JP2003327657A - Functional polyurethane and/or polyurethane urea and method for manufacturing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a safe and highly functional polyurethane improved in stability to heat during processing and stability to hydrolysis during use, while keeping its favorable characteristics and functionality which is a favorable material from the view point that functional polyurethanes are easy in hardness control and good in biocompatibility, but have problems in sterilizing treatment, the decrease in strength by hydrolysis during use in living bodies, and the generation of elusion materials in the conventional technology. <P>SOLUTION: The polyurethane and/or polyurethane urea is obtained by using a functional polyol, a macropolyol, a chain extending agent, an aliphatic diisocyanate, and an aromatic diisocyanate at least as a part of starting materials, and the functional polyol forms a domain structure by exclusively adding to the aliphatic diisocyanate. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a functional polyurethane and / or polyurethane urea composed of specific constituents and a method for producing the same. The polyurethane and / or polyurethane urea of the present invention is particularly suitable for application to medical materials.

[0002]

2. Description of the Related Art Materials used for various purposes are required to have properties according to the uses, but generally, materials having excellent mechanical properties, that is, strength and durability are suitable in general. . Materials researched and developed to obtain excellent mechanical properties are also applied to medical materials due to their excellent properties.

At the same time, since medical materials are used in direct contact with a living body having a complicated defense system, it is necessary to satisfy biocompatibility, which is a property not usually required for other applications. The method of imparting biocompatibility to a material includes, for example, (1) a method of using a material which is originally inactive to a living body, (2) modification of the material surface to obtain negative charge, hydrophilicity, bio-component mimicking structure, etc. And (3) immobilizing a physiologically active substance capable of improving biocompatibility such as mucopolysaccharide such as heparin or urokinase on the surface of the material. Of these, the method (3) further includes (A) a method of coating a physiologically active substance,
(B) a method of immobilizing a physiologically active substance by ionic bonding, and (C) a method of immobilizing a physiologically active substance by covalent bonding.

Of these methods, the method (1) is to examine the biocompatibility of existing materials and use a preferable material, but obtain the biocompatibility superior to that required at present or in the future. It is hard to say that this is an effective method. Further, even if a new material is developed, this method is not efficient because it is necessary to start the study from the very basic part and build up the material. Therefore, the above method (2) or (3) is adopted to realize further biocompatibility improvement while utilizing the excellent properties of the conventional material, but the existing material is modified. For this reason, it is effective to introduce a functional group into the material as a starting point of the modification. Polyurethane and / or polyurethaneurea and / or polyurea (hereinafter abbreviated as polyurethanes) is a material having a preferable functional group, for example, an amino group-containing material can be prepared by using an amino group-containing diol as one of raw materials. It is relatively easy to prepare.

Further, since medical materials are used in direct contact with the living body, sufficient safety is an important requirement.
Until recently, the biological properties including safety of medical materials tended to lack sufficient consideration and consideration. In particular, conditions of use for medical purposes, that is, decomposition products and unreacted monomers contained in the material by contact with body fluids such as blood,
Elution of by-products and oligomers is a serious drawback as a medical material.

[0006] For example, polyvinyl chloride (PVC) is very widely used as a medical material because its hardness can be freely changed by the amount of plasticizer added, it is relatively stable under general use conditions, and it is inexpensive. It's being used. However, PVC has a problem in terms of safety in that plasticizers such as phthalate ester may elute during use, and that many studies show that phthalate ester is toxic. is there.

Silicone is also used as a medical elastomer in various catheters and tubes, and is also used as a membrane material for artificial lungs due to its gas permeability, but when it is left in the body for a long time, it is released as an eluate. There is concern about the toxicity of silicone.

Polyurethanes can be prepared by appropriately setting the compounding ratio of macropolyol, which is a soft segment, and diisocyanate or a chain extender, which is a hard segment.
It is possible to prepare materials of preferred hardness without the use of additives. In addition, segmented polyurethanes are known to form microphase separated structures, thereby exhibiting excellent blood compatibility. Further, it is already described that the functional group can be introduced relatively easily.
Due to these advantages, polyurethanes are one of the polymer materials favorably used as medical materials.

