JPS6343109B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a polymeric material having antithrombotic properties, and more particularly to a material in which antithrombotic properties are imparted to a medical molded article made of polyurethane.

In recent years, various polymer materials have been used in the field of medical materials, but polyurethane-based polymers in particular have good mechanical properties (strength, elongation,
It has become widely used because of its flexibility (e.g. flexibility) and relatively good biocompatibility.

However, when these polymers are used for applications such as artificial blood vessels, catheters, and artificial hearts that come into contact with blood, blood easily coagulates on the material surface to form a thrombus. There is a great risk that this thrombus may stop the blood flow or move along with the blood flow, causing complications such as pulmonary thrombosis, cerebral thrombosis, myocardial infarction, and phlebitis.

Therefore, conventionally, when these medical materials are used, anticoagulants such as heparin and coumarin are administered systemically to make blood non-coagulable to prevent thrombus formation. However, systemic administration of heparin and the like has a major disadvantage in that the risk of bleeding is significantly increased. Therefore, if the surface of medical materials containing polyurethane as a main component could be made antithrombotic, it would be possible to prevent the formation of blood clots without the need for systemic administration of heparin, etc., making it possible to use polyurethane as a useful medical material that takes advantage of its many advantages. It becomes possible to safely perform treatment or diagnosis using the material.

From this perspective, the present inventors investigated how to easily make the surface of medical molded products containing polyurethane antithrombotic, and as a result, we found that it is possible to easily make the surface of medical molded products made of polyurethane antithrombotic, and to make the surface antithrombotic for a long period of time without impairing the useful properties of polyurethane. We have successfully developed a medical material with excellent antithrombotic properties.

That is, a monomer having a polyethylene glycol moiety in polyvinyl chloride and a tertiary or quaternary
The present invention provides an antithrombotic medical material obtained by forming a hydrophilic copolymer layer by graft polymerizing a monomer having a class amino group, and then converting the layer into heparin.

In the present invention, the composition constituting the medical molded article containing polyurethane as a main component is preferably a composition containing 30% by weight or more of polyurethane in view of its mechanical properties, moldability, etc. Such compositions include, in addition to polyurethane, blends, grafts, and block copolymer compositions with other polymers (eg, polyvinyl chloride, polymethyl methacrylate, polydimethyl siloxane, etc.).

Any polyurethane having a urethane bond in its main chain may be used. Such polyurethanes are obtained by reacting diisocyanates such as tolylene diisocyanate and diphenylmethane diisocyanate with polyester diols or polyether diols.
Polyether-type polyurethane is preferred in terms of flexibility, strength, and in vivo deterioration.

Medical molded products made from such compositions include rods such as guide wires, various catheters, monitoring tubes, artificial blood vessels, tubes such as blood circuits, artificial kidney dialysis membranes, and oxygen permeable membranes for artificial lungs. , film-like or hollow fiber-like molded products such as film for film-type oxygenators, leaf-like, spherical and disc-like molded products such as artificial heart valves, tubular and sac-like artificial heart pumping chambers, and blood storage bags. There are sac-shaped, tubular-shaped molded products, and complex-shaped molded products that combine these.

The hydrophilic graft copolymer layer has vinyl chloride as a main component, a monomer having a polyethylene glycol moiety as a hydrophilic component, and a tertiary or quaternary monomer.
It consists of a monomer having a class amino group. The ratio (hydrophilic monomer/vinyl chloride: weight ratio) is determined based on adhesiveness with the base material, heparin content after heparinization, etc.
A copolymer layer having a ratio of 1/9 to 8/2, preferably 2/8 to 7/3 is formed on the substrate to be coated using a common solvent, and then brought into contact with a heparin solution. can get.

Here, the monomer having a polyethylene glycol moiety that constitutes the hydrophilic graft copolymer is
Examples include polyethylene glycol, methacrylic acid esters of methoxypolyethylene glycol, and copolymers thereof.

Contains heparin evenly inside the polymer layer,
In addition, even under physiological conditions, heparin is easily eluted and does not cause changes in blood properties, and in order to maintain antithrombotic properties for a long period of time, the hydrophilic component is a tertiary amino group or its tertiary amino group. It is necessary to use monomers with class salts.

An example is the general formula (R ₁ is H or CH ₃ , R ₂ , R ₃ is CH ₃ or C ₂ H ₅ , n
1 to 3) Acrylic acid or methacrylic acid derivatives and quaternary salts thereof, and 2- or 4-
Examples include vinylpyridine, derivatives thereof, and quaternary salts thereof.

The copolymer containing these components needs to be a graft copolymer with polyvinyl chloride as the backbone polymer in view of adhesion to the base material, balance between antithrombotic properties and mechanical properties.

