JP2002263183A - Biocompatible material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a biocompatible material which suppresses the multilayer adsorption of protein and is advantageous for medical materials, etc., for which excellent biocompatibility is called in the long term use. SOLUTION: This biocompatible material consists of a polymer formed of a functional group of sulfone and/or sulfoxide and aliphatic chain. This material is suitable for artificial organs, such as artificial kidneys and artificial lungs, medical treatment appliances, such as blood tubes and catheters used for the same, blood filters, blood component adsorbents, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical device which comes into contact with a living body or a living body component, specifically, an artificial organ such as an artificial kidney or an artificial heart-lung machine, a medical device such as a blood tube used therein, a blood filter or blood. The present invention relates to a biocompatible material made of a polymer having excellent biocompatibility suitable for a component adsorbent and the like. More specifically, the present invention relates to a biocompatible material suitable for medical materials and the like, comprising a polymer formed from a functional group of sulfone and / or sulfoxide and an aliphatic chain.

[0002]

2. Description of the Related Art In recent years, with the advancement of medical technology, opportunities for various materials to come into contact with living tissues and blood have increased, and the biocompatibility of the materials has become a major problem. Above all, the denaturation of biological components such as proteins and blood cells by adsorbing on the material surface not only causes unusual adverse effects on the living body, such as thrombus formation and inflammatory reaction, but also leads to deterioration of the material, It is becoming a fundamental and urgent problem for medical materials that must be solved urgently.

[0003] For example, members such as a blood circuit used for extracorporeal circulation of blood and a catheter inserted into a blood vessel are indispensable in surgical medical treatment, and have greatly contributed to the development of these techniques. As medical materials, general-purpose resins such as polyethylene, polypropylene, polyvinyl chloride, polymethyl methacrylate, silicone rubber, polytetrafluoroethylene, and cellulose are used from the viewpoint of high mechanical strength and moldability. While the mechanical properties of these materials have been greatly considered in the properties required as members, their blood compatibility has not been improved at all, and blood coagulation has been barely achieved, mainly due to the administration of anticoagulants such as heparin in the blood. Foreign body reaction such as was suppressed.

[0004] However, it has been recently recognized that long-term continuous administration of heparin causes side effects such as liver disorders such as abnormal lipid metabolism, prolonged bleeding time, and allergic reactions. Based on the above background, when using these blood-contacting medical devices, the use of anticoagulants should be reduced, or the development of materials with excellent blood compatibility that would not cause blood coagulation even if they were not used at all. It has become strongly desired. Also, biocompatibility is required for a carrier for cell culture, a carrier for DDS (drug delivery system), a wound dressing, and the like. From this background, various materials have been developed.

[0005] For example, there is a material in which the surface of a base material is formed into a network structure, on which vascular endothelial cells are proliferated, and the surface of which is used to inhibit thrombus formation (A. Voorhees et al., Ann Sur.
g., 332 (1952)). The problem is how these materials can make the fake intima thinner and less likely to fall off.
Stable materials have not yet been obtained. A material with improved blood compatibility by immobilizing heparin, an anticoagulant, on the substrate surface was also developed (V. Gott et al., Science, 142, 1297).
(1963)). However, since heparin-degrading enzyme is present in blood, heparin is eventually deactivated, and this type has a problem that it cannot be used for a long time.

A method of immobilizing urokinase, a thrombolytic agent, on the surface of a substrate has also been proposed (B. Kussero).
w et al., Trans.Am.Soc.Artif.Int.Organs., 17, 1 (197
However, the immobilized urokinase has a problem that the activity of the immobilized urokinase is low and an expected effect cannot be obtained. Therefore, an immobilization method in which the activity of urokinase is not reduced is desired. Attempts have also been made to immobilize synthetic polymers on the surface that suppress the adsorption of blood components (EM
errill, Ann. NY. Acad. Sci., 6, 283 (1977)). The immobilization of water-soluble, highly mobilizable polyethylene oxide is one example. The movement of molecular chains forms a so-called diffuse layer, which inhibits protein adsorption and makes thrombus less likely to form. Report that they have the disadvantage of easily damaging platelets (BDRATNER et
al, J. of Polymer Sci .: Polymer Symposium 66, (197
9)).

[0007] In the surface modification, from the viewpoint that endothelial cells covering the inner surface of blood vessels are the most ideal material, various polymers utilizing phospholipids, which are the main components of the cell membrane, have been synthesized and studied. ing. Among them, a methacrylic acid ester having a phosphorylcholine group, 2-methacryloyloxyethyl phosphorylcholine (MPC) shows excellent blood compatibility (Y. Iwasaki et al., J. Biomed. Mat.
er. Res., 36, 508 (1997)), and application to various medical devices is being studied. However, high cost due to the complexity of the material itself and the fixing method, difficulty in obtaining a uniform fixed surface layer,
There remains a problem in terms of such.

On the other hand, unlike the surface immobilization method as described above, there is also an attempt to develop antithrombotic properties by controlling the structure of the material surface. This method fundamentally solves the problems of the method described above, such as the falling off of the immobilization material, and is expected to be widely applied. These are designed focusing on the interaction based on physicochemical factors between the material surface and plasma proteins and platelets.
In particular, it has been reported that a material having a small surface free energy difference formed on the surface of the material exhibits high blood compatibility. A typical example is a hydroxyethyl methacrylate-styrene-hydroxyethyl methacrylate block copolymer having a hydrophilic-hydrophobic microdomain structure on the polymer surface (C. Nojima et al., ASAIO Transactions, 3).
3,596 (1987)) and a polypropylene oxide block copolymer having a polyamide segment with controlled polymer crystallinity (N. Yui et al., J. Biomed. Mater. Res., 20,
929 (1981)), but it has a functional group such as an amino group or a hydroxyl group that promotes the activation of complement upon contact with blood, and is insufficient as a blood compatible material.

