JPH0624593B2 - Anticoagulant material - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention can maintain excellent anticoagulant property (antithrombotic property) for a long period of time, and can be used for various medical treatments such as artificial organs and artificial blood vessels. The present invention relates to an anticoagulant material applicable as a constituent material of a tool.

[Prior Art] When blood comes into contact with a foreign substance, it has the property of coagulating due to the action of various components in the blood. Therefore, a constituent material of a medical device used in a site in contact with blood such as an artificial heart, an artificial heart valve, an artificial blood vessel, a blood vessel catheter, a cannula, a heart-lung machine, a blood vessel bypass tube, an aortic balloon pumping, a blood transfusion device and an extracorporeal circulation circuit. Is required to have high anticoagulant properties. However, many of the constituent materials of conventional medical devices inevitably cause blood coagulation when used for a long period of time,
It is not sufficient in terms of persistence of anticoagulability.
Further, when the above medical device is applied to a patient, it is usually performed in combination with an anticoagulant such as heparin. However, for example, when heparin is systemically administered, there is a problem that the risk of multiple hemorrhagic foci increases.

Therefore, many methods of introducing heparin into an anticoagulant material have been attempted as methods for solving such problems. The method of introducing heparin into such a material includes
There are the following three methods.

First, first, a method of introducing heparin into a material by physically mixing it; second, a method of covalently bonding heparin and a constituent component of the material; and third, an anionic residue of heparin. A method of ionic bonding with a cationic residue of a constituent component of the material; and a method of using these methods together.

However, such a method has various problems. In the first method, heparin is soluble in water but insoluble in most organic solvents, so that the specific method and usable materials are greatly limited. In addition, since heparin introduced into the material is water-soluble, when it comes into contact with blood during practical use, it will flow out of the material in a very short time, and as a result, the anticoagulant property cannot be maintained.

In the second method, since the covalent bond is carried out by utilizing the reactive residue of heparin, the material synthesis is complicated,
Also, there is a problem that the anticoagulant property of heparin itself is lowered.

As a specific example of the third method, science, vol. 142,
On page 1297 (1963), a method of treating the surface of the material with graphite-benzalkonium chloride-heparin is disclosed, and Japanese Patent Publication No. 55-15222 discloses isotactic polymethyl methacrylate and syndioctatic poly. A polymer material obtained by confining a heparin-cationic surfactant, a radical-polymerizable vinyl monomer and a polymerization initiator in a stereocomplex with methyl methacrylate and polymerizing the monomer is disclosed. However, in both cases, since heparin forms a complex with a low molecular weight ammonium salt such as benzalkonium chloride by an ionic bond, heparin is eluted into the blood in a short period of time, and not only heparin Since the low molecular weight ammonium salt also elutes at the same time, there is a serious problem that a hemolytic phenomenon occurs.

In addition, a method has been proposed in which a polymer compound having a cationic residue introduced therein is brought into contact with an aqueous solution of heparin to introduce heparin into the polymer compound through an ionic bond. For example, Japanese Examined Patent Publication Nos. 52-36779 and 54.
No. 17797, No. 54-18317, No. 5
JP-A-5-38963 and JP-A-55-38964 disclose a method of introducing heparin after introducing a cationic residue into a copolymer such as vinyl chloride-acrylonitrile by graft polymerization, and Kosho 54-1
No. 8518, No. 58-34494, No. 59-
50335, 59-53058, and 60.
No. 16260 and No. 60-23626 disclose a method of introducing heparin after introducing a cationic residue by copolymerization, addition polymerization or polycondensation. However, in any of these methods, the amount of heparin introduced into the polymer compound is such that the amount of the cationic residue present in the compound or the water absorption based on the degree of hydrophilicity of the compound is high. It will vary greatly depending on the chemical and physical properties of the compound and the temperature and time of contact with the aqueous solution of heparin. Therefore, even when introducing a desired amount of heparin, it is difficult to set the optimum conditions, and as a result, the quality of the obtained anticoagulant material cannot be made constant. Further, the material obtained by such a method is superior in anticoagulant property to the material obtained by the above-mentioned first method, but is not yet sufficient, and there is room for further improvement.

