JPH0149408B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to an antithrombotic medical material suitable as a material for artificial blood vessels and artificial organs. BACKGROUND ART Medical materials that come into contact with blood, such as vascular catheters, artificial kidney A-V shunts, heart-lung membranes, artificial blood vessels, artificial heart blood pumps, and aortic balloon pumps, have a high degree of flexibility, elasticity, and durability. In addition to mechanical properties such as strength and wet strength, it is also necessary to have biocompatibility such as antithrombotic properties. Until now, silicone and soft polyvinyl chloride have been mainly used as medical materials that require elasticity. However, when these materials come into direct contact with blood, the blood coagulates on the surface, forming a thrombus. When using these materials, it is necessary to administer anticoagulants such as heparin systemically; The use of anticoagulants carries the risk that if bleeding occurs for some reason, the bleeding will not stop. By the way, polyurethane and block copolymers of polyurethane and silicone are known to have better antithrombotic properties than other general-purpose polymer materials, and are commercially available as medical materials. There are problems such as changes in the properties and complexity of the manufacturing process, so it cannot be said that the results are necessarily satisfactory. On the other hand, it has also been proposed to use polyurethane obtained from polyethylene glycol, organic diisocyanate, and organic diamine as a medical material, but although this material exhibits good antithrombotic properties, its wet strength is extremely low. It cannot be put to practical use at all. In general, improving antithrombotic properties and other biocompatibility through hydrophilicity inevitably reduces mechanical strength, so it is important to develop materials with a good balance between the two. has become an important issue in the world. For example, an A-B-A type block copolymer of polyoxyethylene (A) and polyoxypropylene (B) is used as a polyurethane with sufficient mechanical properties and antithrombotic properties that can be used as a medical material. , polyurethane used as a polyether diol component has been proposed (Japanese Patent Publication No. 1987-8700). This material has not only antithrombotic properties but also fairly high mechanical strength, so it can be widely used as a variety of medical materials, but even higher mechanical strength is required depending on the purpose of use. Problems to be Solved by the Invention The purpose of the present invention is to further improve the antithrombotic properties and other biocompatibility of conventionally known medical polyurethanes, as well as further improve their mechanical properties. The goal is to further expand the fields in which it can be used as a material. Means for Solving the Problems As a result of extensive research to achieve the above object, the present inventors have discovered that the A-B-A type of polyoxyethylene (A) and polyoxytetramethylene (B) It was discovered that a polyurethane containing a block copolymer as a polyether diol component exhibits better antithrombotic properties and mechanical properties than conventional ones, and based on this knowledge, the present invention was accomplished. That is, the present invention has the general formula HO—(CH ₂ CH ₂ O) _a —[(CH ₂ ) ₄ O] _b —
( _CH2CH2O ) _c - _H ...() (in the formula, a, b and c are integers of 1 or more), number average molecular weight 500-8000, polyoxyethylene content 10-50 mol% The present invention provides a method for producing an antithrombotic polyurethane elastomer, which comprises reacting 1 mole of polyether diol with 2 to 5 moles of an organic diisocyanate and 1 to 4 moles of an organic diamine. General formula () in the polyurethane of the present invention
The polyether diol component has a number average molecular weight of
Must be in the range 500-8000. If a number average molecular weight smaller than this is used, the antithrombotic properties and elastic properties of the resulting polyurethane elastomer will be generally reduced, and if a number average molecular weight larger than this is used, the mechanical properties of the resulting polyurethane elastomer will deteriorate. The mechanical strength is reduced and the workability is also poor. Next, the polyoxyethylene content in this polyether diol, ie, the amount expressed as (a+c)/(a+b+c)×100, must be in the range of 10 to 50 mol%. If the amount is less than 10 mol%, the resulting polyurethane will not exhibit sufficient antithrombotic properties, and if it exceeds 50 mol%, the elasticity, flexibility and wet strength will be poor. Medical materials that come into contact with blood for a long period of time include:
A polyurethane elastomer having a number average molecular weight in the range of about 1000 to 6000 and a molecular weight of about 20000 to 60000 obtained using a polyoxyethylene content of 10 to 40 mol % is preferred. The polyether diol of the general formula () described above can be produced by either the anionic polymerization method or the cationic polymerization method shown below. (1) Anionic polymerization method PTMG obtained by reacting polyoxytetramethylene glycol (PTMG, HO-[(CH ₂ ) ₄ O] _b -H, b is an integer of 1 or more) with metallic potassium under a nitrogen stream. potassium alcoholate (KO [(CH ₂ ) ₄ O] _b -K) is produced, and this is used as an anionic polymerization initiator to inject ethylene oxide (EO).
