JP3347132B2 - Medical device having lubricating surface when wet and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a medical device and a method for manufacturing the same. More specifically, the present invention relates to a medical device having excellent lubricity when wet by a polymer bonded to a substrate and a method for producing the same.

[0002]

2. Description of the Related Art Medical devices such as catheters inserted into the trachea, gastrointestinal tract, urethra, blood vessels, and other body cavities or tissues, and the base material surfaces of medical devices such as guidewires and stylets inserted therein. In general, thrombosis, tissue adhesion, tissue damage, foreign body reaction, etc. are observed.
For this reason, these medical devices are required to be smooth so as not to damage the tissue and to be able to be securely inserted into a target site, and to damage the mucous membrane by friction while being placed in the tissue. Good lubricity is required to avoid rubbing and causing inflammation.

For this reason, a low friction material is used as a base material, and the surface of the base material is coated with a hydrophilic polymer. For example, using a low friction material such as fluororesin or polyethylene resin as the base material of these medical devices,
Further, a fluororesin, silicone oil, olive oil, glycerin, or the like is applied to the surfaces of these surfaces.

However, in these methods, permanent lubricity cannot be expected, and there is a problem in terms of safety such as desorption, peeling, and elution of the lubricating substance from the substrate surface. For example, when using a low-friction material such as high-density polyethylene or applying a surface coat with them, there is a problem that the coefficient of friction is not sufficiently low, and in the case of oil surface application, the dynamic friction coefficient is low. But there is no sustained effect,
Since the oil or the like is washed away or the surface is sticky, and it is difficult to store the product, the application is performed immediately before use, and there is a problem that the handling becomes complicated.

Further, US Pat. No. 4,100,309 discloses that a copolymer of polyvinylpyrrolidone and polyurethane is used as a substance having lubricity. Although this method is satisfactory in terms of lubricity and durability, it requires two or more kinds of applied polymers and the presence of an isocyanate group as a reactive group is indispensable. Reaction with a base material having low reactivity and a polymer having lubricity is impossible and is not preferred.

Japanese Patent Application Laid-Open No. Sho 59-81,341 discloses that
A method is disclosed in which unreacted isocyanate groups are formed on the surface of a medical device, and the surface is treated with a hydrophilic copolymer covalently bonded to the isocyanate groups to impart lubricity. According to this method, good lubricity is obtained on the surface of the base material, and it is expected that the lubricity can be maintained to some extent. However, in this method, when the hydrophilic copolymer is mainly composed of N-vinyl-2-pyrrolidone or the like, the film strength of the polymer is not sufficient, so that the film is damaged by repeated friction and has a sufficient durability. There is a problem that can not be obtained.

[0007] Japanese Patent Publication No. 1-55,023 discloses that a compound having two or more copolymers of monomers and having an active hydrogen as a main chain is bonded to the surface of a medical device via a polyisocyanate compound. And imparts biocompatibility. However, in this method, the presence of at least one of an amino group, an imino group, a carboxyl group, and a mercapto group is indispensable on the surface of the base material constituting the medical device. There is a disadvantage that treatment is not possible with a medical device having no base.

Further, Japanese Patent Publication No. 1-33,181 discloses that
A method is disclosed in which a reactive functional group present on the surface of a substrate constituting a medical device and a maleic anhydride-based polymer substance are covalently bonded to impart lubricity to the surface of the substrate when wet. . However, this method also has a disadvantage that a reactive functional group must be present on the surface of the substrate constituting the medical device, and cannot be directly introduced into a substrate that does not have a reactive functional group. When a substrate having no reactive functional group is used, a method in which a reactive functional group is present on the surface of the substrate by treating the substrate in advance with a solution of a compound having a reactive functional group is used. As described in the above publication, there is a problem that the water-swellable polymer cannot be stably bound unless the compound is stably bound to the substrate surface.

[0009]

Therefore, the present invention is not limited to the material of the base material, and can be used in permanent fluids such as body fluids such as saliva, digestive juice and blood, and aqueous solvents such as physiological saline and water. It is an object of the present invention to provide a highly safe medical device having frictional properties and a method for manufacturing the same.

[0010]

The above objects are achieved by introducing at least one reactive functional group into at least a part of the surface of a substrate constituting a medical device by a plasma-initiated graft polymerization method. And a water-swellable polymer combined with a medical device exhibiting lubricity when wet.

[0011] The present invention also provides a medical device wherein the medical device is a catheter. The present invention also provides a medical device wherein the water-swellable polymer is a polysaccharide.

