JP3239953B2 - Gas permeable material with excellent blood compatibility - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a heart-lung machine for maintaining blood circulation and oxygen supply in open heart surgery accompanying heart surgery, an artificial lung for substituting the lung function of a patient with lung failure, and an ECMO for long-term extracorporeal circulation. (Extra
Corporate Membrane Oxygen
ator) and the like.

[0002]

2. Description of the Related Art At present, a gas exchanger (a part for adding oxygen to blood and removing carbon dioxide to convert venous blood into arterial blood) of a commercially available artificial heart-lung machine used for open heart surgery is provided with the oxygenation. There are three main types according to the mechanism: (1) Gas-
Blood direct contact type (bubble type, film type, etc.); (2) type that exchanges gas through small holes (hundreds to several thousand angstroms in diameter) (hollow fiber type, laminated type, etc.);
(3) Gas diffusion type (type in which gas is dissolved and diffused in a homogeneous film and passes through the film).

[0003]

Among the above-mentioned prior arts, (1) is a method in which oxygen is directly bubbled and injected into venous blood.
It is a type that causes arterial blood. In this method, the blood and oxygen gas come into direct contact, thereby destroying the erythrocyte membrane and increasing free hemoglobin. That is, hemolysis is likely to occur. Further, since oxygen gas is directly blown, this gas remains as fine bubbles in blood. It is difficult to remove it and the blood is severely damaged. Therefore, it is difficult to substitute cardiopulmonary function for a long period of time.

In the type (2) in which gas is exchanged through small holes, there is no direct contact between blood and gas as in the type (1), so that blood cells are damaged and gas bubbles are mixed into blood. Such a problem is solved. However, since the water and plasma components in the blood exude through the small holes, the gas exchange ability decreases with time. Furthermore, the material of such a membrane is
Usually, such as polypropylene, which have poor blood compatibility. That is, when these materials are used, activation of blood coagulation factors and activation of complement occur, and further, aggregation and melting of platelets and white blood cells are liable to occur. In order to suppress these reactions, it is necessary to administer a large amount of an anticoagulant such as heparin. High doses of heparin can cause bleeding and can be life-threatening. As described above, it is impossible to use the gas exchanger of the type (2) for a long period of time due to frequent occurrence of organ failure due to bleeding or damage to blood cell components.

In the type (3), gas exchange is performed through a uniform membrane surface, so that there is no problem of damage to blood cells and mixing of gas bubbles into blood as in the type (1), and (2). There is no drawback of exudation of water and plasma components as in the type. This type of membrane is usually prepared with silicone rubber (silicone-based polymer). Silicone rubber is said to have relatively better blood compatibility than other materials. Thus, in the gas exchangers of the types (1) to (3), the type (3) is considered to be the most suitable. However, this film also has the following disadvantages. (A) Since silicone rubber alone has low strength, it is necessary to increase the film thickness or to fill a filler as a reinforcing agent to maintain strength. For this reason, the diffusion of the gas becomes slow and the oxygen exchange capacity is low.
(B) The blood compatibility of silicone rubber is not yet sufficient, and blood coagulation occurs. Therefore, large doses of heparin are required for use, and bleeding is likely to occur, which is life-threatening. Effect. (C) The activation of complement causes a change in the blood cell coagulation system,
Increased permeability (such as lymphocytes), increased white blood cells, etc. occur. As a result, fever and shock symptoms may be life-threatening, or post-operative recovery may be delayed. The usable period of the heart-lung machine having this type of gas exchanger is also at most a few days, and the rescue rate when the device is used for a longer period is close to zero.

As a material that can be used in place of the silicone rubber film of the above (3), for example, the following polymers have been studied. Examples of improving the strength of (a) include U.S. Pat. No. 3,419,634 and U.S. Pat.
No. 419,635 discloses the preparation of a silicone-polycarbonate copolymer. Further, U.S. Pat.
No. 7737 discloses a method for producing a thin film using the copolymer. JP-A-61-430 discloses a selective gas permeable membrane made of polyurea obtained by reacting a diaminopolysiloxane, an isocyanate compound and a polyvalent amine. Further, JP-A-60-241
No. 567 (Polymer Technology Research Group No .: PM-8
No. 0) discloses a gas selective permeable membrane made of polyurethaneurea obtained by reacting a diaminopolysiloxane, an isocyanate compound and a polyvalent hydroxy compound having a tertiary nitrogen. These polymers have relatively high strength but are not yet sufficiently blood compatible, and have not solved the problems (b) and (c). Further, the polymers described in JP-A-61-430 and JP-A-60-241567 have two kinds of bonds having completely different polarities, ie, a siloxane bond and a urea bond, in the molecule, so that the polymer is not suitable for film formation. Is difficult to select, and it is difficult to form a thin film.

