JPH0732799B2 - Blood compatible medical materials - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention provides a substrate polymer having an amide group such as polyurethane, polyamide, and polyacrylamide with a sulfo group (-
SO ₃ H) -bound polyethylene oxide (hereinafter, sulfonated polyethylene oxide or sulfonated PEO or P
EO- of (SO ₃ H) n) is replaced chemically relates to a process for the preparation of a new modified polymeric material and the material having excellent blood compatibility.

(Problems to be Solved by the Invention) Requirements for medical materials are excellent physical and mechanical properties, in-body stability of physical properties, disinfectability and biocompatibility. Of these, biocompatibility that suppresses the rejection reaction of the living body that essentially occurs when the material comes into contact with living tissue or blood is important.

When blood vessels are damaged or blood comes into contact with foreign substances, a clotting phenomenon occurs. The detailed process of this phenomenon is not completely understood yet, but it is initiated by adhesion and activation of proteins and platelets in blood, accompanied by activation of coagulation factors, and red blood cells and white blood cells, as summarized in the following scheme. It is known that coagulation proceeds due to the formation of a fibrin network structure under the involvement of.

As described above, the coagulation phenomenon is caused by the artificial heart, artificial blood vessel, artificial kidney, artificial heart-lung machine or other circulatory system artificial organ material or venous catheter, arterial catheter, intra-aortic balloon pump, etc. It is an urgent problem when using a therapeutic device inserted into a blood vessel of the blood vessel, and a fatal result such as a blood vessel occlusion is caused by a blood clot or a micro blood clot (emboli). Therefore, developing a blood-compatible, anticoagulant material that suppresses blood clotting when in contact with blood is a significant problem with enormous potential promise.

The conventional blood-compatible polymer materials can be roughly classified into the following two types. One of them is a material essentially having blood compatibility, which is a material that suppresses adhesion and activation of blood components, particularly proteins and platelets. Furthermore, similar intimal-forming materials that utilize the blood compatibility of the similar intimal membrane formed on the surface of the material have also been investigated. And the other one is
It is a method of obtaining blood compatibility by immobilizing or gradually releasing a physiologically active substance (heparin, prostaglandin, eurokinage, etc.) which suppresses blood clot formation on the surface of the material.

Actually, an artificial blood vessel made of polyester woven fabric or stretched Teflon is a similar intimal-forming material that causes a blood clot layer to form on the surface after contact with blood, and the clot layer becomes blood compatible. However, it is difficult to apply to blood vessels with small diameter or slow blood flow. Although the development of catheters and materials using physiologically active substances such as heparin has been reported (Trans, ASAIO, 24, 736-745, 1978), their effects are limited due to loss of physiologically active substances and decrease in activity. Yes,
Does not last long.

Therefore, much research is underway to develop polymeric materials that are inherently blood compatible. The hemocompatibility of a material is determined by the physical and chemical structure of the surface,
In particular, it is greatly affected by the polarity, surface energy, surface charge, hydrophilicity and hydrophobicity of the material, surface smoothness and porosity.

The free energy of the material surface is an important factor for blood compatibility. Hydrogels rich in water exhibit extremely low interfacial energy when interacting with blood,
It is known to have excellent blood compatibility. However, this has poor processability and weak mechanical strength, and therefore, methods for surface-grafting or coating on a substrate having good mechanical properties have been studied. Especially, PE of hydrophilic polymer
Although much research has been done on O, Nagaoka et al.
ns.ASAIO, 28,459-463,1982) reported an anticoagulant material obtained by grafting PEO on the surface of polyvinyl chloride resin. In this report, they reported that the volume-excluding effect and kinetic action of water-soluble polymer grafted on the surface showed the function of preventing adhesion of blood proteins and platelets.

On the other hand, it was reported that a polymer having a hydrophilic / hydrophobic micro-domain structure exhibits excellent anticoagulant properties by suppressing the activation of proteins and platelets. Okano et al. (J. Biomed. Mat
Res., 15, 393-402, 1981) reported excellent anticoagulant properties of polystyrene-polyhydroxyethylmethacrylate block copolymers. Polyurethane composed of polyol / diisocyanate also shows excellent anticoagulant property due to such hydrophilic / hydrophobic structure (J. Biomed.
r.Res., 20, 433-468, 1986), and because of its excellent mechanical properties, it is currently widely used in blood contact medical devices such as artificial hearts, intra-aortic balloon pumps, and vascular catheters.

