JP2003082053A - Phosphorus-containing polymer - 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 phosphorus-containing polymer containing phosphorus introduced by urethane bond and/or urea bond and covalent bond and/or ionic bond in the molecule. In the polymer, the phosphorus 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 <=300 ppm. The phosphorus-containing polymer is preferably a polymer containing urethane bond and/or urea bond and a phosphate bond, obtained by combinedly using an aliphatic diisocyanate and an aromatic diisocyanate as a diisocyanate component in the molecule, more preferably a phosphorus-containing polymer having a structure represented by the chemical formula (2) or the chemical formula (3).

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 phosphorus-containing 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, materials having excellent mechanical characteristics, that is, strength and durability are commonly used. Materials that have been researched and developed to obtain excellent mechanical properties are also applied to medical applications due to their excellent properties.

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, elution of decomposed materials, unreacted monomers, by-products, and oligomers under conditions of use for medical purposes, that is, contact with body fluids such as blood, is said to be a serious drawback for medical materials. I have no choice.

For example, polyvinyl chloride (PVC) is extremely useful 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. Widely used in. However, with PVC, the phthalate ester of the plasticizer may elute during use. Phthalates have been shown to be toxic in many studies, 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 and / or polyurea and / or polyurethaneurea (hereinafter abbreviated as polyurethanes) can be prepared by appropriately setting the compounding ratio of macropolyol as a soft segment, diisocyanate as a hard segment and chain extender. It is possible to prepare materials of preferred hardness without the use of additives. 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.

[0007] The medical material is required to have a characteristic that it is difficult for a living body to recognize it as a foreign substance, that is, biocompatibility. Cells constituting a living body are composed of a phospholipid bilayer membrane in which hydrophilic portions are arranged on the outside, and attempts have been made to realize excellent biocompatibility by using a material that mimics this structure. Japanese Patent Application Laid-Open No. 54-063025 discloses 2-methacryloxyethylphosphorylcholine, which has a choline group similar to lecithin which is a phospholipid. Therefore, a polymer of this compound has excellent affinity for living tissues. There is a description that it has. As a similar material, JP-A-57-036868 and JP-A-59-199696 disclose methods for producing phospholipid-like compounds. Also,
JP-A-60-067489 discloses a method for producing a naturally-occurring polymerizable phospholipid in which an unsaturated carbon-carbon bond is introduced into a long-chain hydrocarbon group portion. In these techniques, a polymer material can be obtained by addition polymerization utilizing an unsaturated carbon-carbon bond. In addition, special table Sho 62-5007
26 discloses a polyurethane containing phosphorylcholine groups. Further, JP-A-60-206835 discloses a polymer material whose main chain is formed of repeating units of phosphorylcholine by ring-opening polymerization of a dioxaphosphorane derivative.

[0008] Although all of these techniques have been studied with a focus on improving biocompatibility, it cannot always be said that sufficient consideration is given to the stability and safety of materials. Since the phosphate ester moiety may be cleaved by hydrolysis, it is pointed out that the material in which the phosphorylcholine group is pendantly introduced may be detached from the phosphate ester moiety. Since the eluted component is a substance that is considered to exist in the body as well, it is unlikely that it will have a fatal effect on safety, but it is concerned with the safety of the material in a complicated pathway in the body. It is quite possible to come. Further, there is great doubt about the persistence of biocompatibility of the material surface which is changed by the cleavage of the phosphate ester moiety. The situation is the same for materials incorporating phosphorylcholine in the main chain, in which case cleavage of the phosphate ester means fragmentation of the main chain, and the strength of the material is greatly reduced, which is a practical problem. Is likely to occur.

