JPH09227702A - Immobilization of hydrophilic polymer on the surface of hydrophobic polymer - Google Patents

Abstract

(57) [Abstract] [Purpose] Development of medical materials with excellent lubricity by immobilizing hydrophilic polymer on the surface of hydrophobic polymer [Composition] Composition of benzoyl peroxide, ditertiary butyl peroxide or dicumyl peroxide A polymer material having a hydrophobic surface, such as silicone rubber, natural rubber, polyvinyl chloride, or polyurethane, is swollen with a solvent using a polyvinyl alcohol solution containing such an initiator. After being impregnated with a hydrophilic polymer such as polyvinyl alcohol, the surface of the hydrophilic polymer is fixed on the surface of the hydrophobic polymer by heat treatment at 140 ° C. or less, and the surface of the hydrophobic polymer is changed to the hydrophilic polymer surface. How to convert to.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION A medical material having a hydrophilic surface, a smooth surface, and excellent lubricity, for example, a catheter inserted by a body incision such as a trachea, an airway, a urethra, and a feeding tube.
Alternatively, various catheters that are inserted into blood vessels often minimize damage to surrounding tissues during insertion and withdrawal as well as shorten the time required for surgery, thus minimizing patient distress during treatment. Are known. Furthermore, the hydrophilic surface enhances the function as a medical material because it reduces the adsorption of proteins on the material surface and the adhesion of platelets, and can be applied to artificial blood vessels and the like.

[0002]

2. Description of the Related Art There are basically two possible methods for improving the lubricity of the surface of a medical material. The method is either to make a medical material with a low-friction material having excellent lubricity, or to apply a material having excellent lubricity to the material surface. Currently, almost no medical materials are obtained from materials having excellent lubricity, and most medical materials are made from materials having poor lubricity. As a result, the latter method is generally used and research and development is being conducted.

At present, when a catether or the like is used to impart lubricity to the surface of a material, glycerin, olive oil, silicone oil or other jelly type temporary lubricant is coated on the surface. The method is the most widely used. However, since this method is a temporary coating, the lubricant is gradually removed from the surface, and the material surface becomes non-lubricant again.

Many attempts have been made to chemically bond a hydrophilic polymer to the surface of a hydrophobic material to permanently impart lubricity. Typical examples of such methods are high energy such as radiation, corona discharge, electron beam and ultraviolet rays on the surface of the material.
Is irradiated and a hydrophilic polymer is grafted from the irradiation site. Although the surface can be hydrophilized by these methods, the graft reaction method after irradiation with high energy such as corona is not economical because of high cost, and it is not easy to control the graft chain length. .

Further, many methods have been reported in which a hydrophilic polymer is chemically bonded to a hydrophobic surface by using a chemical agent such as reactive isocyanate. However, it is not preferable to use the samples obtained by these methods in the medical field because isocyanate has a high toxicity and it is difficult to remove residual unreacted chemicals.

[0006]

As described above, a method of low cost, excellent in safety, and permanently bonding a hydrophilic polymer to the material surface has not been obtained yet.

Therefore, the inventors of the present invention fixed the hydrophilic polymer on the surface of the hydrophobic polymer material by a simpler and lower cost method than the conventional method to enhance the lubricity of the material surface and to adsorb the protein. We have attempted to develop a medical material that can reduce the adhesion of platelets.

Polyvinyl alcohol is a typical hydrophilic general-purpose polymer having a hydroxyl group in the side chain. From its chemical structure, research as a medical material has been conducted for a long time, and it is well known that it is a material excellent in biocompatibility with low protein adsorption and low platelet adhesion.

Further, since polyvinyl alcohol has a relatively highly reactive hydroxyl group in the side chain, it is known that it easily gels with various crosslinking agents or coupling agents and reacts with other polymer materials. Has been.

Furthermore, the inventors of the present invention have used polyvinyl alcohol
It has been found that the bisphenol is readily soluble not only in a single solvent such as dimethyl sulfoxide, but also in various solvent systems such as various water / organic solvents or organic solvent / organic solvents.

The inventors of the present application have paid attention to the characteristics of these polyvinyl alcohols, and a hydrophobic polymer material currently used as a medical material by a polyvinyl alcohol solution,
For example, after swelling silicone rubber, natural rubber, polyurethane, polycarbonate, polymethylmethacrylate, or polyvinyl chloride to impregnate polyvinyl alcohol into a hydrophobic polymer, the polyvinyl alcohol is simply heat-treated. A method of immobilizing alcohol on the surface was examined.

