JPH0769931A - Anti-thrombogenic composition and production of tool for anti-thrombogenic medical treatment - Google Patents

Abstract

PURPOSE:To obtain a coating composition for coating an anti-thrombogenic material on a plastic used for general medical treatments, such as a polycarbonate or an acrylic polymer without generating cloudiness and cracks on the surface of the plastic. CONSTITUTION:The solution of an anti-thrombogenic material in an organic solvent is mixed with a small amount of water to enable the coating of the anti-thrombogenic material on a plastic without generating cloudiness, cracks, etc., on the surface of the plastic.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a composition having antithrombogenicity and a method for producing a medical device.

[0002]

BACKGROUND OF THE INVENTION The present invention relates to the composition of a coating solution for imparting antithrombotic properties to medical devices. In recent years, many attempts have been made to give a medical device a property of preventing blood from coagulating, that is, an antithrombotic property. Among them, segmented polyurethane and segmented polyurethane urea are well known as those using a synthetic polymer material. For example, in Japanese Examined Patent Publication No. 58-8700, a block polyether of polyethylene glycol-polypropylene glycol-polyethylene glycol is used as a soft segment, and this is used in dimethyl sulfoxide.
It is stated that the polyether type polyurethane urea obtained by reacting with 4'-diphenylmethane diisocyanate to prepare a prepolymer and further adding ethylenediamine as a chain extender can obtain good antithrombotic property compared with conventional materials. Has been. In addition to this, Japanese Patent Publication Sho 53-15
556 is known as an antithrombotic material such as a polymer in which a hydrophilic acrylic resin is graft-copolymerized with a polymer material by applying the excluded volume effect. It has been reported that all of these have good antithrombotic properties when dissolved in an organic solvent and coated on a tube or the like. Also,
As another approach to the antithrombotic material, a material in which heparin, which is an anticoagulant derived from a living body, is immobilized on the surface of the material by ionic bond or covalent bond has been developed. This antithrombotic material has been widely applied particularly clinically and has become important. Heparin is a mucopolysaccharide having many anionic groups, and is widely used as an anticoagulant. As a material to which this is applied, Japanese Patent Publication No. 54-183
17 is a graft polymer obtained by graft-polymerizing a vinyl compound containing a tertiary amino group onto polyvinyl chloride.
Is quaternized, dissolved in dimethylformamide and coated on the tube to form a film layer of the above polymer on the tube, and then treated with heparins to form anion groups and ions of heparin. It has been reported that by forming a bond, it is immobilized and good antithrombotic properties can be obtained. Also, as a similar material, in Polymer Proceedings, 36, 223 (1979), the amino group of a terpolymer of dimethylaminoethyl methacrylate, methoxy polyethylene glycol methacrylate and glycidyl methacrylate was quaternized. It has been reported that a material obtained by blending polyurethane with N, N-dimethylformamide and then cross-linking it by heat treatment to obtain heparin ion-bonded has good antithrombotic properties. Also,
In the artificial organs 20 (2), 434-437 (1991), a quaternized monomer of N, N-dimethylaminoethyl methacrylate was blended with heparin so that the amount of ions would be equivalent to that of an ion complex. This was polymerized in a N, N-dimethylformamide solution in which polyurethane was dissolved together with 2-hydroxyethylmethacrylate etc. using a polymerization initiator, and this was coated on a tube to successfully obtain good antithrombotic properties. ing.

