JPH01262869A - Anticoagulant medical treatment implement - Google Patents

Abstract

PURPOSE:To prevent the elution of the implement in blood and the generation of a hemolysis by using an anticoagulant material formed by using a basic compd. having a polymerizable functional group and the polymer obtainable from an ion conjugated complex synthesized from heparin or the salt thereof for the part in contact with the blood. CONSTITUTION:The above-mentioned material is formed of the basic compd. having the polymerizable functional group and the polymer of the ion conjugated complex formed from the heparin or the salt thereof. The anticoagulant material having such compsn. is used as the medical treatment implement to be used for the sections which come into direct contact with the blood such as artificial blood vessel, vascular catheter and external circulation circuit. The ratio of the ion conjugated complex is preferably in a 5-90wt.% range of the total weight. The above-mentioned heparin is not only held in the material by the ion conjugation with the cationic group of the basic compd. but is also taken into the network structure formed by copolymn. of the basic compd. and vinyl. The heparin is, therefore, extremely securely held and the elution thereof to the outside of the material is substantially prevented. Since the basic compd. is formed to the high mol. wt. by the polymn., the elution of the compd. into the blood and the generation of the hemolysis are obviated.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to medical devices for use in areas that come into contact with blood.

[Prior Art] Blood has the property of coagulating due to the action of various components in the blood when it comes into contact with foreign substances. Therefore, artificial hearts, artificial heart valves, artificial blood vessels, vascular catheters,
High anticoagulability is required for the constituent materials of medical devices used in areas that come into contact with blood, such as cannulae, heart-lung machines, vascular bypass tubes, aortic balloon pumps, blood transfusion devices, and extracorporeal circulation circuits. However, many of the constituent materials of conventional medical devices inevitably cause blood coagulation when used for a long period of time, and do not have sufficient sustained anti-coagulant properties. Therefore, when a medical device is used on a patient, an anticoagulant such as heparin is usually used in combination. However, when heparin is administered systemically, there is a problem in that there is an increased risk of generating multiple bleeding foci.

In order to solve these problems, various attempts have been made to introduce heparin into the material of the medical device itself.

First, attempts were made to incorporate heparin into the material by physical mixing. However, since heparin is insoluble in most organic solvents, there is a problem in that the specific methods and materials that can be used in this method are limited. In addition, since heparin is only physically bound to the material, when this material is actually used in medical devices, heparin dissolves into the blood in a short period of time and maintains its anticoagulant properties for a long period of time. I couldn't do it.

In order to solve these problems, attempts have been made to covalently bond reactive residues of heparin to constituent components of materials.

However, this method had problems in that the synthesis of the material was complicated and the anticoagulant properties of heparin were reduced.

On the other hand, various methods have been studied for introducing heparin by ionic bonding of anionic residues of heparin with cationic residues of constituent components of the material. Such methods include treating the surface of the material with graphite-benzalkonium chloride-heparin (Science, 14).
2, p. 1297 (1963)), heparin-
Attempts have been made to polymerize vinyl chloride by trapping a cationic surfactant, a vinyl monomer, and a radical polymerization initiator (Japanese Patent Publication No. 55-15222).

However, in these methods, heparin is ionically bonded to a low-molecular ammonium salt such as benzalkonium chloride, and therefore has the disadvantage that it elutes into the blood in a short period of time. Furthermore, since not only heparin but also low-molecular-weight ammonium salts are eluted at the same time, there is a serious drawback in that a dissolution surface phenomenon occurs.

As a method to solve the above problem, a method has been proposed in which heparin is introduced into a polymer compound through ionic bonding by contacting an aqueous heparin solution with a polymer compound into which cationic residues have been introduced. A method in which a cationic residue is introduced into a copolymer such as vinyl-acrylonitrile by graft polymerization, and then heparin is introduced (Japanese Patent Publications No. 52-36779, No. 54-17797, No. 54-18317, 55-38963 and 55-38964), a method of introducing heparin after introducing a cationic residue into a polymer compound by copolymerization, addition polymerization, or polycondensation (Japanese Patent Publication No. 54-18
No. 518, No. 58-34494, No. 59-5
No. 0335, No. 59-53058, No. 6 (1)
No. 16260, No. 60-23626), etc. have been attempted.

