JP3509829B2 - Anticoagulant material - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medical material that is in direct contact with a living body or a biological component, and more particularly to an anticoagulant material having good anticoagulant properties and mechanical properties.

[0002]

2. Description of the Related Art Artificial materials excellent in workability, elasticity and flexibility have been widely used in recent years as medical materials, but artificial kidneys, artificial lungs, auxiliary circulation devices, artificial blood vessels, etc. It is expected that its use will be further expanded in the future as disposable products such as artificial organs, syringes, blood bags, and cardiac catheters. As these medical materials, in addition to sufficient mechanical strength and durability, safety for living bodies, in particular, blood does not coagulate when contacted with blood,
That is, anticoagulant property is required.

Conventionally, as a method for imparting anticoagulant properties to medical materials, (1) a method in which a mucopolysaccharide such as heparin or a fibrinolytic factor such as urokinase is immobilized on the surface of the material,
It can be roughly classified into three types: (2) a material surface modified to have a negative charge and hydrophilicity, and (3) a material surface deactivated. Of these, the method (1) (hereinafter abbreviated as surface heparin method) further includes (A) a blending method of a polymer and heparin, (B) a method of coating a material surface with an organic solution of fat-solubilized heparin, (C) ) It is subdivided into a method of ionically binding heparin to a cationic group in the material, and a method (D) of covalently bonding the material and heparin.

[0004]

Of the above methods,
When the methods (2) and (3) are in contact with a body fluid for a long period of time, proteins are adsorbed on the surface of the material to form a biological membrane-like surface, and stable anticoagulant properties can be obtained. However, at the initial stage when the material is introduced into the body (blood contact site), various coagulation factors and the like are activated in the body, so it is sufficient without administering anticoagulant therapy such as heparin administration. It is difficult to obtain good anticoagulant properties.

On the other hand, in the case of (1), heparin and urokinase on the surface exert anticoagulant properties or the lytic performance of the generated thrombus in the initial stage of introduction, but the performance is generally improved by long-term use. Tends to decrease. That is, in (A), (B), and (C), usually, heparin is easily desorbed due to long-term use under physiological conditions, and sufficient performance is obtained as a medical material to be used by fixing in a living body. Hateful. The material obtained in (D) has the advantage that heparin is covalently bonded and thus is difficult to desorb, but the conventional bonding method often results in conversion to D-glucosamine and D-glucuronic acid, which are heparin constituents. There is a drawback that it causes a change in the formation and reduces the anticoagulant effect.

In the methods (C) and (D), it is necessary to select or newly introduce a material containing a functional group that can be used for immobilizing heparin. Therefore, there is a possibility that the range of selection of the material is narrowed or the mechanical strength of the material is lowered due to the introduction of the functional group. There is also a problem that the number of steps for obtaining a medical material increases due to the complicated operation.

As a means for solving such a problem,
Japanese Unexamined Patent Publication (Kokai) No. 2-270823 discloses a technique for a fat-solubilizing method of heparin. This method is characterized by forming a complex of a natural mucopolysaccharide and a natural lipid or a synthetic lipid, and a technique of coating the material surface with a complex of heparin and in vivo phospholipid is mentioned as a preferred example. There is.

However, even with this method, it is hard to say that the decrease in anticoagulability due to the elution of heparin when used for a long period of time has been completely solved. Since the method disclosed in this patent uses a natural lipid or a synthetic lipid as a fat-solubilizing agent for heparin, the fat-solubilizing agent released with elution of heparin is unlikely to adversely affect the living body. Only useful.

Further, in this patent, an anticoagulant material having a structure imitating phospholipid, which is one of the substances used as a fat-solubilizing agent, is also reported (for example, Japanese Patent Laid-Open No. Hei 3).
-39309, JP-A-5-177119, etc.). A typical example of a copolymer containing 2-methacryloyloxyethylphosphorylcholine has a structure similar to that of phosphatidylcholine, which is one of the constituents of the outer wall of the cell membrane, and positively adsorbs phospholipids of biological origin. By forming a biological membrane-like surface, it has excellent blood compatibility. However, this method obtains blood compatibility by forming a biomembrane-like surface by adsorption of phospholipids, and its performance is not sufficiently exhibited at the initial stage of introduction.

