JP2577245B2 - Antithrombotic composite material - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an antithrombotic medical polymer material,
More specifically, the present invention relates to an antithrombotic composite material that can freely control the release of prostacyclin (PGI ₂ ) having the ability to inhibit platelet aggregation, and can release the prostacyclin as needed over a long period of time.

(Prior art) Conventionally, medical polymer materials include pharmaceuticals, medical device materials, sanitary materials, dental materials, and artificial organs.
In the field of medicine or medical treatment, it is widely applied, and for this purpose, many polymer materials have been used. Of these, medicines and their application to artificial organs are areas that will become even more important in the future.

Artificial organs are extremely important in terms of maintaining their life by assisting organs whose function has deteriorated due to disease or trauma, or as substitutes for organs that have stopped, or as alternative organs, and their importance will increase in the future. It seems to go.
Moreover, artificial organs of the type that dialyses waste and toxic substances in the blood in vitro, such as conventional artificial kidneys, are inadequate in various respects, so their functions will be further improved, and their size, weight, and portability will increase. In addition, it is necessary to achieve implantation in a living body, and the same is said for other artificial organs.

For example, when used for an artificial blood vessel or the like, it is necessary not only to adapt to a living body without causing a reaction for a long period of time, but also to use a material that does not coagulate blood or promote thrombus formation (antithrombotic property). Material) is very important.

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

1) Weaker interaction with blood components.

2) Use substances that inhibit thrombus formation.

3) Use the living body itself.

(Problems to be Solved by the Invention) Among them, in 1), for example, there are polymers (silicone rubber, fluorosilicone rubber and Teflon) having a low surface energy and an inert surface. Although it is highly sexual, its antithrombotic properties are not perfect. Fluorosilicone rubber also has no significant antithrombotic effect. Teflon is more suitable for the pseudointimal method than the anticoagulant, but when used as an intima method, there remains anxiety in preventing thrombus formation and promptly bringing it into the intima formation. Next, since a negative ζ potential is observed on the surface of the blood vessel that is in contact with blood, for example, activated carbon is mixed into polyurethane to improve conductivity, and a microcurrent similar to physiological conditions of normal blood vessels flows While some efforts have been made to maintain the condition, there are drawbacks such as sustained antithrombotic properties and tissue damage.

For biocompatibility, a copolymer having a hard crystalline segment of a suitable length and a soft flexible segment is desirable. So, Cardiothane, a copolymer of polyurethane and polydimethylsiloxane
And segmented polyurethane biomers,
Although TM-3 (Toyobo) and polystyrene-polyhydroxyethyl methacrylate block copolymers have been put into practical use, they have disadvantages such as poor organization and peeling without adhering to living tissue.

Further, hydrogels having a three-dimensional network structure with a high moisture content are:
Although it has excellent blood compatibility, blood compatibility is likely to be affected by the water content, the size of the mesh of the gel, and the like, and there are problems in synthesis conditions and reproducibility.

In 2), heparin, which is a substance having a blood coagulation inhibitory action, is fixed to the polymer surface by a covalent bond. However, heparin is insoluble in many organic solvents, so the reaction conditions are limited, the reaction is complex due to the polyvalent hydroxyl group of heparin, the amount of bound heparin is small, and the conformation of the bound heparin is low. There are drawbacks such as easy deactivation due to change.

In 3), expanded Teflon (expand)
ed teflon)
The fibrin is deposited on the surface, and the surface is covered with fibroblasts and endothelial cells. However, there are disadvantages such as detachment of endothelial tissue from the surface and delay of organization.

An object of the present invention is to provide an antithrombotic composite material capable of freely controlling the release time of prostacyclin and capable of sustained release over a long period as needed.

(Means for Solving the Problems) According to the present invention, there is provided an antithrombotic composite material comprising a polymer material in which a hydrogel containing prostacyclin is dispersed.

 Hereinafter, the present invention will be described in more detail.

Commercially available prostacyclin used in the present invention can be used.