As a technique of applying phosphorus from a viewpoint different from the biocompatibility improving technique using a phosphorylcholine-like structure, the inventors of the present invention disclosed in JP-A-09-176379 a material having antibacterial properties and antithrombotic properties at the same time. There is. This is a technology that combines the antibacterial action of phosphonium salts and the antithrombotic action of mucopolysaccharides, and is disclosed in JP-A-11-0472.
No. 64 discloses that when the phosphorus concentration in the extract is within a specific range, sufficient antibacterial and antithrombotic properties, its sustainability, and safety to living bodies are exhibited. In the technique disclosed in JP-A-11-047264, although attention is paid to the safety of the compound as a whole of the quaternary phosphonium-containing ionic complex and the polymer material, it is an antibacterial substance by nature. Since an ionic complex containing a quaternary phosphonium salt, which is toxic to the living body, has been added, it cannot be denied that there is still concern about safety.

Although various indexes for evaluating the stability and safety of polymers can be considered, it is surprisingly easy to carry out, good reproducibility and comprehensively evaluating the overall stability and safety. Few. There are acute systemic toxicity tests, subacute toxicity tests, cytotoxicity, etc. to evaluate the safety to living organisms, but it is difficult to say that they can be easily performed because it is necessary to use animals or cultured cells for the experiments. In addition, manufacturing approval standards for various medical devices are stipulated (for example, “Dialysis-type artificial kidney device approval standards” Notification of the Director General of the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare on June 20, 1983). Although the values are shown, there are some aspects in which it cannot be said that polymers that meet this standard value have sufficient safety.

[0011]

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, the present invention maintains biocompatibility due to a phosphorylcholine-like structure containing a phosphate bond, and has stability against heat during processing, hydrolysis during use, and oxidative degradation, which are problems in the prior art. An object of the present invention is to provide a highly safe phosphorus-containing polymer having improved properties.

[0012]

[Means for Solving the Problems]
We have found a polyurethane or polyurethane urea containing a phosphate ester bond and having improved antithrombogenicity, which is obtained by using one or more kinds of aliphatic (including alicyclic) diisocyanates in combination (JP-A 2000-128950). Furthermore, as a result of continuing earnest studies in view of such a situation,
In a polymer containing a urethane bond and / or a urea bond and a phosphorus introduced by a covalent bond and / or an ionic bond in the molecule, ASTM F7
In accordance with the extraction conditions described in ASTM F619 (Medical plastic extraction method), which is the extraction conditions quoted in the method of 50 (systemic toxicity test of material extracts in mice), extraction is performed with physiological saline, and extraction is performed. It was found that the safety of the polymer was high when the phosphorus concentration in the liquid was a specific value or less, and the present invention was accomplished.

That is, the present invention has a urethane bond and / or a urea bond, and a covalent bond and / or an intramolecular bond.
Alternatively, a polymer containing phosphorus introduced by ionic bonding, wherein 2 g of physiological saline is added to 4.0 g of the polymer.
It is a phosphorus-containing polymer characterized in that the concentration of phosphorus in the extract when the extraction operation is carried out at 50 ° C. for 72 hours at a bath ratio of 0 ml is 300 ppm or less. In a preferred embodiment, the phosphorus-containing polymer has a urethane bond and / or
Or a urea bond, and the above-mentioned phosphorus-containing polymer that is a polymer containing a phosphate ester bond, a further preferred embodiment, the phosphorus-containing polymer, in the molecule, an aliphatic diisocyanate and an aromatic diisocyanate as a diisocyanate component. The above-mentioned phosphorus-containing polymer, which is a polymer containing a urethane bond and / or a urea bond derived from polyurethane and / or a polyurethane urea obtained in combination, and a phosphoric acid ester bond.

The ionic complex of the anticoagulant mucopolysaccharide and the quaternary phosphonium disclosed in Japanese Patent Laid-Open No. 09-176379 considers the mucopolysaccharide as a polymer, and phosphonium is introduced into this by a ionic bond. However, since it does not contain a urethane bond and / or a urea bond in the molecule, it does not correspond to the phosphorus-containing polymer referred to in the present invention. Japanese Patent Application Laid-Open No. 09-187502 discloses an ionic complex of a mucopolysaccharide and a quaternary phosphonium, and a composition containing polyurethane or polyurethaneurea as a main component. In this composition, polyurethane or polyurethaneurea is commonly used. Since phosphorus is not introduced by a bond and / or an ionic bond, it does not correspond to the phosphorus-containing polymer in the present invention.

