JP3129469B2 - Artificial lung membrane with excellent blood compatibility - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an artificial heart-lung machine used for maintaining blood circulation and oxygen supply in open heart surgery accompanying heart surgery, an artificial lung for substituting a lung function for a patient with lung failure, and a long term extracorporeal circulation. ECMO (Extr) used for
a Corporate Membrane Oxyg
an oxygen exchange membrane of a gas exchanger such as a gas exchanger.

[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 performs gas exchange through small holes (several 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 time.

In the type (2) in which gas is exchanged through small holes, there is no direct contact between the blood and the gas as in the type (1), so that blood is damaged and gas bubbles are mixed into the 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 changes in the blood 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 production of a silicone polycarbonate copolymer. In addition, US Pat.
No. 737 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 diaminoliposiloxane, isocyanate compound and polyamine. Further, JP-A-60-24156
No. 7 (Polymer Technology Research Group No .: PM-80)
Discloses a gas selective permeable membrane made of a 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. Moldings obtained from this material cause slow release of heparin from its surface, thereby preventing blood clotting. 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 hardly practical for a membrane material for an artificial lung.

Further, Japanese Patent Publication No. 54-18518 discloses that heparin and a copolymer containing a new aqueous component, a hydrophobic component and a quaternary ammonium salt component as essential units, and that the standard membrane potential difference shows a negative value. An anticoagulant medical material characterized by the following is disclosed. 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. 5 to 80% by weight when the cationic copolymer is in equilibrium with water
When water is contained, moisture and plasma pass through the membrane made of this copolymer (wet rung), and the gas permeability decreases over time, and the active ingredient in the body leaks out. It becomes difficult to maintain the life of the living body.

In order to improve the above-mentioned conventional drawbacks, as a result of intensive studies, we have developed a gas permeable material which has a long-term gas permeability without causing a wet rung and has excellent long-term blood compatibility. And has already filed a patent application. However, since this material has a limited content of polysiloxane, which is a gas-permeable segment, the gas permeability was slightly inferior to that of a commercially available silicone rubber film. Further, although polyurethane is introduced to maintain the strength, the strength is still not sufficient, and when formed into a hollow fiber, there is a drawback such that a part of the fiber is blocked.

[0011]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned drawbacks, and has as its object to reduce the gas permeability over a long period of time without causing a wet rung for a long period of time with almost no blockage. An object of the present invention is to provide a gas exchange membrane for a heart-lung machine, which has excellent long-term blood compatibility.

[0012] The artificial lung membrane excellent in blood compatibility according to the present invention comprises diisocyanate (DI), polysiloxane (NOPS) having a hydroxyl group or an amino group capable of reacting with an isocyanate group at the molecular terminal, and a tertiary amino group. Obtained by reacting a polyether polyol (NPO) having
Polyurethane or polyurethane urea obtained by quaternizing some or all of the tertiary amino groups contained in the polyurethane or polyurethane urea (P
U) or polyurethane urea (PUU) is used to coat polyolefin hollow fibers. The total number of carbon atoms contained in the side chain group bonded to the quaternary chlorinated nitrogen is desirably 7 to 16. The number of carbon atoms in the side chain as used herein refers to the number of carbon atoms in the side chain bonded to the tertiary amine in the NOP of the present invention, and is represented by the following formula 1, which is preferably included in the NOP of the present invention. It refers to the sum of the carbon number of R ^{2 and} the carbon number of the group from the quaternizing agent. The artificial lung membrane having excellent blood compatibility according to the present invention is characterized in that a cyclic ether is used as a solvent when coating with PU or PUU. The membrane for oxygenator excellent in blood compatibility according to the present invention has a ratio of PU and PUU of 1 in the coated membrane for oxygenator.
To 50% by weight. The oxygenator membrane excellent in blood compatibility of the present invention is obtained by treating the above-mentioned coated oxygenator membrane with heparins.

