JPS63145662A - Production of antithrombogenic medical material - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing an antithrombotic medical material in which a monomer having a polyethylene glycol group is graft-polymerized to a polyolefin polymer.

[Prior Art] Various polymeric materials are widely used as medical materials due to their ease of molding, stretchability, flexibility, and the like. However, when used in a living body, it is necessary that the material has no adverse effect on the living body and has good affinity with surrounding tissues. Special code: When used as a medical material, blood itself has the property of coagulating when it comes into contact with foreign substances, so it must have antithrombotic properties that do not cause blood coagulation in areas that come into contact with blood. required. Polymer materials commonly used in other fields have insufficient antithrombotic properties when used as medical materials, so attempts have been made to develop polymeric materials with sufficient antithrombotic properties. ing.

In the development of polymeric materials with antithrombotic properties, attempts have been made to create new polymeric materials and to perform surface treatment on conventional polymeric materials.

Regarding the former, it is a method of changing the composition of the polymer base material itself, and many attempts have been made, particularly with respect to polyurethane, and various segmented polyurethanes and the like are commercially available or under research and development. However, when these new polymeric materials are used as medical materials, they must satisfy properties such as moldability and mechanical properties, and many problems remain.

On the other hand, the latter method has great advantages such as being able to use currently used medical materials as they are, since surface treatment is performed on conventional general polymer materials.

[Problem to be Solved by the Invention 1] Methods for imparting antithrombotic properties through surface treatment include methods for supporting physiologically active substances exhibiting antithrombotic properties and methods for providing a structure inert against blood coagulation on the surface of a polymeric material. A method of forming a is being considered. Regarding the former method, as an example of supporting heparin, which is an anticoagulant, Japanese Patent Application Laid-Open No. 57-1197
56, JP-A-51-194, and JP-A-54-135494 as an example of supporting prostaglandin.
Methods using various physiologically active substances have been disclosed. However, this method has the disadvantage that the effect is not permanent due to release or deactivation of the physiologically active substance. On the other hand, the latter method, which forms a surface structure that is inert to blood coagulation, has the potential to create a permanent antithrombotic surface, but it also reduces the interaction between blood and polymeric materials. ,
There are still many unknowns about the initiation of the blood coagulation process, and fundamental research is required.

On the other hand, a graft polymerization method is one method for surface modification of polymeric materials. This method is a method of generating graft chains using other monomers in a polymeric material, and has been applied in various fields.

Applications to antithrombotic materials have also been attempted, including 2-hydroxymethacrylate (HEMA) and acrylamide (A
Examples of the use of various monomers including Am) are given in
Publication No. 0-32554.53-15556, Japanese Unexamined Patent Publication No. 1973
No. 72294.58-5320.60-242857, etc. are disclosed. A number of detailed studies have been conducted regarding antithrombotic am using this method, and it has been found that the graft chains on the polymer surface generate a diffuse layer structure, which lowers the interfacial free energy with blood, resulting in platelets and reported that this is due to decreased interaction with coagulation factors (W/, 11 et al., Polyller
Preprint, Japan, Vol.

29, Consideration 7 p1461-1464 (1980 1 Populated Organs Vol. 15 No. 1 p12-15. 1986), basic research has been conducted on the creation of antithrombotic surfaces by graft polymerization, and antithrombotic properties have been demonstrated in animal experiments. Improvement has also been reported (Toshiko Hayashi et al. Polymer Papers Vol. 39, p. 179)
~182.1982, Volume 42, p77-83.198
5 years) This is a promising method for creating antithrombotic surfaces.

[Means for Solving the Problems] As a result of various studies regarding the production method of antithrombotic materials by applying graft polymerization, the present invention has been developed by pre-irradiating a monomer having a polyethylene glycol group with ionizing radiation. By graft polymerization using this method, we succeeded in creating a medical material with excellent antithrombotic properties. The purpose is to provide a method for producing medical materials with excellent antithrombotic properties by applying the present invention to polymeric materials that have been commonly used.

That is, the present invention provides an antithrombotic method in which a polyolefin polymer is irradiated with ionizing radiation in advance and then immersed in a solution of a monomer represented by the following general formula to generate graft polymer chains. This is a method for producing medical materials.

In the general formula, R1 is H or a CH3 group, R2 is a CH3 or C2Hs group, and n is an integer of 2 to 20 [Function] As shown in the general formula, the monomer used in the present invention has a methyl or It is an ethylated acrylate or methacrylate derivative having a polyethylene glycol group, and is introduced into a base material by generating graft chains by a graft polymerization method. In order for the graft chains introduced into the base material to form an antithrombotic surface, it is necessary to form a surface diffuser layer to lower the interfacial free energy.

The polyethylene glycol group of this monomer is a nonionic hydrophilic group, and the terminal hydroxyl group is alkylated, so there is no ionic interaction with blood, and there is little hydrogen bond formation with water molecules. A loose bonding state based mainly on hydrophilic-hydrophobic interactions with water molecules can be maintained. In addition, this monomer is a monomer with low crosslinking reactivity,
Unlike hydroxyethyl methacrylate, acrylamide, etc. used in other examples, formation of crosslinking reactants such as popcorn polymerization is hardly observed. This monomer has the above-mentioned properties and is therefore the most suitable monomer for forming a surface diffusion layer.