[0012] The present invention further provides a method for introducing at least one reactive functional group into at least a part of the surface of a substrate constituting a medical device by a plasma-initiated graft polymerization method. And a method of manufacturing a medical device exhibiting lubricity when wet, characterized by combining

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The medical device according to the present invention, which exhibits lubricity when wet, has at least a reactive functional group on at least a part of the surface of a substrate constituting the medical device by a plasma-initiated graft polymerization method. One type is introduced, and the functional group is bonded to a water-swellable polymer.

The compound having these functional groups introduced on the surface of the substrate has a hydroxyl group, a thiol group, an amino group, an imino group, a carboxyl group, a carbamate group, an isocyanate group, an epoxy group, and an acid halogen group. Any one may be used as long as acrylic acid, methacrylic acid, glutaric acid, pimelic acid, allyl alcohol, ethyleneimine, glycidyl (meth) acrylate, (meth) acrylic acid chloride, (meth) And) acryloyloxyethyl isocyanate. The compounds having these functional groups to be introduced may be two or more kinds, and are esterified, amidated, sulfonated, oxidized, hydrolyzed, quaternized, at least before or after introduction. A water-swellable polymer after performing at least one chemical treatment of cross-linking to convert it into a hydroxyl group, thiol group, amino group, imino group, carboxyl group, carbamate group, isocyanate group, epoxy group, or acid halogen group. It may be combined with.

The water-swellable polymer that binds to these functional groups is a polymer that swells or dissolves by absorbing water, such as body fluids such as saliva, digestive juice, blood, and physiological saline and water. There is no particular limitation as long as it has low friction in an aqueous solvent, and specific examples thereof include a maleic anhydride-based polymer substance and a polysaccharide. The maleic anhydride-based polymer substance may be a homopolymer or a copolymer of maleic anhydride.
A maleic anhydride copolymer is preferably used. Examples of such a device include: A. F. Corporation to GA
An approximately 1: 1 copolymer commercially available as NTREZAN can be mentioned. Further, the derivative of the maleic anhydride-based polymer substance is not limited to water-soluble, and if the above-mentioned maleic anhydride-based polymer substance is used as a basic component, the insolubilized one has a degree of freedom in the molecular chain, and Any material that contains water may be used. Specifically, an ester, a salt, an amidate, an anhydride, a halide, an ether, a hydrolyzate, an acetal obtained by condensation, addition, substitution, oxidation, reduction, or the like of the maleic anhydride-based polymer substance. Compound, formal compound, alkylol compound, quaternary compound, diazo compound, hydrazide compound, sulfonate, nitrate, ion complex, diazonium group, azide group, isocyanate group, acid chloride group, acid anhydride group, imino carbonate A crosslinked product with a substance having two or more reactive functional groups such as an ester group, an amino group, a carboxyl group, an epoxy group, a hydroxyl group, and an aldehyde group, and further, a vinyl compound, acrylic acid, methacrylic acid, a diene compound, and the like. And the like. Of these,
Partial alkyl esters are preferred. Such a maleic anhydride-based polymer substance is well dissolved in water, and by treating with such a solution, the frictional resistance can be significantly reduced, and a base material having excellent lubricity can be obtained. Also,
Derivatives obtained by condensation or addition reaction or substitution reaction of these maleic anhydride-based polymer substances and so-called insolubilized ones partially cross-linked or the like can similarly obtain lubricity. Further, the average molecular weight of the maleic anhydride-based polymer substance used in the present invention,
Although not particularly limited, those having a lubricating property of about 3 to 5,000,000 are preferable because a lubricating layer having a high lubricating property, an appropriate thickness and a degree of swelling when containing water is not remarkably large is obtained.

The polysaccharides usable as the water-swellable polymer include, specifically, hyaluronic acid, chondroitin, chondroitin sulfate, keratan sulfate, keratan polysulfate, heparanic acid, and those widely present in animal tissues and body fluids. Examples thereof include mucopolysaccharide which is a salt and alginic acid and salts thereof which are usually taken by humans. These polysaccharides are preferable because they can be expected to impart high safety when used in medical devices.

Further, in order to bond these functional groups to the polymer having water swelling properties, it is preferable to bond via a compound having a reactive group at both terminals such as diamine, diisocyanate and diepoxy groups. preferable.

As a method for introducing the compound having a reactive functional group onto the surface of a substrate, a plasma-initiated polymerization method is used in the present invention. Generally, as a method for introducing such a compound to the substrate surface, a method for generating radicals on the substrate surface includes a method using a hydrogen abstracting agent, neutron beam irradiation, γ-ray irradiation, electron beam irradiation, plasma irradiation, or the like. However, neutron irradiation, γ-ray irradiation, and electron beam irradiation are not preferable because radicals may be generated on the surface of the substrate and inside the substrate, and the physical properties of the substrate may be impaired. For this reason, in the present invention, a plasma-initiated polymerization method using a plasma irradiation method capable of generating radicals only on the surface is used.

