JPS645905B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for applying a polymeric compound having antithrombotic properties to a blood contacting part of a medical device made of a polymeric compound.

In recent years, research on antithrombotic materials has progressed rapidly, new substances with excellent antithrombotic properties have been developed one after another, and antithrombotic materials that are sufficiently practical for short-term use have been discovered.

On the other hand, blood contact medical instruments are required to have various mechanical properties depending on their use. For example, soft polyvinyl chloride tubes are preferred for blood circuits used in artificial kidneys due to their excellent drapeability and flexibility, while for medical devices that undergo constant bending motion, such as artificial heart pumps. Excellent rebound resilience and fatigue resistance are required. These are all medical devices that come into contact with blood, and the antithrombotic properties of the blood contact surfaces are important. In order to obtain an excellent blood-contacting medical device, it is necessary to select a polymer compound for the blood-contacting part that has excellent properties and mechanical properties according to its purpose.

At present, there is no antithrombotic substance itself that has both these mechanical properties suitable for medical devices and excellent antithrombotic properties. Therefore, in order to obtain a blood-contacting medical device with the most advantageous antithrombotic properties at present, it is necessary to use a blood-contacting medical device composed of a medical device polymer compound that has properties and mechanical properties suitable for the purpose of the medical device. It is necessary to apply an excellent antithrombotic substance to the area.

The present invention provides a method for forming an antithrombotic polymer compound coating on a blood contacting portion of a blood contacting medical device made of a polymer compound.

Blood contact medical devices used in the present invention include blood circuits, intravascular catheters, cannulae,
These include artificial kidneys and related parts, artificial hearts, auxiliary artificial hearts, and related parts.

The present invention also provides a method for forming a coat of an antithrombotic polymer compound that does not cause problems such as peeling during use.

The present invention provides that when a blood contacting part is constantly mechanically extended and contracted with bending, such as in the blood pump part of an artificial heart, the applied antithrombotic polymer compound is applied to the blood pump. The present invention provides an effective method that fulfills its function without peeling off from the constituent materials.

The object of the present invention is to provide a large number of fine holes in advance in a blood contacting part made of a polymer of a medical device to which an antithrombotic polymer compound is to be applied, and then apply the antithrombotic substance thereon. Provided is a method for applying an antithrombotic substance, characterized in that the antithrombotic substance is brought into contact with a solution containing the antithrombotic substance and penetrates into the pores, and then the solvent is removed by evaporation means or coagulation means. It is.

An object of the present invention is to form a film of an antithrombotic polymer compound on a blood contacting part of a blood contacting medical device, which is made of a polymeric compound. Contact with a solution consisting of at least 3% by weight of a water-soluble salt dissolved in a dissolving solvent, evaporate the solvent, wash with water to create micropores in the blood contact area, and then add an antithrombotic polymer compound. This is achieved by applying a solution of

When the present invention is carried out, the adhesion between the antithrombotic polymer coating formed and the blood contacting part of the medical device becomes extremely strong, and even if repeated bending deformation is applied, the coating does not peel off. This method is particularly suitable for forming an antithrombotic coating on the blood pump portion of an auxiliary artificial heart.

The polymer compound constituting the blood contact part of the blood contact medical device applied to the present invention is not particularly limited as long as it has the properties required for a medical device such as flexibility and fatigue resistance. Typical compounds include soft vinyl chloride resin, polyester-based or polyether-based polyurethane, and epoxy resin.

Typical examples of blood contact medical devices made of soft vinyl chloride resin include blood bags, blood circuits,
Typical examples using polyurethane include blood pumps for artificial hearts or auxiliary artificial hearts, and blood circuits, catheters, and artificial hearts. Epoxy resin is used for connecting blood circuits.

At present, the blood pump portion of an artificial heart or auxiliary artificial heart, which is currently under research and development, is mainly composed of polyether-based or polyester-based polyurethane or soft vinyl chloride resin due to the required performance such as bending resistance.

