JP3130364B2 - Surface lubricity imparting agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel surface lubricity-imparting agent for imparting surface lubricity to medical instruments and the like. More specifically, the present invention relates to a photoreactive surface lubricity imparting agent.

[0002]

2. Description of the Related Art Conventionally, methods for imparting lubricity to a surface include chemical treatment such as chemical treatment, solvent treatment, coupling agent treatment, surface graft polymerization, and surfactant treatment, ultraviolet irradiation treatment, low-temperature plasma treatment, and sputtering. Although physical treatments such as etching treatments are performed, the treatments are complicated, cannot be applied to all base materials, and have poor long-term lubricity. For example, high lubricity can be imparted by graft-polymerizing acrylamide or dimethylacrylamide by a surface graft polymerization method, but it is impossible on an inert surface such as polyester (PET) or engineering plastic.

[0003] In recent years, in order to solve such problems, attempts have been reported to apply nitrene radicals having extremely high activity generated by photodecomposition of azide to hydrophilize the material surface. That is, this is a technique in which a hydrophilic polymer having an azide group is used to fix light onto the surface of a polymer material. For example, Biomaterials [198
7, vol. 8,481] discloses a method in which chitosan is reacted with 4-azidobenzimidate hydrochloride to introduce an azide group into chitosan. However, the reaction between chitosan and azide compound is extremely slow, and a long time (~). Several days), the introduction rate is 1 mol% or less, and the coating of the medical device surface is subject to various restrictions because the generated chitosan derivative is soluble only in a dilute acidic aqueous solution. I was holding it.

Japanese Patent Application Laid-Open No. 3-103264 discloses that azide groups are introduced into a synthetic hydrophilic polymer such as polyacrylamide to make the surface hydrophilic. Specifically, a dimethylacrylamide-acrylamide copolymer is subjected to Hoffman decomposition, a part of the amide group is converted to an amino group, and then reacted with an azide compound in the presence of triethylamine to introduce an azide group. Thereafter, dialysis is performed to remove the low-molecular-weight compounds and purification is performed. However, in this example, the synthesis is extremely troublesome, which is a major drawback.

[0005]

SUMMARY OF THE INVENTION The present invention provides a surface lubricity-imparting agent which is easy to synthesize and process, can be applied to a wide range of organic substrates, and imparts lubricity over a long period of time.
And a method of manufacturing a medical device using the same, and a medical device provided with surface lubricity using the method.

[0006]

The above objects are achieved by the present invention described below.

(1) An azide compound having a hydroxyl group and / or an amino group is reacted with a copolymer obtained from an acid anhydride having an unsaturated bond and a non-conjugated vinyl monomer or styrene to form an azide compound on the side chain of the copolymer. A medical surface lubricity-imparting agent comprising, as a component, a polymer electrolyte derived from a polymer into which a group is introduced.

(2) The lubricity imparting agent according to the above (1), wherein the substituent having an unsaturated bond is maleic anhydride, itaconic anhydride or citraconic anhydride.

(3) The lubricity imparting agent according to the above (1), wherein the non-conjugated vinyl monomer is vinyl ether, vinyl acetate, N-vinylpyrrolidone or styrene.

(4) After forming the above (1) surface lubricity imparting agent layer on at least a part of the surface of the medical device, light irradiation irradiates a nearby atom via a highly reactive nitrene as an intermediate. A medical device provided with surface lubricity, characterized in that it is chemically fixed to the surface of a medical device by utilizing the property of forming a covalent bond, and a method of manufacturing the same.

Hereinafter, the present invention will be described in more detail. In the present invention, examples of the acid anhydride having an unsaturated bond include maleic anhydride, itaconic anhydride, citraconic anhydride and the like, but maleic anhydride is preferred from the viewpoint of availability.

Non-conjugated vinyl monomers include vinyl ethers such as methyl vinyl ether, ethyl vinyl ether and propyl vinyl ether, vinyl esters such as vinyl acetate and vinyl propionate, N-vinylpyrrolidone, N-vinylacetamide, and the like.
Examples include vinyl compounds such as N-methylvinylacetamide and isobutylene, and styrene.

By copolymerizing using at least one monomer selected from each of these groups, the copolymer having an acid anhydride structure according to the present invention can be obtained. As the polymerization method, ordinary radical-initiated polymerization can be performed, and known techniques such as solution polymerization, bulk polymerization, and precipitation polymerization can be used.

