polyurethanes that may cause problems such as strength reduction and eluate formation due to hydrolysis and oxidative decomposition during use, thermal decomposition and hydrolysis which are problematic in the conventional technology while maintaining favorable characteristics. It is an object of the present invention to provide a highly safe polyurethane and / or polyurethane urea having improved stability against decomposition and oxidative decomposition.

[0015]

[Means for Solving the Problems]
A polyurethane or polyurethane urea having improved antithrombogenicity, which is obtained by using at least one aliphatic diisocyanate (including alicyclic diisocyanate) in combination, was found (JP 2000
-128950). Furthermore, as a result of continuing intensive studies in view of such a situation, it is described in ASTM F619 (extraction method of medical plastics) which is the extraction condition cited in the method of ASTM F750 (mouse systemic toxicity test of material extract). The total organic carbon concentration (TO) in the extract extracted with physiological saline based on the specified extraction conditions.
When C) is below a specific value, it was found that the safety of the polymer was high, and the present invention was reached.

That is, the present invention is a polymer having a urethane bond and / or a urea bond in the molecule, and the extraction operation is carried out at a bath ratio of 4.0 g of the polymer to 20 ml of physiological saline at 50 ° C. for 72 hours. It is a polymer having excellent safety, which is characterized in that the total organic carbon concentration in the extract is 400 ppm or less.

As a polymer having a urethane bond and / or a urea bond in the molecule, polyurethanes are typical polymers, but the present invention is not limited to polyurethanes. For example, the urethane bond and / or the urethane bond in the molecule may be used. It also includes a polymer in which a vinyl-based monomer having a urea bond has a high molecular weight by addition polymerization. However, polyurethanes are preferred in the present invention, with polyurethane and / or polyurethaneurea being especially preferred.

Polyurethanes are prepared from three components of diisocyanate, soft segment macropolyol, and chain extender. Of these, diisocyanates are roughly classified into aromatic diisocyanates and aliphatic diisocyanates (including alicyclic diisocyanates). Since aromatic diisocyanates are relatively highly reactive, the molecular weight of the resulting polyurethane and polyurethane urea is improved during the preparation of polyurethane and polyurethane urea, which is preferable. However, there is a possibility that coloring due to oxidative decomposition and hydrolysis may generate an aromatic amine having a carcinogenic risk. Aliphatic diisocyanates are less likely to be colored, and even if hydrolyzed, carcinogenic substances are unlikely to be produced. However, on the other hand, the reactivity is slightly inferior to that of the aromatic diisocyanate, so that the polymer preparation requires more severe conditions and the addition of a catalyst.

The means for obtaining the polymer of the present invention is not particularly limited, but a method of preparing polyurethanes by using an aliphatic diisocyanate and an aromatic diisocyanate in combination is preferable. The aliphatic diisocyanate in the present invention also includes an alicyclic diisocyanate. For example, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate,
Examples thereof include, but are not limited to, decamethylene diisocyanate, dodecamethylene diisocyanate, 3,3′-diisocyanatopropyl ether, cyclopentane diisocyanate, cyclohexane diisocyanate, and 4,4′-methylenebis (cyclohexyl isocyanate). Further, the hydrogen atom of the hydrocarbon skeleton forming diisocyanate may be substituted with another atom or a functional group.

The aliphatic diisocyanate which can be used when the polymer of the present invention is a polyurethane is preferably a linear hydrocarbon diisocyanate having an isocyanate group at both ends. Specific examples include, but are not limited to, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, dodecamethylene diisocyanate, and the like. The hydrogen atom of the hydrocarbon skeleton forming diisocyanate may be substituted with another atom or a functional group. Of these, tetramethylene diisocyanate, hexamethylene diisocyanate and octamethylene diisocyanate are preferable, and hexamethylene diisocyanate is particularly preferable.

Aromatic diisocyanates which can be used when the polymer of the present invention is polyurethanes include, for example, tolylene diisocyanate, xylylene diisocyanate, phenylene diisocyanate, naphthalene diisocyanate, isocyanatobenzyl isocyanate, 4,4'- Examples thereof include methylene bis (phenyl isocyanate), but are not limited thereto. Further, the hydrogen atom of the hydrocarbon skeleton forming diisocyanate may be substituted with another atom or a functional group. Of these, 4,4'-methylenebis (phenylisocyanate) is particularly preferable. The aliphatic diisocyanate and aromatic diisocyanate used in the present invention may each be a single type of diisocyanate or a mixture of two or more types.

