JPH04325161A - Membrane for artificial lung having excellent blood affinity - Google Patents

Abstract

PURPOSE:To provide the membrane for artificial lungs which has high strength, does not clog, does not induce a wet lung over a long period of time, and has excellent blood affinity and gas permeability. CONSTITUTION:This membrane for artificial lungs consists of hollow fibers of a polyolefin system as a base material and is formed by coating the surface of this base material with polysiloxane or polyurethane or polyurethane urea contg. specific polyether polyol.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to an artificial heart-lung machine used to maintain blood circulation and oxygen supply during open-heart surgery, an artificial lung that takes over the lung function of patients with lung failure, and long-term extracorporeal circulation. ECMO (Extr
a Corporate Membrane O
It relates to oxygen exchange membranes for gas exchangers such as xygenator).

0002

[Prior Art] Currently, the gas exchanger (the part that adds oxygen to blood and removes carbon dioxide to convert venous blood into arterial blood) of commercially available heart-lung machines used in open heart surgery Depending on the mechanism, it is roughly divided into the following three types: (1) Gas-
Direct blood contact type (bubble type, film type, etc.); (2) Type that performs gas exchange through small holes (several hundred to several thousand angstroms in diameter) (hollow fiber type, laminated type, etc.); (3)
) Gas diffusion type (a type in which gas dissolves and diffuses into a homogeneous membrane and permeates through the membrane).

0003

[Problems to be Solved by the Invention] Among the above-mentioned conventional techniques, (1) injects oxygen directly into venous blood in the form of bubbles,
It is the type that causes arterial blood. In this method, direct contact between blood and oxygen gas destroys red blood cell membranes and increases free hemoglobin. In other words, hemolysis is likely to occur. Furthermore, since oxygen gas is directly blown into the blood, this gas remains in the blood in the form of fine bubbles. This is difficult to remove and causes great damage to the blood. Therefore, it is difficult to provide cardiopulmonary function for a long period of time.

[0004] In the type (2) in which gas exchange occurs through the small holes, there is no direct contact between blood and gas as in the type (1), so there is a risk of damage to the blood or the mixing of gas bubbles into the blood. Such problems will be resolved. However, because water in the blood and plasma components seep out through the small pores, the gas exchange ability decreases over time. Furthermore, the material of such a membrane is
Usually, polypropylene is used, and these materials have poor blood compatibility. In other words, when these materials are used, activation of blood coagulation factors and complement occurs, and furthermore, platelets and white blood cells are likely to aggregate or thaw. To suppress these reactions, it is necessary to administer large amounts of anticoagulants such as heparin. Large doses of heparin tend to cause bleeding, which can be life-threatening. As described above, it is impossible to use the type (2) type gas exchanger for a long period of time because organ failure due to bleeding or damage to blood cell components occurs frequently.

In type (3), gas exchange is performed through a homogeneous membrane surface, so there is no problem of damage to blood cells or incorporation of gas bubbles into the blood as in type (1), and (2) Unlike other types, it does not have the disadvantage of exuding water and plasma components. Membranes of this type are usually prepared from silicone rubber (silicone-based polymers). Silicone rubber is said to have relatively good blood compatibility compared to other materials. Thus, among the gas exchangers of types (1) to (3), type (3) is considered to be the most suitable. However, this film also has the following drawbacks. (a) Since silicone rubber alone has low strength, it is necessary to increase the film thickness or fill it with filler as a reinforcing agent to maintain the strength. For this reason, gas diffusion slows down and oxygen exchange capacity is low. (b) The blood compatibility of silicone rubber is still not sufficient, and blood coagulation occurs, so large doses of heparin are required when using it, which can easily cause bleeding, which can be life-threatening. I'm going to call you. (c) Activation of complement causes changes in the blood coagulation system, increased permeability of blood vessel walls (for white blood cells, lymphocytes, etc.), and an increase in white blood cells. As a result, fever and shock symptoms may occur, which can be life-threatening, and recovery after surgery may be delayed. An artificial heart-lung machine having this type of gas exchanger can only be used for two to three days at most, and the survival rate is close to zero if the machine continues to be used for a longer period of time.