On the other hand, as a medical material using a polymer containing a sulfur oxide, aliphatic sulfones are reported, for example, by Endo (Kanazawa University Juzen Medical Association, Vol. 94, No. 3, P466-478 (1985)) and
Japanese Patent No. 92446 discloses an aliphatic polysulfone membrane synthesized by copolymerization of 1,5-cyclooctadiene and sulfur dioxide. All of these are aimed at improving oxygen permeability as a material used for an artificial lung, and do not mention suppression of adsorption of plasma proteins or improvement of biocompatibility such as antithrombotic properties. Also, DNGr
aliphatic polysulfone (Polymer Engin) obtained by copolymerizing an α-olefin having 6 to 18 carbon atoms with sulfur dioxide by ay.
eering and Science, October, Vol. 17, No. 10, 719-723
(1997)), which is also reported as a material for an artificial lung, but it has only confirmed the blood coagulability of an aliphatic polysulfone having 16 carbon atoms for biocompatibility. The authors found that thrombus formation time was prolonged compared to glass and siliconized glass surfaces, but concluded that this was due to the low free energy of long aliphatic chains.

[0010] As described above, there has not been found any one in which a sulfone functional group is actively introduced for the purpose of biocompatibility such as antithrombotic properties. For sulfoxide, Li Den
g et al. reported that in a self-assembled monolayer composed of a mixture of alkanethiolate and undecanethiol having a tri (propylene sulfoxide) group formed on a simple substance of gold, protein adsorption on the surface was reduced. (J. Am. Chem. Soc., Vol. 118, No. 21, 5136-5137 (196
6).) However, this sulfoxide is an oligomer having about 3 repeating units, and no example has been found for examining the biocompatibility of sulfoxide as a polymer.

[0011]

SUMMARY OF THE INVENTION It is an object of the present invention to solve the above-mentioned problems and to provide a medical device which comes into contact with a living body or a biological component.
Specifically, an object of the present invention is to provide a biocompatible material suitable for artificial organs such as an artificial kidney and an artificial heart-lung machine, medical instruments such as blood tubes used for the same, blood filters and blood component adsorbents.

[0012]

In general, plasma proteins such as albumin, γ-globulin and fibrinogen are adsorbed on the surface of a material that has come into contact with blood, and then these proteins change their higher-order structure. This change in the higher-order structure promotes further protein adsorption, and a multilayer protein adsorption layer is formed on the material surface. Such a multi-layer protein adsorption layer activates the platelets in contact therewith, and eventually causes the blood to coagulate. Therefore, it is considered important to suppress the adsorption of plasma proteins to the surface of the material and avoid the activation of platelets in order to obtain biocompatibility such as blood compatibility.

For example, according to “Polymer and medical treatment” (Kiichi Takemoto et al., P5, Mita Publishing Co., Ltd. (1989)), a material surface having extremely low interaction with plasma protein shows excellent anticoagulant property. Has been pointed out. Regarding protein adsorption on the material surface, the structure of water sorbed on the material is an important factor that controls the interaction between the material surface and proteins, and the structure of sorbed water is similar to that of bulk water. The present applicant has already found that the adsorption of protein is greatly suppressed in the case of (Japanese Patent Application Laid-Open No. 09-122462).

That is, various interface phenomena are usually observed on the surface where the material surface and the aqueous solution containing the polymer solute are in contact. For example, if the polymer solute is a protein and the material is strongly hydrophobic, adsorption of a large amount of protein is observed. By processing the material surface to be hydrophilic, it is possible to suppress adsorption to some extent, but there are many exceptions, and the phenomenon is not as simple as hydrophilic (wetting), that is, a protein non-adsorbing surface. It is known.

The present applicant has focused on the water structure near the material,
Using the infrared absorption spectrum to analyze the sorption water structure,
As a result of studying the sorption water structure and protein adsorption characteristics of materials having various functional groups, the closer the distribution of the absorption band of water interacting with the material surface in the infrared absorption spectrum to that of bulk water, It has been found that the adsorption of proteins to the surface tends to be suppressed. The present inventors have conducted intensive studies on the structure of water that interacts with various functional groups, and have found that the structure of water that interacts with sulfone groups and sulfoxide groups is particularly close to bulk water. The present inventors have found that the contained polymer can significantly suppress protein adsorption, and have completed the present invention.

That is, the present invention is a biocompatible material comprising a polymer formed from a sulfone and / or sulfoxide functional group and an aliphatic chain. Since the material of the present invention is excellent in biocompatibility, particularly, medical devices that come into contact with a living body or a biological component, specifically, artificial organs, various devices for using artificial organs, materials such as medical base materials When used as, it can be used for a long time.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
I do. To evaluate the sorption water structure on the material surface, the present invention
We found that 340 from the sorption water in the infrared absorption spectrum
0cm^-1The centroid wave number of the nearby absorption peak was used. Infrared absorption
3400 cm in the yield spectrum^-1Near absorption peak
3650cm ^-1Around, 3550cm^-1Nearby, 3450
cm^-1Near 3250cm^-14 types of components nearby
Using a curve fitting program
You. Peak wave number and relative surface of each component obtained
From the product ratio, the relative area ratio is used as the weight and the weighted average is used.
Center of gravity wave number (C_wn).

