JPS60168463A - Anti-thrombotic film forming solution composition - 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 The present invention relates to a solution composition prepared by dissolving polyurethane and a silicon-containing crosslinking agent for forming an excellent antithrombotic film.

Conventionally, polydialkylsiloxane-polyurethane has been used as an antithrombotic substance based on polydialkylsiloxane-polyurethane. Rock copolymers are known (Japanese Patent Publication No. 49-29350, Japanese Patent Publication No. 55-8177), and the former is a block copolymer in which blocks of polyurethane pro, ri and polydialkylsiloxane are bonded through silicon-nitrogen bonds. is proposed. On the other hand, antithrombotic properties are exhibited when the blood-contacting surface coated with polydimethylsiloxane-polyurethane block copolymer exhibits a micro-heterogeneous structure in which particles with a diameter of 0.1 to 3μ are almost uniformly dispersed. It is argued that the polymer material is preferably a block copolymer in order to have such a micro-heterogeneous structure. It is also said that the above block copolymers exhibit far superior antithrombotic properties than polydimethylsiloxane or polyurethane homopolymers.

All of these previously known antithrombotic materials are made from polyurethane polymers or polysiloxane polymers as starting materials. That is, in antithrombotic materials made from known blends, the starting materials polyurethane and polysiloxane are each provided as polymers, while in the case of copolymers, even random copolymerization Furthermore, even if the copolymer is a block copolymer or a graft copolymer, the block units constituting the copolymer are polymers each having a high molecular weight.

While searching for an antithrombotic material based on polyurethane and a silicon-containing polymer, the present inventor discovered an innovative method for producing an antithrombotic material using a method completely different from conventionally known techniques, and completed the present invention.

The present invention provides a new method for producing an antithrombotic material in which polyurethane and a crosslinked silicon-containing polymer form an interpenetrating network structure, and the method for producing this material is a unique and novel method found in known techniques. The inventors have also found that the material produced by this method exhibits excellent antithrombotic properties.

That is, the present invention provides a solution composition for forming an antithrombotic film, in which the silicon-containing crosslinking agent is dissolved in a soluble solvent at a ratio of 0.1 to 200 parts by weight to 100 parts by weight of Polytavituff. It is something to do.

In the solution composition of the present invention, the urethane and the low-molecular silicon-containing cross-linking agent are completely compatible, and therefore the composition is a mixed solvent system consisting of the solvent used for solution formation and the silicon-containing cross-linking agent. It can also be considered as a solution composition in which jl' IJ urethane is dissolved.

In the present invention, it is preferable to dehydrate the system to an anhydrous state as much as possible, and when using a silicon-containing cross-linking agent that is activated by water, the silicon-containing cross-linking agent is inactive as long as it is kept anhydrous. condition and is extremely stable over time.

When this solution is used to form a film, as the solvent evaporates, the silicon-containing cross-linking agent with a high boiling point remains in the film, and the amount of solvent decreases due to evaporation. The cross-linking agent forms independent micro- and black-domains, absorbs moisture in the air, activates the functional groups in the cross-linking agent, causes a mutual condensation reaction, and finally the cross-linking agent
Converted to resiloxane. The polysiloxane produced in this manner constitutes microdomains, and of course polyurethane molecules are entangled therein to form an interpenetrating network structure.

The polyurethane used in the present invention is not particularly limited, and polyester polyurethanes and polyether polyurethanes obtained by conventional methods can be used. In addition, polyurethane urea using diamine as a chain extender, polyurethane and polyurethane urea containing an organosilicon polymer in the main chain (for example, JP-A-56-136565, JP-A-57
-211359) can also be used. Particularly preferred are polyether polyurethanes and preether polyurethane ureas whose soft segments are polyalkylene glycols such as polyethylene glycol, polypropylene glycol or polytetramethylene glycol. When using the polyurethane, it is preferable to remove impurities from the polyurethane or the raw materials for the polyurethane in order to improve antithrombotic properties.