For example, the following polymers have been studied as materials that can be used in place of the silicone rubber film in (3) above. Examples for improving the strength of (a) include U.S. Pat.
No. 419,635 discloses the production of silicone polycarbonate copolymers. Additionally, U.S. Patent No. 3767
No. 737 discloses a method for producing a thin film made of the copolymer. JP-A-61-430 discloses a selective gas permeable membrane made of polyurea obtained by reacting diaminoliposiloxane, an isocyanate compound, and a polyvalent amine. Furthermore, JP-A-60-2415
Specification No. 67 (Polymer Basic Technology Research Group Number: PM-80
) discloses a gas selective permeation membrane made of polyurethaneurea obtained by reacting diaminopolysiloxane, an isocyanate compound, and a polyhydric hydroxy compound containing tertiary nitrogen. Although these polymers have relatively high strength, their blood compatibility is still not sufficient.
Problems (b) and (c) above have not yet been solved. Furthermore, the polymers described in JP-A-61-430 and JP-A-60-241,567 have two types of bonds with completely different polarities, siloxane bonds and urea bonds, in their molecules, so when forming a film, It is difficult to select a solvent for this, making it difficult to form a thin film.

As a material that can solve the blood coagulation problem described in (b) above, there is a material described in Kobunshi Ronshu, 36, 223 (
(1979) discloses heparin bound to certain polymers through ionic bonds. The polymer used is a tertiary copolymer of dimethylaminoethyl methacrylate, methoxypolyethylene glycol methacrylate, and glycidyl methacrylate, whose tertiary amino groups are quaternized, blended with polyurethane, and crosslinked by heat treatment. . Moldings made from this material slow release of heparin from its surface, thus inhibiting blood clotting. However, the gas permeability is not sufficient and it cannot be used for artificial heart-lung machines. JP-A-58-188458 discloses an antithrombotic elastomer made of polyurethane or polyurethane urea containing polysiloxane in its main chain. but,
The antithrombotic properties of this elastomer cannot be said to be sufficiently high. Furthermore, gas permeability is not sufficient and complement activity is not suppressed, so it cannot be used for the above-mentioned purposes.

Many materials that can solve the problem of complement activation in blood described in (c) are found in the field of dialysis membranes for dialysis-type artificial kidneys. For example, artificial organs 16(2), 818
-821 (1987), the diethylaminoethylated cellulose membrane has the following properties compared to the original cellulose membrane:
It has been reported that it significantly suppresses complement activation during dialysis. However, this membrane has poor gas permeability and is therefore difficult to be used as a membrane material for oxygenators.

Furthermore, Japanese Patent Publication No. 54-18518 discloses that a new copolymer containing an aqueous component, a hydrophobic component, and a quaternary ammonium salt component as essential units and heparin exhibits a negative standard membrane potential difference. An anticoagulant medical material is disclosed. However, since this material does not have gas permeable segments, it not only has no gas permeability at all, but even if a gas permeable segment is introduced into this copolymer, it is not mentioned in the text. 5 to 80% by weight of the cationic copolymer in equilibrium with water.
If the copolymer contains water, water and plasma will pass through the membrane made of this copolymer (wet rung), and gas permeability will decrease over time, and active ingredients in the body will leak out. It becomes difficult to sustain the life of living organisms.

[0010] In order to improve the above-mentioned conventional drawbacks, as a result of intensive research, we have developed a gas permeable material that has long-term gas permeability without causing wet lungs and has excellent long-term blood compatibility. We succeeded in this and have already applied for a patent. However, since this material has a limited content of polysiloxane, which is a segment having gas permeability, its gas permeability was slightly inferior compared to commercially available silicone rubber membranes. Further, although polyurethane has been introduced to maintain strength, the strength is still not sufficient, and when formed into hollow fibers, there are drawbacks such as clogging in some parts.