Many reports have already been made on the technology for obtaining functional polyurethanes. For example, as polyurethanes containing a phospholipid-like structure JP 61-207395 JP, JP 08-134085 JP, JP 08-259654 JP, JP 09-235342 JP, JP 09- 241330 gazette,
JP-A-10-287687 and the like, as the polyurethane containing a sugar chain residue, JP-A-11-071391 and the like,
As a polyurethane containing an unsaturated bond, JP-A-11
-315126, JP2000-256426, JP2001-172
No. 338 publication is cited.

Of these, JP-A-61-207395 discloses polyurethanes having a phospholipid-like structure obtained from a diol having a phospholipid-like structure and diphenylmethane diisocyanate. When the strength is insufficient during molding,
It was pointed out in Japanese Patent Laid-Open No. 08-134085 by the inventor himself. The polyurethanes disclosed in JP-A-08-134085 are diols having a phospholipid-like structure and phospholipid-like structure-containing polyurethanes obtained from hexamethylene diisocyanate or tolylene diisocyanate, but in this technology, There is no idea that the functionality, safety and stability are improved by using two or more kinds of diisocyanates, which is one of the points of the present invention. The same applies to the techniques disclosed in JP-A 08-259654, JP-A 09-235342, and JP-A 10-287687. Japanese Patent Laid-Open No. 09-241330 discloses a phosphorylcholine group-containing (meth) acrylic acid ester, a prepolymer composed of a copolymer of a (meth) acrylic acid derivative, and polyurethanes obtained from a diisocyanate compound. Since the polymer is a polyhydric alcohol, the resulting polyurethanes have a cross-linking structure, the mobility of the conformation of the polymer chain is significantly limited, and it is difficult to exert a sufficient function.

The prior art exemplified as polyurethanes containing a phospholipid-like structure was individually discussed as described above. In all of the existing functional polyurethanes including these, the functional polyol is one of the raw materials. However, the state of existence in the polymer chain is insufficiently considered. For polyurethanes prepared using functional polyol as one of the raw materials, it is necessary to fully consider whether or not the functional polyol-derived moiety is in an environment in which it can be sufficiently exerted in the polymer chain. . It is pointed out that polyurethanes obtained by the existing technology may not be able to exert a sufficient function due to this part being buried in the material depending on the use environment.

Although there are some deviations from the viewpoint of functional polyurethanes, examples of polyurethanes in which an aliphatic diisocyanate and an aromatic diisocyanate are used in combination with a clear intention include, for example, Kaihei 05-295063, JP 07-026096 JP, JP
07-097560, JP 07-166052, JP 08-0
52939, JP 08-067814, JP 09-25586
No. 6, JP-A-11-349805, JP-A-2000-034439, and the like.

Among these, Japanese Patent Laid-Open No. 05-295063,
JP-A 07-026096, JP-A 09-255866, JP-A 11-349805, JP 2000-034439 in the polyisocyanate diisocyanate group formation by isocyanurate group formation, cross-linking prepared using this Polyurethanes are disclosed. In these techniques, raw materials for imparting special functions to polyurethanes are not particularly used, and it is difficult to obtain the functional polyurethane and / or polyurethane urea targeted by the present application. Further, since these polyurethanes have a cross-linked structure, even if a functional structure is introduced, the conformational mobility of the polymer chain is significantly limited, and it is difficult to exert a sufficient function. Further, since these patents are intended for use as paints and adhesives, they do not give consideration to stability and safety against heat and hydrolysis, which are one of the purposes of the present application.

Further, JP-A-08-052939 discloses a polyisocyanate containing an allophanate group,
Although it is described that the polyisocyanate is derived from an aromatic diisocyanate and an aliphatic diisocyanate, positively introducing an allophanate group means introducing a crosslinked structure in the obtained material, and forming an isocyanurate group. Even if a functional structure is introduced, as in the case of using the polyisocyanate according to, the mobility of the conformation of the polymer chain is significantly limited, and it is difficult to exert a sufficient function.

