JPS6121419B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel antithrombotic elastomer that has both excellent antithrombotic properties and mechanical properties as an elastomer. More specifically, the present invention relates to an antithrombotic elastomer for use in blood contact parts, which is composed of a polyurethane or polyurethane urea containing an organosilicon polymer in its main chain and an elastomer containing no organosilicon polymer. Antithrombotic elastomers are particularly useful when used as materials for areas that come into direct contact with blood, and are used in medical devices that come into direct contact with blood.
It is especially needed in the production of artificial organs such as artificial hearts. Specific applications include vascular catheters, monitoring tubes, blood bags, extracorporeal circulation circuits such as artificial kidneys and heart-lung machines, A-V shunts, blood bypass tubes, artificial hearts, auxiliary artificial hearts, blood pumps, and materials for balloon pumps. These applications require antithrombotic properties, mechanical strength, elasticity, and durability. Conventionally, antithrombotic elastomers used for blood contact parts include general-purpose polymeric materials such as soft vinyl chloride, polyurethane, and silicone rubber, as well as segmented polyurethanes (for example, Ethicon's
Biomer), heparinized urethane elastomer (Japanese Patent Publication No. 55-13729), and a copolymer in which polysiloxane and polyurethane are directly bonded with nitrogen and silicon (US Pat. No. 3,562,352) have been developed. However, conventional general-purpose polymer materials have insufficient antithrombotic properties, segmented polyurethane has strong mechanical strength but poor antithrombotic properties, and heparinized urethane elastomers have extremely poor antithrombotic properties after heparin is released. However, since bioactive heparin is used, moldability and sterilization methods are complicated and costs are high. In addition, a copolymer (trade name: Avcothane), in which polysiloxane and polyurethane are directly bonded with nitrogen and silicon, described in U.S. Patent No. 3,562,352, has excellent antithrombotic properties among currently existing materials, and has many clinical examples. . However, this product is manufactured by mixing a pre-synthesized polyurethane and a polysiloxane having reactive end groups in a solution state, and then reacting the two during molding, as shown in the reaction formula below, for example. Since antithrombotic properties are used, the finding of antithrombotic properties varies greatly depending on the molding conditions, and there is a drawback that it is difficult to stably obtain excellent antithrombotic properties. Although this product is generally called a block copolymer, as can be seen from the example chemical reaction formula above, it is actually a grant copolymer, and has two reactive end groups of polysiloxane. Because of the presence of the above, it is a thermosetting resin in which polysiloxane is used as a crosslinking agent, and therefore has the drawback that the molding method is limited to coating methods, dipping methods, etc. Due to limited molding methods, it is often stored in a solution state, and when the polyfunctional unterminated groups of polyurethane and polysiloxane react, the solution becomes highly viscous or gels, making it unusable. There are drawbacks. The present inventors have made extensive studies to improve these drawbacks, to provide an antithrombotic elastomer for use in blood contact parts that stably exhibits excellent antithrombotic properties and can be used in a wide range of molding methods. The inventors have discovered that a composition consisting of a polyurethane or polyurethane urea containing an organosilicon polymer in its main chain and an elastomer containing no organosilicon polymer has excellent antithrombotic properties and mechanical properties, resulting in the present invention. That is, the present invention contains 2 to 56% by weight of an organosilicon polymer with a molecular weight of 200 to 30,000 in the main chain, and a soft segment containing an organosilicon polymer with a molecular weight of 500 to 30,000 in addition to the organosilicon polymer as a soft segment.
Polyurethane or polyurethane urea (hereinafter referred to as component A) containing polyester or polyether with a molecular weight of 6000 and polyurethane elastomer or polyurethane urea containing polyether or polyester with a molecular weight of 500 to 6000 in the soft segment and not containing an organosilicon polymer. The present invention provides an antithrombotic elastomer for use in blood contact parts, which is made of a composition comprising an elastomer (hereinafter referred to as component B). The organosilicon polymer contained in component A of the present invention contains organosilicon and has a molecular weight of at least 200 or more, more preferably a molecular weight of 500 to 30,000, particularly preferably 1,000 to 20,000. Although the method of binding organosilicon is not particularly limited, polysiloxane is preferable in order to exhibit antithrombotic properties, and examples thereof include methylphenylpolysiloxane, fluoroalkylmethylpolysiloxane, and polydimethylsiloxane. Particularly preferred is polydimethylsiloxane. The content of the organosilicon polymer contained in component A of the present invention is preferably 2 to 56% by weight, more preferably 4 to 30% by weight, particularly 7 to 25% by weight. The soft segment ratio of component A of the present invention (molecular weight of all soft segments/total molecular weight x 100 (%)) is not particularly limited, but may be 40 to 80% by weight, or even
The content is preferably 50 to 70% by weight. The soft segment here refers to a segment between urethane bonds, between urea bonds, or between urethane bonds and urea bonds, which has a molecular weight of 500 or more and whose homopolymer Tg is below room temperature. Examples include polysiloxane, Examples include polyether polyester. As soft segments other than polysiloxane, polyethers and polyesters with a molecular weight of 500 to 6000 are preferable, and polyethers with high hydrolytic stability in vivo are more preferable, especially (-CH ₂ -CH ₂ - CH ₂ −CH ₂ −O)− _26
~30 and