[0011]

[Means for Solving the Problems] The present invention solves the above-mentioned conventional drawbacks, and its purpose is to provide long-term gas permeability with almost no occlusion and without causing wet rung over a long period of time. It is an object of the present invention to provide a gas exchange membrane for an artificial heart-lung machine, which has the following properties and has excellent long-term blood compatibility.

[0012] The oxygenator membrane having excellent blood compatibility of the present invention is made of diisocyanate (DI): a polysiloxane (NOPS) having a hydroxyl group or an amino group capable of reacting with an isocyanate group at the molecular end (NOPS): a tertiary amino group. A polyurethane or polyurethane urea obtained by reacting a polyether polyol (NPO) with: and other polyamines or polyols as necessary, some or all of the tertiary amino groups contained in the polyurethane or polyurethane urea Quaternary chlorinated polyurethane (PU)
Alternatively, it is characterized in that a polyolefin hollow fiber is coated with polyurethane urea (PUU). The total number of carbon atoms contained in the side chain groups bonded to the quaternary chlorinated nitrogen is preferably 7 to 16. The number of carbon atoms in the side chain referred to here refers to the number of carbon atoms in the side chain bonded to the tertiary amine in the NOP of the present invention, for example, as shown in the following chemical formula 1, which is preferably summarized and included in the NOP of the present invention. It refers to the total number of carbon atoms in R2 and the number of carbon atoms in the group from the quaternizing agent. The membrane for an artificial lung having excellent blood compatibility of the present invention is characterized in that a cyclic ether is used as a solvent when coating with the above-mentioned PU or PUU. The oxygenator membrane having excellent blood compatibility of the present invention is characterized in that the proportion of PU and PUU in the coated oxygenator membrane is 1 to 50% by weight. The oxygenator membrane having excellent blood compatibility of the present invention is characterized in that it is obtained by treating the above-mentioned coated oxygenator membrane with heparin.

[0013]

[Chemical 1] (R1 and R3 in Chemical 1 are hydrogen or have 1 carbon number
to 3 alkyl group, R2 has 1 to 1 carbon atoms
0 alkyl group. )

The diisocyanate used in the polyurethane or polyurethaneurea that is the coating material of the present invention includes diisocyanates (aromatic, aliphatic,
alicyclic) can be utilized. Two or more diisocyanates may be used in combination. Hereinafter, two or more of the components used in the polymer serving as the coating material of the present invention, such as polysiloxane and polyether polyol having a tertiary amino group, may be used in combination.

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

[0016]

[Chemical Formula 2] (X and Y in Chemical Formula 2 are each independently -OH,
-NH2 or a substituted amino group having 2 to 10 carbon atoms, R1
and R3 are each independently an alkylene group, oxyalkylene group, aralkylene group, or arylene group having 2 to 10 carbon atoms, and R2 is each independently a carbon number 1 group.
~10 alkyl, aryl, or aralkyl groups, and n is an integer of 5 to 300. )

The molecular weight of this polysiloxane is from 200 to
20,000, preferably 500-8,000, more preferably 1,000-4,000. The content of this polysiloxane in the polyurethane or polyurethane urea obtained is between 20 and 95%, preferably between 30 and 85%.

The polyether polyol (NPO) having a tertiary amino group used in the polyurethane or polyurethane urea serving as the coating material of the present invention is not particularly limited, but preferably NOP containing an amine diol of formula 1.
It can be obtained by polycondensing the amine diol of formula 1 with a strong acid catalyst, but the total number of carbon atoms of R1, R2 and R3 of formula 1 is 2 to 10, preferably 3 to 10.
Preferably, the amine diol No. 8 is used. When the total number of carbon atoms is 3 or less, it has high hydrophilicity, high water and plasma permeability, and high water absorption, so even if it is converted into heparin after quaternization, the heparin release rate is high and it lasts for a long time. Blood compatibility cannot be achieved. Moreover, when the total number of carbon atoms exceeds 10, steric hindrance around the nitrogen atom of the tertiary amino group increases, making quaternization difficult. Furthermore, even if quaternization is allowed to proceed, the steric hindrance is too large, and the salt-forming bond with heparin is weakened, resulting in insufficient heparinization and making it difficult to achieve long-term blood compatibility. Further, it is preferable that R1, R2 and R3 are all linear alkyl groups.