In the copolymer, the content of the repeating unit having an acid anhydride structure is preferably 30 to 70 mol%, and more preferably 40 to 60 mol%. Desirable.

The azide compound having an amino group and / or a hydroxyl group in the present invention is preferably an aromatic azide, a sulfo azide or the like from the viewpoint of the stability of the azide group. Specifically, azidoaniline, azidobenzylamine, azidobenzyl alcohol, sulfonyl azidoaniline, 2
-Hydroxyethyl azido phenyl ether, 2-aminoethyl azido phenyl ether, 2-aminoethyl azido benzyl ether and the like.

Since the reaction between the copolymer and the azide compound is a reaction between an acid anhydride and an amino group and / or a hydroxyl group, the reaction can be carried out under very easy and mild conditions. The reaction proceeds almost quantitatively only by heating to room temperature to 80 ° C. in an organic solvent having no. Azide group introduction rate is 100 mol per acid anhydride part.
%, Which is appropriately selected depending on the usage of the polymer electrolyte. That is, when the polymer electrolyte is used alone as a lubricity imparting agent, the content is 0.2 mol% to 60 mol%. When mixed with a hydrophilic polymer as described below, it may be introduced up to 100 mol%.

The presence of the aromatic azide group can be confirmed by infrared absorption spectrum (IR) and nuclear magnetic resonance spectrum.
In IR, there is a characteristic absorption of an aromatic azide group near 2130 cm ^-1 .

The polymer electrolyte in the present invention can be obtained by adding the remaining acid anhydride of the azide group-containing copolymer to water or an aqueous alkali solution to form a carboxylic acid type and / or a carboxylate type. Further, the acid anhydride portion is converted into a half ester by alcoholysis to obtain a carboxylic acid group, and as it is and / or as a carboxylate, a target polymer electrolyte can be obtained. When a carboxylate is used, examples of the counter cation include an alkali metal ion such as lithium, sodium, and potassium, and an ammonium ion, and a sodium ion is particularly preferable in terms of safety.

The alcohol used for carrying out the alcoholysis is methanol, ethanol, n
-, Iso-propanol, n-, iso-, ter-
An aliphatic alcohol such as butanol is desirable, and the whole or a part of the residual anhydride can be half-esterified. Aminolysis using various amines instead of alcoholysis may be used to form a half amide.

In the present invention, the azide group-containing polymer electrolyte may be used alone as a lubricity-imparting agent, but may be used after being diluted with a water-soluble polymer. In this case, it is desirable that the concentration of the azide group relative to the whole polymer is 0.1% or more, preferably 0.5% or more. If it is lower than this, the reaction with the material surface or the cross-linking reaction does not sufficiently occur, and the outflow of the lubricating layer may occur. Examples of the water-soluble polymer used for this dilution include a polymer electrolyte derived from a vinyl methyl ether / maleic anhydride copolymer, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, polyacrylic acid and the like. Therefore, a water-soluble polymer having a structure similar to that of the lubricity imparting agent is desirable. The structure does not need to be similar as long as they are compatible.

As a procedure for imparting lubricity to the surface of a medical device, a polymer having an acid anhydride structure in which an azide group is introduced and a polymer having a carboxylic acid structure in which an acid anhydride ring is decomposed are applied. Thereafter, it is also possible to irradiate with light and immobilize the surface, neutralize, and form a salt.

In the present invention, as a method for forming the surface lubricity-imparting agent layer on at least a part of the surface of the medical device, a method of dissolving the surface lubricity-imparting agent in water or an organic solvent and coating or spraying is used. Applicable. The thickness of the surface lubricity imparting agent layer can be controlled by the concentration of the solution and the number of times of application, and is preferably 0.1 μm or more, more preferably 2.0 μm or more.

As a method of chemically fixing to the surface of a medical device by utilizing the property of forming a covalent bond with a nearby atom via a highly reactive nitrene as an intermediate by light irradiation, a high pressure mercury lamp, a xenon lamp, etc. This is achieved by irradiation using a commercially available ultraviolet irradiation apparatus, preferably in a nitrogen atmosphere. 200 to 50 aromatic azide groups
Irradiation with ultraviolet light of 0 nm releases nitrogen gas to form nitrene radicals, which are chemically fixed to double bonds on the surface of the medical device by a crosslinking reaction, a hydrogen abstraction reaction, or the like. Although the irradiation time varies depending on the conditions, about 1 second to 5 minutes at an illuminance of ² mW / cm ² is sufficient.

