JPH10211273A - Medical tool - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prevent the thrombosis from being formed by fixing poly(N- vinylpyrrolidone) on the surface of a synthetic resin, quarternizing the amino group, letting it carry heparin and drying to provide the surface with lubricity due to the contact with aqueous solution and sustained release property of heparin. SOLUTION: For example, a rod is molded by extrusion of a polyurethane resin. The rod is dipped in a 1,4-dioxane solution of approximately 5% methylene diisocyanate and dried. This is rinsed with 1,4-dioxane so as to remove excessive methylene diisocyanate. Then, it is dipped in approximately 5% 1,4- dioxane solution of poly(N-vinylpyrrolidone) having part of lactam ring opened. This is dried so as to fix poly(N-vinylpyrrolidone) on the surface of the rod. When the rod treated thereby is compared with a rod without this treatment by an animal experiment, it is confirmed that this treatment provides high thrombosis resistance.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the treatment of a surface of a medical device which is inserted or detained in a body for the purpose of examination or treatment and is used in contact with blood, in contact with blood and living tissue. More specifically, angiographic catheters, vascular dilatation balloon catheters, vascular occlusion catheters, blood flow measurement catheters, vascular endoscopes, percutaneous transluminal drug infusion catheters, percutaneous transluminal bodily fluid discharge catheters, The present invention relates to a medical device used for diagnosis and treatment of a disease.

[0002]

2. Description of the Related Art In recent years, when a medical device is inserted into or removed from a blood vessel percutaneously or transluminally, various surface lubrication techniques for reducing pain caused by friction between the surface of the medical device and a living tissue have been developed. A technology for imparting antithrombotic properties to the surface of medical devices that come into contact with blood has been developed, but lubricity and antithrombotic properties are imparted to the surfaces of medical devices that come into contact with blood by percutaneous or transluminal insertion into the body. There is no technology that has both. In some reports, hydrogel itself exhibits antithrombotic properties due to its high hydrophilicity effect, but these materials inhibit the adhesion and denaturation of blood proteins due to their high hydrophilicity, Although the blood coagulation reaction caused by the reaction is suppressed, percutaneous insertion of a catheter involves damage to blood vessels and tissues, and the blood coagulation system of blood itself is enhanced by damaged blood vessels and tissues at the beginning of catheter insertion In practice, the formation of blood clots cannot be prevented only by the hydrophilic effect of the surface of the medical device, and the formation of microthrombi in blood vessels, the attachment of blood clots to catheters, and the There is a problem that blockage or the like occurs.

[0003]

SUMMARY OF THE INVENTION The present invention is to solve such a conventional problem. Thus, by heating poly (N-vinylpyrrolidone) under high pressure, some lactam rings are cleaved but uncleaved lactam rings remain. Focusing on the fact that heparin, an anticoagulant, can be easily ionically supported by quaternizing the tertiary amino group contained, as a result of intensive research, the carboxyl group or amino group of the cleaved lactam ring was examined. Thus, poly (N-vinylpyrrolidone) can be immobilized on the polyurethane surface with diisocyanate, and the tertiary amino group in the unreacted lactam ring can be quaternized, leading to the present invention.

[0004]

According to the present invention, poly (N-vinylpyrrolidone) is immobilized on the surface of a synthetic resin, the amino group of the solidified poly (N-vinylpyrrolidone) is quaternized, and heparin is supported. And dried,
The present invention relates to a medical device characterized in that the surface thereof has lubricity upon contact with an aqueous solution and heparin is gradually released.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION As the diisocyanate which can be used in the present invention, any of aliphatic diisocyanate and aromatic isocyanate can be used. The heparin that can be used in the present invention is not particularly limited, but sodium and potassium salts of heparin can be used. Ethyl bromide can be used as a reagent for quaternizing the amino group of poly (N-vinylpyrrolidone) that can be used in the present invention. Further, the substrate made of a synthetic resin that can be used in the present invention is a polyurethane or a polyurethane having an amino group on its surface that can be reacted with diisocyanate,
A substrate other than polyurethane, which is a synthetic resin other than polyurethane and whose surface is coated with polyurethane, can be used. Hereinafter, effects of the present invention will be described with reference to examples.