Together with the amine diol represented by formula 1,
Other diols may 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 2,000.

[0020] To prepare the aminopolyether polyol, first, mix other diols as necessary with the amine diol of Chemical Formula 1, add a catalyst, and reduce the amine diol to 150 to 27% under normal pressure.
Heating to 0°C, preferably 200 to 250°C, and distilling off the water produced for 1 to 30 hours, preferably 3 to 20 hours.
Allow to react over time. Then, the pressure is reduced to 10 mmHg or less, preferably 3 mmHg or less, over a period of 0.5 to 6 hours, preferably 1 to 4 hours. When reacted in this reduced pressure state and at the above temperature for 1 to 10 hours, preferably 2 to 7 hours, the molecular weight is 200 to 8000, preferably 500 to 4.
000 aminopolyether polyol is obtained. The basic nitrogen content of this aminopolyether polyol is 1
．． It is 0 to 15.0%, preferably 2.0 to 11.0%. When preparing the polyurethane or polyurethane urea to be used as the coating material of the present invention, the aminopolyether polyol obtained by each of the above methods has 0 tertiary amino groups present in the molecule in the polyurethane or polyurethane urea.
．． 01-3.00 mmol/g, preferably 0.05-3.00 mmol/g
It is used in a proportion of 2.00 mmol/g.

[0021]Other polyols or polyamines which may be used as necessary in the preparation of the polyurethane or polyurethane urea to be used as the coating material of the present invention include, for example, low molecular chain extenders and high molecular weight polyols. Low molecular weight chain extenders include diols, diamines and oxyalkylene glycols. The low molecular weight extenders include ethylene glycol, 1,4-butanediol, 1,
6-hexanediol, neopentyl glycol, ethylene diamine, propylene diamine, 1,4-butylene diamine and 1,6-hexamethylene diamine are preferred. Examples of the high molecular weight polyol include polyoxyalkylene glycol and polyester diol. As polyoxyalkylene glycol, molecular weight is 300
-15,000, preferably 800-8,000 polyethylene glycol, polypropylene glycol, polytetramethylene glycol, and the like. Examples of polyester diols include polyester diols obtained from aliphatic diols having 2 to 10 carbon atoms and aliphatic dicarboxylic acids having 6 to 16 carbon atoms, and polyester diols obtained from caprolactones such as ε-caprolactone. Among these high molecular weight polyols, polyester diols are preferred. The content of the high molecular weight polyol in the resulting polymer is 50% or less, preferably 30% or less.

[0022] The polyurethane or polyurethane urea used as the coating material of the present invention can be prepared by any known method. For example, to prepare polyurethane by a solution polymerization method, first, a polysiloxane represented by Chemical Formula 2 and having a hydroxyl group or an amino group at the molecular end, a diisocyanate, and if necessary, the above-mentioned high molecular weight polyol are added to the isocyanate group. Dissolved in active solvent, 30-15
The reaction is carried out at 0°C, preferably 40-120°C, for 5-300 minutes, preferably 15-120 minutes, with stirring under a nitrogen stream. To this, the above-mentioned aminopolyether polyol (NPO) and, if necessary, the above-mentioned low molecular weight chain extender (low molecular weight diol) were added and heated to 0 to 100°C.
, preferably at 5 to 80°C for 15 to 300 minutes to extend the chain and increase the molecular weight.

Solvents used here include dioxane, tetrahydrofuran, chloroform, carbon tetrachloride, benzene, toluene, acetone, methyl ethyl ketone, N
, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, mixtures thereof, and the like. In particular, dioxane, tetrahydrofuran,
Methyl ethyl ketone, N,N-dimethylformamide,
N,N-dimethylacetamide and mixtures thereof are preferred. During the reaction, a polymerization catalyst is added as necessary. 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 concentration of 1 to 500 ppm, preferably 5 to 100 ppm. For the preparation of polyurethane, a method may also be adopted in which the above-mentioned monomer components to be used are charged at once and melt-polymerized.

