JP3173615B2 - Blood compatible material - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical material which comes into direct contact with a living body or a living body component, and more particularly to a blood compatible material having good anticoagulant and mechanical properties.

[0002]

2. Description of the Related Art In recent years, polymer materials excellent in processability, elasticity, flexibility and the like have been widely used as medical materials, but artificial kidneys, artificial lungs, assisted circulation devices, artificial blood vessels, and the like. In addition to artificial organs, such as syringes, blood bags, heart catheters, etc., they will be increasingly used in disposable containers in the future. The problem here is the safety of whether various abnormal reactions to the living body occur and cause danger of life support, and in the case of blood, the condition that blood coagulation does not occur is required. Is done. The anticoagulant polymer materials provided to date are (1) those with heparin or its analogs attached to the surface of the polymer material, and (2) those with a negative charge applied to the surface of the polymer material. (3) Classified into three types, those in which the surface of the polymer material is inactivated, the material provided by the present invention is:
It is classified into (1) among the above.

[0003]

The means (1) (hereinafter referred to as surface heparinization method) further comprises (A) a blending method of polymer and heparin, and (B) heparin to a cationic group in the polymer. The method is subdivided into a method of ionic bonding and a method of covalently bonding (C) the polymer and heparin.
In the methods (A) and (B), heparins are eliminated by long-term use under physiological conditions, and are unsuitable as a medical material to be fixed and used in a living body. On the other hand, the material obtained in (C) has an advantage that heparins are hardly detached because they are covalently bonded. However, the conventional covalent bonding system has a heparin component D-glucosamine or D-glucuronic acid. Has the disadvantage that the anticoagulant effect is reduced because it gives conformational changes.

On the other hand, Japanese Patent Application Laid-Open No. 50-139173 discloses that the general formula HO (R ¹ O) _m R ² N (R ³ ) R ⁴ (OR ⁵ ) _n OH (where R ¹ , R ² , R ⁴ , R ⁵ are an alkylene group having 2 to 4 carbon atoms, R ³ is an alkyl group having 1 to 20 carbon atoms, m and n
A tertiary amino group and a polyhydric alcohol having a polyether chain in the molecule) represented by the following formula: There has been proposed a "method of producing an anticoagulant polymer material" in which "a polyether type polyester or a polyether type polyurethane having a quaternary ammonium salt in the molecule" is reacted with heparin. In this method, if the value of m or n is too large, the number of tertiary amino groups and, consequently, the number of quaternized ammonio groups decreases, so that the amount of adhering heparin becomes insufficient, and the anticoagulant effect is reduced. There is a disadvantage that it becomes smaller. In addition, it is not possible to form a hydrophilic domain. On the other hand, when m and n are small, the mechanical properties, particularly the elasticity, are reduced, and they are not suitable for use as artificial organs. Furthermore, Japanese Patent Publication No. 54-185
18. An anticoagulant medical material comprising heparin and a copolymer containing a hydrophilic component, a hydrophobic component and a quaternary ammonium salt component as essential units, and having a negative standard membrane potential difference. In this case, too, as shown in the examples, the water absorption is as large as 5 to 80%, so that heparin is rapidly desorbed, and the effect is not maintained for a long period of time. Due to the rate, there is a drawback that the strength is greatly reduced in blood and is not used in places where a force is applied (the squeeze portion of the roller pump).

In order to eliminate these drawbacks, the present applicant has previously filed a patent application (JP-B-60-16260).
However, even in this case, when the water absorption exceeds 4%, heparin is rapidly released, and the antithrombotic property cannot be maintained for a long time.