In general, protein adsorption on the surface is considered to be relatively large. For example, toluene, acetic acid having an aromatic ring, an ester bond, or a nitrile group, which are main functional groups of aromatic polysulfone, polymethyl methacrylate, and polyacrylonitrile. Examining the infrared absorption spectrum of water that interacted with 1% by mass of water added to methyl and acetonitrile,
Its center of gravity wave numbers are 3653 cm ^-1 and 3573 cm, respectively.
^-1, a 3549Cm ^-1, the bulk water 3366Cm ^-1
Larger bias toward higher wavenumbers.

On the other hand, water is generally added to tetrahydrofuran or dimethylformamide having an ether bond or an amide bond, which is a main functional group of polyethylene glycol or polyvinylpyrrolidone, which tends to suppress the adsorption of protein, to 1% by mass of water. Examination of the infrared absorption spectrum of the added and interacted water shows that the centroid wave number is 3507.
cm ^-1, showed relatively close to the bulk water numerals as 3480cm ^-1. From this, it is presumed that the surface of a material having a functional group in which the structure of interacting water is closer to that of bulk water suppresses protein adsorption.

However, it was surprisingly found that 1% by mass of water was added to dimethyl sulfone or dimethyl sulfoxide having a sulfone group or a sulfoxide group as a hydrophilic functional group, and the interacted water was examined for infrared absorption spectrum. ,
The center of gravity wave numbers are 3405 cm ^-1 and 3440 cm, respectively.
^{At -1} , it turned out to be even closer to that of bulk water. Based on this finding, the present inventors synthesized an ethylene sulfone propylene sulfone copolymer and an ethylene sulfoxide propylene sulfoxide copolymer as a polymer having a sulfone group and a sulfoxide group, and prepared a membrane to absorb protein. Upon examination, it was confirmed that a significant effect of suppressing protein adsorption was achieved as expected.

As for the structure of the polymer, the influence of other structures should be as small as possible so that the characteristics of the sulfone group and the sulfoxide group can be more remarkably exhibited. Strongly aromatic chains should be avoided, aliphatic chains are preferred,
Moreover, the shorter the chain length, the better. Aliphatic chains forming the biocompatible material of the present invention may be linear or branched, and include, for example, those having a sulfone group or a sulfoxide group in the main chain of the polymer. In the case of the number 2, the ethylene chain, in the case of the carbon number 3, 1,3-propylene chain, 1-methylethylene chain, in the case of the carbon number 4, 1,4-butylene chain, 1-methyl-1,3-
Propylene chain, 2-methyl-1,3-propylene chain,
1,1-dimethylethylene chain, 1,2-dimethylethylene chain, 1,5-pentylene chain, 1-methyl-1,4-butylene chain, 2-methyl-1,4-butylene chain in the case of 5 carbon atoms A 1,1-dimethyl-1,3-propylene chain,
1,2-dimethyl-1,3-propylene chain, 1,3-dimethyl-1,3-propylene chain, 1-ethyl-1,3-
Propylene chain, 2-ethyl-1,3-propylene chain, 1
-Propylethylene chain, 2-propylethylene chain, and 1,6-hexylene chain in the case of 6 carbon atoms, 1-methyl-1,
5-pentylene chain, 2-methyl-1,5-pentylene chain, 3-methyl-1,5-pentylene chain, 1,1-dimethyl-1,4-butylene chain, 1, dimethyl-1,4-butylene chain A 1,3-dimethyl-1,4-butylene chain,
1,4-dimethyl-1,4-butylene chain, 2,3-dimethyl-1,4-butylene chain, 1-ethyl-1,4-butylene chain, 2-ethyl-1,4-butylene chain, 1- (1-
Propyl) 1,3-propylene chain, 1- (2-propyl) 1,3-propylene chain, 2- (1-propyl) 1,
3-butylene chain, 2- (2-propyl) 1,3-propylene chain, 1-ethyl-2-methyl-1,3-propylene chain, 1-ethyl-3-methyl-1,3-propylene chain,
1-methyl-2-methyl-1,3-propylene chain, 1,
2,3-trimethyl-1,3-propylene chain, 1-butylethylene chain, 1-methylpropylethylene chain, 2-methylpropylethylene chain, 2-methyl-2-propylethylene chain, 1- (1-propyl) -2-methylethylene chain, 1- (2-propyl) -2-methylethylene chain, 1
-(1-propyl) -1-methylethylene chain, 1- (2
-Propyl) -1-methylethylene chain, 1,2-diethylethylene chain and the like. When a sulfone group or a sulfoxide group is present in a side chain such as a graft, the basic skeleton of carbon is the same as described above.

As an example of a method for synthesizing the compound of the present invention, there is a method obtained by oxidizing a polymerized polyalkyl sulfide using a catalyst. Polyalkyl sulfides include anionic polymerization using potassium tert-butoxide of episulfides, ring-opening polymerization catalyzed by diethyl zinc, magnesium perchlorate, etc., radical polymerization of vinyl sulfide and allyl sulfide, condensation of dihaloalkane and dithiol It can be obtained by a method such as polymerization. The sulfide group in the polyalkyl sulfide is oxidized by a mixture of hydrogen peroxide and acetic acid or a mixture of hydrogen peroxide and formic acid,
A desired polymer having an aliphatic chain containing a functional group of sulfoxide or sulfone can be obtained. The functional groups of sulfoxide and sulfone may be each alone,
Both may be mixed at an arbitrary ratio.

