JPH0790166A - Coated polycarbonate object and its preparation - Google Patents

Abstract

PURPOSE:To provide the title object surface-coated with an antithrombotic material without detriment to the excellent transparency, mechanical properties, etc., inherent in polycarbonate and excelling in antithrombotic properties. CONSTITUTION:A structural material for a medical implement made of a polycarbonate is coated with a coating material obtained by dissolving or dispersing an antithrombotic material in an organic solvent containing at least 10wt.% water and dried.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a polycarbonate coating and a method for producing the same. More specifically, the present invention relates to a polycarbonate coated body having excellent antithrombogenicity and transparency as a medical device and a method for producing the same.

[0002]

2. Description of the Related Art In recent years, many attempts have been made to provide a medical device with 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 JP-B-58-8700, polyethylene glycol-polypropylene glycol block polyether is used as a soft segment, and this is reacted with 4,4'-diphenylmethane diisocyanate in dimethyl sulfoxide to prepare a prepolymer, and a chain extender is further added. It is disclosed that the polyether-type polyurethane urea obtained by adding ethylenediamine has a good antithrombotic property as compared with conventional materials.

In addition to this, Japanese Patent Publication No. 53-15556 discloses a polymer in which a hydrophilic acrylic resin is graft-copolymerized with a polymer material by applying the excluded volume effect, as an antithrombotic material. The graft copolymerized polymer is dissolved in an organic solvent and coated on a tube or the like to impart antithrombogenicity to the tube or the like.

As another approach as an antithrombotic material, a material in which heparin, which is an anticoagulant derived from a living body, is immobilized on the material surface by an ionic bond or a covalent bond has been developed. This antithrombotic material has been widely applied particularly clinically and has become an important material. Heparin is a mucopolysaccharide having many anionic groups and is widely used as an anticoagulant. As a material to which this is applied, a vinyl compound containing a tertiary amino group, which is disclosed in Japanese Patent Publication No. 54-18317, is graft-polymerized, and the resulting graft polymer is quaternized. In some cases, a good antithrombotic material is obtained by dissolving it in formamide and coating it on a tube to form a film of the polymer, and then treating with heparin to form an ionic bond with an anion group of heparin and immobilize it. High Polymer Papers, 36.223. In (1979), after quaternizing the amino group of a terpolymer of dimethylaminoethyl methacrylate, methoxypolyethylene glycol methacrylate, and glycidyl methacrylate, blending with polyurethane in N, N-dimethylformamide, followed by heat treatment. It is described that the material obtained by crosslinking and ionically binding heparin has good antithrombotic properties.

Artificial organs, 20 (2). 434. (199
In 1), a monomer obtained by quaternizing N, N-dimethylaminoethyl methacrylate was blended with heparin so as to have an ion equivalent to form an ion complex, and N was prepared by dissolving polyurethane with 2-hydroxyethyl methacrylate and the like. It was shown that polymerization was carried out in N, N-dimethylformamide using a polymerization initiator, and this solution was coated on a tube to obtain a good antithrombotic material.

[0006]

In any of the above-mentioned conventional techniques, the antithrombotic material is once dissolved in an organic solvent and surface-coated on the structure of a medical device intended for this purpose.
It is intended to obtain an antithrombogenic medical device. When applying the above-mentioned technique to a polycarbonate having excellent mechanical properties, chemical resistance, especially its transparency, the use of N, N-dimethylformamide or tetrahydrofuran as a solvent for the antithrombogenic material As a result, cracks and white turbidity occurred in the polycarbonate coating, and it could not be used as a medical device. Further, alcohols such as methanol and ethanol or alkanes such as n-hexane, which do not cause the above problems with respect to the polycarbonate resin or have little problem, are unsuitable as a solvent for the above antithrombotic material. Yes, there is no smooth coating. Therefore, the above-mentioned technique cannot be applied to a polycarbonate having excellent mechanical properties, chemical resistance, and particularly its transparency.

[0007]

SUMMARY OF THE INVENTION The inventors of the present invention have originally solved the problems of the above-mentioned prior art by providing a polycarbonate having excellent mechanical properties, chemical resistance, and particularly transparency thereof. It retains the performance it has, and
As an antithrombotic property required as a medical device,
The present invention has been studied and studied. That is, the present invention is a polycarbonate coating for medical devices, characterized in that at least the surface of the polycarbonate structure is a layer that is antithrombogenic and is a high molecular weight polymer, and is a polycarbonate structure. At least the surface of the body is coated with a coating material in which an antithrombotic polymer is dissolved or dispersed in an organic solvent containing 10% by weight or more of water, and the coating material is dried. This is a method for producing a polycarbonate coating for tools.