As the hydrogel component used in the present invention, for example, a polymer synthesized from a monomer having a hydrophilic functional group, a monomer having an amide group, a monomer having a hydroxyl group or a monomer having a carboxyl group, and other substances are preferably exemplified. it can.

More specifically, as the hydrogel component, for example,
(Meth) acrylamide ((meth) acryl means methacryl and acryl), N, N-dimethyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N, N-dipropyl (meth) acrylamide, N, N-dibutyl (meth) acrylamide, N, N-dimethylaminoethyl (meth) acrylate, N, N-diethylaminoethyl (meth) acrylate, N, N-dipropylaminoethyl (meth) acrylate, N, N-dimethylamino Propyl (meth) acrylamide, N, N-diethylaminopropyl (meth) acrylamide, N, N-dipropylaminopropyl (meth) acrylamide, N-ethyl (meth) acrylamide, N-propyl (meth) acrylamide, (meth) acryloyl Morpholine, 2-hydroxyethyl (meth) acrylate, 2-hydrido Kishipuropiru (meth) acrylate, 3-hydroxypropyl (meth) acrylate, (meth) acrylic acid, p- vinyl benzoate, N- vinylpyrrolidone, p- aminostyrene,
pN-methylaminostyrene, pN, N-dimethylaminostyrene, pN, N-diethylaminomethylstyrene, pN, N-dimethylaminoethylstyrene, pN, N
-Dimethylaminomethylstyrene, pN, N-diethylaminomethylstyrene, pN, N-dimethylaminoethylstyrene, pN, N-dimethylaminopropylstyrene, p-sulfonic styrene, p-methylsulfonic styrene And the like, and a hydrophilic copolymer obtained by radical copolymerization of such a monomer with a crosslinking agent such as bisacrylamide.

Further, there may also be mentioned hydrogels such as polyvinyl alcohol and naturally occurring substances such as starch, konjac flour and carrageenan.

Examples of a general method for synthesizing a hydrogel include radical polymerization, cationic polymerization, anionic polymerization, and redox polymerization. However, since the polymerization temperature is high in normal radical polymerization and prostacyclin may be deactivated, it is preferable to perform radical polymerization at a low temperature, and it is particularly preferable to synthesize a hydrogel by a redox polymerization method. . As the redox initiator, for example, potassium persulfate, potassium persulfate-Na
_{HSO 3, H 2 O 2 -Fe} 2+, H 2 O 2 - Chiookizaru acid, KMnO ₄ - oxalic acid, NaClO ₃ -NaHSO _3, ammonium persulfate -N, N,
N ', N'-tetramethylenediamine and the like can be mentioned.

As the polymer material for dispersing the hydrogel used in the present invention, there are hydrophobic substances, for example, polyvinyl chloride, polystyrene, polyethylene, polypropylene, polycarbonate, polysiloxane, polyurethane, polyacrylonitrile, polyfluorocarbon, polyester, poly Examples include various copolymers such as ether, poly (meth) acrylate, styrene-acrylonitrile copolymer, styrene-methyl methacrylate copolymer, and synthetic or natural rubbers. Further, as the polymer material used in the present invention, there is a substance having a hydrophilic / hydrophobic layer separation structure. For example, as the hydrophilic portion, polyether, polyacrylamide, hydroxyethyl (meth) acrylate, poly-N-methyl-2- Pyrrolidone, hydrophilic polymers such as poly-N-vinylpyridine and macromonomers thereof, and polyolefins as hydrophobic portions, and various copolymerizable polymers and macromers thereof, and polyamides, polyimides, polyethers, polyesters, Examples thereof include condensable polymers such as polysulfone, macromers thereof, and synthetic or natural rubbers.

The method for producing a hydrogel containing prostacyclin of the present invention comprises, for example, adding a water-soluble monomer and a water-soluble polyfunctional monomer to an aqueous solution containing the redox polymerization initiator and the like, and prostacyclin, and cooling the mixture under ice cooling. It is desirable to perform radical polymerization to synthesize a hydrogel. The content of prostacyclin in the hydrogel is 0.1
-30% by weight, especially 1-10% by weight, is preferred. 0.1% by weight
If it is less than 10%, the amount of prostacyclin is too small to obtain antithrombotic properties, and it is technically difficult to contain prostacyclin in an amount of more than 30% by weight,
It is not preferable because the sustained release amount of prostacyclin becomes too large.

