JP3079555B2 - Blood compatible material - Google Patents

Description

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, and a method for controlling the lung function of a patient with lung failure. ECMO (Extra Corporeal Membrane O) used for substitute artificial lung and long-term extracorporeal circulation
The present invention relates to a material having excellent blood compatibility used for an oxygen exchange membrane material of a gas exchanger such as an xygenator.

(Prior art) At present, the gas exchanger (the part that adds enzymes to blood and removes carbon dioxide to convert venous blood into arterial blood) used in the open heart surgery, The mechanism is roughly classified into the following three types: gas-blood direct contact type (bubble type, film type, etc.); type that performs gas exchange through small holes (several hundred to several thousand angstroms in diameter) (hollow fiber type, laminated A gas diffusion type (a type in which gas dissolves and diffuses in a homogeneous film and passes through the film).

Of these, oxygen is directly bubbled into venous blood and blown into the arterial blood. In this method, the blood and oxygen gas come into direct contact, destroying the red blood cell membrane,
Free hemoglobin increases. That is, hemolysis is likely to occur. Further, since oxygen gas is directly blown, this gas remains as fine bubbles in blood. It is difficult to remove it and the blood is severely damaged. Therefore, it is difficult to substitute cardiopulmonary function for a long period of time.

In the type that performs gas exchange through small holes,
Since there is no direct contact between the blood and the gas as in the above type, problems such as damage to blood cells and mixing of gas bubbles into the blood are eliminated. 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 membranes is usually polypropylene or the like, which has 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 use a large amount of an anticoagulant such as heparin. High doses of heparin can cause bleeding and can be life-threatening. Thus, using a gas exchanger of the type for a long time is
This is not possible due to frequent occurrence of organ failure due to bleeding or damage to blood cell components.

Gas exchange is carried out through a homogeneous membrane surface in this type, so there is no problem of damage to blood cells and the incorporation of gas bubbles into blood as in the type, and there is a drawback of exudation of water and plasma components as in the type Nor. 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. As described above, this type is considered to be the most suitable for the gas exchangers of the following types. However, this film also has the following disadvantages. (A) Since silicone rubber alone has low strength, it is necessary to increase the film thickness or to fill a filler as a reinforcing agent to maintain strength. For this reason, the diffusion of the gas becomes slow and the oxygen exchange capacity is low. (B) The blood compatibility of silicone rubber is not yet sufficient, and blood coagulation occurs. Therefore, large doses of heparin are required for use, and bleeding is likely to occur, which is life-threatening. Effect.
(C) The activation of complement causes a change in the blood cell coagulation system, an increase in permeability of blood vessel walls (such as leukocytes and lymphocytes) and an increase in leukocytes. 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, for example, the following polymers have been studied. As an example for improving the strength of (a),
U.S. Pat. Nos. 3,419,634 and 3,419,635 disclose the preparation of silicone-polycarbonate copolymers. Further, U.S. Pat. No. 3,767,737 discloses a method for producing a thin film using the copolymer. JP-A-61-43
No. 0 discloses a selective gas permeable membrane made of polyurea obtained by reacting a diaminopolysiloxane, an isocyanate compound and a polyvalent amine. In addition,
62-102815 discloses a gas selective permeable membrane made of polyurethane urea 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).

As a material capable of solving the blood coagulation problem described in the above (b), a material in which heparin is bound to a certain polymer by an ionic bond is disclosed in Jpn. Polymers, 36 , 223 (1979). ing. The polymer used is, after quaternizing the tertiary amino groups of the terpolymer of dimethylaminoethyl methacrylate, methoxypolyethylene glycol methacrylate and glycidyl methacrylate,
A polymer blended with polyurethane and crosslinked by heat treatment. A molded body made of this material causes heparin to be slowly released from its surface, thereby preventing blood coagulation. However, the gas permeability is not sufficient and cannot be used for heart-lung machine and the like. JP-A-58-188458 discloses an antithrombotic elastomer comprising 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) and 818-821 (1987) reported that a membrane obtained by diethylaminoethylating a cellulose membrane significantly suppressed complement activation during dialysis, as compared to the original cellulose membrane. ing. However, since this membrane has poor gas permeability, it is difficult to practically use it as a membrane material for an artificial lung.

(Problems to be Solved by the Invention) The present invention is to solve the above-mentioned conventional drawbacks, and it is an object of the present invention that oxygen permeability is good, blood compatibility is excellent, and it is easy to form a thin film. An object of the present invention is to provide an optimum material for a gas exchange membrane of a heart-lung machine.

