JPH04343852A - Material adapted to blood - Google Patents

Abstract

PURPOSE:To provide a coagulation resistant medical material excellent in mechanical properties, especially elasticity, and in the maintenance of coagulation resistance due to heparinization. CONSTITUTION:A material in which when a polymer containing quaternary ammonium salt is heparinized the polymer after the heparinization has an alkaline metal or an alkaline earth metal(M) and sulfur atom(S) in a ratio (M/S) of not more than 0.5 due to the heparinization.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to medical materials that come into direct contact with living organisms or biological components, and particularly to blood-compatible materials with good anticoagulant properties and mechanical properties.

0002

[Prior Art] Polymer materials with excellent processability, elasticity, and flexibility have recently come to be widely used as medical materials, including artificial kidneys, artificial lungs, auxiliary circulation devices, and artificial blood vessels. They will be used in increasing quantities in the future as disposable containers for artificial organs such as syringes, blood bags, cardiac catheters, etc. In this case, the issue is safety, that is, whether various abnormal reactions occur in the living body and pose a danger to life support, and in the case of blood, the condition that blood coagulation does not occur is required. be done. The anticoagulant polymer materials that have been provided to date include (1) those in which heparin or its analogues are attached to the surface of a polymer material, and (2) those in which a negative charge is imparted to the surface of a polymer material. , (3) There are three types of polymer materials whose surfaces are inactivated, and the material provided by the present invention is classified into (1) among the above.

0003

[Problems to be Solved by the Invention] Means (1) (hereinafter referred to as surface heparinization method) further includes (A) a blending method of a polymer and heparins, and (B) a method of adding heparins to cationic groups in the polymer. method of ionic bonding,
(C) Methods are subdivided into methods in which polymers and heparin are covalently bonded, but in methods (A) and (B), heparins are desorbed and fixed in vivo due to long-term use under physiological conditions. It is unsuitable as a medical material. On the other hand, the material obtained in (C) has the advantage that it is difficult to release because heparins are covalently bonded, but the conventional covalent bonding method is based on the heparin constituents D-glucosamine and D-glucuronic acid. It has the disadvantage that the anticoagulant effect is reduced because it causes a conformational change in the blood.

On the other hand, Japanese Patent Application Laid-open No. 139173/1983 describes the general formula HO(R1 O)mR2 N(R3)R4 (OR5
) nOH (where R1, R2, R4, R5 are alkylene groups having 2 to 4 carbon atoms, R3 is an alkyl group having 1 to 20 carbon atoms, m and n are integers of 1 to 30)
A polyester or polyurethane whose diol component is partially or entirely a dihydric alcohol having a tertiary amino group and a polyether chain in its molecule is converted into a quaternary salt.
A ``method for producing an anti-blood coagulant polymer material'' has been proposed in which a ``polyether-type polyester or polyether-type polyurethane'' having an ammonium salt in its molecule is reacted with heparin. In this method, if the values of m or n are too large, the number of tertiary amino groups and even quaternized ammonio groups will decrease, resulting in insufficient heparin deposition and anticoagulant effect. It has the disadvantage of being smaller. Moreover, it does not lead to the formation of hydrophilic domains. On the other hand, if m or n is small, the mechanical properties, especially the elasticity, will deteriorate, making it unsuitable for use as an artificial organ. Furthermore,
Japanese Patent Publication No. 54-18518 discloses an antiseptic material consisting of heparin and a copolymer containing a hydrophilic component, a hydrophobic component, and a quaternary ammonium salt component as essential units, and characterized in that the standard membrane potential difference shows a negative value. A coagulable medical material is disclosed, but as shown in the examples, the water absorption rate is as high as 5-80%, so heparin is rapidly desorbed and the effect does not last for a long time. At the same time, due to its high water absorption rate, it has the disadvantage that its strength in blood is greatly reduced, and it cannot be used in places where force is applied (such as the squeezing part of a roller pump).

[0005] In order to eliminate these drawbacks, the present applicant previously filed a patent application (Japanese Patent Publication No. 16260/1983). However, even in this case, if the water absorption exceeds 4%, heparin is rapidly desorbed and antithrombotic properties cannot be maintained for a long period of time.