Therefore, as a result of intensive studies, we have arrived at an invention that solves all the above-mentioned disadvantages. That is, the present invention is a blood-compatible material obtained by treating a quaternized polyurethane or a quaternized polyurethane urea having a structure represented by the following general formula (1) with heparin or an analog thereof. -DI-PAE-DI-A-DI- (1) (In the above formula (1), DI is -CO-NH- <B> -NH
Represents —CO—, and <B> is a hydrocarbon group having 2 to 25 carbon atoms. In the above formula (1), PAE is -O-(<C
>-<D>-<E>) _x- . Where <C
> Represents -CH (R ¹ ) CH ₂ N (R ² ) CH ₂ CH (R ³ ) O-, and R ¹ , R ³
Represents an alkyl group having 1 to 5 carbon atoms which may be the same or different, R ² represents an alkyl group having 1 to 15 carbon atoms,
Represents an aralkyl group or an aryl group. Also <C>
Is contained in PAE by 30 mol% or more. Part or all of N is quaternized and has the following structure.

Embedded image Here, R is a hydrocarbon group having 1 to 10 carbon atoms derived from a quaternizing agent, and the total number of carbon atoms of R ² and R is 7 to 16. Z ^- is a halide derived from a quaternizing agent or a group derived from an active ester. <D> represents —R ⁸ —O—, and R ⁸ represents an alkylene group having 2 to 20 carbon atoms. <E> is
-(R ⁹ -O-) _n- , wherein R ⁹ is an alkylene group having 2 to 5 carbon atoms, and n is an integer of 2 or more. x represents an integer of 2 or more. The above <C>, <D
>, <E> may be random. The above (1)
In the formula, A is -O- (XO) _m- , -O- (X-CO) _m --OYO-, -NH-Y-NH-, -OY-NH-, NH-YO- or -NH- NH
Represents CO-Y-CONH-NH-. Here, X has 2 to 2 carbon atoms.
15 hydrocarbon groups, m is an integer of 2 or more, Y is 2 to 2 carbon atoms
Represents 10 hydrocarbon groups. The present invention relates to a polyurethane or polyurethane urea containing a polyaminoether.
When the quaternary amino group is quaternized, there is a gist in selecting the chain length of the quaternizing agent so that the water absorption becomes 4% or less.

[0007] In the general formula, HO-R ⁸ -OH (2) and ^{HO- (R 9 O) n-} H [3] (the above formulas, R ⁸ is an alkylene group having 2 to 20 carbon atoms, R ⁹ is A diol represented by the formula (1) and a tertiary amino alcohol represented by the general formula (1):
Is used in the present invention because a segmented polyether urethane using a polyaminoether reacted so that the ratio thereof is 30 mol% or more of the polyaminoether raw material is used, and the tertiary amino group is quaternized. The anticoagulant function of the material used is extremely high. In addition, the polymer material of the present invention can be used as an antithrombotic material for a long time because heparin is adsorbed and desorbed in vivo in a moderate amount. Further, the sizes of the hydrophilic domain and the hydrophobic domain can be freely adjusted by selecting the ratio of the amino alcohol or the molecular weight of the polyaminoether, respectively.

[0008] In general, when a polymer material is used in contact with blood, in addition to the above-mentioned anticoagulant properties, additives (plasticizers, stabilizers, polymerization catalysts, etc.) in the material and unreacted raw materials ( Although it is necessary to consider the detrimental effects due to the dissolution of monomers and oligomers, the present invention does not require the addition of a plasticizer or the like and forms a segmented polymer. Absent. Polymer materials are susceptible to complex effects such as oxidative degradation and metabolism by free radicals and enzymes in the living body.However, since they are based on segmented polyether urethane, they have high chemical stability and harmful elution It rarely generates things.

The material of the present invention is composed of a quaternary chlorinated polyaminoether segment having a high hydrophilicity, a hydrophobic polyether segment, and a crystalline urethane or urea bond. Form a microdomain structure, which is similar to the structure of the vascular lining. Therefore, anticoagulant properties are also expected from the structural aspect. Next, each component constituting the polymer material of the present invention will be described. First, as the alkyl group having 1 to 5 carbon atoms represented by R ¹ and R ³ in the general formula [1], methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Saturated lower alkyl such as tertiary butyl, pentyl, isopentyl and the like. As the alkyl group having 1 to 15 carbon atoms represented by R ² , in addition to the above-mentioned saturated lower alkyl, a chain or a chain such as hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc. There are branched alkyls, and other examples include saturated cyclic alkyls such as cyclopentyl, cyclohexyl, and cycloheptyl. Examples of the aralkyl group represented by R ² include benzyl, phenethyl and the like, which may be substituted with an alkyl group such as methyl, ethyl and propyl. Further, examples of the aryl group represented by R ² include phenyl, naphthyl and the like, which may be substituted with an alkyl group such as methyl, ethyl and propyl. However, among these, an alkyl group having 1 to 15 carbon atoms is preferable. In addition, as a raw material used for producing a polyaminoether together with these amino alcohols, diols represented by the general formula [2] or [3] are shown.

