JPS5949017B2 - Manufacturing method of anticoagulant medical polymer material - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel anticoagulant medical polymeric material.

One of the problems with medical polymer materials currently in practical use is that they cause various undesirable foreign body reactions in living organisms, and materials that come into contact with blood have the property of coagulating blood. It is that you are.

One way to solve this problem is to use heparin, a natural anticoagulant, in combination with polymeric materials.
For example, Go 廿 et al. (Science 142, 1297)
(1963)) obtained an anticoagulant material by treating the surface of the material with graphite-benzalkonium chloride-heparin. Polymers of alkyl acrylates or methacrylates having a hydroxy group or alkoxy group, such as 2-hydroxyethyl methacrylate, and copolymers thereof become hydrogels that are hydrophilic and insoluble in water,
Since it has good biocompatibility and high chemical stability, it is used as a medical material.

Heparinization treatment may be effective in improving the anticoagulant properties of these polymers, but these polymers are often used in a state swollen with water or body fluids. If heparin is simply absorbed or adsorbed onto the surface, heparin will be eluted into the blood in a short period of time, and blood clots will not occur during that time, but blood clots will easily occur after the heparin is eluted. Therefore, heparin must be fixed in some way to the polymer in order to create a material that does not cause blood clots over a fairly long period of time. The present invention has solved the above problems, and according to the present invention, a hydrophilic acrylate system containing an acrylate or methacrylate monomer having a quaternary ammonium salt as a substituent as one of the copolymerization components. Alternatively, by reacting heparin with a methacrylate polymer, it is possible to obtain a medical polymer material that does not cause blood clots over a long period of time, has good biocompatibility, and has high chemical stability.

In the present invention, "acrylate-based or methacrylate-based" may be abbreviated as "(meth)acrylate-based". Heparin is a mucopolysaccharide containing anionic substituents such as carboxyl groups and sulfonic acid groups, so to fix it, cationic substituents are introduced into the polymer.
Advantageously, it is ionically bonded to heparin.

Conventionally, as a method for introducing a cationic substituent into polymer 1 in order to make an ionic bond with heparin, Leininge
r et al. (Trans. Am. SOc. A [Tif. Int.
em. Organs. 12, 151 (1966)), complicated methods such as chloromethylation of polystyrene or styrene-grafted polymers and quaternization with amines and alkyl halides. was taken. In contrast, in the present invention, which targets (meth)acrylate polymers that form hydrophilic hydrogels, one (meth)acrylate monomer having an ammonium salt as a substituent is used as a copolymerization component. This has the advantage that the amount of cationic substituents can be changed arbitrarily, and furthermore, such monomers have a structure similar to the monomers constituting the hydrophilic (meth)acrylate polymer. Therefore, there is an advantage that the mechanical and chemical properties of the polymer, which are desirable as medical materials, are not significantly changed. Although it is possible to use a homopolymer of (meth)acrylate monomers having an ammonium salt as a substituent, this polymer is water-soluble and is unsuitable as a medical polymer material. Even if it is made insolubilized by a method, the content of cationic substituents is too large, which is disadvantageous.

Therefore, when synthesizing a hydrophilic (meth)acrylate polymer according to the present invention, it is most effective to use the above monomer as one of the copolymerization components. In order to maintain the water resistance and strength of the resulting polymer, a difunctional monomer such as ethylene glycol dimethacrylate or a monomer with a post-crosslinkable functional group such as glycidyl methacrylate is used in combination. It is desirable to carry out copolymerization. Furthermore, water resistance can be improved by copolymerizing hydrophobic vinyl monomers that can be easily copolymerized with these monomers, such as methyl methacrylate and styrene.
Therefore, more specifically, the present invention relates to the general formula (wherein R1
is hydrogen or a methyl group, R2 is a divalent alkylene group having 2 to 3 carbon atoms) The main polymerization component is a hydroxyalkyl (meth)acrylate represented by / or a divalent alkylene group with 2 to 3 carbon atoms,
R3, R4 and R5 are alkyl groups having 1 to 2 carbon atoms, x
A (meth)acrylate monomer having a quaternary ammonium salt represented by (halogen) as a substituent, especially methacryloxypropyltrimethylammonium chloride, a derivative thereof having a hydroxyl group, or a quaternized product such as diethylaminoethyl methacrylate, By reacting a polymer obtained by copolymerization with heparin in a small proportion, preferably 1 to 5 mol% of the total monomers, an anticoagulant medical polymer material with heparin immobilized can be obtained. It's something you get.