[0006]

[Means for Solving the Problems] As a result of intensive research, we have arrived at an invention that solves all of the above-mentioned drawbacks. That is, when a polymer containing a quaternary ammonium salt is subjected to ion-exchange heparinization using an alkali metal salt or alkaline earth metal salt solution of heparin or a heparin-related compound, the heparin in the polymer after heparinization is completed. The blood-compatible material is characterized in that the content molar ratio of alkali metal or alkaline earth metal atoms to sulfur atoms is 0.5 or less. The polymer containing this quaternary ammonium salt is not particularly limited, but preferably has the general formula [1] HOCH(R1)CH2N(R2)
CH2 CH(R3)OH [1] (In each of the above formulas, R1 and R3 are the same or different and have an alkyl group having 1 to 5 carbon atoms, and R2 is an alkyl group having 1 to 15 carbon atoms, an aralkyl group, and A polyaminoether obtained by condensation containing at least 30 mol% of diols represented by (representing an aryl group) and a compound having two or more active hydrogens capable of reacting with other isocyanates are reacted together with a polyisocyanate. The tertiary amino group of polyurethane or polyurethane urea obtained by
It is a material obtained by grading. In order to obtain the blood-compatible material of the present invention, the solvent of the heparin solution is characterized in that it is a mixture of a water-soluble organic solvent and water.

[0007] The present invention deals with the treatment of alkali metal or alkaline earth metal atoms (hereinafter abbreviated as M)/sulfur atoms (hereinafter abbreviated as S) derived from heparin in a polymer after heparinization.
The gist lies in that the content molar ratio of is 0.5 or less. Heparinization of the material of the present invention is carried out by the reaction shown below (formula 1
).

[Formula 1] In Formula 1, Hep. -SO3 M represents heparin or a related compound, P4 represents a quaternizing material, A represents a counter anion derived from the quaternizing agent, and M represents an alkali metal or alkaline earth metal atom. S contained in heparin
O3 − undergoes ion exchange with the counter anion in the polymer containing the quaternary ammonium salt, and is bonded to the polymer through an ionic bond. At this time, the alkali metal or alkaline earth metal M, which was the counter cation of SO3 − in heparin, binds to the counter anion derived from the quaternizing agent in the polymer and is liberated. Therefore, as the number of binding sites between heparin and the polymer increases, the M/S content molar ratio decreases, and the bond between heparin and the polymer becomes stronger. It should be noted here that the S content of the heparinized material is
) Indicates the amount of adsorbed heparin, unless it has a component containing
The M/S content ratio indicates the number of binding sites between the adsorbed heparin and the polymer, and thus the strength of the binding. The material obtained in the present invention is characterized by an M/S content ratio of 0.5 or less, preferably 0.4 or less. By setting the M/S content ratio within this range, heparin-
The bond between polymers becomes moderately strong, and the polymer material becomes
Heparin desorption in vivo is controlled and can be used as an antithrombotic material for a long period of time.

[0008] In addition to the above-mentioned anticoagulant properties, general problems when using polymeric materials in contact with blood include additives (plasticizers, stabilizers, polymerization catalysts, etc.) in the materials and unreacted raw materials (
Although it is necessary to consider the harmful effects caused by elution of monomers, oligomers, etc., the present invention does not require the addition of plasticizers, etc., and since a segmented polymer is formed, there is no possibility of such inconveniences occurring. do not have. Polymer materials are susceptible to complex effects such as oxidative decomposition and metabolism due to free radicals and oxygen in living organisms, but since they are based on segmented polyether urethane, they have high chemical stability and are free from harmful elution. It rarely generates anything.

Since the material of the present invention is composed of a highly hydrophilic quaternary chlorinated polyaminoether segment, a hydrophobic polyether segment, and a crystalline urethane or urea bond, phase separation occurs in the solid phase. It forms a microdomain structure, which is similar to the structure of the inner wall of blood vessels. Therefore, anticoagulant properties are expected from the structural aspect. Next, each component constituting the polymer material of the present invention will be explained. First, in general formula [1], R1 and R3
Examples of the alkyl group having 1 to 5 carbon atoms include saturated lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and isopentyl. Also, R2 has 1 or more carbon atoms.
In addition to the above saturated lower alkyl, examples of the alkyl group 15 include hexyl, heptyl, octyl, nonyl, decyl,
There are chain or branched alkyls such as undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl, as well as saturated cyclic alkyls such as cyclopentyl, cyclohexyl, and cycloheptyl. Examples of the aralkyl group represented by R2 include benzyl and phenethyl, which may be substituted with alkyl groups such as methyl, ethyl, and propyl. Furthermore, examples of the aryl group represented by R2 include phenyl and naphthyl, 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 preferred. In addition, the diols represented by the general formula [2] or [3] can be used as raw materials for producing the polyamino ether together with these amino alcohols. HO-R8-OH
[2] HO-(R9O)n-H
[3] (R8 is an alkylene group having 2 to 20 carbon atoms, R9 is an alkylene group having 2 to 5 carbon atoms, and n is 2 or more.)