(Means for Solving the Problems) The present invention relates to an aminopolyester polyol (A) having a structure represented by the following general formula (1): HO-[-A-OCO-R'-COO-A-] _x -OH ( 1) (wherein A represents the following general formula (i), (ii) or (ii)
a group represented by i) or an alkylene group, which may be used alone or as a mixture of two or more of them; however, at least one of the groups represented by general formula (i), (ii) or (iii) The seed is contained as an essential component. R 'is an alkylene group and x is a positive integer. ) Aminopolyether (B) having the structure of the following general formula (2), HO-[-A-O-] _y -H (2) (wherein A represents the following general formulas (i) and (ii) Or (ii
a group represented by i) or an alkylene group, which may be used alone or as a mixture of two or more of them; however, at least one of the groups represented by general formula (i), (ii) or (iii) The seed is contained as an essential component. R 'is an alkylene group, and y is a positive integer. ) And an aminopolyamide (C) having the structure of the following general formula (3) H ₂ N-[-B-NHCO-R'-CONH-B-] _z- NH ₂ (3) (wherein B represents the following general formula: A group represented by the formula (iv) or (v) or an alkylene group, which may be used alone or as a mixture of two or more of them, and a group represented by the general formula (iv) or (v) R ′ is an alkylene group, and z is a positive integer.) A polyurethane or polyurethane urea having at least one of the following as the whole or a part of the soft segment is represented by the following general formula: A blood-compatible material obtained by treating with an active ester having the structure of (vi) to quaternize a tertiary amino group, or obtained by treating the above-mentioned blood-compatible material with heparins. Blood compatible material.

(Where R ₄ , R ₆ , R ₇ and R ₁₂ are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; R ₅ , R ₁₀ and
R ₁₁ is an alkyl group having 1 to 20 carbon atoms, a cycloalkyl group,
Aryl group, aralkyl group or R ₈ , R ₉ , R ₁₃ and R ₁₄ each independently have 1 to 10 carbon atoms
An alkyl group, an aryl group or an aralkyl group;
However, R ₈ and R ₉ , and R ₁₃ and R ₁₄ may be the same alkylene group and form a heterocyclic ring together with the nitrogen atom. R-OX (vi) (where R is an alkyl group, aryl group or aralkyl group having 1 to 10 carbon atoms, X is CF ₃ SO ₂ —, It is. The soft segment other than (A), (B) and (C) contained in the polyurethane or polyurethane urea used in the present invention is, for example, a low molecular weight chain extender or a high molecular weight polyol. Low molecular weight chain extenders include diols, diamines and oxyalkylene glycols. Examples of the diols include ethylene glycol, propylene glycol, 1,4-butanediol, neopentyl glycol, 1,5-pentanediol, 1,6-
2 carbon atoms such as hexanediol, 1,4-dichlorohexanedimethanol, and 1,3-cyclohexanedimethanol
There are up to 20 aliphatic and / or alicyclic diols.
Examples of the diamines include ethylenediamine, propylenediamine, 1,4-tetramethylenediamine, 1,6-hexamethylenediamine, 1,4-diaminocyclohemisan,
There are aliphatic and / or aromatic diamines such as 4,4'-diaminodiphenylmethane, xylylenediamine. Examples of the oxyalkylene glycols include oxyalkylene glycols having 5 to 30 carbon atoms such as diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, tripropylene glycol and / or tetrapropylene glycol. Among these low molecular weight chain extenders, ethylene glycol, 1,4-butanediol, 1,6-hexanediol, neopentyl glycol, ethylenediamine, 1,2-propylenediamine and 1,6-hexamethylenediamine are particularly preferred. preferable.

Examples of the high molecular weight polyol include polyoxyalkylene glycol and polyester diol.
Polyoxyalkylene glycol has a molecular weight of 300
Up to 15,000, preferably 800 to 8,000, of 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 diol acids having 6 to 16 carbon atoms; polyester diols obtained from caprolactones such as ε-caprolactone.

Further, as the high molecular weight polyol, the following general formula (I)
In the case where a polysiloxane having a hydroxyl group or an amino group at the molecular terminal represented by the formula (1) is used, this is an example of a preferable example because the polysiloxane portion works effectively as a gas-permeable portion.

(Wherein, X and Y are each independently -OH, -NH ₂
Or a monosubstituted 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 is each independently a carbon number group. 1-10 alkyl, aryl or aralkyl groups; n is an integer from 5-300. The molecular weight of this polysiloxane is from 200 to 20,000, preferably from 500 to 8,000. The content of all soft segments in the polyurethane or polyurethane urea used in the present invention is 30 to 95%, preferably 50 to 85%.