Furthermore, Japanese Patent Laid-Open Nos. 07-097560 and 0-9
Japanese Patent No. 7-166052 discloses a polyurethane in which an aromatic diisocyanate and an aliphatic diisocyanate are used in combination for use as an adhesive and as a charging member, respectively, but no consideration is given to safety. .

Japanese Unexamined Patent Publication (Kokai) No. 08-067814 discloses a resin composition containing, as one component, a polyurethane resin prepared from an aliphatic diisocyanate and / or a mixed diisocyanate of an alicyclic diisocyanate and an aromatic diisocyanate as a raw material. These are polyurethanes with improved yellowing resistance, chemical resistance, solvent solubility, and scratch resistance, and are not intended to improve safety (cytotoxicity, acute toxicity, etc.), especially hydrolyzed products. There is a problem in the safety of the material in that the polycaprolactone polyol, which easily produces propylene, is used as an essential component.

Regarding the functional polyurethanes, the present inventors have already disclosed in JP-A 04-153211, JP-A 04-235724, JP-A 04-248826, JP-A 04-250168,
Japanese Patent Application Laid-Open Nos. 04-298523 and 04-325161 have been filed. These are all technologies relating to polyurethanes containing a tertiary amino group or a quaternary ammonio group. In the techniques disclosed in these, an amino group or an ammonio group is contained in a polyester polyol or a polyether polyol, and is introduced into polyurethanes by polymerizing this as one of the raw materials. Since the amino group or ammonio group is contained in the soft segment, the mobility in the polymer chain is relatively large, but an amino polyester polyol or amino polyether polyol was prepared for introducing the amino group or ammonio group. It is necessary to say that it is not always a simple method.

The inventors of the present invention have disclosed WO98 / 46659 as a biocompatible and antithrombotic material, and JP 2000-1.
Japanese Patent Application No. 28950 and Japanese Patent Application Laid-Open No. 2000-126566 are applied. These techniques disclose a polyurethane or polyurethane urea obtained by using a diol having a phosphorylcholine structure as at least a part of the diol component for the purpose of improving biocompatibility and antithrombotic property. In JP-A-2000-128950 and JP-A-2000-126566, segmentation of a material is promoted by using two or more diisocyanates, particularly two or more aliphatic diisocyanates (including alicyclic compounds). , It is disclosed that the antithrombotic property is remarkably improved by forming a microphase-separated structure. However, these materials have a drawback that they have a large amount of eluate, although they are mainly used for medical purposes.

[0019]

Functional polyurethanes may cause problems such as reduction in strength and formation of eluate due to hydrolysis reaction during sterilization or in-vivo use. Characteristics, ease of processing, ease of hardness adjustment,
It is a preferable material from the viewpoint of good biocompatibility.
The present invention maintains these preferable properties and further has a structure advantageous for exhibiting functions, and at the same time, has improved stability against heat during processing and hydrolysis during use, which are problems in the prior art. The purpose of the present invention is to provide functional polyurethanes with high safety.

[0020]

[Means for Solving the Problems] The inventors of the present application have already found that many functional polyurethanes and antithrombotic properties obtained by using two or more kinds of aliphatic (including alicyclic) diisocyanates in combination have been obtained. Although the patent application for the improved polyurethane or polyurethane urea has been made as described above, the present invention has been achieved as a result of further intensive studies. That is, the present invention relates to a functional polyurethane, a macropolyol, a chain extender, an aliphatic diisocyanate, and a functional polyurethane and / or polyurethaneurea obtained by using an aromatic diisocyanate as at least a part of a raw material, and the functional polyol Relates to polyurethane and / or polyurethaneurea exclusively added with an aliphatic diisocyanate to form a domain structure, and a medical material comprising the same.

