JPH11276574A - Antithrombotic medical appliance - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical appliance of which surface is antithrombotic even if it comes into contact with bloods for a long-term. SOLUTION: On the surface of the medical appliance made of resin and used as it in contact with bloods, choline phosphoric acid group is exposed and fixed. Also, heparin can be ionically bonded to quaternary amino of choline phosphoric acid group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method of inserting or retaining blood in a blood vessel, collecting blood, discharging blood, injecting a drug solution into blood or organs, extracorporeal circulation for dialysis or oxygenation of blood, and surgery. The present invention relates to a medical device used for a vascular bypass during an operation and a medical device that comes into contact with blood, such as a vascular prosthesis and an artificial organ.

[0002]

2. Description of the Related Art A method for imparting antithrombotic properties to the surface of a medical device is to form a microphase-separated structure on the surface of the medical device, adsorb proteins such as albumin in blood, inactivate the surface, and improve antithrombotic properties. Acquisition method, a method of binding platelets with hydrophilic chains such as polyethylene glycol chains to suppress platelet adhesion and obtain antithrombotic properties, dispersing anticoagulants and thrombolytic agents in the base There is a method of acquiring antithrombotic properties by ionically binding to the surface and gradually releasing it to the substrate surface.
In the case of applying a choline phosphate group, a product obtained by copolymerizing a monomer having a choline phosphate group and a hydrophobic monomer is coated on the surface of a medical device to selectively adsorb phospholipids in blood to obtain antithrombotic properties. There are things to try.

[0003] A method of forming a microphase-separated structure to adsorb proteins in blood, a method of bonding hydrophilic chains to the surface,
Neither method of coating a polymer consisting of a monomer having a choline phosphate group and a hydrophobic monomer actively seeks to obtain antithrombotic properties, and thus blood coagulation activated by blood vessel damage or surgery. The reaction cannot be suppressed, and there is a problem that an initial minute thrombus is generated. In addition, the method of forming a microphase-separated structure on the surface of a medical device to obtain antithrombotic properties has a problem in that the adsorbed protein is unstable and easily detached by the blood flow, and a thrombus is formed from the site where the protein has fallen off. However, the method of bonding the hydrophilic chain to the surface of the medical device has a problem that the hydrophilic chain is easily embedded in the base material of the medical device, and a sufficient hydrophilic effect cannot be obtained.

In the method in which an anticoagulant or thrombolytic agent is gradually eluted from the surface of a substrate, the absorption of blood proteins on the surface of the substrate or the consumption of the supported anticoagulant or blood lysate causes a problem. Since the amount of released drug gradually decreases, there is a problem that long-term antithrombotic properties cannot be obtained. In a method of coating a polymer obtained by copolymerizing a monomer having a choline phosphate group and a hydrophobic monomer on the surface of a medical device,
Since the choline phosphate group is hydrophilic, increasing the component of the choline phosphate group increases the hydrophilicity of the polymer, and has a problem that the polymer phase is easily peeled from the base surface of the medical device in blood, and the medical device has a problem. After coating on the surface,
There is a problem that the choline phosphate group is buried in the hydrophobic monomer or the resin of the base medical device, and good antithrombotic properties cannot be obtained.

[0005]

DISCLOSURE OF THE INVENTION The present invention is intended to solve such a conventional problem. Choline phosphate groups selectively adsorb phospholipids in blood to form a phospholipid phase. By suppressing the adhesion of platelets by suppressing the blood coagulation reaction for a long time, a compound having a photofunctional azide group or an aromatic ketone group is brought into contact with the surface of a resin having a C--H bond and irradiated with ultraviolet light. Focusing on the fact that a covalent bond can be firmly covalently bonded to the surface of the resin, a mixture of a compound having a choline phosphate group on the surface of the synthetic resin and a bifunctional photofunctional reagent or succinimide group, isocyanate group, aldehyde group, amino group Coating a photofunctional reagent linked to a choline phosphate group by one functional group that can be selected from group, carboxyl group, epoxy group and acid anhydride Focusing on the fact that it is possible to expose the choline phosphate group to the surface of the medical device and to form a covalent bond by irradiating with ultraviolet light, and that the choline phosphate group has a quaternary amino group, and heparin is supported ionically. And during the initial period of contact of the medical device with the blood,
The present inventors have found that ion-coupled heparin can be released to the surface of a base material and can suppress damage to blood vessels and coagulation of blood activated by surgical operation, and have made intensive studies to arrive at the present invention.