However, in these methods, the amount of heparin introduced is greatly influenced by the chemical and physical properties of the polymer compound and the conditions under which it is brought into contact with the aqueous heparin solution. Therefore, it is difficult to set optimal conditions for obtaining a material with excellent anti-blood coagulability, and there is a problem in that the quality of the anti-blood coagulant materials obtained varies widely.

[Technical means for solving the problems] The present invention relates to artificial blood vessels, straight tube catheters, cannulae, vascular bypass chains, intra-aortic balloon pumping, artificial hearts, artificial heart valves, heart-lung machines, blood transfusion devices, extracorporeal It relates to medical devices used in areas that come into direct contact with blood, such as circulation circuits.

The anti-blood coagulant material used in the medical device of the present invention includes (a) a polymer of an ionic bond complex synthesized from a basic compound having a polymerizable functional group and heparin or a salt thereof;
If necessary, it is obtained by copolymerizing with b) a monomer copolymerizable with the ionic bond complex, and/or (C) a crosslinking agent.

The proportions of each component (a) to (C) in the above anti-blood coagulant material are as follows.

The ratio of ionic bond complexes of component (a) is (a) to (C
) is 5% by weight or more, and 10% by weight or more based on the total amount of
A range of 90% by weight is preferred. If it is less than 5 city ￥%,
Anticoagulant properties become insufficient.

The ratio of the monomer copolymerizable with the ionic bond complex of component (a) to 0.05 to (C) relative to the total amount of (a) to (C).
It is in the range of 95%, and preferably in the range of 0.1 to 90%.

The proportion of the crosslinking agent as component (C) is in the range of 0 to 60%, preferably in the range of 0.05 to 40%, based on the total amount of (a) to (C).

Next, each component will be explained.

The ionic bond complex of component (a) is a complex that is difficult to dissolve in water but soluble in organic solvents and is obtained by reacting a basic compound having a polymerizable functional group with heparin or its salt. be.

Heparin or its salt content ■ is 0 as sulfur content V
．． It is necessary that it is in the range of 5 to 12 weight γ%, and 1 to
A range of 8 double stars is preferred.

Although there are no particular restrictions on the type of heparin salt, heparin sodium is usually used.

A basic compound having a polymerizable functional group is a compound having a radically polymerizable or ionically polymerizable group such as a vinyl group, an acrylic group, or a methacryloyl group, and having a basic residue capable of ionically bonding with heparin or a salt thereof. It is. Examples of the basic residue include a tertiary ammonium group, a quaternary ammonium group, and a quaternary vidinium group.

Such compounds include, for example, the following formula (1)% formula% (wherein R1 represents a hydrogen atom or a methyl group; R4 represents an alkyl group having 6 to 22 carbon atoms; X represents a negative atom or a negative atom group; n represents an integer of 1 to 6; Compounds represented by the following formula can be mentioned: Life CH yo=c Rz IHl (The meaning of each symbol in the formula is the same as in formula (1).)

In the compounds represented by formula (N and formula (II)), X is preferably a halogen atom.

Examples of the compound represented by formula (1) include.

Further, examples of the compound represented by formula (II) include the following.

These compounds represented by formula (1) or formula (tl) can be synthesized by the route shown in reaction formula (1) or (2) below.

Reaction formula (1) %formula% : The reaction can be carried out as described below.

First, a compound represented by formula (1)″ or (■)°,
The compound represented by formula (1)'' is dissolved in an organic solvent such as dimethylformamide. Then, di-LerL-
By adding a polymerization inhibitor such as butylated hydroxytoluene (BH'l') and heating at 60 to 80°C for several hours to several tens of hours, a compound represented by formula (1) or 2 (If) is obtained. be able to.

Specific examples of compound (1)° include the following. That is, N,N-dimethylaminomethyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, N,N-dimethylaminobutyl (meth)acrylate, Examples include N-dimethylaminohexyl (meth)acrylate, N-diethylaminoethyl (meth)acrylate, and N-dipropylaminoethyl (meth)acrylate.

