JP2009082257A - Medical equipment having lubricative surface and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To realize medical equipment having a new function and showing lubrication durability when wetted by reducing the film thickness of a coating resin layer as much as possible with respect to a base material such as a metal material, an inorganic material, a fluororesin, and a polyolefin resin whose lubrication durability has been difficult to secure. <P>SOLUTION: The medical equipment realizes lubrication durability when wetted by forming a diamond-like carbon membrane, whose surface is activation-treated, on the surface of a base material forming the medical equipment and chemically fixing a hydrophilic polymer having a crosslinked structure to the surface and then treating it by an alkali. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention provides a medical device having excellent durability when wet and a method for manufacturing the same, and functionalization of the surface of a medical device such as a catheter, a guide wire, a blood filter or a blood extracorporeal circulation system, and an artificial lung. It is a useful invention.

In the medical field, a medical device such as a trachea, digestive tract, urinary tract, blood vessel, other body cavity, catheter inserted into a tissue, introducer, etc., or a guide wire inserted therein is a target site at the time of insertion. In order to improve the operability for accessing the body and minimize the tissue damage to the inner wall of the blood vessel or the mucous membrane, a surface having lubricity is required. In order to reduce surface frictional resistance, low friction materials such as fluororesins and polyolefin resins are used as the base material, or hydrophilic polymer is coated on the base material surface to improve lubricity when wet. .

As base materials for medical devices, polymer materials such as polyurethane resins, polyamide resins, fluorine resins and polyolefin resins, metal materials such as nickel / titanium alloys and stainless steel, inorganic materials such as ceramics or hydroxyapatite , Etc. are used.

However, when these substrates are directly coated with a hydrophilic polymer, a great problem that the hydrophilic polymer is easily peeled off and dropped off is not practically useful. In particular, this problem is more serious when a metal material, an inorganic material, a fluororesin, a polyolefin resin or the like is coated directly.

If the substrate is a polyurethane resin or polyamide resin, pre-treat the surface of the substrate with a compound having a reactive functional group such as an isocyanate compound in advance before coating the hydrophilic polymer, or It is known that by performing modification of the hydrophilic polymer or modification by blending, the peeling and dropping off of the hydrophilic polymer are suppressed, and the lubrication durability is improved. (For example, refer to Patent Document 1, Patent Document 2, and Patent Document 3). However, when the base material is a metal material, an inorganic material, a fluororesin, a polyolefin resin, etc., even if these methods are adopted, the improvement effect is small and it is difficult to ensure lubrication durability to withstand practical use. . Also, use of toxic compounds such as isocyanate compounds is not preferable from the viewpoint of safety.
On the other hand, a stent patent characterized by fixing a surface activated DLC thin film on the surface of a stent (metal material) and fixing a biodegradable polymer with a drug having an anti-restenosis effect on the surface. Became public (Patent Document 4). However, this invention has no description regarding a medical device excellent in high lubricity and lubrication durability and a method for producing the same.

JP-A-59-081341 JP 59-19582 U.S. Pat. No. 4,100,309 JP2007-195883

The object of the present invention is to chemically fix a specific hydrophilic polymer to a base material such as a metal material, an inorganic material, a fluororesin, or a polyolefin resin, which has been difficult to ensure lubrication durability. Therefore, it is an object of the present invention to provide various medical devices having lubricity excellent in durability. Furthermore, in the case of a guide wire for treatment, the diameter of the metal core material used as the base material is thinner than that of the guide wire for inspection, so it is necessary to make the coating resin layer on the base material as thin as possible. The object of the present invention is to solve the above-mentioned problems.

As a result of intensive studies, the present inventor has found that the above object can be achieved by the present inventions (1) to (7) below, and has reached the present invention.

(1) The surface-activated diamond-like carbon thin film is present on the surface of the base material constituting the medical device, and the hydrophilic polymer having a crosslinked structure is chemically immobilized on the surface. A medical device having lubricity when wet.
(2) The medical device according to (1), wherein the surface activation treatment of the diamond-like carbon thin film is performed by plasma irradiation, and a functional group is introduced on the film surface.
(3) The medical device according to (1) or (2), wherein the diamond-like carbon thin film has a thickness of 1 nm to 300 nm.
(4) The hydrophilic polymer has a functional group capable of reacting with a surface functional group of the diamond-like carbon thin film and a functional group capable of forming a crosslinked structure in the molecule. (1) to (3) Medical tools.
(5) The medical device according to any one of (1) to (4), wherein the hydrophilic polymer is a maleic anhydride copolymer or a modified product thereof.
(6) On the surface of the base material constituting the medical device,
1. After forming a diamond-like carbon thin film and performing surface activation treatment by plasma irradiation to introduce functional groups on the thin film surface,
2. The surface is coated with a mixed solution of a maleic anhydride copolymer or a modified product thereof and a crosslinking agent, dried and heated,
3. A method for producing a medical device having a lubricious surface by alkali treatment.
(7) On the surface of the base material constituting the medical device,
1. After forming a diamond-like carbon thin film and performing surface activation treatment by plasma irradiation to introduce reactive functional groups on the thin film surface,
2. The surface is coated with a mixed solution of a maleic anhydride copolymer or a modified product thereof and a crosslinking agent, dried and heated,
3. A method for producing a medical device having a lubricious surface by treatment with an alcohol solution of an alkali metal alkoxide.