[0010] The meanings of each symbol have been explained above, and further specific explanations for each individual compound are as follows. First, as the tertiary amino alcohol represented by the general formula [1], 3-methyl-3-aza-1.
5-pentanediol, 3-ethyl-3-aza-1.5
-pentanediol, 3-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-pentanediol, 4-ethyl-4-
Aza-2,6-pentanediol, 4-n-propyl-
4-aza-2,6-pentanediol, 4-isopropyl-4-aza-2,6-pentanediol, 4-n-butyl-4-aza-2,6-pentanediol, 4-isobutyl-4-aza -2.6-pentanediol, 4-hexyl-4-aza-2.6-pentanediol, 4-cyclohexyl-4-aza-2.6-pentanediol,
4-benzyl-4-aza-2,6-pentanediol,
4-phenyl-4-aza-2,6-pentanediol,
Examples include 4-n-lauryl-4-aza-2,6-pentanediol.

Further, as the diols represented by the general formula [2], ethylene glycol, propylene glycol,
Examples include alkylene glycols such as tetramethylene glycol, 1,6-hexanediol, and neopentyl glycol. Examples of diols represented by the general formula [3] include diethylene glycol, triethylene glycol, and polyethylene glycol with a molecular weight of 200 to 2,000; dipropylene glycol and tripropylene glycol; and polypropylene glycol with a molecular weight of 200 to 1,000; polytetramethylene glycol; polyhexamethylene glycol having a molecular weight of 200 to 1000, and the like.

[0012] The polyamino ether according to the present invention refers to a product obtained by polymerizing the same or different tertiary amino alcohols [1], or a product obtained by polymerizing the same or different tertiary amino alcohols [1].
] and polymerized with diols [2] and/or [3]. The polymerization reaction conditions for obtaining such a polyaminoether are not limited to the present invention, but generally a condensation catalyst such as phosphoric acid, phosphorous acid or polyphosphoric acid is used, and the reaction temperature is 150 to 280°C, preferably 200 to 250°C. The reaction is heated to 0.degree. C., and the produced water and unreacted monomers and oligomers are distilled off under normal pressure or reduced pressure. The polyaminoether obtained here has a molecular weight of 3
00 to 8,000, preferably 800 to 3,000. The segmented polyether urethane in the present invention is obtained by reacting the above-mentioned polyaminoether and a compound containing two or more active hydrogens capable of reacting with other isocyanate groups, if necessary, with a polyisocyanate.

The method for producing the segmented polyether urethane is not particularly limited, but for example, the above polyaminoether and a compound containing two or more active hydrogens capable of reacting with other isocyanate groups are reacted together with a polyisocyanate to form terminal isocyanate. There is a method of producing a group-containing prepolymer and elongating 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 polyaminoether is preferably contained in the segmented polyether urethane finally obtained in an amount of 1 to 90% by weight, and the more recommended content is 5 to 70% by weight.

[0014] In addition to the above-mentioned polyaminoether, active hydrogen-containing compounds forming soft segments in the production of segmented polyether urethane include:
Polyols used in the production of common segmented polyether urethanes (usually with a molecular weight of 200 to 8,000)
is used. 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, 1,4-dihydroxymethylcyclohexane (preferably 2 carbon atoms)
~15) and dicarboxylic acids or their ester-forming derivatives (e.g. aliphatic dicarboxylic acids such as sebacic acid, adipic acid, dodecanedicarboxylic acid, glutaric acid, succinic acid, malonic acid, oxalic acid, azelaic acid, terephthalic acid, isophthalic acid, etc.) aromatic dicarboxylic acids or halides thereof,
Examples include polyester diols obtained by reacting active esters, amides, etc.; polylactone diols obtained by ring-opening polymerization of ε-caprolactone, etc.

