JPH01232968A - Antithrombogenic composite material - Google Patents

Abstract

PURPOSE:To obtain a heparin-containing polymer material, by immobilizing heparin and a salt thereof by electrostatically attracting the same to a hydrogel of every kind to synthesize a fine particle of a heparin supported bydrogel and kneading said fine particle along with a polymer material or dispersing the same in said polymer material using an org. solvent. CONSTITUTION:A heparine-containing dry hydrogel fine particle is dispersed in a polymer material equipped with the characteristics as a medical material such as polyvinyl chloride, segmented polyurethane, a polyurethane- polydimethylsiloxane copolymer or the like by a mechanical processing method such as kneading or the above-mentioned material is dissolved in a proper org. solvent to prepare a high concn. polymer solution. A synthesized fine particulate hydrogel is dispersed therein and the solvent is removed from the resulting dispersion to form a solid solution of heparin to make it possible to prepare an antithrombogenic composite material.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to an antithrombotic medical polymer material, and more specifically, a material containing heparin, which is a blood coagulation inhibitor,
The present invention relates to an antithrombotic composite material that can freely control the release of heparin and can sustainably release it over a long period of time as necessary.

(Prior art) Conventionally, medical polymer materials have been widely applied in the medical field, such as pharmaceuticals, medical device materials, sanitary materials, dental materials, and artificial organs. Polymer materials such as these have been used.

Among these, applications to pharmaceuticals and artificial organs are areas that will become even more important in the future.

Artificial organs are extremely important in maintaining life by supporting organs whose function has decreased or stopped due to disease or trauma, or as substitute organs, and their importance will continue to increase in the future. I think it will go well. Furthermore, existing artificial organs, such as artificial kidneys, which dialyze waste products and poisons in the blood outside the body, have various deficiencies, so in the future, we will need to improve their functionality, make them smaller, lighter, and more portable. , and it is necessary to aim for in-vivo implantation.
Similar things have been said about other artificial organs.

For example, when used in something like an artificial blood vessel, it is not only necessary to be compatible with the living body over a long period of time without causing a reaction, but also to use materials that do not coagulate blood or promote thrombus formation (antithrombotic). material) is very important.

Therefore, antithrombotic properties have been considered the most important methods for evaluating the biocompatibility of materials, and the following methods have been devised as methods for producing antithrombotic materials.

1) Weakens interaction with blood components.

2) Utilize substances that inhibit thrombus formation.

3) Utilize the living body itself.

(Problems to be Solved by the Invention) Among these, for example, there are polymers (silicone rubber, fluorosilicone rubber, and Teflon) that have low surface energy and inert surfaces, but silicone rubber has problems with processability and refraction. Although it is rich in sex, its antithrombotic properties are not perfect. Also, fluorosilicone rubber does not have much antithrombotic effect. Although Teflon is more suitable for the pseudointernal method than its anticoagulant property, there are concerns that it prevents thrombus formation and promptly leads to intimal formation when used as an intimal method. Next, the surface of blood vessels that are in contact with blood has a negative ζ
Because of this potential, efforts have been made, for example, to improve conductivity by mixing activated carbon into polyurethane, or to maintain a state in which a microcurrent flows similar to the physiological conditions of normal blood vessels, but the antithrombotic properties have not been maintained. There are disadvantages in terms of performance and tissue damage.

For biocompatibility, copolymers having hard crystalline segments and soft refractive segments of appropriate length are also desirable. Therefore, we developed Cardiothan, a copolymer of polyurethane and polydimethylsiloxane.
ane) and segmented polyurethane biomer (B
iomer), TM-3 (Toyobo Co., Ltd.), and polystyrene-polyhydroxyethyl methacrylate block copolymers have been put into practical use, but they have drawbacks such as slow organization and non-adherence to living tissue, resulting in peeling.

Furthermore, hydrogels with a three-dimensional network structure with a high water content have excellent blood compatibility, but blood compatibility is likely to be affected by the water content, gel mesh size, etc. (due to synthesis conditions and reproducibility). I have a sexual problem.

In 2), heparin, a substance that inhibits blood coagulation, is immobilized on the polymer surface through covalent bonds. However, heparin is insoluble in many organic solvents, so there are restrictions on the reaction conditions, the reaction is complicated because the hydroxyl group of heparin is polyvalent, the amount of bound heparin is small, and the conformation of bound heparin is limited. Disadvantages include easy deactivation due to changes.