The compounds of the present invention having a sulfone group can be industrially synthesized directly by copolymerization of the corresponding olefins and sulfur dioxide. Further, conversion to a compound having a sulfoxide group is easily possible using a reducing agent. By controlling the degree of reduction, a polymer containing a sulfone group and a sulfoxide group at an arbitrary ratio can be obtained. This method has a very low raw material cost and is an excellent production method suitable for mass production.

As a method for synthesizing a compound having a sulfone group or a sulfoxide group in a side chain, a monomer having a sulfide group and an ethylene bond (carbon double bond) in a molecule, such as vinyl methyl sulfide or allyl methyl sulfide, is used. And a method obtained by oxidizing a polymer polymerized by cleavage of a carbon double bond by radical polymerization or ionic polymerization in the same manner as described above. Not a sulfide group,
As long as the monomer has a sulfone group or a sulfoxide group, it is not necessary to oxidize after polymerization.

The compounds of the present invention, the infrared absorption spectrum characteristic absorption derived sulfoxide groups in the vicinity of 1020 cm ^-1, it indicates characteristic absorption derived from a sulfonic group in the vicinity of 1,120 cm ^-1 and 1320 cm ^-1, be identified by this Can be. The compounds of the present invention can control the solubility in water or organic solvents by selecting the structure of the aliphatic chain. When the compound of the present invention is water-soluble, when it comes into contact with a living body or a biological component having a high water content, it cannot maintain sufficient strength to withstand use, which is not preferable as a base material. In addition, when coated on a base material of another material or when blended with a base material polymer, the compound of the present invention elutes into a living body or a biological component having a high water content when used, and the living body applied to the base material Compatibility may be compromised.

When the compound of the present invention is coated or blended with another material, it is preferably soluble in an organic polar solvent such as dimethylacetamide, dimethylsulfoxide and N-methylpyrrolidone. In the case of aliphatic polysulfoxide, for example, when the aliphatic chain is an ethylene chain and a propylene chain, the ethylene: propylene ratio is 6:
If it exceeds 4, it will not be dissolved in an organic solvent, and if it is less than 2: 8, it will be dissolved in water. On the other hand, aliphatic polysulfone tends to have lower water solubility than aliphatic polysulfoxide. When the ethylene: propylene ratio is 4: 6 or less, it is substantially soluble in organic polar solvents such as dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone, and is insoluble in water. When the ethylene: propylene ratio exceeds 4: 6, it becomes insoluble in organic solvents.

When the compound of the present invention is used as a substrate, the number average molecular weight of the compound is preferably from 30,000 to
300,000 is preferred. Number average molecular weight of 300,0
If it exceeds 00, molding becomes difficult, and if it is less than 30,000, the mechanical strength decreases. When used by blending or coating with another base material, the number average molecular weight is preferably 5,000 to 100,000. When the number average molecular weight exceeds 100,000, coating becomes difficult, and when the number average molecular weight is less than 5,000, elution to water becomes easy.

The compound of the present invention can be used as a base material itself by appropriately selecting the molecular weight and the structure of the aliphatic chain. However, depending on the application, the product of the present invention may be dissolved in a solvent and the surface of another base material may be dissolved. Or a blend with other polymers. In any case, since the polymer of the present invention is insoluble in water, it does not elute at the time of use and can continuously exhibit excellent biocompatibility.

[0029]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

[0030]

Reference Example 1 0.1 g of distilled water (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 10 g of dimethyl sulfone (manufactured by Kanto Kasei), and the mixture was sufficiently stirred and mixed at 60 ° C. Using FT / IR300 manufactured by JASCO, sandwiched between two calcium fluoride plates as window materials,
The total number of times of measurement was measured, and the transmission method infrared absorption spectrum was determined. The infrared absorption spectrum of dimethyl sulfone to which no distilled water was added was measured in advance, and an infrared absorption spectrum of water interacting with dimethyl sulfone was obtained by taking a difference spectrum.

In the obtained infrared absorption spectrum, the absorption peak at around 3400 cm ⁻¹ due to the absorption of stretching vibration of water was changed to about 3650 cm ⁻¹ , about 3550 cm ⁻¹ , about 34
Were separated using curve fitting program four components centered at 50 cm ^-1 and about 3250cm ^-1. From the obtained peak wave number and relative area ratio of each component, the center-of-gravity wave number was obtained by weighted averaging using the relative area ratio as a weight, and C _wn = 3405 cm ⁻¹ was obtained.

[0032]

Reference Example 2 Dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries) 10
0.1 g of distilled water (manufactured by Wako Pure Chemical Industries, Ltd.) was added to the resulting mixture, and the mixture was sufficiently stirred and mixed at 25 ° C. A small amount was collected and sandwiched between two calcium fluoride plates serving as window materials for infrared absorption spectrum measurement. The infrared absorption spectrum was measured under the same conditions as in Reference Example 1. Separately, an infrared absorption spectrum of dimethyl sulfoxide to which distilled water was not added was measured in advance, and a difference spectrum was obtained to obtain an infrared absorption spectrum of water interacting with dimethyl sulfoxide. The center-of-gravity wave number was obtained from the obtained infrared absorption spectrum in the same manner as in Reference Example 1,
C _wn = 3440 cm ⁻¹ was obtained.