Further, artificial organ Vol. 20, No. 2, 488-49
2 (1991), the following method is reported.
That is, the amino group of 2-dimethylaminoethyl methacrylate is quaternized with a long-chain alkyl bromide, and this is ionically bonded to heparin. By this operation, the fat-solubilized heparin-lipidizing agent is copolymerized with other components in the solution to obtain a heparin-immobilized material. In this material, since the heparin fat-solubilizing agent is cross-linked, elution of the heparin-lipophilic agent complex is suppressed, but there is a possibility that this complex will dissociate and heparin will elute with long-term use. Is left. Since the quaternary ammonium group is exposed on the material after elution of heparin, it is not preferable from the viewpoint of blood compatibility. That is, although this material can exhibit excellent anticoagulant properties at the initial stage of introduction, it is considered that the anticoagulant properties are deteriorated by long-term use.

[0011]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned drawbacks of the prior art and is capable of stably exhibiting excellent anticoagulant properties both in the initial stage of introduction and during long-term use. It provides blood material.

[0012]

The anticoagulant material of the present invention comprises:
A complex containing at least one mucopolysaccharide having an anticoagulant action and a compound having a phosphorylcholine residue represented by the above chemical formula 1 in the molecule (hereinafter simply referred to as chemical formula 1), or the complex The body is polymerized 1 of the polymer
It is a polymer compound.

The anticoagulant material of the present invention is a compound having a phosphorylcholine residue in which A of Chemical formula 1 is represented by Chemical formula 2 (a compound having a structure containing a carboxylic acid derivative residue containing a carbon-carbon double bond at the same time; hereinafter simply referred to as phosphorylcholine). Or a phosphatidylcholine residue in which A in Chemical formula 1 is represented by Chemical formula 3 (a compound having a structure that simultaneously contains an aliphatic hydrocarbon group containing a carbon-carbon multiple bond; hereinafter simply abbreviated as phosphatidylcholine) and at least one kind It is characterized by being a complex with the mucopolysaccharide.

In the present invention, due to the effect of the anticoagulant mucopolysaccharide on the surface of the material, excellent anticoagulant properties are exhibited at the time of introducing the material into the living body and at the initial stage after the introduction. In the anticoagulant material of the present invention, the release of the anticoagulant mucopolysaccharide is suppressed to a low level, so long-term anticoagulant property is obtained, but even if the anticoagulant mucopolysaccharide on the material surface is peeled off, The anticoagulant property is maintained due to the use of a phosphorylcholine residue-containing material having a structure similar to a biological membrane.

The present invention is characterized in that the complex of the anticoagulant mucopolysaccharide and the chemical compound 1 is cross-linked alone or as a copolymer with other components, and this is used alone as an anticoagulant material. It may be used, or may be used by coating it on another substrate. It is also possible to use it by blending it with other materials. The base material when the anticoagulant material of the present invention is used as a coating agent or a blending agent is not particularly limited, and polyether urethane, polyurethane, polyurethane urea, polyvinyl chloride, polyester, polypropylene, polyethylene, etc. ,
The materials conventionally used and the materials that will be used in the future can be widely applied. Further, it is possible to coat a blood treatment agent such as a hemodialysis membrane, a plasma separation membrane, or an adsorbent made of existing or new materials for the purpose of imparting anticoagulant properties. The coating method can be applied without any particular limitation, such as a coating method, a spray method and a dipping method. It is possible to appropriately change the timing of the coating or the blending and the polymerization. That is,
After coating the anticoagulant mucopolysaccharide-compound 1 complex,
Both the method of polymerizing by utilizing the carbon-carbon multiple bond of Chemical formula 1 and the method of coating the obtained polymer after the polymerization of the anticoagulant mucopolysaccharide-Chemical 1 complex are possible. When the anticoagulant of the present invention is used as a blending agent, the anticoagulant mucopolysaccharide-Chemical 1 complex is blended with a base polymer and then polymerized by a suitable method. Any method of polymerizing the coagulant mucopolysaccharide-Chemical 1 complex and then blending the obtained polymer is possible.

