JPS60238315A - Antithrombotic polyurethane or polyurethane urea, its preparation, and medical supply contacting with blood - Google Patents

Abstract

PURPOSE:To obtain the titled polymer exhibiting stable antithrombotic property, formable by various forming methods, and useful for artificial heart, etc., by reacting a specific siloxane or a mixture of siloxane and a polyether with a diisocyanate compound and a chain extender. CONSTITUTION:The objective polyurethane or polyurethane urea can be produced by using the polysiloxane block of formula (R and R' are bivalent aliphatic hydrocarbon group; R'' and R''' are substituent group; m is integer of >=2; n is integer of >=1) as a soft segment, and reacting the block with a polyether, a diisocyanate compound (e.g. 4, 4'-diphenylmethane diisocyanate, etc.) and a chain extender (e.g. ethylene glycol). the polymer is preferably used to at least the contacting part of medical supplies contacting with blood.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel antithrombotic polyurethane or polyurethane urea having excellent antithrombotic properties and favorable mechanical properties, more specifically to a polysiloxane block and an I-reather block. Polyurethane or polyurethane urea having a soft segment bonded via a -8t-R-bond (R represents a divalent aliphatic hydrocarbon group), a method for producing the same, and a blood contacting part made of these elastomers This relates to blood-contact medical devices.

(Prior Art and Problems to be Solved by the Invention) Conventionally, antithrombotic elastomers include general-purpose polymeric materials such as soft vinyl chloride, polyurethane, and silicone rubber surfaces, and segmented polyurethanes (for example, Eth
Heparinized urethane elastomer (Japanese Patent Publication No. 55-13729), a block copolymer in which polysiloxane and polyurethane are directly bonded with nitrogen and silicon (US Pat. No. 3,562,352) were developed. ing.

However, these conventional general-purpose polymeric materials are still insufficient to meet a wide range of required performance; for example, segmented polyurethane has strong mechanical strength but poor antithrombotic properties, and heparinized urethane elastomer has short-term Heparin is released and the antithrombotic properties tend to be extremely reduced after the heparin is released. Since bioactive heno-4-phosphorus is used, molding and sterilization are complicated and the cost is high. In addition, the block copolymer (trade name: Cardiosan: formerly known as Abcosan), in which polysiloxane and polyurethane are directly bonded with nitrogen and silicon, described in U.S. Patent No. 3,562,352, is one of the currently available materials. It has excellent antithrombotic properties and has many clinical cases.

However, this copolymer uses a manufacturing method in which pre-synthesized polyurethane and polysiloxane with reactive end groups are mixed in a solution state and reacted during molding, so the expression of antithrombotic properties varies depending on the molding conditions. Strict process control is required to create a blood contacting surface that varies in width and provides consistent and excellent antithrombotic properties.

Furthermore, Kira et al. claim that polyurethane or polyurethane having an organosilicon polymer represented by the general formula (1) as a soft segment in the main chain has antithrombotic properties and excellent mechanical properties (3rd Bio (Presentation at a medical conference) is (in the formula, a, b, and c represent integers) The soft segment is polyether + cH2-CH2-o
->.

The block and the polysiloxane block ÷51(CH3)2-enzyme are bonded via a 5l-0-C bond, and this Si-0-C bond is easily and sensitively formed by contact with water. cleaved in response to s
It decomposes into t-o-cμ 5i-OI (+HO-C-). This reaction is extremely sensitive and even reacts with moisture in the air, so this elastomer is extremely unstable and cannot be used in contact with blood. When medical devices come into contact with blood during treatment, the above-mentioned decomposition reaction progresses, and the decomposition products diffuse into the blood, potentially causing adverse effects on patients, causing undesirable phenomena and There are many problems, such as structural changes on the antithrombotic surface due to decomposition.