Regarding the macropolyols that can be used as the soft segment component when the polymer of the present invention is polyurethanes, macropolyols used for general polyurethanes are widely available, but substantially carboxylic acid is used. Macropolyols containing no ester bonds are preferred. Specifically, for example, low molecular weight diols (for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol, 2,2-dimethyltrimethylene glycol, 1, 4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, etc.) and a dicarboxylic acid or an ester-forming derivative thereof (for example, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, dodecanedicarboxylic acid,
Polycarboxylic acid ester diols obtained by reacting terephthalic acid, isophthalic acid or their acid halides, active esters, amides, etc., polylactone diols obtained by ring-opening polymerization of ε-caprolactone (also polycarboxylic acids in a broad sense) A macropolyol containing a carboxylic acid ester bond such as (included in acid ester diol) is not preferable because a low molecular weight product is produced by a hydrolysis reaction when it is used as a medical material and becomes an eluate. Examples of the macropolyol that is a soft segment component that does not substantially contain a carboxylic acid ester bond include polyethylene glycol, polypropylene glycol, polytetramethylene glycol, and other polyether diols, polybutadiene diol, polyisoprene diol, hydrogenated polyisoprene diol, and the like. Examples include polyalkylene diols and various polycarbonate diols. Of these, polyether diols are particularly preferred. The macropolyols may be used alone or in combination of two or more.

The chain extender that can be used when the polymer of the present invention is a polyurethane is not particularly limited, and a chain extender used for general polyurethanes and a chain that will be developed in the future. Extenders are widely available. Specifically, for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol, 2,
2-dimethyltrimethylene glycol, 1,4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, diethylene glycol, triethylene glycol and other diols, ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, xylylenediamine, phenylenediamine, 4,
Diamines such as 4′-methylenebis (phenylamine), 2-aminoethanol, 3-aminopropanol,
Examples include amino alcohols such as 4-aminobutanol, and further diamines in a broad sense such as dihydrazides (eg, oxalic acid dihydrazide, malonic acid dihydrazide, succinic acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, isophthalic acid dihydrazide).
Not limited to these, all of low molecular weight diols, diamines, and amino alcohols can be applied regardless of whether they are publicly known, new, or applied to polyurethanes. These chain extenders may be used alone or in combination of two or more.

The polymer having excellent safety according to the present invention may incorporate a specific component for application to a specific application. For example, introduction of an antibacterial group for the purpose of imparting antibacterial properties to the material, and introduction of an antithrombotic group for application to medical materials can be considered. Introducing a tertiary amino group for immobilizing heparin, introducing a component having a phosphorylcholine-like structure that is a cell membrane constituent, and further introducing polydimethylsiloxane with an application to a gas permeable material in mind. This is exemplified.

In particular, the method of preparing polyurethanes by using the phosphorylcholine-like structure-containing diol represented by the following chemical formula (6) or (7) as one of the raw materials improves the blood compatibility of the obtained material. It is effective to let.

[Chemical 6]

[Chemical 7] [In the above chemical formulas (6) and (7),
R ¹ , R ² , R ³ and R ⁶ are alkylene groups having 1 to 10 carbon atoms,
Arylene group having 6 to 12 carbon atoms or 7 to 15 carbon atoms
Of aralkylene groups, which may be the same or different, and the hydrogen atom may be substituted with another atom or a functional group. R ⁴ , R ⁵ and R ⁸ are each an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a carbon number of 7 to 1
5 aralkyl groups, which may be the same or different, and the hydrogen atom of each group may be substituted with another atom or a functional group. R ⁷ is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure of the following chemical formula (4). X is N, HC or the following chemical formula (5)
Is a group having the structure of ]

[Chemical 8]

[Chemical 9] [In the formula, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more kinds of oxyalkylene groups may be mixed, and the bonding order thereof may be block or random. In addition, n is an integer of 1 to 30. R ⁹ and R ¹⁰ are an alkyl group having 1 to ¹⁰ carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group is substituted with another atom or a functional group. It may have been done. ]

