JPH04325160A - Composite material for medical use - Google Patents

Abstract

PURPOSE:To provide the material for medical use which is extremely excellent in an antithrombotic property. CONSTITUTION:This composite material for medical use is a material which comes into direct contact with blood or is detained for a specified period of time within a living body and is constituted of a TFE/VOH copolymer or is constituted of this polymer in a part thereof or the entire surface or a part of its surface.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to a composite material useful in the medical field, and more specifically, it can be applied to fields that require plasma separation such as a) plasmapheresis, artificial dialysis, and artificial lungs. blood separation membrane, b) blood circuit or blood storage container during blood transfusion/extracorporeal circulation, c) artificial blood vessel,
Artificial organs that perform biological functions, such as artificial valves, artificial hearts, or artificial joints; d) Materials that are temporarily placed in the body, such as catheters and drains; e) Various types of devices that are intended to be placed in the body. sensor,
The purpose of the present invention is to provide f) a drug controlled release system and g) a medical material having excellent blood compatibility on the body or surface of the medical material such as a bioseparator or culture device.

0002

BACKGROUND OF THE INVENTION The biocompatibility of medical materials that come into contact with a living body has different meanings depending on which tissue or component of the living body the material comes into contact with. However, blood compatibility and anti-resistance of materials are important because blood reactions are extremely drastic among biological reactions, and many artificial devices for treatment and diagnosis are likely to come into contact with blood. Thrombotic potential is often discussed. Antithrombotic materials are classified into three types based on their mechanism of action: pseudointima-forming surfaces, antithrombotic surfaces, and thrombolytic surfaces. , various attempts have been made in each classification.

0003

[Problems to be Solved by the Invention] Medical materials with a pseudointima-forming surface include expanded PTFE (Gore-Tex).
) and Dacron-based artificial blood vessels. These materials allow host endothelial cells to engraft and grow on the surface of the material, so to speak, they acquire antithrombotic properties with the help of the living body; rather, it is desirable that the material surface itself has moderate thrombogenicity. It will be done. Also, since endothelial cell engraftment naturally requires a certain amount of time, it may be necessary to temporarily indwell the body with a catheter, or use an extracorporeal circulation circuit such as an artificial dialysis machine or blood processing device.
Another problem is that it cannot be used as a material for devices such as sensor surfaces or artificial lungs where material permeation is an important function. A thrombolytic surface refers to a material that has the function of dissolving blood clots on its surface, and typical examples include materials on which fibrinolytic system activating enzymes such as urokinase and streptokinase are immobilized. For this type of surface, it is necessary that the rate of thrombolytic dissolution exceeds the rate of fibrin formation on the surface, but in order to do so, the method of immobilizing the enzyme used must be carefully examined to maintain high activity. is necessary. However, it is difficult to say that the enzyme activity is sufficiently maintained by conventional immobilization methods, and furthermore, the enzyme activity may be deactivated during the sterilization process, which is essential for medical materials.

[0004] In addition, attempts to obtain a surface that inhibits thrombus formation include creating a structure that allows sustained release of a physiologically active substance that inhibits thrombus formation on the surface of the material, or biochemical techniques such as immobilizing a physiologically active substance. There is a materials science approach that attempts to suppress thrombus formation by controlling the structure of the material surface. Among these methods, many studies have been conducted on sustained release and immobilization of heparin using physiologically active substances, and some of them have been put into practical use. However, these devices have difficulty retaining their antithrombotic properties over a long period of time, and are only used for relatively short-term indwelling purposes. In contrast, devices that acquire antithrombotic properties by controlling the structure of the material surface are expected to have stable performance regardless of whether they are left in the body for long or short periods of time, and have been actively researched for a long time. ing. The first thing that attracted attention in the relationship between antithrombotic properties and material surface structure was chargeability. These are the so-called electrostatic repulsion theory and the concept of optimal charge density. However, in reality, it is not that simple, and at least currently there are no artificial devices that pursue only electrostatic interactions on material surfaces.