3) Expanded Teflon (expa) is placed inside the body.
An artificial material such as fused teflon is implanted, and fibrin is quickly deposited on the surface, which is then covered with fibroblasts and endothelial cells, but the endothelial tissue may detach from the surface or the organization may be delayed. There is a drawback.

An object of the present invention is to provide an antithrombotic composite material that can freely control the release time of heparin, can perform sustained release over a long period of time if necessary, and has practical strength.

(Means for Solving the Problems) According to the present invention, there is provided an antithrombotic composite material made of a polymeric material in which a hydrogel containing one or more selected from the group consisting of heparin and its salts is dispersed. Ru.

The present invention will be explained in more detail below.

Commercially available heparin can be used as the heparin used in the present invention, and preferred examples of the salt include sodium salt or potassium salt.

Preferred examples of the hydrogel component used in the present invention include polymers synthesized from monomers having a hydrophilic functional group, monomers having an amide group, monomers having a hydroxyl group, or monomers having a carboxyl group, and other substances. can.

More specifically, the hydrogel components include, for example, (meth)acrylamide ((meth)acrylic refers to methacryl and acrylic), N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide,
N,N-dipropyl(meth)acrylamide, N,N-
Diptyl (meth)acrylamide, N,N-dimethylaminoethyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N,N-dipropylaminoethyl (meth)acrylate, N.

N-dimethylaminopropyl (meth)acrylamide,
N,N-diethylaminopropyl (meth)acrylamide, N,N-dipropylaminopropyl (meth)acrylamide, N-ethyl (meth)acrylamide, N-propyl (meth)acrylamide, (meth)acryloylmorpholine, 2-hydroxy Ethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3
-Hydroxypropyl (meth)acrylate, (meth)
Acrylic acid, p-vinyl benzoate, N-vinylpyrrolidone, p-aminostyrene, p-N-methylaminostyrene, p-N, N-dimethylaminostyrene, p-N, N
-diethylaminostyrene, p-N, N-dimethylaminomethylstyrene, p-N, N-dimethylaminoethylstyrene, p-N, N-diethylaminomethylstyrene, p-N.

Obtained by radical copolymerization of monomers such as N-dimethylaminoethylstyrene, p-N, N-dimethylaminopropylstyrene, p-styrene sulfonate, and p-methylstyrene sulfonate using a crosslinking agent such as bisacrylamide. Hydrophilic copolymers may be mentioned.

Other hydrogels include polyvinyl alcohol and naturally derived substances such as starch, konjac powder, and carrageenan.

Examples of common hydrogel synthesis methods include radical polymerization, cationic polymerization, anionic polymerization, and redox polymerization. However, in normal radical polymerization, the polymerization temperature is high and heparin may be deactivated, so it is preferable to carry out radical polymerization at a low temperature, and it is particularly preferable to synthesize the hydrogel by redox polymerization. Examples of the redox initiator include potassium persulfate, potassium persulfate-NaHSOz,
H2O2-Fe”, uzot-thioxalic acid, KMn
O4-oxalic acid, NaCl0z NaHSOz ammonium persulfate-N,N.

N',N'-tetramethylenediamine and the like can be mentioned.

Examples of the polymer material for dispersing the hydrogel used in the present invention include hydrophobic substances, such as polyvinyl chloride, polystyrene, polyethylene, polypropylene,
Polycarbonate, polysiloxane, polyurethane, polyacrylonitrile, polyfluorocarbon, polyester, polyether, poly(meth)acrylate, and various copolymers such as styrene-acrylonitrile copolymer, styrene-methyl methacrylate copolymer, and synthetic natural Rubbers etc. can be exemplified. There is a substance having a hydrophilic/hydrophobic layer separation structure as a polymer material used in the present invention.
For example, as its hydrophilic moiety, polyether, polyacrylamide, hydroxyethyl (meth)acrylate,
Hydrophilic polymers such as poly-N-methyl-2-pyrrolidone and poly-N-vinylpyridine and their macromonomers,
In addition, as hydrophobic parts, polyolefins, various copolymerizable polymers and their macromers, polyamides,
Examples include condensing polymers such as polyimide, polyether, polyester, and polysulfone, macromers thereof, and synthetic or natural rubbers.