[Problems to be Solved by the Invention] In an anticoagulant material containing heparin, which has been conventionally applied as a constituent material of a medical device such as an artificial organ or an artificial blood vessel, it was introduced into the material during its use. There is a problem that heparin gradually elutes in blood and is lost, and as a result, the anticoagulability of the material decreases with the passage of time. Further, there are also problems that the method of introducing heparin is complicated and that an anticoagulant material of constant quality cannot be obtained.

The present invention solves such a problem, and heparin can be introduced into a polymer material as a complex by a simple method. Further, in this anticoagulant material, since heparin is firmly retained. It is an object of the present invention to provide an anticoagulant material capable of maintaining an excellent anticoagulant property for a long period of time.

[Means for Solving the Problems] In the anticoagulant material into which heparin or a salt thereof has been introduced, the present inventors have limited elution of water-soluble heparin or a salt thereof into blood to suppress In order to maintain the coagulability, the present invention is focused on that it can be achieved by holding the introduced heparin or a salt thereof in a poorly water-soluble form to hold the heparin or a salt thereof. It came to completion.

That is, the present invention relates to a polymer obtained from (a) an ionic bond complex synthesized from a basic compound having a polymerizable functional group and heparin or a salt thereof; and (b) a cross-linking agent if necessary. It is related with the anticoagulant material characterized by being comprised.

The polymer constituting the anticoagulant material of the present invention is produced from the component (a) and, if necessary, the component (b).

The ionic bond complex as the component (a) is produced from a basic compound having a polymerizable functional group and heparin or a salt thereof, is sparingly water-soluble, and is soluble in an organic solvent.

The basic compound having a polymerizable functional group used herein has a polymerizable functional group such as a vinyl group, an acryloyl group or a methacryloyl group, and a basic residue such as a tertiary group. A compound having a basic residue such as an amino group, a quaternary ammonium group or a quaternary pyridinium group, which forms a complex which is poorly water-soluble and soluble in an organic solvent by ionic bond with heparin or a salt thereof. It is possible. Examples of such a basic compound include the following formula (I): (In the formula, R ₁ represents a hydrogen atom or a methyl group; R ₂ and R ₃ represent identical there may be different even if an alkyl group having 1 to 3 carbon atoms from each other; R ₄ is 6 carbon atoms 22 represents an alkyl group; X represents a negative atom group; n represents an integer of 1 to 6) or the following formula (II), (The meaning of each symbol in the formula is the same as in formula (I)). In the compounds represented by the formulas (I) and (II), the group R ₄ is a carbon atom because it makes the ionic bond complex sparingly soluble in water and soluble in an organic solvent, and is easy to handle. It is preferably an alkyl group of the number 8 to 18, and the negative atom group of X is preferably a halogen atom.

Specific examples of the compound represented by the above formula (I) include N, N-dimethyl-N-hexylammonioethyl (meth) acrylate bromide N, N-dimethyl-N-octylammonioethyl (meth) acrylate bromide. N, N-Dimethyl-N-decylammonioethyl (meth) acrylate bromide N, N-Dimethyl-N-dodecylammonioethyl (meth) acrylate bromide N, N-dimethyl-N-tetradecylammonioethyl (meth) Acrylate bromide N, N-Dimethyl-N-hexadecylammonioethyl (meth) acrylate bromide N, N-Dimethyl-N-octadecylammonioethyl (meth) acrylate bromide N, N-dimethyl-N-eicosylammonioethyl (Meth) acrylate bromide N, N- Methyl -N- docosyl ammonio ethyl (meth) acrylate bromide and the like. Further, specific examples of the compound represented by the formula (II) include N (N ′, N′-dimethyl-N′-hexylammoniopropyl) (meth) acrylamide bromide N (N ′, N′-dimethyl-N). ′ -Octylammoniopropyl) (meth) acrylamide bromide N (N ′, N′-dimethyl-N′-decylammoniopropyl) (meth) acrylamide bromide N (N ′, N′-dimethyl-N′-dodecylammoni Opropyl) (meth) acrylamide bromide N (N ', N'-dimethyl-N'-tetradecylammoniopropyl) (meth) acrylamide bromide N (N', N'-dimethyl-N'-hexadecylammoniopropyl ) (Meth) acrylamide bromide N (N ', N'-dimethyl-N'-octadecylammoniopropyl) (meth ) Acrylamide bromide N (N ', N'-dimethyl-N'-eicosylammoniopropyl (meth) acrylamide bromide N (N', N'-dimethyl-N'-docosylammoniopropyl) (meth) acrylamide bromide Etc. can be mentioned.