In the chemical formula 1 used in the present invention, it is essential that the molecule contains a phosphorylcholine residue and a unit having a carbon-carbon multiple bond at the same time (the carbon-carbon multiple bond is a bridge in the present invention. It functions to generate the body). The carbon number in the unit having a carbon-carbon multiple bond is 2 to 50, preferably 5 to 40. In addition, this unit may contain other functional groups.
Examples of other functional groups include a hydroxyl group for imparting hydrophilicity to the material, a carboxyl group for imparting a negative charge to the material, a sulfonic acid group, a diazo group for improving the reactivity of the material with light, There are azido groups. Among them, phosphorylcholine in which A of Chemical formula 1 is represented by Chemical formula 2, and Chemical formula 1
The phosphatidylcholine in which A is represented by Chemical formula 3 is preferable. As the phosphatidylcholine, either a natural product or a synthetic product can be used. These compounds may be used alone or in a mixture of two or more.

Specific examples of phosphorylcholine include 2-
Acryloyloxyethylphosphorylcholine, 2-methacryloyloxyethylphosphorylcholine and the like are exemplified, but not limited to these as long as A of Chemical formula 1 is a compound having a structure represented by Chemical formula 2. As the phosphatidylcholine, 1,2-diacryloylphosphatidylcholine, 1,2-dimethacryloylphosphatidylcholine, 1-acryloyl-2-methacryloylphosphatidylcholine, 1-methacryloyl-2-acryloylphosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, 1- Examples include myristoyl-2-oleoylphosphatidylcholine and the like.
If A of is a compound having a structure represented by Chemical formula 3, it is not limited thereto.

The anticoagulant material of the present invention contains a complex of the above-mentioned compound having a phosphorylcholine residue and a mucopolysaccharide having anticoagulant action, or a polymer obtained by polymerizing the complex as a component 1. It is characterized in that it is a high molecular weight compound, such as heparin, chondroitin sulphate, hyaluronic acid, dermatan sulphate, keratan sulphate, or the like, or metal salts thereof, among which heparin or heparin metal Salts are particularly preferred.

The method for obtaining a complex of mucopolysaccharide having an anticoagulant action and the chemical formula 1 is not particularly limited, but, for example, a weak acid buffer solution or dispersion of the mucopolysaccharide and the weak acid buffer of the chemical formula 1 are used. Examples include a method of mixing liquid solutions or dispersions, collecting the resulting precipitates, and freeze-drying. The solute used in the buffer solution at this time includes 2- (N-morpholino) ethanesulfonic acid and piperazine-1,4-bis (2
-Ethanesulfonic acid), N- (2-acetamido) -2
-Aminoethanesulfonic acid, N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid, 3- (N
-Morpholino) propanesulfonic acid, 3- (N-morpholino) -2-hydroxypropanesulfonic acid, 2- [4
-(2-Hydroxyethyl) -1-piperazinyl] ethanesulfonic acid is preferable, and 2- (N-morpholino) ethanesulfonic acid (hereinafter abbreviated as MES) and piperazine-1,4-bis (2-ethane) are particularly preferable. Sulfonic acid) (hereinafter abbreviated as PIPES), 3- (N-morpholino) propanesulfonic acid (hereinafter abbreviated as MOPS)
Is.

