JP6678959B2 - A method for forming a coating layer on the surface of a resin molded product. - Google Patents

Description

  TECHNICAL FIELD The present invention relates to a method for forming a coating layer on the surface of a resin, and particularly to a method for coating the surface of a medical resin molded product with a highly hydrophilic substance.

  BACKGROUND ART As a medical device, which is molded from a synthetic resin such as polyethylene, polyurethane, or a silicone resin, there is a tubular body made of a synthetic resin that is left in the body for a long time. For example, a bile duct made of a synthetic resin (for example, polyethylene) (hereinafter referred to as a resin bile duct) is implanted and placed in the body as a bypass for bile duct damage caused by bile duct cancer, liver cancer, or the like. As a serious problem caused by the indwelling of the resin bile duct, a substance contained in bile is deposited as a biofilm on the inner surface of the resin, and the resin bile duct becomes clogged within 1 month at the earliest, or about 3 months on average, and it is necessary to replace it each time. Is at the point where

  A similar problem occurs in a resin ureter and a resin blood vessel left in the body due to urethral disorder or vascular disorder.

  For this problem, it is known that by making the inner surface of the tube made of a material such as polyethylene hydrophilic, the frictional resistance against bodily fluids such as bile is reduced, and the deposition of biofilm is reduced. It is known that a hydrophilic substance can suppress the adhesion of bacteria to the surface and the ability to form a biofilm as compared with the material of the hydrophobic unprocessed resin itself.

  On the other hand, a 2-methacryloyloxyethylphosphorylcholine polymer (MPC polymer) has been attracting attention as a substance that mimics a biological cell membrane that is an ideal biocompatible surface. This MPC polymer is a polymer having both a phospholipid polar group (phosphorylcholine group) which is a constituent of a biological membrane and a polymerizable methacryloyl group in one molecule. In addition to exhibiting excellent biocompatibility without being recognized as a foreign substance, interaction with the living body is also suppressed, and thus protein adsorption and thrombus formation can be suppressed. In addition, since the MPC polymer has the above-mentioned hydrophilicity, it has excellent properties such as low frictional resistance to body fluids such as bile and blood, and the possibility of suppressing adhesion of bacteria and cells. Therefore, if the surface of a resin molded product such as a polyethylene pipe is modified with the MPC polymer, an extremely effective medical device can be expected to be obtained.

  Due to its high hydrophilicity and biocompatibility, MPC polymers are currently applied to surface modification of many medical devices such as vasodilating stents, catheters, contact lenses, artificial hearts, and artificial joints. ing.

  For example, in WO2010 / 122817 (Patent Document 1), as an application to an exhalation assisting tube, by coating the tube with a polymer containing MPC, suppression of cell adhesion to the tube and exfoliation of mucous membrane after the tube is used. It is disclosed that the tissue damage can be prevented, and as a result, the inflammatory reaction can be avoided. Here, a vinyl chloride resin as a main component is used as a base material of the tube, and as a coating method, a step of immersing the tube in a coating liquid containing 0.01 to 50% by weight of a polymer containing MPC and the immersed tube It is supposed that the drying process of 2 is repeated 2 to 20 times.

  Further, in JP-A-2015-84848 (Patent Document 2), a method of imparting hydrophilicity to the surface of a molded product by repeating the step of immersing a plasma-treated resin molded product in an MPC polymer-containing liquid and drying it multiple times Is disclosed.

WO2010 / 122817 JP, 2005-84848, A

  However, in any of the above-mentioned methods, only by applying it to the base material and physically adhering it, there is a problem in durability. Particularly, in Patent Document 2, it is applied to a resin-molded product that has been plasma-treated, but this effect also only improves the familiarity between the resin-molded product and the MPC polymer, and no covalent bond is formed between the MPC polymer and the substrate. There is still a problem with durability.

  The present invention has been proposed in view of the above-mentioned conventional circumstances, and the MPC polymer is easily and strongly coated on the resin surface through a covalent bond by dipping treatment, and as a result, the MPC polymer can be used for a long period of time. It is an object of the present invention to provide a method capable of stably maintaining high water immersion property and biocompatibility.