In the above polymerization reaction, the mixing molar ratio of each component is as follows. The molar ratio of polysiloxane polyol and aminopolyether polyol is 100/1 to 1
/3, preferably 20/1 to 1/5; the molar ratio of the polysiloxane polyol and aminopolyether polyol, i.e. NOPS+NPO, and the polyol (used if necessary) as a low molecular weight chain extender is 1/3. 10
0 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.

[0025] Any polyurethane urea to be used as a coating material of the present invention can be prepared by a known method. Among these, solution polymerization method is particularly suitable. When polyurethane urea is prepared by solution polymerization, polysiloxane polyols, aminopolyether polyols, and, if necessary, high molecular weight polyols are used. In this case, these and the diisocyanate are dissolved in an inert solvent. This is heated to 0 to 150°C as in the case of polyurethane above.
, preferably at 10 to 100°C for 5 to 300 minutes, preferably 15 to 120 minutes. This is 0-4
Cool to 0°C, preferably 5 to 20°C, and dissolve the polysiloxane shown in Chemical Formula 2 above and having an amino group at the end, and optionally a low molecular weight chain extender (low molecular weight diamine) in an inert solvent. A polyurethane urea having a desired molecular weight is obtained by adding the solution dropwise and reacting. In this reaction, since the resulting polymer has urea bonds,
The solvent used is N,N-dimethylformamide,
Amide solvents such as N,N-dimethylacetamide and N-methylpyrrolidone; or mixed solvents of these with dioxane, tetrahydrofuran, etc. are suitable. For the purpose of increasing the solubility of the resulting polymer, LiCl,
Addition of salts such as LiBr, CaCl2 is also recommended. Other conditions such as the orientation ratio of each component are the same as in the case of polyurethane.

The polyurethane or polyurethane urea thus obtained can be prepared by quaternizing the tertiary amino group in the molecule and by bonding heparin or a similar compound thereof (hereinafter referred to as heparins) to it. is necessary. By doing so, blood compatibility is further improved. Binding of heparins is carried out by treating 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 a carbon number of 1 to
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 carbon atoms, preferably 2 to 8 carbon atoms are suitable. The quaternizing agent is used in an amount of 0.1 to 10.0 times the tertiary amino group in the polymer, preferably 0.
．． It is used at a ratio of 5 to 5.0 moles. For quaternization of polyurethane or polyurethane urea, for example, these polymers are melted in a suitable solvent, and the above-mentioned 4.
A method of adding a grading agent solution is preferred. For example, in a solution of polyurethane or polyurethane urea after polymerization,
Add a grading agent and heat to 20-100°C, preferably 40-8°C.
The reaction is carried out at 0°C for 0.1 to 60 hours, preferably 1 to 30 hours. The quaternization rate of the tertiary amino group thus quaternized is 1 to 100%, preferably 10% or more.

[0027] The polyurethane or polyurethane urea containing quaternized amino groups is dissolved in a cyclic ether solvent and coated on an existing polyolefin porous hollow fiber. Solvents that are inert and exhibit good solubility for the polyurethane or polyurethane urea include amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; tetrahydrofuran and tetrahydrofuran. Examples include 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; however, consider the wettability of the solvent to the polyolefin porous hollow fiber. In this case, it is desirable to use a cyclic ether solvent. Tetrahydrofuran is particularly suitable. The concentration of the polyurethane or polyurethane urea containing a quaternized amino group dissolved in the cyclic ether solvent is adjusted to be 0.5 to 20% by weight, preferably 1 to 15% by weight.