When the highly safe polymer of the present invention is a polyurethane, for example, the following production method is exemplified: Macropolyol and aliphatic diisocyanate are mixed and reacted in a suitable solvent. After adding an aromatic diisocyanate to this to prepare a prepolymer, a chain extender is added to obtain a high molecular weight polyurethane or polyurethane urea. At this time, in the reaction of the macropolyol and the aliphatic diisocyanate, and subsequently in the reaction of adding the aromatic diisocyanate to obtain the prepolymer, since the aromatic diisocyanate is generally higher in activity than the aliphatic diisocyanate, the latter It is preferable to set the reaction temperature of 1) lower than the reaction temperature of the former. If the aromatic diisocyanate is added at a temperature suitable for the reaction of the aliphatic diisocyanate, gelation may occur, and if the reaction of the aliphatic diisocyanate is performed at a temperature suitable for the reaction of the aromatic diisocyanate, the reaction is It may not proceed sufficiently and the resulting polyurethane and / or polyurethaneurea may be unusable as a material.

When the highly safe polymer of the present invention is a polyurethane to which a phosphorylcholine-like structure-containing diol is added, for example, the following method is exemplified: phosphorylcholine-like structure-containing diol and fat. A group diisocyanate is mixed and reacted in a suitable solvent, and then an aromatic diisocyanate and then a macropolyol are added to prepare a prepolymer, and then a chain extender is added to form a high molecular weight polyurethane or polyurethane urea. obtain. Also in this case, it is preferable that after the phosphorylcholine-like structure-containing diol is reacted with the aliphatic diisocyanate, the temperature is lowered to add the aromatic diisocyanate and subsequently the macropolyol.

When producing polyurethanes,
A polymerization catalyst may be added for efficient polymerization.
Examples of the polymerization catalyst include tin-based catalysts such as tin dibutyl dilaurate and titanium-based catalysts such as tetrabutoxy titanium.

When the highly safe polymer of the present invention is a polyurethane obtained by using an aliphatic diisocyanate and an aromatic diisocyanate in combination as the diisocyanate component, for example, the following production conditions can be used. . The following production conditions do not limit the present invention. The aliphatic diisocyanate and aromatic diisocyanate are used in a molar ratio of aliphatic diisocyanate / aromatic diisocyanate = 1/9 to 9/1, preferably 2/8 to 7/3, more preferably 2/8. ~ 6/4. If the amount of the aliphatic diisocyanate is larger than this, the reaction is difficult to proceed, and if the amount of the aromatic diisocyanate is larger than this, the obtained polyurethane and / or polyurethane urea may be colored. The reaction temperature when reacting the aliphatic diisocyanate is 50 ° C to 120 ° C.
C., preferably 60.degree. C. to 100.degree. C., the reaction temperature when reacting the aromatic diisocyanate is 30.degree. C. to 100.degree. C., preferably 40.degree. C. to 80.degree. C., lower than the temperature when reacting the aliphatic diisocyanate. Is preferred.

The solvent used in the reaction is not particularly limited, but a solvent which is inert to the raw materials and is excellent in the solubility of the raw materials is preferable. Specifically, for example, N-methylformamide, N, N-dimethylformamide, N, N-
Examples thereof include dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, dimethylsulfoxide, and toluene, and among them, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone are preferable. The solvent may be used alone or in combination of two or more kinds. Also, a method of carrying out the reaction without a solvent can be applied.

In order to obtain the highly safe polymer of the present invention, one of the effective methods is to carry out sufficient washing after preparing the polymer. Specifically, for example, immersed in warm water,
A technique of removing impurities while stirring can be adopted. At this time, the temperature of the warm water is 40 ° C to 95 ° C, preferably 50 ° C.
To 90 ° C, more preferably 60 ° C to 80 ° C, and the washing time is 30 minutes to 48 hours, preferably 60 minutes to 24 hours, and more preferably 90 minutes to 12 hours. Also,
Bath ratio of polymer to warm water for washing is 1 g / 10 ml to 1
g / 500 ml, preferably 1 g / 20 ml to 1 g / 4
00 ml, more preferably 1 g / 50 ml to 1 g / 2
It is 00 ml. Cleaning at a temperature lower than this for a short period of time is insufficient in the effect of removing impurities, and cleaning at a temperature higher than this for a long period of time may cause decomposition and deterioration of the polymer. Further, if the bath ratio is lower than this, it is difficult to sufficiently obtain the effect because the polymer is difficult to be sufficiently immersed in the wash warm water, and if the bath ratio is higher than this, a large amount of wash warm water is used, which is not efficient. It is also possible to repeat the hot water washing under the above conditions twice or more. Although a method of using an organic solvent for washing can also be used, it is more preferable to wash with warm water as described above from the viewpoint of the possibility of remaining solvent and treatment of the washing solvent.