Specific examples of the compound represented by formula (1) include the following: hexylbromide, octylbromide, decylbromide, dodecylbromide, tetradecylbromide, hexadecylbromide, octadecyl Specific examples of the compound represented by formula (II), which includes bromide, eicosylbromide, tocosylbromide, etc., include the following. That is, N,N-dimethylaminomethyl (meth)acrylamide, N,N-dimethylaminoethyl (meth)acrylamide, N,N-dimethylaminopropyl (meth)acrylamide, N,N-dimethylaminobutyl (meth)acrylamide, Examples include N-dimethylaminohexyl (meth)acrylamide, N-diethylaminoethyl (meth)acrylamide, and N-dipropylaminoethyl (meth)acrylamide.

The reaction between compound (1) or compound (II) and heparin or its salt is preferably carried out by the method described below.

An aqueous solution of compound (1) or compound (II) and an aqueous solution of heparin or a salt thereof were mixed at 10 to 40°C at 10 to
It is appropriate to react for 300 minutes. In particular, 15-3
Preferably, the reaction is carried out at 0°C for 30 to 180 minutes. Compound (1) or (■) is preferably reacted in an amount of 1=12 mmo+ per 1 g of heparin sodium (provided that when heparin sodium is used instead of heparin) .

Component (a) may be hydrophilic or hydrophobic as long as it is a monomer that can be copolymerized with the ionic complex of component (a).

Examples of hydrophilic monomers include sodium methacrylate, N-methylacrylamide, acrylglycinamide, hydroxyethyl methacrylate, methoxypolyethylene glycol methacrylate, N-vinylpyrrolidone, N-vinyllactam, and diacetoacrylamide. Vinyl compounds are mentioned as an example. Also,
Examples of hydrophobic monomers include hydrophobic vinyl compounds such as styrene, vinyl chloride, vinyl acetate, methyl methacrylate, methacrylatelyl, alkyl-substituted styrene, vinyl isobutyl ether, vinyl propionate, and vinyl butyrate. Depending on the degree of hydrophilicity required for the anticoagulant material, these hydrophilic or hydrophobic monomers may be used alone or in combination.

As the crosslinking agent for component (C), 1 m or more selected from divinylbenzene, alkylene bismethacrylamide, alkylene glycol dimethacrylate, dialkylene glycol dimethacrylate, etc. can be used.

The anticoagulant material used in the present invention can be synthesized by polymerizing component (a) alone or by copolymerizing component (a) with component (a) and/or component (C). Polymerization is preferably carried out in a solution. Polymerization solvents include:
For example, dimethylformamide, dimethylacetamide,
Tetrahydrofuran, dimethyl sulfoxide, ethanol, propyl alcohol, butyl alcohol, dioxane, N-methylpyrrolidone can be used.

The polymerization method may be radical polymerization or ionic polymerization, but
The radical polymerization initiator, which is particularly preferable for radical polymerization, is
Such initiators may be those commonly used, such as azo compounds such as azobisisobutyronitrile, t-
Examples include hydroperoxides such as butyl hydroperoxide and cumene hydroperoxide, dialkyl peroxides such as di-t-butyl peroxide and lauroyl peroxide, and organic peroxides such as diacyl peroxides such as dicumyl peroxide and benzoyl peroxide. 0 polymerization initiator crab contains components (a) ~ (
A preferred range is from about 5 x 1 O-4 to 30% by weight, based on the total amount of component C).

The polymerization temperature is preferably room temperature to 100"C, and 40 to 90"C.
The temperature range is particularly preferred, and the polymerization time is from 1 hour to 5 °C.
A range of 1 day is preferred, and a range of 2 hours to 3 days is particularly preferred.

The anticoagulant material made in this way may be directly molded into medical devices, or may be mixed with other polymeric compounds and then molded into medical devices, or may be preformed with other polymeric materials. The surface of the molded medical device may be coated with this anticoagulant material; the coating may be applied only to the surfaces that come into contact with blood.

As other polymeric materials, those used in medical devices can be used in -a. Such polymeric materials include polyvinyl chloride, polyvinyl acetate, polyacrylonitrile, polyepichlorohydrin, polyester, polyurethane, polyurea, acetyl cellulose, and polyhyperoxymethacrylate, or mixtures thereof. Among these polymer materials, polyurethane and polyurea are particularly preferred because they are flexible and have excellent JI mechanical properties.