The polyol or polyamine having a tertiary amino group for obtaining (A), (B) or (C) used in the present invention includes polyols represented by the following general formulas (II) to (IV); Polyols obtained by adding ethylene oxide or propylene oxide to the polyols of (II) to (IV);
And polyamines of the following general formulas (V) to (VI): (Where R ₄ , R ₆ , R ₇ and R ₁₂ are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; R ₅ , R ₁₀ and
R ₁₁ is an alkyl group having 1 to 20 carbon atoms, a cycloalkyl group,
Aryl group, aralkyl group or (M is an integer of _{1~5); R 8, R 9} , R 13 and R ₁₄ are each independently an alkyl group having 1 to 10 carbon atoms, an aryl group or an aralkyl group; provided that, R ₈ And R ₉ ,
R ₁₃ and R ₁₄ may be the same alkylene group and may form a heterocyclic ring together with the nitrogen atom. The above-mentioned polyols having a tertiary amino group (II) to (IV)
Among the following (hereinafter referred to as amine diol), the type represented by (II) includes the following compounds: 3-methyl-3-aza-1,5-pentanediol, 3-ethyl-3
-Aza-1,5-pentanediol, 3-n-propyl-
3-aza-1,5-pentanediol, 3-iso-propyl-3-aza-1,5-pentanediol, 3-n-butyl-3-aza-1,5-pentanediol, 3-sec-butyl -3-aza-1,5-pentanediol, 3-tert-butyl-3-aza-1,5-pentanediol, 3-pentyl-3-aza-1,5-pentanediol, 3-hexyl-
3-aza-1,5-pentanediol, 3-cyclohexyl-3-aza-1,5-pentanediol, 3-phenyl-3-aza-1,5-pentanediol, 3-benzyl-
3-aza-1,5-pentanediol, 3-heptyl-3
-Aza-1,5-pentanediol, 3-octyl-3-
Aza-1,5-pentanediol, 3-nonyl-3-aza-1,5-pentanediol, 3-decyl-3-aza-1,5
-Pentanediol, 4-methyl-4-aza-2,6-heptanediol, 4-ethyl-4-aza-2,6-heptanediol, 4-n-propyl-4-aza-2,6-heptanediol , 4-iso-propyl-4-aza-2,6-heptanediol, 4-n-butyl-4-aza-2,6-heptanediol, 4-iso-butyl-4-aza-2,6-heptane Diol, 4-sec-butyl-4-aza-2,6-heptanediol, 4-tert-butyl-4-aza-heptanediol, 4-pentyl-4-aza-2,6-heptanediol, 4-hexyl -4-aza-2,6-heptanediol, 4-cyclohexyl-4-aza-2,6-heptanediol, 4-phenyl-4-aza-2,6-heptanediol, 4-benzyl-4-aza- 2,6-heptanediol, 4-heptyl-4-aza-2,6-hepta Diol, 4-octyl-4-aza-2,6-heptanediol, 4-nonyl-4-aza-2,6-heptanediol,
4-decyl-4-aza-2,6-heptanediol, 3-
N, N-dimethylaminoethyl-3-aza-1,5-pentanediol, 3-N, N-diethylaminoethyl-3-aza-1,5-pentanediol, 3-N, N-di-n-propyl Aminoethyl-3-aza-1,5-pentanediol, 3
-N, N-di-iso-propylaminoethyl-1,5-pentanediol, 3-N, N-di-n-butylaminoethyl-
3-aza-1,5-pentanediol, 3-N, N-di-sec
-Butylaminoethyl-3-aza-1,5-pentanediol, 3-N, N-dipentylaminoethyl-3-aza-
1,5-pentanediol, 3-N, N-cyhexylaminoethyl-3-aza-1,5-pentanediol, 3-dicyclohexylaminoethyl-3-aza-1,5-pentanediol, 3-dibenzyl Aminoethyl-3-aza-1,5
-Pentanediol, 3-N, N-dimethylaminopropyl-3-aza-1,5-pentanediol, 3-N, N-diethylaminopropyl-3-aza-1,5-pentanediol, 3-N, N -Di-n-propylaminopropyl-3-
Aza-1,5-pentanediol, 3-N, N-di-iso-propylaminopropyl-3-aza-1,5-pentanediol, 3-N, N-di-n-butylaminopropyl-3-
Aza-1,5-pentanediol, 3-N, N-di-iso-butylaminopropyl-3-aza-1,5-pentanediol, 3-N, N-di-sec-butylaminopropyl-3- Aza-1,5-pentanediol, 3-N, N-dipentylaminopropyl-3-aza-1,5-pentanediol, 3-
N, N-dihexylaminopropyl-3-aza-1,5-pentanediol, 3-N, N-dicyclohexylaminopropyl-3-aza-1,5-pentanediol, 3-N, N-dibenzylaminopropyl -3-aza-1,5-pentanediol, 4-N, N-dimethylaminoethyl-4-aza-
2,6-heptanediol, 4-N, N-diethylaminoethyl-4-aza-2,6-heptanediol, 4-N, N-di-
n-propylaminoethyl-4-aza-2,6-heptanediol, 4-N, N-di-iso-propylaminoethyl-
4-aza-2,6-heptanediol, 4-N, N-di-n-
Propylaminoethyl-4-aza-2,6-heptanediol, 4-N, N-di-iso-propylaminoethyl-4-
Aza-2,6-heptanediol, 4-N, N-di-n-butylaminoethyl-4-aza-2,6-heptanediol,
4-N, N-di-iso-butylaminoethyl-4-aza-2,
6-heptanediol, 4-N, N-di-sec-butylaminoethyl-4-aza-2,6-heptanediol, 4-N, N
-Diheptylaminoethyl-4-aza-2,6-heptanediol, 4-N, N-dihexylaminoethyl-4-aza-2,6-heptanediol, 4-N, N-dicyclohexylaminoethyl-4- Aza-2,6-heptanediol,
4-N, N-dibenzylaminoethyl-4-aza-2,6-heptanediol, 4-N, N-dimethylaminopropyl-
4-aza-2,6-heptanediol, 4-N, N-diethylaminopropyl-4-aza-2,6-heptanediol,
4-N, N-di-n-propylaminopropyl-4-aza-2,6-heptanediol, 4-N, N-di-iso-propylaminopropyl-4-aza-2,6-heptanediol, 4-N, N-di-n-butylaminopropyl-4-aza-2,6-heptanediol, 4-N, N-di-iso-butylaminopropyl-4-aza-2,6-heptanediol, 4-N, N-di-sec-butylaminopropyl-4-aza-2,6-heptanediol, 4-N, N-dipentylaminopropyl-4-aza-2,6-heptanediol, 4-
N, N-dihexylaminopropyl-4-aza-2,6-heptanediol, 4-N, N-diheptylaminopropyl-
4-aza-2,6-heptanediol, 4-N, N-dicyclohexylaminopropyl-4-aza-2,6-heptanediol, 4-N, N-dioctylaminopropyl-4-aza-2,6- Heptanediol, 4-N, N-dinonylaminopropyl-4-aza-2,6-heptanediol, 4-N, N
-Didecylaminopropyl-4-aza-2,6-heptanediol, 4-N, N-dibenzylaminopropyl-4-
Aza-2,6-heptanediol.