As a result of studying various solvents, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, glycerin, ethylene glycol and N, N-
A single organic solvent such as dimethylformamide, water / dimethyl sulfoxide, water / 1,3-dimethyl-2-imidazolidinone, water / N, N-dimethylformamide, water /
Water / organic solvent mixed solvents such as glycerin, water / ethylene glycol, water / tetrahydrofuran, water / ethyl acetate, and water / 2-butanone, dimethyl sulfoxide /
Tetrahydrofuran, 1,3-dimethyl-2-imidazolidinone / tetrahydrofuran, glycerine / tetrahydrofuran, ethylene glycol / tetrahydrofuran, dimethyl sulfoxide / ethyl acetate, 1,3-dimethyl-2-imidazolidinone / ethyl acetate, glycerin / Ethyl acetate, ethylene glycol / ethyl acetate, dimethyl sulfoxide / 2-butanone, 1,3-dimethyl-
2-imidazolidinone / 2-butanone, glycerin / 2
-Butanone, and organic solvent / organic solvent mixed solvent such as ethylene glycol / 2-butanone or water / dimethyl sulfoxide / tetrahydrofuran, water / dimethyl sulfoxide / ethyl acetate, and water / dimethyl sulfoxide / 2-butanone It has been found that the mixed solvent dissolves polyvinyl alcohol and swells hydrophobic polymer surfaces such as silicone rubber, natural rubber, polyvinyl chloride and polyurethane.

As a result of further investigation on various hydrophilic polymers, polyethylene glycol, sodium alginate, polyacrylic acid, polyacrylic acid soda, polyacrylamide and dextran were added to the above-mentioned organic solvent and mixed solvent. It was confirmed that such hydrophilic polymer was also dissolved.

The invention of the present application is as follows. First, benzoyl peroxide, dicumyl peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, and peroxide are added to a hydrophilic polymer solution completely dissolved in the above-mentioned solvent. Add initiators such as acetyl, lauroyl peroxide, and azobisisobutyronitrile, and stir until uniform. After reacting a hydrophobic polymer such as silicone rubber, natural rubber, polyurethane and polyvinyl chloride at a temperature of 140 ° C or lower, a heat treatment at a relatively low temperature of 140 ° C or lower is applied to the surface of the hydrophobic polymer. This is a method of immobilizing a hydrophilic polymer.

The present invention uses the above-mentioned initiator to immobilize a hydrophilic polymer such as polyvinyl alcohol impregnated in the hydrophobic polymer by mere heating onto the hydrophobic polymer to form a hydrophobic polymer surface. Is converted into a hydrophilic surface.

Although the reaction temperature and reaction time depend on the characteristics of the hydrophobic polymer and the solvent used, all polymer materials can easily be incorporated into the hydrophilic polymer at a relatively low temperature (140 ° C. or lower). Is impregnated.

The heat treatment temperature after impregnating the hydrophilic polymer into the hydrophobic polymer depends on the initiator used. For mesophilic initiators such as benzoyl peroxide, acetyl peroxide, lauroyl peroxide, and azobisisobutyronitrile, heat treatment temperatures below 100 ° C are sufficient, and cumene hydroperoxide, tert-butyl hydroperoxide, dicumyl peroxide, And high temperature initiators such as di-tert-butyl peroxide require heat treatment at temperatures above 100 ° C.

The initiator used is determined by the temperature of impregnation into the hydrophobic polymer, and for a polymer material requiring a reaction temperature of 100 ° C. or higher, a high temperature initiator such as dicumyl peroxide is used, and For polymeric materials that can be impregnated at temperatures below 80 ° C, mesophilic initiators such as benzoyl peroxide are used. The initiator concentration depends on the hydrophilic polymer concentration, and is preferably 0.1 to 7.5 wt%.

Polyvinyl alcohol has a degree of polymerization of 250 to
If the degree of saponification is 5,000 and the degree of saponification is 80 mol% or more, it can be easily fixed on the surface of the hydrophobic polymer, and the solution concentration depends on the polyvinyl alcohol used. It was possible for almost all polymers to other hydrophilic polymers.

As described above, after the hydrophilic polymer such as polyvinyl alcohol is impregnated in the hydrophobic polymer, the hydrophilic polymer is fixed by simple heating, and the surface of the hydrophobic polymer has an obvious hydrophilicity. And showed excellent lubricity, and the lubricity was maintained for a long period of time.

According to the present invention, the hydrophilic polymer solution can be fixed only in the tube by circulating the hydrophilic polymer solution in the tube at a certain temperature. It is possible to easily fix only the outer surface or the inner surface and the outer surface at the same time.

In the present invention, it is possible to use polyvinyl alcohol in which a part of hydroxyl groups is substituted with various functional groups such as acetalization or amination.