There are no restrictions on the solvent for dissolving the polymer compound constituting the blood contacting part of the blood contact medical device applied to the present invention, as long as it dissolves the polymer compound and the water-soluble salt described below. Not allowed.
For example, solvents for dissolving the above-mentioned polymer compounds include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, etc., or aqueous solutions thereof containing up to 50% by weight.

The concentration of water-soluble salts dissolved in the abovementioned solvents is at least 3% by weight, preferably from 5% to saturation. If it is less than 3% by weight, the antithrombotic coating formed on the blood contact area will peel off in a short period of time due to repeated deformation, making it impossible to achieve the object of the present invention.

Any water-soluble salt may be used as long as it is an organic or inorganic salt that is soluble in the above-mentioned solvents, such as sodium chloride, potassium chloride, potassium bromide, calcium chloride, lithium bromide, sodium sulfate, carbonate, etc. Contains sodium, sodium acetate, etc.

Next, a solution containing the water-soluble salt dissolved therein is brought into contact with the blood contacting part of the medical device. The solution is applied to the blood contact portion of the medical device by spraying or using a brush. The medical device may be quickly dipped into the solution or may be quickly slushed. After application, the solvent in the solution is allowed to evaporate naturally or forcefully. Since the solvent is a solvent for the polymer compound constituting the blood contacting part of the medical device, a part of the surface swells and a part dissolves. Therefore, the water-soluble salts penetrate deep into the blood contact area and precipitate out when the solvent evaporates. When the solvent has sufficiently evaporated, the membrane is washed thoroughly with water, and the water-soluble salts that have burrowed into the blood-contact area and precipitated therein dissolve out, leaving numerous pores. The size of the pores is 0.1 μ to several tens of μ.
Generally, pores with an average pore diameter of 0.1μ to 30μ can be created using this method.

The blood pump parts of artificial hearts or auxiliary artificial hearts that are currently under research and development are mainly made of polyether-based or polyester-based polyurethane or soft vinyl chloride resin due to the requirements for mechanical properties such as bending resistance. There is.

Therefore, in order to apply the present invention to the above-mentioned blood pump parts etc. that use these polymer compounds, a large amount of water-soluble salts, such as tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, etc., can be used as the solvent. ,
The latter three are particularly desirable because they can be dissolved at high concentrations. In order to apply the present invention to an artificial heart or an auxiliary artificial heart, water-soluble salts such as non-toxic sodium chloride, potassium chloride, calcium chloride, and sodium phosphate are preferable.

When dimethylmoformamide is used as a solvent, it is possible to dissolve 20% by weight or more of these salts.

As mentioned above, after making a large number of micropores in the blood contact area, it is thoroughly dried, a solution of an antithrombotic polymer compound is applied, and the solvent is evaporated to form an antithrombotic coating on the blood contact area. to form.

The antithrombotic polymer compound used in the present invention is not particularly limited, but representative examples include:
Polydialkylsiloxane such as polydimethylsiloxane and polydiethylsiloxane, polyester polyurethane, polyether polyurethane, so-called segmented polyurethane composed of soft and hard segments, block copolymerization of polyurethane and polydialkylsiloxane such as polydimethylsiloxane gelatin, hydroxyethyl methacrylate polymer or copolymer, vinylpyrrolidone polymer or copolymer gelatin, and mixtures thereof.

The solvent used to dissolve the antithrombotic polymer compound should be determined as appropriate depending on the combination of the polymer compound that makes up the blood contacting part of the medical device and the antithrombotic polymer compound applied to its surface. However, it is preferable to use a common solvent or a solution containing a common solvent that also dissolves the high molecular compound constituting the blood contacting part.

It is desirable that the amount of the common solvent in the solution is at least 1/4 (by weight); if the amount is less than 1/4, the ability to swell the polymeric compound constituting the blood contacting part will be insufficient and the effect of the present invention will be impaired. It may be reduced by half.