[0007] Materials which can solve the blood coagulation problem described in the above (b) include Polymer Collection, 36, 223.
(1979) discloses that heparin is bound to a certain polymer by an ionic bond. The polymer used is dimethylaminoethyl methacrylate,
It is a polymer obtained by quaternizing the tertiary amino group of a terpolymer of methoxypolyethylene glycol methacrylate and glycidyl methacrylate, blending the resulting tertiary amino group with polyurethane, and crosslinking by heat treatment. A molded article obtained from this material causes heparin to be slowly released from its surface, thereby preventing blood coagulation. However, the gas permeability is not sufficient and cannot be used for heart-lung machine and the like. JP-A-58-188458 discloses an antithrombotic elastomer composed of polyurethane or polyurethaneurea containing a polysiloxane in the main chain. However, the antithrombotic properties of this elastomer are not sufficiently high. Furthermore, since the gas permeability is not sufficient and the complement activity is not suppressed, it cannot be used for the above purpose.

Materials that can solve the problem of complement activation in blood described in (c) are often found in the field of dialysis membranes for dialysis type artificial kidneys. For example, artificial organs 16 (2), 818
In -821 (1987), a membrane obtained by subjecting a cellulose membrane to diethylaminoethylation was compared with the original cellulose membrane.
It has been reported to significantly suppress complement activation during dialysis. However, since this membrane has poor gas permeability, it is difficult to practically use it as a membrane material for an artificial lung.

Further, Japanese Patent Publication No. 54-18518 discloses that
An anticoagulant medical material comprising heparin and a copolymer containing a hydrophilic component, a hydrophobic component and a quaternary ammonium salt component as essential units and having a negative standard membrane potential difference is disclosed. ing. However, since this material does not have a gas-permeable segment, it does not have a gas-permeable segment at all, and even if a gas-permeable segment is introduced into the present copolymer, it is described in the text. When 5 to 80% by weight of water is contained when the cationic copolymer is in equilibrium with water, moisture and plasma pass through a membrane made of this copolymer (wet rung), and The gas permeability is reduced, and the active ingredient in the body leaks out.

[0010]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned drawbacks, and has as its object to have a gas permeability for a long period of time without causing a wet rung, It is another object of the present invention to provide a material which is excellent in blood compatibility for a long period of time and can be easily formed into a thin film and which is optimal for a gas exchange membrane of a heart-lung machine.

The gas-permeable material excellent in blood compatibility according to the present invention comprises diisocyanate (DI), a polysiloxane having a hydroxyl group or an amino group capable of reacting with an isocyanate group at the molecular terminal (NOPS), and a tertiary amino group. Polyurethane or polyurethane urea obtained by reacting a polyether polyol (NPO) having tertiary amino groups contained in the polyurethane or polyurethane urea is partially or entirely quaternized with an alkyl halide or an active ester. Polyurethane or polyurethane urea, characterized by having a water absorption of 4% by weight or less. The gas-permeable material having excellent blood compatibility according to the present invention includes diisocyanate (DI), polysiloxane having a hydroxyl group or an amino group capable of reacting with an isocyanate group at the molecular terminal (NOPS), and a polyether having a tertiary amino group. Polyurethane or polyurethane urea obtained by reacting a polyol (NPO) and other polyamines or polyols is used to convert a part or all of the tertiary amino groups contained in the polyurethane or polyurethane urea with an alkyl halide or an active ester. 4
Grade-chlorinated polyurethane or polyurethane urea having a water absorption of 4% by weight or less.
The gas-permeable material having excellent blood compatibility according to the present invention is a polyether polypol having the tertiary amino group.
And condensed by containing 50 mol% or more of the amine diol represented by the formula (1). The gas-permeable material having excellent blood compatibility according to the present invention is obtained by treating the above-mentioned polyurethane or polyurethaneurea with heparins.

The diisocyanate used for the polyurethane or polyurethane urea which is the gas permeable material of the present invention includes diisocyanates (aromatic, aromatic, etc.) usually used for preparing polyurethane or polyurethane urea.
(Aliphatic, alicyclic). As the aromatic diisocyanate, p-phenylene diisocyanate,
o-phenylene diisocyanate, m-phenylene diisocyanate, 2,4-tolylene diisocyanate,
8 to 25 carbon atoms such as 2,6-tolylene diisocyanate, xylylene diisocyanate, 4,4'-diphenylmethane diisocyanate, 4,4'-diphenylpropane diisocyanate, and naphthalene diisocyanate
Of aromatic diisocyanates. Examples of the aliphatic diisocyanate include C6-C20 aliphatic diisocyanates such as hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, and decamethylene diisocyanate. Examples of the alicyclic diisocyanate include those having 8 to 20 carbon atoms such as 4,4'-dicyclohexylmethane diisocyanate and isophorone diisocyanate.
Alicyclic diisocyanates. The above diisocyanates may be used as a mixture of two or more. Hereinafter, components used in the polymer of the present invention, such as polysiloxane and polyether polyol having a tertiary amino group, may be used as a mixture of two or more kinds.