If the amount of (11) used is less than 1 mol% based on the total monomers,
The amount of heparin that can be bound to the polymer is small, making it difficult to obtain sustained anticoagulant properties. Moreover, when the amount of (11) used exceeds 5 mol %, the water resistance of the resulting polymer tends to decrease. In order to maintain the water resistance and strength of the polymer material according to the present invention to a practically sufficient level, the copolymerization component is further added to the general formula (where Rl and R2 are hydrogen or methyl groups, and R3 is a carbon number of 2 to 3 carbon atoms). About 0.2 to 0.5 mol% of a difunctional monomer represented by a divalent alkylene group, a divalent cycloalkylene group, or a divalent phenylene group is added to the total monomers, and polymerization is carried out in an appropriate mold. It is advantageous to let them do so.

If water is used as a solvent in this case, an insoluble polymer swollen with water can be obtained. Furthermore, a monomer represented by the general formula (wherein R1 is hydrogen or a methyl group, R2 is a divalent alkylene group having 1 to 3 carbon atoms) is added in an amount of 1 to 5 mol% based on the total monomers,
Solution polymerization in a solvent such as methanol yields a soluble polymer, which can be molded and then made insolubilized by heat treatment, ultraviolet irradiation, or the like. If this soluble polymer solution is applied to the surface of the material, dried, and heat treated, a coating layer that can be treated with heparin can be obtained. Various monomers that can be easily copolymerized with these monomers, such as methyl methacrylate, methyl acrylate, vinyl chloride, styrene, acrylamides, vinyl esters,
By copolymerizing a small amount of vinyl ethers, etc., if necessary, various properties such as water absorption and mechanical properties of the resulting polymer can be changed. When the insoluble polymer material prepared by these methods is immersed in an aqueous heparin solution, heparin is absorbed into the polymer and fixed by ionic bonds. Heparin aqueous solution concentration is 1000 units/
About ml is enough. In the case of a soluble polymer, it is possible to dissolve both the polymer and heparin in a suitable solvent (for example, formamide) and cast from a suitable mold. Further, the heparin-containing polymer solution can be applied to the surface of various materials and dried to prepare a heparin-containing coating layer, thereby imparting anticoagulant properties to the surface of the material. The heparin-containing hydrophilic (meth)acrylate polymer material of the present invention thus obtained maintains excellent biocompatibility and has sustained anticoagulant properties.

EXAMPLES The present invention will be specifically explained below with reference to Examples, but these are not intended to limit the present invention in any way.

Example 1 2-Hydroxyethyl methacrylate (abbreviated as HEMA) 14 ml. 0.7 g of 2-hydroxy-3-methacryloxypropyltrimethylammonium chloride (abbreviated as HMAC) and 0.7 g of ethylene glycol dimethacrylate (abbreviated as EGDMA).
028ml was dissolved in 6ml of water, 0.05ml of a 50% hexane solution of diisopropyl peroxydicarbonate (abbreviated as IPP) was added, defoamed under reduced pressure, placed between two glass plates, and heated at 60°C. Keep it for 24 hours with
Cast polymerization was performed to form a film with a thickness of 1 mm.

This was immersed in boiling water for 24 hours to remove unreacted substances, and then immersed in a 1000 units/ml heparin aqueous solution (manufactured by Tsubo, Denmark). The surface of this heparin-containing film was washed with water, and Imai et al.
．． Res. The anticoagulant property was evaluated by the method proposed by (1972)).