[Formula] is preferred. As the elastomer which is component B of the present invention, any ordinary elastomer can be used as long as it does not contain an organosilicon polymer. Polyurethane elastomers or polyurethane urea elastomers are preferred for application to objects. Among them, molecular weight as a soft segment
Those having a polyether or polyester of 500 to 6000 are preferred, and more preferably polyether urethane elastomers or polyether urethane urea elastomers having a polyether in the soft segment, which has high hydrolytic stability in vivo, and exhibit antithrombotic properties. Especially as a soft segment, (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -O) - _{26 to 30}
and/or

A polyether urethane elastomer or a polyurethane urea elastomer having the formula is preferred. Also, when component B is a polyurethane elastomer or polyurethane urea elastomer, its soft segment ratio is 40 to 80.
% by weight, preferably 50 to 70% by weight. In the composition forming the antithrombotic elastomer used in the blood contacting part of the present invention, the weight ratio of component A to component B is preferably 1/9 to 9/1 from the viewpoint of the balance between antithrombotic properties and mechanical properties; Furthermore, from 3/17 to 7/3,
Particularly preferred is 1/4 to 3/2. Further, the content of the organosilicon polymer in the composition is 1
From the viewpoint of antithrombotic properties, the content is preferably 50% by weight, more preferably 3% to 20% by weight, particularly 4% to 15% by weight. Further, the antithrombotic elastomer used in the blood contact portion of the present invention is preferably an essentially thermoplastic elastomer consisting of a linear polymer that does not contain a crosslinked structure. Next, a method for producing polyurethane or polyurethane urea containing an organosilicon polymer in the main chain, which is component A of the present invention, will be explained. Component A consists of an isocyanate compound, an active hydrogen group-containing compound that does not contain an organosilicon polymer, and an organosilicon polymer having an active hydrogen group or an isocyanate group as essential components for polymerization, and a chain extender is added as necessary. It is most preferable to manufacture using As the manufacturing method, a normal thermoplastic polyurethane manufacturing method can be applied. First, the synthetic components are added and dissolved in a solvent, and a reaction is carried out. The synthetic components may be added all at once, but preferably, an isocyanate compound and an active hydrogen group-containing compound that does not contain an organosilicon polymer are reacted to obtain a so-called prepolymer having isocyanate groups at the terminals, and then the active hydrogen is added. An organosilicon polymer having a group and, if necessary, a chain extender are added to carry out a reaction. Furthermore, it is preferable to add highly reactive components such as organic silicon polymers having active hydrogen groups or aliphatic diamines gradually and continuously. The reaction is carried out using heat or a catalyst, and all catalysts used for urethane synthesis can be used, but considering that the final product will be used in the blood contact area, amines such as triethyldiamine and diazine may be used. It is preferable to use a material that can be removed during molding, such as bicycloundecene. As the isocyanate compound used, all isocyanates used in the production of conventional polyurethanes can be used, but diisocyanates are particularly preferred. Examples of preferred diisocyanates include tetramethylene diisocyanate, hexamethylene diisocyanate, cyclohexane-1,4-diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate, 2,4-tolylene diisocyanate and 2,6-tolylene diisocyanate. - Mixtures of tolylene diisocyanate, xylylene diisocyanate, 4,4'-diphenylmethane diisocyanate, 1,4-phenylene diisocyanate, 1,3-phenylene diisocyanate, naphthalene-1,5-diisocyanate, etc. Alternatively, it can be used as a mixture. The isocyanate compounds of the present invention also include isocyanate compounds generated from recycled compounds. As the active hydrogen group-containing compound that does not contain an organosilicon polymer, any compound conventionally used when reacting with isocyanate to produce polyurethane can be used, but active hydrogen containing a soft segment with a molecular weight of about 500 to 6000 is preferable. It is a group-containing compound, and diol compounds such as polyether, polyester, and polycaprolactane are preferred. Preferred among these are polyether diol compounds that have high hydrolytic stability in vivo, such as polyethylene ether glycol, polypropylene ether glycol, polytetramethylene ether glycol, etc., which may be used alone or as a mixture. Particularly preferred are HO( _-CH2 - _CH2 - _CH2 - _CH2 -O) _-26~30H and

