JPH0333340B2 - - Google Patents

Description

Detailed Description of the Invention <Field of Industrial Application> The present invention relates to an antithrombotic medical polymer material, and more specifically, the release time of heparin, a blood coagulation inhibitor, can be freely controlled. The present invention relates to an antithrombotic material that can be released in a sustained manner over a long period of time if necessary. <Conventional technology and problems> Traditionally, medical polymer materials include pharmaceuticals,
Materials for medical devices, sanitary materials, dental materials, and artificial organs have been widely applied in the medical field, and many polymer materials have been used. Application to artificial organs will become more important in the future. Artificial organs are extremely important in the sense that they can be used to sustain life by supporting organs that have deteriorated or stopped functioning due to disease or trauma, or as substitute organs, and the demand for them will continue to increase. It seems that it will go well. Furthermore, conventional artificial organs, which dialyze waste products and poisons from the blood outside the body, have various deficiencies, so in the future, we will need to improve their functionality, make them smaller and lighter, and make them more portable. It is necessary to develop and rationalize the process in vivo, and the same is said to be true for other artificial organs. For example, when used in things like artificial blood vessels, 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 materials). ) is very important. Therefore, antithrombotic properties have been considered the most important method 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) Use substances that inhibit blood clot formation. (3) Use the living organism itself. etc. are listed. For (1), for example, there are polymers (silicone rubber, fluorosilicone rubber, and Teflon) that have low surface energy and inert surfaces, but although silicone rubber has good processability and flexibility, it does not have perfect antithrombotic properties. Also, fluorosilicone rubber does not have much antithrombotic effect. Although Teflon is more suitable for the pseudointimal method than its anticoagulant properties, there remain concerns about its ability to prevent thrombus formation and quickly lead to intimal formation when used as an intimal method.
Next, since a negative ζ potential is observed on the surface of blood vessels that are in contact with blood, for example, activated carbon may be mixed into polyurethane to improve conductivity, allowing a minute current to flow that is equivalent to the physiological conditions of normal blood vessels. Efforts have been made to maintain this condition, but there are drawbacks such as durability of antithrombotic properties and tissue damage. Copolymers having hard crystalline segments and soft flexible segments of appropriate length are also desirable for biocompatible materials. Therefore, Cardiothane, a copolymer of polyurethane and polydimethylsiloxane, Biomer, a segmented polyurethane, and 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 lack of close contact with 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 the water content and the size of the gel network, and the synthesis conditions There are problems with reproducibility. In (2), heparin, a substance that inhibits blood coagulation, is immobilized on the polymer surface through covalent bonds. However, heparin is not soluble in many organic solvents, so there are restrictions on pseudo-reaction conditions, the hydroxyl groups of heparin are multivalent and the pseudo-reaction is complicated, the amount of bound heparin is small, and the conformation of bound heparin is limited. Disadvantages include the fact that it is easily deactivated due to changes in its composition. In (3), an artificial material called expanded teflon (EPTFE) is implanted into the body, and fibrin is immediately deposited on the surface, which is then covered with fibroblasts and endothelial cells. Disadvantages include detachment of endothelial tissue from the surface and delayed organization. <Objective of the Invention> An object of the present invention is to provide an antithrombotic material that can freely control the release time of heparin and allow sustained release over a long period of time if necessary. <Means for solving the problem> According to the present invention, there is provided an antithrombotic material comprising a hydrogel obtained by polymerizing an aqueous solution containing a water-soluble monomer, a water-soluble crosslinking agent, and heparin and/or its salt with a redox developer. is provided. 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. As the water-soluble monomer used in the present invention, for example, a monomer having a hydrophilic functional organ, a monomer having an amide group, a monomer having a hydroxyl group, or a monomer having a carboxyl group can be preferably mentioned, and specifically, for example, N,N-dimethyl(meth)acrylamide (meth)acrylic refers to methacrylic and acrylic), 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-methyl (meth)acrylamide, N-ethyl (meth)acrylamide Acrylamide, N-propyl (meth)acrylamide, (meth)acryloylmorpholine, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, (meth)
Preferred examples include acrylic acid and N-vinylpyrrolidone, which can be used alone or as a mixture. In this case, a cationic monomer such as dimethylaminopropylacrylamide is particularly preferably used because it can act with anionic heparin to firmly retain heparin in the hydrogel. The water-soluble crosslinking agent used in the present invention is not particularly limited as long as it is a crosslinking monomer and is water-soluble, but preferably N,N'-methylene-bis(meth)acrylamide, polyethylene Glycol di(meth)acrylate (degree of polymerization =
6 to 30) and the like can be preferably mentioned. Further, in the present invention, the mixing ratio of the water-soluble monomer and the water-soluble crosslinking agent is 1000:1 to 1000:1 in molar ratio.
