JPH0819599A - Medical device having lubricative surface upon wetting and manufacture thereof - Google Patents

Abstract

PURPOSE:To provide an excellent surface lubricity and a high thrombus resistance by forming a layer made an insolubilization product of a water-soluble or -swelling polymer having a reactive functional group in molecule, and an antithrombus agent, and adapted to produce hydrogel upon wetting, over the surface of a medical device. CONSTITUTION:A solution containing a water-soluble or -swelling polymer having a reactive functional group in molecule, and an antithrombus agent is prepared. With the use of the solution, a layer adapted to produce hydrogel upon wetting is formed over the outer surface of a medical device. That is after the outer surface of a base material of the medical device is coated thereover with the solution, the water-soluble or water-swelling polymer is insolubilized so as to form the layer adapted to produce hydrogel upon wetting is formed over the outer surface of the medical tool. With the provision of such a layer, damage to the tissues such as blood vessels can be reduced during use of the medical device such as catheter, and further, the manipulatability of the medical device for access to a desired part can be enhanced. An epoxy group is preferably used as the reactive functional group.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical device having excellent antithrombogenicity and lubricity and a method for producing the same.

2. Description of the Related Art Generally, medical devices such as catheters are
A lubricant is used to reduce the tissue damage such as blood vessels and to improve the operability for accessing the target site, and to reduce the friction on the surface of the base material of the medical device. , Low friction resin, hydrophilic polymer, etc. are coated.

For example, fluororesin or polyethylene resin is used as the low friction material, or the surface of the base material is coated with fluororesin, silicone resin, silicone oil, olive oil, glycerin or the like. However,
Many of these methods have problems in terms of safety and sustainability of effects such as desorption, peeling, and elution of the lubricating substance from the surface of the base material.

In recent years, a method of coating the surface of a substrate with a hydrophilic polymer has been studied from the viewpoint of practicality. For example, US Pat. No. 4,100,309 discloses a method of coating a hydrophilic polymer (polyvinylpyrrolidone) with an isocyanate. Further, a method of coating a hydrophilic polymer obtained by copolymerizing a reactive functional group using isocyanate (JP-A-59-81341)
And polyethylene oxide (JP-A-58-19376)
A method of coating 6) is disclosed. Further, in Japanese Patent Publication No. 1-55023, an amino group, an imino group, a carboxyl group, a surface on which at least one or more kinds of mercapto groups are present, a polyether via a polyisocyanate,
A method for binding a copolymer such as polyamide or polysiloxane is described.

In the above various surface lubrication methods, two kinds of compounds, an isocyanate compound and a hydrophilic polymer, must be uniformly coated, or a plurality of coating operations (for example, a crosslinking compound such as polyisocyanate) can be used. Coating and hydrophilic polymer coating) were required, which was not preferable in terms of operability.

Further, a compound having a plurality of reactive functional groups such as isocyanate groups in the molecule has high reactivity and easily reacts with moisture and impurities in the air, so that the process and the reagent can be controlled. It has drawbacks such as being complicated and being harmful to the human body.

Yet another problem is the blood compatibility of lubricated surfaces. Since thrombus formation and activation of platelets lead to functional deterioration of medical devices and occurrence of complications for living bodies, medical devices having a highly blood compatible surface are required. However, many conventional lubricious surfaces do not have sufficient antithrombotic properties, or have some antithrombogenic properties but lack sufficient slippage, and the adhesive strength of the lubricating layer to the base material. However, it was difficult to insert into a complicatedly bent blood vessel.

[0007]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to solve the above problems and to provide a medical device having excellent surface lubricity and antithrombotic property, and a simple manufacturing method thereof.

[0008]

Such an object is achieved by the invention described below. That is, (1) a surface of a medical device is provided with a layer that forms a hydrogel when wet, which is composed of an insoluble substance of a water-soluble or water-swellable polymer having a reactive functional group in the molecule and an antithrombotic agent And medical equipment. (2) The medical device according to (1), wherein the reactive functional group is an epoxy group. (3) After coating a solution containing a water-soluble or water-swellable polymer having a reactive functional group in the molecule and an antithrombotic agent on the surface of a base material of a medical device, the water-soluble or water-swellable high The method for producing a medical device according to (1) or (2), wherein a layer that forms a hydrogel when wet is formed on the surface of the medical device by insolubilizing molecules. (4) A solution containing a water-soluble or water-swellable polymer having a reactive functional group in the molecule and a solution containing an antithrombotic agent are separately applied to the surface of a base material of a medical device, and then the water-soluble solution is prepared. By insolubilizing the water-soluble or water-swellable polymer,
The method for producing a medical device according to (1) or (2), wherein a layer that forms a hydrogel when wet is formed on the surface of the medical device.