The compound represented by the formula (I) or (II) can be synthesized by the following reaction formula (1) or (2).

Reaction formula (1) Reaction formula (2) Next, the method for synthesizing the basic compound will be described in detail based on the above reaction formulas (1) and (2). First, equimolar amounts of formula (I) 'or formula (II)' and a compound represented by formula (I) "are added to an organic solvent such as dimethylformamide and dissolved. Next, di-tert-butyl. After further adding a polymerization inhibitor such as hydroxytoluene, 60 to 80 ° C
The compound represented by the formula (I) or (II) can be obtained by heating and reacting at the temperature of several hours to several tens of hours.

Specific examples of the compound represented by the formula (I) ′ used in the reaction formula (I) include N, N-dimethylaminomethyl (meth).
Acrylate, N, N-dimethylaminoethyl (meth)
Acrylate, N, N-dimethylaminopropyl (meth) acrylate, N, N-dimethylaminobutyl (meth) acrylate, N, N-dimethylaminohexyl (meth) acrylate, N, N-diethylaminoethyl (meth) acrylate and N , N-dipropylaminoethyl (meth) acrylate and the like.

Specific examples of the compound represented by the formula (I) ″ include hexyl bromide, octyl bromide, decyl bromide, dodecyl bromide, tetradecyl bromide, hexadecyl bromide, octadecyl bromide, eicosyl bromide or docosyl bromide, or their respective compounds. Examples thereof include chloride and iodide.

Specific examples of the compound represented by the formula (II) ′ used in the reaction formula (2) include N (N ′, N′-dimethylaminoethyl) (meth) acrylamide and N (N ′, N′-dimethylaminopropyl). ) (Meth) acrylamide, N
(N ', N-dimethylaminobutyl) (meth) acrylamide, N (N', N'-dimethylaminohexyl)
(Meth) acrylamide, N (N ', N'-diethylaminopropyl) (meth) acrylamide and N (N',
Examples thereof include N'-dipropylaminopropyl) (meth) acrylamide.

The ionic bond complex can be produced by reacting the aqueous solution of the basic compound monomer having a polymerizable functional group with an aqueous solution of heparin or a salt thereof.

Although the salt form of heparin or a salt thereof used here is not particularly limited, heparin sodium is usually used.

The amount of the basic compound and heparin or a salt thereof used in the reaction is, for example, the amount of the compound represented by the formula (I) or (II):
When heparin sodium is used, the amount of the compound represented by the formula (I) or (II) is preferably 1 to 12 mmol, and more preferably 2 to 8 mmol relative to 1 g of heparin sodium.

The reaction conditions are 10 to 40 ° C., preferably 15 to 30 ° C.
At 10 to 300 minutes, preferably 30 to 180 minutes.

Although the ionic bond complex can be obtained in this manner, according to such a method, compared with a conventional heparinization method in which a polymeric material having a cationic group is contacted with an aqueous solution of heparin or a salt thereof, Since the compound having a group has a relatively low molecular weight, the compound and heparin or a salt thereof bind to each other at more bonding points,
When polymerized, heparin or its salt can be retained more firmly. Further, the amount of heparin or a salt thereof contained in such an ionic bond complex is not particularly limited, but in order to maintain a certain level of anticoagulant property, as the sulfur content contained in heparin or a salt thereof,
Heparin or a salt thereof is preferably contained in an amount of 0.5 to 12% by weight, and more preferably heparin or a salt thereof is contained in an amount of 1 to 8% by weight.

The cross-linking agent as the component (b) is not an essential component, but by blending the cross-linking agent, the polymer obtained can have a strong network structure, and as a result, the heparin retention power can be increased.

Examples of the cross-linking agent as the component (b) include divinylbenzene, alkylenebis (meth) acrylamide such as methylenebis (meth) acrylamide and ethylenebis (meth) acrylamide.
One or more selected from alkylene glycol di (meth) acrylates such as acrylamide, ethylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, and diethylene glycol di (meth) acrylate can be used.

The mixing ratio of the component (b) is 0 to 3 with respect to the component (a).
It is 0% by weight, preferably 0.5 to 10% by weight. (b)
If the blending ratio of the components exceeds 30% by weight, the mechanical strength of the anticoagulant material becomes insufficient.