[0013]

Embedded image (R ¹ and R ³ in Chemical Formula ¹ represent hydrogen or an alkyl group having 1 to 3 carbon atoms, and R ² represents an alkyl group having 1 to 10 carbon atoms.)

The diisocyanate used for the polyurethane or polyurethane urea used as the coating agent of the present invention includes diisocyanates (aromatic, aliphatic, and aliphatic) usually used for preparing polyurethane or polyurethane urea.
(Alicyclic). Two or more diisocyanates may be used as a mixture. In the following, two or more components used for the polymer serving as the coating agent 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.

The polysiloxane having a hydroxyl group or an amino group capable of reacting with an isocyanate group at the molecular terminal is preferably represented by the following formula (2).

[0016]

Embedded image (X and Y in Chemical Formula 2 are each independently -OH,
—NH ₂ or a substituted amino group having 2 to 10 carbon atoms, R ¹ and R ³ are each independently an alkylene group, oxyalkylene group, aralkylene group, or arylene group having 2 to 10 carbon atoms, 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 tertiary amino group-containing polyether polyol (NPO) used in the polyurethane or polyurethane urea used as the coating agent of the present invention is not particularly limited, but is preferably a NOP containing an amine diol of the formula (1).
Which is obtained by polycondensation of the amine diol of Chemical Formula 1 with a strong acid catalyst, wherein the total number of carbon atoms of R ¹ , R ² and R ³ of Chemical Formula ¹ is 2 to 10, preferably 3 to 8 It is preferred to use a diol. 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, due to the 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 the quaternization is advanced, the steric hindrance is too large, so that the salt-forming bond with heparin is weakened, the heparinization is insufficient, and it is difficult to achieve long-term blood compatibility. R ¹ ,
Both R ² and R ³ are preferably linear alkyl groups.

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.

In order to prepare the aminopolyether polyol, first, the amine diol of the formula (1) is mixed with other diols as required, a catalyst is added thereto, and the mixture is added under normal pressure at 150 to 27.
While heating to 0 ° C, preferably 200 to 250 ° C, and distilling off generated water, 1 to 30 hours, preferably 3 to 20 hours.
Let react over time. Then, over a period of 0.5 to 6 hours, preferably 1 to 4 hours, 10 mmHg or less, preferably 3 mmHg.
Reduce the pressure to not more than mmHg. When the reaction is carried out for 1 to 10 hours, preferably 2 to 7 hours under the reduced pressure and the above temperature, the molecular weight is 200 to 8000, preferably 500 to 40.
An amino polyether polyol of 00 is obtained. The aminopolyether polyol has a basic nitrogen content of 1.
0 to 15.0%, preferably 2.0 to 11.0%.
At the time of preparing the polyurethane or polyurethane urea to be the coating agent of the present invention, the aminopolyether polyol obtained by each of the above methods has a tertiary amino group present in the molecule in the polyurethane or polyurethane urea. -3.00 mmol / g, preferably 0.05-2.
It is used at a rate of 00 mmol / g.

Other polyols or polyamines used as needed in preparing the polyurethane or polyurethane urea used as the coating agent of the present invention are, for example, low molecular chain extenders and high molecular weight polyols. Low molecular weight chain extenders include diols, diamines and oxyalkylene glycols. In particular, ethylene glycol, 1,4-butanediol,
1,6-hexanediol, neopentyl glycol,
Ethylenediamine, propylenediamine, 1,4-butylenediamine, and 1,6-hexamethylenediamine are preferred. Examples of the high molecular weight polyol include polyoxyalkylene glycol and polyester diol. Examples of the polyoxyalkylene glycol include polyethylene glycol, polypropylene glycol, and polytetramethylene glycol having a molecular weight of 300 to 15,000, preferably 800 to 8000. 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 high molecular weight polyol has a content in the obtained polymer of 50% or less, preferably 30% or less.
It is as follows.