[0003]

In any of the above methods for imparting antithrombotic properties to a medical device with an antithrombotic material, the antithrombotic material is once dissolved in an organic solvent and the surface of the intended medical device is dissolved. The anti-thrombotic property was obtained by coating to obtain anti-thrombotic property, or by further treating the coating film with heparin to bind heparin. However, this method has the following problems. That is, many plastic materials used as medical devices are vulnerable to organic solvents. For example, due to its excellent mechanical strength and transparency, polycarbonate, which is widely used as a case for connectors, artificial kidneys and artificial lungs, is dimethylformamide or tetrahydrofuran which is used as a solvent for the above materials. If the treatment is carried out, the molded product may be cracked or may cause problems such as cracks and cloudiness, which is not preferable. Similar to polycarbonate, acrylic resin is used in medical devices such as centrifugal pumps and artificial lung cases, but this material also cracks, cracks, or becomes cloudy when exposed to organic solvents such as tetrahydrofuran or dimethylformamide. Such problems arise. Generally, these plastic materials are vulnerable to organic solvents. Therefore, the above antithrombogenic material is relatively free from problems such as cracks and the like in polyvinyl chloride containing a plasticizer or a tube of polyurethane, and tetrahydrofuran which is widely used as a solvent of the antithrombotic material in injection molded articles. It is only partially used for polyvinyl chloride products, and there has been a big problem that the antithrombogenic material has not reached widespread use as a general medical device.

[0004]

SUMMARY OF THE INVENTION The present invention is to solve the above-mentioned drawbacks, and an object of the present invention is to form an antithrombotic material by injection molding which is widely used. Another object of the present invention is to provide a composition capable of coating a plastic material, particularly polycarbonate or acrylic, and a method for producing a medical device using the composition. The coating composition of the present invention is a solution prepared by dissolving an antithrombotic material in an organic solvent, and adding water in an amount of 10% by weight or more based on the organic solvent. The present invention also relates to a method for producing an antithrombotic medical device obtained by coating the above composition on a medical device and then drying it to remove an organic solvent and water. Furthermore, the antithrombogenic (material) polymer is a polymer containing a tertiary amino group,
A coating composition characterized in that a part or all of the quaternary amino groups are quaternized ammonium chloride, which is obtained by treating the coating composition with heparin after coating. A method for manufacturing a medical device is provided.

Further, the above antithrombogenic polymer is diisocyanate, polyoxyalkylene glycol having a hydroxyl group capable of reacting with diisocyanate at a molecular end, polyether polyol having a tertiary amino group, and other polyamines if necessary. The diisocyanate that provides the antithrombogenic composition, which is a polyurethane or polyurethaneurea obtained by reacting a polyol, is a diisocyanate used in the production of polyurethane (aromatic,
Both aliphatic and alicyclic can be used. Examples of the aromatic diisocyanate include 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate, xylylene diisocyanate, 4,4'-diphenylmethane diisocyanate and 4,4'-diphenylpropane diisocyanate. As the aliphatic diisocyanate,
There are hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, and the like. Examples of the alicyclic disocyanate include 4,4'-dicyclohexylmethane diisocyanate. As the polyether polyol having a tertiary amino group, 3-methyl-3-aza-1,5-pentanediol, 3-ethyl-3-aza-1,5-pentanediol, 3-n-propyl-3- Aza-1,5-pentanediol, 3-is
Examples thereof include those obtained by condensing o-propyl-3-aza-1,5-pentanediol. Examples of the polyoxymethylene glycol include polyethylene glycol, polypropylene glycol and polytetramethylene glycol having a molecular weight of 300 to 15,000, preferably 800 to 4000. As the polysiloxane having a hydroxyl group at the terminal, those shown in Chemical formula 1 are preferably used.

[0006]

[Chemical 1] Examples of the chain-extending polyol include ethylene glycol, propylene glycol, 1,4-butanediol, neopentyl glycol, 1,5-pentanediol and 1,6.
As the hexanediol and the chain-extending diamine, ethylenediamine, propylenediamine, 1,4-tetramethylenediamine and 1,6-hexamethylenediamine are particularly preferable. It was also found that it is preferable to use cyclic ether as the organic solvent for preparing the coating composition. Hereinafter, steps for carrying out the present invention will be described.