The present invention is applied to a medical device, and examples of the medical device include an artificial kidney, an artificial heart, an artificial lung, an artificial blood vessel, a blood processing device, and the like, and parts used therefor. At least all structural materials used in contact with blood can be mentioned. As the anti-thrombogenic and high-molecular-weight polymer in the present invention, the materials described in the above-mentioned prior art are dissolved in an organic solvent containing 10% by weight or more of water, which is the method of the present invention. Alternatively, any material can be used as long as it forms a transparent film when dispersed, coated and dried, and does not cause any inconvenience as a polycarbonate coating. Is antithrombotic,
As the high molecular weight polymer, preferred is a high molecular weight polymer having a tertiary amine in the molecule, or a high molecular weight polymer capable of being modified so as to have a tertiary amine in the molecule. And a quaternary ammonium salt obtained by quaternizing a tertiary amine in these molecules, and a quaternary ammonium salt obtained by quaternizing a tertiary amine in these molecules. Heparin is treated and bound. The high molecular polymer is not particularly limited as long as it satisfies the above requirements, but segmented polyurethane and segmented polyurethane urea are preferable as the type of the high molecular polymer.

The organic solvent in the present invention is not particularly limited as long as it is antithrombogenic, is a high molecular weight polymer, is a good solvent, and is well soluble in water. . Specific examples thereof include N, N dimethylformamide, N, N, depending on the polymer used.
Dimethylacetamide, N-methyl-2-pyrrolidone,
Examples include N-2-hydroxyethyl-2-pyrrolidone, tetrahydrofuran, tetrahydropyran, dioxane, acetone, methyl ethyl ketone, chloroform, chloromethylene, carbon tetrachloride, and the like. These organic solvents are segmented polyurethanes and segmented polyurethaneureas, which are high molecular weight polymers having a tertiary amine in the molecule, or high-molecular compounds that can be modified to have a tertiary amine in the molecule. It is a molecular polymer and is a quaternary ammonium salt obtained by quaternizing a tertiary amine in these molecules, and a quaternary ammonium salt obtained by quaternizing a tertiary amine in these molecules. Tetrahydropyran, dioxane, which is a solvent for segmented polyurethane and segmented polyurethaneurea, which is a combination of a secondary ammonium salt treated with heparin and which has a good compatibility with water, that is, a good miscibility, Is preferred, and among them, tetrahydrofuran is particularly preferred.

In the present invention, it is essential that these organic solvents contain 10% by weight or more of water. A preferable weight ratio of water to the organic solvent is 1: 4 to 4: 1, and a more preferable weight ratio of water to the organic solvent is 1: 3 to 3:
It is 1.

The process of the present invention will be described in detail. (1) A step of preparing a solution by dissolving a polymer which is an antithrombotic polymer and is a high molecular weight polymer in the organic solvent or by polymerizing the polymer in the organic solvent. Among the polymers that are antithrombogenic and are high molecular weight polymers, those having a tertiary amine in the molecule as described above are quaternized with a quaternary ammonium in this step by quaternizing the tertiary amine in the molecule. It is preferably salted. The solvent used at this time is the above-mentioned solvent. If the polymerized dope is used as it is, oligomers and unreacted monomers remain. Therefore, it is preferable to purify the polymer once and redissolve the purified polymer in a solvent. The concentration of the polymer, which is an antithrombogenic and high molecular weight polymer, in the coating material is 2 to 40% by weight,
This is preferably 4 to 30% by weight.

(2) A step of gradually adding water to the solution. When gradually adding water to the above solution, water is antithrombogenic and is a non-solvent for the polymer, which is a high molecular weight polymer,
Since the polymer precipitates when water is added at once, it is preferable to gradually add water while stirring the solution. The amount of water added is in the above-mentioned range and varies depending on the polymer and solvent used, but if it is 10% by weight or less, there is no difference from the conventional technique. At this time, among the polymers, which are high molecular weight polymers obtained in the step (1), those having a tertiary amine in the molecule as described above, the tertiary amine in the molecule is quaternized in this step. The formation of a quaternary ammonium salt may be carried out. The quaternization of the tertiary amine in the molecule to form a quaternary ammonium salt may be carried out after coating.