Polyether diol of the general formula () is produced by polymerizing and stopping the polymerization with hydrochloric acidic isopropanol. This can be expressed as a chemical formula as follows. HO― [(CH ₂ ) ₄ O] _b ―H+2K→ KO― [(CH ₂ ) ₄ O] _b ―K+nEO→ KO― [(CH ₂ CH ₂ O) _a ― [(CH ₂ ) ₄ O] _b ― (CH ₂ CH ₂ O) _c ―KHCl ―――→ HO― (CH ₂ CH ₂ O) _a ― [(CH ₂ ) ₄ O] _b ―
(CH ₂ CH ₂ O) _c —H (a, b, c, n in the chemical formula are integers of 1 or more,
Further, n=a+c, which is ac. ) (2) Cationic polymerization method Ring-opening polymerization of tetrahydrofuran (THF) is performed using trifluoromethanesulfonic anhydride [(CF ₃ SO ₂ ) ₂ O] as a cationic polymerization initiator, and then EO is added to the polymerization reaction system. Then, a dilute aqueous sodium hydroxide solution is added to terminate the polymerization to produce the desired polyether diol of the general formula ().The chemical formula of these is as follows. (a, b and c in the formula have the same meanings as above) Next, as the organic diisocyanate component to be reacted with such a polyether diol component,
Previously used in the production of polyurethane,
Any one selected from aliphatic, alicyclic and aromatic diisocyanates can be used. Examples of such are 4,4'-diphenylmethane diisocyanate (MDI), 2,4
(or 2,6)-tolylene diisocyanate (TDI), p-xylylene diisocyanate, hexamethylene diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, etc., and 4,4'-diphenylmethane diisocyanate is particularly preferred. be. These may be used alone or in combination of two or more. Further, the organic diamine component can be arbitrarily selected from those used as chain extenders in the production of ordinary polyurethane. Examples of such substances include alkylene diamines such as ethylene diamine, propylene diamine, and hexamethylene diamine, and aromatic diamines such as p-xylylene diamine and p-diphenylmethane diamine. It is ethylenediamine. These may be used alone or in combination of two or more. These organic diisocyanate components and organic diamine components are usually used at a ratio of about 2 mol and about 1 mol, respectively, per 1 mol of the polyether diol component, but if a hard polyurethane elastomer is required, an additional organic diisocyanate component and an organic diamine component are used. Increase the proportion of dicyanate component and organic diamine component used. In such a case, the ratio of each component is 2.1 to 5 mol of organic diisocyanate component and 1.1 to 4 mol of organic diamine component per 1 mol of polyether diol component.
It is appropriately selected within the molar range. To produce the polyurethane of the present invention, for example, the required amounts of polyether diol of general formula () and diisocyanate are added to a reaction solvent,
Heat to ℃ to react. As the reaction solvent in this case, for example, N,N-dimethylacetamide, dimethylsulfoxide, dibutyl ether, dimethylformamide, etc. are used. Also, 1,8
If a reaction accelerator such as -diazabicyclo[5.4.0]undecene-7 or dioctyltin dilaurate is used, the reaction can be carried out at around room temperature. Next, the prepolymer obtained in this way is
By adding the required amount of organic diamine and carrying out a chain extension reaction at around room temperature, the desired antithrombotic polyurethane elastomer can be obtained. Effects of the Invention The polyurethane elastomer of the present invention has excellent antithrombotic properties, biocompatibility, flexibility, elasticity, durability, hydrolysis resistance, and wet toughness, and is suitable as a medical material, especially as a material for blood contact devices. be. In addition, as for its usage mode, for example, the polyurethane elastomer of the present invention may be used as a base material and molded into the shape of various medical devices, or it may be dissolved in a soluble solvent such as dimethylformamide or dimethylacetamide and applied to various devices. It may also be used as a surface coating. Furthermore, it can be formed into a sheet or film and used as a secondary processed product. Examples Next, the present invention will be explained in more detail with reference to Examples. Reference example (manufacture of polyether diol) a Anionic polymerization method Commercially available polyoxytetramethylene glycol (PTMG, number average molecular weight 1830) was heated under a stream of dry air.