In order to introduce the reactive functional group on the surface of the substrate by plasma-initiated polymerization, 0.001 to 100 To
After irradiating low-temperature plasma for 0.5 to 60 seconds, preferably 1 to 30 seconds under an atmosphere of argon, nitrogen, air, various monomers and the like under a reduced pressure of rr, preferably 0.01 to 10 Torr, the plasma It is carried out by supplying the compound having the functional group in the presence and performing graft polymerization.

It is not necessary to directly bond a compound having these reactive functional groups to radicals generated on the surface of the substrate, and a glass transition point such as ethyl acrylate is required to maintain the physical properties of the substrate. After bonding a polymer having a low molecular weight, a compound having a hydroxyl group, a thiol group, an amino group, an imino group, a carboxyl group, a carbamate group, an isocyanate group, an epoxy group, or an acid halogen group may be introduced to the surface of the base material. Absent.

The shape of the medical device of the present invention is as follows:
A flat membrane, a hollow fiber, a solid thread, a sheet, a tube, a nonwoven fabric, a woven fabric, or a composite thereof can be considered. In particular, it is preferably a tube-shaped so-called catheter that can be inserted into a blood vessel or other body cavity or tissue.

Examples of the form of the medical device of the present invention include an artificial kidney membrane, a plasma separation membrane, a catheter, an artificial lung membrane, an artificial blood vessel, an anti-adhesion membrane, an artificial skin, a wound dressing, and an implant material. can do. In particular, it is suitably used as a catheter to be inserted into a blood vessel or other body cavity or tissue.

Further, the base material constituting the medical device used in the present invention varies depending on the intended medical device, and includes, for example, polyolefin, halogenated polyolefin, polyether, polyester, polyurethane,
Examples include polyimine, polyimide, nylon, a polymer containing tertiary carbon, or a mixture thereof. In particular, polyolefins, halogenated polyolefins, polyurethanes or mixtures thereof are preferred in view of operational considerations.

The medical device of the present invention has a water-soluble or water-swellable polymer chemically firmly introduced into the surface of a substrate. For this reason, the medical device of the present invention does not observe platelet adhesion, which is one of the causes of thrombus formation, on the surface of the substrate, as in the case of using a conventional polyolefin, halogenated polyolefin, or polyurethane as a low friction substrate. Long lasting contact with blood. Furthermore, the medical device of the present invention does not show the phenomenon of detachment, peeling, and elution of the coating agent from the substrate surface, which is observed in the method of applying silicon oil, olive oil, glycerin, etc. to the substrate surface. Safety is ensured.

As described above, the medical device of the present invention has a permanent platelet-suppressing action, low friction in body fluids and aqueous solvents, and furthermore, excellent safety is ensured.

[0026]

The present invention will be described more specifically with reference to the following examples. However, the material of the substrate used in the present invention may be one type or two or more types as long as it is as described above. It may be a composite shape.

(Examples 1 to 3) Polypropylene sheet (FOP # 60, thickness 60 μm, manufactured by Nimura Chemical Co., Ltd.)
Was irradiated with low-temperature plasma (Ar, 1 Torr) for 10 seconds, and then the compounds (monomers) shown in Table 1 were supplied in a gas phase to perform surface graft polymerization at a temperature of 288K. The sheet was washed with a good solvent for 1 day, dried, and then washed in a 1,4-diaminobutane 5% acetone solution.
The reaction was performed at 6 ° C. for 6 hours.

After drying, the mixture was reacted in a 2% acetone solution of maleic anhydride polymer at 40 ° C. for 1 hour to obtain a sample having lubricity.

Further, as a continuous index of lubricity, the sheet thus obtained was extracted with a good solvent at 70 ° C. for 30 minutes, and the UV of the extract was measured.

The results are shown in Table 1.

Comparative Examples 1-3 The same sheets as in Examples 1-3 were coated without a plasma-initiated graft polymerization with a 2% solution of the polymer for 5 minutes at 25 ° C.

Thereafter, the sheet was treated with a 1,4-diaminobutane solution and a maleic anhydride solution in the same manner as in Examples 1 to 3.

Similarly, as a continuous indicator of lubricity, the polymer was extracted with a good solvent at 70 ° C. for 30 minutes, and the UV of the extract was measured.

The results are shown in Table 1.

