JPH1147263A - Anticoagulant surface-treatment material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a material that can sustainedly release an anticoagulation activate substance from the surface of a base material and can be treated in detail. SOLUTION: The antithrombotic property is given to the surface of a medical instrument by treating the surface of a base material using an application liquid, a mixture of an anticoagulation active substance and a dispersion liquid of polymer particles. When a polymer particle dispersion liquid mixed with an anticoagulation active substance is applied to a base material, the polymer particles form a matrix on the base material, and a layer where the anticoagulation active substance is dispersed uniformly in the matrix, is formed. The anticoagulation active substance can give the superior antithrombotic property to the surface of a base material by being released gradually by diffusion in the matrix.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a material for imparting anticoagulant properties to medical and surgical tools. More specifically, the present invention relates to an anti-coagulation surface treatment material which imparts anti-coagulation performance to surfaces of artificial blood vessels, catheters, artificial hearts, artificial kidneys and the like.

2. Description of the Related Art When an antithrombotic treatment is performed on a medical device surface using an anticoagulant active substance, the anticoagulant active substance is immobilized on a substrate surface by covalent bonding or is gradually released from the substrate surface. Used by being released. When the anticoagulant active substance is immobilized on the substrate surface by covalent bonding, the motility of the anticoagulant active substance is immobilized by immobilization, and the anticoagulant active site reacts during the immobilization operation. The decrease in activity becomes a problem (J. Biomed. Mater. Res. 29.1317-1329 (19.
95), J. Biomater. Sci.4.217-234 (1993)), and the immobilization efficiency is poor and the amount of immobilization is small for some substances. When the anticoagulant active substance is slowly released from the surface of the base material, when a sustained release method is used by an ion exchange reaction between the anticoagulant active substance supported on the base material by ionic bonding and components in blood. There are many. However, this method has problems in that the sustained release mechanism is complicated and that blood components are nonspecifically adsorbed. An anticoagulant active substance may be dispersed in a polymer matrix and released slowly by diffusion. In this case, a relatively high-viscosity coating solution must be used to form the matrix layer, and the substrate to be treated is small (eg, a small-diameter catheter) or complicated (eg, a tube). Connection part).

In view of these problems, that is, long-term sustained release of an anticoagulant substance and treatment of fine parts, the present inventors have proposed to release an anticoagulant active substance from the surface of a substrate. The inventors of the present invention have made extensive studies on materials that can be processed and that can process fine details, and have led to the present invention.

According to the present invention, the surface of a substrate is treated with a coating solution obtained by mixing a dispersion of polymer fine particles with an anticoagulant active substance to impart antithrombotic properties to the surface of a medical device. Technology. When the treatment is performed according to the method of the present invention, a polymer matrix in which the anticoagulant active substance is uniformly dispersed is constructed on the surface. The polymer matrix is formed by the polymer particles of the emulsion. Since the anticoagulant active substance is water-soluble, when the matrix is formed using an aqueous emulsion, when the coating layer is dried, ultrafine particles of the anticoagulant active substance are formed in the matrix, and the anticoagulant is uniformly dispersed. Layers can be obtained. The anticoagulant active substance is gradually released by the water content of the polymer matrix from the time of blood contact.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS First, a polymer fine particle dispersion serving as a matrix is selected and prepared. The polymer microparticles serving as a matrix are not particularly limited, but microparticles prepared using a phospholipid-based surfactant are preferable because of their good safety in the living body. Good. Examples include polymethyl methacrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol, vinyl acetate, polystyrene, and polyurethane particles. Next, an aqueous solution of the anticoagulant is added to the polymer fine particle dispersion. At this time, the concentration of the polymer fine particles is adjusted by the amount of the aqueous solution of the anticoagulant substance added. The concentration of the polymer fine particles is desirably about 50 wt%, and the thickness of the coating layer is controlled by the concentration of the polymer fine particles. The anticoagulant active substance is not particularly limited, but heparin, urokinase,
Streptokinase, thrombomodulin, plasminogen activator, hirudin, prostacyclin,
Antithrombin is preferred. By treating the substrate using the coating solution obtained as described above, an anticoagulant layer can be provided on the surface of the substrate.

【Example】

(Example 1) 70 g of polyurethane was added to tetrahydrofuran 700
2 g of a surfactant (phosphatidylcholine) was mixed with the solution dissolved in ml. This solution was dropped into water under a high pressure to obtain a polyurethane emulsion. This emulsion was centrifuged, and the supernatant was purified by replacing the supernatant with pure water to obtain a polyurethane emulsion (0.66 g / ml, 100 ml). Heparin (10 g) was dissolved in the above emulsion to prepare a coating solution. The viscosity of the prepared emulsion was 50 mPa. (Example 2) Using the emulsion solution prepared in Example 1, treatment (inner and outer surfaces) of a polyurethane catheter (5 Fr, 75 cm) was performed. The outer surface of the catheter was prepared by immersing the catheter in the solution and lifting it vertically. The results are shown in FIG. The treatment on the inner surface of the catheter was performed by sucking the coating solution from one end of the catheter, and then penetrating the coating solution through the catheter lumen using compressed nitrogen from the side where the coating solution was sucked, and then drying it. The results are shown in FIG. Uniform processing was possible. (Example 3) The change over time of the amount of heparin released from the catheter prepared in Example 2 was measured. The catheter treated only on the outer surface of the catheter was cut into 2 cm (treated surface area: 1 cm 2) to obtain a measurement sample. Heparin was released by adding the sample to 50 ml of PBS, maintaining the temperature at 37 ° C., and stirring. They were transferred to new containers every two hours. Heparin was quantified by using test team heparin (Daiichi Pure Chemicals) on the PBS solution from which heparin was released. Figure 2 shows the measurement results.
Shown in Heparin was released for over 200 hours.

According to the present invention, there is provided a material capable of uniformly constructing a matrix capable of releasing an anticoagulant active substance on a substrate surface uniformly. The treatment of the lumen of a small-diameter catheter, which was conventionally difficult using the coating material of the present invention,
Processing into complicated shapes becomes possible. Since the anticoagulant active substance is present in the voids of the emulsion, it is possible to uniformly disperse the anticoagulant active substance in the coating layer.
Further, since the dispersion medium is aqueous and does not use an organic solvent, a highly safe material can be obtained.

[Brief description of the drawings]

FIG. 1 shows the results obtained by treating the outer surface and inner lumen of a 75 cm catheter with the coating solution prepared in Example 1 and measuring the formed coating thickness. The vertical axis in the figure indicates the coating thickness, and the horizontal axis indicates the axial direction of the catheter. The measurement of the coating layer was performed at n = 5. Outer surface about 30μm, lumen 15μm
Was applied. As a result of measuring the thickness change in the length direction, it can be seen that the coating is applied uniformly.

FIG. 2 shows the change over time in the amount of heparin released from the catheter treated in Example 2. Measurement is n =
3 went. The vertical axis of the figure shows the heparin release rate. The horizontal axis shows the release time. Samples treated only on the outer surface of the catheter released heparin for more than 200 hours.

Claims (3)

[Claims] 1. An anti-coagulant surface characterized by mixing an anti-coagulant active substance with a polymer fine particle dispersion and treating the substrate surface of a medical device with the mixture to give an anti-coagulant surface. Processing material. 2. The anticoagulant surface-treated material according to claim 1, wherein the anticoagulant active substance is heparin. 3. The anticoagulant surface treatment material according to claim 1, wherein the polymer fine particles are non-degradable in vivo.