The anticoagulant mucopolysaccharide-conjugated 1 complex thus obtained is crosslinked (polymerized) to form the anticoagulant material of the present invention. The crosslinking method is not particularly limited, and known means such as ultraviolet rays, visible rays, heat, electron rays, plasma rays, and use of radical initiators can be widely applied. At this time, a component other than the anticoagulant mucopolysaccharide-Chemical 1 complex may be added as a copolymerization component. As the copolymerization component,
Compounds containing negative charges such as acrylic acid and methacrylic acid,
Examples of the hydrophilic compound include acrylamide and 2-hydroxyethyl methacrylate (HEMA), and alkyl acrylate and alkyl methacrylate, but the compounds are not limited to these compounds. The copolymerization components may be used alone, or a plurality of types may be used simultaneously to form a multicomponent copolymer containing the anticoagulant mucopolysaccharide-conjugated 1 complex.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION Thus, a complex of a mucopolysaccharide having an anticoagulant effect and a compound having a phosphorylcholine residue is obtained. In the anticoagulant material of the present invention, the anticoagulant polysaccharide was eluted from the material in the early stage when a large amount of the anticoagulant mucopolysaccharide was introduced to the surface of the material, as well as contact with biological components for a long time. Even in this case, good anticoagulant property can be maintained by the effect of phosphorylcholine residue having excellent blood compatibility. That is, it is possible to obtain a material that stably exhibits good anticoagulant properties from the initial contact with a biological component to the long-term contact. Utilizing such advantages, the anticoagulant material and the method for producing the same of the present invention can be widely applied to various medical instruments or devices. Specifically, it can be used as a hemodialysis membrane, a plasma separation membrane, a coating agent thereof, or a coating agent for adsorbing waste products in blood. In addition, membrane material for artificial lung (separation of blood and oxygen)
It can be used in a wide range of fields such as a sheet material for a lung in a heart-lung machine, a sheet material for a lung, an aortic balloon, a blood bag, a catheter, a cannula, a shunt, and a blood circuit.

[0022]

EXAMPLES The present invention will be described below with reference to examples. <Example 1> Report text (Polym. J., Vol. 22,
No. 5,355-360,1990), 2.80 g of 2-methacryloyloxyethylphosphorylcholine (hereinafter abbreviated as MPC) was dissolved in a MES buffer solution having a pH of 5.5 to make a total amount of 148 ml. Heparin sodium salt 10.00 g MES of pH 5.5
It was dissolved in a buffer solution and the total amount was 100 ml. Both solutions were mixed under ice-cooling, allowed to stand at 4 ° C. for 15 hours, then centrifuged at 3300 rpm to collect the precipitate,
The MPC-heparin complex was obtained by freeze-drying this. This MPC-heparin complex is benzene,
It was soluble in organic solvents such as DMF, THF and chloroform.

The above MPC-heparin complex (hereinafter referred to as MPC
-Hep) 8.70 g, n-butyl methacrylate (hereinafter abbreviated as BMA) 7.54 g, HEMA
6.90 g and AIBN 0.15 g were dissolved in DMF 100 ml. After thoroughly replacing the inside of the reaction vessel with argon gas, immerse this vessel in a shaking thermostat at 60 ° C,
The polymerization reaction was carried out by heating for 24 hours with gentle shaking. After completion of the reaction, the reaction solution was cooled and poured into hexane to collect a precipitate formed. Subsequently, the obtained precipitate was redissolved and poured into diethyl ether to recover the precipitate, which was dried under reduced pressure to give MPC-Hep / B.
MA / HEMA terpolymer A was obtained.

The above copolymer A was dissolved in THF to prepare a 5% solution. 20 g of this solution was kept horizontally 12 cm x 1
The film was evenly placed on a 2 cm glass plate, dried at 40 ° C. for 8 hours under a nitrogen stream, and dried under reduced pressure at 40 ° C. for 15 hours to obtain a film A having a thickness of about 60 μm. The plasma relative coagulation time on this film was evaluated by the following method.
Cut film A into a circle with a diameter of about 3 cm
It was attached to the center of the cm watch glass. On this film, take 200 μl of ACD-supplemented plasma of rabbit (white Japanese species),
0.025 mol / l calcium chloride aqueous solution 200μ
1 was added, and the watch glass was floated in a constant temperature bath at 37 ° C. and gently shaken so that the liquids were mixed. The elapsed time from the time when the aqueous solution of calcium chloride was added to the time when the plasma clots (when the plasma stopped moving) was measured, and divided by the time required for plasma clotting when the same operation was performed on glass to obtain the relative clotting time. expressed. However, when the plasma did not coagulate even if it exceeded 12 times the coagulation time on the glass plate, the evaluation was discontinued and the relative coagulation time was expressed as> 12. The results are shown in Table 1 below.

The sulfur content in film A was quantified by elemental analysis using ion chromatography. Since sulfur is not contained in the synthetic polymer material, it can be considered that all of the quantified sulfur is derived from the heparin of MPC-Hep, and the heparin content in the film is calculated by calculating from the sulfur content of heparin. be able to. The value calculated as the heparin content is shown in Table 1 below.