The polymer having excellent safety of the present invention may be used alone, or may be added to other materials by a method such as blending, coating, grafting or copolymerization. It is also possible to modify the polymer of the present invention having excellent safety as a substrate by a method such as blending, coating, grafting or copolymerization.

The polymer having excellent safety of the present invention has excellent stability and safety. Taking advantage of these advantages,
The polymer having excellent safety according to the present invention can be widely used not only for general-purpose use but also as a medical material. Specifically, for example, hemodialysis membranes and plasma separation membranes, adsorbents for blood waste, membranes for artificial lungs, intravascular balloons, blood bags, catheters, cannulas, shunts, materials for medical devices such as blood circuits, And coating materials for these medical devices are exemplified.

[0034]

EXAMPLES The present invention will be described below with reference to examples.
The invention is not limited by these examples.

Example 1 (Preparation of Polymer) 18.63 g of polytetramethylene glycol (PTMG) having a number average molecular weight of 2000 was weighed in a separable flask, and 62 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 7.26 g of hexamethylene diisocyanate (HDI) was added, and the mixture was stirred for 1 hour. The reaction temperature was lowered to 55 ° C. and stirred for 30 minutes, and 4,4′-methylenebis (phenylisocyanate) (MDI) 25.2
0 g was added and stirred at 55 ° C. for 1 hour to prepare a prepolymer. 1,4-butanediol (B
D) 10.00 g was added in two portions, and the mixture was stirred at 55 ° C. for 1 hour. 62 ml of NMP was added to dilute the reaction mixture, and the mixture was stirred at 55 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the end, and stirring was continued from 55 ° C. to room temperature gradually. The reaction mixture was dropped into 5000 ml of water to collect the product, and washing with warm water at 70 ° C. for 2 hours was repeated 3 times, followed by drying under reduced pressure to obtain a polymer A.

(Molecular weight) Polymer A was added to DMF containing 0.1% of lithium bromide and dissolved, and the molecular weight was measured by gel permeation chromatography (GPC). The gel column is Shodex AD-803 /
S, AD-804 / S, AD-806 / S, AD-80
Using 2 / S connected in series and using a calibration curve made of polyethylene glycol, the temperature was 50 ° C. and the mobile phase was DMF containing 0.1% lithium bromide. The results are shown in Table 1.

(Extract TOC) In accordance with the extraction conditions described in ASTM F619 (Medical plastic extraction method), which is the extraction conditions quoted in the method of ASTM F750 (material systemic toxicity test of mice). , 4.0 g of the polymer was immersed in 20 ml of physiological saline, and
Extraction operation was performed at 0 ° C. for 72 hours. The total amount of organic carbon (TOC) in this extract was measured by TOC-5050A, a total organic carbon meter manufactured by Shimadzu Corporation. The results are shown in Table 1.

[Table 1]

(Eluate Test) “Dialysis Type Artificial Kidney Device Approval Criteria” In accordance with the extraction conditions in the eluate test of dialysis membrane described in the notification of the Director General of the Pharmaceutical Affairs Bureau on June 20, 1983, Polymer 1 0.5 g was immersed in 150 ml of distilled water for injection, and elution operation was carried out at 70 ° C. for 1 hour. Using this eluate, pH, potassium permanganate reducing substance (KMnO ₄ ), evaporation residue (residue), ultraviolet absorption spectrum (UV) among the items of the eluate test in the quality and test of blood circuit are used. Was evaluated.
The results are shown in Table 2.

(Cytotoxicity) Pharmaceutical Machine No. 99 (June 27, 1995) Method of cytotoxicity test using extract of medical device or material described in the notice of Medical Device Development Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare V79 cells were used in accordance with
C50 (%) was determined. The results are shown in Table 2.

(Acute toxicity) Polymer A was extracted according to the extraction conditions described in ASTM F619 (extraction method for medical plastics), and the extract solution was
Based on the method of F750 (mouse systemic toxicity test of material extract), the dose was 50 μl / g (mouse weight) from the tail vein of the mouse, and changes in the condition were observed. The results are shown in Table 2.