[Formula] is mentioned. Preferred polyester diol compounds include ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, pentamethylene glycol, cyclohexane-1,4-diol, and cyclohexane-1,4-diol.
Polycondensation of glycols such as dimethanol alone or a mixture thereof with dibasic acids such as adipic acid, maleic acid, succinic acid, phthalic acid, isophthalic acid, terephthalic acid, or derivatives of these acid esters, acid halides, etc. Examples include polyesters obtained by the following methods, which can be used alone or as a mixture. The organosilicon polymer synthesis component to be used preferably contains the constituent organosilicon polymer in its main chain and has two functional groups selected from active hydrogen groups and isocyanate groups, and more preferably has active hydrogen groups and two groups selected from isocyanate groups. Those having two groups are preferred, and in consideration of reactivity, those having two carbinol groups are particularly preferred.
Preferred examples include carbinol polydimethylcycloxane with unterminated ends, carbinol methylphenyl polysiloxane with both ends, carbinol fluoroalkylmethyl polysiloxane with both ends, and the like, which may be used alone or as a mixture. Examples of chain extenders include chain extenders having a bifunctional active hydrogen group, such as aliphatic diamines such as ethylene diamine, propylene diamine, butylene diamine, and hexamethylene diamine; alicyclic diamines such as cyclohexane diamine, piperazine, and xylene diamine; Fat aromatic acid diamines, tolylene diamine,
Aromatic diamines such as phenylene diamine and diphenylmethane diamine, hydrazines, glycols such as ethylene glycol and 1,4-butanediol, and water are suitable. Suitable solvents include dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, dioxane, and tetrahydrofuran, but it is important to sufficiently dissolve the organosilicon polymer, and from this point of view dioxane , tetrahydrofuran, and a mixed solvent mainly composed of these are preferred. The polyurethane or polyurethane urea of component A synthesized in this way can be prepared in the state of a synthesized solution, or after precipitating component A in water or the like and thoroughly washing with water or ethanol to remove impurities.
Mix with the B component elastomer in a dry pellet state. The A component and the B component are mixed in a solution state or in a solid state. The solvent used for mixing in a solution state must be able to dissolve components A and B well, and suitable examples include dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dioxane, and tetrahydrofuran. Moreover, the mixture in a solid state can be applied to a normal thermoplastic resin molding method. The thus obtained antithrombotic elastomer of the present invention was tested in an in vitro antithrombotic test [Lee et al.
White method (edited by Izumi Kanai and Masamitsu Kanai, Summary of Clinical Testing Methods, -81, Kanehara Publishing Co., Ltd., 1971)] showed that the coagulation time of whole blood was improved compared to segmented polyurethane elastomer. It showed excellent antithrombotic properties. Furthermore, even when the molding conditions of the test sample were varied, excellent antithrombotic properties were stably obtained. It is generally said that the mechanical properties of an antithrombotic elastomer used in blood contact areas are good if the tensile strength is 100 g/cm ² or more and the elongation is 300 to 500% or more. 500Kg/
It exhibited excellent mechanical properties, with a tensile strength of cm ² and an elongation of more than 500%. In addition, the elastomer of the present invention can be molded as a solution by a coating method, a dipping method, or a casting method, and can also be molded from pellets using conventional thermoplastic synthetic resin molding methods such as extrusion molding, injection molding, and calendering. can do. In addition, this elastomer is extremely stable not only in dry pellet form but also when stored in solution form, and exhibits excellent properties as an antithrombotic elastomer for use in blood contact areas with easy handling and good reproducibility. . From these results, the antithrombotic elastomer of the present invention can be suitably used for blood contact surfaces of medical devices that come into direct contact with blood. Specific applications of these include artificial hearts, pumping chambers for auxiliary circulation devices, balloon pumps, extracorporeal circulation circuits for auxiliary circulation devices such as artificial kidneys and heart-lung machines, blood bags, and catheters. The present invention will be explained below with reference to Examples. Example 1 <Production of component A> 54.7 parts of polytetramethylene ether glycol (molecular weight 2000) was dehydrated for 30 minutes at 90° C. under reduced pressure of 0.1 mmHg or less. Next, after adjusting the temperature to 50°C, 250 parts of dehydrated and purified dioxane was added thereto, and after dissolving polytetramethylene ether glycol, 27.3 parts of 4,4-diphenylmethane diisocyanate and dioxane as a catalyst were added. Bicycloundecene was added and stirred for 1 hour. Then add 4.8 parts of ethylene glycol, then dioxane
13.2 parts of terminal carbinol polydimethylsiloxane (molecular weight approximately 2400) dissolved in 150 parts was gradually added dropwise to carry out the reaction. <Production of Component B> 62.8 parts of polytetramethylene ether glycol (molecular weight 2000) was dehydrated for 30 minutes at 90° C. under reduced pressure of 0.1 mmHg or less. Next, adjust the temperature to 50℃,
After adding 200 parts of dehydrated and purified dioxane,
4,4'-diphenylmethane diisocyanate 31.4
A reaction was carried out by adding diazabicycloundecene as a catalyst and a prepolymer having isocyanate groups at the terminals. Next, a solution of 5.8 parts of ethylene glycol dissolved in 200 parts of dioxane was added to produce a polyether urethane elastomer. <Manufacture and evaluation of the elastomer of the present invention> The component A solution and the component B solution thus manufactured were mixed as polymers at a ratio of 1:2, and stirred at room temperature for 1 hour. For mechanical properties, tensile strength, tear strength, and elongation were measured using Shimadzu Autograph IS2000. Antithrombotic properties were tested by coating the inner wall of a test tube with an inner diameter of 10 mm and a length of 100 mm with this synthetic solution diluted with dioxane to a polymer concentration of 5%, and adding approximately 1 ml of freshly drawn blood into the tube.37 The solidification time was measured at °C. For comparison, test tubes coated with only component A, test tubes coated with component B, and uncoated test tubes were simultaneously tested using the same blood. The results are shown in Table 1. As can be seen from this table, the elastomer of the present invention had an excellent balance between antithrombotic properties and mechanical properties.