The prostacyclin-containing hydrogel thus obtained is freeze-dried, and then dried fine particles are obtained by a method such as mechanical pulverization at a low temperature, or a water-soluble monomer is added to the redox polymerization initiator and the aqueous solution containing prostacyclin. And a water-soluble polyfunctional monomer, and further, a water-insoluble organic solvent such as benzene, toluene, hexane, and petroleum ether, and a surfactant such as Aracel C,
There is a method of producing a reversed-phase suspension system by performing treatments such as ultrasonic waves, radical-polymerizing the suspension under ice cooling, synthesizing a fine hydrogel containing prostacyclin, and then freeze-drying to obtain dried fine particles. .

The prostacyclin-containing dried hydrogel fine particles synthesized by these methods are converted into polymer materials having characteristics as medical materials such as polyvinyl chloride, segmented polyurethane (polyether type polyurethane), and polyurethane-polydimethylsiloxane copolymer. Either disperse by a mechanical processing method such as kneading, or dissolve the above material in a suitable organic solvent to form a high-concentration polymer solution, and disperse the hydrogel microparticles synthesized by the method described above, and then remove Prostacyclin can be immobilized in a solvent to obtain an antithrombotic composite material.

In addition, general polymer materials which have been conventionally unsuitable as antithrombotic materials, for example, polystyrene, polyacrylonitrile, poly (meth) acrylates, polyvinyl esters, styrene-acrylonitrile copolymer, styrene-butadiene copolymer Polymers, such as styrene- (meth) acrylate copolymer, styrene-acrylonitrile-butadiene copolymer, or polyolefins such as polyethylene, polypropylene, polybutene, polytetrafluoroethylene, and other polycarbonates, polyamides, or polyimides , Polysulfones, etc., also disperse the dried microparticles of the above-mentioned prostacyclin-supported hydrogel by kneading or the like, or use a high-concentration polymer obtained by dissolving the polymer in an appropriate organic solvent, After dispersing, performing desolvation,
A prostacyclin-supported hydrogel-containing polymer is obtained, which can be used as an antithrombotic composite material.

(Effect of the Invention) The antithrombotic composite material of the present invention immobilizes prostacyclin, which is a substance excellent in exhibiting antithrombotic properties, by, for example, electrostatically adsorbing it to various hydrogels. Fine particles of a cyclin-supporting hydrogel were synthesized, and the fine particles were kneaded with various polymer materials or dispersed using an organic solvent or the like, so that a prostacyclin-containing polymer composite material could be obtained.

In addition, it is also possible to freely control the sustained release of prostacyclin from the material over a long period of time by selecting the hydrogel, the amount of prostacyclin to be contained, and the amount of dispersion of the prostacyclin-loaded hydrogel fine particles to be dispersed. Conditions can be selected according to the purpose. In addition, despite its excellent mechanical strength, physical and chemical stability, workability, etc., antithrombotic treatment of various polymer materials that have never been used because of lack of biocompatibility It has been made possible to use the composition as an antithrombotic composite material having excellent physical properties.

(Examples) Hereinafter, the present invention will be specifically described based on examples.
The present invention is not limited to these.

Example 1 50 ml of a 1% alacel C-benzene solution was placed in a glass ampoule having a content of 100 ml and nitrogen replacement was continued at 10 to 15 ° C. for 30 minutes, while N, N-dimethylacrylamide 5 mmol, N-methyl Diacrylamide 5 mmol, 4.5 g / l
1 / 15M phosphate buffer containing prostacyclin (pH
7.0) 5 ml and 1 mol% of ammonium persulfate were mixed, and 1 mol% of N, N, N ', N'-tetramethylenediamine was quickly added under ice-cooling. Ultrasonic irradiation for a minute. While the temperature was gradually returned to room temperature, polymerization was carried out with stirring for 30 minutes under a nitrogen stream, and the mixture was allowed to stand for about 10 minutes, and benzene in the supernatant was sufficiently replaced with purified benzene.