[0006]

【Example】

(Example 1 and Comparative Example 1) 1) Cleavage of a part of lactam ring of poly (N-vinylpyrrolidone) Poly (N-vinylpyrrolidone) having a molecular weight of about 360,000 (manufactured by Wako Pure Chemical Industries, Ltd.) 90g for 30g for cosmetics)
The mixture was stirred in pure water at 12 ° C. for 12 hours to break a part of the lactam ring. The obtained poly (N-vinylpyrrolidone) was titrated with 0.5N NaOH using phenolphthalein as an indicator, and the equivalent amount of free carboxyl groups was measured.
1.6 to 2 molar equivalents.

2) Fixation to Polyurethane Rod and Carrying of Heparin A polyurethane resin (Biomer manufactured by Ethicon, USA) was extruded into a rod-shaped rod having an outer diameter of 3 mm and a length of 15 cm.
Next, the polyurethane rod was immersed in a solution of 5% methylene diisocyanate (manufactured by Wako Pure Chemical Industries, Ltd., reagent grade) in 1,4-dioxane (chemical manufactured by Wako Pure Chemical Industries, Ltd.) for 1 hour, Dry at 60 ° C. for 1 hour. Then
The rod was washed with a large amount of 1,4-dioxane to remove excess methylene diisocyanate. After drying the rod, poly (N) in which a part of the lactam ring was cleaved in 1)
(Vinylpyrrolidone) in a 5% 1,4-dioxane solution. After 20 minutes, the rod was pulled up and dried at 80 ° C. for 15 hours to fix poly (N-vinylpyrrolidone) on the polyurethane surface.

After fixing poly (N-vinylpyrrolidone),
The rod was immersed in a solution of 500 ml of 1,4-dioxane and 50 ml of ethyl bromide at 60 ° C. for 2 hours to quaternize the amino group of the lactam ring, and the rod was dried at 60 ° C. under reduced pressure. Next, insert the rod into heparin (Novo Heparin Note 25000,
6% in 3% pure aqueous solution of Marion Merrell Dow
The sample was immersed at 0 ° C for 4 days, and the poly (N-vinylpyrrolidone) immobilized on the polyurethane surface was made to carry heparin ionically, washed with deionized water, and freeze-dried at -5 ° C for 48 hours. A polyurethane rod subjected to the surface treatment according to the invention was obtained. As a comparative example, a rod was prepared by merely fixing poly (N-vinylpyrrolidone) to a polyurethane rod obtained by extruding a polyurethane resin (Biomer, manufactured by Ethicon Corporation, USA) into a rod shape having an outer diameter of 3 mm and a length of 15 cm.

3) Animal experiment One adult beagle dog (female) weighing 11 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, heparin (100 U / kg) was intravenously injected, and the femur was incised while maintaining anesthesia with Frosen to expose both left and right femoral arteries by about 5 cm each. Next, the distal end of the left femoral artery, a few centimeters at the bifurcation of the circumflex femoral artery, was temporarily ligated, and the femoral artery was incised in a small incision into the artery, and the surface-treated polyurethane rod of the present invention prepared in 2) was subjected to 10c.
m was inserted. The rod insertion part tied the rod with a ligature together with the blood vessel wall, and placed the polyurethane rod in the femoral artery. After the rod was placed, the thread that ligated the distal part of the left femoral artery to the peripheral portion of the circumflex femoral artery several cm away was removed, and blood flow was resumed.

Similarly, a few cm of the peripheral portion of the external femoral circumflex artery of the right femoral artery is temporarily ligated, a small incision is made in the femoral artery, and intraarterial poly (N-vinylpyrrolidone) is fixed on the surface. 10 cm was inserted in the polyurethane rod of the comparative example which did not carry. The rod insertion part tied the rod with a ligature together with the blood vessel wall, and placed the polyurethane rod in the femoral artery. After the rod was placed, the thread that ligated the peripheral part of the external femoral circumflex artery of the right femoral artery by several cm was removed, and the blood flow was resumed. After the indwelling of the surface-treated polyurethane rod of the present invention and the polyurethane rod of the comparative example in the femoral artery was completed, the wound of the thigh was sutured, and the dog was awake from anesthesia. Three days after the rod was placed in the femoral artery, the dog was anesthetized in the same manner as when the rod was placed, and heparin (100 U / k)
g) intravenously while maintaining anesthesia with Flösen
The femur was incised to expose both left and right femoral arteries by about 5 cm each. The central femoral artery at the rod insertion portion was ligated, and the surface treated polyurethane rod of the present invention and the polyurethane rod of the comparative example were placed in both the left and right arteries. Immediately after removing the rod, use a syringe for 2500 IU
Both rods were gently washed with a saline solution containing / 500 mL of heparin, and the blood was washed away. Thereafter, the degree of thrombus adhering to both rods was visually observed, and the antithrombotic properties were comparatively evaluated.