[0033]

[Reference Example 3] 0.1 g of distilled water (manufactured by Wako Pure Chemical) was added to 10 g of methyl acetate (manufactured by Wako Pure Chemical), and the mixture was sufficiently stirred and mixed at 25 ° C. Sandwiched between two calcium fluoride plates as materials, Reference Example 1
The infrared absorption spectrum was measured under the same conditions as described above. Separately,
An infrared absorption spectrum of methyl acetate to which no distilled water was added was measured in advance, and an infrared absorption spectrum of water interacting with methyl acetate was obtained by taking a difference spectrum. The center-of-gravity wave number was determined from the obtained infrared absorption spectrum in the same manner as in Reference Example 1 to obtain C _wn = 3573 cm ^-1 .

[0034]

[Reference Example 4] A small amount of distilled water (bulk water) was
Two calcium fluoride plates that are window materials
Then, the infrared absorption spectrum was measured under the same conditions as in Reference Example 1.
Specified. The same as Reference Example 1 from the obtained infrared absorption spectrum.
The wave number of the center of gravity as _wn= 3366cm^-1Get
Was. Curve fitting with its infrared absorption spectrum
1 is shown in FIG.

[0035]

EXPERIMENTAL EXAMPLE 1 As a method for evaluating the amount of protein attached used in this example, a quantitative method by the micro BCA method will be described. Bovine γ-
20 mg of globulin (manufactured by SIGMA) was dissolved in 2 ml of 1M phosphate buffer (manufactured by Wako Pure Chemical Industries), and a test flat membrane (about 1 × 1 cm) was immersed in the protein solution at 37 ° C. for 1 hour. Thereafter, the test piece was washed with 1 M phosphate buffer, and immersed in 0.5 ml of 1 M phosphate buffer in which 1% sodium dodecyl sulfate (manufactured by Wako Pure Chemical) was dissolved at 37 ° C. for 4 hours to dissolve the adsorbed protein. I let it. The protein concentration in this solution was quantified using a micro BCA protein assay kit (manufactured by PIERCE).

The protein was quantified using the micro BCA kit according to the instruction manual. 0.5 ml of a sample was collected, 0.5 ml of the prepared micro BCA reagent solution was added, the mixture was gently stirred, heated at 60 ° C. for 1 hour, and the absorbance at a wavelength of 562 nm was measured with an ultraviolet spectrophotometer. The protein concentration was determined using a previously prepared calibration curve, and the protein adsorption amount per unit area of the membrane was calculated.

[0037]

EXAMPLE 1 4.9 g of ethylene sulfide and 14.0 g of propylene sulfide (manufactured by Kanto Kasei) were mixed with 254 mg of ethyl acetate in which 44.8 mg of magnesium perchlorate (manufactured by Wako Pure Chemical Industries) was dissolved, and the mixture was placed in a closed container. 70 ° C
For 5 hours to carry out polymerization. This was dissolved in 40 ml of 1-methyl-2-pyrrolidone (manufactured by Wako Pure Chemical Industries) and 1000
The solution was added dropwise to ml of ethanol to obtain a white precipitate of the polymer.

The precipitate is thoroughly washed with ethanol, and
13. The ethanol is removed under reduced pressure with a polysulfide.
0 g was obtained. Next, 1 g of this polysulfide was added to 60 ml
Dissolved in 1-methyl-2-pyrrolidone in
A mixed solution of 4% aqueous hydrogen peroxide and 20 ml of formic acid was slowly added dropwise with stirring. Immediate exotherm occurred, sulfide was oxidized to sulfone, and a precipitate of ethylene sulfone propylene sulfone copolymer was formed. This was purified by repeating the washing method of centrifuging and replacing the supernatant three times, and then dried under reduced pressure at 60 ° C. for 4 hours to obtain 0.85 g of a white solid ethylene sulfone propylene sulfone copolymer.

Next, a solution prepared by dissolving 0.1 g of this ethylene sulfone propylene sulfone copolymer in 0.6 g of dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries) was cast on a polyethylene sheet with a doctor blade, and the solution was heated at 60 ° C. under reduced pressure at 60 ° C. The solvent was removed by heating for 5 hours to obtain a flat membrane A of an ethylene sulfone propylene sulfone copolymer. 70% humidity
After standing for 1 hour in an atmosphere of RH and a temperature of 25 ° C., an infrared absorption spectrum was immediately measured between two calcium fluoride plates. Separately, an infrared absorption spectrum of the dried film was measured, and a difference spectrum was obtained to obtain an infrared absorption spectrum of water sorbed on the film.

Under the same measurement conditions and curve fitting conditions as in Reference Example 1, the gravity wave number (C _wn ) of the _sorption water of the flat membrane A was determined. Table 1 shows the results. The obtained flat membrane A was subjected to a protein adsorption test according to Experimental Example 1. Table 2 shows the results.

[0041]

Example 2 10 mg to 10 g of allyl methyl sulfide
Of azoisobutyronitrile was added, and the mixture was charged into a closed vessel, deaerated, and then polymerized by stirring at 60 ° C. for 10 hours. Thereafter, 40 ml of 1-methyl-2-
It was dissolved in pyrrolidone (manufactured by Wako Pure Chemical Industries) and dropped into 1000 ml of ethanol to obtain a brown precipitate of a polymer. The precipitate was thoroughly washed with ethanol, and ethanol was removed at 60 ° C. under reduced pressure to obtain 7.5 g of polysulfide.

