JP3233677B2 - Medical devices surface modified by surface polymerization - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a material whose surface has been modified by surface polymerization, and more particularly to a medical device having excellent surface lubricity and biocompatibility.

[0002]

2. Description of the Related Art As a method for forming a surface-modified layer containing a block or graft copolymer, a method of coating a block or graft copolymer is generally used. For example, Journal of biomedical materials
Reseaech. Vol.20., 919-927 (1986) discloses that a substrate is coated with a block copolymer composed of a hydrophilic polymer chain and a hydrophobic polymer chain to provide excellent blood compatibility. It is described to produce a surface having properties. However, in this method, since the solvent in which the block copolymer dissolves is limited, the base material that can be coated is also limited. For example, it has been difficult to coat a substrate which is easily deteriorated by the solvent or a substrate having poor wettability (a solvent having a large contact nucleus with the solvent).

As a method of forming a surface modified layer by surface polymerization, a method of generating a radical capable of initiating polymerization by using plasma, ozone, electron beam, γ-ray or the like and performing surface graft polymerization has been disclosed. (Japanese Unexamined Patent Application Publication No. 2-263
845, JP-A-59-152913, US Pat.
46, USP 3,826,678). However, since these do not have a polymer compound having a polymerization initiating group in the main chain on the material surface, radicals capable of initiating polymerization are limited to radicals generated on a substrate or the like.
The amount of generated radicals and the radical stability differ depending on the base material, and there are many materials that are difficult to be graft-polymerized.
For example, materials that are easily dehydrogenated, such as hydrogen bonded to tertiary carbon, such as polypropylene, are susceptible to surface graft polymerization, and are not easily dehydrogenated, such as polyphenylene sulfide, polystyrene, and nylon. It was difficult to graft polymerize to metals such as aluminum and ceramics. In addition, depending on the substrate, surface graft polymerization is required, but high-power plasma or long-time plasma prepolymerization is required.Thus, thin materials or specially shaped materials may deform or generate small cracks. There was a problem in practical use.

Japanese Patent Application Laid-Open No. 2-229839 describes a method in which two kinds of monomers are separately supplied by a plasma surface graft polymerization method to form a surface modified layer containing a block copolymer. Also in this method, since the amount of generated radicals and the radical stability vary depending on the base material, there are materials that are difficult to be graft-polymerized.

Conventionally, surface modification methods using a polymer compound having a polymerization initiating group or a prepolymer include:
A general method is to coat a polymer compound having a polymerization initiating group such as an azide group, an azo group, or a peroxide group on the side chain of a monomer as a photosensitive polymer on the material surface and photo-cur with UV. (Eg, “Photosensitive polymer” from Kodansha Scientific, a functional polymer series), after the photosensitive polymer is pre-existing on the surface of the base material and then contacted with a monomer gas. Post-polymerization processes have not been investigated. In particular, for the purpose of creating a medical material surface, formation of a surface modified layer containing a block copolymer using a polymer compound having a polymerization initiation group in the main chain has not been studied.

On the other hand, polymer compounds having a polymerization initiating group in the main chain are known as polymeric peroxides (Polymer, vol. 3).
2, p19-28 [1991]) and macroazo compounds (Journal of Polymers, vol. 47, No. 4, 321-329 [1990]).
It is used for the synthesis of block copolymers. Block copolymers synthesized using polymeric peroxide and the like have been used for surface modification of polymer materials as a solvent coating method, but due to restrictions on solvents and base materials,
There is a limit to the application to medical materials with special shapes and functions.

[0007]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a medical or medical device in which a surface modified layer containing a block copolymer having excellent surface lubricity and biocompatibility is formed firmly and uniformly. To provide tools.

[0008]

SUMMARY OF THE INVENTION Polymethoxyethyl acrylate or polymethyl methacrylate having a peroxide group in the main chain is preliminarily present on the surface of a substrate, and a radically polymerizable monomer is supplied in a gas phase to form the group. This is achieved by a surface-modified medical material characterized in that a block copolymer is formed on the surface of the substrate by polymerizing on the surface of the material.

The present invention also provides a surface-modified material characterized in that radically polymerizable monomers are supplied in the gas phase after or during irradiation with low-temperature plasma and polymerized on the material surface. It is. The present invention further provides a surface-modified material, wherein a surface-modified layer containing a copolymer of a hydrophilic polymer and a hydrophobic polymer is formed by surface polymerization. This shows a surface-modified material characterized in that a surface-modified layer containing a copolymer having a water-soluble polymer chain insolubilized by polymerization is formed.