As a result, by immobilizing polyvinyl alcohol having various functional groups on the hydrophobic polymer, blood anticoagulants such as heparin, various drugs such as adriamycin, enzymes, etc. on the surface thereof. Can be easily fixed physically or chemically, and the function as a medical material can be further enhanced.

[0024]

EXAMPLES The present invention will be described in detail below with reference to examples.

[0025]

Example 1 Using dimethyl sulfoxide as a solvent,
Polyvinyl alcohol containing 3 wt% of dicumyl peroxide (polymerization degree 1,700, saponification degree 99.5 mol)
%) The silicone rubber film is immersed in a solution having a concentration of 3, 4, 6, 8 and 10 wt% and stirred at 100 ° C.
The reaction was carried out for 1 hour. Then, the silicone rubber film was taken out from the solution and heat-treated at 120 ° C. for 1 hour. After the heat treatment, the silicone rubber film was immersed in distilled water. After immersion in distilled water, all silicone rubber films showed obvious hydrophilicity and high lubricity. However, when a color reaction of the immobilized polyvinyl alcohol was carried out using an iodine solution, the polyvinyl alcohol was immobilized at a PVA concentration of 4 wt% or less, but it was non-uniform.

[0026]

Example 2 Under the same conditions as in Example 1, polyvinyl alcohol was fixed on the surface of natural rubber. Similar to Example 1,
It showed obvious hydrophilicity and high lubricity for all natural rubbers, but in the color reaction using iodine solution, the polyvinyl alcohol
Was fixed unevenly.

[0027]

Example 3 Polyvinyl alcohol (degree of polymerization: 1,70
0, saponification degree 99.5 mol%) 10 g 90 g of water /
After completely dissolving in a mixed solvent of dimethyl sulfoxide = 20/80 (weight ratio), 3 g of benzoyl peroxide was added to obtain a uniform solution. A tube made of polyvinyl chloride having a degree of polymerization of 1,300 is dipped in the solution to form 50, 60, 70,
After reacting for various times at a temperature of 80 ° C., the polyvinyl chloride tube was heat treated at 80 ° C. for 1 hour. The obtained sample was immersed in an iodine solution, and it was confirmed whether polyvinyl alcohol was immobilized on the surface of the polyvinyl chloride tube. The results are shown in Table 1.

[0028]

[Table 1]

It was confirmed that in a polyvinyl chloride tube having a low degree of polymerization, polyvinyl alcohol was uniformly immobilized on the surface even after 3 minutes of reaction at all temperatures. Further, even when immersed in distilled water for a long period of time, the hydrophilicity and lubricity of the polyvinyl chloride tube were maintained.

[0030]

Example 4 Polyvinyl alcohol (degree of polymerization: 1,70
0, saponification degree 99.5 mol%) 10 g of dimethylsulfoxide / tetrahydrofuran = 80/20 (weight ratio)
After completely dissolving it in 90 g of the mixed solvent of 3), 3 g of benzoyl peroxide was added. The degree of polymerization in the solution is 2,500
Immerse a polyvinyl chloride tube of 50, 60, 7
The reaction was carried out at temperatures of 0 and 80 ° C. for various times.
The obtained polyvinyl chloride tube was heat-treated at 80 ° C. for 1 hour, and it was confirmed by color reaction using an iodine solution whether or not polyvinyl alcohol was fixed on the surface of the polyvinyl chloride tube. . Table 2 shows the results.

[0031]

[Table 2]

At all reaction temperatures, polyvinyl alcohol was uniformly fixed on the vinyl chloride surface after a reaction time of 3 minutes. However, as the reaction temperature became higher and the reaction time became longer, the polyvinyl chloride tube was partially dissolved and the strength was remarkably reduced, and the initial shape of the polyvinyl chloride tube was not retained. It was

[0033]

Example 5 Polyethylene glycol (molecular weight 7,000
0) 10 g was completely dissolved in 90 g of a mixed solvent of dimethyl sulfoxide / tetrahydrofuran = 80/20 (weight ratio), and then 3 g of benzoyl peroxide was added. A polyvinyl chloride tube with a degree of polymerization of 2,500 in the solution.
The mixture was reacted at 40 ° C. for 30 minutes and then heat-treated at 80 ° C. for 1 hour. The resulting polyvinyl chloride tube exhibited a clear hydrophilicity.

[0034]

Example 6 Using dimethyl sulfoxide as a solvent,
Polyvinyl alcohol containing 0.5 wt% of di-tert-butyl peroxide (polymerization degree 1,700, saponification degree 98.
(0 mol%) The silicone rubber film is immersed in a solution having a concentration of 6, 8 and 10 wt% and stirred at 110 ° C.
The reaction was carried out for 1 hour. Then, the silicone rubber film was taken out from the solution and heat-treated at 125 ° C. for 1 hour. After the heat treatment, the silicone rubber was washed in distilled water at 50 ° C. for 8 hours. After washing, all silicone rubber films showed obvious hydrophilicity and high lubricity. As a result of color reaction of the immobilized polyvinyl alcohol using an iodine solution, it was found that the polyvinyl alcohol was uniformly fixed on the surface of the silicone film.