A range of 1000:20 is preferable. If the proportion of the water-soluble crosslinking agent is less than 1, a hydrogel with sufficient strength cannot be obtained, and if it exceeds 20, heparin will not be sufficiently released from the hydrogel, which is not preferable. In the hydrogel synthesis method of the present invention, the polymerization temperature is high in the usual radical polymerization method,
Since heparin may be deactivated, a redox initiator is used to synthesize the hydrogel. _Examples of the redox initiator include potassium persulfate, potassium persulfate- _NaHSO3 , _H2O2-
Fe ²⁺ , H ₂ O ₂ -thioxalic acid, KMnO ₄ -oxalic acid, NaClO ₃ -NaHSO ₃ , ammonium persulfate -
Preferred examples include N,N',N'-tetramethylenediamine. The antithrombotic material of the present invention can be easily prepared by, for example, mixing the redox polymerization initiator and a monomer raw material containing heparin and/or its salt, and performing redox polymerization under ice cooling. Obtainable. The amount of heparin impregnated into the hydrogel is preferably 0.1 to 30% by weight, particularly 1 to 10% by weight; less than 0.1% by weight is too little heparin to provide antithrombotic properties, and an amount exceeding 30% by weight Impregnation with heparin is technically difficult and is therefore not preferred. <Effects of the Invention> The antithrombotic material of the present invention electrostatically supports heparin, a substance with excellent antithrombotic properties, in a hydrogel, which is a material with excellent antithrombotic properties. Allows for sustained release and controlled release. That is, the amount of heparin released can be arbitrarily controlled by selecting the type of hydrogel, especially by adjusting the amount of the monomer having an amide group. Therefore, it is possible to solve the problem that it has been difficult to sustainably release heparin over a long period of time, and to provide a hydrogel that has excellent antithrombotic properties, which is the performance required for biomaterials. . <Examples> The present invention will be explained in more detail by the following examples, but the present invention is not limited thereto. Example 1 N,N-dimethylacrylamide (hereinafter referred to as
AAm) 9.95 mmol, N,N'-methylenebisacrylamide (hereinafter bisA) 0.05 m
mol, 4.5 g/heparin Na salt (hereinafter referred to as HpNa
) (manufactured by Kodak) in 5 ml of 1/15M phosphate buffer. Redox initiator (ammonium persulfate (hereinafter abbreviated as APS)-N,N,N',N'-tetramethylenediamine (hereinafter abbreviated as TEMED))
Put 1 mol% into a cylindrical sample tube with a capacity of 50 ml,
The interior of the reactor was replaced with nitrogen, and polymerization was carried out for 24 hours under ice cooling.
Add 40ml of saline to the gel mass in the sample bottle above.
In addition, approximately 20μ of the supernatant liquid of the sample was collected on the line of the flow injection device, and this and 0.16%
About 30μ of a 0.64M NaCl solution containing cetylpyridinium chloride (hereinafter abbreviated as CPC) was mixed, and the turbidity of the resulting heparin-CPC complex was measured using an absorbance meter equipped with a flow cell. Convert to heparin concentration,
The amount of heparin released was determined. The results are shown in FIG. 1 and Table 1. Example 2 By the same method as Example 1, AAm19.9m
mol, bisA 0.2 mmol, 5 ml of 1/15M phosphate buffer containing 4.5 g/HpNa, APS-
1 mol% of TEMED was placed in a 50 ml cylindrical sample tube, the inside was replaced with nitrogen, and polymerization was performed under ice cooling for 24 hours. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in FIG. 1 and Table 1. Example 3 By the same method as Example 1, AAm9.75m
mol, bisA 0.05 mmol, N,N-dimethylaminopropylacrylamide (hereinafter abbreviated as DMAPAA) 0.2 mmol, 1/ containing 4.5 g/HpNa
15M phosphate buffer 5ml, APS-TEMED 1mol%
was placed in a 50 ml cylindrical sample tube, the inside was replaced with nitrogen, and the mixture was polymerized for 24 hours under ice-cooling. below,
The same procedure as in Example 1 was conducted to determine the amount of heparin released. The results are shown in FIG. 1 and Table 1. Example 4 By the same method as Example 1, AAm9.85m
mol, bisA0.05mmol, DMAPAA0.1mmol, 4.5
1/15M phosphate buffer containing 5 g/g of HpNa
ml, APS-TEMED 1 mol% into a 50 ml cylindrical sample tube, replace the inside with nitrogen, and cool on ice.