That is, four heparin-containing films were kept at 37°C,
Place 0.25 ml of fresh dog ACD blood on each film, and add 1 drop of 0.1 M CaC12 aqueous solution (0.02
5 ml) was added to each to initiate clotting. The clot was taken out at appropriate time intervals, washed with water, identified with formalin, washed again with water, water removed and weighed, and the weight of the clot was expressed as a percentage of the saturated clot amount on the glass plate over time. A coagulation curve was obtained by plotting against the blood pressure. Coagulation curves for glass and silicone rubber were similarly obtained and compared, and it was found that the heparin-containing film prepared by the above method had excellent anticoagulant properties. Films containing no heparin or films containing no HMAC immersed in an aqueous heparin solution have inferior anticoagulant properties.

In addition, a heparin-containing film containing HMAC is
Anticoagulant properties did not decrease even after storage for weeks.

In contrast, the anticoagulant properties of a heparin-containing film without HMAC significantly decreased when stored in water for one week. Table 1 shows the clot formation rate of various samples after 10 minutes of blood contact, with the saturated clot amount on glass being 100.

Example 2 99 mol% HEMA and mol% HMAC1
at 60 °C using an IPP initiator (0.3% of monomer) in methanol solvent with a total monomer concentration of 20%.
, HEMA obtained by solution polymerization in an ampoule for 17 hours:
The HMAC copolymer was made into a dimethylformamide solution, mixed with an aqueous heparin solution, poured into a rectangular mold made of a glass plate, and the solvent was evaporated to prepare a heparin-containing film.

This film and HE without HMAC as a control.
A film prepared from a dimethylformamide solution of MA homopolymer and heparin was stored in water overnight and then evaluated in the same manner as in Example 1. As a result, as shown in Table 2, the former film showed excellent anticoagulant properties. Example 3 HEMA (80 mol%), methyl methacrylate (1
Copolymerization of HMAC (5 mol%) and HMAC (5 mol%) was carried out in methanol using an IPP catalyst at a temperature of 60°C for 17 hours, and the resulting polymer was made into a film from a methanol solution by a casting method. A heparin-containing film was obtained by immersing it in an aqueous solution.

This film showed better anticoagulant properties than silicone. Example 4 2-Hydroxypropyl acrylate and 1-methinoto2
- 14 g of mixture with hydroxyethyl acrylate, 0.75 acryloxyethyltriethylammonium chloride
g and ethylene glycol dimethacrylate 0.07
g was mixed with 6 ml of water, 0.05 ml of 50% hexane solution of IPP (7) was added, and cast polymerization was carried out in the same manner as in Example 1 to obtain a film-like copolymer.

After washing it by boiling, it was immersed in a heparin aqueous solution of 1000 units/MI overnight at 4°C. The anticoagulant properties of this film were evaluated in the same manner as in Example 1, and the coagulation rate of the hevarin-containing film of this example was 40%, assuming the saturated coagulation amount on glass as 100. In this case, the coagulation rate of the control silicone film was 65%. Example 5 Diethylaminoethyl methacrylate was reacted with ethyl chloride to form a quaternary ammonium type monomer, which was used in place of HMAC in Example 1, copolymerized with HEMA and EGDMA in exactly the same manner as in Example 1, and converted into a heparin aqueous solution. A heparin-containing film was prepared by immersion treatment.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R_1 is hydrogen or a methyl group, R_2 has 2 carbon atoms
The main polymerization component is hydroxyalkyl (meth)acrylate represented by a divalent alkylene group of A hydrophilic (meth) monomer obtained as a copolymerization component of a monomer represented by a divalent alkylene group having 2 to 3 carbon atoms, R_3, R_4 and R_5 are alkyl groups having 1 to 2 carbon atoms, and X is a halogen. A method for producing a hydrophilic medical polymer material imparted with anticoagulant properties, which comprises reacting an acrylate polymer with heparin.