[0028] After immersing a polyolefin porous hollow fiber for an oxygenator in the above-mentioned dissolved polyurethane or polyurethane urea, it was pulled up and heated at 100°C from 10°C.
Dry at 15 to 60°C, preferably 1 to 180 minutes, preferably 5 to 90 minutes. By performing this operation at least once, the content of polyurethane or polyurethane urea as a coating agent in the coated hollow fiber after drying is 1 to 50% by weight.

A polyolefin porous hollow fiber for an oxygenator coated with polyurethane or polyurethane urea containing a quaternized amino group is brought into contact with heparin to bind the heparin (heparinization). For example, the coated polyolefin porous hollow fiber for oxygenator lungs is coated with 0.1 heparin.
to 10%, preferably 0.5 to 5%, at 20 to 100°C, preferably 40 to 80°C.
Heparinization is carried out by soaking for 1 to 40 hours, preferably 0.5 to 30 hours. The solvent used here is water, cyclic ethers, amides,
Mixtures of water and water-soluble solvents such as ketones and alcohols are preferred, particularly tetrahydrofuran and water, tetrahydropyran and water, N,N-dimethylformamide and water,
A mixture of N,N-dimethylacetamide and water is preferred. Furthermore, the term "heparins" as used herein includes heparin: natural or synthetic polymer compounds having chondroitin sulfate, -SO3H, -NHSO3H groups, and the like.

When the material of the present invention is utilized as an oxygen exchange membrane in an artificial heart-lung machine, oxygen/carbon dioxide gas exchange is advantageously carried out. Moreover, since the material has excellent blood compatibility, shock symptoms caused by blood coagulation and complement activation are extremely unlikely to occur. The use of heparinized materials provides even better anticoagulant properties due to the slow release of heparins on the polymer. In this way, the material of the present invention can be effectively used, for example, in ECMO, which replaces lung function for a long period of time. Furthermore, the present invention can be utilized for medical oxygen enrichment membranes used in oxygen inhalation therapy for respiratory patients.

[0031]

[Examples] The present invention will be explained below using 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 heated at 200 to 230°C at normal pressure under a nitrogen stream while stirring. The mixture was heated for 26 hours to carry out the reaction while distilling off the produced water. Then 760mm at 230℃
The reaction was continued for 3 hours at 0.3 mmHg. In this way, OH number 58.7, basic nitrogen 6.30 m
mol/g of aminopolyether polyol (a) was obtained. 3240 parts of polydimethylsiloxane diol represented by the following formula 3 having a number average molecular weight of 1800, 0.3 part of dibutyltin dilaurate, 1195 parts of 4,4'-diphenylmethane diisocyanate (hereinafter abbreviated as MDI), 827 parts of the above aminopolyether polyol .3 parts and 1
, 191.1 parts of 4-butanediol were dissolved in a mixed solvent of 3802 parts of tetrafodrofuran (hereinafter abbreviated as THF) and 7604 parts of N,N-dimethylformamide (hereinafter abbreviated as DMF), and the mixture was dissolved under a nitrogen stream. , 1 hour at 20℃,
After raising the temperature to 40°C and reacting for 20 hours, the solid content was 32%,
A base polymer solution with a viscosity of 1830 poise (30°C) (
A) was obtained. DMF was added to this solution and stirred to make a 5% solution. After uniformly applying 10 g of a 5% solution onto a 100 cm2 glass plate held horizontally, it was dried at 40°C for 1 hour and at 60°C for 2 hours under a nitrogen stream, and then dried under reduced pressure at 60°C for 15 hours to form a 50 μm layer. A thick base polymer film (A) was obtained. Furthermore, 8.14 parts of hexyl iodide was added to 100 parts of the base polymer solution (A) and reacted with stirring at 60° C. to quaternize the tertiary amino groups in the base polymer. This quaternized polymer solution (A) was diluted with dioxane to make a 5% solution, and the above base polymer solution (A)
A 50 μm thick quaternized polymer film was obtained in the same manner as in the case of Example 1. Accurately weigh about 0.2 g of this base polymer film (A) and quaternized polymer solution (A),
Dioxane/ethanol (7/3 volume ratio) mixed solvent 50
Potentiometric titration device (manufactured by Hiranuma Seisakusho, Comt
When the basic nitrogen content of the base polymer film (A) was titrated with N/10-HC104 dioxane solution and measured from the inflection point, the basic nitrogen content of the base polymer film (A) was 0.67 mmol/g. , that of the quaternized polymer film (A) was 0.25 mmol/g. From this result, it can be seen that the quaternization rate is about 63%.