In addition, since the polyethylene glycol group itself is a polymer, it is possible to increase the chain length of the hydrophilic group, and in the case of a long chain, the mobility of the graft chain at the interface increases, which prevents the attachment of blood clots. It is expected to have the effect of preventing but,
In the case of Changchu, the molecular weight of the monomer itself increases and the concentration of vinyl groups that contribute to graft polymerization decreases.
In the case of pheasant chains, the efficiency of graft polymerization decreases, which is undesirable.On the other hand, in the case of pheasant chains, the efficiency of graft polymerization is high, but the hydrophilicity is poor, so the chain length of polyethylene glycol is in the range of 2≦n≦20 in the general formula. is preferable, and 4≦n≦10
The range is more preferable.

The polyolefin polymer used in the present invention serves as a base material for graft polymerization and contributes to mechanical strength and shape retention. In order to apply the present invention, it is necessary to have excellent graft polymerizability and suitability as a medical material such as non-toxicity, and polyolefin polymers are desirable. The polyolefin polymer is a polymer material produced by polymerizing monomers having carbon-carbon unsaturated bonds. Examples include polyethylene, polypropylene, polybutadiene, and the like.

The graft polymerization method used in the present invention is a method of generating graft chains on a polymer material serving as a base material, and is a method of performing pre-irradiation using ionizing radiation. There are many types of graft polymerization methods, but the method using ionizing radiation is
This method has excellent permeability, radical generation efficiency, and high graft polymerization efficiency. In addition, the pre-irradiation method is a method in which the base material is irradiated with ionizing radiation in advance to generate radicals, and then immersed in a monomer water or alcohol solution to generate graft chains. Although a high monomer concentration of 60 to 90% is required from the viewpoint of performance, radical generation does not occur in the reaction solution compared to the simultaneous irradiation method in which irradiation is performed together with the monomer solution.
This method is suitable for the purpose of the present invention because it is possible to generate graft chains that are more linear with less crosslinking and branching, and the resulting graft chains have high mobility. As ionizing radiation,
Any radiation that has an ionizing effect directly or indirectly on the base polymer material can be used; specifically, alpha rays, beta rays, gamma rays, X-rays, accelerated electron beams, etc. Examples include accelerated particle beams.

The grafting rate required to improve antithrombotic properties depends on the type of substrate, as antithrombotic properties depend only on the surface, and cannot be determined strictly by the grafting rate, but for example, the grafting rate depends on the thickness. In the case of a film with a diameter of 50 μm, a graft ratio of 12 to 50%, preferably 15 to 45% is desirable.

[Effects of the Invention] The present invention is a method for providing a medical material with high antithrombotic properties by modifying the surface of polyolefin, which is a polymeric material commonly used in daily life, and is a method for providing a medical material with high antithrombotic properties. We provide medical materials that are useful in tubes, sheets, catheters, cannulas, biological implant materials, artificial blood vessels, artificial organs, etc.

〔Example] The present invention will be explained below based on examples.

Example A low-density polyethylene film (thickness: 50 μm) was pre-irradiated with an electron beam at 30M RACL under a nitrogen atmosphere, and then Motsuma-A and B were irradiated in a glass container under a nitrogen atmosphere.
, C, and a graft polymerization reaction was carried out in a constant temperature water bath at 45°C. After a predetermined period of time had elapsed, the glass container was opened, the film was taken out, washed with water and dried under reduced pressure, and the grafting rate was measured from the difference in weight of the film before and after the reaction.

The results are shown in Table 1.

All of the films produced were transparent and smooth.

Comparative Example A low-density polyethylene film (thickness: 50 μm) was pre-irradiated with an electron beam at 20 Mrad in a nitrogen atmosphere, and then 2-hydroxyethyl methacrylate (HEMA) and Immersed in acrylamide (AAm) solution at 25°C and 40°C, respectively.
The graft polymerization reaction was carried out in a constant temperature water bath. After a predetermined period of time had elapsed, the glass container was opened, the film was taken out, washed with water, dried under reduced pressure, and the grafting rate was measured from the difference in weight of the film before and after the reaction.

The results are shown in Table 2.

The produced film was white for HEMA, and for A m, a spherical structure of several microns was produced.
Although it was transparent, unevenness was formed on the surface.

Measurement of antithrombotic properties The clot formation rate of the prepared film was measured by the full valve method. 0.8% Ca in fresh rabbit ACD blood 250μm
After adding 25 μm of Cj2 liquid, it was held between two films and blood coagulation was allowed to proceed on a constant temperature bath at 37°C. For each measurement, a medical PVC sheet was used as a standard sample.
Set the blood coagulation time so that the blood coagulation rate is 0%, divide the clot weight generated in the measurement sample by the clot weight generated in the standard sample to obtain the relative clot production rate, and calculate the blood clot production rate at each measurement time. The difference in coagulation ability was eliminated.

The results are shown in Table 3.

Table 3 Measurement of platelet adhesion PRP platelet-rich plasma was prepared from fresh rabbit blood,
The measurement sample was brought into contact with the sample at 37°C for 10 minutes. After completion, the sample was washed with physiological saline, fixed with glutaraldehyde, washed with ethanol, stained with Giemsa, and subjected to light microscopy (10
The number of platelets adhering to the sample surface was counted at a magnification of 0.00 times.

In addition, the number of adherent platelets was calculated by calculating the ratio to the low density polyethylene film that was the base material before the graft reaction.

The results are shown in Table 4.

Table 4

Claims (1)

[Claims] The method is characterized in that a polyolefin polymer is irradiated with ionizing radiation in advance and then immersed in a solution of a monomer represented by the following general formula to generate graft polymer chains. Method for producing antithrombotic medical material. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R_1 is H or CH_3 group R_2 is CH_3 or C_2H_5 group, and n is 2 or more 2
integer less than or equal to 0