JP2745558B2 - Lubricious medical materials - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to a medical material that exhibits excellent low friction when wet, that is, easy lubricity.
It is a useful material that can be widely applied to guidewires, cannulas and the like.

[Prior art] Low friction (slippery) on the surface of medical materials including physiological hygiene materials, especially catheters and guide wires
Is a required item. For example, when the catheter is not slippery, it may be painful when the catheter is inserted into a human body, and may damage tissue mucous membranes or cause inflammation.

Conventional techniques for imparting lubricity include a method of applying various oils to the surface of a substrate, a method of coating a polymer having a low coefficient of friction such as Teflon, and a method of coating a hydrophilic polymer. In particular, it is said that a method of coating a hydrophilic polymer is excellent in terms of practicality and safety.

Specific methods for coating the hydrophilic polymer include fixing polyvinylpyrrolidone using isocyanate (Japanese Patent Laid-Open No. 59-19582 and US Pat. No. 4,100,309), using a hydrophilic polymer copolymerized with a reactive functional group. A method using isocyanate (JP-A-59-81341),
Fixation of polyethylene oxide using isocyanate (JP-A-58-193766) and the like are disclosed.

[Problems to be Solved by the Invention] However, the method of applying various oils to the surface of the base material has low durability and has a problem in terms of safety due to leached substances. The method of coating a polymer having a low coefficient of friction, such as Teflon, has difficulty in obtaining sufficient lubricity. The method of coating a hydrophilic polymer has better lubricity than these methods, but has a problem in durability.
For example, in the fixing of polyvinylpyrrolidone using isocyanate (JP-A-59-19582, U.S. Pat. No. 4,100,309), elution occurs due to insufficient bonding between polyvinylpyrrolidone and a substrate. Furthermore, even in a method using a hydrophilic polymer obtained by copolymerizing a reactive functional group and an isocyanate (JP-A-59-81341), these methods have not been completely solved. This is considered to be due to the fact that the bond (amide bond or the like) is relatively easily hydrolyzed. Also, in the fixing of polyethylene oxide using isocyanate (JP-A-58-193766), there was a problem in durability as well.

As described above, conventionally, there has been no method for imparting lubricity having both performance, durability and safety. That is, an object of the present invention is to provide an excellent lubricity imparting technique which solves the problem of the conventional technique.

[Means for Solving the Problem] The present invention is intended to achieve the above object, and has the following configuration.

That is, the present invention relates to "a component (A) having a tertiary amino group and / or a quaternary ammonium salt, a component (B) having a polyethylene oxide group having a degree of polymerization of 50 or more, and hydrophobic components (C) and (A). And a slippery medical material comprising an ion-bonded acidic polysaccharide (D). "

The component (A) having a tertiary amino group and / or a quaternary ammonium salt of the present invention is, for example, a monomer having a tertiary amino group and / or a quaternary ammonium salt in a side chain. Preferably a monomer having a quaternary ammonium salt in the side chain, for example, It is shown by.

As the component (B), for example, And the like.

In order to obtain sufficient lubricity, the degree of polymerization of polyethylene oxide must be 50 or more, and preferably 80 or more.

Methods for producing such addition-polymerizable compounds are known. For example, compounds having R ₁ ＝ R ₂ CHCH ₃ can be obtained by adding ethylene oxide to methanol (addition number n ≧ 50). It can be obtained by transesterification of acid methyl. The degree of polymerization n of polyethylene oxide in such a compound can be determined by measuring the molecular weight of the compound by gel permeation chromatography or the like.

The hydrophobic component (C) is a component characterized by its homopolymer exhibiting water insolubility. Examples of the monomer include alkyl (meth) acrylate, vinyl chloride, vinylidene chloride, ethylene, propylene, Examples include vinyl acetate, (meth) acrylonitrile, styrene and derivatives thereof.

Although the copolymerization form of each of these components is not limited, the polymer of component (C) is used as a trunk polymer, and the components (A),
The grafted (B) is a preferred copolymer form in that it has the physical properties required as a medical material. At this time, as the polymer of the component (C) used as the backbone polymer, a vinyl chloride-containing polymer is particularly preferably used. Examples of the trunk polymer include, in addition to polyvinyl chloride, a copolymer of polyvinyl chloride with vinyl acetate and other monomers, a polymer obtained by grafting vinyl chloride on an ethylene-vinyl acetate copolymer, and a mixture of these polymers. Can be

In producing these copolymers, the component (A) may be polymerized in the state of a tertiary amino group, and may be quaternized after the polymerization.