Polyurethanes are generally prepared from three kinds of raw materials: diisocyanate, soft segment macropolyol, and chain extender. Of these, diisocyanates are roughly classified into aromatic diisocyanates and aliphatic diisocyanates. Since aromatic diisocyanates are relatively highly reactive, the molecular weight of the resulting polyurethane and polyurethane urea is improved during the preparation of polyurethane and polyurethane urea, which is preferable. However, there is a possibility that coloring due to oxidative decomposition and hydrolysis may generate an aromatic amine having a carcinogenic risk. Aliphatic diisocyanates are less likely to be colored, and even if hydrolyzed, carcinogenic substances are unlikely to be produced. However, on the other hand, the reactivity is slightly inferior to that of the aromatic diisocyanate, so that the polymer preparation requires more severe conditions and the addition of a catalyst. The present invention is a functional polyurethane and / or polyurethane urea obtained by using all of a functional polyol, a macropolyol, a chain extender, an aliphatic diisocyanate, and an aromatic diisocyanate as a part of a raw material.

The aliphatic diisocyanate referred to in the present invention also includes alicyclic diisocyanates. For example,
Ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, dodecamethylene diisocyanate, 3,
Examples include, but are not limited to, 3'-diisocyanatopropyl ether, cyclopentane diisocyanate, cyclohexane diisocyanate, 4,4'-methylenebis (cyclohexyl isocyanate), and the like.
Further, the hydrogen atom of the hydrocarbon skeleton forming diisocyanate may be substituted with another atom or a functional group.

The aliphatic diisocyanate of the present invention is preferably a linear hydrocarbon diisocyanate having an isocyanate group at both ends. Specific examples thereof include, but are not limited to, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, dodecamethylene diisocyanate, and the like. The hydrogen atom of the hydrocarbon skeleton forming diisocyanate may be substituted with another atom or a functional group. Of these, tetramethylene diisocyanate, hexamethylene diisocyanate and octamethylene diisocyanate are preferable, and hexamethylene diisocyanate is particularly preferable.

Examples of the aromatic diisocyanate referred to in the present invention include tolylene diisocyanate, xylylene diisocyanate, phenylene diisocyanate, naphthalene diisocyanate, isocyanatobenzyl isocyanate, 4,4'-methylenebis (phenyl isocyanate) and the like. However, it is not limited to these. Further, the hydrogen atom of the hydrocarbon skeleton forming diisocyanate may be substituted with another atom or a functional group. Of these, 4,4′-methylenebis (phenylisocyanate) (hereinafter abbreviated as MDI) is particularly preferable. An aliphatic diisocyanate used in the present invention,
As the aromatic diisocyanate, one type of diisocyanate may be used, or two or more types may be mixed and used.

As the macropolyol referred to in the present invention,
Macropolyols, which are soft segment components used in general polyurethanes, are widely available. Of these, macropolyols that do not substantially contain a carboxylic acid ester bond are preferable because they have high hydrolysis resistance. Specifically, for example, low molecular weight diols (for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol, 2,2-dimethyltrimethylene glycol, 1, 4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, etc. and a dicarboxylic acid or an ester-forming derivative thereof (for example, oxalic acid,
Malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, dodecanedicarboxylic acid, terephthalic acid, isophthalic acid or polycarboxylic acid ester diols obtained by reacting these acid halides, active esters, amides, etc. Polylactone diol obtained by ring-opening polymerization of caprolactone (also included in polycarboxylic acid ester diol in a broad sense), polyether diol such as polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polybutadiene diol, polyisoprene diol , Polyalkylene diols such as hydrogenated polyisoprene diol, and various polycarbonate diols. Of these, polyether diols are particularly preferred. The macropolyols may be used alone or in combination of two or more.