The reaction is carried out at 130°C for 4 hours with metallic potassium in excess of the theoretical amount to produce potassium alcoholate of PTMG. The reaction system solidifies when cooled.
A predetermined amount of ethylene oxide (EO) is added to this while cooling, and the EO is polymerized at 45°C using PTMG potassium alcoholate as a polymerization initiator.
The polymerization time is usually 4 hours. Thereafter, it is diluted with benzene, hydrochloric acidic isopropanol is added to stop the polymerization, the generated potassium chloride is filtered off, and benzene, isopropanol, hydrochloric acid, and water are removed using a rotary evaporator. Furthermore, the EO homopolymer was removed by extraction with diethyl ether,
Drying under reduced pressure yields the desired polyether diol. Experiment Nos. 1, 2, and 3 in Table 1 show the results of characterization of three types of polyether diols obtained in experiments in which the amount of EO charged was varied. b Cationic polymerization method In a two-necked round-bottomed flask, add 150 g of thoroughly dehydrated tetrahydrofuran (THF) and 6.2 g of trifluoromethanesulfonic anhydride [(CF ₃ SO ₂ ) ₂ O] as a catalyst.
and polymerize for 10 minutes at 0°C with vigorous stirring. Cool the flask to -64°C, draw out a portion of the reaction solution, and add it to a 2% aqueous sodium hydroxide solution to polymerize the extracted liquid. Stop. From this, a THF homopolymer (polyoxytetramethylene glycol) is obtained. On the other hand, the polymerization flask was frozen in liquid nitrogen and dehydrated and purified.
Prepare 100g of EO for vacuum distillation. flask is 25
Continue polymerization of EO by raising the temperature to ℃. After a predetermined period of time, a large amount of 2% aqueous sodium hydroxide solution is poured into the reaction solution to stop the polymerization. The polymerization time of this EO depends on the length of the polymerization time in polyether diol.
EO content can be varied. The polyether diol produced may contain some THF units in its EO chain part.
This was determined from NMR spectrum measurements. This is probably due to some copolymerization of EO and THF because THF monomer remained during the polymerization of EO. However, in reality, polyether diols of general formula () are obtained. An example of the characterization of polyether diol obtained by this cationic polymerization method is shown in Experiment No. 4 in Table 1.

[Table] Example 0.02 mol of polyether diol obtained in Reference Example and 4,4'-diphenylmethane diisocyanate (0.04 mol) were uniformly dissolved in 200 ml of dimethyl sulfoxide, and the mixture was heated at 80°C while introducing dry nitrogen gas. After reacting for 5 hours with stirring, the mixture was cooled. To this reaction solution, 150 ml of a solution containing 0.02 mol of ethylenediamine of the same type as the reaction solution is added dropwise, and the mixture is stirred at room temperature to 30° C. for 7 hours to react. This reaction solution was poured into water to precipitate and separate the produced polyurethane, and low molecular weight compounds were removed with acetone using a Soxhlet extractor, and the remainder was vacuum dried at room temperature to obtain the target polyurethane elastomer. . 15% of the polyurethane elastomer thus obtained
The dimethylformamide solution was poured into a flat shear dish placed on a mercury plane, and the solvent was gradually vaporized under reduced pressure to prepare a uniform film. Cut this approximately 0.3mm thick film into strips and
The strength at break, elongation at break and 100% modulus at ℃ were measured. The results are shown in Table 2. Separately, for comparison, as a polyether component, PTMG (average molecular weight 1830), A-B-A type block copolymer (abbreviated as EPE) of polyoxyethylene (A) and polyoxypropylene (B) were used. 58―
Table 2 shows the mechanical properties of polyurethane produced by the same method as in the above example using Polyurethane (see Japanese Patent No. 8700) as a polyether component. Indicated. From Table 2, the polyurethane according to the present invention has the following mechanical strength:
It can be seen that it is equivalent to polyurethane and biomer made from PTMG, and superior to polyurethane made from EPE. Note that polyurethane made using polyether diol with a number average molecular weight of 8,500 and an EO content of 74% had poor film forming properties, and its mechanical properties could not be measured. Furthermore, in order to evaluate the fatigue resistance of these polyurethane elastomer films, they were stretched by 50% and subjected to a stretching deformation of ±10% at a speed of 5 Hz.