[0006]

SUMMARY OF THE INVENTION The present invention relates to an antithrombotic medical device characterized in that a choline phosphate group is exposed on the surface of a medical device made of a resin used in contact with blood and fixed. is there. Alternatively, there is provided an antithrombotic medical device in which a choline phosphate group is exposed on the surface of the medical device and fixed, or an antithrombotic medical device characterized in that heparin is ion-bonded to a quaternary amino group of the choline phosphate group.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION As the resin that can be used in the present invention, any resin having a C—H bond in a molecule can be used.
Although not particularly limited, polyvinyl chloride resin, silicone resin, polyurethane resin, polyethylene resin, polycarbonate resin, nylon resin, polystyrene resin, polystyrene-based thermoplastic elastomer, polyolefin-based thermoplastic elastomer, polydiene-based thermoplastic elastomer, polyvinyl chloride-based Thermoplastic elastomer, polyurethane thermoplastic elastomer, polyester thermoplastic elastomer, polyamide thermoplastic elastomer, fluorine thermoplastic elastomer, styrene butadiene rubber, acrylonitrile butadiene rubber, butadiene rubber, isoprene rubber, chloroprene rubber, chlorosulfonated polyethylene rubber , Ethylene propylene rubber, butyl rubber, silicone rubber, fluoro rubber, urethane rubber,
Acrylic rubber, natural rubber and the like can be mentioned.

The compound having a choline phosphate group that can be used in the present invention is not particularly limited, and examples thereof include phosphatidylcholine, phosphorylcholine and chlorides thereof, lecithin and lysolecithin. Examples of the bifunctional reagent that can be used in the present invention include dicarboxylic acid, diisocyanate, and dialdehyde, and those in which two functional groups are both photofunctional groups or one functional group is a photofunctional group. One of which has a functional group that can be selected from succinimide group, isocyanate group, aldehyde group, amino group, carboxyl group, epoxy group and acid anhydride, and an aromatic azide group is used as a photofunctional group. Alternatively, those having an aromatic ketone group can be used.

Examples of these bifunctional reagents include, but are not limited to, 6- (4-azido-2-nitrophenylamino) hexanoic acid-N-hydroxysuccinimide ester and 6- (4-azido-2 -Nitrophenyl) hexamethylene isocyanate, 6- (4-azido-2-nitrophenyl) hexanal, 6- (4-azido-2-nitrophenylamino) hexanoic acid ethylenediamine ester, 6- (4-azido-2-nitro (Phenylamino) hexanoic acid, 3- (4-azido-2-nitrophenyl) propylene oxide, benzoylbenzoic acid, benzoylbenzoic N-oxysuccinimide, benzoylbenzoic-polyethylene glycol, benzoylbenzoic-polyethylene glycolamine and the like are preferable. .
Heparin that can be used in the present invention can be derived from animals. Hereinafter, effects of the present invention will be described with reference to examples.

[0010]

[Example] (Example 1) Preparation of antithrombotic bypass tube having immobilized choline phosphate group Polyurethane resin (Tecoflex EG80A, manufactured by Thermedics)
By extrusion molding, outer diameter 5mm, inner diameter 3mm, length 15
cm), and both ends 10 mm were cut at 45 degrees to obtain a polyurethane tube. Next, 300 ml of a benzene solution in which 22.6 g of O-benzoylbenzoic acid (Kanto Chemical Co., Ltd., special grade) was dissolved and 1 ml of sulfuric acid (Wako Pure Chemical Industries, Ltd., special grade) in a light-shielded three-necked flask. Was added and stirred well, and 26 g of phosphorylcholine hydrochloride (manufactured by Sigma-Aldridge Japan Co., Ltd.) was added thereto, and the mixture was refluxed for 5 hours while trapping water to remove the ester of phosphorylcholine and O-benzoylbenzoic acid. Synthesize and
Recrystallized from benzene.

Next, 5 g of an ester of phosphorylcholine and O-benzoylbenzoic acid was dissolved in 100 ml of a 3: 1 mixed solution of isopropyl alcohol and pure water, and applied to the inner and outer surfaces of the above-formed polyurethane tube. After the tube was dried, the tube was irradiated with light for 10 minutes using a tungsten lamp, a phosphorylcholine group was covalently fixed on the surface of the tube, and the tube was ultrasonically washed in pure water for 15 minutes to wash unreacted substances. To obtain an antithrombotic bypass tube.

Example 2 Preparation of Antithrombotic Bypass Tube Fixing Choline Phosphate Group and Carrying Heparin Polyurethane Resin (Tecoflex EG80A, manufactured by Thermedics)
By extrusion molding, outer diameter 5mm, inner diameter 3mm, length 15
cm), and both ends 10 mm were cut at 45 degrees to obtain a polyurethane tube. Next, 300 ml of a benzene solution in which 22.6 g of O-benzoylbenzoic acid (Kanto Chemical Co., Ltd., special grade) was dissolved and 1 ml of sulfuric acid (Wako Pure Chemical Industries, Ltd., special grade) in a light-shielded three-necked flask. Was added and stirred well, and 26 g of phosphorylcholine hydrochloride (manufactured by Sigma-Aldridge Japan Co., Ltd.) was added thereto, and the mixture was refluxed for 5 hours while trapping water to remove the ester of phosphorylcholine and O-benzoylbenzoic acid. Synthesize and
Recrystallized from benzene.