As the polyisocyanate, all polyisocyanates conventionally used in the production of polyurethane and polyisocyanates that will be developed in the future can be used. Preferred examples include 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,
Mixture of 2,4-tolylene diisocyanate and 2,6-tolylene diisocyanate, xylylene-1,4-diisocyanate, xylylene-1,3-diisocyanate, 4,4'-diphenylmethane diisocyanate, 4
・4-diphenylpropane diisocyanate, 4-isocyanatobenzyl isocyanate, m-phenylene diisocyanate, p-phenylene diisocyanate, naphthalene-1, 4-diisocyanate, naphthalene-1・
Examples include 5-diisocyanate.

Although the reaction conditions for producing the segmented polyether urethane are not intended to limit the present invention, generally the isocyanate group/hydroxyl group (molar ratio) is 1.1 to 5.
．． 0 (preferably 1.5 to 3.0), each raw material is reacted to produce a prepolymer. This prepolymer has isocyanate groups at both ends, and when it is reacted with an active hydrogen-containing compound that reacts with the isocyanate groups, such as a low molecular weight diol, diamine, or amino alcohol to extend the molecular chain, it becomes a segmented polyester. Ether urethane is obtained. The molecular chain extender used here,
For example, all low molecular weight diols, diamines and amino alcohols, regardless of whether they are known or new, can be applied to the present invention. Particularly preferred diols include ethylene glycol, propylene glycol,
Examples include tetramethylene glycol, 1,5-pentanediol, 1,6-hexanediol, 1,10-decanediol, 1,4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, diethylene glycol, triethylene glycol, etc. Examples of diamines include ethylene diamine, propylene diamine, butylene diamine, hexamethylene diamine, xylidene diamine, phenylene diamine, 4,4'-diaminodiphenylmethane, as well as diamines in a broader sense, such as hydrazine and dihydrazide of dicarboxylic acids ( For example, oxalic acid dihydrazide, succinic acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, isophthalic acid dihydrazide, etc.) can also be used, and as amino alcohols, methanolamine, 2-aminoethanol, 3-
Examples include aminopropanol and 4-aminobutanol.

The segmented polyether urethane thus chain-extended is then subjected to a quaternary chlorination reaction. Quaternary chlorination can be carried out before or after molding the segmented polyether urethane, but it can be carried out in a solvent such as dimethylformamide before molding, or as it is after molding, with carbon atoms of 1 to 10, preferably 2. -8 alkyl halides, at a temperature between room temperature and boiling point. At this time, the quaternizing agent is selected such that the sum of the number of carbon atoms in R2 in general formula [1] and the number of carbon atoms in the hydrocarbon chain length of the quaternizing agent is 7 or more and 16 or less, preferably 8 or more and 14
It is preferable to do the following. If the sum is 6 or less, the water absorption rate exceeds 4%, heparin is rapidly desorbed, long-term blood compatibility cannot be maintained, and mechanical strength also decreases.
This poses a practical problem. Also, if the sum is 17 or more, the third
Since the area around the class amino group becomes bulky, the quaternization rate does not improve, and the amount of heparin adsorbed is small, making it difficult to achieve blood compatibility. As the quaternizing agent, cycloalkyl halides, active esters, etc. can also be used, but alkyl halides are preferred in the present invention. Aromatic halides have poor heparinization efficiency.

The content of tertiary amino groups contained in polyurethane or polyurethaneurea is 0.05 to 5.0 m
mol/g, preferably 0.1 to 3.0, more preferably 0.2 to 2.0 mmol/g. Further, the quaternization rate of this tertiary amino group is 10% or more, preferably 20%.
It is more preferably 30% or more. Finally, heparin is added, and this reaction can occur before or after the polymer material is molded. However, preferably, the molded article is immersed in a solution of a heparin analog compound described below. The solution used usually has a concentration of 0.1 to 10%, preferably 0.5 to 5%. Although the reaction proceeds at room temperature, it is most preferably carried out by heating to about 40 to 100°C. The heparin analogs used here include heparin, heparin metal salts,
It includes not only derivatives such as 4-heparin and 4-heparin metal salts, but also heparinoids such as chondroitin sulfate and dextran sulfate, and even heparin analogs such as PVA sulfate. In addition, as the solvent used for heparinization, water-soluble organic solvents such as acetone,
A mixed solvent of ethanol, tetrahydrofuran, dimethylformamide or dimethylacetamide, and water is used.