The present invention employs the following procedure to coat the surface of a medical resin molded product with a copolymer polymer mainly composed of 2- methacryloyloxyethylphosphorylcholine (MPC) (hereinafter referred to as a hydrophilic polymer).

  The procedure is as follows: a step of plasma-treating the resin-molded product, a step of forming the hydrophilic polymer, and a step of immersing the plasma-molded resin-molded product in a hydrophilic polymer solution to cause a reaction to form a covalent bond. And a process.

The medical resin molded product is a tube made of polyethylene, polyurethane, silicone resin or the like, and is a device such as a bile duct that is left in the body for a long period of time. In the plasma treatment, a plasma gas is caused to flow to the resin molded product for surface treatment. Examples of the hydrophilic polymer include a polymer containing MPC and a functional group (for example, a hydroxyl group or an amino group) having active hydrogen on the surface of the substrate, which is capable of forming a covalent bond with the functional group (for example, a carboxyl group) as an essential component. . A copolymer with n-butyl methacrylate is more preferable, and specifically, a covalent bond is formed with MPC, n-butyl methacrylate, and a functional group having active hydrogen on the substrate surface (for example, a hydroxyl group or an amino group). It is preferable to use an acrylic acid copolymer polymer having a carboxyl group as the functional group. Further, as the solvent immersion Engineering low in hydrophilic polymers, hydrogen carbonate-based solvent (n- hexane, toluene, etc.), ester solvents (ethyl acetate, butyl acetate), ether solvents (diethyl ether, tetra hydrofuran, etc.), aprotic solvents (dimethyl sulfoxide, N, N-dimethylformamide and the like). Among these, we have use the tetrahydrofuran, further dicyclohexylcarbodiimide and N. It is preferable to use a solution in which N-dimethylaniline is dissolved.

  As described above, by immersing the plasma-treated resin molded product in the hydrophilic polymer solution, a hydroxyl group or an amino group formed on the surface of the molded product by the plasma treatment, and acrylic acid which is a component of the hydrophilic polymer. Provide a medical device that can react with a carboxyl group to form a covalent bond, firmly fix a hydrophilic polymer on the surface of a resin molded product, and prevent biofilm of biogenic origin from adhering to the inner wall of the tube for a long period of time. can do.

  The resin molded product is a bile duct, a ureter, a polyethylene tube, a polyurethane tube, a silicone resin, or the like that is left in the body for a long time as a blood vessel.

The figure (photograph) which shows the contact angle of the polyethylene plate which does not process of this invention. The figure (photograph) which shows the contact angle of the polyethylene board which processed the present invention.

<Workpiece>
The medical resin molded product coated according to this embodiment is, for example, a synthetic resin tube such as a polyethylene tube, a polyurethane tube, or a silicone resin tube used as a bile duct. A polyethylene tube with an outer diameter of 3.3 mm (inner diameter of about 3.0 mm) to be placed in the body was adopted. Incidentally, since it is difficult to observe hydrophilicity in a tubular body such as a bile duct, a polyethylene plate sample was separately treated in the same manner.

  The inside of this polyethylene tube (manufactured by Cook Co., 10 cm in length) (and one side of a polyethylene plate (2 × 7 cm): hereinafter simply referred to as polyethylene tube) was exposed to atmospheric pressure plasma at room temperature for 3 minutes. As a result, hydroxyl groups and amino groups are generated on the inner surface of the polyethylene pipe. The plasma device is manufactured by Kaiki Semiconductor Co., Ltd., and the gas type is nitrogen.

<Hydrophilic polymer>
In the present invention, the hydrophilic polymer prepared as described below is coated on the inner surface of the polyethylene pipe.

2.0 g of 2-methacryloyloxyethylphosphorylcholine (MPC) (manufactured by Tokyo Chemical Industry Co., Ltd.), 0.73 g of n-butyl methacrylate (manufactured by Nacalai Textile Co., Ltd.), and 0.1 g of acrylic acid (manufactured by Nacalai Textile Co., Ltd.) in ethyl alcohol. And bubbling argon gas into the liquid phase to replace the argon in the reaction system.

