JPS6343107B2 - - 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 polyvinyl chloride.

In recent years, various polymer materials have been used in the field of medical materials, but polyvinyl chloride-based polymers in particular are economical and copolymerizable.
It is widely used because polymers with a wide range of physical properties can be easily obtained through plasticization.

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 polyvinyl chloride 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., and take advantage of the many advantages of polyvinyl chloride. It becomes possible to safely perform treatment or diagnosis using useful medical materials.

From this perspective, the present inventors investigated how to easily make the surface of a medical molded product mainly composed of polyvinyl chloride antithrombotic. Furthermore, we succeeded in developing a medical material that has excellent antithrombotic properties for a long period of time.

That is, a hydrophilic copolymer layer obtained by graft-polymerizing polyvinyl chloride with a monomer having a polyethylene glycol moiety and a monomer having a tertiary or quaternary amino group is formed on the surface of a medical molded article mainly composed of polyvinyl chloride. The object of the present invention is to provide an antithrombotic medical material obtained by forming a heparinized material and then converting it into heparin.

In the present invention, the composition constituting the medical molded article mainly composed of polyvinyl chloride contains 30% by weight of polyvinyl chloride due to its mechanical properties, moldability, etc.
Compositions containing the above are preferred. Such compositions include, in addition to polyvinyl chloride, copolymers of vinyl chloride and other vinyl monomers such as ethylene, vinyl acetate, vinylidene chloride, acrylonitrile, methacrylic acid derivatives, polyvinyl chloride, and copolymers thereof. Soft products made of polymers and other polymers (e.g. polyurethane, polymethyl methacrylate, etc.) and blends, or the above polymers and plasticizers such as linear dibasic acid esters such as dioctyl phthalate and dioctyl azelate or phosphoric esters. Examples include polyvinyl chloride compositions.

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 molded products such as film for film-type oxygenators, leaf-like, spherical and disk-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 with 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
is an acrylic acid or methacrylic acid derivative represented by 1 to 3) and its quaternary salt, and further 2- or 4
-Vinylpyridine and its derivatives and their 4
There are grade salts, etc.

The copolymer containing these components needs to be a graft copolymer containing polyvinyl chloride as a 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 the tertiary amino group intact, 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, benzine group, etc., where X=negative atom group capable of forming a salt with amine nitrogen), Examples include methyl bromide, ethyl bromide, methyl iodide, benzine chloride, and hydrogen chloride.

Next, a method for forming a hydrophilic copolymer layer on the surface of a medical molded article containing polyvinyl chloride as a main component and converting it into hevarin will be described.

The copolymer is applied to the surface to be coated, which is mainly composed of polyvinyl chloride, 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, dimethyl sulfoxide, cyclohexanone, tetrahydrofuran, chloroform, and a mixed solution thereof are used, but there are some issues such as ease of molding. Preferably, those having a boiling point of 30 to 80°C, such as tetrahydrofuran.

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. When using a soft polyvinyl chloride molded product containing a plasticizer as a base material, an extraction medium containing 50% or more of water is used for the above-mentioned impurity removal effect and plasticity elution prevention effect.
For example, water/methanol=2/1 (volume ratio) is preferable. It goes without saying that when a medium having a greater affinity for polyvinyl chloride than methanol, such as acetone, is used as the organic medium, this preferred ratio shifts toward a higher water content.

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 a predetermined sterilization operation is performed 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, its 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 is clear that the medical material of the present invention has extremely excellent antithrombotic properties for a long time. It became.

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 applied to a commercially available soft polyvinyl chloride blood circuit for artificial dialysis (inner diameter 5 mm, outer diameter 7 mm, length
50 cm, containing 30 parts of dioctyl phthalate as a plasticizer) was coated on the inner surface.

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. are extracted for one day using a mixed medium of water/methanol (2/1: volume ratio) at 60°C, and the product contains 2% by weight of heparin.
It was immersed in a 0.1N NaCl aqueous solution and heparinized 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 a growth test.

That is, the descending thoracic aorta is anesthetized by intravenously injecting pentobarbital soda using a large tube (approximately 13 kg), and 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, to determine the outcome of the experiment, 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 their degree of deformation were much lower than in the non-coated polyvinyl chloride tube used as a comparative example.