Among these, a mixed solvent of tetrahydrofuran, dimethylacetamide or dimethylformamide is preferred, and a mixed solvent with tetrahydrofuran is most preferred in order to achieve the M/S content ratio of 0.5 or less, which is the gist of the present invention. Further, the mixing ratio is 20/1 to 3/7, preferably 10/1 to 3/5 in volume ratio of water/organic solvent.
It is. In the present invention, as described above, a polymeric material with a large amount of heparin adhesion is obtained, so that during extracorporeal circulation of blood,
High anticoagulability can be obtained even without the use of heparin. It also has good mechanical properties such as elasticity, and produces little harmful eluate when it comes into contact with body fluids such as blood. Taking advantage of these advantages, it can be widely applied to various medical instruments or equipment. To give specific examples, it can be used as a sheet, tube, or hollow fiber for hemodialysis of patients with renal failure, or as a coating agent for adsorbing waste products in blood. In addition to such artificial kidneys, membrane materials for artificial lungs (blood and oxygen barrier)
It is also used as a sheet material for sheet lungs in heart-lung machines. It is also used in a wide range of other fields such as aortic balloons, artificial blood, blood bags, catheters, cannulas, shunts, and blood circuits.

The present invention will be explained below using examples. Parts in the examples mean parts by weight.

【Example】

<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 a nitrogen stream at constant pressure 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 polytetramethylene glycol with a number average molecular weight of 1500,
300 parts of the above aminopolyether polyol (a), 1
, 90.1 parts of 4-butanediol, 0.3 parts of dibutyltin dilaurate, and 554 parts of 4,4'-diphenylmethane diisocyanate (hereinafter abbreviated as MDI) were mixed with 1994 parts of tetrahydrofuran (hereinafter abbreviated as THF) and dimethylformamide (hereinafter abbreviated as THF). (abbreviated as DMF)3
Dissolved in 887 parts of mixed solvent and heated at 40°C under nitrogen stream to 1
The reaction was further continued at 60° C. for 15 hours. In this way, 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 make a 5% solution. After uniformly applying 10 g of a 5% solution onto a 100 cm2 glass plate held horizontally,
After drying under a nitrogen stream at 40° C. for 1 hour and 60° C. for 2 hours, drying was performed under reduced pressure at 60° C. for 15 hours to obtain a base polymer film A having a thickness of 50 μm.

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 in the same manner as in the case of base polymer A, a 50 μm thick quaternized polymer film A was obtained. 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 Titrated with a dioxane solution and measured the basic nitrogen content from its inflection point. 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%.

[0022] Next, each film was immersed in a 1% heparin solution (solvent: tetrahydrofuran/water = 1/4 weight ratio) and treated at 70°C for 2 hours to perform heparinization, thereby forming a heparinized base polymer film A. And heparinized quaternized polymer film A was obtained. These films were cut into circles with a diameter of 3 cm, thoroughly rinsed with distilled water, and water on the film surface was absorbed with filter paper. This film is 10cm in diameter
Collect 200 μl of rabbit (Japanese white) citrated plasma on the film, add 200 μl of 1/40 molar calcium chloride aqueous solution, and place in a thermostatic water bath at 37°C. Float the watch glass on top of the glass and stir it by hand to mix the internal fluid.Measure the time from the time calcium chloride is added until coagulation (the point at which the plasma stops moving).The coagulation time on the glass (measured separately as a control) do)
It is expressed as a relative value.

[0023] Each solution was diluted with DMF to 1%
40 to 60 mesh glass beads were immersed in 100 ml of this solution for 30 minutes, filtered through a glass filter, and heated at 40°C under a nitrogen stream for 3 hours under reduced pressure at 60°C.
The beads were dried at ℃ for 12 hours to coat each polymer on the surface of the glass beads. This coated beads 200mg, 50
Add 0 μl of veronal buffer and serum (pooled serum from healthy individuals was used) to a plastic test tube and incubate at 37°C.
Table 1 shows the results of measuring the hemolytic complement value (abbreviated as CH50) and the amount of C3a and C5a produced after incubation for 30 minutes with gentle shaking. Note that CH50 was measured using the Meyer method (Meyer, M., M., “Com
pliment and complement
fixation"Experimental I
mmune Chemistry, 2ndEdi
tion p133, Charles C.
Thomas Publisher, Stutt
C3a and C5a were measured using a radioimmunoassay kit sold by Upjon.