Hereinafter, the present invention will be described in detail. The polymethoxyethyl acrylate or polymethyl methacrylate (polymerization initiator) having a peroxide group in the main chain of the present invention is a polymer polymerization initiator having a radical polymerization initiating group in the main chain. The peroxide groups present in the main chain of polymethoxyethyl acrylate or polymethyl methacrylate are based on heat, light (ultraviolet rays, vacuum ultraviolet rays,
Laser, etc.), plasma, electron beam, reducing substance (redox system), etc., to generate radicals at the terminals, and the radicals are used as polymerization initiation points to polymerize the monomers to form block copolymers. Coalescence will be produced. When there is no polymerizable monomer, a surface modified layer is formed by a crosslinking reaction due to a reaction between radicals or a graft reaction due to a reaction with a substrate.

As a method for pre-existing polymethoxyethyl acrylate or polymethyl methacrylate having a peroxide group in the main chain in the main chain on the surface of the material, a blending method or a coating method can be considered. This is a coating method that can be held. The material serving as the base material is not particularly limited, such as a polymer material, ceramics, and metal.

The high molecular weight polymerization initiator has an average molecular weight of 5,000 or more, preferably 10,000 or more.
If the molecular weight is small and the number of polymerization initiator groups present in the molecule is large, the chain length of the polymer forming the high molecular weight polymerization initiator becomes short, and the expected effects, such as the adhesion effect with the base material, This is because the separation effect, the elution prevention effect, and the like cannot be sufficiently exhibited.

Examples of the polymerizable monomer used in the present invention include acrylic, methacrylic, acrylamide, and vinyl monomers having a radically polymerizable unsaturated bond.

According to the surface polymerization method of the present invention, a block copolymer is formed on the substrate surface as described above. In addition to the block copolymer, a homopolymer, a graft copolymer or a crosslinked product thereof is obtained. , Additives, fillers and the like may be present on the surface.

The surface polymerization is required to be carried out under the condition that the high molecular polymerization initiator is not eluted, so that the monomer supplied in the gas phase is polymerized on the surface of the substrate. Since this method does not use a solvent, it is excellent in operability and is a clean method. For example, under an atmosphere from which oxygen has been removed, the polymer polymerization initiator is cleaved by heating, light irradiation (ultraviolet light, vacuum ultraviolet light, laser, etc.), plasma irradiation, electron beam irradiation, and the like to generate radicals. The monomer can be supplied and polymerized under reduced pressure. The method of initiating polymerization by plasma treatment is preferable because of excellent operability since the surface can be modified by a series of vacuum processes until the polymerization is completed. The plasma processing is a method of processing a material surface using a discharge phenomenon called “low-temperature plasma” or “non-equilibrium plasma”. A low-frequency gas, a microwave electric field, or a DC electric field is applied to a low-pressure gas of 100 mmHg or less to generate a low-temperature plasma, and the plasma gas flow, the plasma atmosphere, or active species or vacuum ultraviolet light generated by the plasma are brought into contact with the material surface. This is a method for performing a surface treatment.

According to the production method of the present invention, the block copolymer is synthesized on the material surface as described above.
The material used in contact with living tissue or blood, such as a medical device, preferably contains a block copolymer made of a hydrophilic to hydrophobic polymer. In general, it is known that a hydrophobic polymer shortens the platelet life when exposed to blood for a long period of time in vivo in the case of a polymer exhibiting high hydrophilicity and a polymer exhibiting high hydrophilicity. In the case of a hydrophilic-hydrophobic block copolymer, it is possible to improve blood compatibility by forming an appropriate hydrophilic surface or forming an appropriate phase separation structure.

In addition, making the surface of a material hydrophilic can improve the feeling of wearing by improving the wettability with a body fluid in a contact lens or the like, or the material and cells and tissues, such as a bioimplant material, can be improved. Improving the adhesiveness of the drug will add value to the medical device, such as reducing bacterial infection. Generally, it is difficult to coat a hydrophilic polymer uniformly on a hydrophobic polymer material because the hydrophilic polymer has poor compatibility with the hydrophobic polymer. However, according to the method of the present invention, the hydrophilic polymer has a high hydrophobicity. A hydrophilic surface can be easily formed by surface-polymerizing a hydrophilic monomer on a molecular polymerization initiator.

Further, in medical devices such as catheters, it is desirable to impart surface lubricity to facilitate insertion into blood vessels and tissues and not to damage tissues. As a method of imparting surface lubricity, a method of insolubilizing a water-soluble polymer to form a water-absorbing gel layer on the surface of a material is excellent.
According to the method of the present invention, by forming a material surface containing a copolymer of a water-soluble polymer and a water-insoluble polymer,
It is possible to provide a medical device having easily provided surface lubrication. The water-absorbing gelling layer is a surface that absorbs water and gels, and can be prepared by holding a water-soluble polymer on the surface. Examples of the water-soluble polymer include a water-soluble polymer and a cellulose having a main component of (meth) acrylic acid, a (meth) acrylic monomer, an acrylamide monomer, a maleic acid monomer, or the like. A preferred example is a polysaccharide such as a derivative.