[0005] Next, attention was focused on the hydrophobicity of the material's surface, and it was believed that the lower the energy of the surface, the more antithrombotic it was. However, it has gradually become clear that antithrombotic properties are not necessarily determined by surface energy alone. Next, the relationship between the hydrophilicity and antithrombotic property of the material surface was studied, and it was pointed out that the material surface may adsorb proteins and come into indirect contact with living organisms. There have been reports of cases of blood clots dislodging, and drawbacks such as easy calcium deposition have also been revealed. In any case, it is impossible to discuss the antithrombotic properties of a material surface unequivocally, and it is currently important to obtain a material surface with an optimal charge density and an excellent balance between hydrophilicity and hydrophobicity. The concept of a microdomain structure corresponds to this, and various segmented polyurethanes (SPUs) have recently attracted attention as materials having such a structure. SPU is a multi-block copolymer of a soft segment made of highly flexible polyether and a hard segment made of urethane and urea bonds. Furthermore, by constructing a blender of SPU and polydimethylsiloxane, or by introducing hydrophobic fluorine into the hard segment,
Efforts continue to be made to provide excellent antithrombotic properties and mechanical properties, but it is said that antithrombotic properties vary due to differences in manufacturing conditions such as extraction of low-molecular substances mixed in during the manufacturing process, heating method, and drying conditions. However, there are some drawbacks, and it is difficult to stably supply excellent performance. Therefore, the purpose of the present invention is to
The object of the present invention is to solve the problems of the prior art described above and provide a medical material with extremely excellent antithrombotic properties.

[0006]

[Means for Solving the Problems] The above object is achieved by the following present invention. That is, the present invention is a material that comes into direct contact with blood or remains in a living body for a certain period of time, and which
A medical composite material characterized in that it is composed of an FE/VOH copolymer, or a part thereof, or the entire surface or at least a part of the surface thereof is composed of the polymer.

[0007]

[Operation] Medical use that comes into direct contact with blood or remains in the living body for a certain period of time by being made of TFE/VOH copolymer or by making the entire surface or at least a part of the surface of other material be made of the above copolymer. When used as a material, it exhibits excellent antithrombotic properties. Therefore, the material of the present invention is extremely useful in the construction of various medical instruments mentioned in the above-mentioned industrial fields of application.

[0008]

[Preferred Embodiment] The copolymer used in the present invention and which mainly characterizes the present invention is a copolymer of TFE (tetrafluoroethylene) and vinyl alcohol (VOH). In the present invention, the copolymerization ratio is preferably TFE
It is preferable that TFE be 20.3 mol% or less and vinyl acetate be 79.7 mol% or more of the total number of moles of TFE and vinyl acetate, but the ratio is not particularly limited to this range. In addition, within these ratio ranges, for example, as the third and fourth monomers, for example, as the fluorine-containing monomer, in addition to monofluoroethylene such as vinyl fluoride, difluoroethylene such as vinylidene fluoride, trifluoroethylene, etc. etc. can also be used. Furthermore, as the hydrophilic group-containing monomer, vinyl monomers having hydrophilic groups such as hydroxyl group, carboxyl group, and sulfone group, such as acrylic acid, methacrylic acid, and sulfonated styrene, can also be used. However, it is not preferable to use these other monomers in an amount exceeding the above-mentioned essential monomers. The copolymer of TFE and vinyl alcohol is the TF obtained as described above.
It can also be obtained by saponifying a copolymer of E and vinyl acetate to convert acetate groups contained in the copolymer into hydroxyl groups. In this case, all of the acetate groups contained in the copolymer do not necessarily need to be converted into hydroxyl groups, as long as they are converted to hydroxyl groups to the extent that the copolymer has hydrophilicity. In the TFE/VOH copolymer used in the present invention, the fluorine content is 2
-60%, preferably 10-60%. If the fluorine content becomes too high, the hydrophilicity of the polymer will deteriorate;
If it is too low, the antithrombotic properties will decrease, and when used in combination with other materials, the adhesion to other materials will decrease, which is not preferable. Further, it is desirable that the vinyl alcohol content of the TFE/VOH copolymer is adjusted to have a hydrophilic group equivalent in the range of 45 to 500, preferably 60 to 500.