The tertiary amine in the molecule is quaternized to form a quaternary ammonium salt, that is, the quaternizing agent used in the quaternization is not particularly limited, but preferred specific examples are as follows. , C1-10, preferably 2-8
Alkyl halides, aralkyl halides, aryl halides and active esters of. The most preferred quaternizing agent is an alkyl halide having 2 to 8 carbon atoms. The amount of the quaternizing agent used is preferably used in excess with respect to the tertiary amine in the polymer, and the quaternizing agent is 1.2 to 10 times, more preferably 1.5 to 3 times the tertiary amine. 4 times. Addition is to the liquid of the polymer that is dissolved or dispersed,
A method of dissolving the quaternizing agent in the above-mentioned solvent is preferable. Thereafter, at 20 to 90 ° C, preferably 50 to 90 °
A polymer solution or dispersion liquid in which the tertiary amine in the molecule is quaternized to form a quaternary ammonium salt is obtained by reacting with C for 0.1 to 25 hours.

(3) Coating process. A structure of polycarbonate, a structure as a medical device, for example, a connector is coated with a polymer solution or dispersion in which a tertiary amine in a molecule is quaternized to form a quaternary ammonium salt. As a coating method, known means can be used. For example, a method of immersing a polycarbonate structure in a coating liquid and pulling it up and drying, a method of applying and drying with a roll or a brush, a method of spraying and drying are applied. The coating film thickness is not particularly limited, but is preferably 2 to 500.
μm, and more preferably 10 to 200 μm. In order to obtain the transparency of the present invention, which is also the object, in addition to controlling the coating film thickness, it is antithrombogenic and depends on the selection of the polymer and the dispersion medium, which are high molecular weight polymers. At least the coated body of the polycarbonate of the present invention has a transmittance of all visible light after coating of 50% or more, preferably 65% or more, more preferably 75% or more with respect to the transmittance of all visible light before coating. .

(4) In the present invention, the structure of the polycarbonate obtained in the above-mentioned process, the structure as a medical device, which is antithrombogenic, is coated with a polymer which is a high molecular weight polymer. In the case of a polymer in which a tertiary amine in the molecule is quaternized to form a quaternary ammonium salt, further heparin treatment is preferable.

[0016]

EXAMPLES Examples will be described below. Parts are parts by weight. <1> 3-n-butyl-3-aza-1,5-pentanediol and phosphorous acid were charged into an autoclave and stirred at 200 to 230 ° C. under atmospheric pressure under a nitrogen stream at a temperature of 2 to 2.
The reaction was carried out by heating for 4 hours to remove water produced.
Then, the reaction was continued at 230 ° C. and 0.3 mmHg for 3 hours. Thus, an aminopolyether polyol having a number average molecular weight of 2000 and basic nitrogen of 6.3 mmol / g was obtained. 3240 parts of polydimethylsiloxane having a number average molecular weight of 1800 and hydroxyl groups at both ends, 1195 parts of 4,4′-diphenylmethane diisocyanate, 827 parts of the above aminopolyether polyol, 191 parts of 1,4 butanediol, and dibutyltin laurate as a catalyst. 0.3
Parts are dissolved in a mixed solvent of 3800 parts of tetrahydrofuran and 7600 parts of N, N-dimethylformamide.

After this, under nitrogen flow at 20 ° C. for 2 hours, 4
The temperature was raised to 0 ° C. and the reaction was carried out 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 was added 6 parts of ethyl iodide and the mixture was heated to 60 °
The reaction was carried out for 20 hours with stirring at C to obtain a quaternized polymer solution (A). The basic nitrogen content before quaternization was 0.63 mmol / g, and the basic nitrogen content after quaternization was 0.20 mmol / g. That is, the quaternization rate is 68
%Met. The polymer solution (A) was precipitated with methanol and water and washed with methanol and water to purify the polymer. 12 parts of this purified polymer was added and dissolved in 60 parts of tetrahydrofuran. 180 parts of water was gradually added to the obtained solution with sufficient stirring. After the addition of water was completed, the mixture was stirred for another hour to obtain a coating composition. The obtained coating composition was used to coat various structural materials for medical devices made of polycarbonate. They are a connector made of polycarbonate, a three-way stopcock made of polycarbonate, a centrifugal pump made of polycarbonate, and a tube made of polycarbonate. The results are shown in Table 1. In any case, the coating thickness of the coating is about 25 μm, and the transmittance of all visible light after coating is 88 to 80% of the transmittance of all visible light before coating.
It was 93%.