When the anticoagulant material of the present invention is produced from the components (a) and (b), the above-mentioned components (a) and (b) are mixed so as to be uniform, and then polymerized. Can be obtained by The polymerization method is not particularly limited, but a method in which each component is dissolved in an appropriate solvent to carry out the polymerization reaction can be applied.

Examples of the solvent used here include dimethylformamide, dimethylacetamide, dimethylsulfoxide,
One or more selected from tetrahydrofuran, ethyl alcohol, propyl alcohol, butyl alcohol, dioxane, N-methylpyrrolidone and the like can be mentioned.

As the polymerization method, radical polymerization or ionic polymerization can be applied, and among these, radical polymerization is preferred. When radical polymerization is carried out, a polymerization initiator can be used if necessary. Examples of the polymerization initiator include azo compounds such as azobisisobutyronitrile; hydroperoxides such as t-butyl hydroperoxide and cumene hydroperoxide; dialkyl peroxides such as di-t-butyl peroxide and dicumyl peroxide; lauroyl. Examples thereof include organic peroxides such as diacyl peroxide such as peroxide and benzoyl peroxide. The amount of the polymerization initiator added is
About 5 × 10 ^{−4 to} 3 based on the total amount of components (a) and (b)
It is 0% by weight.

The polymerization temperature is room temperature to 100 ° C, preferably 40 to 9
It is 0 ° C. The polymerization time is 1 hour to 5 days,
It is preferably 2 hours to 3 days.

The anticoagulant material of the present invention is an artificial heart, an artificial heart valve,
It is useful as a constituent material of various medical devices used in a site in contact with blood such as artificial blood vessels, blood vessel catheters, cannulas, artificial heart-lung machines, blood vessel bypass tubes, intra-aortic balloon pumping, blood transfusion devices and extracorporeal circulation circuits.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples. In the following, "%" means "% by weight".

Example 1 N, N-dimethylaminoethyl methacrylate 10 g,
15.8 g of dodecyl bromide and di- as a polymerization inhibitor
1.2 g of tert-butylhydroxytoluene was dissolved in 160 ml of dimethylformamide, and then 60 ° C. at 60 ° C.
N, N-dimethyl-N that is a quaternized monomer by heating for a time
-Dodecyl ammonioethyl methacrylate bromide,
22.0 g was obtained.

Then, 5 g of the obtained N, N-dimethyl-N-dodecylammonioethyl methacrylate bromide and 5 g of sodium heparin were dissolved in 100 ml of water, respectively,
The mixture was mixed at room temperature for 60 minutes to form an ionic bond complex, which was then separated and collected. The sulfur content in this ionic bond complex was 4.5% as a result of elemental analysis.

Then, 5 g of the above ion-bonded complex, 0.7 g of ethylene glycol dimethacrylate and 50 g of dimethylformamide were mixed. Next, this mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere, then heated to 70 ° C., and 1.0 g of lauroyl peroxide was added as a polymerization initiator. Then, the mixture was stirred for 8 hours while heating at the same temperature to carry out polymerization to obtain a solution of the anticoagulant material.

Then, the obtained material solution was applied to the inner wall of the glass test tube and dried. In this way, a polymer layer (layer of anticoagulant material) was formed on the inner wall surface of the test tube.

Next, after filling the test tube with physiological saline, 3
It was kept at 7 ° C for 1 hour, and then the physiological saline was removed. Then, after injecting 1 ml of fresh rabbit blood into the test tube, the clinical test method is recommended (Kanehara Publishing, revised 29th edition, 19th edition).
The white test described in 83) was performed to observe the condition of the infused blood. As a result, no coagulation of blood was observed even after 2 hours, and no thrombus was observed on the inner wall of the test tube.

After that, the blood in the test tube was removed, and after thoroughly rinsing with physiological saline, the re-white test was performed again. As a result, blood coagulation and thrombus on the inner wall of the test tube were not observed at all.

Thereafter, the blood in the test tube was removed, and after thoroughly rinsing with physiological saline, the whitening test was performed again, and thereafter, the whitening test was performed 15 times in total. As a result, blood coagulation and thrombus on the inner wall of the test tube were not observed at all.