The meaning of each symbol has been described above. The specific description of each compound is as follows. First, the tertiary amino alcohol represented by the general formula [1] includes 3-methyl-3-aza-1,5-pentanediol, 3-ethyl-3-aza-1,5-pentanediol, Propyl-3-aza-1,5-pentanediol, 3-isobutyl-3-aza-1,5-pentanediol, 3-n-pentyl-3-aza-1,5-pentanediol, 3-n-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, 4-methyl-4-aza-
2,6-heptanediol, 4-ethyl-4-aza-
2,6-heptanediol, 4-n-propyl-4-aza-2,6-heptanediol, 4-isopropyl-4
-Aza-2,6-heptanediol, 4-n-butyl-
4-aza-2,6-heptanediol, 4-isobutyl-4-aza-2,6-heptanediol, 4-hexyl-4-aza-2,6-heptanediol, 4-cyclohexyl-4-aza-2 , 6-Heptanediol, 4-benzyl-4-aza-2,6-heptanediol, 4-phenyl-4-aza-2,6-heptanediol, 4-n
-Lauryl-4-aza-2,6-heptanediol and the like.

Further, diols represented by the general formula [2] include ethylene glycol, propylene glycol,
Examples include alkylene glycols such as tetramethylene glycol, 1.6-hexanediol, and neopentyl glycol. Examples of the diols represented by the general formula [3] include diethylene glycol and triethylene glycol, and also polyethylene glycol having a molecular weight of 200 to 2,000; dipropylene glycol and tripropylene glycol, and further polypropylene glycol having a molecular weight of 200 to 1,000; And polyhexamethylene glycol having a molecular weight of 200 to 1,000.

The polyaminoether according to the present invention is obtained by polymerizing the same or different tertiary amino alcohols [1], and using the same tertiary amino alcohol [1] in an amount of 30 mol% or more. Diols [2]
And / or those obtained by polymerizing [3]. The polymerization reaction conditions for obtaining such a polyaminoether do not limit the present invention, but generally use a condensation catalyst such as phosphoric acid, phosphorous acid or polyphosphoric acid, at 150 to 280 ° C, preferably 200 to 250 ° C. The reaction is carried out by heating at a temperature of ° C., and the generated water and unreacted monomers and oligomers are distilled off under normal pressure or reduced pressure. The polyaminoether obtained here has a molecular weight of 300 to 8000, preferably 800 to 3000. The segmented polyether urethane in the present invention is obtained by reacting a compound containing the above polyaminoether and, if necessary, two or more active hydrogens capable of reacting with another isocyanate group, with a polyisocyanate.

The method for producing the segmented polyether urethane is not particularly limited. For example, the above polyaminoether is reacted with a compound containing two or more active hydrogens capable of reacting with other isocyanate groups together with the polyisocyanate to form a terminal isocyanate. There is a method of producing a group-containing prepolymer, extending the molecular chain with a compound containing two or more active hydrogens capable of reacting with a low molecular weight isocyanate group to obtain a segmented polyether urethane. The finally obtained segmented polyether urethane preferably contains 1 to 90% by weight of the polyaminoether, and the recommended content is 5 to 70% by weight.