The method for preparing the phosphorus-containing polymer of the present invention containing phosphorus in the molecule is not particularly limited, and phosphorus and polymerization introduced in the molecule by urethane bond and / or urea bond, covalent bond and / or ionic bond. A method of obtaining a polymer by addition polymerization of a monomer containing a reactive carbon-carbon unsaturated bond can also be used. However, polyurethanes are preferred in the present invention, with polyurethane and / or polyurethaneurea being especially preferred.

Polyurethanes are prepared from three components: 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. On the other hand, the reactivity is slightly inferior to that of the aromatic diisocyanate, so that more severe conditions and addition of a catalyst are required for polymer preparation.

When the phosphorus-containing polymer of the present invention is polyurethane, it is preferably polyurethane and / or polyurethane urea obtained by using an aliphatic diisocyanate and an aromatic diisocyanate together. Aliphatic diisocyanate in the present invention also includes alicyclic diisocyanates, aliphatic diisocyanates conventionally used in the production of polyurethane and polyurethane urea, and all aliphatic diisocyanates that will be developed in the future Can be used. Specifically, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, dodecamethylene diisocyanate,
Examples thereof include, but are not limited to, 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. Of these, tetramethylene diisocyanate,
Hexamethylene diisocyanate and octamethylene diisocyanate are preferable, and hexamethylene diisocyanate is particularly preferable.

The aromatic diisocyanate that can be used when the phosphorus-containing polymer of the present invention is a polyurethane is an aromatic diisocyanate that has been conventionally used for producing polyurethane and polyurethane urea, and will be developed in the future. All waxy aromatic diisocyanates can be used. Specific examples thereof include, but are not limited to, tolylene diisocyanate, xylylene diisocyanate, phenylene diisocyanate, naphthalene diisocyanate, isocyanatobenzyl isocyanate, and 4,4′-methylenebis (phenyl isocyanate). 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.

When the phosphorus-containing polymer of the present invention is a polyurethane and / or a polyurethane urea obtained by using an aliphatic diisocyanate and an aromatic diisocyanate in combination, the ratio of the aliphatic diisocyanate to the aromatic diisocyanate used is mol. Aliphatic diisocyanate / aromatic diisocyanate = 1/9 to 9 /
1, preferably 2/8 to 7/3, more preferably 2 /
It is 8 to 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 polyurethanes may be colored.

When the phosphorus-containing polymer of the present invention is a polyurethane, the macropolyol used as a component is not particularly limited, and macropolyols used for general polyurethane and polyurethaneurea and those to be developed in the future. Wax macropolyols are widely available. 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 dicarboxylic acids or ester-forming derivatives thereof (eg, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, dodecanedicarboxylic acid, terephthalic acid, isophthalic acid or their acid halides, active esters, amides, etc. A polyester diol obtained by reacting), polylactone diol obtained by ring-opening polymerization of ε-caprolactone, polyether diol such as polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polybutadiene diol, polyisoprene diol, hydrogenation Unsaturated hydrocarbon polymers such as polyisoprene diol have diols having hydroxyl groups at both ends (also referred to as polyalkylene diols even when unsaturated hydrocarbons are dienes), Such as ball sulfonate diol are exemplified. Among them, polyether diol and polycarbonate diol are preferable. These macropolyols may be used alone or in combination of two or more.