Next, the obtained acrylamide beads / benzene dispersion solution was frozen in liquid nitrogen and dried under reduced pressure to obtain a fine-particle acrylamide-based hydrogel. Next, 0.10 acrylamide-based hydrogel fine particles were uniformly dispersed in 9.00 g of a 10% by weight polyvinyl chloride-tetrahydrofuran solution, and the solvent was evaporated to prepare a polyvinyl chloride film containing a hydrogel carrying prostacyclin. Next, an acrylamide / polyvinyl chloride-tetrahydrofuran solution was prepared, and this solution was uniformly applied to the inner surface of a glass tube (inner diameter 5.5 mm, length 49 mm) for measuring platelet aggregation,
The sample tube was dried at room temperature for 30 minutes and further under reduced pressure for 12 hours to obtain a sample tube.

Then 9: 1 of fresh human blood and Titrato®
The mixture is centrifuged (800 rpm, 10 minutes) to produce platelet rich plasma (PRP), and when collagen is added to this PRP (white turbidity), platelets immediately aggregate and decrease turbidity The phenomenon in which the transmittance increases was measured over time with an absorbance meter. That is, 200 μl of PRP was put into the obtained sample tube, and 1 minute later, 5 μl of collagen (2 μg / ml) was added, and the transmittance at this time was measured. Was investigated.

A: transmittance of blank (T%) B: transmittance of sample (T%) The results are shown in Table 1.

Example 2 A prostacyclin-containing composite material was synthesized in the same manner as in Example 1 except that the content of prostacyclin was different, and the ability to inhibit platelet aggregation was measured. The results are shown in Table 1.

Example 3 A prostacyclin-containing composite material was synthesized in the same manner as in Example 1 except that 2-hydroxyethyl methacrylate was used instead of acrylamide, and the ability to inhibit platelet aggregation was measured. The results are shown in Table 1.

Example 4 Prostacyclin-containing hydrogel fine particles were synthesized in the same manner as in Example 1 except that acrylic acid was used instead of acrylamide. Next, the hydrogel was dispersed in a benzene solution (10% by weight) of polystyrene, and a tube was prepared in the same manner as in Example 1, and the performance was examined. The results are shown in Table 1.

Example 5 A sample tube was prepared in the same manner as in Example 1 except that a benzene solution of polymethyl methacrylate (10% by weight) was used instead of polyvinyl chloride, and the performance was examined.
The results are shown in Table 1.

AAm in the table is N, N-dimethylacrylamide, HEMA is 2
-Hydroxyethyl methacrylate, AA is acrylic acid,
PVC indicates polyvinyl chloride, PSt indicates polystyrene, and PMMA indicates polymethyl methacrylate.

From the above results, it can be understood that the hydrogel containing prostacyclin releases prostacyclin over a period of 107 hours or more, and the platelet aggregation inhibitory effect is maintained.

Continued on the front page (72) Inventor Seiro Maruyama 6-45-10 Sakuragaoka, Kagoshima City, Kagoshima Prefecture (72) Inventor Tokuyuki Miyauchi 9-32 Shinshoin, Kagoshima City, Kagoshima Prefecture (72) Inventor Eiji Yashima Kagoshima City, Kagoshima Prefecture 2-11-20 Kamoike (72) Inventor Tsuyoshi Miyazaki 4610 Kamifukumotocho, Kagoshima City, Kagoshima Prefecture (72) Inventor Takashige Murata 2-30-13 Higashi, Tsukuba City, Ibaraki Prefecture (56) References JP-A Sho 54- 135494 (JP, A)

Claims (1)

(57) [Claims] 1. An antithrombotic composite material comprising a polymer material in which a hydrogel containing prostacyclin is dispersed.