The polysiloxane having a hydroxyl group or an amino group at the molecular terminal capable of reacting with an isocyanate group is preferably represented by the following formula:

[0014]

Embedded image

(Where X and Y are each independently —OH, —NH ₂ or a substituted amino group having 2 to 10 carbon atoms, and R ₁ and R ₃ are each independently 2 to 10 carbon atoms. An alkylene group, an oxyalkylene group, an aralkylene group or an arylene group, and R ₂ are each independently an alkyl group, an aryl group or an aralkyl group having 1 to 10 carbon atoms; and n is an integer of 5 to 300.)

The molecular weight of this polysiloxane is from 200 to
It is 20,000, preferably 500-8000, more preferably 1000-4000. The content of this polysiloxane in the resulting polyurethane or polyurethaneurea is from 20 to 95%, preferably from 30 to 85%.

The polyether pole having a tertiary amino group used in the present invention (NPOs) are obtained by one of the amine diol of polycondensation by a strong acid catalyst, of one of R ^1, R ^2, And the total number of carbon atoms of R ³ is 2 to 10,
Preferably, 3 to 8 amine diols are used. When the total number of carbon atoms is 3 or less, the hydrophilicity is high, the permeability of water and plasma is high, and at the same time, because of high water absorption, even if heparinized after quaternization, the release rate of heparin is fast and long. Blood compatibility is not obtained. On the other hand, when the total number of carbon atoms exceeds 10, steric hindrance around the nitrogen atom of the tertiary amino group increases, and quaternization becomes difficult. Even if quaternization proceeds, steric hindrance is too large, so that salt formation with heparin is weakened, heparinization is insufficient, and it is difficult to achieve long-term blood compatibility. Preferably, R ¹ , R ² and R ^{3 are} all linear alkyl groups.

Preferred examples of the amine diol used in the present invention include 3-ethyl-3-aza-1,5-pentanediol, 3-propyl-3-aza-1,5-pentanediol, 3-butyl -3-aza-1,5-pentanediol, 3-pentyl-3-aza-1,5-pentanediol, 3-hexyl-3-aza-1,5-pentanediol, 3-heptyl-3-aza- 1,5-pentanediol, 3-octyl-3-aza-1,5-pentanediol, 3-decyl-3-aza-1,5-pentanediol, 4-methyl-4-aza-2,6-heptane Diol, 4-ethyl-4-aza-2,6-heptanediol, 4-propyl-4-aza-2,6-heptanediol, 4-butyl-4-aza-2,6-heptanediol, 4-heptyl − - aza 2,6-heptane diol, and 4-octyl-4-aza-2,6-heptane diol and the like. Examples of the strong acid used as a catalyst include phosphorous acid, hypophosphorous acid, pyrophosphoric acid, p-toluenesulfonic acid, methanesulfonic acid and the like, and these are 0.01 to 8 mol%, preferably 0 to 8 mol%, based on the above amine diol. Used in a proportion of 1 to 3 mol%.

Along with the amine diol represented by Chemical formula 1,
Other diols can be used if desired. Such diols include aliphatic or alicyclic diols having 2 to 20 carbon atoms and / or polyoxyalkylene glycols having a molecular weight of 150 to 2000. Examples of the aliphatic or alicyclic diol, ethylene glycol,
Propylene glycol, butanediol, neopentyl glycol, cyclohexanedimethanol and the like.
Examples of the polyoxyethylene glycol include polyethylene glycol, polypropylene glycol, and polytetramethylene glycol. These DI, N
It goes without saying that the selection of OPS, NPO and other diols should be made without departing from the scope of the present invention.

To prepare the aminopolyether polyol, first, the amine diol of the formula (1) is mixed with other diols, if necessary, and the above catalyst is added thereto.
While heating to 270 ° C, preferably 200 to 250 ° C, and distilling off the generated water, 1 to 30 hours, preferably 3 to 30 hours.
React for 20 hours. Then, the pressure is reduced to 10 mmHg or less, preferably 3 mmHg or less over 0.5 to 6 hours, preferably 1 to 4 hours. Under this reduced pressure and at the above temperature for 1 to 10 hours, preferably 2 to 10 hours
After reacting for 7 hours, an aminopolyether polyol having a molecular weight of 200 to 8000, preferably 500 to 4000 is obtained. The aminopolyether polyol has a basic nitrogen content of 1.0 to 15.0%, preferably 2.0 to 15.0%.
11.0%. At the time of preparing the polyurethane or polyurethane urea of the present invention, the aminopolyether polyol obtained by each of the above methods has a tertiary amino group present in the molecule containing 0.01 to 3.00 mmol in the polyurethane or polyurethane urea. / G, preferably 0.
It is used in such a ratio as to be 0.05 to 2.00 mmol / g.