The properties of the copolymer thus obtained depend on the components (A),
Although it can be changed over a wide range by the composition of (B) and (C),
In order to satisfy excellent lubricity and durability, the component (A) should be 5 to 5 parts.
20 wt%, component (B) 20-50 wt%, component (C) 30-75
wt% (however, component (A) + component (B) + component (C) = 100
%) Is preferred.

On the other hand, the acidic polysaccharide component (D) capable of ion-bonding with the component (A) in this copolymer includes mucopolysaccharides such as hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin and heparan sulfate, and chitosan Sulfuric acid, cellulose sulfate, amylopectin sulfate, pectin sulfate, alginic acid, alginic acid sulfate and the like can be mentioned.

Among them, heparin or a derivative thereof (heparinoid) is particularly preferable because it can impart anti-thrombotic properties as well as lubricity to the material.

The lubricity of the medical material of the present invention in a wet state is determined by the component (B)
It depends on the content of these acidic polysaccharides, in addition to the polyethylene oxide chain stream n therein.

The content of these acidic polysaccharides in the copolymer is 1 to 50% by weight, preferably 5 to 25% by weight.

The material of the present invention can be formed from each of the components (A), (B), (C) and (D), but the same effect can be obtained by coating an existing substrate.

Next, as an example, a method of forming a slippery surface using the material of the present invention will be described in detail using a solvent coating method as an example.

The substrate used for forming the coating is variously selected depending on the purpose of use, but various plastics, various inorganic materials, metal materials, and the like are preferably used. Specifically, polyvinyl chloride, polyethylene, polypropylene,
Examples include polystyrene, polyurethane, polyurea, polymethyl methacrylate, nylon, polyester, polyacrylonitrile, metal wires coated with them, stainless steel, elastic metals, ceramics and wood.

As a method for coating the surface of the substrate with the material of the present invention, first, a solution obtained by dissolving a predetermined amount of a copolymer composed of the components (A), (B) and (C) in an appropriate good solvent is used. After performing dip and spin coating, drying, and further usually, in a solution having an acid polysaccharide concentration of 0.5% or more containing 20% or more of water or formamide at a temperature of 50 to 100 ° C for 30 minutes to 100 hours, preferably 12 to 100 hours. It is desirable that the component (D) be ion-bonded by immersion for 36 hours.

Solvents used for coating the copolymer include alcohols, aromatic hydrocarbons, chain or cyclic hydrocarbons, halogenated hydrocarbons, ketones and amides which dissolve the copolymer. However, cyclic ethers such as tetrahydrofuran and dioxane, and aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and dimethylacetamide are preferably used. The concentration of the copolymer in the solution can be appropriately selected depending on the desired coating film thickness.
It is preferably used in the range of 01 to 50 wt%. Especially 1 ~ 10wt
% Is preferred. The method for forming a coating of the present invention is widely applicable to various fields. Because it has particularly excellent slipperiness and durability (safety), it can be applied to surface treatment of medical materials such as catheters, guidewires, endoscopes, contact lenses, and sanitary materials such as condoms. It is. In addition, since hydrophilic coatings are generally excellent in biocompatibility, applying them to medical materials in particular is expected to exhibit superior performance such as higher antithrombotic properties in addition to the above-mentioned properties.

(Examples) Examples are shown below, but the present invention is not limited to these examples.

Example 1 A diethyldithiocarbamate group having a photofunctional group content of 0.03
50 g of polyvinyl chloride having a polymerization degree of 1100 containing 2 mol% and 50 g of methoxypolyethylene glycol monomethacrylate (M-900G, manufactured by Shin-Nakamura Chemical Co., Ltd.) having polyethylene glycol units having a polymerization degree of 90 and 20 g of dimethylaminoethyl methacrylate (Tokyo Kasei) Is dissolved in 500 g of tetrahydrofuran, and a photopolymerization device (Ushio's ULO
-6DQ) using a high-pressure mercury lamp at 30 ° C. for 8 hours under a stream of argon under an argon stream to apply polyvinyl chloride to the above 2
A graft copolymer obtained by grafting various kinds of monomers was obtained. The chemical composition of this co-vertical and horizontal body determined by elemental analysis was 60.5% of polyvinyl chloride, 28.2% of methoxypolyethylene glycol monomethacrylate, and 11.3% of dimethylaminoethyl methacrylate.