4) Evaluation Results The evaluation results of the antithrombotic properties of the polyurethane rods of Examples and Comparative Examples were as follows.

[0012]

[Table 1]

(Example 2) 1) Preparation of a sheet having a surface lubricating treatment according to the present invention and a sheet of a comparative example A polyurethane resin (Biomer manufactured by Ethicon, USA) was hot-press molded to prepare six 15 cm x 30 cm sheets. . Next, one polyurethane sheet was placed in a solution of 5% methylene diisocyanate (manufactured by Wako Pure Chemical Industries, Ltd., chemical) in 1,4-dioxane (manufactured by Wako Pure Chemical Industries, Ltd., chemical) for 1 hour. It was immersed and dried at 60 ° C. for 1 hour. Next, the sheet was washed with a large amount of 1,4-dioxane, and 5% of a part of the lactam-cleaved poly (N-vinylpyrrolidone) prepared in 1) of Example 1, 1.4).
After immersion in a dioxane solution, after 20 minutes, the sheet was pulled up, dried at 80 ° C. for 15 hours, and poly (N-vinylpyrrolidone) was fixed on the polyurethane surface.

After fixing the poly (N-vinylpyrrolidone),
The sheet was immersed in a solution of 500 ml of 1,4-dioxane and 50 ml of ethyl bromide at 60 ° C. for 2 hours to quaternize the amino group of the lactam ring, and the sheet was dried at 60 ° C. under reduced pressure. Next, heparin (Novo Heparin Note 25000,
6% in 3% pure aqueous solution of Marion Merrell Dow
After immersion at 0 ° C. for 4 days, heparin was ionically supported on poly (N-vinylpyrrolidone) fixed on the surface of the polyurethane sheet, washed with deionized water, and then washed at −5 ° C. for 48 days.
The polyurethane sheet subjected to the surface treatment according to the present invention was obtained by freeze-drying for a time.

2) Measurement of Surface Friction Coefficient To compare and study the lubricity of the surface produced by the surface treatment of the present invention, poly (N-vinylpyrrolidone) was fixed on the polyurethane sheet produced above and heparin was supported. The prepared sheet and a sheet made of only polyurethane were prepared as a comparative example, and these were swollen with pure water for 1 hour. Thereafter, a weight of 50 g weight is placed on the sheet, and the weight is combined with a digital force gauge (Shinpo Kogyo KK, D
FG1K type) with a nylon suture, moving the digital force gauge at a constant speed of 10 cm / min, pulling the weight on the sheet, and measuring the tensile load with the digital force gauge. The coefficient of friction on the sheet surface was determined by a load one minute after the start of the tensile load measurement, and a comparative evaluation was made. 3) The measurement results of the coefficient of friction are shown in FIG.

[0016]

As described above, a medical device in which poly (N-vinylpyrrolidone) is immobilized on polyurethane, the amino group of poly (N-vinylpyrrolidone) is quaternized, and heparin is carried, is excellent. It has become clear that it has both excellent surface lubricity and excellent antithrombotic properties. The present invention, as a surface treatment of a medical device that is percutaneously and / or percutaneously inserted and placed in the body and comes into contact with blood, reduces pain of a patient when inserting and removing a medical device into and from a body, and is excellent. A useful medical device exhibiting improved blood compatibility can be provided.

[Brief description of the drawings]

FIG. 1 shows a sheet in which poly (N-vinylpyrrolidone) is immobilized on a polyurethane, an amino group is quaternized, and a sheet carrying heparin and a sheet containing only a polyurethane of a comparative example are each swollen with pure water for 1 hour. The surface friction coefficient was shown.

Claims (4)

[Claims] 1. The method according to claim 1, wherein the surface of the substrate made of synthetic resin is poly (N
-Vinylpyrrolidone), quaternizing the amino groups of poly (N-vinylpyrrolidone), carrying heparin, and drying. A medical device characterized by sustained release. 2. Poly (N) on the surface of a substrate made of synthetic resin
The medical device according to claim 1, wherein the fixation of (vinylpyrrolidone) is carried out with diisocyanate. 3. The medical device according to claim 1, wherein the substrate made of a synthetic resin is polyurethane. 4. The medical device according to claim 1, wherein the substrate made of a synthetic resin is a substrate other than polyurethane, and the surface thereof is coated with polyurethane.