The polyurethane or polyurethane urea used as the coating agent of the present invention can be prepared by any known method. 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 active solvent, 30-15
The reaction is carried out at 0 ° C., preferably 40 to 120 ° C., for 5 to 300 minutes, preferably 15 to 120 minutes, with stirring under a nitrogen stream. The above-mentioned aminopolyether polyol (NPO) and, if necessary, the above-mentioned low-molecular-weight chain extender (low-molecular-weight diol) are added thereto.
The chain is extended by reacting at 15 ° C., preferably 5 to 80 ° C. for 15 to 300 minutes to increase the molecular weight.

The solvent used here is 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. The molar ratio between the polysiloxane polyol and the aminopolyether polyol is 100/1 to 1
/ 3, preferably 20/1 to 1/5; the molar ratio between the polysiloxane polyol and the aminopolyether polyol, ie NOPS + NPO, and the polyol (optionally used) which is a low molecular weight chain extender is 1 / 10
0 to 1/1, preferably 1/30 to 1/2; molar ratio of total polyol to diisocyanate is 10/8 to 8/1
0, preferably 10/9 to 9/10.

The polyurethaneurea used as the coating agent of the present invention can be prepared by any known method. Among them, the solution polymerization method is particularly preferable. When preparing a polyurethane urea 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 0 to 150 as in the case of the above polyurethane.
C., preferably at 10 to 100.degree. C. for 5 to 300 minutes, preferably for 15 to 120 minutes. This is 0
After cooling to 40 ° C., preferably 5 to 20 ° C., 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 dissolved in an inert solvent. By dropping and reacting the resultant, polyurethaneurea having a desired molecular weight is obtained. In this reaction, since the resulting polymer has a urea bond, the solvent used is an amide-based solvent such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; A mixed solvent with tetrahydrofuran or the like is suitable. In order to enhance the solubility of the resulting polymer, LiC
It is also recommended to add salts such as 1, LiBr, CaCl ₂ . Other conditions such as the mixing ratio of each component are the same as in the case of polyurethane.

The polyurethane or polyurethane urea thus obtained can be quaternized with a tertiary amino group in the molecule, and bound with heparin or a similar compound (hereinafter referred to as heparins). is necessary. Doing so further improves blood compatibility. The binding of heparins is performed by treating the polyurethane or polyurethane urea with a quaternizing agent to quaternize the tertiary amino groups in the molecule, and then treating with heparins to form a polyion complex. . Such a quaternizing agent has 1 to 1 carbon atoms.
At least one of 10, preferably 2 to 8, alkyl halides, aralkyl halides, aryl halides and active esters is used. Among these quaternizing 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 these polymers are dissolved in an appropriate solvent and the above quaternizing agent solution is added thereto is preferable. For example, a quaternizing agent is added to the solution after the polymerization of polyurethane or polyurethane urea, and the temperature is 20 to 100 ° C, preferably 40 to 100 ° C.
The reaction is carried out at 80 ° C. for 0.1 to 60 hours, preferably 1 to 30 hours. The quaternization ratio of the tertiary amino group thus quaternized is 1 to 100%, preferably 10% or more.

The quaternized amino group-containing polyurethane or polyurethane urea is dissolved in a cyclic ether-based solvent and coated on the existing polyolefin-based porous hollow fiber. Solvents which are inert to the polyurethane or polyurethaneurea and exhibit good solubility include amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; tetrahydrofuran, tetrahydrofuran Cyclic ether solvents such as pyran and dioxane; ketone solvents such as acetone and methyl ethyl ketone; halide solvents such as chloroform and methylene chloride; and the like. Consideration of solvent wettability with polyolefin porous hollow fibers. Then, it is desirable to use a cyclic ether solvent. Particularly, tetrahydrofuran is preferred. The concentration of the quaternary amino group-containing polyurethane or polyurethane urea dissolved in the cyclic ether solvent is adjusted to 0.5 to 20% by weight, preferably 1 to 15% by weight.

