JPH0583264B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to an antithrombotic material in which a silicon polymer is uniformly dispersed in a polyurethane phase without forming a particle structure in which the particles are unevenly aggregated. (Prior Art) Polysiloxane-polyurethane antithrombotic substances include compositions in which polysiloxane is dispersed in polyurethane in a phase-separated state
139351, 139352; Yoji Imai, Akihiko Watanabe, Artificial Organs, Vol. 11, p. 209 (1982)], polyurethane and polysiloxane are reacted with a room temperature crosslinking agent in the presence of water to form a stable emulsion. Antithrombotic substances (Japanese Patent Application No. 57-41865) have been proposed. (Problem to be solved by the invention) In materials that are a blend of polyurethane and polysiloxane, polysiloxane in a phase-separated state is usually
It is a dispersed unit of about 0.2 to 10μ that can be observed under an optical microscope with agglomeration unevenly distributed, and the shape of the dispersed particles is non-uniform, the antithrombotic property is not satisfactory, and the level of the antithrombotic property is also not constant. (Means for Solving the Problems) The present invention aims to provide a novel antithrombotic material that solves the above problems. The antithrombotic material of the present invention is composed of polyurethane and a silicon polymer, and is an antithrombotic material in which the silicon polymer is uniformly dispersed in the polyurethane phase without forming agglomerated and unevenly distributed units. be. The antithrombotic material of the present invention is a blend of conventional polyurethane and silicon polymer shown in Fig. 1 (transmission electron micrograph of an ultra-thin section). There are no unevenly distributed dispersion units, and the silicon polymer is uniformly dispersed as shown in FIG. The antithrombotic material properties of the present invention cannot be obtained by mixing polyurethane and silicon polymer. One method for obtaining the material of the present invention is to form a film by casting or the like from a solution prepared by adding and mixing a low-molecular silicon-containing compound capable of condensation polymerization to a polyurethane solution. The polyurethane used in the present invention is not particularly limited, and may be a polyester polyurethane or a polyether polyurethane. Polyester polyurethane is produced by synthesizing a polyester with a terminal hydroxyl group between a glycol such as ethylene glycol or diethylene glycol, or a polyhydric alcohol such as trimethylolpropane or glycerin, and a polyhydric carboxylic acid such as adivic acid or succinic acid. diisocyanate,
2,4-Tolylene diisocyanate, 4,4-diphenylmethane diisocyanate, and other isocyanate group-containing compounds conventionally used in the production of polyurethane are reacted to produce a prepolymer having isocyanate groups at both ends, and a known prepolymer is produced. It may also be prepared by extending the chain with a chain extender. In addition, polyether polyurethanes include, for example, polyethylene glycol, polypropylene glycol, or their copolymers, tetramethylene glycol, polytetramethylene glycol, or alkylene oxide and propylene glycol, 1,
A polyol obtained by reacting a polyhydric alcohol such as 2,6-hexanetriol with the above-mentioned isocyanate group-containing compound is reacted to form a terminal isocyanate prepolymer, and the molecular chain is extended using a known chain extender. It may also be prepared by In preparing the polyurethane used in the present invention, a diamine such as ethylenediamine, diethylenediamine, hexamethylenediamine, etc. may be used as a chain extender to form a polyurethane urea. It goes without saying that known diols such as ethylene glycol and butanediol may be used as the chain extender. The low-molecular silicon-containing compound capable of condensation polymerization used in the present invention is a room-temperature crosslinking agent or a silane coupling agent used in the production of silicone resins and rubbers, and is activated by water to undergo condensation. Particularly preferred are compounds having at least two functional groups in one molecule that can be polymerized and converted into a crosslinked silicon polymer. Representative functional groups include ≡SiO−COR, ≡Si
-OR, ≡Si-NR (R is a hydrocarbon residue such as methyl, ethyl, propyl, butyl group); ≡Si-OX,
Examples include ≡Si-X (X is a halogen such as chlorine or bromine). A low-molecular silicon-containing compound having such a functional group is converted into a silicon polymer to form a polysiloxane structure. Examples of silicon-containing compounds having at least three functional groups in the molecule include general formulas (), (), and ().