The active hydrogen-containing compound forming a soft segment in the production of a segmented polyether urethane includes, in addition to the above polyaminoether,
Polyols used for the production of general segmented polyether urethanes (typically 200-8000 molecular weight)
Is used. Examples of such polyols include polyoxyalkylene diols such as polyethylene glycol, polypropylene glycol and polytetramethylene glycol; ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol,
Diols such as 2,2-dimethyltrimethylene glycol, hexamethylene glycol, decamethylene glycol, 1,4-dihydroxycyclohexane, and 1,4-dihydroxymethylcyclohexane (preferably having 2 carbon atoms)
To 15) and a dicarboxylic acid or an ester-forming derivative thereof (for example, aliphatic dicarboxylic acids such as sebacic acid, asipic acid, dodecanedicarboxylic acid, glutaric acid, succinic acid, oxalic acid, and azelaic acid, and aromatics such as terephthalic acid and isophthalic acid). Polyester diols obtained by reacting dicarboxylic acids or their halides, active esters, amides and the like); polylactone diols obtained by ring-opening polymerization of ε-caprolactone and the like.

As the polyisocyanate, all polyisocyanates conventionally used in the production of polyurethane and all polyisocyanates which will be developed in the future can be used. Preferred are ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, octamethylene diisocyanate, undecamethylene diisocyanate, dodecamethylene diisocyanate, 3,3′-diisocyanatopropyl ether, cyclopentylene-1. 3-diisocyanate, cyclohexane-1,4-diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate,
A mixture of 2,4-tolylene diisocyanate and 2,6-tolylene diisocyanate, xylylene-1,4-diisocyanate, xylylene-1,3-diisocyanate, 4,4'-diphenylmethane diisocyanate,
4-diphenylpropane diisocyanate, 4-isocyanatobenzyl isocyanate, m-phenylene diisocyanate, p-phenylene diisocyanate, naphthalene-1,4-diisocyanate, naphthalene-1.
5-diisocyanate and the like are exemplified.

Although the reaction conditions for producing the segmented polyether urethane do not limit the present invention, generally, the isocyanate group / hydroxyl group (molar ratio) is 1.1 to 1.1.
The raw materials are reacted to produce a prepolymer so as to have a value of 5.0 (preferably 1.5 to 3.0). The prepolymer has isocyanate groups at both ends, and is reacted with an active hydrogen-containing compound that reacts with the isocyanate group, for example, a low molecular weight diol, diamine or amino alcohol to extend the molecular chain, thereby obtaining a segmented poly-polymer. Ether urethane is obtained. As the molecular chain extender used herein, for example, low molecular weight diols, diamines and amino alcohols, all known and novel ones can be applied to the present invention. Particularly preferred examples include diols such as ethylene glycol, propylene glycol, tetramethylene glycol, 1.5-pentanediol, 1.6-hexanediol, 1.10-decanediol, 1.4-dihydroxycyclohexane, 1.4
-Dihydroxymethylcyclohexane, diethylene glycol, triethylene glycol and the like are exemplified, and as the diamine, ethylene diamine, propylene diamine,
In addition to butylenediamine, hexamethylenediamine, xylidenediamine, phenylenediamine, 4,4'-diaminodiphenylmethane, etc., diamines in a broader sense such as hydrazine and dihydrazide of dicarboxylic acid (for example, oxalic acid dihydrazide, succinic dihydrazide, adipin) Acid dihydrazide, sebacic acid dihydrazide, isophthalic acid dihydrazide, etc.) and the like, and further, as the amino alcohol, methanolamine, 2-aminoethanol,
Examples thereof include 3-aminopropanol and 4-aminobutanol.

