JPH01280466A - Antithrombic composite material - Google Patents

Abstract

PURPOSE:To obtain a prostacyclin deposited hydrogel-contg. high polymer so that an antithrombic composite material can be obtd. by constituting the material of the high-polymer material dispersed with the hydrogel contg. the prostacyclin. CONSTITUTION:The production of the hydrogel is executed by a method of adding a water soluble monomer and water soluble functional monomer to an aq. soln. contg., for example, a redox polymn. initiator, etc., and the prostacyclin and effecting radical polymn. under ice cooling to synthesize the hydrogel. The fine particles of the synthesized dry hydrogel contg. the prostacyclin are dispersed in the high-polymer material such as polyvinyl chloride, segmented polyurethane or polyurethane/polydimethyl siloxane copolymer having the properties as the medical material by a mechanical working method such as kneading or the above-mentioned material is dissolved in a suitable org. solvent to prepare a high-polymer soln. of a high concn. The synthesized hydrogel pulverized to fine particles is dispersed therein and is then subjected to solvent removal to immobilize the prostacyclin. The antithrombic composite material is thus obtd.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to an antithrombotic medical polymer material, and more specifically, it relates to an antithrombotic medical polymer material, and more specifically, a polymeric material that freely releases prostacyclin (PGId), which has platelet aggregation inhibiting activity. The present invention relates to an antithrombotic composite material that can be controlled and, if necessary, released over a long period of time.

(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. Many polymeric materials 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.

l) Weakens the 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 poor processability and bendability. Although it is highly potent, its antithrombotic properties are not perfect. Also, fluorosilicone rubber is not very effective as an antithrombotic agent, and Teflon is more suitable for the pseudointimal method than anticoagulant, but when used as an intimal method, it prevents thrombus formation and quickly forms the intima. There remain concerns about bringing the situation to the next level. 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 flexible 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 high water content have excellent blood compatibility, but blood compatibility is likely to be affected by water content, gel mesh size, etc., and synthesis conditions and reproducibility may be affected. There is a 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) Ex-Van Def Teflon (expa) is added to 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 prostacyclin and can perform sustained release over a long period of time if necessary.

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

The present invention will be explained in more detail below.

Commercially available prostacyclin can be used in the present invention.

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
-dibutyl (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, ri-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 prostacyclin may be deactivated, so it is preferable to perform radical polymerization at a low temperature, and it is particularly preferable to synthesize drogel by redox polymerization method. It is desirable to do so. As a redox initiator, for example, potassium persulfate, potassium persulfate-Na
H3Os, H=O, -pe! +, H2O2-thioxalic acid, MnO,-oxalic acid, NaCl0s NaH
5O=, ammonium persulfate-N, N, N', N'-tetramethylenediamine, and the like.

Examples of the polymer material for dispersing the hydrogel used in the present invention include hydrophobic substances, such as polyvinyl chloride, polystyrene, polyethylene, polypropylene,
Various copolymers and synthetic or Examples include natural rubbers. Further, as polymeric materials used in the present invention, there are substances having a hydrophilic/hydrophobic layer separation structure, such as polyether, polyacrylamide, hydroxyethyl (meth)acrylate, poly-N-methyl-2- pyrrolidone, poly-
Hydrophilic polymers such as N-vinylpyridine and their macromonomers, and hydrophobic portions such as polyolefins,
and various copolymerizable polymers and their macromers, as well as polyamides, polyimides, polyethers, polyesters,
Examples include condensing polymers such as polysulfone, macromers thereof, and synthetic or natural rubbers.

The method for producing a prostacyclin-containing hydrogel of the present invention includes, for example, adding a water-soluble monomer and a water-soluble polyfunctional monomer to an aqueous solution containing prostacyclin and the redox polymerization initiator, and then under water cooling to form radicals. It is desirable to perform polymerization and 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
If it is less than 30% by weight, the amount of prostacyclin is too small and antithrombotic properties cannot be obtained, and it is not only technically difficult to contain prostacyclin in an amount exceeding 30% by weight, but also the amount of sustained release of prostacyclin is large. I don't like it because it's too much.

After freeze-drying the prostacyclin-containing hydrogel obtained in this way, dry fine particles can be obtained by a method such as mechanically pulverizing at a low temperature, or water-soluble monomers can be added to the aforementioned redox polymerization initiator and prostacyclin-containing aqueous solution. and water-soluble polyfunctional monomer processing, and benzene,
A water-insoluble organic solvent such as toluene, hexane, or petroleum ether and a surfactant such as Aracel C are added, treated with ultrasound, etc. to create a reversed phase suspension system, and this is radically polymerized under water cooling. There is a method of synthesizing microparticulate prostacyclin-containing hydrogel, followed by freeze-drying to obtain dry microparticles.