[0009] In order to manufacture the hydrophilic resin material of the present invention alone into an appropriate shape according to the purpose, for example, after melting the TFE/VOH copolymer in a nitrogen atmosphere, extrusion molding, injection molding, etc. In addition to being able to apply conventional thermoplastic resin molding methods as is, tubes can be made by dissolving the copolymer in a suitable solvent, such as DMF or DMA, and repeating the process of dipping a metal rod into the solution, pulling it up, and drying it. Alternatively, the solution can be placed in a cylindrical container, centrifuged, heated and dried to form tubes, bottles, and other bag shapes.

[0010] The TFE/VOH copolymer used in the present invention can be used alone as described above, or preferably used in combination with other medical polymer materials or polymer materials for medical support purposes as a composite material. There are many cases. Examples of these other materials include the following. (1) Soft or hard polyvinyl chloride (2) Polystyrene (3) Polypropylene (4) Polyethylene (5) Polyolefin (6) General-purpose or flame-retardant ABS (7) Polymethylpentene (8) Styrene-ethylene -Styrene copolymer (9) Styrene-butadiene block copolymer (10) Polyglycolic acid (11) Polymethyl methacrylate (12) Polydimethylsiloxane (13) Polytetrafluoroethylene (14) Polyethylene terephthalate (15) Polyaryl sulfone (16) Polysulfone (17) Polyetherimide (18) Polycarbonate (19) Polybutylene terephthalate (20) Polyacetal (21) Nylon or segmented nylon (22) Nylon/ABS alloy (23) Polysulfone/thermoplastic polyester Alloy (
24) Nylon block copolymer (25) Modified PPE (26) Styrene hydrogenated butadiene block copolymer (27) Cellulose type (28) Polyacrylonitrile type (29) Polyvinyl alcohol type (30) Ethylene-vinyl alcohol copolymer Polymer (31)
Polyurethane, segmented polyurethane, segmented polyurethane urea (32) Natural rubber (33) Other block/graft copolymers

00
11] Known medical polymer materials such as those mentioned above and TFE/V
Conventionally known means can be used to composite the OH copolymer; for example, the polymer may be dissolved in an organic solvent and then coated on the surface of the target polymer molded body, or if the target is porous. If it has a structure, it can be impregnated in a similar solution. In addition, chemical vapor deposition, grafting, etc. are also suitable, and as a special method, it is also possible to adhere or laminate the polymer previously formed into a thin film onto the surface. The composite material of the present invention can be prepared by dissolving a copolymer of TFE and another hydrophobic monomer (for example, vinyl acetate) in, for example, an organic solvent, applying it to a suitable molded body as described above, drying it, It can also be produced by converting at least a portion of a hydrophobic group into a hydrophilic group.

Next, preferred embodiments of the uses of the resin (copolymer of the present invention) will be explained for each purpose. 1) Separation membrane for blood A separation membrane for blood with excellent antithrombotic properties can be obtained by forming a porous membrane using the resin having excellent antithrombotic properties, or by covering an existing porous surface with the resin. As porous membranes in this case, cellulose membranes that are already used as blood separation membranes and hydrophilic membranes such as ethylene vinyl alcohol can be used, as well as expanded PTFE membranes that are hydrophobic and have traditionally been difficult to use for this purpose. It can also be used, and is rather preferable due to its chemical resistance. Vapor deposition is a method for covering the surface of a porous expanded PTFE membrane with the resin.
A method of impregnating with TFE is suitable. At this time, stretched PT
The thickness, pore diameter, and pore ratio of the FE membrane are freely selected depending on the object to be separated. 2) Blood circuits, blood storage containers, catheters, drains, etc.In addition to molding the resin into the necessary tube or bag shape by conventionally known methods such as extrusion molding or injection molding, it is also possible to mold By coating the blood contact surface of a conventional product with the resin, an antithrombotic blood circuit or blood storage container can be obtained.