The segmented polyether urethane thus extended is subjected to a quaternary salification reaction. The quaternary salification may be performed before or after the formation of the segmented polyether urethane. However, before the formation, in a solvent such as dimethylformamide, and after the formation, the quaternary chloride has 1 to 10 carbon atoms, preferably 2 carbon atoms. The reaction is carried out at a temperature between room temperature and the boiling point using at least one of the alkyl halides of (1) to (8). At this time, a quaternizing agent is selected, and the sum of the carbon number of R ² in the general formula [1] and the carbon number of the hydrocarbon group chain length of the quaternizing agent is 7 or more and 16 or less, preferably 8 or more and 14 or less.
The following is the gist of the present invention. With this selection, the water absorption rate is 4% regardless of the quaternization rate.
It is kept below. If the sum is 6 or less, the water absorption is 4%
In addition, heparin is rapidly desorbed, and not only long-term blood compatibility cannot be maintained, but also mechanical strength is reduced, which is a practical problem. In addition, when the sum is 17 or more, the tertiary amino group becomes bulky, the quaternization rate is not improved, and the adsorbed amount of heparin is small, so that it is difficult to achieve blood compatibility. . As the quaternizing agent, cycloalkyl halides, active esters and the like can be used, but in the present invention, alkyl halides are preferred. Aromatic halides have poor heparinization efficiency.

The content of tertiary amino groups contained in the polyurethane or polyurethane urea is 0.05 to 5.0 m.
mol / g, preferably 0.1 to 3.0, more preferably 0.2 to 2.0 mmol / g. The quaternization ratio of the tertiary amino group is 10% or more, preferably 20% or more.
More preferably, it is 30% or more. Finally, heparin is applied, and this reaction may be performed before or after the molding of the polymer material. However, it is preferably carried out by immersing the molded article in a solution of a heparin analog compound described below. The solution is usually one having a concentration of 0.1 to 10%,
Preferably, 0.5 to 5% concentration is used. Although the reaction proceeds even at room temperature, it is most preferably carried out by heating to about 40 to 100 ° C. The heparin analog compound used herein includes not only derivatives such as heparin, heparin metal salt, 4-heparin, and 4-heparin metal salt,
Heparinoids such as chondroitin sulfate and dextran sulfate, as well as heparin analogs such as PVA sulfate. Further, as the solvent used for heparinization, water or a water-soluble organic solvent, for example, acetone,
A mixed solvent of ethanol, tetrahydrofuran, dimethylformamide or dimethylacetamide, and water may be used.

Among them, a mixed solvent with tetrahydrofuran, dimethylacetamide or dimethylformamide is particularly preferred. The mixing ratio is from 9/1 to 7/3, preferably from 8/2 to 6/4, in terms of volume ratio with water / organic solvent. In the present invention, as described above, a polymer material having a large amount of heparin attached can be obtained, so that high anticoagulability can be obtained without extra use of heparin during extracorporeal circulation of blood. It also has good mechanical properties such as elasticity, and has little harmful elution when it comes in contact with body fluids such as blood. By utilizing such advantages, it can be widely applied to various medical instruments or devices. Specifically, it can be used as a sheet, tube, or hollow fiber for hemodialysis of a renal failure patient, or as a coating agent for adsorbing waste products in blood. In addition to such an artificial kidney, it is also used as a membrane material for an artificial lung (a partition wall for blood and oxygen) and a sheet material for a sheet lung in a heart-lung machine. Other aortic balloons, artificial blood, blood bags,
It is used in a wide range of fields such as catheters, cannulas, shunts, and blood circuits.

Hereinafter, the present invention will be described with reference to examples.
Parts in the examples mean parts by weight.

EXAMPLES Example 1 4-Methyl-4-aza-2,6-heptanediol 14
72 parts, 591 parts of 1,6-hexanediol and 12.3 parts of phosphorous acid were charged into an autoclave, and the mixture was stirred and heated at a constant pressure of 200 to 220 ° C. for 26 hours while distilling off generated water. The reaction was performed. Then 2
At 20 ° C., the pressure was reduced from 760 mmHg to 0.3 mmHg over 2 hours.
The reaction was continued for a time. In this way, the OH value of 57.
3. An aminopolyether polyol (a) having a basic nitrogen of 6.11 mmol / g was obtained. 1,800 parts of polytetramethylene glycol having a number average molecular weight of 1500, 300 parts of the aminopolyether polyol (a), 90.1 parts of 1,4-butanediol, and 0.1 part of dibutyltin dilaurate.
3 parts and 554 parts of 4,4'-diphenylmethane diisocyanate (hereinafter abbreviated as MDI) are dissolved in a mixed solvent of 1994 parts of tetrahydrofuran (hereinafter abbreviated as THF) and 3887 parts of dimethylformamide (hereinafter abbreviated as DMF), The reaction was carried out at 40 ° C. for 1 hour and further at 60 ° C. for 15 hours under a stream of air. Thus, a base polymer solution A having a solid content of 32% and a viscosity of 3200 poise (30 ° C.) was obtained. DMF was added to this solution and stirred to give a 5% solution. 100 g of 5% solution kept horizontal
After uniformly coated on a glass plate of cm ² , dried at 40 ° C. for 1 hour, at 60 ° C. for 2 hours under a nitrogen stream, and then dried at 60 ° C. under reduced pressure for 15 hours to obtain a base polymer film A having a thickness of 50 μm. Obtained.