The copolymer A solution was diluted with THF to 1%, and 40 to 60 mesh glass beads were added to this solution.
After soaking for 0 minute, the mixture was filtered through a glass filter and dried under a nitrogen stream at 40 ° C. for 8 hours and at 40 ° C. under reduced pressure for 15 hours to coat the glass beads with the copolymer A. 100 mg of the coated beads were immersed in 1 ml of PBS (−) 2-fold dilution of human serum, and incubated at 37 ° C. for 30 minutes while gently shaking. Using this solution as a sample, the Mayer method (Mayer, MM, “Comple
ment and Complement fixat
Ion ”Experimental Immunoc
hemistry 2nd Ed. p. 133-24
0, C.I. C. Thomas Publisher, 1
961), the hemolytic complement value (CH50) was measured. The results are shown in Table 1 below by percentage as the complement value in 1 ml of the diluted serum without adding beads.

The film A is dipped in PBS (-),
Elution was carried out for 2 weeks in a shaking thermostat at 0 ° C. PB
S (-) was exchanged every day. Hereinafter, the film after elution will be referred to as film A ′. The plasma relative coagulation time in film A ′ was evaluated in the same manner as in film A. Further, the amount of heparin contained was calculated from the sulfur content of the film A ′ as in the case of the film A. The results are shown in Table 1 below.

Copolymer A was dissolved in THF to prepare a 2% solution, and the existing polypropylene hollow hollow fiber for artificial lung was immersed in each solution and lifted up.
The hollow fibers were coated by drying for an hour. In this hollow fiber
Antithrombogenicity was evaluated in vivo. The experimental method is as follows. Under pentobarbital anesthesia, the femoral vein of a rabbit (Japanese white breed, ♂, 2.5-3.0 kg) was removed,
The distal side was ligated with a thread, and the area 2-3 cm from the thread was clamped with a vascular forceps. The central side of the ligated portion was cut into 1/4 to 1/3 of the diameter of the blood vessel with a scissors under the eye, and a hollow fiber as a sample was inserted from there by 10 cm toward the central side. About 1 cm from the insertion position, the end of the hollow fiber protruding outside the blood vessel was sewn to prevent the hollow fiber from being washed away. The incision was sutured, antibiotics were administered, and the animals were kept for 2 weeks until the samples were taken out thereafter. Two weeks later, a median incision was performed under anesthesia with heparinized pentobarbital, the blood was removed from the abdominal aorta using an appropriate tube to sacrifice the rabbit, and then the blood vessel at the portion into which the hollow fiber was inserted was cut. The blood vessel was incised and a hollow fiber and the inside of the blood vessel were photographed, and visually observed to make a 5-grade evaluation. The results are shown in Table 1 below.

[0029]

[Table 1]

5 in vivo antithrombotic properties in Table 1
The graded evaluation is as follows. a: Neither platelet aggregation, thrombus formation nor fibrin formation was observed. b: Fibrin formation or platelet aggregation is observed but thrombus formation is not observed. c: Fibrin formation or platelet aggregation is observed, and thrombus formation is slightly observed. d: Fibrin formation or platelet aggregation is observed, and thrombus formation is considerably observed. e: Fibrin formation or platelet aggregation is observed, and a large amount of thrombus formation is observed.

Example 2 MPC-He obtained in Example 1
p8.70 g, BMA7.54 g, commercially available polyurethane (Pellethane (trade name), abbreviated as PU hereinafter) 6.90 g, AIBN 0.15 g DMF 100 m
It was dissolved in 1. After sufficiently replacing the inside of the reaction vessel with argon gas, the vessel was immersed in a shaking thermostat at 60 ° C. and heated for 24 hours while gently shaking,
A polymerization reaction was carried out. After completion of the reaction, the reaction solution was cooled and poured into hexane to collect a precipitate formed. Then, the obtained precipitate was redissolved and poured into diethyl ether to collect the precipitate, which was dried under reduced pressure to obtain MPC-Hep.
/ BMA / PU copolymer B was obtained.