Comparative Example 1 The soft polyvinyl chloride circuit 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). However, the blood flow began to decrease after 1.5 hours of extracorporeal circulation, and completely stopped due to an embolus after 2 hours. After the evaluation, the inner surface of the tube was observed using a scanning electron microscope, and numerous deformations, aggregated platelets, fibrin networks, and red blood cells were observed.

Example 2 A film cut from a disposable film for a film-type oxygenator, 0.5 cm wide, 2 cm long, and 100 μ thick, was added to the graft copolymer (unquaternized) solution of Example 1.
A graft copolymer containing tertiary amino groups with a thickness of about 30 μm is obtained by dipping a film consisting of ethylene/vinyl acetate/vinyl chloride copolymer (57% by weight of vinyl chloride units) four times on the film with a thickness of about 30 μm. A layer was applied. Drying and extraction conditions are as in Example 1.
Heparinization was carried out in exactly the same manner as above, by immersing the obtained film in a 5% by weight aqueous heparin solution at 70° C. for one day. As a result of measurement in the same manner as in Example 1, the heparin content of the heparinized layer was 10.3% by weight.

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, Seidai (approximately 15 kg) was anesthetized by intravenously injecting pentobarbital soda, and after opening the chest, one end of the evaluation film was fixed to the left atrial appendage with a suture thread, and the evaluation sample was suspended in 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 was found that an antithrombotic film-type oxygenator can be created using a film made of this material.

Example 3 The copolymer (non-quaternized product) of Example 1 was coated on the inner and outer surfaces of a catheter for measuring central venous pressure made of soft polyvinyl chloride (plastic dioctyl phthalate content: 40 parts) with an inner diameter of 2 mm and an outer diameter of 3 mm. A copolymer layer containing tertiary amino groups was formed with a thickness of about 40 μm by coating. This catheter was immersed in water/methanol (2/1: volume ratio) mixed medium 1 at 50°C containing 10 g of ethyl bromide for 3 hours to quaternize the tertiary amino groups in the copolymer layer, and further After extraction treatment in the water/methanol mixed medium at 600°C, heparinization was performed under the same conditions as in Example 1.

The heparin content of the heparinized layer was 15% by weight.

The cross-sectional view of this material corresponds to FIGS. 2-3.

The antithrombotic properties of this catheter were evaluated using the inferior vena cava indwelling catheter method.

Specifically, an adult dog (approximately 15 kg) is anesthetized by intravenous injection of pentobarbital soda, the right femoral vein is incised, and this catheter is inserted from the incision to the vicinity of the right atrium inflow of the inferior vena cava. After indwelling for two weeks, blood was removed, the abdomen was opened, the inferior vena cava was opened, and the material surface and blood vessel wall were observed.

As a result of this in vivo test, the catheter having the heparinized copolymer layer on its surface did not show any thrombus adhesion.

For comparison, when uncoated catheters were evaluated using the same method, thrombus was formed covering the entire surface of the catheter in all cases.

[Brief explanation of drawings]

Figures 1 to 5 show cross-sectional views of a medical molded article (black area) mainly composed of polyvinyl chloride 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 soft polyvinyl chloride, and Figure 2 shows the case of a tube-shaped molded product such as a blood circuit made of soft polyvinyl chloride (Figure 2-1). , No. 2-2
Figures 1 and 2-3 show inner coatings,
Fig. 3 shows a spherical molded product such as a ball valve made of hard polyvinyl chloride, and Fig. 4 shows a film made of ethylene/vinyl acetate/vinyl chloride copolymer. In the case of a film-like molded product such as a film for an artificial lung (Figures 4-1 and 4-2 show single-sided coating and double-sided coating, respectively), Figure 5 shows a polyvinyl chloride polyurethane blend composition. The case of a bag-shaped molded article such as the main body of a blood storage bag is shown.

Claims (1)

[Claims] 1. Forming a hydrophilic copolymer layer on the surface of a medical molded product mainly composed of polyvinyl chloride, 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. The antithrombotic medical material is then converted into heparin.