The method for producing a hydrogel containing heparin of the present invention includes, for example, adding a water-soluble polymer and a water-soluble polyfunctional monomer to an aqueous solution containing the redox polymerization initiator, etc., and one or more of heparin and its salts. In addition, it is desirable to perform radical polymerization under water cooling to synthesize a hydrogel.

The content of heparin in the hydrogel is 0.1 to 30
% by weight, especially 1 to 10% by weight is preferred. 0.1% by weight
If it is less than 30% by weight, the heparin content is too small and antithrombotic properties cannot be obtained, and it is not only technically difficult to contain heparin in an amount exceeding 30% by weight, but also the sustained release amount of heparin becomes too large, which is not preferable. .

After freeze-drying the heparin-containing hydrogel obtained in this way, dry fine particles can be obtained by a method such as mechanically pulverizing at a low temperature, or a water-soluble polymer can be added to the above-mentioned redox polymerization initiator and heparin-containing aqueous solution. and water-soluble polyfunctional monomers, and further benzene, toluene, hexane,
By adding an insoluble organic solvent such as petroleum ether and a surfactant such as Aracel C to water, and performing treatment such as ultrasonication,
Create a reverse phase suspension system and radically polymerize it under ice cooling.
There is a method of synthesizing a heparin-containing hydrogel in the form of fine particles and then freeze-drying it to obtain dry fine particles.

Heparin-containing dry hydrogel fine particles synthesized by these methods are combined with polyvinyl chloride, segmented polyurethane (polyether type polyurethane), and polyurethane.
A highly concentrated polymer solution can be obtained by dispersing a polymer material with properties suitable for medical use, such as a polydimethylsiloxane copolymer, using a mechanical processing method such as kneading, or by dissolving the above material in an appropriate organic solvent. After dispersing the micronized hydrogel synthesized by the method described above in this, the solvent is removed to immobilize heparin, thereby making it possible to obtain an antithrombotic composite material.

In addition, common polymer materials that have traditionally been considered unsuitable as antithrombotic composite materials, such as polystyrene, polyacrylonitrile, poly(meth)acrylates, polyvinyl esters, styrene-acrylonitrile copolymers, and styrene-butadiene copolymers, are also used. Polymer, styrene (meth)
Acrylate copolymer, styrene-acrylonitrile
The above-mentioned heparin-supported hydrogel can be used against polymers such as butadiene copolymers, polyolefins such as polyethylene, polypropylene, and polybutene, polytetrafluoroethylene, polycarbonates, polyamides, polyimides, polysulfones, etc. A heparin-supported hydrogel-containing polymer can be obtained by dispersing dry fine particles by kneading or the like, or by dispersing the fine particles in a high-concentration polymer in a suitable organic solvent, and then removing the solvent. , an antithrombotic composite material.

(Effects of the Invention) The antithrombotic composite material of the present invention immobilizes heparin and/or its salts, which are excellent substances for expressing antithrombotic properties, by electrostatically adsorbing them onto various hydrogels, for example. By doing this, we synthesized microparticles of heparin-supported hydrogel, and then kneaded these microparticles into various polymeric materials or dispersed them using an organic solvent, etc., making it possible to obtain a heparin-containing polymeric composite material.

Moreover, it is possible to freely control the sustained release of heparin from the material over a long period of time by selecting the hydrogel, the amount of heparin it contains, and the amount of heparin-supported hydrogel particles dispersed, etc. You can choose according to your needs. In addition, various polymeric materials that have antithrombotic properties have not been used due to lack of biocompatibility despite their excellent mechanical strength, physical and chemical stability, and processability. give gender,
It has become possible to use it as an antithrombotic composite material with excellent physical properties.

(Examples) Hereinafter, the present invention will be specifically described based on Examples, but the present invention is not limited thereto.

Example 1 Fifty volumes of 1% Aracel C-benzene solution was placed in a glass ampoule with an internal capacity of 100 mm, and nitrogen substitution was continued at 10 to 15 °C for 30 minutes, while 9.95 mmol of acrylamide, N, N' -Methylenebisacrylamide 0.
05 mmol, 1/15 molar phosphate buffer containing 4.5 g/l heparin sodium salt (manufactured by Kodak) (
pH7.0) 5 yd, ammonium persulfate 0.0
1 mmol of N and 0.01 mmol of N under water cooling.
.