[0032]

[Chemical 3] The quaternized polymer solution (A) was diluted with THF to give 1%, 7
%, and after soaking the existing polypropylene porous hollow fiber for oxygenator lungs in each of these solutions,
The quaternized polymer was coated by drying at 40° C. for 1 hour. The weight of the hollow fibers before and after the coating operation was measured to determine the coating agent fixation rate. The coating agent fixation rate was calculated using the following formula. [Coating agent fixation rate (%)] = [(WD)/W] x 100
In the above formula, W is the weight of the coating material hollow fiber (A), D
indicates the weight of the hollow fiber before coating. (The same applies to Table 1.) The results are shown in Table 1 below.

[0033]

[Table 1]

[0034] Each coating hollow fiber (A) was mixed with a 2% heparin solution (solvent: THF/water = 1/9 weight ratio).
The fibers were immersed in water for heparinization at 60° C. for 12 hours to obtain heparinized hollow fibers (A).

The above-mentioned heparinized hollow fiber was placed in the femoral vein of a rabbit, and its antithrombotic properties were evaluated in vivo. The detailed experimental method is as follows. A domestic rabbit (Japanese white, male, 2.5-3.0 kg) was anesthetized with pentobarbital, the femoral vein was dissected, the distal end was ligated with a thread, and the part 2-3 cm from the thread was clamped with vascular forceps. After that,
Use ophthalmological scissors to cut 5 mm from the thread to 1/4 to 1/4 of the blood vessel diameter.
3, and the hollow fiber used for the test was inserted 17 cm toward the central side from there. 1 from the insertion position
It was sewn to the end of the hollow fiber protruding outside the blood vessel at a distance of about 1.5 cm to prevent the hollow fiber from being washed away. The avulsed area was sutured and antibiotics were administered.
Thereafter, the animals were kept for 2 weeks until sample removal. To take out,
Under anesthesia with heparinized pentobarbital, a midline incision is made, blood is removed from the abdominal aorta using an appropriate tube, and the patient is sacrificed.The hollow fiber insertion site is incised and removed along with the blood vessel, and the blood vessel is incised. In addition to taking photographs of the hollow fibers and the inside of the blood vessels, the hollow fibers were visually observed and evaluated on a five-point scale. The results are shown in Table 2.

The heparinized hollow fibers are bundled into a 90-turn loop, one end is placed in a cylindrical container made of a suitable material, and an epoxy or urethane potting agent is poured in and hardened. A module for measuring gas permeability was created by cutting the solidified part along with the cylindrical container at a position where all the hollow fibers were cut. This module was set in a metal pressure vessel with an airtight structure and designed so that the inner wall of the hollow fiber communicated with the outside air by setting the cylindrical vessel part in a predetermined position. The gas permeability of the sample was measured by feeding oxygen or carbon dioxide gas at a pressure of cm2 and measuring the amount of gas that permeated through the hollow fiber wall surface and led out to the outside of the pressure vessel. The results are shown in Table 2.

[0037]

[Table 2] In Table 2, in the antithrombotic column, a means no platelet aggregation, thrombus, or fibrin formation, b means fibrin or platelet aggregation but no thrombus formation, c means b d is the same as b, but a large amount of thrombus formation is observed; e is the same as b, but a large amount of thrombus formation is observed. It is something.