As the chain extender of the present invention, a chain extender used for general polyurethanes and a chain extender which will be developed in the future can be widely used and are not particularly limited. Specifically, for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol,
Diols such as 2,2-dimethyltrimethylene glycol, 1,4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, diethylene glycol and triethylene glycol, ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, xylylenediamine, phenylene Diamine,
Diamines such as 4,4′-methylenebis (phenylamine), amino alcohols such as 2-aminoethanol, 3-aminopropanol, and 4-aminobutanol, and further dihydrazides (for example, oxalic acid dihydrazide,
Examples include broadly defined diamines such as malonic acid dihydrazide, succinic acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, and isophthalic acid dihydrazide. Not limited to these, all of low molecular weight diols, diamines, and amino alcohols can be applied regardless of whether they are publicly known, novel, or applied to polyurethanes. These chain extenders may be used alone or in combination of two or more.

In the present invention, a functional polyol is further used as a component other than the diisocyanate, macropolyol and chain extender. As the functional polyol, for example, a tertiary amino group-containing polyol for immobilizing heparin, a polyol having a phosphorylcholine-like structure that is a cell membrane constituent, a negative charge is introduced on the surface of the material, and adhesion is caused by electrostatic repulsion with platelets. Organic acid group-containing polyol for the purpose of suppressing, and further reactive carbon-
Examples thereof include a polyol containing a carbon unsaturated bond, and polydimethylsiloxane diol for the purpose of application to a gas permeable material. In addition, in the macropolyol having a reactive carbon-carbon unsaturated bond and the polyurethanes obtained by using polydimethylsiloxane diol as a soft segment, the functional polyol simultaneously serves as a raw material as the macropolyol. Therefore, the "functional polyurethane and / or polyurethane urea obtained by using at least a functional macropolyol, a chain extender, an aliphatic diisocyanate and an aromatic diisocyanate as a part of raw materials" is also included in the present invention.

As the functional polyol, the phosphorylcholine-like structure-containing diol represented by the following chemical formula (2) or chemical formula (3) is particularly effective for improving the blood compatibility of the obtained material.

[Chemical 6]

[Chemical 7] [In the above chemical formulas (2) and (3),
R ¹ , R ² , R ³ and R ⁶ are alkylene groups having 1 to 10 carbon atoms,
Arylene group having 6 to 12 carbon atoms or 7 to 15 carbon atoms
Of aralkylene groups, which may be the same or different, and the hydrogen atom may be substituted with another atom or a functional group. R ⁴ , R ⁵ and R ⁸ are each an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a carbon number of 7 to 1
5 aralkyl groups, which may be the same or different, and the hydrogen atom of each group may be substituted with another atom or a functional group. R ⁷ is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure of the following chemical formula (4). X is N, HC or the following chemical formula (5)
Is a group having the structure of ]

[Chemical 8]

[Chemical 9] [In the formula, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more kinds of oxyalkylene groups may be mixed, and the bonding order thereof may be block or random. In addition, n is an integer of 1 to 30. R ⁹ and R ¹⁰ are an alkyl group having 1 to ¹⁰ carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group is substituted with another atom or a functional group. It may have been done. ]

In the present invention, it is an important requirement that the functional polyol is exclusively added with the aliphatic diisocyanate to form a domain structure.

The method for producing the polyurethane and / or polyurethane urea of the present invention is not particularly limited, but it is particularly preferable to carry out the reaction stepwise. For example, the following method is exemplified: A functional diol and an aliphatic diisocyanate are mixed and reacted in a suitable solvent, and then an aromatic diisocyanate and subsequently a macropolyol are added to prepare a prepolymer. Then, a chain extender is added to obtain a high molecular weight polyurethane and / or polyurethane urea. At this time, in the reaction of the macropolyol and the aliphatic diisocyanate, and subsequently in the reaction of adding the aromatic diisocyanate to obtain the prepolymer, since the aromatic diisocyanate is generally higher in activity than the aliphatic diisocyanate, the latter It is preferable to set the reaction temperature of 1) lower than the reaction temperature of the former. If the aromatic diisocyanate is added at a temperature suitable for the reaction of the aliphatic diisocyanate, gelation may occur, and if the reaction of the aliphatic diisocyanate is performed at a temperature suitable for the reaction of the aromatic diisocyanate, the reaction is It may not proceed sufficiently, and the obtained polyurethanes may be difficult to use as a material.