(Means for Solving the Problems) The present inventors have worked hard to improve these drawbacks and provide an antithrombotic elastomer that stably exhibits excellent antithrombotic properties and can be applied to a wide range of molding methods. As a result of our investigation, we found that polyurethane or J
The present invention was achieved by discovering that polyurethane urea has excellent antithrombotic properties, favorable mechanical properties, and excellent stability.

That is, the present invention provides the above-mentioned antithrombotic yj? The present invention provides a polyurethane or polyurethaneurea and a method for producing the same, as well as a blood-contacting medical device in which the blood-contacting part of the blood-contacting medical device is composed of a polymer containing at least the above-mentioned antithrombotic polyurethane or polyurethaneurea.

The antithrombotic polyurethane or polyurethane urea of the present invention is preferably used in the production of various blood contact medical devices, artificial organs such as intra-aortic balloon pumps, and artificial hearts by taking advantage of its antithrombotic properties, mechanical strength, elasticity, and durability. be done. Specifically, vascular catheters, blood bags, monitoring tubes, extracorporeal blood circulation circuits such as artificial kidneys and heart-lung machines, A-V shafts, blood bypass tubes, artificial hearts, auxiliary artificial hearts, blood pumps, and balloon pumps. Used for blood contact surfaces such as

In the polyurethane or polyurethane urea of the present invention, the content of polysiloxane block is 1 to 50% by weight,
Furthermore, it is preferable that the amount is 2 to 30% by weight, particularly 3 to 20% by weight from the viewpoint of antithrombotic properties. If the content of the block exceeds 50% by weight, the antithrombotic properties tend to decrease and the mechanical properties tend to deteriorate. The molecular weight of the polysiloxane is 200 or more, preferably 400 to 30,00
0. Particularly preferably, it is 500 to 10,000, more preferably 800 to 6,000. Although the type of polysiloxane is not particularly limited, polydimethylsiloxane is preferred in order to exhibit antithrombotic properties, and other examples include methylphenylpolysiloxane and fluoroalkylmethylpolysiloxane.

The soft segment in the polyurethane or polyurethane urea of the present invention includes cases in which a segment represented by the following general formula (1) and a polyether segment are contained in the same molecular chain, and cases in which only a segment represented by general formula (1) is contained. There is.

R and R′ in the formula may be the same or different, and represent a divalent aliphatic hydrocarbon group, R〃 and R# represent a substituent, and m represents 2
n represents an integer of 1 or more, and n represents an integer of 1 or more. R
If R and R' are the same, the segment may tend to crystallize and become poorly soluble in the solvent; however, it is preferable that R and R' are different because they have better solubility.

The method for producing the elastomer of the present invention having the above-mentioned soft segment in its molecular chain will be described below, but the elastomer synthesis reaction itself can be applied to a conventional method for producing polyurethane.

In order to form a polysiloxane block having the structure of general formula (1), for example, a polysiloxane component having a structure in which the terminal silicon is represented by 1'' at R is used.

The substituents R〃 and R11 in the formula may be the same or different and include a methyl group, a phenyl group, a fluoroalkyl group, etc., but it is particularly preferable that both R〃 and R'' are methyl groups. R' may be the same or different, and may be a divalent aliphatic hydrocarbon group and may be linear or branched.As mentioned above, it is preferable that R and R' are different. .

Specifically, R and R' are -CH2-1-CH2C
H2-1 The method for producing the polysiloxane represented by the general formula (2) is not particularly limited.
It is obtained by the method disclosed in Publication No. 0, that is, by reacting the reaction product of an olefinic alcohol with an I-ether diol or a low-molecular diol and the terminal with R〃R''.

In general formula (2), when n is 1, an olefinic alcohol, for example, a reaction product of allyl alcohol and ethylene glycol, allyl alcohol and propylene glycol, and a terminal R〃 R'' can be obtained. When n is 2 or more, In some cases, polyethylene ether glycol, polypropylene ether glycol, polytetramethylene ether glycol, undumco I remer diol of ethylene oxide and propylene oxide, and block copolymer diols (A-B type, A-B-A type, etc.) diols are used. Ether diols are used.

