JPH03188868A - Manufacture of medical material - Google Patents

Abstract

PURPOSE:To improve the anti-thrombogenic property and easily mold a medical material by graft-polymerizing a vinyl compound indicated by the formula I and a vinyl compound indicated by the formula II to a thermoplastic resin. CONSTITUTION:Acryloxysuccinimide, acryloylbenzotriazole, and methacryloylbenzotriazole are preferably used for a vinyl compound (1) indicated by the formula I and graft-polymerized to a thermoplastic resin. These compounds substituted with the oxysuccinimide or benzotriazole react easily with amines, therefore, an anti-thrombogenic material such as heparin can be firmly bonded by covalent bond. Methoxypolyethylene glycol methacrylate, methoxypolyethylene glycol acrylate, and polyethylene glycol methacrylate are used for a vinyl compound (2) indicated by the formula II, and these compounds have a large copolymerization capability with the vinyl compound (1) in addition to the hydrophilic property.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing an antithrombotic polymer material to which heparin, urokinase, TPA, etc. are added.

[Conventional technology]

Sulfate polysaccharides such as heparin, chondroidin sulfate, and dextran sulfate, and fibrinolytic active enzymes such as urokinase and TPA are known to have antithrombotic properties, and heparin in particular is widely used clinically as an antithrombotic agent. ing. In order to apply heparin as an antithrombotic agent to materials used in contact with blood, it is necessary to immobilize heparin on the material. Kaisho 48-698
Publication No. 90) has been inspected.

However, due to its ionic bond, in some cases heparin is known to be effluxed and lose its potency within a short period of time. Therefore, in order to obtain a material that maintains stable antithrombotic properties, it is considered necessary to bind heparin to the material through a strong bond such as a covalent bond. Many methods have been attempted to bond heparin to the surface of polymer materials through covalent bonds, but the most commonly used method is to react between polymers and heparin in solution by reacting functional groups on the surface of the polymer with heparin in solution. This is a solid-liquid heterogeneous reaction. However, with this method, it is difficult to increase the reaction rate, and as a result, it is difficult to increase the amount of heparin immobilized on the material. JP-A-503494 discloses a method of using a hydrogel of a hydrophilic acrylate polymer containing an epoxy group as a functional group as a polymer material, and bonding heparin by reacting the epoxy group with heparin. .

However, since the polymeric material is limited to hydrophilic acrylate copolymers and has a low epoxy group content, the amount of heparin that can be bound is limited.

As a method to solve this problem, attempts have been made to modify heparin in advance to improve its reactivity.

For example, Japanese Patent Publication No. 59-19562 is one such example.
These methods have the disadvantage that heparin into which double bonds have been introduced must be denatured and synthesized in advance, and their effectiveness is limited.

[Problems to be solved by the present invention]

Therefore, the present inventors conducted intensive studies on methods that do not have these drawbacks, and found that by using a certain type of monomer, antithrombotic properties were significantly improved compared to conventionally known antithrombotic materials. It has been found that it is possible to achieve an antithrombotic medical material that has increased flexibility, becomes easier to mold, and does not cause the outflow of antithrombotic agents such as heparin, which is seen in ionic bonded heparin.

[Means to solve the problem]

Thus, the present invention provides a thermoplastic resin with a general formula (R1 is H or c113, R2 is a hydrocarbon chain or a polyamide chain)
A medical polymer characterized by graft-polymerizing a vinyl compound (1) represented by the general formula % and a vinyl compound (2) represented by the general formula %H, CI+, or C211, where n is 1 to 3o. It provides a method for manufacturing materials,
-6 An antithrombotic polymer material can be obtained by reacting the obtained graft polymer with an antithrombotic agent such as valine, urokinase, TPA, etc.

The present invention will be explained in detail below.

Examples of the vinyl compound (1) include those represented by the above general formula, such as acryloxysuccinimide, methacryloxysuccinimide, acryloyloxysucciniminopolyamide, acryloylbenzotriazole, methacryloylbenzotriazole, and acryloylbenzotriazylpolyamide.

Acryloxysuccinimide, acryloylbenzotriazole, and methacryloylbenzotriazole are preferably used in terms of availability and economy.

The above compounds easily react with amines by substitution with oxysuccinimide or benzotriazole groups. By applying this reaction, antithrombotic agents such as heparin can be firmly bound by covalent bonds.

Further, as the vinyl compound (2), those represented by the above general formula, such as methoxypolyethylene glycol methacrylate-1, methoxybolyethylene glycol acrylate, polyethylene glycol methacrylate, etc., are used. In addition to its hydrophilicity, such a compound has characteristics such as a high ability to copolymerize with the vinyl compound (1).

Chemically bonding an antithrombotic agent such as heparin to the vinyl compound (1) to produce a polymeric material with antithrombotic properties is achieved by graft polymerizing the vinyl compound (1) to a suitable backbone polymer. This is effectively accomplished by merging.