The method for producing polyurethane and / or polyurethaneurea will be described in more detail. The following production conditions do not limit the present invention. The aliphatic diisocyanate and aromatic diisocyanate are used in a molar ratio of aliphatic diisocyanate / aromatic diisocyanate = 1/9 to 9/1, preferably 2/8 to 7/3, more preferably 2/8. ~ 6/4. If the amount of the aliphatic diisocyanate is larger than this, the reaction is difficult to proceed, and if the amount of the aromatic diisocyanate is larger than this, the obtained polyurethane and / or polyurethane urea may be colored. The reaction temperature for reacting the aliphatic diisocyanate is 50 ° C to 120 ° C, preferably 60 ° C to 100 ° C.
C., the reaction temperature when reacting with an aromatic diisocyanate is 30.degree. C. to 100.degree. C., preferably 40.degree. C. to 80.degree. C., which is preferably lower than the temperature when reacting with an aliphatic diisocyanate. The solvent used in the reaction is also not particularly limited, but a solvent that is inert to the raw materials and has excellent solubility of the raw materials is preferable. Specifically, for example, N-methylformamide, N, N-dimethylformamide,
Examples include N, N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, dimethylsulfoxide, toluene, among which N, N-dimethylformamide,
N, N-dimethylacetamide and N-methylpyrrolidone are preferred. The solvent may be used alone or in combination of two or more kinds. Also, a method of carrying out the reaction without a solvent can be applied.

In producing the polyurethane and / or polyurethaneurea of the present invention, a polymerization catalyst may be added in order to carry out the polymerization efficiently. Examples of the polymerization catalyst include tin-based catalysts such as tin dibutyl dilaurate and titanium-based catalysts such as tetrabutoxy titanium.

The polyurethane and / or polyurethaneurea of the present invention may be used alone or may be added to other materials by a method such as blending, coating, grafting, copolymerization and the like. It is also possible to modify the polyurethane and / or polyurethaneurea of the present invention by a method such as blending, coating, grafting or copolymerization.

Unlike PVC and the like, polyurethanes are different from
One of the major characteristics is that the desired mechanical properties can be realized without adding an additive, but in the present invention, an additive may be added. For example, an antibacterial agent can be kneaded for the purpose of imparting antibacterial properties to the material.

In the polyurethane and / or polyurethane urea of the present invention, the functional polyol has a relatively low molecular chain, although the detailed mechanism is not clear in addition to the inherent properties of polyurethanes such as mechanical properties and processability. The effect derived from the addition of the aliphatic diisocyanate, which has a high degree of freedom, to form the domain structure is sufficient to exert the function derived from the functional polyol, and at the same time, the aliphatic diisocyanate and the aromatic Due to the influence of the systematic diisocyanate, which is considered to be a complementary and synergistic effect, it is possible to realize higher stability and safety.

Taking advantage of such advantages, the polyurethane and / or polyurethane urea of the present invention can be widely used not only for all the applications to which polyurethanes have been conventionally applied but also as a medical material in particular. Specifically, for example, hemodialysis membranes and plasma separation membranes, adsorbents for blood waste products, membranes for artificial lungs, intravascular balloons, blood bags,
Examples include main base materials of medical devices such as catheters, cannulas, shunts, blood circuits, modifying additives, laminating materials, and coating materials.

[0037]

EXAMPLES The present invention will be described below with reference to examples.
The invention is not limited by these examples.

Example 1 Preparation of Polyurethane A compound represented by the following chemical formula (6) (hereinafter abbreviated as choline diol): 10.00 g was weighed in a separable flask, and N-methylpyrrolidone (N
MP): 106 ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution is heated to 75 ° C. and hexamethylene diisocyanate (HDI): 2
4.25 g was added and stirred for 1 hour. The reaction temperature was lowered to 55 ° C. and the mixture was stirred for 30 minutes, MDI: 84.20 g was added, and the mixture was stirred at 55 ° C. for 1 hour, then, polytetramethylene glycol (PTMG) having a number average molecular weight of 2000: 26.65.
g was dissolved in NMP: 53 ml and added. 1 at 55 ° C
It stirred for time and prepared the prepolymer. 32.60 g of 1,4-butanediol (BD) was added to this reaction mixture in two divided portions, and the mixture was stirred at 55 ° C. for 1 hour. NMP106
ml was added to dilute the reaction mixture, and the mixture was stirred at 55 ° C. for 12 hours for reaction. BD3g was added to terminate the end,
Stirring was continued from 55 ° C. to room temperature gradually. The reaction mixture was poured into 10 l of water to collect the product,
It was washed with warm water of 0 ° C. for 2 hours and dried under reduced pressure to obtain a polymer A.

[Chemical 10]

(Molecular weight) Polymer A was added and dissolved in N, N-dimethylformamide (DMF) containing 0.1 wt% of lithium bromide, and the molecular weight was measured by gel permeation chromatography (GPC). Gel columns are Shodex AD-803 / S, AD-804 / S, AD-806 / S,
Using AD-802 / S connected in series and using a calibration curve made of polyethylene glycol, the temperature was 50 ° C. and the mobile phase was DMF containing 0.1 wt% of lithium bromide. The results are shown in Table 1.

(Eluate) Based on the extraction conditions described in ASTM F619 (Medical plastic extraction method), which are the extraction conditions quoted in the method of ASTM F750 (mouse systemic toxicity test of material extract), Polymer A: 4.0 g was extracted with physiological saline: 20 ml, and the total amount of organic carbon (TOC) in the extract was measured. The results are shown in Table 1.

(Cytotoxicity) Drug Machine No. 99 (June 27, 1995) Method of a cytotoxicity test using an extract of a medical device or a material, as described in the notice of the Director of Medical Device Development Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare V79 cells were used in accordance with
C50 (%) was determined. The results are shown in Table 1.

[0042]

[Table 1]

(Production of film) 2 wt% of polymer A
It was dissolved in NMP so that the concentration became. This solution was placed on a slide glass kept horizontally, and NMP was evaporated in a nitrogen atmosphere at 80 ° C. for 12 hours. Then another 60
The film was dried under reduced pressure at 12 ° C. for 12 hours to obtain a film A. The film A was used for the next evaluation without being peeled off from the slide glass.

(Anti-plasma coagulability) The slide glass on which the film A obtained in the above operation was placed was placed on a petri dish placed on a water bath at 37 ° C. On this film, 100 μl of citric acid-added bovine plasma was dropped, and a 0.025 mol / l calcium chloride aqueous solution was added and gently mixed. The elapsed time from the time when the aqueous solution of calcium chloride was added to the time when plasma coagulated was measured, and divided by the time required for plasma coagulation when the same operation was performed on glass, and expressed as a relative coagulation time. The results are shown in Table 1.

(Preparation of Hollow Fiber Containing Functional Polyurethane) Polyethersulfone (Sumika Excel 4800P manufactured by Sumitomo Chemical Co., Ltd.) as a polymer: 5.00 kg,
Polyvinylpyrrolidone (Kolidon K90 manufactured by BASF): 250 g and polymer A: 150 g as a hydrophilizing agent were added to a solvent NMP: 14.04 kg and a non-solvent triethylene glycol: 9.45 kg and dissolved by stirring at 100 ° C. for 4 hours. Then, the mixture was allowed to stand for 1 hour for defoaming. This solution was filtered through a sinter filter to remove undissolved material, and a spinning dope was obtained. The spinning stock solution is supplied from the outside of a tube-in-orifice type nozzle having a slit outer diameter of 300 μm, a slit inner diameter of 200 μm, and an inner liquid discharge hole diameter of 100 μm, and NMP2 is supplied from the inner liquid discharge hole.
The inner liquid of the mixed solution of 0 wt% NMP and water was discharged. The spinning dope discharged from the nozzle was guided to the coagulation bath directly below the nozzle after running in the air for 30 cm. Coagulation liquid is NMP20
The temperature was set to 70 ° C. with a mixed solution of wt% NMP and water.
The spun hollow fiber was washed with water and then wound with a winder at a winding speed of 45 m / min to obtain a hollow fiber A. The hollow fiber A had an inner diameter of 190 μm, an outer diameter of 250 μm, and a film thickness of 30 μm.