On the other hand, blood components and vascular endothelial cells are all negatively charged, and the prevention of blood coagulation in living blood vessels is explained to be due to electric repulsion between them (Ame).
rJPhysiol., 175, 113, 1953).

Therefore, the surface of the polymer containing anions also has excellent blood compatibility. As an example, the unique anticoagulant effect of heparin, a linear anionic carbohydrate, has been reported to be due to anions such as included sulfo or sulfoamino groups (Biochem.Biophys.Res.Commun. ,
93,1339,1978). As such anionic polymer, C.
Fougnot et al. (Ann. Biomed. Eng., 7, 429-439, 1979) reported polystyrene sulfonic acid and SL Cooper et al. (J. Coll.
(iod Interface Sci., 104, 422-439, 1985) have also reported that sulfonated polyurethane improves blood compatibility.

(Means for Solving the Problems) The present inventors designed a new type of polymer having various advantages judged from the results obtained by analyzing the above-mentioned conventional techniques, and As a result of research over a period of time, they have invented a new polymer material having excellent blood compatibility.

The present invention, by substituting the sulfonated polyethylene oxide water-soluble polymer with the above-mentioned substrate polymer, the anticoagulant effect due to the repulsive force of the sulfo group anion charge, and the polyethylene oxide (hereinafter referred to as PEO) polymer protein and The synergistic effect with the anticoagulant effect due to the suppression of platelet adhesion makes it possible to obtain an effect with extremely excellent blood compatibility. In particular, when polyurethane is used as a substrate, the original hydrophilic / hydrophobic fine phase separation structure effect is added, and a material having extremely excellent anticoagulant properties can be obtained.

That is, the present invention is a blood-compatible modified polymer substance in which the amide group of a substrate polymer having an amide group is substituted with polyethylene oxide sulfonate.

The blood compatible modified polymer of the present invention is completely different in the concept of structural design from the sulfonated polyurethane reported by SL Cooper et al. This is because SL Cooper et al. Reported the anion effect by simply introducing a sulfo group into polyurethane, whereas in the present invention, the effect of the hydrophilic PEO polymer is newly introduced, and the effect of the sulfo group is additionally added. It is added.

In order to produce the modified polymer according to the present invention, a surface reaction may be performed on an already molded medical product, or the modified polymer produced by a bulk reaction in a solution state may be used as a molding material or a coating material. It can also be used as. These will be described in more detail below.

In the modified polymer of the present invention, a PEO derivative containing a functional group capable of reacting with the active site of the above-mentioned substrate polymer is introduced by the manufacturing process, and then a sulfonic acid derivative capable of binding to the PEO derivative is reacted. Or sulfo group in common with functional groups that can react with active sites in a single step.
It can be produced by directly reacting a PEO derivative. Furthermore, when the substrate polymer is reacted with a diisocyanate or dicarboxylic acid chloride and a PEO derivative is bonded using a free monofunctional group to be introduced, PEO is reacted under simple and mild conditions. This is extremely advantageous because it can be performed.

Useful PEO derivatives include PEO and its amine derivatives,
P-toluenesulfonic acid esters, acid chlorides, isocyanates, epoxies, halogen derivatives and the like, and as the sulfonic acid derivative capable of binding to the PEO derivative, sulfurous acid or its salt, bisulfite or its salt, aminoalkylsulfonic acid, Hydroxyalkyl sulfonic acid, alkyl sultone, etc. can be appropriately selected depending on the functional group of the PEO derivative introduced.

As the hydrophilic polymer derivative bonded to the substrate polymer,
Synthetic polymers such as PEO, polyvinyl alcohol, polyhydroxyethyl methacrylate and poly N-vinylpyrrolidone, and natural polymers such as alkyl cellulose, carboxyalkyl cellulose, starch and agarose may be used. Of these, PEO has the highest blood compatibility because it is highly water-soluble, flexible, and has a large effect of suppressing adhesion of plasma proteins and platelets. The content and molecular weight of PEO are particularly important for blood compatibility, and generally, the molecular weight of PEO having excellent blood compatibility is 100-20,000, and that of 200-10,000 shows particularly excellent blood compatibility.

The method of introducing the sulfonated PEO into the substrate polymer is to react the substrate polymer with an appropriate PEO derivative and then to sequentially react the sulfonic acid derivative, or to directly react the sulfonated PEO derivative in a single step. It can also be introduced into the molecule.

Substrate macromolecules that are compatible with the present invention are polyurethanes, polyamides, polyacrylamides, etc. that contain hydrogens that can be substituted like amide groups.