Next, 1 g of this polysulfide was added to 60 ml
Dissolved in 1-methyl-2-pyrrolidone in
A mixed solution of 4% aqueous hydrogen peroxide and 20 ml of formic acid was slowly added dropwise with stirring. An exotherm occurred immediately and the sulfide was oxidized to the sulfone and a precipitate of polyallylmethyl sulfone formed. This was purified by repeating a washing method of centrifuging and replacing the supernatant three times, followed by drying under reduced pressure at 60 ° C. for 4 hours to obtain 0.8% of white solid polyallylmethyl sulfone.
1 g was obtained.

Next, the polyallylmethyl sulfone 0.1.
A solution prepared by dissolving 1 g in 0.6 g of dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries) was cast on a polyethylene sheet by a doctor blade, and heated at 60 ° C. for 5 hours under reduced pressure to remove the solvent.
A flat membrane B of polyallylmethyl sulfone was obtained. After the obtained flat film B was allowed to stand for 1 hour in an atmosphere at a humidity of 70% RH and a temperature of 25 ° C., the infrared absorption spectrum was quickly measured by immediately sandwiching the two calcium fluoride plates. The infrared absorption spectrum of the separately dried film was measured, and a difference spectrum was obtained to obtain an infrared absorption spectrum of water sorbed on the film. Under the same measurement conditions and curve fitting conditions as in Reference Example 1, the gravity wave number (C _wn ) of the _sorption water of the flat membrane B was determined.
Table 1 shows the results. A protein adsorption test was performed on the obtained flat membrane B in accordance with Experimental Example 1. Table 2 shows the results.

[0044]

Comparative Example 1 1 g of polyvinyl chloride (manufactured by Wako Pure Chemical Industries) was
A solution dissolved in 6 g of N-dimethylformamide (manufactured by Wako Pure Chemical Industries, Ltd.) was cast on a glass plate with a doctor blade, and heated at 60 ° C. for 5 hours under reduced pressure to remove the solvent, thereby obtaining a polyvinyl chloride flat film C. The obtained flat film C was subjected to a humidity of 98% RH and a temperature of 25%.
After standing for 1 hour in an atmosphere of ° C, the infrared absorption spectrum was quickly measured between two calcium fluoride plates.
Separately, an infrared absorption spectrum of the dried film was measured, and a difference spectrum was obtained to obtain an infrared absorption spectrum of water sorbed on the film. Under the same measurement conditions and curve fitting conditions as in Reference Example 1, the centroid wave number (C _wn ) of the _sorption water of the flat membrane C was determined. Table 1 shows the results. A protein adsorption test was performed on the obtained flat membrane C in accordance with Experimental Example 1. Table 2 shows the results.

[0045]

[Experimental Example 2] As a method for evaluating the amount of attached protein used in this example, a quantitative method using an infrared absorption spectrum is shown. Bovine γ-
20 mg of globulin (manufactured by SIGMA) was dissolved in 2 ml of 1M phosphate buffer (manufactured by Wako Pure Chemical Industries), and a test flat membrane (about 1 × 1 cm) was immersed in the protein solution at 37 ° C. for 1 hour. The test piece was washed with a 1 M phosphate buffer, then washed with purified water, and dried in a desiccator. The infrared absorption spectrum of the sufficiently dried test flat membrane was measured.

The measurement conditions were as follows: infrared spectrophotometer F manufactured by JASCO
The transmission was measured using a T / IR300 at a temperature of 25 ° C. and a humidity of 20% or less. In the obtained spectrum, 1600 cm ⁻¹ to 1720 cm based on the absorption of γ-globulin
The absorption intensity in the range of ^-1 was determined and used as an index of the amount of adsorbed protein.

[0047]

Example 3 9.7 g of ethylene sulfide and 8.0 g of propylene sulfide were added to 44.8 m of magnesium perchlorate.
g was dissolved in 254 mg of ethyl acetate, and the mixture was placed in a closed container and stirred at 70 ° C. for 5 hours to carry out polymerization. This is 40
dissolved in 1-methyl-2-pyrrolidone
The solution was added dropwise to ml of ethanol to obtain a white precipitate of the polymer.

The precipitate is thoroughly washed with ethanol,
The ethanol was removed under reduced pressure with to obtain 16 g of polysulfide. Next, 1 g of this polysulfide was added to 60 ml of 1-
A mixture of 4 ml of 30% aqueous hydrogen peroxide and 20 ml of acetic acid was slowly added dropwise to the solution dissolved in methyl-2-pyrrolidone with stirring. Upon standing overnight at 30 ° C., polysulfoxide precipitated. After thoroughly washing the precipitate with ethanol, the ethanol was removed under reduced pressure at 60 ° C. for 4 hours to obtain 0.70 g of a white solid ethylene sulfoxide-propylene sulfoxide copolymer.