Other polyols or polyamines optionally used in preparing the polyurethane or polyurethaneurea of the present invention are, for example, low molecular weight chain extenders and high molecular weight polyols. Low molecular weight chain extenders include diols, diamines and oxyalkylene glycols. Examples of the diols include ethylene glycol, propylene glycol, 1,4-butanediol, neopentyl glycol, 1,5-pentanediol, 1,6-hexanediol, 1,4-cyclohexanedimethanol, and 1,3-cyclohexane. There are aliphatic and / or alicyclic diols having 2 to 20 carbon atoms such as dimethanol. Examples of the diamines include ethylene diamine, propylene diamine, 1,4-tetramethylene diamine, 1,6-hexamethylene diamine, 1,4-
There are aliphatic and / or aromatic diamines such as diaminocyclohexane, 4,4'-diaminodiphenylmethane, xylylenediamine.

The oxyalkylene glycols include diethylene glycol, triethylene glycol,
Tetraethylene glycol, dipropylene glycol,
There are oxyalkylene glycols having 5 to 30 carbon atoms such as tripropylene glycol and / or tetrapropylene glycol. Among these low molecular weight chain extenders, ethylene glycol, 1,4-butanediol, 1,6-hexanediol, neopentyl glycol, ethylenediamine, propylenediamine, 1,4-
Butylenediamine and 1,6-hexamethylenediamine are particularly preferred. As the high molecular weight polyol,
Examples include polyoxyalkylene glycol and polyester diol. As the polyoxyalkylene glycol, a molecular weight of 300 to 15,000, preferably 800 to
8000 polyethylene glycol, polypropylene glycol, polytetramethylene glycol, and the like.
Examples of the polyester diol include a polyester diol obtained from an aliphatic diol having 2 to 10 carbon atoms and an aliphatic dicarboxylic acid having 6 to 16 carbon atoms; and a polyester diol obtained from caprolactones such as ε-caprolactone. Of these high molecular weight polyols, polyester diols are preferred. The content of the high molecular weight polyol in the obtained polymer is 50% or less, preferably 30% or less.

The polyurethane and the polyurethane urea of the present invention can be prepared by known methods. For example, to prepare a polyurethane by a solution polymerization method, first, a polysiloxane having a hydroxyl group or an amino group at a molecular terminal represented by the chemical formula 2, and a diisocyanate, and if necessary, the above-mentioned high-molecular-weight polyol is converted into an isocyanate group. Dissolve in an active solvent, and at 30 to 150 ° C, preferably 40 to 120 ° C for 5 to 300 minutes, preferably 1
The reaction is carried out with stirring under a stream of nitrogen for 5 to 120 minutes. The above-mentioned aminopolyether polyol (NPO) and, if necessary, the above-mentioned low-molecular-weight chain extender (low-molecular-weight diol) are added thereto and reacted at 0 to 100 ° C, preferably 5 to 80 ° C for 15 to 300 minutes. Extend the chain and increase the molecular weight.

The solvents used here are dioxane, tetrahydrofuran, chloroform, carbon tetrachloride,
Benzene, toluene, acetone, methyl ethyl ketone,
N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, a mixture thereof and the like. Particularly, dioxane, tetrahydrofuran, methyl ethyl ketone, N, N-dimethylformamide, N, N-dimethylacetamide and a mixture thereof are preferable. During the reaction, a polymerization catalyst is added as needed. Catalysts include tin based catalysts such as dibutyltin dilaurate, titanium based catalysts such as tetrabutoxytitanium or other metal catalysts. The catalyst is added to the reaction solution at a content of 1 to 500 ppm, preferably 5 to 100 ppm. For the preparation of the polyurethane, a method in which the above-mentioned monomer components to be used are charged at a time and then melt-polymerized may be employed.

In the above polymerization reaction, the mixing molar ratio of each component is as follows: polysiloxane polyol;
The molar ratio with the aminopolyether polyol is 100/1.
The molar ratio of the polysiloxane polyol and aminopolyether polyol, ie, NOPS + NPO, to the polyol (optionally used) which is a low molecular weight chain extender is .about.1 / 3, preferably 20/1 to 1/5. 1
/ 100 to 1/1, preferably 1/30 to 1/2; molar ratio of total polyol to diisocyanate is 10/8 to 8
/ 10, preferably 10/9 to 9/10.