Although the hydrogen of such an amide group is not highly active, it can be substituted depending on the reaction conditions. That is, the hydrogen can be introduced with a highly reactive functional group by reacting with a highly nucleophilic compound such as an isocyanate or a carboxylic acid chloride. Further, the hydrogen is released by a strongly basic compound and can form an amide ion, and since the ion has extremely high chemical activity, it can be subjected to a substitution reaction with a halogen, an epoxy, a toluenesulfonic acid ester derivative or the like.

Further, as a feature of the present invention, it is more effective to introduce a functional group having high reactivity into the substrate polymer and then react the sulfonated PEO derivative or the PEO and the sulfonic acid derivative sequentially. That is, when a diisocyanate or dicarboxylic acid chloride is reacted and an isocyanato group (-N = C = O) or a chlorocarbonyl group (-COCl) introduced into a substrate polymer is used to bond a PEO derivative, PEO
Since it can be used as it is without being converted into a derivative, simple and mild reaction conditions can be selected, and chemical damage can be avoided, which is advantageous.

The sulfonated PEO derivative having a functional group that can be directly bonded to the substrate polymer can be produced by various methods. PEO is usually manufactured and sold as a polymer having hydroxy groups at both ends, but the hydroxy group can be converted into various functional groups by a known method (J. Macromol. Sci., C25 (3. ), 325, 1985). Important examples are the method of introducing a brom atom by reacting with sulfobromide, the method of oxidizing with potassium manganese manganese peroxide to convert to a carboxyl group, and the method of reacting with epichlorohydrin to convert into an epoxy compound. There is a method of reacting with diisocyanate to convert it to an isocyanate compound, and further, a method of reacting with ammonium bromide to convert it into an amino group and a method of converting a carboxyl group into an acid chloride are also possible. It can be converted to almost any form of functional group.

Therefore, the method of introducing a sulfo group into PEO can be variously changed depending on the functional group of the PEO derivative. As a useful method, a method of reacting a hydroxy group of PEO with an alkylsultone and sodium bisulfite, a method of reacting bromine with sodium sulfite, a method of reacting an isocyanato group with an aminoalkylsulfonic acid or a hydroxyalkylsulfonic acid, an epoxy There is a method of reacting the group with sodium bisulfite or hydroxyalkyl sulfonic acid.

Next, a method for introducing sulfonated PEO into a substrate polymer will be described with a specific example.

The first method is a method in which a substrate polymer is reacted with a compound such as diisocyanate, and a PEO derivative is bonded using the introduced free monofunctional group. As such a bifunctional compound, Diisocyanates and dicarboxylic acid chlorides can be used.

Example 1: Polyurethane, polyamide, polyacrylamide _{[Here, PEO = - (CH 2 CH} 2 O) is n-] Useful diisocyanates include hexamethylene diisocyanate (HMDI), toluene diisocyanate (TDI),
Such as diphenylmethane diisocyanate (MDI),
Polyurethane polymerization catalysts such as tartaric acid and amines can be used. Since this reaction is carried out under mild conditions, it has the advantage of proceeding without loss of material.

Example 2: Polyacrylamide, polyamide, polyurethane A useful dicarboxylic acid chloride is a dicarboxylic acid chloride of a fatty acid in which R has 2 to 30 carbon atoms.

The second method is a method of reacting a PEO derivative having an isocyanato group or a chlorocarbonyl group that can be directly bonded to the substrate polymer.

Example 3: Polyurethane, polyamide, polyacrylamide Polyurethane, polyamide and polyacrylamide react with the isocyanato group and are converted into urea derivatives.

Example: 4 polyacrylamide, polyamide, polyurethane The third method is a method in which the substrate polymer is treated with a strongly basic compound to form an amide anion and then reacted with a PEO derivative having a halogen, epoxy, or tolylsulfonyl group. Useful strong basic compounds are sodium or potassium hydride, sodium or potassium ethoxide, sodium or potassium butyrate, methyl magnesium bromide and the like.

Example 5: Polyamide, polyurethane, polyacrylamide Example 6: Polyurethane, polyamide, polyacrylamide Example 7: Polyacrylamide, polyamide, polyurethane The method for producing a modified polymer substance described above can also carry out a surface reaction on a substrate polymer product that has already been molded, or dissolve the substrate polymer in an appropriate solvent to modify it in a solution state, It can also be used as a molding and coating material.