The surface lubricity-imparting agent of the present invention thus obtained is easy to treat and can impart excellent lubricity over a long period of time, and can be used for various catheters such as angiographic catheters and guide wires, and for endoscopy. It is suitably used as a surface treatment agent for medical instruments that require lubricity such as mirrors, contact lenses, artificial joints, and artificial cartilage or that come into contact with living tissues.

Hereinafter, the present invention will be described by way of examples, but the present invention is not limited thereto.

[0026]

【Example】

Example 1 Poly (maleic anhydride-vinyl methyl ether) alternating copolymer (Gantreds AN-169 [GA
NTREZ AN-169]; General Aniline and Film Corporation [General
Aniline & Film Corporation
n]) was dissolved in 100 ml of anhydrous acetone,
In a dark place, 0.5 g of triethylamine and 0.76 g of azidoaniline hydrochloride were added and reacted at room temperature for 3 days.

After adding 20 ml of absolute ethanol to the reaction solution and reacting at room temperature for 1 day, the solution was dialyzed in ethanol for 5 days, and the polymer (I) was recovered by reprecipitation in hexane. The yield was 1.6 g. All reactions were performed in the dark. The structure of the recovered polymer (I) was confirmed by an infrared absorption spectrum and a nuclear magnetic resonance spectrum.
The absorption attributable to the azide group at m ^-1 (shown in FIG. 1) was 7.2 ppm and 7.9 p in the proton nuclear magnetic resonance spectrum.
A peak attributable to an aromatic ring was observed in pm. From the proton ratio, about 50 m to the maleic anhydride part of the poly (monoethyl maleate-vinyl methyl ether) alternating copolymer
ol% azide group was introduced.

A 1% by weight ethanol solution of the polymer (I) was prepared and coated on a polyurethane sheet by a spin coater. Place this sheet under a stream of nitrogen
3 with a high-pressure mercury lamp (H-400P manufactured by Toshiba Corporation)
After irradiating with ultraviolet rays at a distance of 0 cm (5.7 mW / cm ² ) for 2 minutes, the substrate was sufficiently washed in ethanol and dried.

When an IR spectrum of the sheet surface was measured by a multiple reflection ATR method, absorption due to the ester was observed at 1740 cm ^-1 (shown in FIG. 1), and poly (monoethyl vinyl methyl methyl maleate maleate) was observed on the polyurethane surface. ) It was shown that the alternating copolymer was fixed.

The friction coefficient μ between the polyurethane sheet having the poly (monoethylvinylmethylether maleate) alternating copolymer fixed on its surface and the silicone rubber was determined by a friction tester (KES-SE manufactured by Kato Tech Co., Ltd.). Was. The coefficient of friction μ between the untreated polyurethane sheet and the silicone rubber is 5.55 when dry and 4.44 when wet, whereas the poly (monoethyl vinyl methyl ether maleate) alternating copolymer of the present invention has a surface The coefficient of friction μ between the polyurethane sheet and the silicone rubber fixed to the sample was 8.12 when dry and 0.58 when wet, and the surface of the medical device of the present invention showed extremely excellent lubricity.

Example 2 0.2 g of the polymer (I) obtained in Example 1 was mixed with a poly (maleic anhydride-vinyl methyl ether) alternating copolymer (Gantrez AN-16).
9 [GANTREZ AN-169]; General Aniline and Film Corporation [Gene
ral Aniline & Film Corpor
1.0 g) in tetrahydrofuran (TH
F) It was dissolved in 50 ml, coated on a polyurethane sheet in the same manner as in Example 1, irradiated with ultraviolet rays, and fixed. The sheet was immersed in a 2% aqueous sodium carbonate solution for 3 hours to form a sodium salt, and then sufficiently washed with distilled water. The sheet surface showed good lubricity and was slimy.