The polyurethaneurea of the present invention can be prepared by using any of known polyurethaneurea production methods. Among them, the solution polymerization method is particularly preferable. When the polyurethaneurea is prepared by a solution polymerization method, a polysiloxane polyol, an aminopolyether polyol, and if necessary, a high molecular weight polyol and the like are used. In this case, these and the diisocyanate are dissolved in an inert solvent. This is carried out at 0 to 150 ° C, preferably at 10 to 100 ° C, as in the case of the above polyurethane.
The reaction is carried out for 300 minutes, preferably for 15-120 minutes. This is cooled to 0 to 40 ° C., preferably 5 to 20 ° C., and the polysiloxane having an amino group at the terminal represented by the above formula (2) and, if necessary, a low molecular weight chain extender (low molecular weight diamine) are not used. A solution dissolved in an active solvent is dropped, and a polyurethaneurea having a desired molecular weight is obtained by reacting. In this reaction, since the resulting polymer has a urea bond, the solvent used is N,
Amide-based solvents such as N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, or mixed solvents thereof with dioxane, tetrahydrofuran and the like are preferred. It is also recommended to add salts such as LiCl, LiBr and CaCl ₂ in order to increase the solubility of the resulting polymer. Other conditions such as the mixing ratio of each component are the same as in the case of polyurethane.

The polyurethane or polyurethane urea of the present invention thus obtained is formed into a hollow fiber or a thin film as described later and is used as a gas-permeable material in an artificial heart-lung machine or the like. Further, the polyurethane or polyurethane urea of the present invention can quaternize a tertiary amino group in the molecule, and can bind heparin or a similar compound thereof (hereinafter, referred to as heparins). Doing so further improves blood compatibility. The binding of heparins is carried out by treating the polyurethane or polyurethaneurea with a quaternizing agent to quaternize the tertiary amino groups in the molecule, and then treating with a heparin to form a polyion complex. As such a quaternizing agent, at least one of an alkyl halide having 1 to 10, preferably 2 to 8 carbon atoms, an aralkyl halide, an allyl halide and an active ester is used. These four
Among the grading agents, alkyl halides having 1 to 10, preferably 2 to 8 carbon atoms are suitable. The quaternizing agent is used in an amount of 0.1 to 10.0 times, preferably 0.5 to 5.0 times, the mole of the tertiary amino group in the polymer. For the quaternization of polyurethane or polyurethane urea, for example, a method in which the polymer is dissolved in an appropriate solvent and the quaternizing agent is added thereto and reacted, or the quaternizing agent solution after forming the polymer And the reaction is carried out by contacting A method in which the reaction is performed in a solution is more preferable. For example, a quaternizing agent is added to a solution after polymerization of polyurethane or polyurethane urea,
00 ° C, preferably 0.1 to 60 hours at 40 to 80 ° C,
The reaction is preferably performed for 1 to 30 hours. In this way 4
The quaternization rate of the graded tertiary amino group is 1 to 100%, preferably 10% or more.

The quaternized amino group-containing polyurethane or polyurethane urea is formed into a desired product such as a membrane or a hollow fiber. By contacting the heparin with the heparin, the heparin is bound (heparinized).
For example, an aqueous solution containing 0.1 to 10%, preferably 0.5 to 5% of heparin in the polyurethane or polyurethane urea molded article having the quaternized amino group, (dimethylformamide, dimethylformamide) Dipping in water (a mixed solvent of a water-soluble solvent such as acetamide, tetrahydrofuran or ethanol) with water at 20 to 100 ° C, preferably 40 to 80 ° C for 0.1 to 40 hours, preferably 0.5 to 30 hours. Performs heparinization. Here, the heparins refers encompasses heparin, chondroitin sulfate, -SO ₃ H, a natural or synthetic polymer compounds having such -NHSO ₃ H group and the like.

The polyurethane or polyurethane urea of the present invention is formed into a hollow fiber membrane by, for example, spinning into a hollow fiber form by a conventional method, or by dissolving it in an appropriate solvent, casting it on a flat plate, and drying it to form a thin film. . If necessary,
This is heparinized as described above to provide the desired gas permeable material. When the material of the present invention is used as an oxygen exchange membrane in a heart-lung machine, oxygen / carbon dioxide exchange is advantageously performed. In addition, since the material is excellent in blood compatibility, blood coagulation and shock symptoms due to activation of complement are extremely unlikely to occur. When a heparinized material is used, heparins on the polymer are slow-released, so that the anticoagulability is further improved. In this way, the material of the present invention can be effectively used, for example, for ECMO that performs long-term lung function. Further, the material of the present invention can be used for a medical oxygen-enriched membrane, an oxygen-enriched membrane for gas combustion, and the like used in oxygen inhalation therapy for respiratory patients. Utilizing the excellent antithrombotic properties, it is also recommended to use as a coating material for medical devices that come into contact with blood.