These diols are used to form the segments of general formula (1) as well as polyether segments as independent soft segments. The molecular weight of these diols is 200 to 6,000, preferably 40
0 to 3,000.

In both cases where n is 1 and 2 or more, the molecular weight of the polysiloxane represented by general formula (2) is 200 or more, preferably 400 to 30,000, more preferably 500 to 10.
,000, particularly preferably 800 to 6,000.

4 Polyurethane or polyurethane urea having a soft segment represented by general formula (1) in the molecular chain can be obtained by reacting the aforementioned polysiloxane represented by formula (2) containing a terminal active hydrogen group with a diisocyanate. It is obtained by polymerizing a prepolymer with a known chain extender. In this case, the polyurethane or polyurethane urea has only the block copolymer segment represented by the general formula (1) as a soft segment.

Alternatively, the polysiloxane represented by the formula (2) and the polyether diol may be reacted with a diisocyanate to obtain a prepolymer, and the prepolymer may be chain-extended using a known diol or diamine. In this case, the soft segment of the obtained polyurethane or polyurethane urea is formed by the copolymer block represented by the general formula (1) and the polyether part used in the reaction.

Although the reaction can be carried out in the presence or absence of a solvent, it is preferably carried out in the presence of a solvent to minimize crosslinking and branching reactions.

Examples of preferred solvents include dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dioxane, N-methylpyrrolidone, cyclohexanone, and mixed solvents mainly containing these.

In carrying out the reaction, first, the ratio of the polysiloxane represented by the above formula (2) and 4-riether diol is determined, and the amounts of both components to be used are determined. Using a nail, add and dissolve both components and the required amount of diisocyanate compound and chain extender in the solvent to carry out the reaction.

Each component may be added all at once, but a prepolymer having terminal incyanate groups is prepared in advance by reacting either the polysiloxane or the diol with a diisocyanate compound, and the prepolymer is added together with the other components. Alternatively, a method may be used in which a prepolymer of the polysiloxane and the diol are prepared separately and then added. In addition, when using a chain extender, a portion of a predetermined amount is first reacted with a separately prepared prepolymer to form a chain of the same type of segment, and then these are mixed and the remainder of the chain extender is used. The reaction may be completed by

Furthermore, it is desirable to add highly reactive components slowly and continuously, such as polysiloxane and aliphatic diamines, which will be described later as chain extenders. When soft segment components are reacted all at once, it is easy to generate soft segments in which soft segments are randomly distributed within the same molecular chain. Polyurethane or polyurethane urea in which soft segments are unevenly present is likely to be produced.

The reaction is carried out by heating or using a catalyst, and all catalysts used for urethane synthesis can be used.
Considering that the manufactured elastomer can be used for medical purposes, it is preferable to use amines such as lyethylenediamine or diazabicycloundecene that can be removed during molding.

As the diisocyanate compound used, all diisocyanates conventionally used in the production of polyurethane can be used. Specific examples include tetramethylene diisocyanate, hexamethylene diisocyanate, cyclohexane-1,4-diisocyanate, 2.4-)lylene diisocyanate, 2.6-lylene diisocyanate,
2.4-) lylene diisocyanate and 2.6-) mixture of lylene diisocyanate, xylylene diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, 4,4'-diphenylmethane diincyane), 1,4-phenylene diisocyanate isocyanate), 1,3-phenylene diincyanate, naphthalene-1,5-diincyanate, etc., which may be used alone or as a mixture.

As the chain extender, a chain extender having a difunctional active hydrogen group, such as ethylene diamine, propylene diamine,
Aliphatic diamines such as butylene diamine and hexamethylene diamine; alicyclic and aliphatic acid diamines such as cyclohexane diamine, piperazine and xylene diamine; aromatic diamines such as tolylene diamine, phenylene diamine and diphenylmethane diamine; Suitable are hydrazines, glycols such as ethylene glycol and 1,4-butanediol, and water.