In the same manner as in Example 1, plasma relative coagulation time, heparin content, complement value, in vivo of copolymer B were determined.
Antithrombotic properties were measured. The results are shown in Table 1. Further, the dissolution test of the film B obtained from the copolymer B was carried out in the same manner as in Example 1, and the plasma relative coagulation time and heparin content of the obtained dissolution film B ′ were also measured. The results are shown in Table 1 above.

<Example 3> MPC-He obtained in Example 1
p8.70g, BMA7.54g, AIBN0.15g
Was dissolved in 70 ml of DMF. After sufficiently replacing the inside of the reaction vessel with argon gas, the vessel was immersed in a shaking thermostat at 60 ° C. and heated for 24 hours while gently shaking to carry out a polymerization reaction. After completion of the reaction, the reaction solution was cooled and poured into hexane to collect a precipitate formed. Subsequently, the obtained precipitate was redissolved and poured into diethyl ether to collect the precipitate, which was dried under reduced pressure to obtain an MPC-Hep / BMA copolymer. 10.00 g of this copolymer was dissolved in THF to a total volume of 100 ml, and 6.00 g of PU was dissolved in THF to a total volume of 60 ml.
Was mixed with the above solution. By this operation, (MPC-H
A solution of ep / BMA copolymer) / PU blend polymer C was obtained.

The plasma relative coagulation time, heparin content, complement value, and in vivo antithrombotic properties of blend polymer C were measured by the same method as in Example 1 using the solution obtained by the above operation. The results are shown in Table 1. Further, the dissolution test of the film C obtained from the blend polymer C was carried out in the same manner as in Example 1, and the plasma relative coagulation time and the heparin content of the obtained dissolution film C ′ were also measured. The results are shown in Table 1 above.

[0035]

[Comparative example]

<Comparative Example 1> MPC 8.38 g, BMA 5.69 g, H
DMF100 with 5.21 g of EMA and 0.15 g of AIBN
It was dissolved in ml. After sufficiently replacing the inside of the reaction vessel with argon gas, the vessel was immersed in a shaking thermostat at 60 ° C. and heated for 24 hours while gently shaking to carry out a polymerization reaction. After the reaction is completed, the reaction solution is cooled,
The precipitate formed by pouring into hexane was recovered. Subsequently, the obtained precipitate was redissolved and poured into diethyl ether to collect the precipitate, which was dried under reduced pressure to give MPC / B.
MA / HEMA terpolymer D was obtained.

In the same manner as in Example 1, plasma relative coagulation time, heparin content, complement value, in vivo of copolymer D were determined.
Antithrombotic properties were measured. The results are shown in Table 1. Further, the dissolution test of the film D obtained from the copolymer D was carried out in the same manner as in Example 1, and the plasma relative coagulation time and heparin content of the obtained dissolution film D ′ were also measured. The results are shown in Table 1 above.

Comparative Example 2 26.00 g of a compound 2-methacryloyloxyethyl dimethylstearyl ammonium bromide having the structure shown in the chemical formula 4 below, abbreviated as MSAB) is dissolved in a MES buffer solution having a pH of 5.5, and the whole amount is dissolved. To 260 ml. Heparin sodium salt 1
0.00 g was dissolved in MES buffer solution having a pH of 5.5 to make 100 ml in total. Mix both solutions under ice cooling,
The mixture was allowed to stand at 4 ° C for 15 hours to obtain a precipitate. This precipitate was collected by centrifugation at 3300 rpm, and freeze-dried to obtain an MSAB-heparin complex. The MSAB-heparin complex is benzene, DMF, TH
It was soluble in organic solvents such as F and chloroform.

[0038]

[Chemical 4]

The above MSAB-heparin complex (hereinafter referred to as MS
AB-Hep) 11.50 g, n-butyl methacrylate (hereinafter abbreviated as BMA) 7.54 g, HE
MA 6.90g, AIBN 0.15g DMF 100m
It was dissolved in 1. After sufficiently replacing the inside of the reaction vessel with argon gas, the vessel was immersed in a shaking thermostat at 60 ° C. and heated for 24 hours while gently shaking,
A polymerization reaction was carried out. After completion of the reaction, the reaction solution was cooled and poured into hexane to collect a precipitate formed. Subsequently, the obtained precipitate was redissolved and poured into diethyl ether to collect the precipitate, which was dried under reduced pressure to remove MSAB-He.
p / BMA / HEMA terpolymer E was obtained.