In the present invention, the water-soluble or water-swellable polymer having a reactive functional group has an epoxy group, an acid chloride group, an aldehyde group or the like as a reactive functional group in the molecule and absorbs water. It is a polymer compound that swells or dissolves. This water-soluble or water-swellable polymer absorbs water and swells when immersed in an aqueous solvent such as physiological saline, buffer solution, blood, etc., but the absorbed water, when the blood vessel wall and the medical device are in contact, The lubrication function will be developed on the surface of the medical device. Therefore, it is necessary that the water-soluble or water-swellable polymer has a water absorption rate of 50 wt% or more in the temperature range (usually 30 to 40 ° C.) used, and preferably 1
It is at least 00 wt%.

The method for producing a water-soluble or water-swellable polymer having a reactive functional group is obtained by copolymerizing a monomer having a reactive functional group in the molecule and a water-soluble monomer. be able to. A block or graft copolymer in which monomers having a reactive functional group are aggregated to form a reactive domain and water-soluble monomers are aggregated to form a hydrophilic domain is preferable. When the block or graft copolymer is used, good results can be obtained in terms of lubricity of the hydrogel layer formed on the surface of the base material of the medical device and adhesive strength with the surface of the base material.

Further, as the monomer having a reactive functional group, a monomer having a reactive heterocycle such as glycidyl acrylate or glycidyl methacrylate in the molecule and an acid chloride such as acrylic acid chloride or methacrylic acid chloride in the molecule. Examples of the monomer include a monomer having an isocyanate group in the molecule such as acryloyloxyethyl isocyanate. A preferred reactive monomer is glycidyl acrylate or glycidyl methacrylate whose reactive group is an epoxy group, whose reaction is accelerated by heat and whose handling is relatively easy. Examples of the water-soluble monomer include polymers having acrylamide and its derivatives, vinylpyrrolidone, acrylic acid and methacrylic acid and their derivatives as main constituent components. For example, N-methylacrylamide, N, N-dimethylacrylamide, N, N-dimethylacrylamide, acryloylmorpholine, N, N-dimethylaminoethyl acrylate, vinylpyrrolidone and the like can be preferably exemplified.

The water-soluble or water-swellable polymer having a reactive functional group of the present invention is insolubilized by a cross-linking reaction between reactive functional groups due to heat or the like. When it comes into contact with body fluid or physiological saline, it absorbs water and forms a hydrogel layer on the surface. This hydrogel layer serves as a “lubrication layer” that avoids direct contact between the surface of the medical device and living tissue, and reduces friction.

The reactive functional group is preferably an epoxy group whose reaction is easily promoted by heat, and after coating the substrate with a water-soluble or water-swellable polymer having an epoxy group in the molecule, By performing the heat treatment at 40 ° C. or higher, the hydrogel layer can be easily formed on the surface of the base material. The heat treatment accelerates the reaction between the water-soluble or water-swellable polymers and the reaction with the surface of the base material when there is a functional group capable of reacting with the reactive functional group on the surface of the base material. Preferably 50 ° C. or higher, more preferably 6
0 ° C. or higher. In order to accelerate the reaction, a catalyst may be added in addition to heat, and for example, for an epoxy group, a trialkylamine compound or a tertiary amine compound such as pyridine is preferably used. However, in order to form a strong hydrogel layer on the surface of the material, it is necessary to cause an intermolecular reaction while the substrate is sufficiently impregnated with a water-soluble or water-swellable polymer having a reactive functional group. is important.

For the purpose of improving the durability of the "lubrication layer" and controlling the lubricity, a water-soluble or water-swellable polymer having a reactive functional group is coated and then subjected to a crosslinking treatment. . That is, by forming a small amount of the three-dimensional network structure, the durability of the "lubrication layer" can be enhanced without significantly reducing the lubricity. However,
If the cross-linking structure is too much, the water swelling property is lowered and the low friction property of the surface is impaired. Various general methods can be applied as the method of crosslinking. For example, light, heat, or radiation is used to generate active radicals to crosslink the polymer, a method of adding a polymerizable polyfunctional monomer in addition thereto, a method of applying a polyfunctional crosslinking agent, a catalyst And a method of crosslinking functional groups in the molecule with each other. For example, if it is a hydrophilic polymer containing a functional group with high reactivity such as an epoxy group, polymerization between epoxy groups,
It can be easily crosslinked with a diamino compound, a dihydroxy compound, a dialdehyde compound or the like.