As the amine diol represented by the above formula (III),
The following compounds may be mentioned: N, N′-di (β-hydroxypropyl) piperazine, N, N′-di (β-hydroxyethyl) piperazine, N, N′-di (β-hydroxypropyl) -2, 5-dimethylpiperazine, N, N′-di (β-hydroxyethyl) -2,6-dimethylpiperazine, N, N′-di (β-hydroxypropyl) -2,6-diethylpiperazine, N, N′- Di (β-hydroxyethyl) -2,6-diethylpiperazine.

Examples of the amine diol represented by the formula (IV) include the following compounds: 2-N, N-methylaminomethyl-
2-methyl-1,3-propanediol, 2-N, N-diethylaminomethyl-2-methyl-1,3-propanediol, 2-N, N-di-n-propylaminomethyl-2-methyl-1 , 3-propanediol, 2-N, N-di-iso-propylaminomethyl-2-methyl-1,3-propanediol, 2-N, N-di-n-butylaminomethyl-2-methyl-1 , 3-propanediol, 2-N, N-di-iso-butylaminomethyl-2-methyl-1,3-propanediol, 2-N, N-di-sec-butylaminomethyl-2-methyl-1 , 3-propanediol, 2-N, N-dipentylaminomethyl-2-methyl-1,3-propanediol, 2-
N, N-dihexylaminomethyl-2-methyl-1,3-propanediol, 2-N, N-dicyclohexylaminomethyl-2-methyl-1,3-propanediol, 2-N, N-dibensylaminomethyl -2-methyl-1,3-propanediol, 2-N, N-dimethylaminomethyl-2-ethyl-1,3-propanediol, 2-N, N-diethylaminoaminomethyl-2-ethyl-1,3 -Propanediol, 2
-N, N-di-n-propylaminomethyl-2-ethyl-
1,3-propanediol, 2-N, N-di-iso-propylaminomethyl-2-ethyl-1,3-propanediol,
2-N, N-di-n-butylaminomethyl-2-ethyl-
1,3-propanediol, 2-N, N-di-iso-butylaminomethyl-2-ethyl-1,3-propanediol,
-N, N-di-sec-butylaminomethyl-2-ethyl-1,
3-propanediol, 2-N, N-dipentylaminomethyl-2-ethyl-1,3-propanediol, 2-N, N-dihexylaminomethyl-2-ethyl-1,3-propanediol, 2-N , N-Dicyclohexylaminomethyl-2
-Ethyl-1,3-propanediol, 2-N, N-dibenzylaminomethyl-2-ethyl-1,3-propanediol.

In the present invention, as described above, a polyol of the type in which ethylene oxide or propylene oxide is added to the amine diols of the general formulas (II) to (IV) (epoxy addition type) may also be used. The number of addition of ethylene oxide or propylene oxide of these compounds is 1 to 20 molecules per molecule of amine diol.

On the other hand, among the polyamines represented by (V) or (VI) (hereinafter referred to as aminodiamine), the type represented by (V) includes the following compounds: 4-methyl-4
-Aza-1,7-diaminoheptane, 4-ethyl-4-aza-1,7-diaminoheptane, 4-n-propyl-4-
Aza-1,7-diaminoheptane, 4-iso-propyl-4
-Aza-1,7-diaminoheptane, 4-n-butyl-4
Aza-1,7-diaminoheptane, 4-iso-butyl-4
Aza-1,7-diaminoheptane, 4-sec-butyl-4
-Aza-1,7-diaminoheptane, 4-tert-butyl-
4-aza-1,7-diaminoheptane, 4-pentyl-4
-Aza-1,7-diaminoheptane, 4-n-hexyl-
4-aza-1,7-diaminoheptane, 4-cyclohexyl-4-aza-1,7-heptanediol, 4-heptyl-4-aza-1,7-heptanediol, 4-octyl-
4-aza-1,7-diaminoheptane, 4-nonyl-4-
Aza-1,7-diaminoheptane, 4-decyl-4-aza-1,7-diaminoheptane, 4-phenyl-4-aza-
1,7-diaminoheptane, 4-benzyl-4-aza-1,7
-Diaminoheptane, 4-dimethylaminoethyl-4-
Aza-1,7-diaminoheptane, 4-diethylaminoethyl-4-aza-1,7-diaminoheptane, 4-di-n
-Propylaminoethyl-4-aza-1,7-diaminoheptane, 4-N, N-di-iso-propylaminoethyl-4
-Aza-1,7-diaminoheptane, 4-N, N-di-n-butylaminoethyl-4-aza-1,7-diaminoheptane, 4-N, N-di-iso-butylaminoethyl-4 -Aza-1,7-diaminoheptane, 4-N, N-di-sec-butylaminoethyl-4-aza-1,7-diaminoheptane, 4
-N, N-dipentylaminoethyl-4-aza-1,7-diaminoheptane, 4-N, N-dihexylaminoethyl-4
-Aza-1,7-diaminoheptane, 4-N, N-dicyclohexylaminoethyl-4-aza-1,7-diaminoheptane, 4-N, N-diheptylaminoethyl-4-aza-1,7
-Diaminoheptane, 4-N, N-dioctylaminoethyl-4-aza-1,7-diaminoheptane, 4-N, N-dinonylaminoethyl-4-aza-1,7-diaminoheptane, 4-N , N-Didecylaminoethyl-4-aza-1,7-
Diaminoheptane, 4-N, N-dimethylaminopropyl-4-aza-1,7-diaminoheptane, 4-N, N-diethylaminopropyl-4-aza-1,7-diaminoheptane, 4-N, N- Di-n-propylaminopropyl-4-
Aza-1,7-diaminoheptane, 4-N, N-di-iso-propylaminopropyl-4-aza-1,7-diaminoheptane, 4-N, N-di-n-butylaminopropyl-4-
Aza-1,7-diaminoheptane, 4-di-N, N-iso-butylaminopropyl-4-aza-1,7-diaminoheptane, 4-N, N-di-sec-butylaminopropyl-4- Aza-1,7-diaminoheptane, 4-N, N-dipentylaminopropyl-4-aza-1,7-diaminoheptane, 4-
N, N-dihexylaminopropyl-4-aza-1,7-diaminoheptane, 4-N, N-dicyclohexylaminopropyl-4-aza-1,7-diaminoheptane, 4-N, N-diheptylaminopropyl -4-aza-1,7-diaminoheptane, 4-N, N-dioctylaminopropyl-4-aza-1,7-diaminoheptane, 4-N, N-dinonylaminopropyl-4-aza-1, 7-diaminoheptane, 4-N, N
-Didecylaminopropyl-4-aza-1,7-diaminoheptane, 4-N, N-dibenzylaminopropyl-4-
Aza-1,7-diaminoheptane.

Examples of the aminodiamine represented by the above (V) include the following compounds: N, N'-di (γ-aminopropyl)
Piperazine, N, N'-di (γ-aminopropyl) -2,6-
Dimethylpiperazine, N, N'-di (γ-aminopropyl) -2,6-diethylpiperazine.

These amine diols having a tertiary amino group (II)
(IV) (including its epoxy adduct; hereinafter, the amine diol includes its epoxy adduct)
And aminodiamines (V) to (IV), of the formula (II)
Alternatively, amine diols and amino diamines wherein R ₅ or R ₁₁ in the formula (V) is a dialkylaminopropyl group are particularly preferred. In each of the amine diols (II) to (IV) and the amino diamines (V) to (VI), a tertiary amino group derived therefrom is contained in the obtained polymer (polyurethane or polyurethane urea) in an amount of 0.01 to 3.00 mmol.
/ g, preferably 0.05 to 2.00 mmol / g.

The active ester (quaternizing agent) used in the present invention includes an ester represented by the following general formula (VII).

R-OX (VII) (where R is an alkyl group having 1 to 10 carbon atoms, an aryl group or an aralkyl group, X is CF ₃ SO ₂ —, It is. Examples of the active ester represented by the above (VII) include the following compounds.

Methyl trifluoromethanesulfonate, ethyl trifluoromethanesulfonate, propyl trifluoromethanesulfonate, hexyl trifluoromethanesulfonate,
Octyl trifluoromethanesulfonate, decyl trifluoromethanesulfonate, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, propyl p-toluenesulfonate, hexyl p-toluenesulfonate, p
-Octyl toluenesulfonate, decyl p-toluenesulfonate, methyl benzenesulfonate, ethyl benzenesulfonate, propyl benzenesulfonate, hexyl benzenesulfonate, octyl benzenesulfonate, decylbenzenesulfonate. Of these active esters, R
Is a hexyl group, and X is a p-toluenesulfonyl group.