Polymerization was allowed for 24 hours. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in FIG. 1 and Table 1. Example 5 By the same method as in Example 1, AAm9.9m
mol, bisA0.05mmol, DMAPAA0.05mmol,
5 ml of 1/15M phosphate buffer containing 4.5 g/HpNa and 1 mol % of APS-TEMED were placed in a 50 ml cylindrical sample tube, the inside of the tube was replaced with nitrogen, and the tube was polymerized for 24 hours under ice cooling. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in FIG. 1 and Table 1. Example 6 Using the same method as in Example 1, but using 9.95 mmol of 2-hydroxyethyl acrylate (hereinafter referred to as 2-HEA) and 0.05 m of bisA instead of AAm.
5 ml of 1/15M phosphate buffer containing 4.5 g/mol of HpNa and 1 mol % of APS-TEMED were placed in a 50 ml cylindrical sample tube, the inside of the tube was replaced with nitrogen, and the tube was polymerized for 24 hours under ice cooling. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in Table 1. Example 7 Using the same method as in Example 1, except that instead of AAm, 9.75 mmol of 2-HEA, 0.05 mmol of bisA,
5 ml of 1/15M phosphate buffer containing 0.2 mmol of DMAPAA, 4.5 g of HpNa, APS-
1 mol% of TEMED was placed in a 50 ml cylindrical sample tube, the inside was replaced with nitrogen, and polymerization was performed under ice cooling for 24 hours. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in Table 1. Example 8 Using the same method as in Example 1, except that 9.95 m of acrylic acid (hereinafter abbreviated as AA) was used instead of AAm.
mol, bisA 0.05 mmol, 5 ml of 1/15 M phosphate buffer containing 4.5 g/HpNa, APS-
1 mol% of TEMED was placed in a 50 ml cylindrical sample tube, the inside was replaced with nitrogen, and polymerization was performed under ice cooling for 24 hours. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in Table 1. Example 9 By the same method as in Example 1, except that 9.75 mmol of AA, 0.05 mmol of bisA, and 0.05 mmol of bisA were used instead of AAm.
5 ml of 1/15M phosphoric acid solution containing 0.2 mmol of DMAPAA, 4.5 g/HpNa, 1 mol of APS-TEMED
% was put into a 50 ml cylindrical sample tube, the inside was replaced with nitrogen, and polymerization was carried out under ice cooling for 24 hours. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in Table 1. Example 10 Using the same method as in Example 1, except that 9.95 mmol of N-vinylpyrrolidone (hereinafter abbreviated as VP), 0.05 mmol of bisA, and 4.5 g/m of bisA were used instead of AAm.
5 ml of 1/15M phosphate buffer containing HpNa, APS-
1 mol% of TEMED was placed in a 50 ml cylindrical sample tube, the inside was replaced with nitrogen, and polymerization was performed under ice cooling for 24 hours. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in Table 1. Example 11 Using the same method as Example 1, except that instead of AAm, VP9.75mmol, bisA0.05mmol,
5 ml of 1/15M phosphate buffer containing 0.2 mmol of DMAPAA, 4.5 g/HpNa, APS-
1 mol% of TEMED was placed in a 50 ml cylindrical sample tube, the inside was replaced with nitrogen, and the tube was polymerized for 24 hours under ice cooling. Thereafter, the same procedure as in Example 1 was carried out to determine the amount of heparin released. The results are shown in Table 1. 【table】

Claims (1)

[Scope of Claims] 1. An antithrombotic material comprising a hydrogel obtained by polymerizing an aqueous solution containing a water-soluble monomer, a water-soluble crosslinking agent, and heparin and/or its salt using a redox initiator. 2. The antithrombotic material according to claim 1, wherein the water-soluble monomer is a monomer having a hydrophilic functional group. 3. The antithrombotic material according to claim 1, wherein the water-soluble monomer is a monomer having an amide group. 4. The antithrombotic material according to claim 1, wherein the water-soluble monomer is a monomer having a hydroxyl group. 5. The antithrombotic material according to claim 1, wherein the water-soluble monomer is a monomer having a carboxyl group. 6. The antithrombotic material according to any one of claims 1 to 5, wherein the content of heparin in the antithrombotic material is 0.1 to 30% by weight.