When producing a copolymer containing a quaternary salt of a tertiary amino group, not only the above-mentioned quaternary chlorinated monomer is used as a copolymerization component, but also the monomer containing the corresponding tertiary amino group is polymerized, and then the polymer is In the solution,
Alternatively, after molding with tertiary amino groups, 4
You may also use a method such as applying a grading agent. In particular, the method of quaternizing the polymer solution after molding is preferred because it is easy to handle the polymer solution and is a simple method. A quaternizing agent for quaternizing a tertiary monomer or polymer is represented by the general formula RX (R=H, alkyl group, benzyl group, etc., X=negative Atsuko group capable of forming a salt with amine nitrogen), Examples include methyl bromide, ethyl bromide, methyl iodide, benzyl chloride, and hydrogen chloride.

Next, a method for forming a hydrophilic copolymer layer on the surface of a medical molded article mainly composed of polyurethane and converting it into heparin will be described.

The copolymer is applied to the surface to be coated, which is mainly composed of polyurethane, using a common solvent, and the application and drying steps are repeated until the coated copolymer layer reaches a predetermined thickness. Here, as a common solvent for the base material and the copolymer, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, and a mixed solvent thereof are used, but from the viewpoint of ease of molding, etc. Those having a boiling point of 30 to 80°C, such as tetrahydrofuran, are preferable.

The thickness of the copolymer layer is determined by the copolymer concentration in the coating solution (preferably 1 to 50% by weight) and the number of times of coating, but it can be applied for a long period of time, at least one day or more.
In order to exhibit effective antithrombotic properties in the body, 1μ
The thickness is preferably 5 μm or more, preferably 5 μm or more.

The drying step after coating is preferably carried out in an air, nitrogen or argon atmosphere, and the drying temperature varies depending on the type of solvent used and ranges from room temperature to 100°C.

Next, the medical molded article coated with the copolymer layer is extracted in water, methanol, etc. at a temperature ranging from room temperature to boiling point in order to remove impurities such as residual solvent, unreacted monomer, catalyst, and polymerization inhibitor. be done.

Heparinization of the coating copolymer layer thus obtained is carried out by bringing the coating layer into contact with an aqueous heparin solution.

The conditions for heparinization include immersion in an aqueous heparin solution having a heparin concentration of 0.5% by weight or more, preferably 0.5 to 5% by weight, preferably at 50°C to 80°C for several hours to 5 days. In this case, the heparin aqueous solution is 0 to
Preferably it contains 0.3N NaCl.

After completion of heparinization, the product is vacuum dried at room temperature for 1 to 3 days, and then subjected to prescribed sterilization operations to complete the production of the antithrombotic medical material.

The medical material thus obtained has antithrombotic properties while maintaining the shape of the base molded material, and as mentioned above, the shape can be rod-like, tube-like, film-like, hollow fiber-like, or leaf-like. Although the shapes are not uniform, such as spherical, spherical, sack-like, and other complex shapes combining these shapes, a few examples are shown in cross-sectional views in FIGS. 1 to 5.

The antithrombotic properties of such medical materials can be demonstrated in vitro,
It is evaluated using various evaluation methods depending on its use, such as in vivo and ex vivo, and as a result of these evaluations, it has become clear that the medical material according to the present invention has extremely excellent antithrombotic properties for a long period of time. The present invention will be explained below with reference to Examples. However, the present invention is not limited thereby.

Example 1 100g of polyvinyl chloride with a degree of polymerization of 1100 was dissolved in dimethylformamide (2), 2.0g of diethyldithiocarbamate sodium salt was added,
C. for 3 hours, reprecipitated in methanol, and dried to obtain photograft-activated polyvinyl chloride (DTC-treated polyvinyl chloride).

Dissolve 30 g of this DTC polyvinyl chloride in 1 part tetrahydrofuran, add 40 g of methoxypolyethylene glycol monomethacrylate (polymerization degree of polyethylene glycol moiety 20 to 23) and 20 g of DTC polyvinyl chloride.
g of dimethylaminoethyl methacrylate was added thereto, and photograft polymerization was carried out by irradiating the mixture with a 100W high-pressure mercury lamp for 6 hours in a light source-internal immersion type photoreactor.

40 g of ethyl bromide is added to the obtained polymer solution and stirred at 50° C. for 3 hours to form a quaternary salt. The composition of this copolymer was, by weight, 55% vinyl chloride, 23% methoxypolyethylene glycol monomethacrylate, and 17% dimethylaminoethyl methacrylate quaternary salt.

This polymer solution was coated on the inner surface of a commercially available medical polyurethane tube (Japan Unipolymer "R-380" thermoplastic polyether type polyurethane).

Coating is done twice, and drying is done at room temperature (22
The experiments were carried out in a nitrogen stream at 10°C. The thickness of the coating layer was 15 μm.