At this time, if the above-mentioned vinyl compound (2) is grafted at the same time as the vinyl compound (1), the hydrophilicity of the resulting grafted polymer will improve, making it easier for antithrombotic agents such as heparin to be incorporated into the polymer chain. The effect of increased antithrombotic properties appears. In addition, the polymer becomes more flexible and easier to mold, and even if blood coagulates after long-term use, it also has excellent properties such as less adhesion of blood clots.

On the other hand, even if the polymer has the same constituent components as the polymer of the present invention, vinyl compounds (1) and (2) are added to the base polymer.
) is incorporated but does not have a graft structure, or is not blended and bonded, it may not have the physical properties necessary as a medical material, or it may not be able to bind to an antithrombotic agent such as heparin sufficiently, making it difficult to use as described in the present invention. Does not exhibit excellent antithrombotic properties.

Further, heparin, which is an antithrombotic agent used in the present invention, is supplied as a sodium salt or the like. Antithrombotic agents other than heparin include fibrinolytic active enzymes such as urokinase and TPA;
Sprebutokinase, thrombomodulin, etc. can be used.

Among these, heparin, urokinase, etc. are superior in terms of effectiveness, economy, and labor efficiency.

In the method of the present invention, the backbone polymer is a thermoplastic resin, particularly preferably polyvinyl chloride, a copolymer of vinyl chloride and vinyl acetate, a copolymer of other monomers, or an ethylene-vinyl acetate copolymer grafted with vinyl chloride. polymers, mixtures of these polymers, and these polymers,
Various copolymers and mixtures can be used, such as those mixed with plasticizers, stabilizers, etc. to the extent that the physical properties of the polymer are not impaired. In these copolymers and mixtures, the content of vinyl chloride can be appropriately selected depending on the purpose as long as it is within the range of 0.1χ to 100χ.

Such polymers can be obtained easily and inexpensively as commercial products, and can be easily graft-polymerized with other polymers by graft activation treatment.

The content of vinyl compound (1) and vinyl compound (2) in the graft polymer is 1 to 70% by weight, preferably 5 to 50% by weight of the total graft polymer.
Good. Further, within this range, the contents of vinyl compound (1) and vinyl compound (2) are preferably selected within the range of 0.5 to 40% by weight, and in particular, substantially equal contents are preferably used. A graft polymer having such a graft ratio and a ratio of vinyl compound (1) to vinyl compound (2) in the graft can be used for medical purposes without losing the properties of vinyl chloride-containing polymers such as strength and flexibility. It also has various properties that a material should have.

The graft polymer is obtained by subjecting a vinyl chloride-containing polymer to graft activation treatment to form a vinyl compound (1) and a vinyl compound (2).
) and polymerization using an appropriate polymerization method.

In this case, as a method for graft activation treatment, for example, a method of substituting the chlorine atom of the vinyl chloride-containing polymer with a dithiocarbamate group, which is easy to give a radical by irradiation with light, etc., is preferably used.

This method involves dissolving a vinyl chloride polymer in a suitable organic solvent such as dimethyl sulfoxide or cyclohexanone, and adding 30 to 7
This is achieved by reacting at about 0°C and substituting about 1 to 10% of the chlorine atoms with dithiocarbamate groups. As the polymerization method in this case, photopolymerization is preferably used. A normal high-pressure mercury lamp is sufficient as a light source. As the solvent, those mentioned above can be used as appropriate.

The appropriate concentration of the vinyl chloride-containing polymer and the two types of vinyl compounds is 1 to 20% by weight, preferably about 3 to 10%, and room temperature is sufficient for the polymerization temperature.

Furthermore, when the vinyl compound (1) and the vinyl compound (2) are grafted, they can be grafted simultaneously or simultaneously. Further, other vinyl monomer components can also be used as required.

The graft activation treatment, polymerization method, etc. are not limited to those described above, and other methods may be used as appropriate.

The reaction of the antithrombotic agent to the graft polymer thus obtained is carried out as follows.

First, the graft polymer is added in an amount of 1 to 20%, preferably 3 to 20%.
A glass tube, glass rod, or other solid with an appropriate surface and shape is immersed in a solution containing about 10%, pulled up and dried, and only the polymer is peeled off to obtain a polymer of the desired shape or an appropriately shaped vinyl chloride. A synthetic resin coated with the graft polymer can be obtained by applying a polymer solution to the surface of the containing polymer or synthetic resin such as polyurethane and then drying it. It is effective for the molding operation to be performed prior to the reaction of the antithrombotic agent.

By reacting the polymer thus obtained with heparin (including its derivatives), etc., the desired product can be easily obtained. This is carried out by an exchange reaction between the oxysuccinimide group or benzotriazole group of the vinyl compound (1) and the amine group of the antithrombotic agent, etc., and the amide bond (-CON
It is thought that the bond is strongly covalently bonded by H-).

Specifically, in the case of a polypeptide such as urokinase, urokinase can be converted into an antithrombotic agent by immersing the graft polymer in water or formamide containing a certain concentration of an antithrombotic agent such as urokinase, and allowing the reaction to occur. achieved. A concentration of the antithrombotic agent of 10% or less is sufficient, preferably 0.1-3%. In addition, the heating temperature is from room temperature to 100℃.
°C1 Preferably room temperature to 70 °C, heating time is 2
The time period ranges from hours to several days, preferably from 3 to 24 hours.