This copolymer was dissolved in N, N-dimethylformamide at a concentration of 5% to prepare a coating solution. A guide wire having a diameter of 70 cm and a diameter of 2 mm in which a stainless steel wire was coated with polyurethane was immersed in this solution for 1 minute, gently pulled up, and dried at 50 ° C. for 1 hour under a stream of nitrogen.

Next, this guide wire was immersed in methanol containing 5% of ethyl bromide at 35 ° C. for 2 hours to quaternize tertiary amino groups in the copolymer. After sufficient washing with water, the guide wire was immersed in a 2% aqueous chondroitin sulfate solution at 50 ° C. for 24 hours to perform immobilization by ionic bonding. Next, unbound chondroitin sulfate and residual salts were removed with ion-exchanged water, followed by vacuum drying at room temperature for two days and nights.

The content of chondroitin sulfate in the coating polymer layer was measured by X-ray microanalyzer for the determination of sulfur atoms, and it was 12.5% by weight. The guide wire was wetted with physiological saline, water or blood, and its lubricity was examined by the following method.

The measurement was performed by a belt hanging method. FIG. 1 shows an outline of the measuring apparatus. The measurement was performed according to the following procedure.

a. On a sliding surface (94 mm ^φ × 30 mmh ring), wrap and secure pig skin that has been immersed in distilled water in advance.

b. After setting the sample on the slide surface and applying a load, wet the sample with distilled water.

c. Drive the test bench and record the load output on the load cell with a recorder.

d. When the measured load becomes stable, stop driving, change the load, and measure again.

Test conditions Test machine: Tensilon UTM-III-LH (manufactured by ORIENTEC) Load cell: Strain gauge (load capacity ± 550 g) Test speed: 50 mm / min Load: 10 to 40 g Friction coefficient μ was calculated by equation (1).

Here, T ₁ : tension, T ₂ : load, θ: contact angle (3.14 radians). As a result, when T ₂ = 40 g, the coefficient of static friction of this guide wire was 0.21. On the other hand, the static friction coefficient of the uncoated comparative sample was as large as 0.85 when measured under the same conditions.

Further, the lubricity of this wire did not change even after 100 or more repeated tests or even after boiling for 1 hour, indicating that the wire was excellent in durability.

Example 2 Polyvinyl chloride containing a photofunctional group used in Example 1
100 g of methoxypolyethylene glycol monomethacrylate (manufactured by Shin-Nakamura Chemical Co., M-110G) having 50 g and a polyethylene glycol unit having a degree of polymerization of 110 and 30 g of dimethylaminoethyl methacrylate (manufactured by Tokyo Chemical Industry) were dissolved in 500 g of tetrahydrofuran. A graft copolymer was obtained in the same manner as described above.

The chemical composition of this copolymer determined by elemental analysis was polyvinyl chloride 56.5%, methoxypolyethylene glycol monomethacrylate 31.3%, and dimethylaminoethyl methacrylate 12.2%.

A guide wire was coated using this copolymer in the same manner as in Example 1, and then quaternized and immobilized with chondroitin sulfate.

The chondroitin sulfate content in the coating polymer layer was 13.0% by weight.

Next, the slipperiness was evaluated by the same method as in Example 1, and the coefficient of static friction was 0.16.

Further, the lubricity of this wire did not change even after 100 or more repeated tests or even after boiling for 1 hour, indicating that the wire was excellent in durability.

Example 3 A guide wire sample was prepared under the same conditions as in Example 1 except that heparin was used instead of chondroitin sulfate.
The heparin content in the copolymer was 15.0% by weight. The lubricity of this guide wire was measured in the same manner as in Example 1, and as a result, the coefficient of static friction was 0.18.