Therefore, when the surface reaction is carried out, the reaction should be carried out in a medium in which the substrate polymer is not dissolved, and it is preferable to select a medium that does not have a large swelling property.

As the solvent of polyurethane, there are tetrahydrofuran, dimethylacetamide, dimethylformamide and the like,
The solvent of polyamide is formic acid, and water, alcohol, etc. can be used as a solvent for polyacrylamide, and thus can be used as a reaction medium in a surface reaction or a solution reaction.

As described above, the anion such as sulfo group exhibits anticoagulant property because its adhesion is suppressed by electric repulsive force with plasma proteins and platelets. It is known that the sulfo group is more effective than the carboxy group which is another anion. The surface charge density of the modified polymer into which the anion is introduced is also an important factor that determines the anticoagulant property.

Therefore, in the present invention, the blood compatibility greatly differs depending on the substitution degree of the sulfonated PEO for the amide group of the substrate polymer, and in principle, the higher the substitution degree, the higher the blood compatibility. On the other hand, increasing the degree of substitution increases the water solubility of the substrate and increases its flexibility. However, in the case of surface reaction, changes in water solubility and mechanical properties are not so large.
Therefore, the adjustment of the degree of substitution should be selected according to the end use and the form. The degree of substitution with excellent blood compatibility in the case of surface reaction is 60-95% with respect to the functional groups on the surface, and the degree of substitution with 5-25% in case of bulk reaction in the solution state shows excellent blood compatibility. It can be modified into a molding material, which can be used as molding material or coating material.

The modified polymer is a medical material having excellent blood compatibility and can be applied as a structural material or coating material such as a film, a sheet, a tube, a fiber, and a mesopore fiber,
Artificial heart, artificial blood vessel, artificial heart valve, which is in contact with blood,
When used for artificial artificial lung materials such as artificial heart-lung machines and artificial kidneys, or therapeutic products inserted into blood vessels such as venous catheters, arterial catheters and aortic balloon pumps, blood clot formation is further reduced and side effects can be prevented. It can be used as a material.

Hereinafter, examples of the present invention will be described in detail. However, the invention is not limited to these examples.

Method for measuring contact angle (hydrophobicity and hydrophilicity) of materials As described above, biocompatibility of materials, particularly blood compatibility, is determined by the physical and chemical structure of the material surface. And hydrophobicity is one of the important factors. The degree of hydrophilicity and hydrophobicity of a material is measured by the size of the contact angle at the time of contact with a liquid. In the present invention, the hydrophilicity and hydrophobicity of the modified polymer are determined by the Wilhelmy Plate method (J.Appl.Polym.S).
ci., 26, 1269, 1982). This method precisely measures the change in weight when the material is immersed in water and when it is taken out, and the advancing contact angle (advancin
g contact angle) and receding contact angle
angle) is a method of determining. The larger the advancing contact angle of the material, the greater the hydrophobicity, and the smaller the receding contact angle, the greater the hydrophilicity. The modified polymer according to the present invention is
When the PEO derivative was bound, the hydrophilicity was greatly increased, and when the sulfo group was introduced, a complete "wetting" phenomenon was exhibited. Therefore, the interaction of the modified polymer with blood is small. Detailed contact angle measurements will be described exactly in the examples.

Anticoagulant (hemocompatibility) assessment of materials Many in vitro or in vivo test methods for assessing anticoagulant properties of materials have been reported in the literature (Guidelines for Blood-Ma).
terial Interactions, National Institutes of Healt
h, publication number 85-2185, 1985). The anticoagulant evaluation method used in the present invention is in vitro activated partial thromboplastin time (APTT), prothrombin time (PT), in vivo using platelet adhesion experiments and rabbits (exactly, in vivo).
The arterial-arterial shunt method was used.

APTT measurement is based on the fibrometer method (Amer.J.Path., 69,27
1,1972) was used.

0.1 ml of sample plasma (37 ° C.) obtained by putting the sample in 300 μ of standard plasma and contacting for 1 hour was added to 0.1 ml of partial thromboplastin preheated for 2 minutes. To be exact, 0.025 after 30 seconds
0.1 ml of M calciur chloride solution was added, and the coagulation time was measured using a fibrin timer. It was shown that the longer the APTT time, the greater the anticoagulant property.

The PT measurement was performed by the one-step prothrombin time ("Lab Med. Hematology". P. 1267, 1982). 0.1 ml thromboplastin and 0.025M calcium chloride aqueous solution 0.1 ml
After mixing and preheating at 37 ° C., 0.1 ml of sample plasma obtained by treating the sample in the same manner as in the measurement of APTT was added, and the coagulation time was measured using a fibrin timer. PT also shows that the longer it is, the better the anticoagulant property is.