In the same manner as in Example 1, the relative plasma coagulation time, heparin content, complement value, in vivo of copolymer E were determined.
Antithrombotic properties were measured. The results are shown in Table 1 above. Further, the dissolution test of the film E obtained from the copolymer E was carried out in the same manner as in Example 1, and the plasma relative coagulation time and the heparin content of the obtained dissolution film E ′ were also measured. The results are shown in Table 1 above.

As can be seen from the results shown in Table 1, excellent antithrombotic properties are exhibited. Heparin is not included in the material,
The material of Comparative Example 1, which relies on the structure of MPC for exerting antithrombogenicity, is inferior to the anticoagulant material of the present invention in plasma relative coagulation time. MPC positively adsorbs proteins and lipids in blood and exhibits excellent antithrombotic properties by forming a pseudo-biological membrane, so data suggesting that the initial antithrombotic properties remain somewhat problematic. Conceivable. In the material of Comparative Example 2 in which the structure of the component forming a complex with heparin is different from that of the present invention, the plasma relative coagulation time is at an excellent level due to the effect of immobilized heparin before elution, but 2 After elution for a week, some of the heparin dissociates and the ammonium groups in the material are exposed, so the relative coagulation time is slightly reduced. In other words, it can be said that this material leaves some problems in long-term antithrombotic properties.

Also, looking at the in vivo antithrombotic data, the material of Comparative Example 2 is considerably inferior in antithrombotic property, probably due to the effect of the exposed ammonium group after heparin elution. This test method gives you the opportunity to contact the proteins and lipids in the blood with the material,
The material of Comparative Example 1 in which was introduced exhibited relatively good performance, but was slightly inferior to the anticoagulant material of the present invention. It can be seen that the anticoagulant material of the present invention exhibits extremely excellent performance due to the synergistic effect of the immobilized heparin and the phosphorylcholine structure.

[0043]

INDUSTRIAL APPLICABILITY The anticoagulant material according to the present invention can stably exhibit excellent anticoagulant performance from the initial contact with biological components to after long-term contact, and is a material for blood-compatible medical materials, It also has excellent suitability as a coating agent or blending agent for improving blood compatibility.

Continuation of the front page (56) Reference JP-A 63-220878 (JP, A) JP-A 5-177119 (JP, A) JP-A 9-52848 (JP, A) JP-A 6-125980 (JP , A) JP-A-8-182756 (JP, A) JP-A-8-24327 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61L 27/00 C08L 5/10

Claims (5)

(57) [Claims] 1. A polymer obtained by polymerizing a complex of at least one mucopolysaccharide having an anticoagulant action and a compound having a phosphorylcholine residue represented by the following chemical formula 1 in the molecule.
An anticoagulant material characterized by containing as one of the ingredients. [Chemical 1] In Chemical formula 1, A has at least one carbon-carbon multiple bond.
And a residue having 2 to 50 carbon atoms capable of forming a stable bond with a phosphorylcholine residue. 2. The anticoagulant material according to claim 1, wherein A in Chemical formula 1 has the structure of Chemical formula 2 below. [Chemical 2] In Chemical formula 2, n represents an integer of 1 to 20, and R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. 3. The anticoagulant material according to claim 1, wherein A in Chemical formula 1 has the structure of Chemical formula 3 below. [Chemical 3] In Chemical formula 3, at least ^one of R ¹ and R ² is
It represents an aliphatic hydrocarbon group having at least one carbon-carbon multiple bond, and may be the same or different. 4. The anticoagulant material according to any one of claims 1 to 3, wherein the mucopolysaccharide having an anticoagulant effect is heparin or a heparin metal salt. 5. At least one mucin having an anticoagulant effect.
Copolysaccharide and phosphorylcholine residue represented by the above chemical formula 1
When preparing a complex with a compound having
A weakly acidic buffer solution or dispersion of mucopolysaccharide,
Having a phosphorylcholine residue shown in Chemical formula 1 in the molecule
Process for mixing weakly acidic buffer solutions or dispersions of compounds
Claims 1 to 4, characterized in that it comprises a degree of any one
Anticoagulant material.