3) Prosthesis that performs biological functions An antithrombotic prosthesis can be obtained by coating the resin on the surface of a conventional product that comes into contact with the living body. At this time, if extracorporeal circulation is required, please refer to the above 2.
It is desirable to use the antithrombotic blood circuit obtained in ), and to use an application method in which the entire extracorporeal circulation route is antithrombotic. 4) Sensor An antithrombotic sensor can be obtained by coating the sensor surface obtained by the conventional technique with the resin or by covering the sensor surface with the separation membrane obtained in 1) above. In this case, depending on the object to be measured with the sensor, it is desirable to actively use a separation membrane for pre-separation. 5) In addition to coating the biocontact surfaces of drug controlled release systems, bioseparators, etc. with the resin, it is also molded into the required shape using conventionally known techniques.

[0014]

EXAMPLES Next, the present invention will be explained in more detail with reference to examples. Example 1 A porous expanded PTFE membrane with a pore size of 0.2 μm, a film thickness of 40 μm, and a porosity of 80% was impregnated with a 2% solution (methanol) of TFE/VOH copolymer, and pre-dried at room temperature.
It was dried for 15 minutes at 0°C. When the membrane thus obtained was used as a plasma separation membrane, good results were obtained with very little thrombus formation. Example 2 A 0.5% solution of TFE/VOH copolymer (methanol) was filled into the blood contact side circuit of a commercially available cellulose diacetate hollow plasma separator for 15 minutes, and then 500 ml of dry nitrogen for gas chromatography was filled at room temperature. 12 at a speed of /h
Allowed to dry for a while. When the plasma separator thus obtained was circulated with bovine blood without anticoagulation treatment at the same time as a commercially available plasma separator, the time until occlusion was significantly increased. Example 3 A commercially available intravenous indwelling catheter was immersed in a 5% methanol solution of TFE/VOH copolymer, pulled up and dried in air at 60°C, and this process was repeated four times. The antithrombotic catheter thus obtained and the commercially available catheter were placed in the vein of a dog without anticoagulation treatment. As a result, while thrombus formation was observed in 10 minutes with the commercially available catheter, no thrombus was observed on the surface of the antithrombotic catheter of the present invention.

The TEF/VOH copolymer used in Example 1 is a saponified product of TFE/vinyl acetate copolymer.
Saponification degree: 100%, fluorine content: 16% by weight, and hydroxyl group content: 18.1 mmol/g. Also, Example 2
The TEF/VOH copolymer used in was a saponified product of TFE/vinyl acetate copolymer, with a degree of saponification of 100%, a fluorine content of 20% by weight, and a hydroxyl group content of 19.1 mmol/g.
belongs to. In addition, TEF/VOH used in Example 3
The copolymer is a saponified product of TFE/vinyl acetate copolymer, and has a degree of saponification of 100%, a fluorine content of 18% by weight, and a hydroxyl group content of 18.6 mmol/g. Comparative Example The antithrombotic properties of the resin molded body obtained in Example 2 and the molded body made of a known material were compared by the Lee-White method, and the results shown in Table 1 below were obtained.

[Table 1] The data in Table 1 above is shown in FIG.

[0016]

[Effects of the Invention] According to the present invention as described above, TFE/V
When used as a medical material that comes into direct contact with blood or remains in a living body for a certain period of time by being composed of an OH copolymer or by having the entire or at least part of the surface of another material composed of the above copolymer. , exhibits excellent antithrombotic properties. Therefore, the material of the present invention is extremely useful in the construction of various medical materials mentioned in the above-mentioned industrial fields of application.

[Brief explanation of the drawing]

FIG. 1: Comparison of antithrombotic properties.

Claims (4)

[Claims] Claim 1: A material that comes into direct contact with blood or remains in a living body for a certain period of time, which is composed of or partially composed of TFE/VOH copolymer, or whose surface is entirely or at least partially composed of a TFE/VOH copolymer. A medical composite material comprising the polymer. 2. The medical composite material according to claim 1, wherein at least a portion of the surface is coated or composited with a TFE/VOH copolymer. 3. The material according to claim 1, wherein the TFE/VOH copolymer has a fluorine content of 2 to 60% by weight and a hydrophilic group equivalent of 45 to 500. 4. The material according to claim 1, wherein the TFE/VOH copolymer has a hydrophilic group equivalent weight of 60 to 500.