Dry prostacytalin-containing hydrogel microparticles synthesized by these methods can be used as polymeric materials with properties as medical materials such as polyvinyl chloride, segmented polyurethane (polyether type polyurethane), and polyurethane-polydimethylsiloxane copolymers. After dispersing by mechanical processing methods such as kneading, or dissolving the above materials in a suitable organic solvent to obtain a highly concentrated polymer solution, and dispersing the micronized hydrogel synthesized by the above method, Solvent removal is performed to immobilize prostacyclin,
It can be an antithrombotic composite material.

In addition, common polymer materials that have traditionally been considered unsuitable as antithrombotic materials, such as polystyrene, polyacrylonitrile, poly(meth)acrylates, polyvinyl esters, styrene-acrylonitrile copolymers, and styrene-butadiene copolymers. polymers such as styrene-(meth)acrylate copolymer, styrene-acrylonitrile-butadiene copolymer, polyolefins such as polyethylene, polypropylene, and polybutene, polytetrafluoroethylene, and other polycarbonates, polyamides, or polyimides. For polysulfones, polysulfones, etc., dry microparticles of the prostacyclin-supported hydrogel described above can be dispersed by kneading, or the above polymer can be dissolved in a suitable organic solvent to form a highly concentrated polymer, and the microparticles can be dispersed in this. After desolvation,
A prostacyclin-loaded hydrogel-containing polymer is obtained and can be made into an antithrombotic composite material.

(Effects of the Invention) The antithrombotic composite material of the present invention is produced by electrostatically adsorbing and immobilizing prostacyclin, which is a substance excellent in expressing antithrombotic properties, to various types of hydrogels. By synthesizing microparticles of cyclin-supported hydrogel and dispersing these microparticles in various polymeric materials by kneading or using an organic solvent, it has become possible to obtain a prostacyclin-containing polymeric composite material.

Furthermore, it is 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 contained, and the amount of prostacyclin-loaded hydrogel microparticles to be dispersed. Conditions can be selected depending on the purpose.

In addition, anti-thrombotic therapy has been applied to various polymeric materials that have not been used due to lack of biocompatibility despite their excellent mechanical strength, physical and chemical stability, and processability. 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 A 1% Aracel C-benzene solution of 50% was placed in a 1100 m glass ampoule and heated at 10 to 15°C for 30 minutes.
17 containing 5 mmol of N,N-dimethylacrylamide, 5 mmol of N-methyldiacrylamide, and 4.5 g/l of prostacyclin.
Mix 15 molar phosphate buffer (pH 7.0) 5 ag and 1 mol% ammonium persulfate, and add 1 mol% under water cooling.
After quickly adding N, N, N', N'-tetramethylene diamine, the mixture was immediately poured into the above benzene and subjected to ultrasonic irradiation for 2 minutes. Polymerization was carried out by stirring for 30 minutes under a nitrogen stream while gradually returning the temperature to room temperature.
The mixture was allowed to stand for a minute, and 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. It was uniformly dispersed in 9.00 g of a polyvinyl chloride-tetrahydrofuran solution, and the solvent was evaporated to prepare a polyvinyl chloride film containing prostacyclin-supported hydrogel. Next, make an acrylamide/polyvinyl chloride-tetrahydrofuran solution, apply this solution uniformly to the inner surface of a glass tube for platelet aggregation measurement (inner diameter 5.5 mm, length 491 mm), and leave at room temperature for 30 minutes, then reduce the pressure. A sample tube was obtained by drying the tube under vacuum for 12 hours.

Next, 9:1 of fresh human blood and Chitrate®
The mixed solution was centrifuged (800 rpm, 10 minutes) and platelet rich hyperemia +31
When collagen was added to this PRP (white cloudy), platelets immediately aggregated, the turbidity decreased, and the transmittance increased, which was measured over time using an absorbance meter. . That is, put P P P 200 #7 into the obtained sample tube, and after 1 minute, collagen (2 g/mff1) 5 μ! Add
The transmittance at this time was measured, and the blood Fi and aggregation inhibition ability were determined according to the following formula, and the relationship with time was investigated.

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

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

Example 4 Prostacyclin-containing hydrogel microparticles 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 of polystyrene (10% by weight), a tube was prepared in the same manner as in Example 1, and its 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 (10% by weight) of polymethyl methacrylate was used instead of polyvinyl chloride, and its performance was examined.

The results are shown in Table 1.

AAm in the table is N, N-dimethylacrylamide, )I
EMA stands for 2-hydroxyethyl methacrylate, AA stands for acrylic acid, PvC stands for polyvinyl chloride, PsL stands for polystyrene, and PMMA stands for polymethyl methacrylate.

From the above results, it can be seen that the hydrogel containing prostacyclin releases prostacyclin in a sustained manner for 107 hours or more and maintains the platelet aggregation inhibiting effect.

Claims (1)

[Claims] An antithrombotic composite material made of a polymeric material in which a hydrogel containing prostacyclin is dispersed.