The silicon-containing crosslinking agent used in the present invention is used as a crosslinking agent for silicone resin and silicone resin, and so-called room temperature crosslinking agents and silane cassilling agents are preferred. There are no particular restrictions5) as long as it can be converted into a polymer having a polysiloxane structure through crosslinking or condensation reactions. Particularly preferred are functional groups activated by water, such as =SiO-COR, 281-OR (R is CH
5゜Hydrocarbon groups such as C2H5, C3H7), Mi5i-
OX (X is Halodan such as CL, Br), Mi5t
-NR2 (R is the same as above) and the like. These silicon-containing crosslinking agents are not necessarily limited to the use of one type, but can be used in a mixture of two or more types. Furthermore, two or more types of silicon-containing crosslinking agents having different functional groups can also be used.

As the silicon-containing crosslinking agent, for example, general formula (1), OI
) and (2) Compounds (1) ω) (wherein R1 is a hydrocarbon group, Y, Y', Y〃and Y〃 represent crosslinkable functional groups activated by the same or different types of water. ), R/nYs-1-8t -0-8l -'RnYI5-
m IQ (in the formula, R' is the same or different hydrocarbon group, Y and Y' (6) are the same as above, and m are 0, 1, 2, 3, n + m = -
(representing an integer of 0, 1, 2, or 3) are mentioned as water-activated crosslinking agents.

A compound represented by the general formula (1), Q[) (wherein R1 is a hydrocarbon group such as an alkyl group, an allyl group, an alkenyl group, an aryl group, an arylalkyl group, Y, Y
', Y'', Y''' is preferably an alkoxy group, acyloxy group, halooxy group, hexagonal group, or amine residue)
Specific examples include tetraacetoxysilane, methyltriacetoxysilane, ethyltriacetoxysilane, propyltriacetoxysilane, ethyltriacetoxysilane, phenyltriacetoxysilane, methyltriethoxysilane, ethyltriethoxysilane,
natho2ethoxysilane, phenyltriethoxysilane,
Propyltriethoxysilane, butyltriethoxysilane, butyltriethoxysilane, dimethoxysilane, ethyltrimethoxysilane, globiltrimethoxysilane, butyltrimethoxysilane or tetrachlorosilane, methyltrichlorosilane, ethyltrichlorosilane, butyltrichlorosilane, Vinyltriacetoxysilane, bis-(N-methylbenzylamide)ethoxymethylsilane, tris-(dimethylamino)methylsilane, tris-(cyclohexyl ai))methylsilane,
vinyltrichlorosilane, vinyltriethoxysilane,
Typical examples include γ-glycidoxypropyltrimethoxysilane and tetraacetoxysilane. Further, representative examples of the silicon-containing crosslinking agent represented by the general formula (g) above include, for example, tetraacetoxydisiloxane, 1,3-tmethyltetraacetoxydisiloxane, 1,3-divinyltetraethoxydisiloxane, l. .

Examples include 3.5-triethoxy-1,1,3,5,5-pentamethyltrisiloxane and 1,1,3,3,5,5-hexaacetoxy-1,5-methyltrisiloxane.

The present invention uses a silicon-containing crosslinking agent that is activated by water and converted into a polymer having a crosslinked and condensed polysiloxane structure, and a difunctional silicon-containing agent that is activated by water and is represented by the general formula (F). R2R4 of the compound (wherein R1 to R4 are the same or different hydrocarbon groups, n is 0
, 1, 2.3, etc.; Y and Y' each represent the above-mentioned cross-linkable functional groups activated by the same or different types of water). The properties can be further improved.