[0030]

The present invention will be described below with reference to examples. Parts in the examples mean parts by weight. <Example 1> 1472 parts of 4-methyl-4-aza-2,6-heptanediol, 591 of 1,6-hexanediol
Parts and 12.3 parts of phosphorous acid were charged into an autoclave, and the mixture was stirred and gasified under a nitrogen stream.
The mixture was heated for 6 hours, and the reaction was carried out while distilling off generated water.
Then, at 220 ° C., 760 mmHg to 0.3 mmHg
The pressure was reduced over 2 hours until reaching 220 ° C, 0.3 m
The reaction was continued at mHg for 3 hours. In this way, O
An aminopolyether polyol (a) having an H value of 57.3 and a basic nitrogen of 6.11 mmol / g was obtained. 1800 parts of a polydimethylsiloxane diol having a number average molecular weight of 1800 and represented by the following formula 3,

[0031]

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The above aminopolyether polyol (a)
300 parts, 1,4-butanediol 90.1 parts, dibutyltin dilaurate 0.3 parts, and 4,4'-diphenylmethane diisocyanate (hereinafter abbreviated as MDI) 5
54 parts of tetrahydrofuran (hereinafter abbreviated as THF)
It was dissolved in a mixed solvent of 1994 parts and 3887 parts of dimethylformamide (hereinafter abbreviated as DMF), and reacted at 40 ° C. for 1 hour and further at 60 ° C. for 15 hours under a nitrogen stream. Thus, a base polymer solution A having a solid content of 32% and a viscosity of 3200 poise (30 ° C.) was obtained. DMF was added to this solution and stirred to give a 5% solution. 5% solution 1
After uniformly applying 0 g on a 100 cm ² glass plate kept horizontally, dried at 40 ° C. for 1 hour, at 60 ° C. for 2 hours under a nitrogen stream, and dried under reduced pressure at 60 ° C. for 15 hours.
A base polymer film A having a thickness of 50 μm was obtained.

Further, 4.58 parts of hexyl iodide was added to 100 parts of a 10% base polymer solution obtained by diluting with DMF, and the mixture was reacted at 70 ° C. with stirring to obtain a tertiary amino group 4 in the base polymer. Grading was performed. This solution was diluted with dioxane to obtain a 5% solution, and a quaternized polymer film A having a thickness of 50 μm was obtained in the same manner as in the case of the base polymer A. Approximately 0.2 g of each of the base polymer film A and the quaternized base polymer film A was accurately weighed, dissolved in 50 ml of a dioxane / ethanol (7/3 volume ratio) mixed solvent, and then subjected to a potentiometric titration device (comitite- manufactured by Hiranuma Seisakusho, Ltd.) 7) using N / 10-HC1
0 ₄ was titrated with dioxane solution was measured for basic nitrogen content than the inflection point, it is 0.25 mmol / g of basic nitrogen content of the base polymer film A is 0.67 mmol / kg, 4 quaternized film A Met. From this result, it can be seen that the quaternization ratio is about 63%. Next, when the oxygen permeability coefficient of this film was measured using a gas permeability measuring device (manufactured by Yanagi Head Office), the base polymer A was 1.23 × 10 ⁻⁸ cm ³ (STP) cm / cm ^2.
・ Sec ・ cmHg, quaternized film A is 1.48 × 1
0 ^-8 (hereinafter, unit cm ³ (STP) · cm / cm ² · s
ec · cmHg is omitted. )Met. Next, each film was immersed in a 1% heparin aqueous solution and treated at 70 ° C. for 2 hours to perform heparinization, thereby obtaining a heparinized base polymer film A and a heparinized quaternized polymer film A. These films were cut into a circular shape having a diameter of 3 cm, immersed in a physiological saline solution at 37 ° C. for one week, rinsed well with distilled water, and blotted on the film surface with a filter paper. Paste this film in the center of the watch glass with a diameter of 10cm,
Rabbit (Japanese white species) citrated plasma 2 on film
After collecting 00 μl, add 200 μl of a 1/40 molar concentration aqueous calcium chloride solution, float the watch glass in a constant temperature water bath at 37 ° C., and stir by hand so that the internal solution is mixed. The time from to clotting (the point at which the plasma stuck) was measured and divided by the clotting time on glass (measured separately as a control) and expressed as a relative value.