The platelet adhesion experiment is to measure the amount of platelets adhered to each material. The sample was immersed in platelet-rich plasma (PRP) obtained by centrifuging human whole blood at 37 ° C for 3 hours, transferred to phosphate buffered saline, and washed at 37 ° C for 1 minute with shaking. The sample thus treated was immersed in a 2% glutaraldehyde buffer aqueous solution for 2 hours to fix the adhered platelets on the surface of the material, dehydrated with an ethanol aqueous solution, freeze-dried and observed with a scanning electron microscope.

Correctly, the ex-vivo arterial-arterial shunt method is a method for simply and quickly measuring the compatibility of materials under the conditions of animal experiments using rabbits, and is extremely reproducible ( ASAIO, J.10,596,1987).

The right carotid artery of the rabbit is exposed and the sample tube (1.5 m inside diameter)
Both ends (m, outer diameter 2 mm, length 30 cm) were inserted into the carotid arteries to circulate blood in a shunt form. The time at which the flow rate was stopped after the blood flow rate in the tube was adjusted to 2.5 ml per minute and allowed to flow was defined as the occlusion time. The longer the occlusion time, the better the blood compatibility of the tubing material.

Example 1 A polyurethane sheet (Peretane 2363-80A, Upjohn Corp., USA, width 2 cm ² , thickness 1 mm) was refluxed in methanol for 18 hours to remove impurities, and then put in 120 ml of toluene to add hexamethylene diisocyanate ( 2 ml of HMDI) and 1 ml of stannous octoate were added and reacted at 20-40 ° C. for 1 to 2 hours, followed by thorough washing with toluene. ATR-FTIR (Attenua
ted total reflection-Fourier trans-from infrared
As a result of measuring the surface by spectroscopy, the free functional groups of the introduced monoisocyanate can be observed.

HO-PEO (200) the obtained sheet in 120 ml of toluene
Add ₃ ml of -SO ₃ H and 1 ml of triethylamine, and add 2 ml at 20-40 ℃.
Reacted for hours. HO-PEO (200) -SO ₃ H was obtained by adding 4 g of polyethylene oxide (molecular weight 200, Aldrich Co., USA) to 12.5 ml of dimethyl sulfoxide and stirring at 85 ° C to dissolve, then 2.5 g of 1.3-propane sultone and 1 g of sodium carbonate. Was added and reacted at 85 ° C. for 16 hours, and then extracted with methanol for separation and production.

The advancing contact angle of the treated modified polyurethane sheet is 29.2
°, the receding contact angle was greatly reduced by "wetting" as compared to the original advancing contact angle of the polyurethane sheet of 86.3 ° and the receding contact angle of 40.6 °, and was completely hydrophilized. Also,
The APTT of untreated sheets was 35.8 and 13.2 seconds (APTT of the reference plasma was 36.0 seconds, PT was 13.0 seconds), but the APTT after treatment was increased to 48.6 seconds and 15.0 seconds and platelet adhesion Was extremely low. In the same way, the inner surface of the treated polyurethane tube (Royalten R380PNAT, Uniroyal Corporation, USA, inner diameter 1.5mm, outer diameter 2.0mm, 30cm) rabbit artery-
The occlusion time of the arterial shunt was 360 minutes, which was significantly increased compared to the occlusion time of the untreated tube of 50 minutes.

Thus, the experimental results of APTT, PT, platelet adhesion and rabbit arterial-arterial shunt of polyurethane sheet and tube before and after the reaction show that the blood compatibility is greatly improved after the polyurethane is modified by the method of the present invention. I was able to confirm that.

Example 2 HO-PEO (200) -SO 3 NH 2 -PEO (3500) in place of H -SO
A method similar to Example 1 was performed except that ₃ H was used. The contact angle is similarly low and AP equal to that of Example 1.
Since it showed TT and PT, it was also excellent in blood compatibility.

_{NH 2 -PEO (3500) NH 2} -SO 3 H is a molecular weight of 3500 -PEO
It was produced by reacting (3500) -NH ₂ (Sigma, USA) with 1 equivalent of 1,3-propanesultone under a strong base catalyst.