Examples of silicon-containing compounds containing two non-crosslinkable hydrocarbon groups on a silicon atom and two crosslinkable functional groups in the molecule are dimethyldimethoxysilane, diethyldiacetoxysilane, and dimethyl. Dimethoxysilane, dimethyldimethoxysilane, zoethylnoethoxysilane,
Soethylsomethoxysilane, methylethyldimethoxysilane, dimethylsochlorosilane, methylphenyldiacetate (9) Toxysilane, diphenyldiacetoxysilane, sopenzylnoacetoxysilane, zovinyldiethoxysilane,
1,1,3.3-tetramethyl-1,3-diacetoxysilane, 1,1,3.3-tetramethyl-1°3-dimethoxysilane, 1,1,3.3-tetraethyl-1,3
-jethoxysilane, 1,1,3,3,5.5-hexamethyl-1,5-diacetoxysilane, 1,1,3.3
゜5.5-Hexaethyl-1,5-jethoxysilane,
1 #1 e 3 p 3.5 * 5-hexamethyl-1,5somethoxylin, 1,1,1,5,5.5-
Hexamethyl-3,3-diacetoxysilane, 1.1,
Examples include 1,3,5,5-hexamethyl-3,5-diacetoxysilane.

The silicon-containing crosslinking agent and silicon-containing compound used in the present invention are not limited to the exemplified compounds.
, Register &R@view Or 197
9) and the company's Silicones (5llioonea◎, 1
A compound satisfying the above requirements can be selected from the compounds described in, eg, 981).

(10) The solution composition of the present invention can be obtained by dissolving polyurethane, a silicon-containing crosslinking agent, and further a silicon-containing compound in a solvent.

The solvent used in the present invention is a cyclic ether that dissolves polyurethane, or an organic polar solvent such as dimethylformamide, dimethylacetamide, or dimethyl sulfoxide. It is desirable that the boiling point is low, and the boiling point is preferably 160°C or lower, more preferably 110°C or lower. Further, it is desirable to use a water-soluble solvent because it can be easily removed by washing with water.

Therefore, preferred cyclic ethers include tetrahydrofuran and dioxane.

In the present invention, solvents can be used alone or in combination. It is most preferred to use a mixture of tetrahydrofuran and dioxane because it provides excellent antithrombotic properties and is easy to apply and remove. The weight ratio of dioxane/tetrahydrofuran is preferably 1 or less, more preferably 1/1 to 1/4, more preferably ], / 1
．． It is 5 to 1/3°0. When it is larger than 1, the solubility of polyurethane decreases, and when it is smaller than 1/4, it becomes difficult to control the evaporation rate of tetrahydrofuran (low boiling point), and it becomes difficult to set conditions to obtain a preferable surface. The excellent antithrombotic properties when the dioxane/tetrahydrofuran mixing ratio is in this range are due to the fact that solvents in this range have excellent antithrombotic properties.
This seems to be due to the subtle effects of evaporation rate and surface formation.

The ethers may also contain small amounts of other solvents, such as alcohol, acetone, dimethylpolamide, etc., as long as they do not significantly affect the practice of the present invention.

The mixing ratio of polyurethane and silicon-containing crosslinking agent can be varied widely. That is, the amount of the silicon-containing crosslinking agent in the mixture can range from 0.1 to 200 parts by weight, preferably from 1.0 to 180 parts by weight, and more preferably from 1.5 to 160 parts by weight, based on 100 parts by weight of polyurethane. parts, more preferably 2 parts
．． 0-150 parts by weight, more preferably 20-120 parts.

If the amount of silicon-containing crosslinking agent is less than 0.1 part by weight based on 100 parts by weight of polyurethane, no difference is observed compared to polyurethane alone, and if the amount of silicon-containing crosslinking agent exceeds 200 parts by weight, the film will deteriorate. Mechanical performance is poor and undesirable.

Further, when a silicon-containing crosslinking agent and a bifunctional silicon-containing compound are used together, the weight ratio of the bifunctional silicon-containing compound/silicon-containing crosslinking agent is in the range of 9515 to 5/95, preferably 90.
/10 to 10/90.

If this ratio exceeds 9515, the silicon-containing compound is not sufficiently cross-linked and condensed after coating with this solution composition and remains in a liquid state, which may come off from the coating surface by washing with water, resulting in inconvenience. The ratio with Mata is 5/95
When the amount is less than that, the hydrophobicity of the silicon polymer decreases, which may cause variations in antithrombotic properties.