Next, 5 g of an ester of phosphorylcholine and O-benzoylbenzoic acid was dissolved in 100 ml of a 3: 1 mixed solution of isopropyl alcohol and pure water, and applied to the inner and outer surfaces of the polyurethane tube formed above. After drying the tube, the tube was irradiated with light for 10 minutes using a tungsten lamp, a phosphorylcholine group was immobilized on the surface of the tube by a covalent bond, and the tube was ultrasonically washed in pure water for 15 minutes to wash unreacted substances. Next, 1% heparin sodium trim (Novo
Heparin Note 25000, Marion Merrell Dow Co., Ltd.
The above tube was immersed in an aqueous solution of (1) for 12 hours at 4 ° C. to carry heparin on the phosphorylcholine group immobilized on the tube surface to obtain an antithrombotic bypass tube according to the present invention.

Comparative Example Polyurethane resin (Thermedics)
Extruded Tecoflex EG80A), 5m outside diameter
m, inner diameter 3mm, length 15cm, both ends 10mm
Was cut at 45 degrees to obtain a polyurethane tube of a comparative example.

Example 3 Animal Experiment One adult beagle dog (female) weighing 18 kg was pretreated with atropine, and induction of anesthesia was performed with flunitrazepam 0.1 mg / kg.
Was performed by intravenous injection of ketamine 3 mg / kg. After fixing the dog on the operating table, while maintaining the anesthesia with Flawsen,
The neck was incised to expose the left and right jugular veins. Next, the central part and the peripheral part of the right and left jugular veins were spaced apart by about 10 cm, and a total of four places were clamped with forceps to temporarily block the blood flow. Approximately 1 cm on the peripheral and central sides of blood vessels that block blood flow
The incision was made at two places approximately 3 cm from the clamp, and the antithrombotic bypass tube according to the present invention described in the above Example 1 and the polyurethane tube of the comparative example, which had been previously primed with physiological saline and clamped with forceps, were used. Cross the central incision of the left jugular vein to the peripheral incision of the right jugular vein, and cross the central incision of the right jugular vein to the peripheral incision of the left jugular vein. And secured with sutures. A probe of an ultrasonic blood flow meter (Trnsonic Systems, T201 type) was set almost at the center of the two tubes.

Next, the inner and outer two of the four forceps, which temporarily interrupted the blood flow, were removed, the two central forceps were simultaneously removed, and the measurement of the blood flow velocity in the tube was started. 12 hours later,
Heparin was injected intravenously at 100 IU / kg, 10 minutes later, the blood flow was stopped by pinching the tube with forceps, and ligated with a suture 4 cm upstream and downstream from the tube insertion part of the left and right jugular vein,
The blood vessel was cut at the ligation part, and the tube was extracted together with the blood vessel.
The inside and outside of the excised tube were gently washed with 5 IU / ml of heparinized saline to wash off the blood. Next, the tube was cut vertically and thrombus attached to the inside and outside blood vessel insertion portions of the tube were comparatively observed.

3) Experimental results The experimental results of the tubes of the examples and comparative examples are as summarized in Table 1.

[0018]

[Table 1]

[0019]

As described above, it has been clarified that the surface of a medical device having a choline phosphate group immobilized with a bifunctional reagent can favorably inhibit the formation of thrombus on the surface. As described above, the present invention can provide a medical device capable of suppressing formation of a thrombus on the surface even in long-term contact with blood.

Claims (6)

[Claims] 1. An antithrombotic medical device wherein a compound having a choline phosphate group is covalently bonded to the surface of the medical device. 2. The antithrombotic medical device according to claim 1, wherein heparin is ionically bound to the compound having a choline phosphate group. 3. The antithrombotic medical device according to claim 1, wherein the compound having a choline phosphate group is covalently bonded to the surface of the medical device made of a resin by a bifunctional reagent. 4. A bifunctional reagent wherein at least one of the functional groups is a photofunctional group and the other is a succinimide group, an isocyanate group, an aldehyde group, an amino group, a carboxyl group,
The antithrombotic medical device according to claim 3, which is a functional group that can be selected from an epoxy group and an acid anhydride. 5. The antithrombotic medical device according to claim 3, wherein the photofunctional group of the bifunctional reagent is a benzophenone derivative or an azide group. 6. A choline phosphate group is covalently bonded to a surface of a medical device made of a resin by applying a compound having a choline phosphate group and a bifunctional reagent or a reaction product thereof to the surface of the medical device and then irradiating light. The antithrombotic medical device according to claim 4 or 5, wherein