Subsequently, aromatic polysulfone (UDEL)
P-1700 (registered trademark, manufactured by Teijin Amoko Engineering Plastics Co., Ltd.) (22 parts by mass) dissolved in 76 parts by mass of 1-methyl-2-pyrrolidone was mixed with ethylene sulfoxide-propylene sulfoxide copolymer 2
A part by mass was added and dissolved to prepare a dope for film formation. After casting the obtained dope on a glass plate using a doctor blade, 1-methyl-2 adjusted to 50 ° C.
-Immersion in a coagulation bath of pyrrolidone: water = 95: 5 for 1 minute, followed by 1-methyl-2-pyrrolidone: water = 50: 5
After immersion in a coagulation bath for 20 minutes to separate phases, 60
Washing was repeated three times with hot water of 20 ° C. for 20 minutes to obtain a flat membrane D.

The obtained flat film D was subjected to a humidity of 98% RH and a temperature of 2%.
After standing for 1 hour in an atmosphere of 5 ° C., an infrared absorption spectrum was measured quickly by sandwiching between two calcium fluoride plates. Separately, an infrared absorption spectrum of the dried film was measured, and a difference spectrum was obtained to obtain an infrared absorption spectrum of water sorbed on the film. Under the same measurement conditions and curve fitting conditions as in Reference Example 1, the gravity center wave number (C _wn ) of the _sorption water of the flat membrane D was determined. Table 3 shows the results. Table 3 shows the results of evaluating the protein adhesion rate of the flat membrane D according to Experimental Example 2.

[0051]

Example 4 The composition of the film forming dope in Example 3 was
17 parts by mass of aromatic polysulfone, 1-methyl-2-pyrroli
76 parts by mass of don, ethylene sulfoxide propylene sulf
A similar operation is performed except that the amount of the hydroxide copolymer is 7 parts by mass.
Then, a flat membrane E was obtained. Example 3 about the obtained flat film E
In the same manner as above, the gravity wave number (C _wn)
Was. Table 3 shows the results. Experimental example 2 for flat membrane E
Accordingly, Table 3 shows the results of evaluation of the protein adhesion rate.

[0052]

Example 5 The composition of the film forming dope in Example 3 was
12 parts by mass of aromatic polysulfone, 1-methyl-2-pyrroli
76 parts by mass of don, ethylene sulfoxide propylene sulf
The same operation except for using 12 parts by mass of the hydroxide copolymer
Was performed to obtain a flat film F. Example of the obtained flat membrane F
In the same manner as in Example 3, the centroid wave number (C _wn)
I did. Table 3 shows the results. In addition, the infrared absorption
Splitting the spectrum into four components
FIG. 2 shows the result of the curve fitting. Generally,
Close to the bulk water of FIG. 1, but 3250 cm^-1Of nearby components
The ratio is slightly small. The flat membrane F was prepared according to Experimental Example 2.
Table 3 shows the results of evaluating the white adhesion rate.

[0053]

Example 6 Ethyl acetate 25 in which 20.0 g of propylene sulfide was dissolved in 44.8 mg of magnesium perchlorate
The mixture was mixed with 4 mg, put in a closed container, and stirred at 70 ° C. for 5 hours to carry out polymerization. This was dissolved in 40 ml of 1-methyl-2-pyrrolidone and added dropwise to 1000 ml of ethanol,
A white precipitate of the polymer was obtained. The precipitate was thoroughly washed with ethanol, and ethanol was removed at 60 ° C. under reduced pressure to obtain 16.0 g of polypropylene sulfide.

Next, 1 g of this polypropylene sulfide
Was dissolved in 60 ml of 1-methyl-2-pyrrolidone, and a mixture of 4 ml of 30% aqueous hydrogen peroxide and 20 ml of formic acid was slowly added dropwise with stirring. An exotherm occurred immediately and the sulfide was oxidized to the sulfone. After sufficiently reacting at room temperature, the mixture was poured into 200 ml of water to produce a precipitate of polypropylene sulfone. This was centrifuged down and the supernatant was replaced with a washing method three times to purify.
Drying under reduced pressure at 0 ° C. for 4 hours gave 0.75 g of white solid polypropylene sulfone.

Subsequently, aromatic polysulfone (UDEL)
P-1700 (registered trademark), Teijin Amoko Engineer
Ring Plastics Co., Ltd.)
Polyethylene was dissolved in 76 parts by mass of tyl-2-pyrrolidone.
Add 2 parts by weight of propylene sulfone and dissolve for film formation
The dope was adjusted. Using a doctor blade,
After casting the dope on a glass plate, adjust the temperature to 50 ° C.
1-methyl-2-pyrrolidone: water = 95: 5
Immerse in a solid bath for 1 minute, then add 1-methyl-2-pyro
Immersion in a 50:50 coagulation bath for 20 minutes
After the phases are separated, it is repeated with hot water of 60 ° C. three times for 20 minutes each.
After washing, a flat membrane G was obtained. Performed on the obtained flat membrane G
In the same manner as in Example 3, the centroid wave number (C _wn)
I asked. Table 3 shows the results. Experimental example of flat membrane G
Table 3 shows the results of evaluating the protein adhesion rate according to Example 2.

[0056]

Example 7 The composition of the film-forming dope in Example 6 was changed.
17 parts by mass of aromatic polysulfone, 1-methyl-2-pyrroli
76 parts by mass of dong and 7 parts by mass of polypropylene sulfone
The same operation was performed except that the flat membrane H was obtained. Got
About the flat membrane H, the sorption water of the flat membrane H
Center of gravity wave number (C _wn). Table 3 shows the results. Sa
The infrared absorption spectrum obtained at that time and the four
After performing curve fitting separately for each component
Is shown in FIG. Generally close to the bulk water of FIG.
0cm^-1The ratio of nearby components is slightly large. About flat membrane H
Table 3 shows the results of the evaluation of the protein adhesion rate according to Experimental Example 2.
Show.