The chain extender that can be used when the phosphorus-containing polymer of the present invention is a polyurethane is not particularly limited, and a chain extender used for general polyurethanes will be developed in the future. Wax 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, diol such as diethylene glycol, triethylene glycol, ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, xylylenediamine, phenylenediamine, 4,4′-methylenebis (phenylamine) ) Such as diamine, 2-aminoethanol, 3-aminopropanol, amino alcohol such as 4-aminobutanol, and further dihydrazide (for example, oxalic acid dihydrazide, malonic acid dihydrazide, succinic acid dihydrazide,
Examples include diamines in a broad sense such as adipic acid dihydrazide, sebacic acid dihydrazide, and 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 phosphorus-containing polymer of the present invention preferably contains the phosphorylcholine-like structure represented by the chemical formula (1) in the molecule. Furthermore, the following chemical formula (6)
Alternatively, the method of preparing polyurethanes by using the compound shown in (7) as one of the diol components is more preferable.

[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] ^{R 9 - (A) n- (} 4)

[Chemical 9] R ¹⁰ -C- (5) [in the formula, A is an oxyalkylene group having 2 to 10 carbon atoms, it may be one or more oxyalkylene groups are mixed, even in their binding order of block It may be 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 phosphorus-containing polymer of the present invention is a polyurethane and a diol containing a phosphorylcholine-like structure is added, for example, the following preparation method is exemplified: phosphorylcholine-like structure-containing diol and aliphatic diisocyanate. Are mixed in a suitable solvent and reacted, aromatic diisocyanate and then macropolyol are added thereto to prepare a prepolymer, and then a chain extender is added to obtain a high molecular weight polyurethane or polyurethane urea. At this time, after reacting the phosphorylcholine-like structure-containing diol and the aliphatic diisocyanate,
It is preferred to lower the temperature and add the aromatic diisocyanate followed by the macropolyol. 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.

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.

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 phosphorus-containing polymer of the present invention, one of the effective methods is to perform sufficient washing after preparing the polymer. Specifically, for example, a method of removing impurities while being immersed in hot water and stirred can be adopted. On this occasion,
The temperature of warm water is 40 ° C to 95 ° C, preferably 50 ° C to 90 ° C.
C., more preferably 60.degree. C. to 80.degree. C., and the washing time is 30 minutes to 48 hours, preferably 60 minutes to 24 hours, more preferably 90 minutes to 12 hours. Cleaning at a temperature lower than this for a short time does not sufficiently remove impurities,
If the cleaning is performed at a temperature higher than this for a long time, the polymer may be decomposed or deteriorated. The bath ratio of the polymer to the warm water for washing is 1 g / 10 ml to 1 g / 500 ml, preferably 1 g / 20 ml to 1 g / 400 ml, and more preferably 1 g / 50 ml to 1 g / 200 ml. If the bath ratio is less than this, the polymer is not sufficiently immersed in the washing hot water, so that the effect is not sufficiently obtained, and if the bath ratio is more than this, a large amount of washing warm water is used, which is not efficient. 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 phosphorus-containing polymer of the present invention may be used alone, or may be blended, coated, grafted,
It is also possible to add it to other materials by a method such as 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 phosphorus-containing polymer of the present invention is excellent in stability and safety. Taking advantage of such advantages, the phosphorus-containing polymer of the present invention can be widely used not only for general-purpose applications but also as medical materials in particular. Specifically, for example, a hemodialysis membrane or a plasma separation membrane, an adsorbent for blood waste,
Examples include materials for medical devices such as artificial lung membranes, intravascular balloons, blood bags, catheters, cannulas, shunts, blood circuits, and coating materials for these medical devices.

[0029]

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 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., HDI (6.63 g) was added, and the mixture was stirred for 1 hr. The reaction temperature is lowered to 55 ° C. and stirred for 30 minutes.
After adding DI23.02g and stirring at 55 degreeC for 1 hour, NPMG15.86g of number average molecular weight 2000 was NMP13.
It was dissolved in ml and added. It stirred at 55 degreeC for 1 hour, and prepared the prepolymer. BD92 (6.92 g) was added to this reaction mixture in two batches, and the mixture was stirred at 55 ° C for 1 hr. 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, followed by drying under reduced pressure to obtain a polymer A.