The polyurethane concentration in the polyurethane solution in which the silicon-containing crosslinking agent used in the present invention is dissolved is 1 to 50% by weight, preferably 3 to 40% by weight, more preferably 5 to 3% by weight.
0% by weight, more preferably 8(13) to 20% by weight. (This range) When the polyurethane concentration is low, the viscosity is too low, leading to problems such as an increase in the number of coatings during film formation and an extremely thin film.If it exceeds this range, the viscosity is too high, making it difficult to adjust the film thickness. The thickness of the coating film becomes uneven.

The solution composition of the present invention is prepared by dissolving each component in a solvent, but it is preferable to first dissolve the polyurethane in the solvent and then add the silicon-containing crosslinking agent and the bifunctional silicon-containing compound. In this case, it is preferable to dehydrate the solvent as much as possible in order to keep the solution composition stable for a long period of time. However, it is also possible to add a predetermined amount of water to the above solution to allow a certain degree of condensation reaction to proceed within the solution and to entangle the polyurethane molecules in the solution to form an appropriate interpenetrating network structure in the solution.

By applying the solution composition of the present invention to the blood-contacting surface of a blood-contacting medical device using a known film-forming method such as coating or dipping, an antithrombotic film is formed on the surface.

At that time, the silicon-containing crosslinking agent is activated during film formation to cause condensation (1
4) Moisture is essential for the crosslinking reaction to proceed, and normally moisture in the air is sufficient, but the reaction may be accelerated by forcibly replenishing moisture, such as by spraying water onto the surface of the coating. You can also do it. To allow the reaction to proceed sufficiently, the temperature should be between room temperature and 100°C.
It usually takes 1 hour to 1 month at a temperature of °C.

The film thus formed has excellent antithrombotic properties as well as toughness and excellent elasticity, so the solution composition of the present invention can be used in devices that come into contact with constantly pulsating blood, such as in artificial hearts and intra-aortic balloon pumps. Although it is particularly suitable for forming blood contacting parts of other blood contacting medical devices where antithrombotic properties are required.

The present invention will be specifically explained below using Examples.

Example 1 Polytetramethylene ether glycol (average molecular weight 2
000) and 4,4'-diphenylmethane diisocyanate as a chain extender! 100 parts by weight of zle ether polyurethane produced by a known method using tandiol was added to dimethylformamide/tetrahydrofuran mixed solvent (weight mixing ratio 1/2) which had been dehydrated to a water content of 10 ppm or less at 35°C and stirred. A viscous solution (polymer concentration 10% by weight) was prepared. This solution finally contained 13.5 ppm water.

To this solution, add 1,4,8°20.5 of methyltriacekidisilane to 100 parts by weight of polyurethane immediately after distillation.
Nine types of solutions were prepared by adding 0, 75, 100, 140, and 180 parts by weight, respectively. Each of these solutions was diluted with 1-(1
), 1-(2), . . . 1-(9).

All of these solutions were colorless and transparent, and remained stable even after storage for 6 months.

Regarding the films formed on glass plates from these solutions, the films formed from solutions 1-(1) and 1-(2) are almost colorless and transparent, and the films formed from solutions 1-(3) are almost transparent. has a slightly opalescent color, and the degree of whitening increases as the content of methyltriacetoxysilane in the solution increases.

When these surfaces were observed using a scanning electron microscope, they were found to be extremely smooth.

Using these films, a Lee-white test (Clinical Test Method Summary, V-86, edited by Izumi Kanai and Masamitsu Kanai, published by Kanehara Publishing) was conducted to measure blood coagulation time. The results are shown in Table 1. For reference, the results for glass, silicone-treated glass (coated with polydimethylsiloxane), and polyurethane of this example are also listed. The test film was prepared by coating a glass watch glass with each of the solutions described above and leaving it for 10 days or more in a 654RHO atmosphere at room temperature to sufficiently crosslink the methyltriacetoxysilane before testing.