Next, when using heparin as an antithrombotic agent, for example, the graft polymer is first reacted with a diamine (preferably a water-soluble diamine such as diaminopropane or diaminopropanol) (the reaction time is within several days, preferably , for 1 to 24 hours), and then immersed in an aqueous solution containing the sodium salt of heparin in the presence of a catalyst (preferably in the presence of a catalyst such as a water-soluble carbodiimide such as morpholinoethylcyclohexylcarbodiimide) to react (the reaction time is several days). (within 1 to 24 hours, preferably 1 to 24 hours), thereby achieving antithrombotic action using heparin. A heparin concentration of 10% or less is sufficient, preferably 1 to 3%.

The methods of molding, antithrombotic preparation, etc. described here are not limited to the above-mentioned methods, and other methods can be used as appropriate.

[Effects of the present invention]

The polymer of the present invention obtained by these methods has significantly improved antithrombotic properties compared to conventionally known polyvinyl chloride-based antithrombotic materials, has increased flexibility and is easier to mold, and It has been found that it exhibits excellent properties such as difficulty in adhering to blood clots even if they occur, and that there is no leakage of antithrombotic agents such as heparin, which is seen with ionically bound heparin.

The medical polymer material of the present invention is not only applicable to the above-mentioned antithrombotic material, but also can be used as a carrier for diagnostic agents, bioreactors, etc., and the effects of the present material are significant. .

Examples are shown below.

Example 1 Various dithiocarbamate-containing polyvinyl chloride-containing polymers (graftomer R-3, graftomer R-5: manufactured by Zeon KK) (dithiocarbamate conversion rate about 2 mol%) were dissolved in cyclohexanone, and methoxypolyethylene glycol methacrylate (MOPEGM and Abbreviation: n-5 to 6 or n
-22~26) and acryloxysuccinimide (AO3
Abbreviated as I. ) in the immersion type photoreactor inside the light source.
0 was irradiated with a mercury lamp to obtain various graft copolymers. The results are shown in Table-1.

The various graft copolymer solutions thus obtained were coated into test tubes with an inner diameter of 8.8 mm and a height of 75 mm (coating times: 2 times, drying temperature: 70°C).

After coating, extraction in methanol - day and night, and in the case of heparinization, after overnight immersion of the tube in a 10% aqueous diaminopropane solution, 2 wt. Heparinization was performed by immersion overnight in an aqueous solution containing sodium heparinide. Next, unbound heparin and residual salts were removed by washing with distilled water.
A test tube to be used for the test was obtained by vacuum drying at °C for 4 hours. Next, the test tube coated with the graft copolymer was immersed overnight in a 0.1x urokinase aqueous solution and a 2% albumin aqueous solution to convert it into urokinase and albumin. Thereafter, test tubes to be subjected to adjustment tests were obtained in the same manner as above.

Table 2 shows the results of a blood test (calcium re-extraction time test) using each of the polymer-coated test tubes thus obtained.

Both polymers containing MOPEGM and AO5I as graft components exhibited excellent antithrombotic properties. Also at this time,
As a comparative example, ionic bonded heparin was polymerized using dimethylaminoethyl methacrylate containing a tertiary amine instead of AO3I, quaternized with ethyl bromide, and then coated and treated with heparinization in the same manner as the above-mentioned composition of the invention. It can be seen that the antithrombotic properties of the samples having the following properties were lower after extraction treatment with saline at 65°C for three days and nights than before the treatment. This was thought to be due to the dissolution of heparin during the extraction process. In comparison, those coated with the heparinized polymer of the present invention,
It shows good antithrombotic properties even after extraction treatment.

In addition, the calcium re-extraction time of the non-heparinized sample, untreated polyvinyl chloride polymer (graftomer R-3), and glass sample tested for comparison was several minutes.

In the above calcium re-extraction time test, blood is collected from a person's arm in an amount equal to 9 volumes per volume of the sodium citrate solution into a blood collection tube containing a 3.8x sodium citrate aqueous solution, and the blood is kept at 0°C.
The samples were centrifuged for 10 minutes at a rotational speed of 150 rpm, and the tests were carried out in test tubes coated with the above-mentioned various materials according to the usual calcium re-extraction time test method. (Izumi Kanai, Masamitsu Kanai, eds., Summary of Clinical Testing Law, Vl-82 Kanehara Publishing Co., Ltd., 1971) Margins below 7 8 Table 1 [Note]

Claims (1)

[Scope of Patent Claims] 1 Thermoplastic resin has a general formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼, ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ or ▲ has a mathematical formula , chemical formulas, tables, etc.▼ (R_1 is H or CH_3, R_2 is a hydrocarbon chain or polyamide chain) Vinyl compounds and general formulas ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ (R_1 is H or CH_3, R_2 is a hydrocarbon chain or polyamide chain) C
H_3, R_2 are H, CH_3 or C_2H_5, n is 1 to 30) A method for producing a medical polymer material, characterized in that a vinyl compound is graft-polymerized.