That is, (1) a step of dissolving a polymer having antithrombogenicity in an organic solvent or polymerizing it in an organic solvent to prepare a polymer solution. Polymers containing tertiary amino groups are preferably quaternized at this stage. The organic solvent used in this case is N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-2.
-Amide solvents such as hydroxyethyl-2-pyrrolidone, cyclic ether solvents such as tetrahydrofuran, tetrahydropyran and dioxane, ketone solvents such as acetone and methyl ethyl ketone, halides such as chloroform, methylene chloride and carbon tetrachloride Examples of the solvent include cyclic ethers, from the viewpoints of compatibility with water, drying speed, toxicity and the like, and tetrahydrofuran is most preferable. Incidentally. If the dope for polymerization is used as it is, an oligomer and an unreacted monomer remain, so that it is usually preferable from the viewpoint of safety to dissolve the antithrombotic material that has once undergone the purification step. When the polymer dope is used as it is, it is preferable to add a step of removing unreacted monomers and oligomers after coating as described below. The concentration of the antithrombotic material dissolved in the cyclic ether is 1% by weight to
It is adjusted to 30% by weight, more preferably 2 to 15% by weight. The term "dissolved solution" in the present invention includes not only complete dissolution as described above but also colloidal dispersion.

(2) A step of gradually adding water to the polymer solution. In this step, since the polymer is usually insoluble in water, it is preferable to add water while stirring the solution in order to prevent precipitation of the polymer. The water content is the most important part of the invention. Generally, as the water content increases, the antithrombotic material changes from a dissolved state to a suspension state. Thus, the state of the liquid varies depending on the content of water, but which state is the best depends on the nature of the medical device as the base. However, the content of water is 10% by weight with respect to the solvent.
Below is almost equivalent to the effect of the solution on the base,
Organic solvents such as white turbidity and cracks when coated on polycarbonate or acrylic resin, which is the object of the present invention, 1
The same problem as in the case of 00% occurs. Therefore, in the present invention, it is preferable that water is contained in an amount of 10% by weight or more, and the weight ratio of water to the solvent is preferably 1: 3 to 3: 1. Further, in the case of a polymer having an antithrombotic property containing a tertiary amino group, a step of quaternizing this may be carried out here. Further, it can be quaternized after coating as described later. The step of quaternizing a tertiary amino group has 1 to 10 carbon atoms, preferably 2 as a quaternizing agent.
One of alkyl halides, aralkyl halides, aryl halides and active ester of ~ 8 is used. Of these quaternizing agents, alkyl halides having 1 to 10 carbon atoms, preferably 2 to 8 carbon atoms are most suitable as the quaternizing agent. The quaternizing agent is preferably used in excess of the tertiary amino group in the polymer, and is used in an amount of 1.2 to 10 times, preferably 1.5 to 4 times. The addition is preferably carried out by adding a solution prepared by dissolving the above-mentioned quaternizing agent in a suitable solvent to the dissolved polymer solution. Then, the reaction is carried out at 20 to 90 ° C., preferably 50 to 90 ° C. for 0.1 to 25 hours to obtain a polymer solution in which the tertiary amino group is quaternized.

(3) The step of coating the intended medical device with the above composition. In this step, various means used when applying the paint can be adopted. That is, a method of immersing an article to be coated in the composition and then pulling it up, a method of applying with a roll or a brush, a method of applying to the surface of a medical device by spraying, and the like can be used. The method can be appropriately selected depending on the intended medical device. Further, in the case of a polymer having an antithrombotic property containing a tertiary amino group, the antithrombotic surface is completed through a step of quaternary chlorination of this polymer and a step of treating it with heparin. In the step of quaternizing the tertiary amino group, the above-mentioned quaternizing agent is similarly used here as the quaternizing agent.