The present invention is characterized in that it is a medical device used in contact with body fluids / tissues of living organisms, but it has low irritation to living tissues such as alkoxyalkyl acrylates such as methoxyethyl acrylate. It is preferable that a surface-modified layer containing a polymer mainly composed of a polymer is formed.
Medical devices include film, thread, tube, etc.
The shape and use of the porous material are not particularly limited.
Ters (catertel, balloon caterpillar balloon,
Suitable examples include a catheter guide wire, a wound dressing, an artificial blood vessel, a storage container for blood and body fluid, and a medical device (port portion or the like) to be implanted in a living body.

[0020]

The present invention will be described more specifically below with reference to examples.

Examples 1 to 5 An oligoester obtained by dropping 29.7 g of triethylene glycol at 50 ° C. in 72.3 g of adipic dichloride and removing hydrochloric acid under reduced pressure at 50 ° C. for 3 hours. 22.5g
Was added dropwise to a solution consisting of 5 g of sodium hydroxide, 6.93 g of 31% hydrogen peroxide, 0.44 g of surfactant dioctyl phosphate, and 120 g of water, and reacted at -5 ° C for 20 minutes. I let it. The obtained product was repeatedly washed with water and methanol, and then dried to obtain a polycondensation polymer-ATPPO having a plurality of peroxide groups in a molecule. Subsequently, 0.5 g of methoxyethyl acrylate (ME
A) 9.5 g, mixed with 30 g of DMF as a solvent, 65 ° C.
After polymerizing under reduced pressure for 24 hours, it was reprecipitated with diethyl ether to obtain PMEA having a peroxide group in the molecule.

The PMEA obtained in this manner is 0.5
As a wt% methanol solution, it was coated on a sheet of polystyrene, polyethylene, polyethylene terephthalate, polyphenylene sulfite, and nylon 610. After irradiating each coated sheet with plasma at 50 Torr for 10 seconds at 0.2 Torr in argon, N, N-dimethylacrylamide (DMAA) is supplied in gaseous form.
Surface polymerization was performed at 0.8 Torr for 3 minutes. After the surface polymerization, the sample was heated at 60 ° C. for 1 hour under reduced pressure, and then washed with water to obtain a sample.

When immersed in water, the surface of each sheet swelled or gelled, and the lubricity increased. This means
These surface-modified materials provide physical damage to tissue.
Suggests reducing the risk.

Comparative Examples 1-5 DMAA was surface-polymerized in the same manner as in Examples 1-5 except that PMEA having a peroxide group in the molecule was not coated. The surface lubricity of the obtained sheet was low, and there was a clear difference as compared with Examples 1 to 5.

Example 6, Comparative Example 6 0.5 g of ATTPO as a polymerization initiator, 9.5 g of methyl methacrylate (MMA), and 30 g of DMF as a solvent
And polymerized under reduced pressure at 65 ° C. for 24 hours, followed by reprecipitation with diethyl ether to obtain PMMA having a peroxide group in the molecule. PMMA obtained in this way
Was coated on an acrylic sheet containing PMMA as a main component as a 0.5 wt% methanol solution. The coated acrylic sheet is treated with 0.2 Torr in argon at 50
After irradiating the plasma with W for 10 seconds, methoxyethyl acrylate (MEA) was supplied in gaseous form, and 0.8 Torr
r Surface polymerization was performed for 3 minutes. After surface polymerization, 60
After heating under reduced pressure at 1 ° C. for 1 hour, the sample was washed with methanol to obtain a sample. (Example 6)

To examine the blood compatibility of the acrylic sheet surface-polymerized with methoxyethyl acrylate, the number of adherent platelets after 30 minutes of contact with platelet-rich plasma was determined. Platelets were hardly adhered to the surface. On the other hand, many platelets adhered to the acrylic sheet used as the substrate (Comparative Example 6).

[0027]

According to the present invention, polymethoxyethyl acrylate or polymethyl methacrylate having a peroxide group in the main chain is pre-existing on the surface of a base material, and a radically polymerizable monomer is polymerized on the material surface. It is possible to provide a material or a medical device in which a surface-modified layer containing a block copolymer having excellent surface lubricity and biocompatibility is formed firmly and uniformly.

Further, a monomer capable of being radically polymerized is supplied in the gas phase after or at the time of irradiation with the low-temperature plasma, and polymerized on the surface of the material. By forming a surface-modified layer containing a coalescence or a surface-modified layer containing a copolymer having a water-soluble polymer chain insolubilized, a more suitable material or medical device can be provided.

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Claims (1)

(57) [Claims] 1. A is present in advance substrate surface poly methoxyethyl acrylate or polymethyl methacrylate having a main chain Paokisai de group and a radically polymerizable monomer is supplied in a gas phase polymerization in the substrate surface A surface-modified medical material, wherein a block copolymer is formed on the surface of the base material.