【formula】

[Formula] (R _o , Y _3-o )≡Si−O−Si≡(R _n , Y′ _3-n )
() [In the above formula, R' is a hydrocarbon residue, R is the same or different hydrocarbon residue, Y, Y', Y'', and Y are the same or different functional groups activated by water. ,m
and n is an integer of 0, 1 to 3, m+n=0, 1 to
Each represents an integer of 3. formula()
For example, if m and n are 1

[C] indicates that the compound is ] These are compounds that can undergo condensation polymerization and be converted into a crosslinked silicon polymer, and one or more of these are used. Also, general formula ()

[C] (R ₁ to _{R 4} are the same as R above, Y, Y' are the same as above, l represents an integer from 0, 1 to number 10) Activated by water represented by A bifunctional silicon-containing compound can be used in combination. This compound forms a linear polysiloxane by condensation polymerization. Specific examples of the silicon-containing compounds represented by the above general formulas () to () include, for example, tetraacetoxysilane, tetraisopronooxysilane, methyltriacetoxysilane, ethyltriacetoxysilane, propyltriacetoxysilane, Butyltriacetoxysilane, phenyltriacetoxysilane, methyltriethoxysilane,
Ethyltriethoxysilane, tetraethoxysilane, phenyltriethoxysilane, propyltriethoxysilane, butyltriethoxysilane, methyltrimethoxysilane, tetramethoxysilane, ethyltrimethoxysilane, propyltrimethoxysilane, butyltrimethoxysilane or tetra Chlorosilane, methyltrichlorosilane, ethyltrichlorosilane, butyltrichlorosilane, vinyltriacetoxysilane, bis-
(N-methylbenzylamide)ethoxymethylsilane, tris-(dimethylamino)methylsilane,
tris-(cyclohexylamino)methylsilane,
Vinyltrichlorosilane, vinyltriethoxysilane, γ-glycidoxypropyltrimethoxysilane, tetrapropoxysilane, tetraacetoxydisiloxane, 1,3-dimethyltetraacetoxydisiloxane, 1,3-divinyltetraethoxydisiloxane, 1, 3,5-trimethoxy-
Examples include 1,1,3,5,5pentamethyltrisiloxane and 1,1,3,3,5,5-hexaacetoxy-1,5-methyltrisiloxane. Specific compounds represented by the general formula () include, for example, dimethyldiacetoxysilane, dimethyldiisopronooxysilane, diethyldiacetoxysilane, dimethyldiethoxysilane, dimethyldimethoxysilane, diethyldiethoxysilane, diethyldimethoxysilane. , methylethyldimethoxysilane, dimethyldichlorosilane, methylphenyldiacetoxysilane, diphenyldiacetoxysilane, dibenzyldiacetoxysilane, divinyldiethoxysilane, 1,1,3,3
-tetramethyl-1,3-diacetoxydisiloxane, 1,1,3,3-tetramethyl-1,3-
Dimethoxydisiloxane, 1,1,3,3-tetraethyl-1,3-diethoxydisiloxane,
1,1,3,3,5,5-hexamethyl-1,5
-diacetoxytrisiloxane, 1,1,3,
3,5,5-hexaethyl-1,5-diethoxytrisiloxane, 11,3,5,5-hexamethyl-1,5-dimethoxytrisiloxane, 1,1,
1,5,5,5-hexamethyl-3,3-diacetoxytrisiloxane, 1,1,1,3,5,5
-hexamethyl-3,5-diacetoxytrisiloxane and the like. The antithrombotic material of the present invention is obtained by adding a silicon-containing compound to a solution of polyurethane and forming a film by any means using the uniformly mixed solution.
It is used in a range of 0.1 to 100 parts by weight per 100 parts by weight. Preferably it is 1.0 to 80 parts by weight, more preferably 1.5 to 50 parts by weight. If it is less than 0.1 part by weight, the antithrombotic properties are the same as polyurethane, but if it exceeds 100 parts by weight, the strength properties of the coating will be poor, which is not preferable. The solvent used is one or more organic polar solvents such as cyclic ethers such as tetrahydrofuran and dioxane that dissolve polyurethane, and dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. From this point of view, it is preferable that the solvent be easily removed from the coating film (by evaporation, washing with water, etc.). Further, a small amount of other solvent such as alcohol or acetone may be included as long as it does not significantly affect the above-mentioned solvent. The concentration of polyurethane in the solution is 1 to 50% by weight, preferably 3 to 40% by weight, more preferably 5 to 30% by weight. When the polyurethane concentration is lower than this range, the viscosity is too low, causing problems such as an increase in