Example 3 A polyurethane sheet reacted with HMDI as in Example 1 was added to 2 g of PEO (200) and 1 stannous octoate in 120 ml of benzene.
After adding ml, the mixture was reacted at 20-40 ° for 4 hours. After taking out the sheet and thoroughly washing it with benzene, ethanol and water, 50 ml of isopropyl alcohol and 2 m of dimethyl sulfoxide.
1, and transferred to a reaction system containing 2 g of sodium carbonate and 2 g of 1,3-propane sultone, and reacted at 60-80 ° for 4 hours. The surface contact angle and blood compatibility of the treated sheets were equally excellent as in Example 1.

Example 4 After dissolving 5 g of polyurethane in 100 ml of dimethylacetamide, 6.3 ml of HMDI was added and reacted at 20-40 ° C. for 1 week,
It was precipitated with anhydrous ether and separated. The product (5 g) was further dissolved in dimethylacetamide (100 ml) and treated with H 2 as in Example 1.
Bulk reaction was performed with ₅ ml of O-PEO (200) -SO3H. HO-
Instead of PEO (200) -SO ₃ H, and allowed to react sequentially with PEO and 1,3-propane sultone. Also, after dissolving 5 g of polyurethane reacted with HMDI in 100 ml of dimethylacetamide, PEO
After adding 5 g and reacting at room temperature for 3 days, it was precipitated in distilled water and dried, and then 100 ml of dimethyl sulfoxide was added.
The mixture was transferred to a reaction system containing 0.25 g of 1,3-propane sultone and 0.1 g of sodium carbonate and reacted at 40-85 ° C for 15-24 hours. The degree of substitution of the introduced sulfo group was 25%.

The obtained modified polyurethane was used as a 2% tetrahydrofuran solution, and the surface properties and blood compatibility of the coated polyurethane sheet were comparable to those in Example 1.

Comparative Example 1 HO-PEO (200) -SO 3 HO-PEO (1000) in place of H -OH
The polyurethane was treated by the same method as in Example 1 except that was used.

As described above, the polyurethane obtained by reacting only PEO having no sulfo group bonded was greatly hydrophilized with an advancing contact angle of 29.9 ° and a receding contact angle of 19.9 °. The hydrophilicity was inferior to that of polyurethane. Platelet adhesion was less similar to the modified polyurethane of Example 1, but APTT was 37.4 seconds and PT was 13.6 seconds,
It was similar to untreated polyurethane. Also,
The rabbit artery of the polyurethane tube treated in this way
The animal shunt occlusion time was extended to 120 minutes, but shorter than in Example 1.

From the above results, the polyurethane to which only PEO is bound has a reduced platelet adhesion and a slightly improved blood compatibility, but lacks the effect of the sulfo group anion as compared with the case of Example 1. It was confirmed that the blood compatibility was poor.

Comparative Example 2 A polyurethane was treated in the same manner as in Example 3 except that dotecandiol was used in place of PEO200 and dibutyltin dilaurate was used in place of stannous octoate as a catalyst. Thus, the advancing contact angle and the receding contact angle of the polyurethane in which the highly hydrophobic dodecyl group and the sulfo group ion are bonded instead of PEO were 68.0 ° and the receding contact angle was shown as “wet”. This means that the hydrophilicity has increased. The APTT of this polyurethane is 40.5
The seconds and PT were 14.2 seconds, which was less than the modified polyurethane of Example 1, although it was increased over the untreated polyurethane. The rabbit arterial-arterial shunt occlusion time was 200 minutes, showing an intermediate value between 50 minutes of untreated polyurethane and 360 minutes of the modified polyurethane of Example 1. That is, the blood compatibility of the modified polyurethane in which the hydrophobic dodecyl group and the sulfo group were substituted was greatly improved by the introduced sulfo group as compared with the untreated polyurethane, but the hydrophilic PEO and the sulfo group of Example 1 were improved. The improvement effect was smaller than that of the modified polyurethane in which the group was introduced. This was confirmed to be due to the lack of the platelet adhesion effect of PEO, as observed in the platelet adhesion test.

Example 5 Polyacrylamide spheres (50-100 mesh size) 1 g
The in benzene 120 ml, was reacted in the adipic acid chloride and room temperature 2g, were reacted in the _{HO-PEO (200) -SO 3} H2g and 40 ° C.. Prolonged APTT and PT time was observed, confirming improved hemocompatibility.