A polyolefin porous hollow fiber for an artificial lung is immersed in the above-mentioned dissolved polyurethane or polyurethane urea, and then lifted up.
C., preferably at 15-60.degree. C. for 1-180 minutes, preferably 5-90 minutes. This operation is performed at least once so that the content of the polyurethane or polyurethane urea as the coating agent in the dried hollow fiber after drying is 1 to 50% by weight.

The polyolefin porous hollow fiber for artificial lung coated with a quaternized amino group-containing polyurethane or polyurethane urea is bonded (heparinized) by contacting the heparin with the heparin. For example, the coated polyolefin-based porous hollow fiber for oxygenator is
At a temperature of 20 to 100 ° C, preferably 40 to 80 ° C, in a solution containing 10 to 10%, preferably 0.5 to 5%.
Heparinization is performed by soaking for 1 to 40 hours, preferably 0.5 to 30 hours. The solvent used here is water, or cyclic ethers, amides,
A mixture of water and a water-soluble solvent such as ketones and alcohols is preferable, and particularly, tetrahydrofuran and water, tetrahydropyran and water, N, N-dimethylformamide and water,
Mixtures of N, N-dimethylacetamide and water are preferred. The term “heparins” as used herein refers to natural or synthetic polymer compounds having heparin, chondroitin sulfate, —SO ₃ H, —NHSO ₃ H groups, and the like.

When used as an oxygen exchange membrane in the material heart-lung machine of the present invention, oxygen / carbon dioxide exchange is advantageously performed. In addition, the material is excellent in blood compatibility, so that blood coagulation and shock symptoms caused by 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 present invention can be used for a medical oxygen-enriched membrane used for oxygen inhalation therapy for respiratory patients.

[0031]

The present invention will be described below with reference to examples. Parts in the examples mean parts by weight. <Example 1> 8738 parts of 3-n-butyl-3-aza-1,5-pentanediol and 10.3 parts of phosphorous acid were charged into an autoclave, and the mixture was stirred at room temperature under a nitrogen stream under normal pressure while stirring.
The mixture was heated at 30 ° C. for 26 hours to carry out a reaction while distilling off generated water. Then, at 230 ° C, 760 mmHg to 0.3 mm
The reaction was continued at Hg for 3 hours. Thus, an aminopolyether polyol (a) having an OH value of 58.7 and a basic nitrogen of 6.30 mmol / g was obtained. Polydimethylsiloxane diol 3 having a number average molecular weight of 1800 and represented by the following formula 3
240 parts, dibutyltin dilaurate 0.3 parts, 4,
4'-diphenylmethane diisocyanate (hereinafter MDI
1195 parts), 827.3 parts of the above aminopolyether polyol and 1,4-butanediol 19
1.1 parts was dissolved in a mixed solvent of 3802 parts of tetrahydrofuran (hereinafter abbreviated as THF) and 7604 parts of N, N-dimethylformamide (hereinafter abbreviated as DMF),
The mixture was reacted at 20 ° C. for 1 hour and at 40 ° C. for 20 hours under a nitrogen stream, and the solid content was 32% and the viscosity was 1830 poise (3
(0 ° C.) to obtain a base polymer solution (A). DMF was added to this solution and stirred to give a 5% solution. 5% solution 1
0 g was uniformly applied on a 100 cm ² glass kept horizontally, dried at 40 ° C. for 1 hour, at 60 ° C. for 2 hours, under a nitrogen stream, and then dried under reduced pressure at 60 ° C. for 15 hours to obtain 50 μm.
An m-thick base polymer film (A) was obtained. further,
7. Hexyl iodide in 100 parts of base polymer solution (A)
14 parts were added and reacted while stirring at 60 ° C. to quaternize the tertiary amino group in the base polymer. This quaternized polymer solution (A) is diluted with dioxane to give 5%
A quaternized polymer film having a thickness of 50 μm was obtained in the same manner as in the case of the base polymer solution (A).
About 0.2 g of the base polymer film (A) and the quaternized polymer solution (A) are accurately weighed, and
It was dissolved in 50 ml of a mixed solvent of ethanol (7/3 volume ratio), and titrated with a N / 10-HC104 dioxane solution using a potentiometric titrator (committe-7, manufactured by Hiranuma Seisakusho). When we measured,
The basic nitrogen content of the base polymer film (A) is 0.5.
67 mmol / g, that of the quaternized polymer film (A) was 0.25 mmol / g. From this result, it can be seen that the quaternization ratio is about 63%.