[0018]

[Table 1]

<2> 3-n-butyl-3-aza-1,5
-Pentanediol and phosphorous acid were charged into an autoclave, and while stirring, under a nitrogen stream and at atmospheric pressure, 200-2.
The reaction was carried out by heating at 30 ° C. for 24 hours to remove produced water. Then, at 230 ° C, 3 at 0.3 mmHg
Reacted for hours. Thus, the number average molecular weight of 200
An aminopolyether polyol having 0 and basic nitrogen of 6.3 mmol / g was obtained. 3240 parts of polydimethylsiloxane having a hydroxyl group capable of reacting with isocyanate at both ends and a number average molecular weight of 1800, 3240 parts, 1,195 parts of 4,4′-diphenylmethane diisocyanate, 830 parts of the aminopolyether polyol, and 1,4 butanediol 170
And 0.3 parts of dibutyltin laurate as a catalyst.
Parts were dissolved in a mixed solvent of 3800 parts of tetrahydrofuran and 7600 parts of N, N dimethylformamide. 20 °
At C, the temperature was raised to 40 ° C. for 1 hour under a nitrogen stream and reacted for 12 hours to obtain a polymer solution having a solid content of 31.5% and a viscosity of 1800 poises. 100 parts of this polymer solution was added, 6 parts of ethyl iodide was added, and the mixture was reacted at 60 ° C. for 20 hours with stirring to obtain a quaternized polymer solution (B). The basic nitrogen content before quaternization was 0.67 mmol / g, and the basic nitrogen content after quaternization was 0.20 mmol / g. That is, the quaternization rate was 70%. The polymer solution (B) was precipitated with methanol and water and washed with methanol and water to purify the polymer. 1 of this purified polymer
Two parts were taken and 60 parts of tetrahydrofuran was added and dissolved. 120 parts of water was gradually added to the obtained solution with sufficient stirring. After the addition of water was completed, the mixture was stirred for another hour to obtain a coating composition. The obtained coating composition was used to coat various structural materials for medical devices made of polycarbonate. They are a connector made of polycarbonate, a three-way stopcock made of polycarbonate, a centrifugal pump made of polycarbonate, and a tube made of polycarbonate. The results are shown in Table 1. In each case, the coating thickness of the coating was about 40 μm, and the transmittance of all visible light after coating was 86 to 92% of the transmittance of all visible light before coating.

[0020]

Comparative Example The polymer solution (A) obtained in Example 1 was diluted with N, N-dimethylformamide to obtain a coating solution having a polymer concentration of 4.76%. Using this coating solution, a connector made of polycarbonate, a three-way stopcock made of polycarbonate, a centrifugal pump made of polycarbonate, and a tube made of polycarbonate were coated in the same manner as in Example 1. The results are shown in Table 1.

The tubes of Examples 1 and 2 were further immersed in a 2% aqueous solution of heparin and treated for 8 hours for heparinization. No change in appearance due to heparinization was observed. The re-addition time of calcium was measured using this tube, a polyvinyl chloride tube, and a polyurethane tube. That is, to the collected fresh blood, 3.8% sodium citrate aqueous solution was added to 1 volume to 9 volumes of blood, and
Citrated plasma was obtained by centrifuging at 0 rpm for 15 minutes, and each plasma was brought into sufficient contact with each tube, and a calcium chloride solution having a normal concentration of 0.05 was added to measure the fibrin precipitation time. The results are shown in Table 2.

[0022]

[Table 2]

Further, each tube used in Table 2 was measured by the Rewhite method. That is, the collected fresh blood was added to each tube and brought into contact with each other, and the time until the blood coagulated was measured. The results are shown in Table 3.

[0024]

[Table 3]

[0025]

As can be seen from the above description and examples, the present invention can coat a polycarbonate material which cannot be coated with a conventional antithrombotic material by a simple method. It is possible to provide a medical device made of polycarbonate having thrombotic properties.

Claims (2)

[Claims] 1. A polycarbonate coated body for medical devices, wherein at least the surface of the polycarbonate structure is coated with a layer which is an antithrombogenic polymer and is a high molecular weight polymer. 2. A coating material in which an antithrombogenic polymer is dissolved or dispersed in an organic solvent containing 10% by weight or more of water on at least the surface of the polycarbonate structure, and the coating material is dried. A method for producing a polycarbonate coating for a medical device, comprising: