JPH04250168A - Manufacture of gas permeable material excellent in blood adaptability - Google Patents

Abstract

PURPOSE:To provide a material having excellent gas permeability over a long period without causing a wet lung and suitable to gas exchange membrane of an artificial heart-lung device by treating a specified polyurethane or polyurethane urea with a heparin. CONSTITUTION:A polyether polyol having a hydroxyl group or amino group reactable with a diisocyanate or isocyanate group at the molecular terminal, and, if necessary, other polyamines or polyols are mutually reacted to provide a polyurethane or polyurethane urea. A part or all of the ternary amino groups contained in such polyurethane or polyurethane urea are made into quaternary salts by use of a halogenated alkyl or active ester. Thereafter, heparin treatment is conducted by use of a mixed solvent of a water-soluble organic solvent and water to provide a desired gas permeable material excellent in blood adaptability.

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
This invention relates to a method for manufacturing oxygen exchange membrane materials 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-
Blood direct contact type (bubble type, film type, etc.); (2) Type that performs gas exchange through small holes (diameter of several hundred to several thousand angstroms) (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 perform cardiopulmonary function for a long period of time.

In the type (2) in which gas exchange occurs through small holes, there is no direct contact between the blood and gas as in the type (1), so damage to blood cells and gas bubbles mixing into the blood may occur. Such problems will be resolved. However, because water in the blood and plasma components seep out through the small pores, the gas exchange capacity 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. 376
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 diamino polysiloxane, an isocyanate compound, and a polyvalent amine. Furthermore, JP-A-60-241
Specification No. 567 (Polymer Basic Technology Research Group Number: PM-8
No. 0) discloses a gas selective permeation membrane made of polyurethaneurea obtained by reacting diaminopolysiloxane, an isocyanate compound, and a polyhydric hydroxy compound having tertiary nitrogen. Although these polymers have relatively high strength, their blood compatibility is still not sufficient, and the above problems (b) and (c) 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. . Molded bodies obtained from this material slowly release heparin from their surfaces, thereby 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, making it difficult to put it to practical use as a membrane material for oxygenators.

Furthermore, Japanese Patent Publication No. 54-18518 discloses that a copolymer containing a hydrophilic 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 a gas permeable segment, 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. If the cationic copolymer contains 5 to 80% water by weight when it is in parallel with water, water and plasma will pass through the membrane made of this copolymer (wet run), and over time Gas permeability decreases and active ingredients in the body leak out, making it difficult to sustain the life of the living body.

0010

SUMMARY OF THE INVENTION The present invention solves the above-mentioned drawbacks of the prior art, and has the object of having long-term gas permeability without causing wet rungs; Another object of the present invention is to provide a material that has excellent long-term blood compatibility and is easy to form into a thin film, which is optimal for a gas exchange membrane for an artificial heart-lung machine.

The gas permeable material having excellent blood compatibility of the present invention is diisocyanate (DI): a polysiloxane having a hydroxyl group or an amino group at the molecular end that can react with an isocyanate group (NOPS): a tertiary amino group. A polyurethane or polyurethane urea obtained by reacting a polyether polyol (NPO) having This method is characterized by converting the group into a quaternary salt with an alkyl halide or an active ester, and treating it with heparin using a mixed solvent of a water-soluble organic solvent and water as the solvent. The gas permeable material with excellent blood compatibility of the present invention is characterized by being formed by condensing the above-mentioned polyether polyol having a tertiary amino group containing 50 mol% or more of an amine diol represented by formula 1. shall be.

The diisocyanates used in the polyurethane or polyurethaneurea, which is the gas permeable material of the present invention, include diisocyanates (aromatic,
aliphatic, alicyclic) can be used. As the aromatic diisocyanate, p-phenylene diisocyanate,
o-phenylene diisocyanate, m-phenylene diisocyanate, 2,4-tolylene diisocyanate, 2
, 6-tolylene diisocyanate, xylylene diisocyanate, 4,4'-diphenylmethane diisocyanate, 4,4'-diphenylpropane diisocyanate,
There are aromatic diisocyanates having 8 to 25 carbon atoms such as naphthalene diisocyanate. Examples of the aliphatic diisocyanate include aliphatic diisocyanates having 6 to 20 carbon atoms, such as hexamethylene diisocyanate, heptamethylene diisocyanate, octamethylene diisocyanate, nonamethylene diisocyanate, and decamethylene diisocyanate. As the alicyclic diisocyanate, 4
, 4'-dicyclohexylmethane diisocyanate, and isophorone diisocyanate. The above diisocyanate is 2
A mixture of two or more species may be used. Hereinafter, two or more of the 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.

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:

[0014]

[Case 2]

(Here, in chemical formula 2, X and Y each independently represent -OH, -NH2 or a carbon number of 2 to 10
R1 and R3 are each independently an alkylene group, oxyalkylene group, aralkylene group, or arylene group having 2 to 10 carbon atoms; R2 is each independently an alkyl group, aryl group having 1 to 10 carbon atoms, or It is an aralkyl group; n is an integer of 5 to 300. )

The molecular weight of this polysiloxane is 20
0 to 20,000, preferably 500 to 8,000, more preferably 1,000 to 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 present invention is obtained by polycondensing the amine diol of formula 1 with a strong acid catalyst. Total number of carbons is 2~
Preference is given to using 10, preferably 3 to 8 amine diols. When the total number of carbon atoms is 3 or less, it has high hydrophilicity and high permeability to water and plasma, and at the same time has high water absorption, so even after quaternization and heparinization, the heparin release rate is fast and 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.

Suitable 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, and 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 -4-aza-2,6-heptanediol,
Examples include 4-octyl-4-aza-2,6-heptanediol. Strong acids used as catalysts include:
Examples include phosphorous acid, hypophosphorous acid, pyrophosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, etc., and these are 0.01 to 8 mol%, preferably 0.
．． It is used in a proportion of 1 to 3 mol%.

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. Examples of the aliphatic or alicyclic diols include ethylene glycol,
These include propylene glycol, butanediol, neopentyl glycol, and cyclohexanedimethanol. Examples of the polyoxyethylene glycol include polyethylene glycol, polypropylene glycol, polytetramethylene glycol, and the like.

To prepare the aminopolyether polyol, first, the amine diol of formula 1 is mixed with other diols as required, the above catalyst is added, and the mixture is heated to
Heating at 270°C, preferably 200-250°C, for 1-30 hours, preferably 3-30 hours while distilling off the water produced.
Allow to react for 20 hours. Next, for 0.5 to 6 hours, preferably 1 to 4 hours, the temperature is 10 mmHg or less,
Preferably, the pressure is reduced to 3 mmHg or less. By reacting under reduced pressure and at the above temperature for 1 to 10 hours, preferably 2 to 7 hours, an aminopolyether polyol having a molecular weight of 200 to 8,000, preferably 500 to 4,000 is obtained. The basic nitrogen content of this aminopolyether polyol is 1.0 to 15.0%, preferably 2.0 to 11%.
．． It is 0%. When preparing the polyurethane or polyurethaneurea of the present invention, the aminopolyether polyol obtained by each of the above methods has a tertiary amino group present in the molecule of 0.01 to 3.00 mmol in the polyurethane or polyurethaneurea. /g, preferably 0.05
It is used in a proportion of ~2.00 mmol/g.

Other polyols or polyamines which are optionally used in the preparation of the polyurethane or polyurethane urea of the 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. The above diols include ethylene glycol, propylene glycol, 1,4-butanediol, neopentyl glycol, 1,5-pentanediol, 1,6-hexanediol, 1,4-cyclohexanedimethanol, 1,3-cyclohexane There are aliphatic and/or alicyclic diols having 2 to 20 carbon atoms such as dimethanol. The above diamines include aliphatic and /or aromatic diamines.

The oxyalkylene glycols mentioned above 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, propylene diamine, 1,4-
Particularly preferred are butylene diamine and 1,6-hexamethylene diamine. As the above-mentioned high molecular weight polyol,
Examples include polyoxyalkylene glycol and polyester diol. The polyoxyalkylene glycol has a molecular weight of 300 to 15,000, preferably 800 to 15,000.
8000 polyethylene glycol, polypropylene glycol, polytetramethylene glycol, etc. 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.

[0023] Both the polyurethane and polyurethane urea of the present invention can be prepared by known methods. 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 an active solvent and heated at 30-150°C, preferably 40-120°C for 5-300 minutes, preferably 15
The reaction is carried out with stirring under a nitrogen stream for ~120 minutes. This is added to the above-mentioned aminopolyether polyol (NPO) and optionally the above-mentioned low molecular weight chain extender (
low molecular weight diol) and reacted at 0 to 100°C, preferably 5 to 80°C for 15 to 300 minutes to extend the chain,
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: polysiloxane polyol,
Molar ratio with aminopolyether polyol is 100/1
~1/3, preferably 20/1 to 1/5; the molar ratio of polysiloxane polyol and aminopolyether polyol, i.e. NOPS+NPO, to polyol, which is a low molecular weight chain extender (used if necessary) is 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 using any of the known polyurethaneurea preparation methods. Among these, solution polymerization method is particularly suitable. When polyurethane urea is prepared by a solution polymerization method, 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 at 0 to 150°C, preferably at 10 to 100°C, as in the case of the polyurethane above.
The reaction is allowed to proceed for 300 minutes, preferably 15-120 minutes. This is cooled to 0 to 40°C, preferably 5 to 20°C, and the polysiloxane shown in Formula 2 above and having an amino group at the terminal and, if necessary, a low molecular weight chain extender (low molecular weight diamine) are added. A solution dissolved in an active solvent is added dropwise and reacted to obtain a polyurethane urea having a desired molecular weight. In this reaction, since the polymer produced has urea bonds, the solvent used is N,N-
Amide solvents such as dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; or mixed solvents of these with dioxane, tetrahydrofuran and the like are suitable. It is also recommended to add salts such as LiCl, LiBr, CaCl3, etc. to increase the solubility of the resulting polymer. Other conditions such as the orientation 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 thin film shape as described below and used as a gas permeable material in an artificial heart-lung machine or the like. Furthermore, in the polyurethane or polyurethane urea of the present invention, it is necessary to quaternize the tertiary amino group in the molecule and to bond heparin or a similar compound thereof (hereinafter referred to as heparins) to it. By doing so, blood compatibility is improved. Binding of heparins is carried out by treating polyurethane or polyurethaneurea with a quaternizing agent to quaternize the tertiary amino groups in the molecule, and then treating with heparins to form a polyion complex. As such a quaternizing agent, at least one of alkyl halides, aralkyl halides, allyl halides, and active esters having 1 to 10 carbon atoms, preferably 2 to 8 carbon atoms, 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 quaternizing polyurethane or polyurethane urea, for example, the polymer is dissolved in a suitable solvent and the above-mentioned quaternizing agent is added thereto and reacted; or the above-mentioned quaternizing agent solution is added after molding the polymer. It is carried out by a method of contacting and reacting. A method of reacting in a solution is more preferred. For example, a quaternizing agent is added to a solution of polyurethane or polyurethane urea after completion of polymerization, and
The reaction is preferably carried out at 40 to 80°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.

[0028] The polyurethane or polyurethane urea containing a quaternized amino group is made into desired molded products such as membranes and hollow fibers. By bringing heparins into contact with this, the heparins are bound (heparinized). The above-mentioned polyurethane or polyurethane urea molded product having a quaternized amino group is mixed with 0.1 to 1 heparin.
0%, preferably 0.5 to 5% aqueous solution (a mixed solvent of water and a water-soluble organic solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran or ethanol) at 20 to 100°C, Preferably at 40-80°C for 0.1-40 hours, preferably 0.
Heparinization is performed by soaking for 5 to 30 hours. Here, heparin includes natural or synthetic polymer compounds having heparin: chondroitin sulfate, -SO3H, -NHSO3H groups, and the like. In the present invention, water-soluble organic solvents include cyclic ethers such as tetrahydrofuran, tetrahydropyran, and dioxane, amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and N-methylsuccinimide, and acetone. Examples include ketones such as , methyl ethyl ketone, and alcohols such as methanol, ethanol, and isopropanol, but cyclic ethers and amides are preferred, and tetrahydrofuran, tetrahydropyran, dimethylformamide, and dimethylacetamide are more preferred. . In the case of a cyclic ether, the mixing ratio of the water-soluble organic solvent (S) and water (W) is expressed as S to W+S (the same applies hereinafter): 5
-40%, preferably 10-30%, amides 40-80%, preferably 55-75%, ketones 5-40%, preferably 10-30%, alcohols Sometimes 40-90%, preferably 60-80%
Among these, the most preferred are 15-25% of tetrahydrofuran and 5% of dimethylformamide.
5-75% (all indications for W+S of S above are weight %).

The polyurethane or polyurethane urea of the present invention can be spun into hollow fibers to form a hollow fiber membrane by a conventional method, or dissolved in an appropriate solvent, cast on a flat plate, and dried to form a thin film. . This is further heparinized as described above to obtain a desired gas permeable material. When the material of the present invention is utilized as an oxygen exchange membrane in a 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. When heparinized materials are used, heparin compounds on the polymer are slowly released, resulting in even better anticoagulation properties. 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 material of the present invention can be used for medical oxygen enrichment membranes used in oxygen inhalation therapy for respiratory patients, oxygen enrichment membranes for gas combustion, and the like. Due to its excellent antithrombotic properties, it is also recommended for use as a coating material for medical devices that come into contact with blood.

[0030]

[Examples] The present invention will be explained below using examples. Parts in the examples mean parts by weight. <Example 1> 1472 parts of 4-methyl-4-aza-2,6-heptanediol, 591 parts of 1,6-hexanediol
and 12.3 parts of phosphorous acid were charged into an autoclave and heated at 200 to 220°C under constant pressure under nitrogen gas while stirring.
The reaction was carried out by heating for 6 hours while distilling off the produced water. Then, from 760 mmHg to 0.3 mmHg at 220°C
The pressure was reduced over 2 hours to
The reaction was continued for 3 hours at mHg. In this way, O
An aminopolyether polyol (a) having an H value of 57.3 and basic nitrogen of 6.11 mmol/g was obtained. 1800 parts of polydimethylsiloxane diol represented by the following formula 3 having a number average molecular weight of 2000,

[0031]

[Chemical formula 3]

[0032] 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 is tetrahydrofuran (hereinafter abbreviated as THF)
It was dissolved in a mixed solvent of 1,994 parts of dimethylformamide (DMF) and 3,887 parts of dimethylformamide (hereinafter abbreviated as DMF), and reacted at 40°C for 1 hour and then at 60°C for 15 hours under a nitrogen stream. In this way, the solid content is 32%, the viscosity is 3200 poise (
A base polymer solution A was obtained. D in this solution
MF was added and stirred to make a 5% solution. 5% solution 10
After applying it uniformly on 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.
A base polymer film A having a thickness of 50 μm was obtained.

Furthermore, 4.58 parts of hexyl iodide was added to 100 parts of the 10% base polymer solution obtained by diluting with DMF, and the mixture was reacted with stirring at 70°C to convert the tertiary amino groups in the base polymer into 4. We graded the results. This solution was diluted with dioxane to make a 5% solution, and a 50 μm thick quaternized polymer film A was obtained in the same manner as in the case of base polymer A above. Accurately weigh approximately 0.2 g of this base polymer film A and quaternized base polymer film A, dissolve them in 50 ml of dioxane/ethanol (7/3 volume ratio) mixed solvent, and use a potentiometric titration device (manufactured by Hiranuma Seisakusho Co., Ltd., Comtite- 7) using N/10-HC10
4 Titration with a dioxane solution and measuring the basic nitrogen content from its inflection point revealed that the basic nitrogen content of base polymer film A was 0.67 mmol/kg, and that of quaternized film A was 0.25 mmol/g. there were. From this result, it can be seen that the quaternization rate is about 63%. Next, the oxygen permeability coefficient of this film was measured using a gas permeability measuring device (manufactured by Yanagimoto Co., Ltd.), and it was found that the base polymer A was 3.35 x 10-8 cm3 (STP) cm/c.
m2 ・sec・cmHg, 3.7 for quaternized film A
8×10-8 (hereinafter, unit: cm3 (STP)・cm/
cm2・sec・cmHg are omitted. )Met. Next, each film was immersed in a 1% aqueous heparin solution (the solvent was a mixture of 30 parts by weight of dimethylformamide and 20 parts by weight of water) and treated at 70°C for 2 hours to perform heparinization. And heparinized quaternized polymer film A was obtained. These films were cut into circles with a diameter of 3 cm and placed in physiological saline at 37°C for 1 hour.
After being immersed for a week, the film was thoroughly rinsed with distilled water and the water on the film surface was absorbed with filter paper. This film was pasted in the center of a watch glass with a diameter of 10 cm, 200 μl of citrated plasma from a rabbit (Japanese white breed) was collected on the film, and 1/2
Add 200 µl of a 40 molar calcium chloride aqueous solution, float the watch glass in a constant temperature water bath at 37°C, and stir by hand to mix the internal solution until it solidifies (the point at which the plasma stops moving) from the time calcium chloride is added. Measure the time until
It was divided by the solidification time on glass (measured separately as a control) and expressed as a relative value.

[0034] Further, the various films obtained were immersed in distilled water at 20°C for 24 hours, the surface water was wiped off, the weight was measured, and the water absorption rate was determined. The water absorption rate was calculated using the following formula. Water absorption rate (%)={(WD)/D}×100 In the above formula, W represents the weight of the film after immersion, and D represents the weight of the film when dried. The above results are shown in Table 1 below. The unit of oxygen permeability coefficient in Table 1 is (cm3 (STP)・cm)
/(cm2・sec・cmHg).

[0035]

[Table 1]

<Example 2> 3-n-butyl-3-aza-
8040 parts of 1,5-pentanediol and 10 parts of phosphorous acid
．． 3 parts were placed in an autoclave and heated at 200 to 230° C. for 26 hours under constant pressure under a nitrogen stream while stirring, and the reaction was carried out while distilling off the produced water. Next, the pressure was reduced from 760 mmHg to 0.3 mmHg at 230°C over 2 hours, and the reaction was further continued at 230°C and 0.3 mmHg for 3 hours. In this way, aminopolyether polyol (b) having an OH value of 64.7 and basic nitrogen of 6.75 mmol/g was obtained. 3240 parts of polydimethylsiloxane represented by chemical formula 3 with a number average molecular weight of 2200, MDI
1195 parts, the above polyaminoether polio 773.
4 parts, dibutyltin dilaurate 0.3 parts and 1,4 parts
-191.1 parts of butanediol with 3782 parts of THF and D
The base polymer solution (solid content 32%, viscosity 1800 poise (30°C)) was dissolved in a mixed solvent with 7564 parts of MF and reacted at 20°C for 1 hour under a nitrogen stream and then heated to 40°C for 20 hours. B) was obtained. This base polymer solution B was treated in the same manner as in Example 1 and quaternized with hexyl iodide. Furthermore, in the same manner as in Example 1, base polymer B, quaternized film B, and heparinized film B were obtained. Their basic nitrogen content is 1.08 mm each
l/g and 0.410 mmol/g. From this result, it can be seen that the quaternization rate is about 62%. Then, in the same manner as in Example 1, the oxygen permeability coefficient, relative coagulation time, complement activity, and water absorption rate were measured. The results are shown in Table 1.

<Example 3> The quaternized film obtained in Example 2 was prepared using a 1% heparin solution (the solvent was 1% tetrahydrofuran).
0 parts by weight and 40 parts by weight of water) and 70 parts by weight.
℃ for 2 hours to perform heparinization, and heparinization 4
A graded film C was obtained. Table 1 shows the results of various measurements.

Comparative Example 1 The quaternized film obtained in Example 2 was treated with a 1% heparin aqueous solution at 70° C. for 2 hours to obtain a heparinized quaternized film D. I got it. Then, in the same manner as in Example 1, the oxygen permeability coefficient, relative coagulation time, complement activity, and water absorption rate were measured. The results are shown in Table 1.

<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 ethyl bromide was added to quaternize it, and then it was formed into a film (E). Then, in the same manner as in Example 1, the oxygen permeability coefficient, relative coagulation time, complement activity, and water absorption rate were measured. The results are shown in Table 1.

As is clear from the results in Table 1, the polymer of Comparative Example 2 (E), which does not contain polydimethylsiloxane units, has poor gas permeability, whereas the polymer of Example has good gas permeability. . At this stage, the polymer (D) of Comparative Example 1 has performance comparable to that of the polymer of Examples.

<Example 5> Examples 1 to 3 and Comparative Example 1
, 200 ml of heparinized fluid A to E obtained in 2.
The film was immersed in a physiological saline solution and eluted for 2 weeks while exchanging the physiological saline solution every day. The relative clotting time of the eluted film was measured and the results are shown in Table 2 below.

[0042]

[Table 2]

From the results in Table 2, it can be seen that the example in which a mixed solvent of a water-soluble organic solvent and water was used as the solvent for heparinization showed good blood compatibility even when elution was performed in physiological saline for 2 weeks. However, in the comparative example in which water was used as the solvent for heparinization, heparin elutes quickly, so if the immersion time exceeds 3 days, the heparin effect is completely lost and solidification occurs. From the above reasons, it is clear that the polymers of the present invention have good gas permeability and long-term blood compatibility.

[0044]

[Effects of the Invention] The specific heparinized polyurethane or polyurethane urea obtained by the specific production method of the present invention has good gas permeability and long-term blood compatibility. , artificial heart-lung machine, artificial lung, EC
It has excellent suitability as a material for MO etc.

Claims (2)

[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 another polyamine or polyol, some or all of the tertiary amino groups contained in the polyurethane or polyurethane urea are converted into a quaternary salt with an alkyl halide or an active ester, A method for producing a gas-permeable material with excellent blood compatibility, characterized by using a mixed solvent of a water-soluble organic solvent and water as a solvent and treating it with heparin. 2. A method for producing a gas permeable material with excellent blood compatibility, characterized in that the NPO according to claim 1 contains 50 mol % or more of an amine diol represented by the following chemical formula 1. [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. )