[Operations and effects of the present invention 1] The anti-blood coagulant material used in the medical device of the present invention is produced by reacting heparin with a relatively low molecular weight basic compound having a polymerizable functional group to form an ionic complex. , made by copolymerization with vinyl compounds. Therefore, heparin is not only retained in the material by ionic bonds with the cationic groups of the basic compound, but also incorporated into the network formed by the copolymerization of the basic compound and vinyl.

Therefore, compared to conventional anticoagulant materials, heparin is retained extremely firmly and hardly dissolves outside the material. In addition, since basic compounds have a high molecular weight due to polymerization, they do not dissolve into the blood and cause hemolysis.Heparin is not covalently bonded to the material, so it has a higher molecular weight than heparin alone. There is almost no difference in anticoagulant properties.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples. In addition, in the following, all "1%" represents "weight %".

Example! N,N'-dimethylaminoethyl methacrylate 50g
, 79.2 g of lauryl bromide and 6.0 g of dibutylhydroxytoluene (BIT) as a polymerization inhibitor were dissolved in 600 mM of dimethylformamide, and the reaction was carried out by stirring at 80° C. for 30 hours under a nitrogen atmosphere, and then the solvent was removed under reduced pressure. Distilled away.

900 mJl of ethyl acetate was added to the residual reaction product, heated to 50°C to dissolve, and cooled to obtain 120 g of the desired N,N''-dimethyl-N-dodecylammonioethyl methacrylate bromide.Elemental analysis value of this product. is as follows.

CHN Br Theoretical value (X) 59.09 9.94 3.45 1
! 9.88 actual value (159,029,853,4820
, 33 Heparin On A solution of 25.0 g of N,N-dimethyl-N-dodecylammonioethyl methacrylate bromide dissolved in 350 g of distilled water was added to a solution of 15.4 g of heparin dissolved in a long glass of distilled water at 30°C for 20 minutes. It dripped. The mixture was continuously stirred at the same temperature for 20 minutes. The precipitated heparin ion-binding complex was separated using a centrifuge.

The extracted heparin ion binding complex was added to 50 g of distilled water.
was added, stirred and washed, and then separated by centrifugation. This operation was repeated twice and then dried. The amount of product was 23g.

The sulfur content in this ionic bond complex was 4.6% as a result of elemental analysis.

5.63 g of the above ionic bond complex, 5.73 g of hydroxyethyl methacrylate) and 80 g of dimethylformamide
A solution consisting of g was heated to 80° C. with stirring under a nitrogen atmosphere. When the internal temperature reached 80° C., 450 mg of lauroyl peroxide was added, and thereafter the same amount of lauroyl peroxide was added every hour for a total of 4 times. After adding the last layer of lauroyl peroxide, the mixture was stirred at the same temperature for 1 hour and then cooled to room temperature.

This reaction solution was poured into 1.5 ft of ethanol, and the resulting precipitate was separated and dissolved in 100 g of dimethylformamide while still containing ethanol (this solution is referred to as solution A).

Coaching polyurethane artificial blood vessel (inner diameter 7.8 mm, wall thickness 1.1 mm)
The solution A was injected into the inner cavity of the tube (mm), and the inner surface was squeezed by inserting a glass squeezing rod. Thereafter, the coating material was placed in water to solidify, and the water was exchanged seven times.

Thereafter, the mixture was kept in ethanol at 40°C for 12 hours, and then extracted and washed with water 5 times (15 hours in total).

It was kept at 38° C. for 24 hours to dry.

11. Cut the antithrombotic artificial blood vessel of the present invention into a length of 1.5 cm, insert it into the canine superior vena cava for 15 minutes, and then remove it.
Rinse with saline and fix with glutaraldehyde.
The lumen surface of the blood vessel was observed. As a result of visual observation, there was almost no deposit on the surface.

On the other hand, the same polyurethane vascular graft without antithrombotic material coating was similarly tested.

There were many red deposits.

Example 2 Polyurethane catheter for placement in the birth canal (outer diameter 2.7 m)
m, inner diameter 1.3 mm, length 12 cm) were coated with solution A from Example 1 on the inner and outer surfaces. After drying under a nitrogen stream, it was immersed in water and ethyl alcohol for 15 hours each, and then dried.