Further, 4.58 parts of hexyl iodide was added to 100 parts of a 10% base polymer solution obtained by diluting with DMF, and the mixture was reacted at 70 ° C. with stirring to obtain a tertiary amino group 4 in the base polymer. Grading was performed. This solution was diluted with dioxane to make a 5% solution, and a quaternized polymer film A having a thickness of 50 μm was obtained in the same manner as in the case of the base polymer A. Approximately 0.2 g of each of the base polymer film A and the quaternized base polymer film A was accurately weighed, dissolved in 50 ml of a dioxane / ethanol (7/3 volume ratio) mixed solvent, and then subjected to a potentiometric titration apparatus (comitite- manufactured by Hiranuma Seisakusho, Ltd.). 7) using N / 10-HC1
The basic polymer content of the base polymer film A was 0.67 mmol / g, and that of the quaternized film A was 0.25 mmol / g. there were. From this result, it can be seen that the quaternization ratio is about 63%.

Next, each film was immersed in a 1% heparin aqueous solution and treated at 70 ° C. for 2 hours to perform heparinization, thereby obtaining a heparinized base polymer film A and a heparinized quaternized polymer film A. These films were cut into a circular shape having a diameter of 3 cm, immersed in a physiological saline solution at 37 ° C. for one week, rinsed well with distilled water, and blotted on the surface of the film with filter paper. This film was adhered to the center of a watch glass having a diameter of 10 cm, and 200 μl of citrated plasma of a rabbit (Japanese white species) was collected on the film, and
200 μl of a 40/40 molar calcium chloride aqueous solution is added, and the watch glass is floated in a constant temperature water bath at 37 ° C., and stirred by hand so that the internal solution is mixed. ) Is measured and the solidification time on the glass (measured separately as a control)
And expressed as a relative value.

Each solution was diluted with DMF to obtain 1%
A solution was prepared, and 40 to 60 mesh glass beads were immersed in 100 ml of this solution for 30 minutes, and then filtered through a glass filter.
After drying at 12 ° C. for 12 hours, the surface of the glass beads was coated with each polymer. 200 mg of these coated beads, 50
Add 0 μl of Veronal buffer and serum (using pooled serum of a healthy person) to a plastic tube and add to 37 ° C.
Table 3 shows the results obtained by measuring the hemolytic complement value (abbreviated as CH50) and the amounts of C3a and C5a produced after gentle shaking and incubation for 30 minutes. The measurement of CH50 was performed by the Meyer method (Meyer, MM, "Compli").
ment and Compliment fixat
ion "Experimental Immune C
hemistry, 2th Edition p13
3, Charles C.E. Thomas Publi
Sher, Stuttgart, 1964), and the measurement of C3a, C5a was performed by Upjo.
The measurement was performed using a radio immunoassay kit sold by n companies.

After immersing each of the obtained films in distilled water at 20 ° C. for 24 hours, the surface water was wiped off, the weight was measured, and the water absorption was determined. The calculation of the water absorption was performed using the following equation. Water absorption (%) = {(WD) / D} × 100 In the above equation, W represents the weight of the film after immersion, and D represents the weight of the film after drying. The above results are shown in Table 1 below.