The base material of the medical device is not particularly limited. It may be metal, ceramic, organic material, or composite material. However, it is preferable that the organic polymer compound is present on the surface of the base material. It may be a base material molded and processed with the polymer alone, or may be a base material that is molded and processed by alloying and is present on the surface of the base material. Examples of the organic polymer material include polyolefin, modified polyolefin, polyether, polyurethane, polyamide, polyimide, polyester and copolymers thereof.

The antithrombotic agent coated on the surface of the substrate together with the water-soluble or water-swellable polymer having a reactive functional group may be any agent that suppresses thrombus formation or a substance that dissolves the formed thrombus, Examples thereof include natural and synthetic substances represented by anticoagulants, antiplatelets, fibrinolytic promoters, and the like.
Such substances include heparin, low molecular weight heparin,
Dermatan sulfate, heparan sulfate, activated protein C,
Hirudin, thrombomodulin, DHG, plasminogen activator, streptokinase, urokinase, aprotinin, nafamostat mesilate (FU
Examples thereof include T) and inhibitors of various coagulation proteases such as gabexate mesylate (FOY), but are not particularly limited thereto.

The following two actions can be considered as the action of the antithrombotic agent, and either action may be used. One is a mechanism in which the antithrombotic agent is retained in the hydrogel layer on the surface of the base material and gradually releases the antithrombotic agent to develop antithrombotic properties. On the other hand, there is a mechanism in which a water-soluble or water-swellable polymer is bound to a reactive functional group in the molecule so as to be immobilized on the hydrogel layer to exert its function.

As a method for applying the antithrombotic agent to the substrate,
The solution may be applied to the substrate using a solution in which a water-soluble or water-swellable polymer and an antithrombotic agent coexist, or a solution containing a water-soluble or water-swellable polymer and a solution containing an antithrombotic agent may be used. You may apply separately. By adding a substance other than the antithrombotic agent to the solution containing the antithrombotic agent, for example, a polymer compound having good adhesion to the substrate, the coating state on the substrate surface can be improved or the antithrombotic agent can be treated. Controlling the sustained release of the agent is performed. By applying a polymer solution containing an antithrombotic agent to the surface of the base material, a surface for sustained release of the antithrombotic agent is formed, and further, a water-soluble or water-swellable polymer is reacted to form a hydrogel layer on the surface. By being formed, a surface having both antithrombogenicity and surface lubricity can be produced.
In addition, by first reacting a water-soluble or water-swellable polymer to form a hydrogel layer on the surface and then applying an antithrombotic agent, the surface hydrogel layer can be impregnated with the antithrombotic agent. It becomes possible to prepare a surface having both antithrombogenicity and surface lubricity.

The surface lubricity (friction resistance) can be measured by preparing a sheet having the same surface as a medical device and measuring it with a measuring instrument as shown in FIG. For simplicity, it can be evaluated by rubbing with a finger. The low-friction surface having a water-soluble or water-swellable polymer bonded thereto is characterized by having a slimy feel like eel, and has a static friction coefficient of 0.15 or less. In addition, the friction resistance obtained by using a measuring device as shown in FIG.
It is 0 g or less.

As the medical device required to have low frictional property and antithrombotic property, catheters and guide wires used especially in blood vessels can be preferably exemplified, but the following medical devices can also be exemplified. 1) Gastric tube catheter, feeding catheter, tube feeding (E
D) Catheter which is inserted or left in the digestive tract orally or nasally such as a tube. 2) Oxygen catheters, oxygen canulas, endotracheal tube tubes and cuffs, tracheostomy tube tubes and cuffs, endotracheal suction catheters and other catheters that are orally or nasally inserted or left in the airway or trachea 3) Urethra Catheter, urinary catheter, balloon catheter and other catheters that are inserted or left in the urethra or ureter such as balloons 4) Suction catheters, drainage catheters, rectal catheters or other body cavities, organs or tissues Catheters. 5) Indwelling needles, IVH catheters, thermodilution catheters, angiography catheters, vasodilation catheters, dilators, introducers, and other catheters that are inserted or placed in blood vessels. Alternatively, guide wires, stylets, etc. for these catheters. 6) Inspection instruments and treatment instruments for inserting various organs, contact lenses, etc. 7) Stents, artificial blood vessels, artificial trachea, artificial bronchus, etc. 8) Medical devices (artificial heart, artificial lung, artificial kidney, etc.) for extracorporeal circulation treatment and their circuits.