[Chemical 10]

(Molecular weight) Polymer A was added to DMF containing 0.1% 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 Phosphorus Concentration) ASTM F750
The extraction conditions, ASTM F619 (Medical
Based on the extraction conditions described in (Plastic extraction method), 4.0 g of the polymer was immersed in 20 ml of physiological saline, and extraction operation was performed at 50 ° C. for 72 hours. Inorganic applied colorimetric analysis (Kyoritsu Shuppan) Vol. 4, pages 127-206, with reference to the method, this extract was wet decomposed with sulfuric acid / nitric acid / perchloric acid system and then phosphorus content was determined by absorptiometry. Was quantitatively analyzed. The results are shown in Table 1.

[0033]

[Table 1]

(Eluate test) "Dialysis-type artificial kidney device approval standard" In accordance with the extraction conditions in the eluate test of the dialysis membrane described in the notification of the Director General of the Pharmaceutical Affairs Bureau on June 20, 1983, Polymer A1 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) Drug Machine No. 99 (June 27, 1995) Method of cytotoxicity test using extract of medical device or material as 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 (Medical plastic extraction method), 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.

[0037]

[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 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., 6.68 g of HDI was added, and the mixture was stirred for 1 hour. The reaction temperature was lowered to 60 ° C. and stirred for 30 minutes, and tolylene-2,4-diisocyanate (TDI) 1 was added.
After adding 6.14 g and stirring at 60 ° C. for 1 hour, 13.62 g of PTMG having a number average molecular weight of 2000 was dissolved in 14 ml of NMP and added. It stirred at 50 degreeC for 1 hour, and prepared the prepolymer. To this reaction mixture, 7.03 g of BD was added in two portions, and the mixture was stirred at 55 ° C. for 1 hour. NMP 30 ml
Was added to dilute the reaction mixture, and the mixture was reacted by stirring at 55 ° C. for 12 hours. Add 1 g of BD to terminate the end,
Stirring was continued from 0 ° C. to room temperature gradually. The reaction mixture was poured into 5000 ml of water to collect the product,
After washing with warm water at 70 ° C. for 2 hours and washing for 2 hours, the washing was repeated 3 times and then dried under reduced pressure to obtain a polymer A.

(Molecular weight) (Phosphate concentration in extract) (Eluate test) (Cytotoxicity) (Acute toxicity) Regarding the molecular weight, phosphorus concentration in extract, eluate test, cytotoxicity and acute toxicity in the same manner as in Example 1. The test was conducted. The results of the molecular weight and the phosphorus concentration of the extract are shown in Table 1, and the results of the eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 1 (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., 22.26 g of HDI was added, and the mixture was stirred for 1 hour, and then PTMG 13.43 having a number average molecular weight of 2000 was added.
g was dissolved in 14 ml of NMP and added. It stirred at 75 degreeC for 1 hour, and prepared the prepolymer. Add B to this reaction mixture.
7.03 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 C.

(Molecular weight) (Phosphate concentration in extract) (Eluate test) (Cytotoxicity) (Acute toxicity) Regarding the molecular weight, phosphorus concentration in extract, eluate test, cytotoxicity and acute toxicity in the same manner as in Example 1. The test was conducted. The results of the molecular weight and the phosphorus concentration of the extract are shown in Table 1, and the results of the eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 2 (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., 33.00 g of MDI was added, and the mixture was stirred for 1 hour, then PTMG16.96 having a number average molecular weight of 2000.
g was dissolved in 18 ml of NMP and added. It stirred at 55 degreeC for 1 hour, and prepared the prepolymer. Add B to this reaction mixture.
D. 6.87 g was added in two 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 collect the product, washed with warm water at 70 ° C. for 2 hours and dried under reduced pressure to obtain a polymer D.

(Molecular weight) (Phosphate concentration in extract) (Eluate test) (Cytotoxicity) (Acute toxicity) Regarding the molecular weight, phosphorus concentration in extract, eluate test, cytotoxicity and acute toxicity in the same manner as in Example 1. The test was conducted. The results of the molecular weight and the phosphorus concentration of the extract are shown in Table 1, and the results of the eluate test, cytotoxicity and acute toxicity are shown in Table 2.