[Table 2] In the value of cytotoxicity in Table 2, 100% indicates that no influence was observed on the cell growth inhibition even in the stock solution for extraction.

Example 2 (Preparation of Polymer) 10.00 g of a compound represented by the following chemical formula (8) (hereinafter abbreviated as choline diol) was weighed in a separable flask, and 50 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 6.65 g of HDI was added, and the mixture was stirred for 1 hour. The reaction temperature is lowered to 55 ° C. and stirred for 30 minutes.
DI23.09g was added, and after stirring at 55 ° C for 1 hour, 20.37g of PTMG having a number average molecular weight of 2000 was added to NMP18.
It was dissolved in ml and added. It stirred at 55 degreeC for 1 hour, and prepared the prepolymer. BD71.71g was added to this reaction liquid mixture in 2 portions, and it stirred at 55 degreeC for 1 hour. NMP4
0 ml was added to dilute the reaction mixture, and the mixture was stirred at 55 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the end, and stirring was continued from 55 ° C. to room temperature gradually.
The reaction mixture was dropped into 5000 ml of water to collect the product, and washing with warm water at 70 ° C. for 2 hours was repeated 3 times, and then dried under reduced pressure to obtain a polymer B.

[Chemical 10]

(Molecular weight) (Extract TOC) (Eluted substance test) (Cytotoxicity) (Acute toxicity) Tests for molecular weight, extract TOC, eluate test, cytotoxicity and acute toxicity were conducted in the same manner as in Example 1. went. The results of molecular weight and extract TOC are shown in Table 1, and the results of eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 1 (Preparation of Polymer) PTMG1 having a number average molecular weight of 2000
Weigh 4.81 g in a separable flask and place NMP50
ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution is heated to 75 ° C. and HDI23.
70 g was added and stirred for 1 hour to prepare a prepolymer.
BD 9.85 g was added to this reaction mixture in two divided portions, and the mixture was stirred at 75 ° C. for 1 hour. 50 ml of NMP was added to dilute the reaction mixture, and the mixture was stirred at 75 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the end, and stirring was continued from 75 ° C. until the temperature gradually reached room temperature. 500 reaction mixture
The product was recovered by pouring it into 0 ml of water, washed with warm water of 70 ° C. for 2 hours, and dried under reduced pressure to obtain a polymer C.

(Molecular weight) (Extract TOC) (Elution test) (Cytotoxicity) (Acute toxicity) Tests for molecular weight, extract TOC, eluate test, cytotoxicity and acute toxicity were conducted in the same manner as in Example 1. went. The results of molecular weight and extract TOC are shown in Table 1, and the results of eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 2 (Preparation of Polymer) PTMG1 having a number average molecular weight of 2000
Weigh 8.06 g into a separable flask and NMP60
ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution is heated to 55 ° C. and MDI32.
35 g was added and stirred for 1 hour to prepare a prepolymer.
BD 8.80 g was added to this reaction mixture in two divided portions, and the mixture was stirred at 55 ° C. for 1 hour. 60 ml of NMP was added to dilute the reaction mixture, and the mixture was stirred at 55 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the end, and stirring was continued from 55 ° C. to room temperature gradually. 500 reaction mixture
The product was collected by pouring it into 0 ml of water, washed with warm water of 70 ° C. for 2 hours, and dried under reduced pressure to obtain a polymer D.

(Molecular weight) (Extract TOC) (Elution test) (Cytotoxicity) (Acute toxicity) Tests for molecular weight, extract TOC, eluate test, cytotoxicity and acute toxicity were conducted in the same manner as in Example 1. went. The results of molecular weight and extract TOC are shown in Table 1, and the results of eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 3 (Preparation of Polymer) 10.00 g of choline diol was weighed in a separable flask and 40 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 22.06 g of HDI was added, and after stirring for 1 hour, PTMG17.11 having a number average molecular weight of 2000
g was dissolved in 17 ml of NMP and added. It stirred at 75 degreeC for 1 hour, and prepared the prepolymer. B in this reaction mixture
6.86 g of D was added in 2 portions and the mixture was stirred at 75 ° C. for 1 hour. Dilute the reaction mixture by adding 30 ml of NMP,
The mixture was reacted at 5 ° C. for 12 hours with stirring. 1 g of BD was added to terminate the end, and stirring was continued from 75 ° C. until the temperature gradually reached room temperature. The reaction mixture was dropped into 5000 ml of water to collect the product, washed with warm water at 70 ° C. for 2 hours, and dried under reduced pressure to obtain a polymer E.