Further, the amounts of sulfur and sodium contained in the obtained heparinized film were determined by elemental analysis (ion chromatography), and the S content (%) and Na/S content molar ratio were determined. The above results are shown in Table 1 below.

<Example 2> 3-n-butyl-3-aza-
8040 parts of 1,5-pentanediol and 10 parts of phosphorous acid
．． Three parts were placed in an autoclave and heated under constant pressure at 200 to 230° C. for 26 hours 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 tetramethylene glycol with a number average molecular weight of 1800, 1195 parts of MDI,
773.4 parts of the above polyaminoether polyol, 0.3 parts of dibutyltin dilaurate, and 191.1 parts of 1,4-butanediol were dissolved in a mixed solvent of 3782 parts of THF and 7564 parts of DMF, and the mixture was heated at 20°C for 1 hour under a nitrogen stream. ,
After raising the temperature to 40°C and reacting for 20 hours, the solid content was 32%,
A base polymer solution B having a viscosity of 1800 poise (30° C.) was obtained. This base polymer solution B was treated in the same manner as in Example 1 and quaternized with hexyl iodide. Furthermore, Example 1
In the same manner as above, base polymer B, quaternized film B, and heparinized film B were obtained. Their basic nitrogen content is 1.08 mml/g and 0.410, respectively.
It was mmol/g. Based on this result, the quaternization rate is approximately 6
It turns out that it is 2%. Then, in the same manner as in Example 1, relative coagulation time, complement activity, S content, and Na/S content molar ratio were measured. The results are shown in Table 1.

<Comparative Example 1> Using the base polymer solution B obtained in Example 2, base polymer B was obtained in the same manner as in Example 1. Furthermore, in the same manner as in Example 1, the quaternized film C was quaternized with hexyl iodide, and the heparinized film C was heparinized with a 1% heparin solution (the solvent was dimethylacetamide/water = 3/2 weight). Obtained. Their basic nitrogen contents were 1.08 mml/g and 0.410 mmol/g, respectively. From this result, it can be seen that the quaternization rate is about 62%. Next, in the same manner as in Example 1, relative clotting time, complement activity, S content, N
The a/S content molar ratio was measured. The results are shown in Table 1.

<Comparative Example 2> The base polymer obtained in Example 2 was heparinized with a quaternized film D and a 1% aqueous heparin solution in the same manner as in Example 1 to obtain a heparinized film D. In the same manner as in Example 1, relative coagulation time, complement activity, S content, and Na/S content molar ratio were measured. The results are shown in Table 1. As is clear from the results in Table 1, both the polymers of Comparative Example 1 and Comparative Example 2 have performance comparable to that of the polymer of Example at this stage.

<Example 3> Examples 1 and 2 and Comparative Example 1
, 200 ml of heparinized films A to D obtained in 2.
The results of measuring the relative coagulation time of the eluted film and the S content of the heparinized film after 2 weeks of elution are shown in Table 2 below. Shown below. From the results in Tables 1 and 2, it can be seen that when the Na/S content ratio is large, the bond between heparin and polymer is loose and heparin is easily released, so as the immersion time becomes longer, the effect of heparin decreases. After two weeks, the effect of heparin has completely disappeared. From the above, it is clear that the polymer of the present invention has good long-term blood compatibility.

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

Effects of the invention: The specific heparinized material of the present invention has long-term blood compatibility (antithrombotic and complement activation suppressing effects).
It has excellent suitability as a raw material for blood-compatible medical materials or a coating agent for blood-contact medical materials.

Claims (1)

[Claims] Claim 1: When a polymer containing a quaternary ammonium salt is subjected to ion-exchange heparinization using an alkali metal salt or alkaline earth metal salt solution of heparin or heparin analogues, the polymer after heparinization is A blood-compatible material characterized in that the content molar ratio of alkali metal or alkaline earth metal atoms/sulfur atoms resulting from heparin is 0.5 or less.