[0035]

EXAMPLE 7 A similar treatment was attempted with sodium alginate, polyacrylic acid, soda polyacrylate, polyacrylamide, and dextran. Silicone rubber, natural rubber, polyurethane, polycarbonate, It was confirmed to be immobilized on the surface of a hydrophobic polymer such as polymethyl methacrylate and polyvinyl chloride.

[0036]

Example 8 92 g of 8 g of aminated polyvinyl alcohol obtained from p-dimethylaminobenzaldehyde
After adding 0.5 g of ditertiary butyl peroxide to a polyvinyl alcohol solution completely dissolved in dimethylsulfoxide of Example 1 at high temperature, stirring was continued until a uniform solution was obtained. A silicone rubber film was added to the obtained homogeneous solution, and the reaction was carried out at 110 ° C. for 1 hour. The silicone rubber film was taken out of the solution and heat-treated at 125 ° C. for 1 hour. The obtained sample was immersed in a 1 wt% heparin aqueous solution for 30 minutes. Air dry after 30 minutes and 1 at 75 ° C.
Heat treatment was performed for 5 minutes. As a result of immersing the obtained sample in toluidine blue solution, it was confirmed that heparin was immobilized on the surface of the silicone rubber film.

[0037]

According to the present invention, it was possible to easily convert the surface of the hydrophobic polymer into the hydrophilic surface. By applying the present invention to a medical polymer material, it will be possible to develop a medical material excellent in lubricity and antithrombotic property by a simpler method at a lower cost than the conventional method.

Claims (4)

[Claims] 1. A method for immobilizing a hydrophilic polymer on a hydrophobic surface such as silicone rubber, natural rubber, polyurethane, polycarbonate, polymethylmethacrylate, and polyvinyl chloride as a method for immobilizing them. Benzoyl peroxide, dicumyl peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, acetyl peroxide, lauroyl peroxide, and hydrophilic polymer solution capable of swelling hydrophobic polymer materials of After dissolving an initiator such as azobisisobutyronitrile, the polymer material having the hydrophobic surface is reacted at a temperature of 140 ° C or lower, and then heat treatment at a relatively low temperature of 140 ° C or lower. According to polyvinyl alcohol, polyethylene glycol, sodium alginate, polyacrylic acid, sodium polyacrylate, poly A method for immobilizing hydrophilic polymers such as acrylamide and dextran on the surface of hydrophobic polymers. 2. A hydrophobic polymer surface such as silicone rubber, polyurethane, polycarbonate, polymethylmethacrylate and polyvinyl chloride is swellable, and polyvinyl alcohol, polyethylene glycol, Dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, glycerin, ethylene glycol-as a solvent for hydrophilic polymers such as sodium alginate, polyacrylic acid, soda polyacrylate, polyacrylamide, and dextran. And a single organic solvent such as N, N-dimethylformamide, water / dimethylsulfoxide, water / 1,3-
Water / organic solvents such as dimethyl-2-imidazolidinone, water / N, N-dimethylformamide, water / glycerin, water / ethylene glycol, water / tetrahydrofuran, water / ethyl acetate, and water / 2-butanone. Mixed solvent, dimethyl sulfoxide / tetrahydrofuran, 1,3-dimethyl-2-imidazolidinone / tetrahydrofuran,
Glycerin / tetrahydrofuran, ethylene glycol / tetrahydrofuran, dimethyl sulfoxide / ethyl acetate, 1,3-dimethyl-2-imidazolidinone / ethyl acetate, glycerin / ethyl acetate, ethylene glycol / ethyl acetate, dimethyl sulfoxide / 2- Butanone,
Organic solvent / organic solvent mixed solvents such as 1,3-dimethyl-2-imidazolidinone / 2-butanone, glycerin / 2-butanone, and ethylene glycol / 2-butanone, or water / dimethyl sulfoxide / tetrahydrofuran, The method for immobilizing a hydrophilic polymer according to claim 1, wherein a mixed solvent such as water / dimethyl sulfoxide / ethyl acetate and water / dimethyl sulfoxide / 2-butanone is used. 3. Immobilization of polyvinyl alcohol by the method according to claim 1 using acetalized or aminated polyvinyl alcohol. 4. A method for physically and chemically immobilizing a blood anticoagulant such as heparin, various agents such as adriamycin, or an enzyme on the surface immobilized by the method according to claim 1 or 3.