(Molecular weight) (Extract TOC) (Eluate test) (Cytotoxicity) (Acute toxicity) Tests for molecular weight, extract TOC, eluate test, cytotoxicity and acute toxicity in the same manner as in Example 1. went. The results of molecular weight and extract TOC are shown in Table 1, and the results of eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 4 (Preparation of Polymer) 10.00 g of choline diol was weighed in a separable flask and 50 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 55 ° C., MDI (33.00 g) was added, and the mixture was stirred for 1 hour.
g was dissolved in 20 ml of NMP and added. It stirred at 55 degreeC for 1 hour, and prepared the prepolymer. B in this reaction mixture
6.65 g of D was added in 2 portions and the mixture was stirred at 75 ° C. for 1 hour. Dilute the reaction mixture by adding 40 ml of NMP,
The mixture was reacted at 5 ° C. for 12 hours with stirring. 1 g of BD was added to terminate the end, and stirring was continued from 55 ° C. to room temperature gradually. The reaction mixture was poured into 5000 ml of water to recover the product, which was washed with warm water at 70 ° C. for 2 hours and dried under reduced pressure to obtain a polymer F.

(Molecular weight) (Extract TOC) (Eluate test) (Cytotoxicity) (Acute toxicity) Tests for molecular weight, extract TOC, eluate test, cytotoxicity and acute toxicity were conducted in the same manner as in Example 1. went. The results of molecular weight and extract TOC are shown in Table 1, and the results of eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 5 (Preparation of Polymer) PTMG1 having a number average molecular weight of 2000
Weigh 9.09 g into a separable flask and use NMP64
ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution is heated to 75 ° C. and HDI 7.2
5 g was added and stirred for 1 hour. The reaction temperature was lowered to 55 ° C. and the mixture was stirred for 30 minutes, 26.39 g of 4,4′-methylenebis (cyclohexyl isocyanate) (HMDI) was added, and the mixture was stirred at 55 ° C. for 1 hour to prepare a prepolymer.
BD 9.90 g was added to this reaction mixture in two divided portions, and the mixture was stirred at 55 ° C. for 1 hour. 64 ml of NMP was added to dilute the reaction mixture, and the mixture was stirred at 55 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the end, and stirring was continued from 55 ° C. to room temperature gradually. 500 reaction mixture
The product was recovered by dropping it in 0 ml of water, washed with warm water of 70 ° C. for 2 hours, and dried under reduced pressure to obtain a polymer G.

(Molecular weight) (Extract TOC) (Eluate test) (Cytotoxicity) (Acute toxicity) Tests for molecular weight, extract TOC, eluate test, cytotoxicity and acute toxicity in the same manner as in Example 1. went. The results of molecular weight and extract TOC are shown in Table 1, and the results of eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 6 (Preparation of Polymer) PTMG1 having a number average molecular weight of 2000
Weigh 9.09 g into a separable flask and use NMP64
ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution is heated to 100 ° C. and HDI7.
25 g was added and stirred for 1.5 hours. Furthermore, HMDI2
6.39 g was added and stirred at 100 ° C. for 1 hour to prepare a prepolymer. To this reaction mixture was added 2.90 g of BD.
The mixture was added in portions and stirred at 100 ° C. for 1 hour. NMP6
4 ml was added to dilute the reaction mixture, and the mixture was stirred at 100 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the terminal, and stirring was continued from 100 ° C. to room temperature gradually. The reaction mixture was dropped into 5000 ml of water to collect the product, which was washed with warm water at 70 ° C. for 2 hours and dried under reduced pressure to obtain a polymer H.