Example 3 10 g of a maleic anhydride / styrene alternating copolymer (manufactured by Aldrich, average molecular weight 350,000) was added to tetrahydrofuran (TH).
F) Dissolve in 500 ml and add azidoaniline 0.3
g of a THF solution containing 30 g was added dropwise, and the reaction was allowed to proceed at 50 ° C. overnight. As a result, the reaction proceeded quantitatively. The polymer solution was added to ether and reprecipitated to obtain a polymer (II). From the IR spectrum of the polymer, 213
A peak at 0 cm ^-1 due to an azide group was observed. Example 1 A 1% ethanol solution of polymer (II) was prepared and
After coating on a polyurethane sheet in the same manner as described above, the sheet was irradiated with ultraviolet rays and washed.

When an IR spectrum of this surface was measured by a multiple reflection ATR method, absorption due to the ester was observed at 1740 cm ^-1 , and the maleic acid monoethyl ester / styrene alternating copolymer was fixed to the polyurethane sheet. It was shown that. After immersing the sheet in a 2% aqueous sodium carbonate solution for 3 hours to form a sodium salt,
Washed thoroughly with distilled water. The sheet surface showed good lubricity and was slimy.

Example 4 A 2% THF solution of the polymer (II) obtained in Example 3 was prepared, coated on a polyethylene sheet in the same manner as in Example 1, and irradiated with ultraviolet light to obtain tetrahydrofuran (THF). Washed thoroughly.
From the IR spectrum of this surface, absorption of carbonyl based on the acid anhydride was observed at 1800 cm ⁻¹ , and the polymer (I
It was shown that I) was fixed to a polyethylene sheet. The sheet was immersed in methanol for 3 hours, immersed in a 2% aqueous sodium hydrogen carbonate solution for 3 hours to form a sodium salt, and then sufficiently washed with distilled water. The sheet surface also exhibited good lubricity and was slimy.

Example 5 0.1 mol of vinyl acetate and 0.1 mol of maleic anhydride were dissolved in 500 ml of benzene, 0.3 mol% of azobisisobutylnitonyl was added, and polymerization was carried out at 70 ° C. for 24 hours. Maleic anhydride-
A vinyl acetate alternating copolymer was obtained. 2 g of the polymer was dissolved in 100 ml of tetrahydrofuran (THF), and 20 ml of a THF solution containing 0.1 g of azidoaniline was added thereto.
Was added dropwise, and the reaction was carried out at 40 ° C. overnight.

The THF solution was cast on a polyethylene terephthalate (PET) film in the same manner as in Example 1, and then irradiated with ultraviolet rays to fix the polymer on the surface of the PET film. After immersing the film in propanol for 5 hours,
After drying and measurement of the surface IR, absorption due to the ester was observed at around 1730 cm ^-1 . The sheet 2
After immersing in a 2% aqueous solution of sodium carbonate for 2 hours to obtain a sodium salt, the resultant was sufficiently washed with distilled water. The sheet surface showed good lubricity and was slimy.

[0037]

The polymer of the present invention reduced the coefficient of friction μ when wet by a simple method and showed extremely excellent lubricity. Various types of catheters such as angiography catheters and guide wires, endoscopes, contact lenses, artificial joints, artificial cartilage, etc., which require lubricity or provide surface lubrication for medical devices that come into contact with living tissue It is suitably used as an agent.

[Brief description of the drawings]

FIG. 1 is an infrared absorption spectrum of one example of the surface lubricity imparting agent of the present invention described in Example 1.

────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Chie Nishio 1500 Inoguchi, Nakai-machi, Ashigarakami-gun, Kanagawa Prefecture Investigator, Terumo Corporation Ikuharu Oya (56) References JP-A-4-144567 (JP, A) JP-A-3-228854 (JP, A) JP-A-2-228970 (JP, A) JP-A-3-103264 (JP, A) JP-A-59-177170 (JP, A) JP-A-55-106241 (JP, A A) JP-A-4-90877 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61B 1/00 A61L 27/00 A61L 29/00 A61L 31/00 G02B 1/10- 1/12 CA (STN)

Claims (1)

(57) [Claims] An azide compound having a hydroxyl group and / or an amino group is reacted with a copolymer obtained from an acid anhydride having an unsaturated bond and a non-conjugated vinyl monomer or styrene, and an azide compound is added to a side chain of the copolymer. A medical surface lubricity-imparting agent comprising, as a component, a polymer electrolyte derived from a polymer into which a group is introduced.