Each solution was diluted with DMF to obtain 1%
A solution was prepared, and 40 to 60 mesh glass beads were immersed in 100 ml of this solution for 30 minutes, and then filtered through a glass filter.
After drying at 12 ° C. for 12 hours, the surface of the glass beads was coated with each polymer. 200 mg of these coated beads, 50
Add 0 μl of Veronal buffer and serum (using pooled serum of a healthy person) to a plastic tube and add to 37 ° C.
After incubation gentle shaking for 30 minutes at, showing hemolytic complement activity (CH ₅₀ for short) and C3a, the results of measurement of the amount of C5a in Table 1. The measurement of CH ₅₀ was performed by the Meyer method (Neyer, MM, “Compli”).
ment and Compliment fixat
ion "Experimental Immune C
hemistry, 2th Edition pl3
3, Charles C.E. Thomas Publi
Sher, Stuttgart, 1964), and the measurement of C3a, C5a was performed by Upjo.
The measurement was performed using a radio immunoassay kit sold by n companies. In addition, the obtained various films
After immersion in distilled water at 0 ° C. for 24 hours, surface water was wiped off, the weight was measured, and the water absorption was determined. The calculation of the water absorption was performed using the following equation. Water absorption (%) = {(WD) / D} × 100 In the above formula, W represents the weight of the film after immersion, and D represents the weight of the film after drying. The above results are shown in Table 1 below. The unit of the oxygen permeability coefficient in Table 1 is (cm ³ (STP)
.Cm) / (cm ² · sec · cmHg).

[0035]

[Table 1]

Example 2 3-n-butyl-3-aza-
8040 parts of 1,5-pentanediol and phosphorous acid 1
0.3 parts were charged into an autoclave, stirred and heated at a constant pressure of 200 to 230 ° C. for 26 hours while stirring, and the reaction was carried out while distilling off generated water. Then 230 ° C
The pressure was reduced from 760 mmHg to 0.3 mmHg over 2 hours, and the reaction was continued at 230 ° C. and 0.3 mmHg for 3 hours. Thus, an aminopolyether polyol (b) having an OH value of 64.7 and a basic nitrogen of 6.75 mmol / g was obtained. 3240 parts of polydimethylsiloxane represented by Chemical Formula 3 having a number average molecular weight of 2040, MDI
1195 parts, polyaminoether polio 773.
4 parts, 0.3 parts of dibutyltin dilaurate and 1,4
-191.1 parts of butanediol were added to 3772 parts of THF and D
Dissolve in a mixed solvent with 7564 parts of MF, and under a nitrogen stream,
The mixture was reacted at 20 ° C. for 1 hour and at 40 ° C. for 20 hours to obtain a base polymer solution (B) having a solid content of 32% and a viscosity of 1800 poise (30 ° C.). This base polymer solution B was treated in the same manner as in Example 1, and quaternized with hexyl iodide. Further, in the same manner as in Example 1, a base polymer B, a quaternized film B and a heparinized film B were obtained. Each of these basic nitrogen contents is 1.08 mm
1 / g and 0.410 mmol / g. From this result, it can be seen that the quaternization ratio is about 62%. Next, the oxygen permeability coefficient, the relative coagulation time, the complement activity and the water absorption were measured in the same manner as in Example 1. Table 1 shows the results.

Example 3 3-n-hexyl-3-aza
8738 parts of 1,5-pentanediol and phosphorous acid 1
0.3 parts were charged into an autoclave and heated at a constant pressure of 200 to 230 ° C. for 26 hours under a nitrogen stream while stirring to carry out a reaction while distilling off generated water. Then 230 ° C
The pressure was reduced from 760 mmHg to 0.3 mmHg over 2 hours, and the reaction was continued at 230 ° C. and 0.3 mmHg for 3 hours. Thus, an aminopolyether polyol (c) having an OH value of 58.7 and a basic nitrogen of 6.30 mmol / g was obtained. 3240 parts of polydimethylsiloxane represented by Chemical Formula 3 having a number average molecular weight of 2040, MDI 1
195 parts of the above-mentioned Poriaminopori all 827.3 parts,
0.302 parts of dibutyltin laurate and 191.1 parts of 1,4-butanediol were combined with 3802 parts of THF and DMF.
Dissolved in a mixed solvent with 7604 parts under a nitrogen stream at 20 ° C
And the temperature was raised to 40 ° C. for 20 hours to obtain a base polymer solution (C) having a solid content of 32% and a viscosity of 1830 poise (30 ° C.). This base polymer solution C was treated in the same manner as in Example 1, and quaternized with butyl iodide. Further, in the same manner as in Example 1, a base polymer C, a quaternized film C, and a heparinized film C were obtained. These basic nitrogen contents were 1.08 mmol / g and 0.410 mmol / g, respectively. From this result, it can be seen that the quaternization ratio is about 62%. Then, in the same manner as in Example 1, oxygen permeability coefficient, relative coagulation time, complement activity,
And the water absorption was measured. Table 1 shows the results.