[0032]

Embedded image The quaternized polymer solution (A) was diluted with THF to give 1%, 7%
%, And immerse the existing porous hollow fiber made of polypropylene for artificial lungs in each of these solutions, then pull it up.
The quaternized polymer was coated by drying at 40 ° C. for 1 hour. The hollow fiber before and after the coating operation was weighed to determine the coating agent fixing rate. The calculation of the coating agent fixing rate was performed using the following equation. [Coating agent fixation rate (%)] = [(WD) / W] × 100 where W is the weight of the coating-only hollow fiber (A), D
Indicates the weight of the hollow fiber before coating. (The same applies in Table 1.) The results are shown in Table 1 below.

[0033]

[Table 1]

Each hollow fiber (A) was coated with a 2% heparin solution (the solvent was THF / water = 1/9 by weight).
And heparinized at 60 ° C. for 12 hours to obtain a heparinized hollow fiber (A).

The above heparinized hollow fiber was placed in the femoral vein of a rabbit, and the antithrombotic properties were evaluated in vivo. The detailed experimental method is as follows. Under rabbit anesthesia with pentobarbital, the femoral vein was peeled off from a rabbit (Japanese white, ♂, 2.5-3.0 Kg), the peripheral side was ligated with a thread, and a portion 2-3 cm from the thread was clamped with vascular forceps. After that, a portion 5 mm from the thread was cut to 1/4 to 1/3 of the blood vessel diameter with an ophthalmic scissor, and a hollow fiber to be used for the test was inserted toward the center of 17 cm from there. About 1cm from the insertion position,
Sew it on the end of the hollow fiber that is out of the blood vessel,
The hollow fiber was prevented from being washed away. The detached area was sutured, antibiotics were administered, and the animals were reared for 2 weeks until the samples were removed. A median incision is made under anesthesia with heparinized pentobarbital, and blood is removed from the abdominal aorta using an appropriate tube and sacrificed.The hollow fiber insertion part is then incised together with the blood vessel and taken out. Was cut, and the hollow fiber and the inside of the blood vessel were photographed, and the hollow fiber was visually observed to evaluate it on a 5-point scale. The results are shown in Table 2.

The heparinized hollow fibers are bundled in a loop of 90 turns, one end of which is placed in a cylindrical container of an appropriate material, and an epoxy or urethane potting agent is poured into the container and hardened. The solidified portion was cut at the position where all the hollow fibers were cut to form a module for measuring gas permeability. The module is set in a metal pressure vessel, which has an airtight structure and is designed such that the hollow fiber inner wall communicates with the outside air by setting the cylindrical vessel portion in a predetermined position, and is set at 1.0 kg / kg. Oxygen or carbon dioxide gas was fed at a pressure of cm ² , and the gas permeability of the sample was measured by measuring the amount of gas that permeated through the hollow fiber wall and led out of the pressure vessel. The results are shown in Table 2.

[0037]

[Table 2] In Table 2, in the column of antithrombotic properties, a indicates that platelet aggregation, thrombus, and fibrin were not formed together, b indicates that fibrin or platelet aggregation was observed, but no thrombus was generated, and c was the same as b. Indicates that a small amount of thrombus formation is observed, d indicates that the formation of thrombus is similar to b, but considerable formation of thrombus is observed, and e indicates that a large amount of thrombus formation is observed as in b.