The object of the present invention is a technology that can impart a high degree of lubrication durability to base materials such as metal materials, inorganic materials, fluororesins, and polyolefin resins, which have been difficult to ensure lubrication durability. And to provide a medical device having a new function. This objective is achieved by forming a surface-activated diamond-like carbon thin film on the surface of these substrates and chemically immobilizing a hydrophilic polymer with an appropriate amount of a crosslinked structure on the surface. I found out that Since various medical devices such as guide wires and catheters according to the present invention have a low coefficient of friction and excellent lubricity when wet, they have excellent operability during actual use and do not change product performance over a long period of time. Various medical devices with excellent lubrication durability can be realized. Furthermore, conventionally, guidewires are also highly hydrophilic to metal substrates without forming an intermediate coat layer by inserting metal into an extruded tube (thickness of several tens of microns) such as polyurethane resin or polyamide resin. By directly coating the molecules to a thickness of several microns, it became possible to produce a therapeutic guidewire with excellent lubricity and durability.

In the present invention, a diamond-like carbon thin film is formed on the surface of a base material constituting a medical device, the surface is subjected to a surface activation treatment by plasma or the like, a functional group is introduced, and the reactive functionalities on the surface are further introduced. By fixing the hydrophilic polymer to the base by chemical bonding and introducing an appropriate amount of cross-linked structure into the hydrophilic polymer, and further by treating with alkali, it has high lubricity when wet and also has excellent lubrication durability It has realized various excellent medical devices.

As the base material constituting the medical device of the present invention, polymer materials such as polyurethane resins, polyamide resins, fluorine resins, polyolefin resins, metal materials such as nickel / titanium alloys and stainless steel, ceramic materials, etc. Inorganic materials, and base materials generally used in the past, such as base materials obtained by combining these materials, can be used. In particular, in the present invention, it is possible to directly apply a hydrophilic polymer to a base material such as a metal material, an inorganic material, a fluororesin, or a polyolefin resin, which is difficult to be directly coated with a hydrophilic polymer. Since the lubrication durability can be secured, it is possible to utilize the base material according to the application and to reduce the thickness of the resin that constitutes the surface. Can be expected.

  The diamond-like carbon thin film (DLC film) formed on the surface of the substrate is a thin film made of carbon similar to diamond, and is a very dense and strong film. DLC films are sputtering, DC magnetron sputtering, RF magnetron sputtering, chemical vapor deposition (CVD), plasma CVD, plasma ion implantation, superimposed RF plasma ion implantation, ion plating, arc It can be formed on the surface of the substrate by a known method such as an ion plating method, an ion beam vapor deposition method or a laser ablation method.

  The thinner the DLC film, the better if the effects of the present invention can be obtained. Further, when the thickness of the film is 300 nm or more, there is a problem that cracks occur during deformation and the DLC film is peeled off. A preferable film thickness range is 1 nm to 300 nm.

  Since the surface of the DLC film is smooth and inert, even if a hydrophilic polymer is directly coated on this surface, it is easily peeled off. However, by performing surface activation treatment by irradiation with plasma or the like on the surface, it is possible to cleave part of the carbon-carbon bonds on the surface and generate free radicals or ionic species on the surface of the DLC film. By using the generated free radical or ionic species, a functional group such as a hydroxyl group, a carboxyl group, or an amino group can be introduced on the surface of the DLC film. The cleavage of the carbon-carbon bond of the DLC film is performed by exposing the DLC film to plasma generated by a gas such as argon, neon, helium, krypton, xenon, nitrogen, oxygen, ammonia, hydrogen, water vapor, acetylene, etc. Just do it. The gas may be used alone or as a mixed gas.

  Further, the carbon-carbon bond may be cleaved by irradiation with ultraviolet light or ultraviolet light in an ozone atmosphere. Since the cleaved carbon-carbon bond easily reacts with water, a hydroxyl group or a carboxyl group can be easily introduced into the surface of the DLC film.

  In addition, if a chain or cyclic hydrocarbon, an organic compound containing oxygen, and an organic compound containing nitrogen are used as the plasma source gas, the carbon-carbon bond is cleaved and reacts with ion species in the plasma. Therefore, it is possible to directly introduce a functional group corresponding to the gas type to the surface of the DLC film.