Example 2 8040 parts of 3-n-butyl-3-aza-1,5-pentanediol and 10.3 parts of phosphorous acid were charged into an autoclave and stirred at a constant pressure of 200 to 230 under a nitrogen stream while stirring.
The mixture was heated at 26 ° C. for 26 hours to carry out a reaction while distilling off generated water. Then, at 230 ° C., 760 mmHg to 0.3
reduced to 2 mmHg over 2 hours.
The reaction was continued at 0.3 mmHg for 3 hours. Thus, an OH value of 64.7 and a basic nitrogen of 6.75 mmol /
g of aminopolyether polyol (b) were obtained. Tetramethylene glycol 3240 having a number average molecular weight of 1800
Parts, 1195 parts of MDI, 773.4 parts of the above polyaminoether polyol, 0.3 part of dibutyltin dilaurate
Parts and 191.1 parts of 1,4-butanediol in THF
Dissolved in a mixed solvent of 3782 parts and 7564 parts of DMF and heated to 20 ° C. for 1 hour and 40 ° C. in a nitrogen stream to obtain 2
The reaction was carried out for 0 hour to obtain a base polymer solution B having a solid content of 32% and a viscosity of 1800 poise (30 ° C.). This base polymer solution B was treated in the same manner as in Example 1, and quaternized with hexyl iodide. Further, in the same manner as in Example 1, a base polymer B, a quaternized film B, and a heparinized film B were obtained. These basic nitrogen contents were 1.08 mmol / g and 0.410 mmol / g, respectively. This result shows that the quaternization ratio is about 62%. Next, in the same manner as in Example 1, the relative coagulation time, complement activity and water absorption were measured. Table 1 shows the results.

Example 3 8738 parts of 3-n-butyl-3-aza-1,5-pentanediol and 10.3 parts of phosphorous acid were charged into an autoclave and stirred at a constant pressure of 200 to 230 under a nitrogen stream while stirring.
The mixture was heated at 26 ° C. for 26 hours to carry out a reaction while distilling off generated water. Then, at 230 ° C., 760 mmHg to 0.3
reduced to 2 mmHg over 2 hours.
The reaction was continued at 0.3 mmHg for 3 hours. Thus, an OH value of 58.7 and a basic nitrogen of 6.30 mmol /
g of aminopolyether polyol (c) was obtained. Polytetramethylene glycol 32 having a number average molecular weight of 1800
40 parts, MDI 1195 parts, the above polyaminoether polyol 827.3 parts, dibutyltin dilaurate 0.
3 parts and 191.1 parts of 1,4-butanediol in TH
F3802 parts and DMF 7604 parts were dissolved in a mixed solvent, and the temperature was raised to 40 ° C for 1 hour at 20 ° C under a nitrogen stream to obtain 2
The reaction was carried out for 0 hour to obtain a base polymer solution (C) having a solid content of 32% and a viscosity of 1830 poise (30 ° C.). This base polymer solution C was treated in the same manner as in Example 1, and quaternized with hexyl iodide. Further, in the same manner as in Example 1,
A base polymer C, a quaternized film C and a heparinized film C were obtained. These basic nitrogen contents were 1.08 mmol / g and 0.410 mmol / g, respectively.
Met. From this result, it can be seen that the quaternization ratio is about 62%. Next, in the same manner as in Example 1, the relative coagulation time, complement activity and water absorption were measured. Table 1 shows the results.