A fatigue test was conducted day and night for 23 consecutive days in physiological saline at 37°C (repetitive expansion and contraction approximately 10 million times).
As a result, nothing broke. From the above results, it was found that these polyurethane elastomers have excellent mechanical strength, elasticity, and fatigue resistance when wet, which are required as medical materials.

[Table] Next, the antithrombotic properties of each sample were examined according to the following method. Place 1 ml of a 10% solution of polyurethane elastomer in dimethylacetamide into a test tube with a ground lid of 12 mm in diameter and 10 cm in length, connect it to a rotary evaporator, and apply a uniform coating to the inner wall of the tube while rotating under reduced pressure. Put 1 ml of freshly collected healthy blood into two test tubes, keep it at 37°C, and after 5 minutes, tilt one test tube 45 degrees every 30 seconds to observe the flow state. After the blood in the test tube stops flowing at all, the same operation is performed on the other test tube, and the elapsed time until the blood in this test tube stops flowing at all is defined as the coagulation time of the sample. On the other hand, the solidification time of the glass is evaluated using the same procedure for two glass test tubes that are not coated with polyurethane elastomer. Although there are individual differences, the solidification time of glass is usually 8 to 14 minutes. The average value of the values obtained from five or more tests for the glass and sample polyurethane elastomer is taken as the solidification time. As an index of antithrombotic properties, the relative values of the coagulation times of each polyurethane elastomer were compared, with the coagulation time of glass being taken as 1. These results are shown in Table 3. For comparison, PTMG that does not contain EO
(number average molecular weight 1830), a polyurethane elastomer made from MDI and ethylenediamine, and a commercially available medical polyurethane, Biomer (manufactured by Ethicon, USA), were also tested. It is clear that the polyurethane elastomer of the present invention has excellent antithrombotic properties. Furthermore, even when compared with the Leawhite test results of polyurethane made from EPE, it can be seen that the polyurethane of the present invention has equivalent antithrombotic properties. Separately, a polished stainless steel rod with a diameter of 4 mm was immersed in a 10% by weight dimethylacetamide solution of the sample polyurethane elastomer, taken out, dried at 60°C, and the operation of forming a polyurethane film on the surface of the stainless steel rod was repeated. After reaching the desired thickness, immerse it in ethanol solution and remove the stainless steel rod to create a short tube. A tube with a wall thickness of 0.5 mm, a length of 17 mm, and an inner diameter of 4 mm.
The tube was implanted into the scapular vein and major vein of an adult dog, and the time taken for the implanted tube to become occluded by thrombus formation due to blood coagulation (patency time) was measured using a Doppler blood flow meter. As an index of antithrombotic properties, polyoxytetramethylene glycol (PTMG, number average molecular weight 1830) was tested as a comparative example.
Comparisons were made based on relative values, with the opening time (within 40 minutes) of polyurethane manufactured from MDI and ethylenediamine set as 1. These are shown in Table 3. The above in vitro and in vivo test results show that the polyurethane elastomer of the present invention has excellent antithrombotic properties.

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Claims (1)

[Claims] 1 General formula HO—(CH ₂ CH ₂ O) _a — [(CH ₂ ) ₄ O] _b —
(CH ₂ CH ₂ O) _c —H (in the formula, a, b and c are each an integer of 1 or more), with a number average molecular weight of 500 to 8000 and a polyoxyethylene content of 10 to 50 mol%. A method for producing an antithrombotic polyurethane elastomer, which comprises reacting 1 mole of polyether diol with 2 to 5 moles of an organic diisocyanate and 1 to 4 moles of an organic diamine.