The nidystomer of the present invention produced in this manner can be used as it is in the reaction solution, or the nidystomer can be separated from the reaction solution, thoroughly purified, dried in a drying oven, and isolated in a solid state. .

Furthermore, the nidistomer 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 a conventional molding method for thermoplastic synthetic resins, such as extrusion molding, injection molding, calendering, etc. can.

In addition, this elastomer is extremely stable when stored not only in a dry pellet state but also in a solution state, and its molecules do not disintegrate at all due to the influence of moisture, making it easy to handle, reproducible, and antithrombotic. It has excellent properties as a sexual elastomer.

The mechanical properties required for an antithrombotic nidistomer are generally a tensile strength of 100 kgΔ or more and an elongation of 300 to 5.
Although it is said that the elastomer has a tensile strength of 1iI/cIIL2 of 100 to 500 and an elongation of 500 or more, it has excellent mechanical properties.

Therefore, the blood-contacting medical device of the present invention in which the blood-contacting portion is made of the elastomer of the present invention can also be used as a medical device that requires durability, such as an artificial heart that is subjected to repeated deformation.

The blood-contacting medical device of the present invention may be constructed entirely of the uninvented elastomer, or only the blood-contacting portion of the device may be constructed of the inventive elastomer. In addition, the elastomer of the present invention may be used alone, or may be used in combination with other polymers that can be used as medical materials.
For example, it may be used in combination with polyether type polyurethane or polyurethane urea. The mixing ratio can also be changed depending on the required performance of the intended medical device, and is not particularly limited. The manufacturing method of the medical device itself is not particularly limited and may be a commonly used method, such as a method of forming a film of the nidistomer of the present invention on the blood contacting part of a preformed blood contacting medical device by coating, dipping, etc., or extrusion. A method of directly forming the material into a tube shape using a machine or the like is used.

Specific examples of the blood contact medical devices of the present invention 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, catheters, etc. However, it is not limited to these.

The present invention will be specifically explained below using examples.

Example 1 54.7 parts of silicon-terminated lydimethylsiloxane (molecule ft2400.yff lysiloxane block: I ether block = 1:2) was placed in a container thoroughly dried in a nitrogen stream, and the mixture was heated to 0 at 90°C. The sample was dehydrated for 6 hours under reduced pressure of .1 mmHg or less. Next, the temperature was adjusted to 50 DEG C., and 250 parts of dioxane dehydrated and purified to reduce water content to 5 ppm or less were added thereto, followed by 27.3 parts of 4,4'-diphenylmethane diincyanate, which was stirred and dissolved.

As a catalyst, 0.05% diazobicycloundecene was added to 4,4'-diphenylmethane diisocyanate, and the mixture was reacted for 2 hours with stirring. Next, ethylene glycol was added to carry out a chain extension reaction using a conventional method. The reaction was carried out for 3 hours after the dropwise addition of the chain extender ethylene glycol, ethanol was added to the reaction product, and when it became cloudy, the addition of ethanol was stopped and the mixture was left overnight to precipitate the polymer, followed by further addition of ethanol. The mixture was stirred to precipitate the polymer into a powder. This polymer was thoroughly washed with ethanol and dried.

This purified polymer was dissolved in a 1:1 mixed solvent of tetrahydrofuran and dioxane (concentration: 5% by weight) and cast onto a glass plate to form a film.

This film was colorless and transparent, and when observed under an optical microscope and a scanning electron microscope, it was extremely smooth and uneven.

This film was also subjected to a tensile test to determine its tensile strength and elongation at break.

Antithrombotic properties were measured using a test tube (inner diameter 10 m, length 100 m) coated twice with the above polymer solution and having a film formed by sufficiently evaporating the solvent1. Izumi, Masamitsu Kanai (ed.), Clinical Test Methods Summary, Vl-81, Kanehara Publishing Co., Ltd., 1971), the blood coagulation time was measured. The above results are shown in Table 1. As a comparative example, commercially available polyurethanes (Biomer, manufactured by Ethicon, Cardiosan 51, Cardlothare, manufactured by Kortron, etc.) were used as comparative examples.
51) was used.