Example 6 The same polyurethane sheet as in Example 1 was treated with 120 ml of benzene.
Among them, HSO ₃ -PEO (200) -O-CONH- (CH ₂ ) ₆ N = C =
A solution of O 3 g in chloroform and 1 ml of stannous octoate were added and reacted at 20-40 ° C. for 2-6 hours. HSO ₃ -PEO (20
_{0) -OCONH- (CH 2) 6} -N = C = O are obtained by reacting 1 equivalent of HMDI in dioxane in HSO ₃ -PEO (200) -OH prepared as in Example 1 .

The treated sheet has an advancing contact angle of 40.5 °, a receding contact angle of “wetting”, APTT of 48.6 seconds and PT of 15.4 seconds,
Platelet adhesion was also small. The same polyurethane tube as in Example 1 was treated by this method, and the result of the rabbit arterial-arterial shunt experiment showed that the occlusion time was 340 minutes, indicating extremely excellent blood compatibility.

Example 7 After dissolving 5 g of polyurethane in 200 ml of dimethylacetamide, bulk reaction was performed using the same reagents as in Example 6 under the same conditions. The degree of substitution of the introduced sulfo group was 45%.

The modified polyurethane solution obtained after purification was coated on the sheet and the tube by the same method as in Example 4, and the same blood compatibility as in Example 6 was obtained as a result of the experiment.

Example 8 The same polyurethane sheet as in Example 1 was added with 120 ml of toluene.
Sodium hydride (1 g) was added thereto, and the mixture was reacted at 0-5 ° C for 20 minutes in a nitrogen stream. Br-PEO (1000) -SO ₃ H3g
After slowly adding the chloroform solution of the above to react with each other, it was dried successively with toluene, alcohol and water.

_{Br-PEO (1000) -SO 3} H was used as prepared as follows. That is, both end groups are hydroxy groups and have a molecular weight of 1000.
PEO (Aldrich, USA) was reacted with excess sulfonyl bromide in toluene in the presence of triethylamine to give Br-PEO (1000) -Br with bromine at both ends. In Br-PEO (1000) -Br2 equivalents of ethanol in aqueous solution, by reacting 1 equivalent of sodium sulfite, could be obtained _{Br-PEO (1000) -SO 3} H.

In this way, the contact angle of the surface-modified polyurethane was measured, and it was found that the reacted polyurethane had an advancing contact angle of 28.7.
° and receding contact angle "wet" indicating complete hydrophilization. The APTT of the reacted polyurethane was 49.7 seconds, the PT was 15.2 seconds, and the APTT before the reaction was 35.8 seconds and PT.
It can be seen that the anticoagulant property was increased, being greatly prolonged compared to 13.2 seconds. In addition, the reacted polyurethane sheet is PRP
As a result of examining the platelet adhesion by the above, it was observed by a scanning microscope that the platelet adhesion was extraordinarily reduced as compared with the sheet before the reaction.

In addition, the same reagent was circulated in the same polyurethane tube as in Example 1 by the same method, and reacted to circulate the same. As a result of circulating blood through the treated tube through the rabbit artery-arterial shunt, the occlusion time was 360
Min, which was greatly extended compared to the 50 min blocking time of the untreated tube. From the above results, it was confirmed that the product modified by the method of the present invention exhibits excellent blood compatibility.

Example 9 Polyurethane (5 g) was dissolved in dimethylformamide (200 ml), and then sodium hydride (1 g) and Br- were added in the same manner as in Example (8).
PEO (1000) and the -SO ₃ H3G is sequentially reacted. The reaction product was precipitated in an excess amount of methanol, decomposed, washed with water and dried. As a result of elemental analysis, the degree of substitution of the bound sulfonic acid group was 50%. A 2% dimethylformamide solution of the obtained modified polymer was prepared, coated on a polyurethane sheet and a tube, and the contact angle, APTT, PT, platelet adhesion experiment, and rabbit arterial-arterial shunt occlusion time were measured. A hemocompatibility equal to that of Example 8 was obtained.

Example 10 A nylon 66 (Dupont, USA) sheet of the same size was treated in the same manner as in Example 8. The contact angle was decreased, the hydrophilicity was increased, and APTT, PT, and platelet adhesion experiments showed equal blood compatibility.

Instead of Example 11 Sodium hydride and _{Br-PEO (1000) -SO 3} H,
Sodium ethoxide and The reaction was performed in the same manner as in Example 8 except that was used.
The advancing contact angle and receding contact angle were 39.2 °, respectively, indicating “wetting”. This confirmed that the molecular weight of the hydrophilic PEO was reduced to 200 and the hydrophilicity was slightly reduced. As a result of APTT, PT, and platelet adhesion experiments, blood compatibility was greatly improved as in Example 8, and the rabbit artery-arterial shunt occlusion time was 350 minutes, confirming excellent anticoagulant properties.