The medical device coated with the antithrombotic material containing quaternized amino groups is then bound by contacting the heparin with the coated portion. For example, heparin is 0.1 to 10%, preferably 0.1.
Heparinization is carried out by contacting the coated surface with an aqueous solution of 5-5% heparin at 20-100 ° C, preferably 40-80 ° C. The heparins referred to herein include heparin, heparin sodium, heparin calcium, heparin lithium and the like. The coating composition of the present invention can solve the problems of conventional antithrombotic materials, particularly cracks and white turbidity that occur when coated on polycarbonate or acrylic. It is possible.

[0011]

EXAMPLES The present invention will be described below with reference to examples. Parts in the examples mean parts by weight. <Example 1> 3-n-butyl-3-aza-1,5-pentanediol and phosphorous acid were charged into an autoclave and stirred at 200 to 230 at normal pressure under nitrogen stream while stirring.
The reaction is carried out while heating at ℃ for 24 hours to remove the produced water. Then, the reaction was continued at 230 ° C. and 0.3 mmHg for 3 hours. In this way, the number average molecular weight is about 200.
An aminopolyether polyol having 0 and basic nitrogen of 6.3 mmol / g was obtained. Polydimethylsiloxane 3240 parts represented by Chemical formula 1 having a number average molecular weight of 1800 4,4'-
1195 parts of diphenylmethane diisocyanate, 827 parts of the above aminopolyether polyol 1, 191 parts of 4-butanediol and 0.3 part of dibutyltin laurate as a catalyst thereto, 3800 parts of tetrahydrofuran, N, N
Dissolve in a mixed solvent of 7600 parts of dimethylformamide. After that, the temperature was raised to 40 ° C. for 2 hours at 20 ° C. in a nitrogen stream and the reaction was performed for 6 hours to obtain a polymer solution having a solid content of 32% and a viscosity of 1830 poise. To 100 parts of this polymer solution, 6 parts of ethyl iodide was added and stirred at 60 ° C. for 20
The solution is reacted for a time to obtain a quaternized polymer solution (A).

As a result, the basic nitrogen content before quaternization was 0.
After the quaternization was 63 mmol / g, it was 0.20 mmol / g, and the quaternization rate was 68%. After purifying the polymer, 12 parts of the polymer was collected and tetrahydrofuran 60
After adding to the solution and stirring for 5 hours, 180 parts of water is gradually added while stirring the solution. After the addition is completed, the mixture is stirred for another hour to obtain a coating composition. Attempts were made to coat various medical devices using the above coating composition. As a sample, a polycarbonate connector, a three-way stopcock, an acrylic centrifugal pump, and a polyvinyl chloride tube (outer diameter 1.2 mm, inner diameter 0.6 mm) were used. The results are shown in Table 1. 2% of heparin after this
The coated medical device was dipped in an aqueous solution and heparinized for 8 hours.

[0013]

[Table 1]

<Example 2> 3-n-butyl-3-aza-
1,5-Pentanediol and phosphorous acid were charged into an autoclave and stirred at a normal pressure of 20 under a nitrogen stream.
The reaction is carried out by heating at 0 to 230 ° C. for 24 hours to remove produced water. Then, the reaction was continued at 230 ° C. and 0.3 mmHg for 3 hours. Thus, an aminopolyetherpolyol having a number average molecular weight of about 2000 and basic nitrogen of 6.3 mmol / g was obtained. Polydimethylsiloxane 32 having a number average molecular weight of 1800 and having a structure shown in Chemical formula 1
40 parts, 4,4′-diphenylmethane diisocyanate 1195 parts, the above aminopolyether polyol 830
Parts, 1.4-butanediol, 170 parts, and 0.3 part of dibutyltin laurate as a catalyst, 3800 parts of tetrahydrofuran, 7600 parts of N, N-dimethylformamide.
Dissolved in part of the mixed solvent. After this, 1 at 20 degrees under nitrogen flow
The solid content is 32.
%, A polymer solution having a viscosity of 1800 poise was obtained. 100 parts of this polymer solution was taken out, 6 parts of ethyl iodide was added, and the mixture was reacted at 60 ° C. for 20 hours while stirring to obtain a quaternized polymer solution.