[0057]

Comparative Example 2 Aromatic Polysulfone (UDEL P-17)
00 <trademark registration>, manufactured by Teijin Amoko Engineering Plastics Co., Ltd.) 24 parts by mass, 1-methyl-2
A dope consisting of 76 parts by weight of pyrrolidone was prepared. After casting the obtained dope on a glass plate using a doctor blade, 1-methyl-2 adjusted to 50 ° C.
-Immersion in a coagulation bath of pyrrolidone: water = 95: 5 for 1 minute, followed by 1-methyl-2-pyrrolidone: water = 50:
After immersion in a coagulation bath for 50 minutes for phase separation, 6
The membrane was repeatedly washed with hot water of 0 ° C. three times for 20 minutes to obtain a flat membrane I.

The obtained flat film I was the same as in Example 3.
And the center of gravity wave number (C_wn). So
Table 3 shows the results. In addition, the infrared absorption spec
Turtle and its four components
FIG. 4 shows the result of the fitting. Figure 1 Bulk water
3250cm on the low wave side^-1near
Disappears, 3450cm^-1The ratio in the vicinity is also small.
3650cm relatively ^-1Near and 3550cm^-1Nearby high
The ratio of components on the wave number side is large.

Table 3 shows the results of evaluating the protein adhesion rate of the flat membrane I in accordance with Experimental Example 2. The absorption intensity in the infrared absorption spectrum of the protein adsorbed on the aromatic polysulfone membrane without additives was set to 1.00 (standard), and compared with the case of the aromatic polysulfone membrane to which aliphatic polysulfoxide or aliphatic polysulfone was added. did.

[0060]

[Table 1]

[0061]

[Table 2]

[0062]

[Table 3]

[0063]

Since the polymer of the present invention is excellent in biocompatibility, it has little adsorption of biological components such as proteins and blood cells, and can suppress denaturation of the adsorbed protein and adhesion and activation of contacted platelets. As a field of application of the polymer of the present invention, for example, as a medical material mainly used in direct contact with blood components, artificial kidneys, artificial organs such as heart-lung machine, artificial blood vessels, hemodialysis membrane and It can be used as a blood tube for artificial heart lung, blood access, a blood bag, a catheter, a blood filter such as a plasma separation membrane or a blood cell separation membrane, or a blood component adsorbent.

Further, since it has little effect on living organisms such as blood and cells, it also exhibits excellent performance as a carrier for various cell cultures, a carrier for DDS, a wound dressing material, and the like. When the polymer of the present invention is used as such a material, not only can the material itself be used as a substrate to form a hollow fiber, a sheet, a film, or a tube, but also a blend with various other polymers can be used. Furthermore, it is also possible to dissolve the polymer of the present invention in a solvent, apply this solution to the surface of various substrates, and modify only the biocontact surface.

[Brief description of the drawings]

FIG. 1 is a diagram showing an infrared absorption spectrum of bulk water and a curve fit obtained by dividing the infrared absorption spectrum into four components.

FIG. 2 is a diagram showing an infrared absorption spectrum of water sorbed on a flat membrane F of Example 5 and a curve fitting of the infrared absorption spectrum divided into four components.

FIG. 3 is a diagram showing an infrared absorption spectrum of water sorbed on a flat membrane H of Example 7 and a curve fitting of the infrared absorption spectrum divided into four components.

FIG. 4 is a diagram showing an infrared absorption spectrum of water sorbed on a flat membrane I of Comparative Example 2 and a curve fitting of the spectrum divided into four components.

Claims (9)

[Claims] 1. A biocompatible material comprising a polymer formed from a functional group of sulfone and / or sulfoxide and an aliphatic chain. 2. The biocompatible material according to claim 1, wherein the functional groups of the sulfone and / or the sulfoxide and the aliphatic chain are alternately bonded to form a main chain copolymer. 3. An aliphatic chain having an ethylene group, a propylene group,
The biocompatible material according to claim 2, wherein the material is one or a combination of two or more selected from a butylene group, a pentylene group, and a hexylene group. 4. An aliphatic chain having an ethylene group, a propylene group,
The biocompatible material according to claim 2, wherein the biocompatible material is one or a combination of two or more selected from a butylene group and a pentylene group. 5. The biocompatible material according to claim 2, wherein said aliphatic chain is one or a combination of two or more selected from an ethylene group, a propylene group and a butylene group. 6. An aliphatic chain having an ethylene group, a propylene group,
3. The biocompatible material according to claim 2, wherein the biocompatible material is a combination of an ethylene group and a propylene group. 7. The living body according to claim 2, wherein the functional group is a sulfone, the aliphatic chain is a combination of an ethylene group and a propylene group, and the molar ratio of the ethylene group to the propylene group is from 4: 6 to 0:10. Compatible material. 8. The functional group is a sulfoxide, the aliphatic chain is a combination of an ethylene group and a propylene group, and the molar ratio of the ethylene group to the propylene group in the aliphatic chain is from 6: 4 to 8.
The biocompatible material according to claim 2, wherein the ratio is 2: 8. 9. The biocompatible material according to claim 1, wherein the material is composed of a polymer having a structure in which an aliphatic chain forms a main chain and a functional group of sulfone and / or sulfoxide is included in a side chain.