Both the polyurethane and the polyurethane urea of the present invention can be prepared by known methods. For example, to prepare a polyurethane by a solution polymerization method, first, an aminopolyether obtained by condensation of the amine diol itself represented by the above general formulas (II) to (IV) (hereinafter simply referred to as aminopolyether). And diisocyanates,
Polysiloxane having a hydroxyl group at a molecular terminal (hereinafter abbreviated as polysiloxane polyol) represented by the above general formula (I) as the high molecular weight polyol is dissolved in a solvent inert to an isocyanate group, and 0 to 100 ° C. The reaction is carried out preferably at 10 to 50 ° C. for 5 to 300 minutes, preferably for 15 to 120 minutes, with stirring under a nitrogen stream. If necessary, the above-mentioned low-molecular-weight chain extender (low-molecular-weight diol) is added, and the mixture is added at 10 to 100 ° C, preferably at 20 to 80 ° C.
The chain is extended by reacting for 3030 hours to increase the molecular weight.

Examples of the solvent used here include dioxane, tetrahydrofuran, chloroform, carbon tetrachloride, benzene, toluene, acetone, methyl ethyl ketone, N, N-dimethylformamide, N-methylpyrrolidone, and mixtures thereof. In particular, tetrahydrofuran, N, N
-Dimethylformamide is preferred. 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 contained in the reaction solution at 1 to 500 ppm, preferably 5 to 500 ppm.
It is added at a content of 100 ppm. For the preparation of polyurethane,
A method in which the above-mentioned monomer components to be used are charged at a time and subjected to melt polymerization may be employed.

In the above polymerization reaction, the mixing molar ratio of each component is as follows: the molar ratio of polysiloxane polyol / aminopolyether is 100/1 to 1/10, preferably 20/1 to 1/5; total polyol / diisocyanate The molar ratio of 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 manufacturing methods. Among them, the solution polymerization method is particularly preferable. To prepare a polyurethane urea by a solution polymerization method, first, a polysiloxane polyol (optionally used), a diisocyanate and, if necessary, a high-molecular-weight polyol are dissolved in an inert solvent. Similarly, the reaction is carried out at 30 to 150 ° C., preferably 50 to 100 ° C., for 5 to 300 minutes, preferably for 15 to 120 minutes. This is cooled to 0 to 40 ° C., preferably 5 to 20 ° C., and a polysiloxane represented by the general formula (I) and having a (substituted) amino group at a terminal (hereinafter abbreviated as polysiloxane polyamine), An aminodiamine represented by (V) or (VI) and, if necessary, a solution obtained by dissolving the above-mentioned low-molecular-weight chain extender (low-molecular-weight diamine) in an inert solvent are added dropwise and reacted to obtain a desired molecular weight. A polyurethane urea 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. Other conditions such as the mixing ratio of each component are the same as in the case of polyurethane.

The tertiary amino groups in the polyurethane and the polyurethane urea thus obtained are quaternized with the active ester represented by the above general formula (VII), and the tertiary amino groups are converted into heparin or a compound similar thereto (hereinafter referred to as heparins). To form a polyion complex, thereby binding the heparins. The quaternizing agent is used in an amount of 0.1 to 10.0 mole times, preferably 0.1 to 10.0 times the tertiary amino group in the polymer.
It is used at a ratio of 0.5 to 5.0 mole times. For the quaternization of polyurethane or polyurethane urea, for example, a method in which the polymer is dissolved in an appropriate solvent and the quaternizing agent is added thereto and reacted, or the quaternizing agent solution after forming the polymer And the reaction is carried out by contacting A method in which the reaction is performed in a solution is more preferable. For example, a quaternizing agent is added to a solution of polyurethane or polyurethane urea at 20 to 100 ° C, preferably at 40 to 80 ° C.
The reaction is carried out for 0.1 to 60 hours, preferably 1 to 30 hours. The quaternization ratio of the tertiary amino group thus quaternized is 1 to
It is 100%, preferably 10% or more.

The quaternized amino group-containing polyurethane or polyurethane urea is formed into a desired product such as a membrane or a hollow fiber. By contacting the heparin with the heparin, the heparin is bound (heparinized). For example, a polyurethane or polyurethane urea molded article having a quaternized amino group is prepared by adding 0.1 to 10% of heparin,
Preferably, an aqueous solution containing 0.5 to 5% of 20 to 100%
Heparinization is carried out by immersion at 0.1C, preferably 40-80C, for 0.1-40 hours, preferably 1-30 hours. Here, the heparins, heparin; refers chondroitin sulfate, -SO ₃ H, encompass such as natural or synthetic polymeric compounds having such -NHSO ₃ H radical.

In a conventional method, as a quaternizing agent, an alkyl halide having 1 to 30 carbon atoms, an aralkyl halide, an allyl halide,
And dialkyl halides, etc., but these quaternizing agents have insufficient quaternization rates, and consequently heparinization has also been insufficient. As a result, the blood compatibility was inferior to the present invention. In the present invention, better blood compatibility was realized by using the active ester represented by the general formula (VII) as the quaternizing agent.

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

(Examples) Hereinafter, the present invention will be described using examples. Parts in the examples mean parts by weight.