The polymer is purified. As a result, the basic nitrogen content before quaternization was 0.67 mmol / g and after quaternization was 0.20 mmol / g, and the quaternization ratio was 70%. 12 parts of this polymer was sampled and added to 60 parts of tetrahydrofuran and stirred for 5 hours, and then 180 parts of water was gradually added while stirring the solution. After the addition is completed, the mixture is stirred for another hour to obtain a coating composition. An attempt was made to coat a medical device similar to that of the example using the above coating composition. As the sample, a polycarbonate connector, a three-way stopcock acrylic centrifugal pump, and a polyvinyl chloride tube (outer diameter 1.2 mm, inner diameter 0.6 mm) were used. The results are shown in Table 1. Thereafter, heparinization was carried out in the same manner as in Example 1.

<Comparative Example 1> The polymer obtained in Example 1
The solution (A) was diluted with N, N-dimethylformamide to obtain a coating solution. An attempt was made to coat a medical device similar to that of Example 1 using the coating composition. As a sample, a polycarbonate connector, a three-way stopcock, an acrylic centrifugal pump, and a polyvinyl chloride tube (outer diameter 1.2 mm, inner diameter 0.6 mm) were used. (The results are shown in Table 1.)

The antithrombogenicity of the polymer thus obtained can be measured by using the calcium re-addition time or the Leigh white method. The calcium re-addition time is measured by adding 3.8% sodium citrate aqueous solution to the collected fresh blood in an amount of 1 volume per 9 volumes of blood and centrifuging at 3000 rpm for 15 minutes to obtain citrated plasma. This plasma is added to a vial coated with the above material, and then a calcium chloride solution having a 1/20 normal concentration is added to measure the deposition time of fibrin. The results are shown in Table 2. The Lee White method is a method in which fresh blood collected is added to a vial coated with the above material, and the time until coagulation is measured. This time, instead of the vial, a connector that was coated and heparinized was plugged and used. The results are shown in Table 3.

[0018]

[Table 2]

[0019]

[Table 3]

The medical device treated with the present antithrombotic composition must naturally be able to exhibit the functionality originally possessed by the medical device. A confirmation test was conducted to confirm whether functional devices and antithrombotic properties are retained by coating medical devices with advanced functions, such as centrifugal pumps used for left or right heart support, on patients with impaired cardiac function. . The antithrombogenic composition prepared in Example 1 is poured into a centrifugal pump having a polycarbonate casing and impeller, the liquid is discharged, and then the composition is dried at 60 ° C. for 24 hours. After the completion of drying, a heparin 2% aqueous solution was filled in the centrifugal pump and treated at 50 ° C. for 6 hours to carry out heparinization. At this time, the impeller rotated normally, and the standard flow rate could be maintained. For comparison, the coating composition prepared in Comparative Example 1 was similarly used for the pump treatment.
To confirm the functionality, a centrifugal pump was connected to a simulated circuit and a drive device was operated to test whether or not a proper flow rate characteristic was obtained, but it was compared with that using the composition of Example 1. , White turbidity and some cracks were found, and the rotation was not smooth.

[0021]

The antithrombotic composition having the specific composition of the present invention can be coated on polycarbonate or acrylic resin, which is impossible by the conventional method, and sufficiently exhibits the antithrombotic property of the material itself. It is possible. In particular, the specific polyurethane having a quaternary amino group has a high antithrombotic property and is useful for imparting the antithrombotic property to those having a high function such as a centrifugal pump.

Claims (2)

[Claims] 1. A solution in which an antithrombotic material is dissolved in an organic solvent system, wherein the organic solvent system comprises water in an amount of 10 relative to the organic solvent.
An antithrombotic composition for coating, which is characterized by being added in an amount of at least% by weight. 2. A method for producing an antithrombotic medical device obtained by coating a medical device with the composition according to claim 1 and then drying the composition to dry the organic solvent and water.