Example 2 A solution consisting of 5 g of the ionic bond complex obtained in Example 1, 50 g of dimethylformamide and 1.5 g of lauroyl peroxide was heated at 70 ° C. for 6 hours under stirring under a nitrogen atmosphere to carry out polymerization. A solution of anticoagulant material was obtained.

When the same whitening test as in Example 1 was performed using the above solution, the same result was obtained.

Example 3 5 g of N- (N, N-dimethylaminopropyl) methacrylamide, 9.3 g of hexadecyl bromide and 0.6 g of dibutylhydroxytoluene as a polymerization inhibitor were dissolved in 80 ml of dimethylformamide, and the mixture was mixed at 60 ° C. for 6 minutes.
After heating for 0 hours, N, N-dimethyl- which is a quaternized monomer
1.4 g of N-hexadecylammonioethyl methacrylate bromide was obtained. Then, 5 g of the obtained N, N-dimethyl-N-hexadecylammonioethyl methacrylate bromide and 5 g of sodium heparin were added to 50 ml each.
Was dissolved in water and mixed to form an ionic bond complex, which was then separated and collected. The sulfur content in the ionic bond complex was 4.0 as a result of elemental analysis.
%Met.

5 g of the above ionic bond complex, dimethylformamide 5
A solution of 0 g and 0.8 g of azobisisobutyronitrile was stirred at 80 ° C. for 10 hours in a nitrogen atmosphere to carry out polymerization to obtain a solution of the anticoagulant material.

When the same whitening test as in Example 1 was performed using the obtained solution of the anticoagulant material, the same result was obtained.

Comparative Examples 1 to 3 Instead of the ion-bonded complex used in Examples 1 to 3, the same composition was obtained except that the quaternized monomer before heparinization was blended in the same amount as the ion-bonded complex. A dimethylformamide solution of a comparative anticoagulant material was prepared. A small amount of ethanol was added to the solution.

Using each of these solutions, a polymer layer was formed on the inner wall of the test tube in the same manner as in Example 1. Then, using these test tubes, a Lee White test was conducted in the same manner as in Example 1.
As a result, in each of the first tests, about 15 to 30
Blood clots in minutes.

Comparative Examples 4 to 6 The same dimethylformamide solution as in Comparative Examples 1 to 3 was used to form a polymer layer on the inner wall of the test tube in the same manner as in Example 1. Then, the dimethylformamide was distilled off and dried, and then a 5% aqueous sodium heparin solution was injected into the test tube, and heated at 60 ° C. for 48 hours for heparinization.
Then, using these test tubes, a Lee White test was conducted in the same manner as in Example 1. As a result, thrombosis was observed in the polymer layer formed on the inner wall of the test tube at the 5th and 6th times,
At 8th to 9th times, blood coagulation was observed within 2 hours.

[Effects of the Invention] As described above in detail, the anticoagulant material of the present invention can maintain a very excellent anticoagulant property (antithrombotic property) for a long period of time. This is because heparin, which has anticoagulant properties, is ionic bond force in the material.
This is because they are firmly bound and held in a water-insoluble mold.

Claims (4)

[Claims] 1. A polymer obtained from (a) an ionic bond complex synthesized from a basic compound having a polymerizable functional group and heparin or a salt thereof; and (b) a crosslinking agent, if necessary. An anticoagulant material characterized in that 2. A basic compound having a polymerizable functional group,
Formula (I) (In the formula, R ₁ represents a hydrogen atom or a methyl group; R ₂ and R ₃ represent identical there may be different even if an alkyl group having 1 to 3 carbon atoms from each other; R ₄ is 6 carbon atoms 22 represents an alkyl group; X represents a negative atom group; n represents an integer of 1 to 6). The anticoagulant material according to claim 1, which is a compound represented by the formula: 3. A basic compound having a polymerizable functional group,
Formula (II) (In the formula, R ₁ represents a hydrogen atom or a methyl group; R ₂ and R ₃ represent identical there may be different even if an alkyl group having 1 to 3 carbon atoms from each other; R ₄ is 6 carbon atoms 22 represents an alkyl group; X represents a negative atom group; n represents an integer of 1 to 6). The anticoagulant material according to claim 1, which is a compound represented by the formula: 4. The content of heparin in the ionic bond complex is
The sulfur content of the heparin is 0.
The anticoagulant material according to claim 1, which has an amount of 5 to 12% by weight.