On the other hand, the coefficient of static friction of the sample before binding heparin was 0.
80, comparable to the uncoated control sample.

The smoothness of the wire did not change even after repeated tests of 100 times or more, or even after boiling for 1 hour, indicating that the wire was excellent in durability.

Furthermore, this heparinized guide wire was sterilized with ethylene oxide gas, and its antithrombotic properties were evaluated by the inferior vena cava method.

Using an adult dog (approx. After indwelling for 1 or 2 hours, blood removal and laparotomy were performed to open the inferior vena cava, and the state of thrombus adhesion on the surface of the guide wire was observed.

As a result, no thrombus was found to adhere to the heparinized slippery surface of the present example either visually or electron microscopically, indicating that this material has both anti-thrombosis and excellent slipperiness. all right.

Comparative Example 1 50 g of polyvinyl chloride containing a photofunctional group and 50 g of methoxypolyethylene glycol monomethacrylate (M-23G, manufactured by Shin-Nakamura Chemical Co.) having a polyethylene glycol unit having a degree of polymerization of 23 used in Example 1, and methacrylic 20 g of dimethylaminoethyl dimethyl acid (Tokyo Kasei) was dissolved in 500 g of tetrahydrofuran, and a graft copolymer was obtained in the same manner as in Example 1.

The chemical composition of this copolymer determined by elemental analysis was 59.5% of polyvinyl chloride, 29.1% of methoxypolyethylene glycol monomethacrylate, and 11.4% of dimethylaminoethyl methacrylate. Example 1 using this copolymer
After coating on the guide wire in the same manner as described above, quaternization and immobilization of chondroitin sulfate were performed. The chondroitin sulfate content in the coating polymer layer was 12.8% by weight.

Next, when the slipperiness was evaluated in the same manner as in Example 1, the coefficient of static friction was 0.85, which revealed that the slipperiness was lower than in Examples 1, 2, and 3.

Comparative Example 2 50 g of methoxypolyethylene glycol monomethacrylate having a polyethylene glycol unit having a degree of polymerization of 90 and 20 g of dimethylaminoethyl methacrylate were dissolved in 500 g of tetrahydrofuran, and 30 mg of azobisisobutyronitrile was added. Polymerization was carried out at 50 ° C. for 16 hours. The composition of this copolymer determined by elemental analysis was methoxypolyethylene glycol monomethacrylate 60.5.
% And dimethylaminoethyl methacrylate 39.5%. This copolymer was coated on a guide wire in the same manner as in Example 1, quaternized, and immersed in a chondroitin sulfate solution to perform immobilization by ionic bonding.

The chondroitin sulfate content of this polymer layer is 11.0%
Met.

Although the slipperiness of the obtained wire was 0.23 in terms of the coefficient of static friction, it was found that the wire did not show slipperiness at all by repeated tests for several times or boiling for several minutes, indicating low durability.

Comparative Example 3 The same polyurethane-coated wire as in the example was dipped in a 2% solution of polyisocyanate (manufactured by Nippon Polyurethane Industry Co., Ltd., trade name: CL, TDI / TMP adduct) in methyl ethyl ketone (MEK) for 1 minute. And dried at 50 ° C. for 1 hour.
Next, this was immersed in a 4% chloroform solution of polyvinylpyrrolidone (Polyscience, molecular weight: 360,000) for 5 seconds, pulled up and dried, and reacted at 80 ° C. for 5 hours.

The slipperiness of the obtained wire was 0.20 in terms of the coefficient of static friction. However, it was found that the wire did not show slipperiness at all by repeated tests and boiling for several minutes, and had low durability.

[Effects of the Invention] The medical material of the present invention has excellent slipperiness, durability and antithrombotic properties.

[Brief description of the drawings]

FIG. 1 shows an apparatus for inspecting friction characteristics of medical materials according to the present invention. 1 ... drum, 2 ... pig skin 3 ... test table, 4 ... load 5 ... load meter

Claims (1)

(57) [Claims] 1. A component (A) having a tertiary amino group and / or a quaternary ammonium salt, a component (B) having a polyethylene oxide group having a degree of polymerization of 50 or more, and hydrophobic components (C) and (A). A slippery medical material comprising an acid-linked acidic polysaccharide (D).