Table 1 Example 2 Polydimethylsiloxane with silicon at both ends (molecule J
i2100. Polyurethane was synthesized and purified under the same conditions as in Example 1 except that polysiloxane block: polyethylene ether block = 1:2) was used. This polyurethane was dissolved in tetrahydrofuran/dioxane (1/1). The polyurethane of Example 1 was easily dissolved, but the polyurethane of this example was somewhat difficult to dissolve.

The Lee-White test and mechanical properties were measured in the same manner as in Example 1. Blood clotting time is 126 minutes, tensile strength is 0.6
9 kgf/++m'', elongation was 63 (l).

Example 3 57.2 parts of polydimethylsiloxane having the same structure as Example 1 (molecular weight 100, polysiloxane block: polyether block = 1:2) and 27.9 parts of 4.4'-diphenylmethane diincyanate were mixed with 200 parts of dioxane. 0.05 g of diazabicycloundecene of Satsuma incyanate was added and reacted at room temperature to produce a sol polymer. A solution prepared by dissolving 5 parts of ethylenediamine in 7,100 parts of dioxa and 100 parts of dimethylacetamide was added dropwise to this reaction solution to effect chain extension, thereby synthesizing polyurethane urea.

After the reaction was completed, methanol was added to precipitate the polymer, which was dissolved in a 7/3 mixed solvent of dioxane/dimethylacetamide, and methanol was added thereto for purification by reprecipitation.

Using this elastomer, a Leawhite test was conducted in the same manner as in Example 1, and the test time was 120 minutes, and the mechanical properties were extremely excellent, with a tensile strength of 0.59 kgf 71 m'' and an elongation of 620 inches. Add this sample to 37℃ water for 1 hour.
The same test was conducted after being in contact for a week, but there was no change in the values.

Comparative Example 1 109.4 parts of polytetramethylene ether glycol (molecular weight 2000) was dehydrated for 30 minutes at 90° C. under reduced pressure of 0.1 mHg or less. Next, after adjusting the temperature to 50°C, 500 parts of dehydrated and purified dioxane was added thereto, and after dissolving polytetramethylene ether glycol, 54.6 parts of 4.4'-diphenylmethane diincyanate and as a catalyst Diazobicycloundecene was added and stirred for 2 hours. Next, after adding 9.5 parts of ethylene glycol, 164 parts of the following terminal carbinol polydimethylsiloxane (molecular weight: about 2400) dissolved in 300 parts of dioxane was gradually added dropwise to carry out a reaction. The polymer was purified according to the method of Example 1.

(m+n):p=0.68:0.32 (value by H'NMR) In order to check the stability of the elastomer according to Comparative Example 1 and the elastomer according to Example 1.2, it was added to water at 33°C for 24 hours.
Changes in antithrombotic and mechanical properties were observed after 72 hours of contact and drying. The results are shown in Table 2.

As is clear from the results in Table 2, the Nidistomer of the present invention shows no decrease in antithrombotic properties or mechanical properties upon contact with water, and has stable quality. When a 5i-0-C bond is present, the mechanical properties are greatly reduced upon contact with water, and the antithrombotic properties are also significantly reduced.

Furthermore, we synthesized elastomers using polyethylene glycol, polypropylene glycol, and random copolymers of both in place of polytetramethylene glycol, and conducted the same tests as above. Both antithrombotic properties and mechanical properties significantly decreased over time.

Comparative Example 2 A polyurethane was synthesized in the same manner as in Comparative Example 1, except that terminal hydroxyethyloxysilane was used in place of the polydimethylsiloxane used in Comparative Example 1.