[0021]

EXAMPLES The present invention will be specifically described with reference to the following examples. (Examples 1 to 3, Comparative Example 1) Adipic acid dichloride 72.
29.7 g of triethylene glycol was added dropwise to 3 g of the mixture at 50 ° C., and then hydrochloric acid was removed under reduced pressure at 50 ° C. for 3 hours to obtain 22.5 g of oligoester.
5 g was added, sodium hydroxide 5 g, 31% hydrogen peroxide 6.93 g, surfactant dioctyl phosphate 0.4
4 g and 120 g of water was added dropwise to the solution, and the mixture was stored at -5 ° C for 2 hours.
The reaction was allowed for 0 minutes. The obtained product was washed with water and washed with methanol repeatedly and then dried to obtain a polyperoxide (PPO) having a plurality of peroxide groups in the molecule.
Subsequently, 0.5 g of this PPO as a polymerization initiator and 9.5 g of glycidyl methacrylate (GMA) were polymerized with 30 g of benzene as a solvent while stirring at 80 ° C. for 2 hours under reduced pressure. The reaction product was reprecipitated with diethyl ether to obtain poly-GMA having a peroxide group in the molecule. Subsequently, 1 g of this poly-GMA was used as a polymerization initiator, and dimethylacrylamide (DMA) was used as a hydrophilic monomer.
A) 8 g was charged in DMSO and polymerized at 80 ° C. for 18 hours to give poly GMA as a reactive domain,
A block copolymer having poly-DMAA as a water-swellable hydrophilic domain (Example 1) was obtained. When the compositional ratio (molar ratio) of Example 1 was analyzed by ¹ H-NMR, DM
It was AA: GMA = 10.1: 1.

4 wt% acetylacetamide polymer solution (containing 1 wt% pyridine) as a polymer solution,
A 0.1 wt% dimethylacetamide / water (weight ratio 95: 5) solution of nafamostat mesylate, which is a synthetic protease inhibitor, was prepared as an antithrombotic agent solution. Immediately before coating, the polymer solution and antithrombotic solution are mixed 1: 1.
After mixing at a ratio of (weight ratio), it was immersed in a sheet (200 μm) made of an ethylene-acrylic acid ester-maleic anhydride terpolymer (Sumika CDF Chemical: Bondine TX8030) at 25 ° C. for 1 minute. Then, the sample was prepared by reacting in an oven at 60 ° C. for 18 hours.

Similarly, a sample was prepared in the same manner as in Example 1 except that the composition ratio (molar ratio) of the block copolymer was DMAA: GMA = 7.1: 1 (Example 2).

Further, a sample was prepared in the same manner as in Example 1 except that vinylpyrrolidone was used instead of DMAA and the composition ratio (molar ratio) was vinylpyrrolidone: GMA = 6.6: 1 (implementation). Example 3).

The surface lubricity was measured by bonding a brass cylindrical weight (1) weighing 1 kg in water (1) to an inclined plastic plate (angle 30 °) as shown in FIG. Gently put it on the evaluation sheet (4), and put it in 100 cm.
The width of 1 cm was repeated 100 times at a speed of / min to move the width up and down.

The final frictional resistance value after 100 tests was used as an index of surface lubricity, and the change in frictional resistance value (Δ frictional resistance value) of the following formula (A) was evaluated as a continuous index of lubricity. Δ frictional resistance value = (final frictional resistance value) − (initial frictional resistance value) (A) The surface of the sheets obtained in Examples 1 to 3 becomes a slimy hydrogel under wet condition (in water) and becomes lubricity. Was excellent. Further, the final frictional resistance value is 70 to 80 gf for all the samples of Examples 1 to 3, and the Δ frictional resistance value is also 10 gf or less, which shows stable low frictional property even in the movement test of 100 times. It was

Next, a scanning electron microscope (JEOL JSM8
As a result of observing the surface and cross section of the sheet in 40), there was no change before and after the test, and it was confirmed that the "lubrication layer" was stably bonded without peeling.

As a test for antithrombogenicity, a strip of human fresh blood of Examples 1 to 3 was used, and as a comparative control, an ethylene-acrylic acid ester-maleic anhydride terpolymer (Sumika CDF) was used. Chemistry: Bondine TX803
The untreated sheet (Comparative Example 1) of 0) was dipped and the state of the thrombus formed on the surface was observed. Adhesion of thrombus was observed after 5 minutes on the surface of the sheet of Comparative Example 1, but no thrombus was formed on the surface of the sheet of Examples 1 to 3.