the number of coatings during film formation and an extremely thin film, and when it exceeds this range, the viscosity is too high, making it difficult to adjust the film thickness. becomes. The antithrombotic material of the present invention can be obtained by applying a homogeneous solution in which a silicon-containing compound and polyurethane are dissolved onto a substrate by a method such as spraying or casting to form a film. During film formation, the silicon-containing compound is activated by moisture in the air and converted into crosslinked polysiloxane. The antithrombotic material of the present invention is produced by adding a predetermined amount of water to a homogeneous solution containing a silicon-containing compound and polyurethane, causing condensation of the silicon-containing compound in the solution, and then forming a film. You can also get Unlike the antithrombotic material of the present invention, which is obtained by mixing polyurethane and polysiloxane, as described above, polysiloxane does not form agglomerated unevenly distributed units on the order of several microns, but is incorporated into the polyurethane phase. Evenly distributed. The difference between the antithrombotic material of the present invention and a conventional material obtained by blending polyurethane and polysiloxane will be explained based on the electron micrographs of FIGS. 1 to 4. Both are composed of 90% by weight of polyurethane and 10% by weight of polysiloxane. Figures 1 and 3 show the conventional blend antithrombotic material, while Figures 2 and 4 show the antithrombotic material of the present invention. It is an antithrombotic material. Figures 1 and 2 are ordinary electron micrographs (transmission images) of ultra-thin sections of both materials, and Figures 3 and 4 are Si of polysiloxane in the same field of view as Figures 1 and 2. This is an electron micrograph using characteristic X-rays (Kα rays) of Si element obtained by surface analysis of the element. The part where the white dots in FIG. 3 are unevenly aggregated is the polysiloxane phase, and corresponds to the black part in FIG. 1. As described above, in the conventional blend type blood-resistant material, polysiloxane is dispersed in the polyurethane phase in agglomerated uneven distribution, but in the material of the present invention, the polysiloxane is dispersed in the polyurethane phase.
As shown in the figure, polysiloxane does not form such agglomerated and unevenly distributed dispersion units, but is uniformly dispersed in the polyurethane phase. In the present invention, uniform dispersion means that an ultrathin section of the antithrombotic material is 500 Å
Si element analysis is performed in the range of 500 Å or less, and it means a dispersion in which the Si concentration difference in any part is at least 10% or less. There is no part with high electron density that indicates the existence (Figure 2),
In the area analysis (FIG. 4) regarding the Si element, a uniform distribution is obtained in which the self-points indicating the density of the Si element are not particularly unevenly distributed. Although it is not clear why the antithrombotic material of the present invention has the above structure, one possible reason is as follows. Generally, polyurethane and high molecular weight dimethyl silicone have poor compatibility, but the low molecular weight silicon compound used in the present invention has good compatibility with polyurethane, and during the condensation reaction, the reaction progresses by passing between the main chains of polyurethane. The silicon polymer produced for this purpose probably does not become unevenly distributed or separated. The antithrombotic material of the present invention is a conventional polyurethane/
It exhibits extremely superior antithrombotic properties compared to polysiloxane blend-based materials, so it can be used in artificial hearts; blood circuits such as artificial kidney circuits and artificial heart-lung circuits; intravascular catheters, cannulae, and various blood bypass tubes; It is the perfect material for constructing the blood-contacting surfaces of all blood-contacting medical devices, such as bags. The present invention will be specifically explained below using Examples. Example 1 Polytetramethylene glycol (average molecular weight