(Molecular weight) (Extract TOC) (Eluate test) (Cytotoxicity) (Acute toxicity) Tests for molecular weight, extract TOC, eluate test, cytotoxicity and acute toxicity in the same manner as in Example 1. went. The results of molecular weight and extract TOC are shown in Table 1, and the results of eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 7 (Preparation of Polymer) 10.00 g of choline diol and 12.20 g of PTMG having a number average molecular weight of 1320 were weighed in a separable flask, and 200 ml of DMAc was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 100 ° C., 24.31 g of HMDI was slowly added, and after the addition, the mixture was stirred for 5 hours. 6.68 g of HDI was slowly added, and after the addition, the mixture was stirred at 100 ° C. for 10 hours. BD
7.81 g was slowly added, and the mixture was further stirred at 100 ° C. for 5 hours. After the reaction, this reaction mixture was dropped into 5000 ml of water. The obtained precipitate was separated by filtration, dissolved in THF and poured into methanol again, and the formed precipitate was recovered and dried under reduced pressure to obtain a polymer I.

(Molecular weight) (Extract TOC) (Eluate test) (Cytotoxicity) (Acute toxicity) Tests for molecular weight, extract TOC, eluate test, cytotoxicity and acute toxicity in the same manner as in Example 1. went. The results of molecular weight and extract TOC are shown in Table 1, and the results of eluate test, cytotoxicity and acute toxicity are shown in Table 2.

As is clear from the Examples and Comparative Examples, it was found that the polymer of the present invention has low eluate, cytotoxicity and acute toxicity and high safety.

[0058]

EFFECT OF THE INVENTION The polymer of the present invention has lower eluate, cytotoxicity and acute toxicity than conventional polymers. Taking advantage of such advantages, the polymer of the present invention is particularly useful as a medical material as well as general applications.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C081 AC08 AC10 BB08 CA211                       DA16                 4J034 CA04 CA15 CD07 DA01 DB04                       DC50 DG02 DG03 DG04 DG05                       GA05 GA06 GA23 HA07 HA15                       HC03 HC12 HC16 HC17 HC22                       HC54 HC64 HC67 HC71 HC73                       JA42 QB19 RA02 RA19

Claims (5)

[Claims] 1. A linear polymer having a urethane bond and / or a urea bond in the molecule, which is extracted at a bath ratio of 4.0 g of polymer and 20 ml of physiological saline for 72 hours at 50 ° C. A polymer having excellent safety, which is characterized in that the total organic carbon concentration in the extract when it is carried out is 400 ppm or less. 2. A linear polymer having a urethane bond and / or a urea bond in the molecule is obtained by using an aliphatic diisocyanate and an aromatic diisocyanate in combination as the diisocyanate component, and the soft segment component is substantially present. The highly safe polymer according to claim 1, which is a segmented polyurethane and / or polyurethane urea containing no carboxylic acid ester bond. 3. The polymer having excellent safety according to claim 1 or 2, which contains phosphorus in the molecule of a linear polymer having a urethane bond and / or a urea bond in the molecule. 4. The polymer having excellent safety according to claim 3, which has a structure represented by the following chemical formula (1) in the molecule of a linear polymer having a urethane bond and / or a urea bond in the molecule. [Chemical 1] [In the above chemical formula (1), R is an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an aralkylene group having 7 to 15 carbon atoms, and the hydrogen atom of each group is another atom or It may be substituted with a functional group. ] 5. The polymer having excellent safety according to claim 4, which has a structure of the following chemical formula (2) or chemical formula (3) in the molecule of a linear polymer having a urethane bond and / or a urea bond in the molecule. . [Chemical 2] [Chemical 3] [In the above chemical formulas (2) and (3),
R ¹ , R ² , R ³ and R ⁶ are alkylene groups having 1 to 10 carbon atoms,
Arylene group having 6 to 12 carbon atoms or 7 to 15 carbon atoms
Of aralkylene groups, which may be the same or different, and the hydrogen atom may be substituted with another atom or a functional group. R ⁴ , R ⁵ and R ⁸ are each an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a carbon number of 7 to 1
5 aralkyl groups, which may be the same or different, and the hydrogen atom of each group may be substituted with another atom or a functional group. R ⁷ is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure of the following chemical formula (4). X is N, HC or the following chemical formula (5)
Is a group having the structure of ] [Chemical 4] [Chemical 5] [In the formula, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more kinds of oxyalkylene groups may be mixed, and the bonding order thereof may be block or random. In addition, n is an integer of 1 to 30. R ⁹ and R ¹⁰ are an alkyl group having 1 to ¹⁰ carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group is substituted with another atom or a functional group. It may have been done. ]