[Table] Example 2 Polypropylene ether glycol (molecular weight approx.
1000) 55.7 parts, 3.1 parts of ethylene glycol,
13.4 parts of terminal carbinol polydimethylsiloxane (molecular weight approximately 2400) were dissolved in 400 parts of tetrahydrofuran. To this solution were added 27.8 parts of 4,4'-diphenylmethane diisocyanate and 0.003 parts of diazabicycloundecene, and the mixture was stirred at 45°C to obtain a clear and viscous solution. A large amount of water was added to this solution to precipitate a polymer, which was thoroughly washed with water and air-dried.Then, the polymer was washed with ethanol in a Soxhlet extractor. This polymer (component A) and Ichihan's polyether urethane elastomer (trade name: Paraprene)
P395RNT) (component B) in a 1:1 ratio,
This was dissolved in tetrahydrofuran (THF) and its antithrombotic properties and mechanical properties were measured in the same manner as in Example 1. The results are shown in Table 2, and both antithrombotic properties and mechanical properties were excellent.

[Table] Example 3 27.2 parts of polytetramethylene ether glycol (molecular weight 2000), 8 parts of 1,4-butanediol, and 4,4'-diphenylmethane diisocyanate
34.1 parts and dissolved in 200 parts of tetrahydrofuran,
Diazadicycloundecene was added as a catalyst and the reaction was carried out at room temperature. Next, 29.4 parts of terminal carbinol polydimethylsiloxane (molecular weight approximately 2400) was dissolved in 150 parts of dioxane and added, and then 1.3 parts of ethylenediamine was dissolved in a mixed solvent of 100 parts of dioxane and 100 parts of dimethylformamide. This was gradually added to carry out the reaction. <Production of component B> 64 parts of polytetramethylene ether glycol (molecular weight 1000), 4 parts of ethylene glycol,
A polyether urethane elastomer was prepared from 32 parts of 4,4'-diphenylmethane diisocyanate. <Manufacture and evaluation of the elastomer of the present invention> The A component solution and the B component solution thus manufactured were mixed in a 1:1 polymer ratio,
Stirred at room temperature for 30 minutes. Antithrombotic properties and mechanical properties were measured using the same method as in Example 1, and the results are shown in Table 3.

【table】

Claims (1)

[Claims] 1 Contains 2 to 56% by weight of an organosilicon polymer with a molecular weight of 200 to 30,000 in the main chain, and contains polyester or polyether with a molecular weight of 500 to 6,000 in addition to the organosilicon polymer as a soft segment. polyurethane or polyurethane urea with a molecular weight of 500
An antithrombotic elastomer for use in a blood contacting part, characterized in that it is composed of a composition comprising a polyether or polyester of ~6000 in the soft segment and a polyurethane elastomer or polyurethaneurea elastomer that does not contain an organosilicon polymer. 2 Claim 1 in which the composition is thermoplastic
Antithrombotic elastomer used in the blood contacting part described in Section 3. 3. The blood according to claim 1, wherein the weight ratio of the polyurethane or polyurethane urea containing an organosilicon polymer in its main chain to the elastomer not containing an organosilicon polymer is 1/9 to 9/1. Antithrombotic elastomer used in contact areas. 4 The content of organosilicon polymer in the composition is 1 to 50
The antithrombotic elastomer used in the blood contacting part according to claim 1, which is % by weight. 5. The antithrombotic elastomer used in the blood contacting part according to claim 1, wherein the organosilicon polymer is polysiloxane. 6. The antithrombotic elastomer used in the blood contacting part according to claim 1, wherein the organosilicon polymer is polydimethylsiloxane.