In order to check the stability of the elastomer according to Comparative Example 2 and the elastomer according to Examples 1 and 2.
The samples were kept in contact for 100 hours (corresponding to I [, I in the table below), and then dried to determine antithrombotic properties and changes in mechanical properties by the Sowhite method. The results are shown in Table 3.

Example 4 Polydimethylsiloxane represented by formula (2) (molecular weight 6
00, R=CH2CH2C) (2, R'=C)T2
-CH2, n=12) and polyethylene ether glycol having a molecular weight of 700, a mixture of 4.4
A prepolymer was prepared by reacting with '-diphenylmethane diisocyanate, and this was chain-extended using butanediol to prepare a polyurethane.

The solvent used in the reaction was dimethylacetamide. Polyurethane was purified by repeated reprecipitation using dimethylacetamide-ethanol system.

The Leewhite test result of this polyurethane was 105, which is extremely excellent, and the mechanical properties showed no deterioration at all after being in contact with water for one month, and the Leewhite test result also showed no deterioration. There wasn't.

Example 5 Polydimethylsiloxane used in Example 4 and molecular weight 5
00 polypropylene ether/'+7 units were reacted separately with 4,4'-diphenylmethane diisocyanate to give their respective prepolymers, which were then mixed and chain-extended with butanediol. The polyurethane produced by this method was tested in a white test in 110 minutes and was shown to have superior antithrombotic properties compared to conventional antithrombotic nidistomers.

Mechanical properties include tensile strength of 0.69 k, q r /w
a2, elongation was 620%, and these values did not change significantly after one month of contact with water (37°C).

Incidentally, as a result of conducting a Lee-white test on the sample after contact with water, virtually no decrease in antithrombotic properties was observed.

Example 6 When chain-extending the polydimethylsiloxane prepolymer (terminated incyanate) and polypropylene glycol prepolymer (terminated incyanate) used in Example 5 with butanediol, a predetermined amount was added before mixing these prepolymers. 20% of the chain extender (butanediol) is separately reacted with the prepolymer to extend the chain of the same type of segment in advance, and then the two components are mixed and the remaining chain extender (butanediol) is reacted with the prepolymer. The chain extension reaction was completed by adding a predetermined amount of 60%.

The polyurethane obtained in this example was dimethylacetamide-
The mixture was purified by reprecipitation using a methanol system (repeated 4 times).

When the thus obtained polyurethane paste was subjected to a white test, it was found to have outstanding antithrombotic properties in 130 minutes. Mechanical properties: Tensile strength: 0.72kg-j/Nn
2. It had an extremely good elongation of 630 inches.

When this polyurethane was brought into contact with water at 37° C. for 45 days and its antithrombotic properties and mechanical properties were measured, no significant decrease was observed and it was found to be extremely stable.

Patent applicant: Zeon Corporation

Claims (1)

[Claims] (In the formula, R and R' may be the same or different and represent a divalent aliphatic hydrocarbon group, Rs and R'' represent a substituent, m is an integer of 2 or more, and n is an integer of 2 or more. An antithrombotic polyurethane or polyurethane urea containing a polysiloxane block as a soft segment, each representing an integer of 1 or more. (In the formula, R and R' may be the same or different, and Hydrocarbon group, R# and R# are substituents, m is 2
n represents an integer of 1 or more, and n represents an integer of 1 or more. )
A method for producing an antithrombotic polyurethane or polyurethane urea, which comprises reacting a polysiloxane represented by #, or a polysiloxane and a polyether with a diisocyanate compound and a chain extender. (3) At least the blood-contacting part of the blood-contacting medical device (wherein R and R' may be the same or different and represent a divalent aliphatic hydrocarbon group, R1 and R#i fit substituent, m is 2
n represents an integer of 1 or more, and n represents an integer of 1 or more. 1. A blood contact medical device characterized in that it is formed of a polymer containing antithrombotic polyurethane or polyurethane urea containing a polysiloxane block shown in ) as a soft segment.