(USA Porisaiansu Inc.) 1 equivalent of _{NH 2 - (CH 2) 3} SO 3
It was prepared by reacting H in an aqueous basic catalyst solution.

(Effects of the Invention) As can be seen from the above examples, the polymer in which the hydrophilic sulfonated PEO is substituted for the substrate polymer having an amide group has the anticoagulant effect of the sulfo group anion and the hydrophilic PEO. Excellent blood compatibility could be obtained due to the synergistic action with the plasma protein and the anti-platelet adhesion effect. Contrary to this, simply
When only PEO was bound, the effect of the sulfo group anion was lacking, and due to the reduced blood compatibility when the hydrophobic dodecyl group was substituted in place of the hydrophilic PEO, such a sulfo group anion effect was obtained. The synergistic effect with the PEO effect was confirmed.

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Claims (19)

[Claims] 1. A blood compatible medical material comprising a polymeric substance in which a sulfonated polyethylene oxide is substituted for the amide group of a substrate polymer having an amide group. 2. The blood compatible medical material according to claim 1, wherein the matrix polymer is selected from polyurethane, polyamide, polyacrylamide and copolymers thereof. 3. The degree of substitution of sulfonated polyethylene oxide is 5-50% in the bulk reaction and 50-% in the surface reaction.
The blood compatible medical material according to claim 1, which is 95%. 4. A medical product which is an artificial heart, an artificial blood vessel, an artificial heart valve membrane, an artificial heart-lung machine, an artificial kidney, or a blood vessel catheter, which is made of the blood-compatible medical material according to any one of claims 1 to 3. . 5. A blood compatibility characterized by reacting a substrate polymer having an amide group with diisocyanate or dicarboxylic acid chloride, and then reacting a sulfonated polyethylene oxide derivative with the introduced free functional group. Manufacturing method of medical material. 6. A method of reacting a substrate polymer having an amide group with an isocyanate or a dicarboxylic acid chloride, and then reacting a polyethylene oxide derivative with a free functional group to be introduced, and further reacting with a sulfonic acid derivative. And a method for producing a blood compatible medical material. 7. A method for producing a blood compatible modified medical material, which comprises reacting a substrate polymer having an amide group with a sulfonated polyethylene oxide derivative having a diisocyanato group or a chlorocarbonyl group. 8. A method for producing a blood compatible medical material, which comprises reacting a substrate polymer having an amide group with a polyethylene oxide derivative having an isocyanato group or a chlorocarbonyl group and then further reacting with a sulfonic acid derivative. Method. 9. A method for producing a blood compatible medical material, which comprises reacting a sulfonated polyethylene oxide derivative with a substrate polymer having an amide group in the presence of a strongly basic compound. 10. A blood-compatible medical material characterized by reacting a substrate polymer having an amide group with a polyethylene oxide derivative in the presence of a strongly basic compound, and further reacting with a sulfonic acid derivative. Production method. 11. The production method according to claim 5, wherein the substrate polymer is selected from polyurethane, polyamide, polyacrylamide and copolymers thereof. 12. The production method according to claim 5, wherein the sulfonated polyethylene oxide derivative is an amino derivative or a hydroxy derivative thereof. 13. The polyethylene oxide derivative is an amino derivative or a hydroxy derivative thereof, claim 6, 8 or
10. The manufacturing method according to 10. 14. The method according to claim 9, wherein the sulfonated polyethylene oxide derivative is a halogen, epoxy, or toluene sulfonic acid ester derivative thereof. 15. The method according to claim 10, wherein the polyethylene oxide derivative is a halogen, epoxy, or toluenesulfonic acid ester derivative thereof. 16. The method according to claim 6, 8 or 10, wherein the sulfonic acid derivative is selected from the group consisting of alkyl sultone, sodium bisulfite, sodium sulfite, hydroxyalkyl sulfonic acid and aminoalkyl sulfonic acid. 17. A polyethylene oxide having a molecular weight of 100.
The production method according to claim 5, wherein the production method is −20,000. 18. The polyethylene oxide has a molecular weight of 200.
The production method according to claim 17, wherein the production method is −10,000. 19. The degree of substitution of sulfonated polyethylene oxide is 5-50% in bulk reaction and 50 in surface reaction.
The production method according to claim 5, wherein the production rate is −95%.