(Example 4) E which is a protease inhibitor
thyl p- (6-guanidinohexanoyl) benzoate methanesulfo
1 containing 1 wt% of nate (ethyl p- (6-guanidinohexanoyl) benzoate methanesulfonate)
0 wt% polyurethane (Puresen 65 manufactured by DuPont)
D) The dimethylformamide solution was applied to a catheter made of polyurethane and having an outer diameter of 5 Fr (5 × 0.33 mm). Subsequently, a 2 wt% acetone solution of a block copolymer of dimethylacrylamide-glycidyl methacrylate (molar ratio 6.8: 1) was coated, and the coating was performed at 60 ° C. 1
The reaction was carried out for 8 hours. When physiological saline was dropped on the catheter surface and the lubricity was examined with a finger, it was found to have a slimy and low friction surface. In addition, the lubricity was not lost even when rubbed with the fingertips about 20 times.

(Example 5, Comparative Example 2) A resin in which 50 wt% of tungsten was kneaded as a sensitizer into an ethylene-acrylic acid ester-maleic anhydride terpolymer (Sumika CDF Chemicals: Bondine AX8390). A coated guide wire was prepared. This guide wire
A heparin benzyl alkonium and a dimethylacrylamide-glycidyl methacrylate (composition ratio 6.8: 1) block copolymer dissolved in a THF solution (containing 1 wt% pyridine) in an amount of 2 wt% each for 3 at room temperature.
Soak for 0 seconds, dry, and place in an oven at 60 ° C for 4
The reaction was allowed for 0 hours. When it was immersed in physiological saline and rubbed with a finger, it had a low-friction surface that was slippery as compared with the untreated product having only the guide wire (Comparative Example 2). Also,
Even when the guide wire of Example 5 was immersed in human fresh blood for 5 minutes, no adherence of thrombus was observed.

(Example 6, Comparative Example 3) A 2 wt% dimethylacrylamide-glycidyl methacrylate (molar ratio 6.8: 1) block copolymer was dissolved in a methyl ethyl ketone solution, and a catheter made of polyurethane and having an outer diameter of 5 Fr was used. And was reacted in an oven at 60 ° C. for 8 hours. When the catheter was immersed in physiological saline and rubbed with a finger, it had a low-friction surface that was slippery as compared with the untreated catheter (Comparative Example 3). Then, it was immersed in a low molecular weight heparin 500 unit / ml solution for 5 minutes and freeze-dried to prepare a heparin-containing catheter. No adhesion of thrombus was observed even when the catheter of Example 6 was immersed in human fresh blood for 5 minutes.

[0032]

In the medical device of the present invention, since the water-soluble or water-swellable hydrophilic polymer reacts on the surface of the base material of the medical device to form a hydrogel layer, silicone oil or The phenomenon of desorption and elution of the lubricant, which is seen in the method of applying a lubricant such as glycerin, is not observed, and it is a low friction medical device having high safety and durability. Further, since the anti-thrombotic agent is fixed or held in the hydrogel layer, it exhibits excellent anti-thrombotic property when it comes into contact with blood. Therefore, it can be easily inserted into or removed from the blood vessel or the living tissue without damaging the living tissue or generating a thrombus, and the medical device is excellent in operability, biocompatibility and safety.

[Brief description of drawings]

FIG. 1 is a schematic view of a measuring device for surface lubricity.

[Explanation of symbols]

 1 Water 2 Brass cylindrical weight 3 Polyethylene sheet 4 Sample

Claims (4)

[Claims] 1. A medical device comprising a surface on which a hydrogel is formed, which is composed of an insoluble substance of a water-soluble or water-swellable polymer having a reactive functional group in the molecule and an antithrombotic agent, when wet. And medical equipment. 2. The medical device according to claim 1, wherein the reactive functional group is an epoxy group. 3. A solution containing a water-soluble or water-swellable polymer having a reactive functional group in the molecule and an antithrombotic agent is coated on the surface of a base material of a medical device, and then the water-soluble or water swellable. The method for producing a medical device according to claim 1, wherein a layer that forms a hydrogel when wet is formed on the surface of the medical device by insolubilizing the hydrophilic polymer. 4. A solution containing a water-soluble or water-swellable polymer having a reactive functional group in the molecule and a solution containing an antithrombotic agent are separately applied to the surface of a base material of a medical device,
The medical device according to claim 1 or 2, wherein a layer that forms a hydrogel when wet is formed on the surface of the medical device by insolubilizing the water-soluble or water-swellable polymer. Manufacturing method.