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

Comparative Example 2 Acrylic nitrile (24 parts) and acrylamide (89)
Parts) with dimethylsulfoxide (126 parts), and then, as a chain transfer agent, dodecyl mercaptan (0.2 parts).
Part) Add bromophorim as a polymerization initiator and add 100 W
By irradiating light at a distance of 10 cm from a high-pressure mercury lamp for 7 hours, the photopolymerized polymerization stock solution was poured into a large amount of methanol to precipitate and solidify, thereby forming a trunk polymer (24.4).
Part). 10 g of the stem polymer thus obtained
Was dissolved in dimethylsulfoxide (120 parts), and dimethylaminoethyl methacrylate was added.
Irradiated with light from a mercury lamp at a distance of 10 cm for 19 hours, photografting was performed, and the undiluted solution was poured into methanol to precipitate and solidify, thereby obtaining a graft polymer (12.8).
Part). The graft polymer thus obtained was dissolved in dimethylformamide, quaternized by adding ethyl bromide, and then formed into a film (E). Next, in the same manner as in Example 1, the relative coagulation time, complement activity and water absorption were measured. Table 1 shows the results. As is evident from the results in Table 1, the polymer of Comparative Example 2 (E) activates complement, whereas the polymer of Example 2 also suppresses complement activity. At this stage, the polymer (D) of Comparative Example 1 has performance comparable to that of the polymer of Example.

Example 5 The heparinized films A to E obtained in Examples 1 to 3 and Comparative Examples 1 and 2 were each 200 m long.
of the eluted film, and the relative coagulation time was measured. The results are shown in Table 2 below. Table 1, Table 2
According to the results, those having a total of 7 to 16 carbon atoms in the two alkyl groups of the side chain directly linked to nitrogen after quaternization show a small water absorption and eluted in physiological saline for 2 weeks. Has good blood compatibility, but the total number of carbon atoms of the two alkyl groups bonded to nitrogen after quaternization is 6 or less, and the water absorption of the comparative example is large. Since the polymer elutes heparin quickly, if the immersion time exceeds 3 days, the effect of heparin is completely lost and the polymer solidifies. From the above, it is clear that the polymer of the present invention has good long-term blood compatibility.

[0030]

[Table 1]

[0031]

[Table 2]

[0032]

The specific polyurethane or polyurethane urea of the present invention has long-term blood compatibility (antithrombotic and complement activity suppressing effects), and is used as a material for a blood-compatible medical material or a blood-contact medical material. It has excellent suitability as a coating agent.

Claims (2)

(57) [Claims] (1) A blood compatible material obtained by treating a quaternized polyurethane or a quaternized polyurethane urea having a structure represented by the following general formula (1) with heparin or an analog thereof. -DI-PAE-DI-A-DI- (1) (In the above formula (1), DI is -CO-NH- <B> -NH
Represents —CO—, and <B> is a hydrocarbon group having 2 to 25 carbon atoms. In the above formula (1), PAE is -O-(<C
>-<D>-<E>) _x- . Where <C
> Represents -CH (R ¹ ) CH ₂ N (R ² ) CH ₂ CH (R ³ ) O-, and R ¹ , R ³
Represents an alkyl group having 1 to 5 carbon atoms which may be the same or different, R ² represents an alkyl group having 1 to 15 carbon atoms,
Represents an aralkyl group or an aryl group. Also <C>
Is contained in PAE by 30 mol% or more. Part or all of N is quaternized and has the following structure. Embedded image Here, R is a hydrocarbon group having 1 to 10 carbon atoms derived from a quaternizing agent, and the total number of carbon atoms of R ² and R is 7 to 16. Z ^- is a halide derived from a quaternizing agent or a group derived from an active ester. <D> represents —R ⁸ —O—, and R ⁸ represents an alkylene group having 2 to 20 carbon atoms. <E> is
-(R ⁹ -O-) _n- , wherein R ⁹ is an alkylene group having 2 to 5 carbon atoms, and n is an integer of 2 or more. x represents an integer of 2 or more. The above <C>, <D
>, <E> may be random. The above (1)
In the formula, A is -O- (XO) _m- , -O- (X-CO) _m --OYO-, -NH-Y-NH-, -OY-NH-, NH-YO- or -NH- NH
Represents CO-Y-CONH-NH-. Here, X has 2 to 2 carbon atoms.
15 hydrocarbon groups, m is an integer of 2 or more, Y is 2 to 2 carbon atoms
Represents 10 hydrocarbon groups. ) 2. The blood-compatible material according to claim 1, wherein the water absorption of the quaternized polyurethane or the quaternized polyurethane urea is 4% or less.