[0035]

[Table 1]

(Examples 4 to 6) Platelets were subjected to the platelet adhesion test in the same manner as in Examples 1 to 3. The sheet (1 cm × 1 cm) was contacted with human fresh blood for 5 minutes, fixed with glutaraldehyde, dehydrated, and the adhesion number of platelets was measured with a scanning electron microscope at a magnification of 300 times.

The results are shown in Table 2.

(Comparative Examples 4 to 6) Using the same method as in Examples 4 to 6, a sheet similar to Comparative Examples 1 to 3 was subjected to a platelet adhesion test.

The results are shown in Table 2.

[0040]

[Table 2]

[0041]

As described above, the present invention introduces at least one reactive functional group into at least a part of the surface of a substrate constituting a medical device by a plasma-initiated graft polymerization method. The medical device of the present invention has a water-soluble or water-swellable weight on the surface of the base material, since the medical device has a lubricating surface when wet, characterized in that the base is bonded to a water-swellable polymer. The coalescence is firmly introduced chemically. Therefore, the medical device of the present invention, as in the case of using a conventional polyolefin or halogenated polyolefin, polyurethane as a low friction substrate, platelet adhesion that is a factor of thrombus formation on the substrate surface is not observed, Long-lasting contact with blood. Furthermore, the medical device of the present invention does not show the phenomenon of detachment, peeling, and elution of the coating agent from the substrate surface, which is observed in the method of applying silicon oil, olive oil, glycerin, etc. to the substrate surface. Safety is ensured.

In addition, the medical device of the present invention has extremely low frictional resistance on the surface of the medical device, and is particularly wet with body fluids such as saliva, digestive juice and blood, and aqueous liquids such as physiological saline and water. The frictional resistance in a wet state is extremely small, which provides advantages such as ease of insertion, reduction of patient pain, and prevention of damage to mucous membranes and intima of blood vessels.

Further, in the present invention, a functional group is introduced by generating radicals on the surface of a substrate by plasma irradiation, and there are almost no restrictions on applicable substrates, so that the present invention can be used for various medical devices. Excellent in versatility.

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-4-202441 (JP, A) JP-A-61-209669 (JP, A) JP-A-61-209670 (JP, A) 54376 (JP, B2) Toshiyuki Okada, Yoshihito Raft, Tissue Reaction to Silicone with Various Surfaces, Proceedings of the 11th Annual Meeting of the Biomaterials Society of Japan, Japan, October 27, 1989, p. 81 Yasushi Tamada, Toshiyuki Okada, Yoshito Raft, Attachment of cells to silicone with collagen immobilized on the surface, The 6th Annual Meeting of the Japanese Society for Biomaterials, Abstracts, Japan, November 22, 1984, p. 17-18 (58) Field surveyed (Int. Cl. ⁷ , DB name) A61L 27/00-33/18

Claims (4)

(57) [Claims] 1. Insertion into a body cavity or tissue where blood is present
A medical device to be used, wherein at least one reactive functional group is introduced into at least a part of the blood contact surface of the base material constituting the medical device by a plasma-initiated graft polymerization method, and the functional group and water swelling are introduced. A medical device exhibiting lubricity when wet, characterized in that a hydrophilic polymer is bonded (except for a bond formed solely by a complex formed by an interacting intermolecular force). 2. Insertion into a body cavity or tissue where blood is present
A medical device to be used, wherein at least one reactive functional group is introduced into at least a part of the blood contact surface of the base material constituting the medical device by a plasma-initiated graft polymerization method, and the functional group and water swelling are introduced. It is characterized in that a hydrophilic polymer is bonded (except for a bond formed only by a complex between interacting molecules), which exhibits lubricity when wet and is inserted into a body cavity or tissue using this lubricity. Medical device configured as follows. 3. Insertion into a body cavity or tissue where blood is present
A medical device to be used, wherein at least one reactive functional group is introduced into at least a part of the blood contact surface of the base material constituting the medical device by a plasma-initiated graft polymerization method, and the functional group and water swelling are introduced. A method for producing a medical device exhibiting lubricity when wet, characterized in that a hydrophilic polymer is bound (except for a bond formed solely by a complex formed by an interacting intermolecular force). 4. Insertion into a body cavity or tissue where blood is present
A medical device to be used, wherein at least one reactive functional group is introduced into at least a part of the blood contact surface of the base material constituting the medical device by a plasma-initiated graft polymerization method, and the functional group and water swelling are introduced. It is characterized in that a hydrophilic polymer is bonded (except for a bond formed only by a complex between interacting molecules), which exhibits lubricity when wet and is inserted into a body cavity or tissue using this lubricity. Of manufacturing a medical device configured as described above.