JPS62207466A - Manufacturing method for molded products with excellent biocompatibility - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a method for producing a molded article with excellent biocompatibility.

More specifically, the present invention relates to a method for producing a molded article in which an ethylene-vinyl alcohol polymer (hereinafter abbreviated as EVA) layer having excellent biocompatibility is formed on the surface of the molded article.

[Conventional technology]

Many studies have been conducted on materials with excellent biocompatibility and are still being actively pursued.

For example, an antithrombotic agent such as heparin or a thrombolytic agent material such as urokinase is immobilized on a polymer, and the heparin or urokinase is gradually released to prevent thrombus formation - or to remove the thrombus that has formed. It is. In addition, in polyurethane-based polymers, there are several dozen hydrophobic segments and hydrophilic segments.
Lamellar microphase separation of OA has also been carried out (Toshiyuki Uryu, “Industrial Materials J33 (10), 45 (19)
85)).

Furthermore, when performing extracorporeal blood circulation using an EVA hollow membrane membrane obtained by wet molding a dimethyl sulfoxide solution of EVA consisting of a hydrophilic part and a hydrophobic part, it is necessary to prevent blood clots such as heparin from forming in the blood. It has been found that dialysis can proceed smoothly without clogging due to thrombus formation even without administering inhibitors (Hidemune Naito et al. [Artificial Organ Jll.
(11, 3 (1982)).

[Problem that the invention seeks to solve]

When immobilizing heparin, urokinase, etc. on a polymer, it is necessary to handle physiologically active substances that are unstable in various respects, and there is a limit to the effective period of thrombosis prevention. In addition, in the case of polyurethane molded products with a lamellar microphase-separated structure, the synthesis of the polymer is complicated, and strict molding conditions must be used to create the microphase-separated structure, making it difficult to obtain reproducibility. is difficult.

The excellent antithrombotic properties of a hollow fiber membrane formed by wet molding a solution of EVA in dimethyl sulfoxide is quite surprising because both the polymer itself and the molding method are simple. However, as mentioned above, this molding method is based on a wet molding method, and only a very limited number of molded products can be obtained by the wet molding method.

In addition, molded products using EVA alone have physical properties such as strength, elasticity, and flexibility that vary widely, so that they are only practical for limited molded products.

Furthermore, as a method of improving the biocompatibility of various molded products, a method of forming the molded product by contacting the molded product with a solution of EVA dissolved in a polar solvent such as dimethyl sulfoxide or N-methylpyrrolidone may be considered. Because it has a high boiling point, it takes a long time to evaporate at room temperature and pressure, making it impractical. Evaporating it at high humidity will damage the molded product itself, and evaporating it at reduced pressure will cause uneven evaporation. It is easy to use, and the operation is troublesome. Furthermore, since these polar solvents have high viscosity, it is difficult to uniformly modify the surface.

Therefore, an object of the present invention is to provide a method for producing a molded article with excellent biocompatibility and free from the above-mentioned problems.

[Means for solving problems]

Molded products that require excellent biocompatibility include, for example, catheters that require appropriate hardness and kinging resistance, circuit tubes for extracorporeal circulation that require flexibility, artificial surface layers that require the same rheological properties as blood vessels, There are filters in blood circuits that have complex shapes, and these filters are molded from materials with physical properties that suit different purposes. In most cases, many of these are used in combination to form one system, and in this case, the biocompatibility of the entire system is dominated by the molded product 1, which has the poorest biocompatibility. Therefore, there is a need to increase the level of biocompatibility of all molded products.

In view of the above points, the present inventors decided to mold each molded product using the most suitable material for each purpose using the most rational method, and to modify the surface that comes into contact with body fluids so that it has excellent biocompatibility. We focused on the fact that the biocompatibility of molded products made from any material and in any shape can be improved, and we conducted extensive studies to make at least the body fluid contact surface of the molded products excellent in biocompatibility, and arrived at the present invention. . That is, the present invention is characterized in that an EVA layer is formed on the surface of the molded article by contacting the molded article with a solution of EVA dissolved in hexafluoro-2-propanol and then removing the hexafluoro-2-propanol. This is a method for producing molded products with excellent biocompatibility.

The main feature of the present invention is the discovery of a solvent that dissolves biocompatible ffVA well and is easy to remove. Hexafluor I:1-2-propanol best exhibits the above characteristics. It is a solvent that

The EVA used in the present invention has an extremely simple composition and is a copolymer of ethylene and vinyl alcohol with no problems in reproducibility or handling. Such copolymers are most commonly produced by copolymerizing ethylene and vinyl acetate and saponifying the resulting ethylene-vinyl acetate copolymer. The copolymerization ratio of ethylene/vinyl alcohol is usually 90/
The range of 10 to 10/90 (molar ratio) is preferably -6
A range of 0/40 to 20/80 is more preferable because the antithrombotic properties are excellent. In addition to ethylene and vinyl aphrecol, the antithrombotic properties of EVA may be inhibited to an extent that does not inhibit the antithrombotic properties of EVA, such as an ester unit of vinyl acetate, an ionic unit such as itaconic acid or acrylic acid, and vinyl pyrrolidone. It may contain hydrophilic units such as.