The reason why a common solvent is used is that the antithrombotic substance and the blood contact area to be applied are partially dissolved in each other, so that the antithrombotic substance can be completely applied and peeling of the formed film can be suppressed. , because it's good to mix.

Examples of solvents that can dissolve soft vinyl chloride resin, polyester-based or polyether-based polyurethane, epoxy resin, segmented polyurethane, polydialkylsiloxane, polyurethane-polydialkylsiloxane block copolymer, etc. include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and dimethylacetamide. , tetrahydrofuran-dioxane mixed solvent, etc.

The antithrombotic polymer compound is prepared as a solution in the solvent as described above, and the concentration of the polymer compound in the solution may be appropriately determined depending on the solubility in the solvent, the thickness of the coated film, etc.

The antithrombotic polymer compound solution can be applied to the blood-contacting part of the medical device by using the most suitable application method depending on the shape of the blood-contacting medical device. Examples include, but are not limited to, a method of applying the solution, and a method of once filling the blood-contacting part of a medical device with the solution and then removing the gradient (splash method). If the immersion time is too long or the time of filling the solution with the slush method is too long, the polymeric compounds that make up the medical device will dissolve, so the contact time should be regulated at an appropriate time and the next evaporation step should be carried out. Must be.

The contact time between the solution of the antithrombotic polymeric compound and the polymeric compound constituting the medical device is such that the polymeric compound constituting the medical device is partially swollen by the solvent in the solution or only a small portion of the surface is dissolved. It is best to mix slightly with the antithrombotic polymer compound, usually within a range of 10 seconds to 10 minutes. If it takes less than 10 seconds, it will not be possible to obtain a film that tightly adheres to the polymers that make up the medical device, and if it exceeds 10 minutes, the polymer compounds that make up the medical device will start to dissolve, causing problems.

The next step is to remove the solvent. After applying the solution, the solvent is removed by evaporation means or coagulation means. The removal by evaporation may be natural evaporation by leaving it in a well-ventilated place, or it may be forcibly removed by means such as reduced pressure.

In addition, when using a coagulation method, a poor solvent such as water is added to the coated surface by spraying, or the coated medical device is directly immersed in a poor solvent such as water to coat the antithrombotic polymer compound. After coagulating and forming a film, it may be dried.

By carrying out the present invention, the polymer compound constituting the blood contacting part of the medical device and the coating of the antithrombotic polymer compound formed on its surface are tightly adhered to each other, and are repeatedly bent and deformed over a long period of time. The coating does not peel off even when applied. Therefore, the coating method of the present invention is particularly suitable for applying an antithrombotic coating to a medical device that continues to undergo intense bending motion, such as a blood pump for an artificial heart or an auxiliary artificial heart.

Hereinafter, the present invention will be specifically explained with reference to Examples.

Example 1 Calcium chloride was dissolved in dimethylformamide to make a 35% solution. A polyvinyl chloride soft film was immersed in the above solution, immediately taken out, and the solvent was removed under reduced pressure at 60° C. for 24 hours. Next, this film was immersed in a water bath to elute the calcium chloride that had bitten into the film surface and precipitated.
When this film is dried, an average of 1
A product with countless microscopic pores of ~3μ was obtained.

Meanwhile, polydimethylsiloxane was dissolved in dimethylformamide and a 16% solution was prepared separately.
This solution was applied with a brush onto the soft polyvinyl chloride film and evaporated at room temperature for 24 hours to form a film on the film. A test piece was made from this film and subjected to repeated bending motions using a bending tester (repeating 90 degree bending at 120 times/min).
No peeling of polydimethylsiloxane was observed after 50,000 bends.

Example 2 A polyether polyurethane film (100 mm x 100 mm, 1 mm thick) was prepared. on the other hand,
A dimethylacetamide solution saturated with sodium chloride was prepared, and this solution was uniformly applied to the polyurethane using a brush.