Example 2 To 100 parts of the base polymer solution (A) obtained in Example 1, 5.99 parts of ethyl iodide was added, and the mixture was reacted at 60 ° C. with stirring to obtain a third polymer in the base polymer. The quaternary amino group was quaternized. This quaternized polymer solution (B) is diluted with dioxane to form a 5% solution,
In the same manner as in Example 1, a quaternized polymer film (B) having a thickness of 50 μm was obtained. The content of basic nitrogen in this quaternized polymer film (B) was 0.20 mmol / g. The results show that the quaternization ratio is about 70%. Using a quaternized polymer film (B) to coat a porous hollow fiber made of polypropylene for artificial lung,
A hollow fiber (B) was obtained with the coating agent. Table 1 shows the coating agent fixing rates. Further, heparinized hollow fiber (B) was obtained in the same manner as in Example 1, and the antithrombotic property and gas permeability were measured by the method of Example 1. The results are shown in Table 2.

<Comparative Example 1> A commercially available porous hollow fiber made of polypropylene for artificial lung was left untreated in Example 1.
The antithrombotic properties and gas permeability were measured in the same manner as described above. The results are shown in Table 2.

Comparative Example 2 Acrylonitrile (24 parts)
And acrylamide (89 parts) were thoroughly mixed with dimethyl sulfoxide (126 parts). Then, dodecyl mercaptan (0.2 part) as a chain transfer agent and bromoform as a polymerization initiator were added, and a distance of 10 cm from a 100 W high-pressure mercury lamp was added. By irradiating with light for 7 hours, the photopolymerized stock solution was poured into a large amount of methanol and precipitated and solidified to obtain a trunk polymer (24.4 parts). 10 g of the stem polymer thus obtained was added to dimethyl sulfoxide (120 g).
Part), add dimethylaminoethyl methacrylate, and add 1
By irradiating with light for 9 hours, photografting was performed, and the stock solution was poured into methanol to precipitate and coagulate, thereby obtaining a graft polymer (12.8 parts). The graft polymer thus obtained was dissolved in dimethylformamide, quaternized by adding ethyl bromide, and then coated with a polypropylene porous membrane for artificial lungs in the same manner as in the Example. I got This coating only hollow fiber (R)
For each sample, the coating agent fixing rate, antithrombotic property, and gas permeability were measured in the same manner as in Example 1. The results are shown in Tables 1 and 2, respectively.

As is apparent from the above results, the hollow fiber of Comparative Example 2 coated with a polymer containing no polydimethylsiloxane unit has poor gas permeability and insufficient antithrombotic properties. Although the polymer of Comparative Example 1 is a porous membrane without coating, it has excellent gas permeability,
The antithrombotic properties are quite poor. On the other hand, the hollow fibers of the examples have good antithrombotic properties and gas permeability. That is, it is clear that the artificial lung membrane of the present invention is extremely useful as a material having good gas permeability and long-term blood compatibility.

[0042]

The artificial lung membrane coated with the specific polyurethane or polyurethaneurea of the present invention has good gas permeability, has no obstruction, and has long-term blood compatibility. , Heart-lung machine, artificial lung, ECM
As a material such as O, it has excellent suitability.

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. , Polyurethane or polyurethane urea,
Polyolefin hollow fibers are coated with polyurethane (PU) or polyurethane urea (PUU) in which some or all of the tertiary amino groups contained in the polyurethane or polyurethane urea are quaternized. An artificial lung membrane with excellent blood compatibility. 2. A membrane for an artificial lung having excellent blood compatibility, wherein a cyclic ether is used as a solvent for coating with PU or PUU according to claim 1. 3. The artificial lung membrane having excellent blood compatibility, wherein the ratio of PU and PUU is 1 to 50% by weight in the artificial lung membrane according to claim 1. 4. The P according to claim 1, 2 or 3,
An artificial lung membrane excellent in blood compatibility, which is obtained by further treating U or PUU with heparins.