Example 1 324 parts of polydimethylsiloxane diol represented by the following formula having a number average molecular weight of 2040, 77.34 parts of an aminopolyether diol represented by the following formula having a number average molecular weight of 1735, And 119.55 parts of 4,4'-diphenylmethane diisocyanate (hereinafter abbreviated as MDI) are dissolved in 210 g of tetrahydrofuran (hereinafter abbreviated as THF), and 3.85 g of a solution obtained by dissolving 0.5 g of dibutyltin dilaurate in 100 ml of THF is added as a catalyst. After reacting at 16 ° C. for 30 minutes, 19.11 parts of 1,4-butanediol and N, N-dimethylformamide (hereinafter DM
F) (abbreviated as F), drop at 850 g for 20 minutes at 16 ° C, then at 40 ° C
For 20 hours.

DMF was added to 2 ml of water, and a mixed solvent of 80 ml in total was added to obtain a desired viscosity. The polymer concentration was 32.5% and the viscosity was 30.
A 32 poise (25 ° C.) base polymer P solution was obtained. DMF was added to this solution and stirred to obtain a 7% solution. 17 g of the 5% solution was uniformly applied on a 144 cm ² glass plate kept horizontally, dried at 60 ° C. for 3 hours, and dried at 60 ° C. under reduced pressure for 15 hours to obtain a base polymer film P having a thickness of 60 μm. .

Furthermore, 10% base polymer solution 1 obtained by dilution with DMF
6.96 parts of hexyl p-toluenesulfonate was added to 80 parts,
The reaction was carried out for 18 hours while stirring at 60 ° C. to quaternize the tertiary amino groups in the base polymer. This solution was diluted with DMF to obtain a 7% solution, and a quaternized polymer film A-1 was obtained in the same manner as in the case of the base polymer.

About 0.5 of the base polymer film P and the quaternized base polymer film A-1 were accurately weighed, and then DMF / THF
(2/1 by volume) mixture is dissolved in a solvent 50ml potentiometric titrator (Hiranuma Seisakusho, Comite7) was titrated with N / 10-HC10 ₄ · dioxane solution was used to measure the basic nitrogen content than the inflection point As a result, the basic nitrogen content of the base polymer film P was 1.079 mmol / g, and that of the quaternized film A-1 was
0.356 mmol / g. From this result, the quaternization rate is 67%
It turns out that it was.

Next, when the oxygen permeability coefficient of this film was measured using a gas permeability measuring device (manufactured by Yanagi Head Office), the base polymer film P was found to be 2.39 × 10 ⁻⁸ cm ³ (STP) cm / cm ² sec.
cmHg and quaternized film A-1 had a value of 2.28 × 10 ⁻⁸ (hereinafter, unit cm ³ (STP) cm / cm ² sec cmHg is omitted).

Next, the quaternized film A-1 is immersed in a 2% heparin-water / glycerin (1/1 volume ratio) solution and treated at 60 ° C. for 24 hours to carry out heparinization, thereby obtaining a heparinized quaternized polymer film. A-2 was obtained. This film is attached to the center of a 10 cm diameter watch glass, and bovine citrated plasma is placed on the film.
Collect 200 μl, add 200 μl of a 1/40 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. Coagulation (point where plasma stops moving)
The results are shown in Table 1 and are expressed as relative values divided by the solidification time on glass (measured separately as a control).

The heparinized quaternary film A-2 was immersed in a physiological saline solution at 37 ° C., and the sustained release rate of heparin was measured by the tolucine blue method. The results are shown in Table 2 and FIG.

Example 2 180 parts of the 10% base polymer P solution obtained in Example 1
-7.72 parts of octyl toluenesulfonate was added, and the mixture was reacted at 60 ° C for 18 hours while stirring to quaternize the tertiary amino group in the base polymer. Thereafter, a quaternized film B-1 and a heparinized quaternized film B-2 were obtained in the same manner as in Example 1. The basic nitrogen content of the quaternized film B-1 was 0.378 mmol / g, that is, the quaternization rate was 65%.

Next, in the same manner as in Example 1, the oxygen permeability coefficient and the relative coagulation time are shown in Table 1, and the heparin sustained release rate is shown in Table 2 and FIG.

Example 3 To 180 parts of the 10% base polymer P solution obtained in Example 1, 6.36 parts of hexyl trifluoromethanesulfonate was added, and
The reaction was carried out for 18 hours while stirring at ℃ to quaternize the tertiary amino groups in the base polymer. Then, Example 1
In the same manner as in the above, a quaternized film C-1 and a heparinized quaternized film C-2 were obtained. The basic nitrogen content of the quaternized film C-1 was 0.313 mmol / g, that is, the quaternization rate was 71%.

Next, the results of measuring the oxygen permeation coefficient and the relative coagulation time in the same manner as in Example 1 are shown in Table 1, and the measurement results of the heparin sustained release rate are shown in Table 2 and FIG.