Furthermore, it is also possible to convert into a different kind of functional group by making the compound which has a functional group which can react with respect to these surface functional groups react. For example, the hydroxyl group introduced on the DLC surface is reacted with various functional group-containing alkoxysilane compounds such as 3-aminopropyltrimethoxysilane, polyisocyanate compounds, 2-isocyanatoethyl acrylate, thioglycolic acid, etc. , An isocyanate group, an acrylic group, a thiol group, and the like.

The present invention chemically fixes a hydrophilic polymer having reactivity to the DLC surface functional group introduced according to the above method, and introduces an appropriate amount of crosslinking into the hydrophilic polymer. It has been found that various medical devices having excellent lubrication durability can be produced using a base material that has been difficult to ensure lubrication durability.

  The hydrophilic polymer in the present invention has a functional group that can be chemically bonded to the functional group introduced on the surface of the DLC in the molecule, and further, by adding a crosslinking agent, the hydrophilic polymer A hydrophilic polymer capable of generating a cross-linked structure by reacting with the functional group is used. For example, various maleic anhydride copolymers, in particular, methyl vinyl ether-maleic anhydride copolymers or modified products thereof, hyaluronic acid, and acrylic monomers having functional groups such as hydroxyl groups, carboxyl groups, and glycidyl groups were copolymerized. Various acrylic polymers, polyethylene glycol and derivatives thereof can be suitably used.

  In particular, a methyl vinyl ether-maleic anhydride copolymer or a modified product thereof is a polymer compound having an acid anhydride ring that is excellent in reactivity with various functional groups on the DLC surface and is advantageous for cross-linking, and Since the safety | security with respect to a human body is fully confirmed, it uses especially preferable.

  In addition, as the crosslinking agent of the present invention, a diol, a polyol, a polyethylene glycol, a dithiol, a thioglycerol, an amino alcohol, a diamine, a polyamine, and the like are reactive with an acid anhydride ring and have two or more functional groups. Can be used.

  The blending ratio of the crosslinking agent to the hydrophilic polymer is in a weight ratio, and is in the range of 0.03 to 3.0 parts of the crosslinking agent with respect to 100 parts of the hydrophilic polymer. A particularly preferred range is 0.05 to 1 part. Outside this range, the lubricity and lubrication durability will be poor.

  A DLC thin film is formed on the surface of a base material such as metal or Teflon constituting the medical device, and further a surface activation treatment is performed by plasma irradiation to introduce a functional group on the surface of the thin film. In order to coat a hydrophilic polymer such as a copolymer or a modified product thereof, a method in which a solution in which these hydrophilic polymer and a crosslinking agent are mixed with the above composition is prepared and immersed in this solution, a solution Conventionally employed methods such as a method for applying a solution and a method for spraying a solution can be used. In particular, the dipping method is preferable because it can be efficiently and uniformly coated.

  As the solvent used in the coating solution, a general organic solvent such as a ketone solvent such as acetone or methyl ethyl ketone, an alcohol solvent such as ethanol or methanol, tetrahydrofuran, or a mixed solvent thereof can be used. A coating solution is prepared by dissolving in these solvents at a concentration of 0.5 to 10% by weight, preferably 1 to 8% by weight.

  After being immersed in the above coating solution, it is dried and subsequently subjected to a heat treatment at a temperature of 60 to 130 ° C. for 10 to 300 minutes. By this treatment, a crosslinked structure is introduced into the hydrophilic polymer, and the lubrication durability is greatly improved.

  Furthermore, by making the carboxyl group of the hydrophilic polymer into an alkali salt by immersing in an alkaline solution, it is possible to produce a medical device having excellent lubricity and lubrication durability. As an alkali used for this alkali treatment, any alkali can be used as long as it can achieve the purpose of converting the carboxyl group into an alkali salt. From the viewpoint of lubrication durability, it is particularly treated with an alcohol solution of an alkali metal alkoxide. To give the best results.

After the alkali treatment, it is preferable to thoroughly remove the alkali by thoroughly washing with ethanol, water or the like.