(17) Table 1 As shown in Table 1, the results of the Lee-white test revealed that solution 1-
It was found that when (7) to (9) were used, blood did not coagulate for approximately 200 minutes or more, demonstrating revolutionary performance beyond conventional wisdom.

Example 2 A polyether polyurethane was prepared using polyethylene glycol (average molecular weight 1600) tomethylenebis(4-phenylisocyanate) and butanediol as a chain extender. This polyether polyurethane 1o
o parts by weight were dissolved in sufficiently dehydrated dioxane/tetrahydrofuran (weight ratio V3) at room temperature with stirring to form a viscous solution with a polymer concentration of 9.0%. Methyltrimethoxysilane and methyltriethoxysilane were added to this solution in the proportions shown in the table below to obtain a homogeneous and transparent solution.

Table 2 summarizes the results of a film formed by casting on a glass plate and a lee-white test applied to a test tube in the same manner as in Example 1.

Example 3 Triacetoxysilane and tetraacetoxysilane were added to the same polyurethane solution as in Example 1 in the amounts listed in Table 3 (parts by weight per 100 parts by weight of polyurethane) to obtain six types of solutions. A Lee-white test was conducted using films formed from these solutions. The results are also listed in Table 3.

Third Cost (21) Example 4 Polyethylene glycol (average molecular weight: 11,200) and 4.
Dioxane/tetrahydrofuran mixed solvent (weight mixing ratio 1/ 2) at 35° C. with stirring to prepare a viscous solution (polymer concentration 10% by weight). This solution finally contained 11.5 ppm water.

Add to this solution a dimethyldiacetoxysilane/methyltriacekidisilane mixture (mixing ratio 90/10, 7
0/30, 50150, 20/80, 5/95) at 1.4.8.14.20 per 100 parts by weight of polyurethane.
A coating solution was prepared by adding 40, 80, 120, and 180 parts by weight, respectively.

These solutions were 4-(1), 4-(2),..., respectively.
4-(9).

All of these solutions are colorless and transparent, and have a concentration of 6 (22) It remained stable even after storage for several months.

Regarding the films formed on glass plates from these solutions, the films formed from solutions 4-(1) and 4-(2) were almost colorless and transparent, and the films formed from solution 4-(3) were has a slightly opalescent color, and as the content of the silicon-containing crosslinking agent in the solution increases, the amount of whitening dust increases.

When these surfaces were observed using a scanning electron microscope, they were found to be extremely smooth.

A Lee-white test was conducted using these films to measure blood coagulation time. The results are shown in Table 1. For reference, the results for glass, silicone-treated glass (coated with polydimethylsiloxane), and polyurethane of this example are also listed. The test film was prepared by coating a glass watch glass with each of the above solutions and leaving it for 10 days or more in an atmosphere of room temperature and 65% RH to sufficiently crosslink dimethyldiacetoxysilane and methyltriacetoxysilane. Tested.

As shown in Table 4, the results of the Leewhite test revealed that solution 4-
When (7) to (9) were used, blood did not coagulate for more than 200 minutes, demonstrating revolutionary performance beyond conventional wisdom.

Example 5 A 10% by weight dimethylacetamide solution of commercially available polyether polyurethane (Biomar, manufactured by Ethicon) was prepared and thoroughly dehydrated. Immediately after distillation, purified nomethoxydimethylsilane, tetramethoxysilane, and tetraethoxysilane were added to this solution in the amounts listed in Table 5 to obtain eight types of solutions. A Lee-white test was conducted using films formed from these solutions. The results are also listed in Table 5.

Table 5 (26)

Claims (2)

[Claims] (1) A solution composition for forming an antithrombotic film, characterized in that the silicon-containing crosslinking agent is dissolved in a soluble solvent at a ratio of 0.1 to 200 parts by weight to 100 parts by weight of polyurethane. thing. (2) The solution composition according to claim (1), which uses a silicon-containing crosslinking agent and a bifunctional silicon-containing compound activated by water.