2500) and methylene bis(4-phenyl isocyanate) and butanediol as a chain extender by a known method, 100 parts by weight of polyether polyurethane was dehydrated to a water content of 7 ppm or less in a dioxane/tetrahydrofuran mixed solvent ( (weight mixing ratio 1/2) at 35℃ under stirring,
A viscous solution (polymer concentration 10% by weight) was prepared.
To this solution, add a dimethyldiacetoxysilane/methyltriacetoxysilane mixture (weight mixing ratio 20/80) immediately after distillation to 90 parts by weight of polyurethane.
They were added in proportions of parts by weight and mixed uniformly. This solution was cast onto a glass plate to form a coating. Further, polydimethylsiloxane was used in place of the above-mentioned low-molecular-weight silicon compound to form a polyurethane/polydimethylsiloxane (90/10% by weight) blend film. Ultrathin sections of these two types of coatings were made and observed using an electron microscope. FIG. 1 shows a transmission image of the blend system, and FIG. 2 shows a transmission image of the material of the present invention. Further, photographs of characteristic X-ray images of the Si element obtained by surface analysis of the same section are shown in Fig. 3 (blend system) and Fig. 4 (example of the present invention). As already mentioned, a comparison between FIG. 3 and FIG. 4 shows that in the material of the present invention, the polysiloxane is uniformly dispersed in the polyurethane phase without forming agglomerated and unevenly distributed dispersion units. Using these two types of coatings, a Lee-White test (Clinical Test Method Summary-86, edited by Izumi Kanai and Masamitsu Kanai, published by Kanehara Publishing) was conducted to measure blood coagulation time. The time was 53 minutes for the blend and 120 minutes for the material of the present invention. Example 2 A polyether polyurethane urea was prepared using polyethylene glycol (average molecular weight 650) and 4,4'-diphenylmethane diisocyanate and propylene diamine as a chain extender. 100 parts by weight of this polyether polyurethane urea was dissolved in sufficiently dehydrated dimethylacetamide at room temperature with stirring to form a viscous solution with a polymer concentration of 9.0%. A mixture of dimethyldimethoxysilane, methyltrimethoxysilane, etc. was added to this solution in the proportions shown in Table 1 to obtain a homogeneous and transparent solution.
Table 1 summarizes the results of a lee-white test performed on a film formed by casting on a glass plate as in Example 1, and on a test piece.

[Table] No clusters of white dots are seen in the image.
PU stands for polyurethane.
Example 3 A 10% by weight dimethylacetamide solution of commercially available polyether polyurethane urea (Biomer, manufactured by Ethieon) was prepared and thoroughly dehydrated. Add diacetoxydimethylsilane/diacetoxydimethylsilane immediately after distillation to this solution.
Tetraacetoxysilane (10/10 parts by weight) was added to obtain a homogeneous solution. A coating was formed in the same manner as in Example 1, and the dispersion state and blood coagulation time were measured using the Lee-White test. Results showed that a uniform dispersion state and a blood coagulation time of 120 minutes or more were obtained.

[Brief explanation of the drawing]

1 to 4 are electron micrographs of Example 1. Figure 1 (comparative example) and Figure 2 (invention example)
3 (comparative example) and FIG. 4 (inventive example) are Si element characteristic X-ray images of surface analysis.

Claims (1)

[Claims] 1. An antithrombotic material in which, in a film composed of polyurethane and a silicon polymer, the silicon polymer is uniformly dispersed in the polyurethane phase without forming micron-order dispersion units that are unevenly distributed in the polyurethane phase.