After the substitution, 40.0 ml of AIBN (azobisisobutyronitrile) which is a polymerization initiator was added, and MPC, n-butyl methacrylate and acrylic acid were separated by heating and refluxing for 8 hours around the boiling point of ethyl alcohol. Initiate polymerization. An operation in which the solution produced by this polymerization reaction is dropped into 50 ml of chloroform, the resulting precipitate is filtered, the obtained solid substance is further dissolved in 20 ml of ethyl alcohol, and the resulting precipitate is dropped into 50 ml of chloroform and filtered. Was repeated twice to obtain 2.3 g of a copolymer polymer (hydrophilic polymer) composed of 2-methacryloyloxyethylphosphorylcholine , n-butyl methacrylate and acrylic acid.

<Hydrophilic treatment of polyethylene pipe>
In 50 cc of dried tetrahydrofuran, 1.5 g of the hydrophilic polymer, 1.00 g of dicyclohexylcarbodiimide (manufactured by Tokyo Chemical Industry Co., Ltd.), N.V. A solution in which 0.06 g of N-dimethylaniline (manufactured by Nacalai Tesque) is dissolved is obtained. The plasma-treated polyethylene tube was immersed in the solution and stirred at room temperature for 3 days. As a result, a hydroxyl group or an amino group formed on the inner surface of the polyethylene pipe by the plasma treatment and a carboxyl group of acrylic acid, which is a component of the hydrophilic polymer, form a covalent bond, and the hydrophilic polymer is formed on the inner surface of the polyethylene pipe. Can be coated.

<Measurement of hydrophilicity>
The hydrophilicity of the surface of the surface-modified polyethylene pipe (surface-modified polyethylene plate) prepared as described above is compared with that of an unmodified polyethylene pipe (unmodified polyethylene plate) which is not subjected to the above treatment.

  Using a contact angle measuring device {Kyowa Interface Chemistry Co., Ltd., DROP MASTER 500, liquid volume 2 μL, measurement interval 1000 ms, number of measurements 30 times}, at any 5 points on the surface of the surface-modified polyethylene plate and the unmodified polyethylene plate, The contact angle was observed. The surface-modified polyethylene plate subjected to the treatment of the present invention was 15.5 degrees as shown in FIG. 2, while the unmodified polyethylene plate was 89 degrees as shown in FIG.

  From the above results, a resin molded article such as polyethylene coated with a hydrophilic polymer containing an MPC polymer formed by the method of the present invention can form a hydrophilic surface. As a result, when used as a bile duct, the substance contained in bile does not deposit as a biofilm on the inner surface of the resin. It can be expected to be placed in the body for a long time.

  As described above, by immersing the plasma-treated resin molded product in the hydrophilic polymer solution, hydroxyl groups and amino groups formed on the surface of the molded product by the plasma treatment, and acrylic acid which is a component of the hydrophilic polymer. It is possible to provide a medical device capable of reacting with the carboxyl group of the above to fix the hydrophilic polymer on the surface of the resin molded product and preventing the biofilm of biogenic origin from adhering to the inner wall of the tube for a long period of time.

Claims (4)

In a method of forming a coating layer of a hydrophilic polymer which is a copolymer mainly composed of 2-methacryloyloxyethylphosphorylcholine (MPC) on the surface of a medical resin molded article,
A step of forming a hydroxyl group or an amino group on the surface of the resin molded product by plasma treatment,
A step of reacting a hydroxyl group or an amino group formed on the surface of the resin molded product and a carboxyl group, which is a component of the hydrophilic polymer , at room temperature in the presence of dicyclohexylcarbodiimide to form a covalent bond,
A method for forming a coating layer on the surface of a resin molded product, comprising:   The method for forming a coating layer on the surface of a resin molded article according to claim 1, wherein the medical resin molded article is a tube of polyethylene, polyurethane, or a silicone resin.   The copolymer polymer mainly composed of 2-methacryloyloxyethylphosphorylcholine (MPC) is a hydrophilic polymer which is a copolymer of MPC, n-butyl methacrylate and acrylic acid. A method for forming a coating layer on the surface of a resin molded product.   The method for forming a coating layer on the surface of a resin molded article according to claim 1, wherein the solution of the hydrophilic polymer which is the copolymer uses tetrahydrofuran as a solvent.