Specific examples and comparative examples according to the present invention will be described in more detail below, but the present invention is not limited to the following examples.
(Synthesis of hydrophilic compounds)

10 g of methyl vinyl ether maleic anhydride copolymer <GANTREZ-AN169> manufactured by IPS Co. was dissolved in 200 ml of ethyl alcohol, and esterification was carried out for 1 hour under heating and refluxing of ethyl alcohol. The reaction solution was dropped into 1000 ml of hexane to reprecipitate the reaction product. The reaction product was separated by filtration and dried under reduced pressure for 24 hours at room temperature to obtain a partially esterified solid methyl vinyl ether maleic anhydride copolymer (hereinafter referred to as PHE). From the measurement of the infrared absorption spectrum, it was confirmed that the acid anhydride ring remained.
This PHE was adjusted to a concentration of 6% by weight of an acetone solution to obtain a coating solution <1>.
(Adjustment of coating solution)

PEG200 as a cross-linking agent was added to the coating solution <1> so as to be 0.15% by weight with respect to PHE to obtain a coating solution <2>.
<Example 1>

A diamond-like carbon thin film was formed on the surface of a NiTi wire with a diameter of 0.45 mm, and surface activation treatment was performed by plasma irradiation to prepare a NiTi wire substrate with reactive functional groups introduced. The substrate was dipped in the coating solution <2> prepared above to apply the coating solution <2> to the surface of the substrate, followed by air drying and then drying at 80 ° C. for 30 minutes.

Furthermore, the heat treatment at 125 ° C for 2 hours reacted the acid anhydride groups in the PHE molecules with the reactive functional groups on the substrate surface and the crosslinking agent, and the lubricating components were immobilized on the substrate surface by chemical bonding.
Then, it was immersed in a 5% by weight sodium ethoxide ethyl alcohol solution and treated at room temperature for 3 minutes. Furthermore, it was thoroughly washed with water and dried at 60 ° C for 30 minutes.

The NiTi wire obtained by the above method showed excellent lubricity in water. In addition, when this wire was handled by hand in water, the number of times of handling until the lubricity disappeared was measured, and it was confirmed that the lubricity was maintained up to 330 times and the lubrication durability was excellent. .
<Example 2>

Processing was performed under the same conditions as in Example 1 except that Teflon was used as the base material instead of the NiTi wire. Teflon coated with a lubricant in this way showed very good lubricity, and the number of times it was handled in water was 350, and it had excellent lubrication durability.
<Example 3>

The NiTi wire processed under the same conditions as in Example 1 except that the concentration of the crosslinking agent was 0.2% by weight with respect to PHE maintained the lubrication durability up to 260 handling times in water.
<Example 4>

NiTi wire processed under the same conditions as in Example 1 except that 1,4-butanediol was used in place of PEG200 as a cross-linking agent and the addition amount was 0.1 wt% with respect to PHE. The lubrication durability was maintained up to 250 times.
<Comparative Example 1>

NiTi wire processed with the same conditions as in Example 1 with no cross-linking agent added to the coating solution <1> has 20 handling operations in water, resulting in poor lubrication durability. It was a thing.
<Comparative example 2>

The NiTi wire processed under the same conditions as in Example 1 except that a NiTi wire base material without a diamond-like carbon thin film was used had almost no lubricity in water, and the number of handling 0 times and lubrication durability was very poor.

With the technology obtained by the present invention, it has become possible to provide various medical devices having excellent durability and lubricity. In particular, even for base materials such as metal materials, inorganic materials, fluorine-based resins, and polyolefin-based resins, which have been difficult to ensure lubrication durability, medical treatment having a new function by the thin film coating technology according to the present invention. A wide range of applications including the development of tools can be expected.

Claims (7)

A hydrophilic medical device having lubricity when wet, wherein a surface-treated diamond-like carbon thin film is present on the surface of a base material constituting the medical device, and the surface thereof has a crosslinked structure Medical device characterized in that is chemically immobilized     The medical device according to claim 1, wherein the surface activation treatment of the diamond-like carbon thin film is performed by plasma irradiation, and a functional group is introduced on the film surface. The medical device according to claim 1 or 2, wherein the diamond-like carbon thin film has a thickness of 1 nm to 300 nm.     4. The medical device according to claim 1, wherein the hydrophilic polymer has a functional group capable of reacting with a surface functional group of the diamond-like carbon thin film and a functional group capable of forming a crosslinked structure in the molecule.     The medical device according to any one of claims 1 to 4, wherein the hydrophilic polymer is a maleic anhydride copolymer or a modified product thereof. On the surface of the base material constituting the medical device,
(1)
After forming a diamond-like carbon thin film and performing surface activation treatment by plasma irradiation to introduce functional groups on the thin film surface,
(2)
The surface is coated with a mixed solution of a maleic anhydride copolymer or a modified product thereof and a crosslinking agent, dried and heated,
(3)
Method for producing medical device having lubricious surface by alkali treatment On the surface of the base material constituting the medical device,
(1)
After forming a diamond-like carbon thin film and performing surface activation treatment by plasma irradiation to introduce functional groups on the thin film surface,
(2)
The surface is coated with a mixed solution of a maleic anhydride copolymer or a modified product thereof and a crosslinking agent, dried and heated,
(3)
Method for producing a medical device having a lubricious surface by treatment with an alcohol solution of an alkali metal alkoxide