After adding N,N',N'-tetramethylenediamine, immediately pour it into the above benzene and irradiate it with ultrasonic waves for 2 minutes.While gradually returning it to room temperature, stir it for 30 minutes under a nitrogen stream. Polymerization was performed using
The benzene in the supernatant was sufficiently replaced with purified benzene.

Next, the obtained acrylamide bead/benzene dispersion solution was frozen in liquid nitrogen and dried under reduced pressure to obtain a particulate acrylamide hydrogel. Next, 0.05 g of acrylamide-based heparin-containing hydrogel particles were uniformly dispersed in 9.5 g of a 10% by weight polyvinyl chloride-tetrahydrofuran solution, poured into a glass flat Petri dish, and the solvent was evaporated to support heparin. A hydrogel-containing polyvinyl chloride film was prepared. Take a certain amount of this film, add 40 μm of physiological saline, and add about 20 μm of the supernatant liquid of the sample on the line of the flow injection device. This was collected and mixed with 30 μl of a 0.64 M NaCl solution containing 0.16% cetylpyridium chloride, and the turbidity of the resulting heparin-cetylpyridium chloride complex was measured using an absorbance needle equipped with a flow cell. ,
The amount of heparin released was determined by converting it into a heparin concentration using a calibration curve prepared in advance.

The results are shown in FIG. In the figure, O indicates an acrylamide hydrogel content of 5% by weight, and Δ indicates an acrylamide hydrogel content of 20% by weight. The figure shows that heparin is sustainedly released from polyvinyl chloride over a long period of time.

Example 2 Using acrylamide hydrogel particles containing heparin sodium salt obtained in the same manner as in Example 1, this hydrogel was dispersed to contain 20% by weight and polychlorinated in the same manner as in Example 1. A vinyl film was prepared and the sustained release properties of heparin were measured. The results are shown in Figure 1.

Example 3 The same method as in Example 1 was used except that 9 mmol of 2-hydroxyethyl methacrylate was used instead of acrylamide, and 0.1 g of 2-hydroxyethyl methacrylate-based heparin-containing hydrogel particles were synthesized.
Further, 0.1 g of this 2-hydroxyethyl methacrylate-based hydrogel was dispersed in polyvinyl chloride, the solvent was evaporated, a composite film was prepared, and the sustained release amount of heparin was calculated after 24 hours using the same device. The results are summarized in Table 1.

Example 4 Acrylic acid-based heparin-containing hydrogel fine particles were synthesized in the same manner as in Example 1 except that 9 mmol of acrylic acid was used instead of acrylamide. Next, after dispersing 0.1 g of the above fine particles in a 10% by weight benzene solution of polymethyl methacrylate, the solvent was evaporated to prepare a polymethyl methacrylate composite film.
In the same manner as above, sustained release heparin after 24 hours was determined. The results are summarized in Table 1.

Example 5 In the same manner as in Example 1, except that 5 mmol of N-vinylpyro+Jl'non was used instead of acrylamide,
N-vinylpyrrolidone-based heparin-containing hydrogel particles were synthesized. Next, 0.1 g of fine particles were dispersed in a 15% by weight polystyrene solution in benzene, and the solvent was evaporated to produce a polystyrene film. The following steps were carried out in the same manner as in Example 3. The results are summarized in Table 1.

Example 6 Polyvinyl alcohol 0.4 instead of acrylamide
A polyvinyl alcohol-based hydrogel was synthesized in the same manner as in Example 1, except that 0.0 g of polyvinyl alcohol was used. After dispersing 0.1 g of this hydrogel in a 20% by weight solution of poly-4-methylpentene in cyclohexanone, the solvent was removed. A film of poly4-methylpentene was made by evaporation, and the sustained release of heparin was measured. The results are summarized in Table 1.

[Brief explanation of the drawing]

FIG. 1 is a diagram showing a device for removing heparin from the composite materials obtained in Examples 1 and 2. This shows the sustained release behavior of heparin from 15 mg of film (in distilled water at 37°C).
It is a figure showing the result of examination about. Figure 1 Time (No. B)

Claims (1)

[Claims] (1) An antithrombotic composite material made of a polymer material in which a hydrogel containing one or more selected from the group consisting of heparin and its salts is dispersed.