The catheter thus anticoagulated and the catheter not coated with this material were punctured into the femoral vein of the dog and left in place for two weeks. As a result, the blood vessels punctured by the uncoated catheters were clotted and occluded, but the anticoagulated catheters remained open.

Example 3 5.10 g of the ionic bond complex prepared in Example 1 and 5.8 g of hydroxyethyl methacrylate.

Solution B is a dimethylformamide solution produced and treated under the same conditions as in Example 1, except that a solution consisting of 0.63 g of ethylene glycol dimethacrylate and 100 g of dimethylformamide was used.

F. Polyurethane artificial blood vessels (inner diameter 7, 6 mm) were prepared in the same manner as in Example 1, except that solution B was used instead of coaching solution A.
, thickness 1.0 to 1.2 mm) and post-processed.

The artificial blood vessel of the present invention was obtained in the same manner as the artificial blood vessel of Example 1, and there were almost no deposits.

On the other hand, there were many red deposits on the samples not coated with the present anticoagulant material.

Example 4 5 g of the ionic bond complex prepared in Example 1, 4 g of ethylene glycol dimethacrylate, and 40 g of dimethylformamide were mixed. The mixture was then stirred at room temperature under a nitrogen atmosphere for 1 hour, and then heated to 70°C. The temperature rises,
As a polymerization initiator, lauroyl peroxide 500m
g, and thereafter the same amount of lauroyl peroxide was added every hour for a total of 4 times. After adding the last layer of lauroyl peroxide, polymerization was carried out by stirring and heating at the same temperature for an additional 5 hours to obtain a solution of an anticoagulant material. This solution was poured into 2 fL of ethanol, the resulting precipitate was collected, and while still containing ethanol, dimethylformamide 10
(This solution will be referred to as solution C).

Coaching polyurethane artificial blood vessel (inner diameter 8.1 mm, wall thickness 1 mm,
The solution C was injected into the inner cavity (0-1.2 mm), and the inner surface was squeezed using a glass rubbing rod.

Thereafter, the coating material was placed in water to solidify, and the water was exchanged seven times. Then in ethanol at 40°C.

The mixture was held for 12 hours, and then extracted and washed with water 5 times (20 times in total). It was kept at 38° C. for 24 hours to dry.

The above-mentioned anti-thrombotic artificial blood vessel of the present invention was cut into a length of 1.5 cm, inserted into the large vena cava for 15 minutes, and then removed.
Rinse with saline and fix with glutaraldehyde.
The lumen surface of the blood vessel was observed. As a result of visual observation, there was almost no deposit on the surface.

On the other hand, when the same polyurethane artificial blood vessel not coated with antithrombotic material was tested in a similar manner, there were many red deposits.

Example 5 Polyurethane catheter for placement in the birth canal (outer diameter 2.7 m)
m, internal diameter 1.3 mm, length 12 cm) were coated with solution C of Example 4 on the inner and outer surfaces. After drying under a nitrogen stream, it was immersed in water and ethyl alcohol for 15 hours each, and then dried.

The catheter thus anticoagulated and the catheter not coated with this material were punctured into the femoral vein of the dog and left in place for two weeks. the result.

Blood vessels punctured with uncoated catheters were clotted and occluded, but anticoagulated catheters remained open.

Claims (4)

[Claims] (1) An anti-blood coagulant material using a polymer obtained from an ionic bond complex synthesized from a basic compound having a polymerizable functional group and heparin or its salt is used at least in the part that comes into contact with blood. A medical tool featuring: (2) (a) An ionic bond complex synthesized from a basic compound having a polymerizable functional group and heparin or its salt; and (b) hydrophilic and/or hydrophobic properties that can be copolymerized with the ionic bond complex. A medical device characterized in that an anti-blood coagulant material using a polymer obtained from a monomer is used at least in a portion that comes into contact with blood. (3) An anti-blood coagulant material made of a polymer compound obtained by crosslinking a polymer obtained from the ionic bond complex according to claim 1 with a crosslinking agent is used at least in the part that comes into contact with blood. A medical tool featuring: (4) A material made of a polymer compound obtained by crosslinking the anticoagulant material according to claim 2 with a crosslinking agent,
A medical device characterized in that it is used at least in a part that comes into contact with blood.