As a molded product, there is little chance of injection into the living body, and there is no E on the surface.
There are no particular restrictions on the material, shape, etc. as long as it can form a VA layer, such as polyvinyl chloride, silicone rubber,
Endotracheal tubes made of polyethylene, polypropylene-EVA, polyurethane, etc., circuit tubes, artificial blood vessels, cannulae, shunts for infusion, blood transfusion tubes, surgical sutures, artificial tracheas, blood conduits, such as heart-lung machines, artificial kidneys, etc. Examples include blood circulation circuits, materials for cardiac auxiliary circulation devices, blood bags, artificial ureters, ligating threads, balloons, etc.

In the method for producing a molded article of the present invention, the above EVA is dissolved in hexafluoro-2-propanol, and the molded article is prepared by dissolving the EVA in hexafluoro-2-propanol.
It may be brought into contact with VA solution. The concentration of EVA solution is 0.
A content of 1 to 20% by weight is practical for carrying out the method of the present invention, but a content of 1 to 10% by weight is preferred in order to roughly and uniformly modify the surface of a molded article.

The method of bringing the molded article into contact with the solution is not particularly limited as long as the surface of the molded article can be sufficiently wetted with the EVA solution, and ordinary dipping methods, spraying methods, etc. can be used. Furthermore, an EVA layer may be formed inside molded articles such as tubes by a method of circulating the solution inside the tube.

Next, it is necessary to bring the molded article into contact with an EVA solution to wet it, and then remove the hexafluoro-2-propanol solvent, and evaporation is a common method for removing the solvent. Although high temperature or reduced pressure may be used for evaporation, since the method of the present invention uses a solvent that evaporates easily, such a method is not necessary and it is sufficient to simply perform natural drying or blow drying. Note that in order to homogenize the +1M amount of the solution before evaporation, it is free to perform centrifugal dehydration, for example, by shaking or rotating.

The thickness of the EVA layer formed on the surface of the molded product is not particularly limited as long as it does not impair its function as a medical material, but 0.01 to 10 μm is practically appropriate.

[For production]

According to the method of the present invention, EVAi can be extremely easily formed on the surface of a molded article. The reason for this is not necessarily clear, but hexafluoro-2-propanol is different from dimethyl sulfoxide, etc., and due to its hydrogen donating property,
The solvent must be a solvent that dissolves VA, the surface tension of the solvent is low, so when the molded article is brought into contact with a solution in which EVA is dissolved, the surface of the molded article will easily become wet, and the solvent will easily evaporate. Therefore, it is considered that the EVA layer is likely to be efficiently formed on the surface of the molded product.

Hereinafter, the manufacturing method of the present invention will be specifically explained with reference to Examples.

〔Example〕

Example 1 Ethylene/vinyl alcohol 33/67 (mole ratio)
Noeval F (manufactured by Kuraray) was dissolved in hexafluoro-2-propanol (manufactured by Central Glass) to form a 5% by weight solution. A PET mesh filter used for extracorporeal circulation of blood was immersed in this EVA solution, thoroughly wetted, pulled out, shaken twice to remove liquid, and then air-dried.

When the obtained mesh filter was observed with a magnifying glass, it was found that all parts were coated with EVA almost uniformly and transparently.

In dog hemodialysis using an EVa hollow fiber module without using an anticoagulant, when a normal mesh filter was used, blood clots in the mesh filter part of the blood circuit, so the hemodialysis could not be performed smoothly. Using the modified mensch filter obtained in the above, hemodialysis could be carried out smoothly for 5 hours without clotting.

Comparative Example 1 A mesh filter was treated in the same manner as in Example except that dimethyl sulfoxide was used as the solvent.

When the resulting mesh filter was observed with a magnifying glass, it was found that the amount of EVA deposited was uneven and abnormal areas in the form of white spots were observed, and a good coating could not be obtained.

〔Effect of the invention〕

By the method of the present invention, the surface of each fence medical molded product is coated with EVA.
It can be modified with Therefore, it is possible to easily obtain biocompatible materials that do not form blood clots without using antithrombotic agents at all, or with less than half the usual amount, and are extremely useful in industry. .

Claims (1)

[Claims] A layer of ethylene-vinyl alcohol polymer is formed on the surface of the molded article by contacting the molded article with a solution of an ethylene-vinyl alcohol polymer dissolved in hexafluoro-2-propanol and then removing the hexafluoro-2-propanol. A method for producing a molded article with excellent biocompatibility.