Comparative Example 3 (Preparation of Polyurethane) 10.00 g of choline diol,
16.16 g of PTMG having a number average molecular weight of 1320 was 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., 24.28 g of HMDI was slowly added, and the mixture was stirred for 5 hours. HDI 6.67g
Was slowly added, and after the addition, the mixture was stirred at 100 ° C. for 10 hours.
BD (7.53 g) was slowly added, and the mixture was further added at 100 ° C for 5
Stir for hours. After the reaction, 5000 ml of this reaction mixture
I dropped it in water. The precipitate obtained is filtered off and washed with THF.
The resulting precipitate was recovered and dried under reduced pressure to obtain a polymer E.

(Molecular weight) (Phosphate concentration in extract) (Eluate test) (Cytotoxicity) (Acute toxicity) Molecular weight, phosphorus concentration in extract, eluate test, cytotoxicity and acute toxicity were measured in the same manner as in Example 1. The test was conducted. The results of the molecular weight and the phosphorus concentration of the extract are shown in Table 1, and the results of the eluate test, cytotoxicity and acute toxicity are shown in Table 2.

[0046]

As is clear from the examples, the phosphorus-containing polymer of the present invention has the following properties: eluate in the eluate test, cytotoxicity,
It was found that acute toxicity is low and safety is high. Some polymers of the comparative example having a phosphorus concentration of more than 300 ppm in the extract have no significant difference in the eluate in the eluate test as compared with the examples, but the cytotoxicity and acute toxicity are relatively high and the safety is high. I found that there was a problem. INDUSTRIAL APPLICABILITY The phosphorus-containing polymer of the present invention can be widely used not only for general-purpose applications but also as a medical material, taking advantage of its excellent safety.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61L 33/00 A61L 33/00 PF term (reference) 4C081 AB32 AC02 AC08 AC10 AC12 AC15 BA01 BB03 BB08 CA211 CA212 CC07 4J034 CA04 CA15 CB03 CB07 CC03 CD01 CD07 DA01 DB04 DB07 DF01 DF02 DG02 DG06 GA06 GA23 GA33 HA01 HA14 HB11 HC03 HC12 HC13 HC17 HC22 HC45 HC52 HC61 HC67 HC71 HC73 JA02 JA14 KA01 RA02

Claims (5)

[Claims] 1. A polymer containing a urethane bond and / or a urea bond, and phosphorus introduced by a covalent bond and / or an ionic bond in the molecule, wherein a bath ratio of 4.0 g of the polymer to 20 ml of physiological saline is used. So 5
A phosphorus-containing polymer characterized in that the phosphorus concentration in the extract is 300 ppm or less when the extraction operation is carried out at 0 ° C. for 72 hours. 2. A polymer containing phosphorus introduced by a urethane bond and / or a urea bond and a covalent bond and / or an ionic bond in the molecule is a polymer containing phosphorus introduced by a phosphate bond. The phosphorus-containing polymer according to claim 1. 3. A polymer containing a phosphorus bond introduced by a urethane bond and / or a urea bond, and a covalent bond and / or an ionic bond in the molecule, and an aliphatic diisocyanate and an aromatic compound as a diisocyanate component in the molecule. The phosphorus-containing polymer according to claim 1 or 2, which is a polymer having a urethane bond and / or a urea bond derived from polyurethane and / or polyurethane urea obtained by using diisocyanate together. 4. A polymer containing a phosphorus bond introduced by a urethane bond and / or a urea bond and a covalent bond and / or an ionic bond in the molecule has a structure represented by the following chemical formula (1) in the molecule. 2 or 3
The phosphorus-containing polymer described. [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 is another atom or a functional group. It may be substituted. ] 5. A polymer containing a urethane bond and / or a urea bond and a phosphorus introduced by a covalent bond and / or an ionic bond in the molecule is represented by the following chemical formula (2) or chemical formula (3): The phosphorus-containing polymer according to claim 2 or 3, having the structure of. [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.