<Example 2> 5.99 parts of ethyl iodide was added to 100 parts of the base polymer solution (A) obtained in Example 1, and the mixture was reacted with stirring at 60°C. The primary amino group was quaternized. This quaternized polymer solution (B) was diluted with dioxane to make a 5% solution,
In the same manner as in Example 1, a 50 μm thick quaternized polymer film (B) was obtained. The basic nitrogen content of this quaternized polymer film (B) was 0.20 mmol/g. This result shows that the quaternization rate is about 70%. A porous hollow fiber made of polypropylene for use in an oxygenator lung was coated with the quaternized polymer film (B) to obtain a coating material-containing hollow fiber (B). The coating agent fixation rate is shown in Table 1. Further, a heparinized hollow fiber (B) was obtained in the same manner as in Example 1, and its antithrombotic properties and gas permeability were measured by the method of Example 1. The results are shown in Table 2.

<Comparative Example 1> Commercially available porous hollow fibers made of polypropylene for artificial lungs were left untreated in Example 1.
Antithrombotic properties and gas permeability were measured in the same manner as above. The results are shown in Table 2.

<Comparative Example 2> Acrylonitrile (24 parts)
After thoroughly mixing acrylamide (89 parts) with dimethyl sulfoxide (126 parts), dodecyl mercaptan (0.2 parts) as a chain transfer agent and bromoform as a polymerization initiator were added, and the mixture was heated at a distance of 10 cm from a 100 W high-pressure mercury lamp. By irradiating the polymer with light for 7 hours, the photopolymerized stock solution was poured into a large amount of methanol and precipitated and coagulated to obtain a backbone polymer (24.4 parts). 10 g of the backbone polymer thus obtained was mixed with dimethyl sulfoxide (12
0 parts), added dimethylaminoethyl methacrylate, and photografted by irradiating with light from a 100 W mercury lamp at a distance of 10 cm for 19 hours,
The stock solution was poured into methanol to cause precipitation and coagulation to obtain a graft polymer (12.8 parts). The thus obtained graft polymer was dissolved in dimethylformamide and quaternized by adding ethyl bromide, and then coated on a polypropylene porous membrane for oxygenator lungs in the same manner as in the example, and coated with a hollow fiber (R). I got it. This coating material hollow fiber (
Regarding R), the coating agent fixation rate was determined in the same manner as in Example 1,
Antithrombotic properties and gas permeability were measured. The results are shown in Table 1.
, shown in Table 2.

As is clear from the above results, the hollow fiber of Comparative Example 2 coated with a polymer not containing polydimethylsiloxane units has poor gas permeability and does not have sufficient antithrombotic properties. The polymer of Comparative Example 1 has excellent gas permeability because it is a porous membrane that is not coated.
Antithrombotic properties are quite poor. In contrast, the hollow fibers of Examples have good antithrombotic properties and gas permeability. That is, it is clear that the membrane for oxygenator lungs of the present invention is extremely useful as a material having good gas permeability and long-term blood compatibility.

[0042]

[Effects of the Invention] The membrane for oxygenator lungs coated with the specific polyurethane or polyurethane urea of the present invention has good gas permeability, is free from occlusion, and has long-term blood compatibility. , artificial heart-lung machine, artificial lung, ECM
It has excellent suitability as a material such as O.

Claims (4)

[Claims] Claim 1: Diisocyanate (DI), polysiloxane (NOPS) having a hydroxyl group or amino group at the molecular end that can react with an isocyanate group, polyether polyol (NPO) having a tertiary amino group, and optionally Polyurethane or polyurethane urea obtained by reacting other polyamines or polyols 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 converted into quaternary chlorides. ) is used to coat polyolefin-based hollow fibers, and has excellent blood compatibility. 2. A membrane for an artificial lung having excellent blood compatibility, characterized in that a cyclic ether is used as a solvent when coating with PU or PUU according to claim 1. 3. A membrane for an oxygenator lung having excellent blood compatibility, characterized in that the proportion of PU and PUU in the membrane for an oxygenator lung according to claims 1 and 2 is 1 to 50% by weight. 4. An artificial lung membrane having excellent blood compatibility, which is obtained by further treating the PU or PUU of claims 1, 2, and 3 with heparin.