Example 4 Polytetramethylene glycol 32 having a number average molecular weight of 2025
1.62 parts, 77.34 parts of the aminopolyether diol used in Example 1 having a number average molecular weight of 1735, and 119.55 parts of MDI were added to TH
F210g dissolved in dibutyltin dilaurate as catalyst
3.85 of a solution of 0.5 g dissolved in 100 ml of THF was added,
After reacting for 1 minute, 19.11 parts of 1,4-butanediol, DMF850
g was added dropwise and reacted at 16 ° C. for 20 minutes and further at 40 ° C. for 20 hours. DMF was added to 2 ml of water, and a mixed solvent of 80 ml in total was added thereto to obtain a desired viscosity to obtain a base polymer Q solution having a polymer concentration of 32.5% and a viscosity of 1620 poise (25 ° C.).
Thereafter, quaternization with hexyl p-toluenesulfonate, film preparation, and heparinization were carried out in the same manner as in Example 1. Base polymer film Q and quaternized film Q
The basic nitrogen content of -1 was 1.062 mmol / g and 0.319 mmol / g, and the quaternization rate was 70%. Table 1 shows the result of measuring the relative coagulation time in the same manner as in Example 1, and Table 2 and FIG. 1 show the result of measuring the sustained release rate of heparin.

Comparative Example 4.23 parts of ethyl iodide was added to 180 parts of the 10% base polymer P solution obtained in Example 1, and the mixture was reacted at 60 ° C. with stirring for 18 hours to quaternize the tertiary amino groups in the base polymer. After that, the quaternized film R-
1. A heparinized quaternized film R-2 was obtained. The basic nitrogen content of the quaternized film R-1 was 0.432 mmol / g, that is, the quaternization rate was 60%. Next, the results of measuring the oxygen permeation coefficient relative coagulation time in the same manner as in Example 1 are shown in Table 1.
The results of measuring the sustained release rate of heparin are shown in Table 2 and FIG.

(Effects of the Invention) As described above, the quaternized polymer and the heparinized quaternized polymer of the present invention, which undergo quaternization using an active ester, have a higher quaternization than the case where an alkyl halide is used.
It can be seen that the grading rate was reduced, and as a result, a better sustained heparin release amount and better antithrombotic properties were realized.

According to the present invention, it is possible to impart excellent gas permeability by being excellent in blood compatibility, easily formed into a hollow fiber membrane or a thin film, and incorporating a polysiloxane polyol or a polysiloxane polyamine as a part of a soft segment. A blood compatible material is provided that can be used.

This material can be used for a wide range of uses, for example, as a gas exchange membrane material for a heart-lung machine, an artificial lung, ECMO, etc., and as a coating material for medical devices.

[Brief description of the drawings]

FIG. 1 shows the sustained release rate of heparin in Examples and Comparative Examples.

Continuation of the front page (51) Int.Cl. ⁷ identification code FI C08G 18/60 C08G 18/60 (58) Investigated field (Int.Cl. ⁷ , DB name) C08G 18 / 46,18 / 50 C08G 18 / 60,18 / 83 A61L 27/00 A61M 1/16

Claims (2)

(57) [Claims] An aminopolyester polyol (A) having a structure represented by the following general formula (1): HO-[-A-OCO-R'-COO-A-] _x -OH (1) wherein A is The following general formula (i), (ii) or (ii)
a group represented by i) or an alkylene group, which may be used alone or as a mixture of two or more of them; however, at least one of the groups represented by general formula (i), (ii) or (iii) The seed is contained as an essential component. R 'is an alkylene group and x is a positive integer. ) Aminopolyether (B) having the structure of the following general formula (2), HO-[-A-O-] _y -H (2) (wherein A represents the following general formulas (i) and (ii) Or (ii
a group represented by i) or an alkylene group, which may be used alone or as a mixture of two or more of them; however, at least one of the groups represented by general formula (i), (ii) or (iii) The seed is contained as an essential component. R 'is an alkylene group, and y is a positive integer. ) And an aminopolyamide (C) having the structure of the following general formula (3) H ₂ N-[-B-NHCO-R'-CONH-B-] _z- NH ₂ (3) (wherein B represents the following general formula: A group represented by the formula (iv) or (v) or an alkylene group, which may be used alone or as a mixture of two or more of them, and a group represented by the general formula (iv) or (v) R ′ is an alkylene group, and z is a positive integer.) A polyurethane or polyurethane urea having at least one of the following as the whole or a part of the soft segment is represented by the following general formula: A blood-compatible material obtained by treating with an active ester having the structure of (vi) to quaternize a tertiary amino group. (Where R ₄ , R ₆ , R ₇ and R ₁₂ are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; R ₅ , R ₁₀ and
R ₁₁ is an alkyl group having 1 to 20 carbon atoms, a cycloalkyl group,
Aryl group, aralkyl group or R ₈ , R ₉ , R ₁₃ and R ₁₄ each independently have 1 to 10 carbon atoms
An alkyl group, an aryl group or an aralkyl group;
However, R ₈ and R ₉ , and R ₁₃ and R ₁₄ may be the same alkylene group and form a heterocyclic ring together with the nitrogen atom. R-OX (vi) (where R is an alkyl group, aryl group or aralkyl group having 1 to 10 carbon atoms, X is CF ₃ SO ₂ —, It is. ) 2. A blood compatible material obtained by treating the blood compatible material according to claim 1 with heparins.