Comparative Example 1 A base polymer B was obtained in the same manner as in Example 1 using the base polymer solution B obtained in Example 2. Further, quaternization was performed with ethyl iodide in the same manner as in Example 1 to obtain a quaternized film D and a heparinized film D. These basic nitrogen contents were 1.08 ml / g and 0.210 mmol / g, respectively. From this result, it can be seen that the quaternization ratio is about 82%. Then, in the same manner as in Example 1, the oxygen transmission coefficient
The relative clotting time, complement activity and water absorption were measured. Table 1 shows the results.

Comparative Example 2 Acrylic nitrile (24 parts) and acrylamide (89)
Parts) with dimethylsulfoxide (126 parts), and then, as a chain transfer agent, dodecyl mercaptan (0.2 parts).
Part) Bromoform was added as a polymerization initiator, and 100 W
By irradiating light at a distance of 10 cm from a high pressure mercury lamp for 7 hours, the photopolymerized stock solution was poured into a large amount of methanol to precipitate and coagulate, thereby forming a trunk polymer (24.4).
Part). 10 g of the stem polymer thus obtained
Was dissolved in dimethylsulfoxide (120 parts), and dimethylaminoethyl methacrylate was added.
Irradiated with light from a mercury lamp at a distance of 10 cm for 19 hours, photografting was performed, and the undiluted solution was poured into methanol to precipitate and coagulate.
Part). The thus obtained graft polymer was dissolved in dimethylformamide, quaternized by adding ethyl bromide, and then formed into a film (E). Next, the oxygen permeability coefficient, the relative coagulation time, the complement activity and the water absorption were measured in the same manner as in Example 1. Table 1 shows the results.

As is evident from the results in Table 1, the polymer of Comparative Example 2 (E) containing no polydimethylsiloxane unit has poor gas permeability and activates the complement, whereas the polymer of the example is Complement activity is also suppressed and it has good gas permeability. At this stage, the polymer (D) of Comparative Example 1 has performance comparable to that of the polymer of Example.

Example 5 The heparinized flumes A to E obtained in Examples 1 to 3 and Comparative Examples 1 and 2 were used for 200 m.
The resulting film was immersed in 1 liter of physiological saline, and was eluted for 2 weeks while changing the physiological saline every day. The relative coagulation time of the eluted film was measured, and the results are shown in Table 2 below.

[0042]

[Table 2]

From the results shown in Table 2, the polymers of Examples having a water absorption of 4% or less have good blood compatibility even after elution in physiological saline for 2 weeks. Since the polymer of the large comparative example elutes heparin quickly, if the immersion time exceeds 3 days, the effect of heparin is completely lost and the polymer solidifies. For the above reasons, it is clear that the polymers of the present invention have good gas permeability and long-term blood compatibility.

[0044]

Industrial Applicability The specific polyurethane or polyurethane urea of the present invention inhibits complement activity, has good gas permeability, and has long-term blood compatibility. It has excellent suitability as a material for artificial lungs and ECMO.

Claims (4)

(57) [Claims] 1. A polyisocyanate obtained by reacting a diisocyanate (DI), a polysiloxane (NOPS) having a hydroxyl group or an amino group capable of reacting with an isocyanate group at a molecular terminal, and a polyether polyol (NPO) having a tertiary amino group. A polyurethane or polyurethane urea obtained by quaternizing some or all of the tertiary amino groups contained in the polyurethane or the polyurethane urea with an alkyl halide or an active ester, and having a water absorption of 4% by weight. % Or less, which is excellent in blood compatibility. 2. A diisocyanate (DI), a polysiloxane having a hydroxyl group or an amino group capable of reacting with an isocyanate group at a molecular terminal (NOPS), a polyether polyol having a tertiary amino group (NPO), and other polyamines. Polyurethane or polyurethane urea obtained by reacting a polyol is polyurethane or polyurethane urea in which some or all of the tertiary amino groups contained in the polyurethane or polyurethane urea are quaternized with an alkyl halide or an active ester. A gas permeable material having excellent blood compatibility, wherein the water absorption is 4% by weight or less. 3. A gas-permeable material excellent in blood compatibility, wherein the NPO according to claim 1 or 2 is condensed by containing at least 50 mol% of an amine diol represented by the following chemical formula 1. . Embedded image (R ¹ and R ³ in Chemical Formula ¹ are hydrogen or a compound having 1 to 3 carbon atoms.
R ² represents an alkyl group having 1 to 10 carbon atoms. ) 4. A gas-permeable material excellent in blood compatibility, which is obtained by further treating the material according to claim 1 with a heparin.