After being left at room temperature and under reduced pressure for a day and night, the film was immersed in water to elute the sodium chloride that had bitten into the surface of the polyurethane film and precipitated. When the polyurethane film treated in this way is dried, the average pore size is 1 to 4 μm due to the above treatment.
It is possible to make countless tiny holes. FIG. 1 shows a photograph of micropores formed on the surface of a treated polyurethane film observed with a scanning electron microscope.

Next, a segmented polyurethane synthesized using 4,4'-diphenylmethane diisocyanate using the polyethylene glycol portion as a soft segment was dissolved in tetrahydrofuran to obtain a 13% solution.

The treated polyurethane film was immersed in this solution, immediately taken out, and dried under reduced pressure at 30°C overnight.

When the polyurethane film coated with antithrombotic segment polyurethane was forcibly repeated in a bending tester under the same conditions as in Example 1, it was found that even after 60,000 bends, the segment polyurethane Peeling of the film occurred in 80 cases
There were no cases seen in 80 cases. For comparison, the same antithrombotic coating was applied to a polyurethane film without the treatment of the invention. In this case, 3 out of 45 cases peeled off after 60,000 bending tests.

FIG. 2 shows a photograph of the surface state of the segmented polyurethane film formed on the treated surface of the polyurethane film shown in FIG. 1, observed with a scanning electron microscope.

Example 3 20% hydrated tetrahydrofuran saturated with sodium acetate was applied to the inner surface of an air-operated sac-type artificial heart made using polyether polyurethane, dried under reduced pressure at 60°C for 24 hours, and then washed with water to coat the surface. The adhering sodium acetate was eluted. As a result of this treatment, the inner surface of the sac portion appears to be whitened due to the countless fine pores generated.

Next, using a mixture of polydimethylsiloxane and polyether polyurethane as an antithrombotic substance, this tetrahydrofuran solution (11.5%) was
It was filled into the treated tank-type blood pump, and after 10 seconds, the tetrahydrofuran solution was removed by tilting and dried at room temperature for 2 days.

A simulated test was carried out in which the air-operated, sac-type artificial heart thus obtained was activated by air pressure, and the test was continued for 6 months by repeatedly compressing and expanding the heart at a rate of 90 beats/minute. No peeling of the antithrombotic material coating was observed.

Example 4 A pneumatic sac-type artificial heart was created using a soft polyvinyl chloride resin.

Separately, a sac-type blood pump section was filled with tetrahydrofuran saturated with potassium chloride, which was immediately poured out with an incline and dried as it was at room temperature for 2 days. Thereafter, the blood pump was thoroughly washed with water to elute the sodium chloride embedded in the internal surface of the blood pump, and numerous micropores with an average diameter of 0.1 to 2 μm were formed on the internal surface.

Next, a polyether polyurethane-polydimethylsiloxane block copolymer (weight ratio 90:10) as an antithrombotic material was dissolved in a tetrahydrofuran-dioxane mixed solvent (weight ratio 2:1), and the same procedure as in Example 3 was carried out. It was applied to the inner surface of the blood pump by the slush method.

An artificial heart assembled with valves was run at a rate of 90 beats per minute under the same conditions as in actual use, and was operated for four months.

As a result of this test, no peeling of the antithrombotic block copolymer coating coated on the inner surface of the blood pump was observed.

[Brief explanation of the drawing]

FIG. 1 is a photograph of the surface condition of the treated film of Example 2, and FIG. 2 is a photograph of the surface condition of the formed film observed with a scanning electron microscope.

Claims (1)

[Claims] 1. When forming a coating of a second polymeric compound having antithrombotic properties on a blood contacting part of a blood contacting medical device made of a first polymeric compound, the blood contacting part is made of a first polymeric compound. A water-soluble salt that is incompatible with the first polymer compound is added to the solvent that dissolves the compound.
After the solvent is evaporated, the precipitated water-soluble salts are removed by washing with water, micropores are created in the blood contact area, and then a second highly antithrombotic solution is applied. A method for applying an antithrombotic substance, comprising applying a solution of a molecular compound.