After drying, residual monomers, solvents, etc. were extracted using methanol at 60°C for one day, washed with water, and immersed in a 0.1N aqueous solution of NaCl containing 2% by weight of heparin.
Heparinization was performed at 60°C for 3 days. Next, unbound heparin and residual salts were removed with ion-exchanged water, and the product was vacuum-dried at room temperature (22°C) for two days and nights. The heparin content of the heparinized layer was determined to be 21% by weight by quantifying the sulfur atoms contained in heparin using an X-ray microanalyzer.

A cross-sectional view of this material corresponds to Figure 2-1.
The antithrombotic properties of this material were evaluated by an extracorporeal bypass experiment using adult dogs.

Specifically, an adult dog (approximately 13 kg) is anesthetized by intravenously injecting pentobarbital soda, the descending thoracic aorta is blocked, and blood is drained from the aortic arch to the descending aorta below the cutoff point using the tube. Bypass was performed and blood was allowed to circulate extracorporeally for 10 hours without systemic heparin administration.

A blood flow meter was installed in the bypass tube in advance and the amount of blood flowing through the tube was continuously monitored to determine whether there was a thrombus forming inside the tube. hardly decreased during the extracorporeal circulation experiment, and it became clear that no thrombus was formed within the tube.

Furthermore, after the experiment was completed, the inner surface of the tube was observed using a scanning electron microscope, and it was found that the number of adhered platelets that cause thrombus formation and the degree of deformation thereof were much lower than in the non-coated polyurethane tube used in the comparative example.

Comparative Example 1 When the polyurethane tube used in Example 1 was not coated with the hydrophilic copolymer of the present invention and its antithrombotic properties were evaluated in the same manner as in Example 1 (extracorporeal bypass method), the extracorporeal circulation time Blood flow began to decrease after 1.5 hours, and completely stopped due to an embolus within 2 hours. After the evaluation, the inner surface of the tube was observed using a scanning electron microscope, and numerous deformations, aggregated platelets, fibrillar networks, and red blood cells were observed.

Example 2 A balloon of 0.5 cm in width, 2 cm in length, and 100 μm in thickness was cut out from a polyurethane-dimethylsiloxane block copolymer balloon for aortic balloon pumping in the graft copolymer (unquaternized) solution of Example 1.
A graft copolymer layer containing tertiary amino groups was coated on the film to a thickness of about 30 μm by dipping the film four times.

The drying and extraction conditions were exactly the same as in Example 1, and the obtained film was immersed in a 5% by weight aqueous heparin solution at 70° C. for one day to effect heparinization. As a result of measurement using the same method as in Example 1, the heparin content of the heparinized layer was 10.3% by weight.
It was hot.

A cross-sectional view of this material corresponds to Figure 4-2. In order to evaluate the antithrombotic properties of this material, we used the left atrium placement method using adult dogs.

That is, an adult dog (approximately 15 kg) is anesthetized by intravenously injecting pentobarbital soda, and after opening the chest, one end of the evaluation film is fixed to the left atrial appendage with a suture, and the evaluation sample is suspended within the left atrium. After indwelling for 2 days, blood was removed, the chest was reopened, the left atrium was incised, and the surface of the material was closely observed with the naked eye and with a scanning electron microscope, and no thrombus formation was observed, indicating that it has excellent antithrombotic properties. showed his sexuality. Therefore, it has been found that a chamber for aortic balloon pumping with better antithrombotic properties can be produced using a film made of this material.

[Brief explanation of drawings]

Figures 1 to 5 show cross-sectional views of a medical molded article (black area) containing polyurethane as a main component and a heparinized hydrophilic copolymer layer (hatched area) formed thereon. Figure 1 shows the case of a rod-shaped molded product such as a medical guide wire made of polyurethane, and Figure 2 shows the case of a tube-shaped molded product such as a blood circuit made of polyurethane (Figures 2-1 and 2-2). and FIGS. 2-3 show inner surface coating, outer surface coating, and inner-outer surface coating, respectively), and FIG.
In the case of a spherical molded product such as a ball valve made of hard polyurethane, Fig. 4 shows the case of a film-shaped molded product such as a film for a film-type oxygenator made of polyurethane film (Figs. Figure 5 shows the case of a sack-shaped molded product such as the main body of a blood storage bag made of a polyvinyl chloride/polyurethane blend composition.

Claims (1)

[Claims] 1. After forming a hydrophilic copolymer layer on the surface of a medical molded article mainly composed of polyurethane, which is obtained by graft polymerizing polyvinyl chloride with a monomer having a polyethylene glycol moiety and a monomer having a tertiary or quaternary amino group. , an antithrombotic medical material made by heparinization.