(Anticoagulant) Ten hollow fibers A obtained by the above operation were bundled and both ends were inserted into a silicon tube,
Micro module A was obtained by hardening with a silicone adhesive.
Citrated whole cow blood was enclosed in this micromodule A, immersed in a dialysate, and after a certain period of time, the enclosed blood was dropped into physiological saline filled in a petri dish and the state was observed. The results are shown in Table 2.

[0047]

[Table 2]

Comparative Example 1 (Preparation of Polyurethane) Choline diol: 10.00 g
Was weighed into a separable flask, and 106 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. Heat the solution to 55 ° C., MDI: 84.20
g was added, and the mixture was stirred at 55 ° C. for 1 hour. Reaction temperature is 75 ℃
To 30 ° C., stirred for 30 minutes, added HDI: 24.25 g, stirred for 1 hour, and then had a number average molecular weight of 2,000 PTMG: 2
6.65 g was dissolved in NMP: 53 ml and added. While gradually lowering the reaction temperature from 75 ° C to 60 ° C, the mixture was stirred for 1 hour to prepare a prepolymer. BD in this reaction mixture:
32.60 g was added in 2 portions and the mixture was stirred at 60 ° C. for 1 hour. NMP: 106 ml was added to dilute the reaction mixture, and the mixture was stirred at 60 ° C. for 12 hours for reaction. BD: 3g
Was added to stop the terminal, and stirring was continued from 60 ° C. to room temperature gradually. The reaction mixture was poured into 10 liters of water to collect the product, which was washed with warm water at 70 ° C. for 2 hours and dried under reduced pressure to obtain a polymer B.

(Molecular weight) (Eluate) (Cytotoxicity) In the same manner as in Example 1, the molecular weight of polymer B, the eluate,
Cytotoxicity was analyzed. The results are shown in Table 1.

(Production of Film) (Anti-plasma coagulability) A film B was produced in the same manner as in Example 1 and used in Example 1.
The anti-plasma coagulant property was examined by the same method as in. The results are shown in Table 1.

(Production of Functional Polyurethane Blend Hollow Fiber) (Anticoagulant) A hollow fiber B was produced in the same manner as in Example 1, and the anticoagulant was examined in the same manner as in Example 1. The results are shown in Table 2.

Comparative Example 2 (Preparation of Polyurethane) Choline diol: 10.00 g
Was weighed into a separable flask, and 106 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. Heat the solution to 60 ° C., MDI: 84.20
g and HDI: a mixture of 24.25 g and added at 60 ° C. for 2
Stir for hours. Then, a PTM with a number average molecular weight of 2000
G: 26.65 g was dissolved in NMP: 53 ml and added. It stirred at 60 degreeC for 1 hour, and prepared the prepolymer. BD: 32.60 g was added to this reaction mixture in two divided portions, and the mixture was stirred at 60 ° C. for 1 hour. NMP: 106 ml was added to dilute the reaction mixture, and the mixture was stirred at 60 ° C. for 12 hours for reaction. BD: 3 g was added to terminate the terminal, and stirring was continued from 60 ° C. to room temperature gradually. The reaction mixture was dropped into 10 l of water to collect the product, which was washed with warm water at 70 ° C. for 2 hours and dried under reduced pressure to obtain a polymer C.

(Molecular weight) (Eluate) (Cytotoxicity) In the same manner as in Example 1, the molecular weight of Polymer C, the eluate,
Cytotoxicity was analyzed. The results are shown in Table 1.

(Production of Film) (Anti-plasma coagulability) A film C was produced in the same manner as in Example 1 and used in Example 1.
The anti-plasma coagulant property was examined by the same method as in. The results are shown in Table 1.

(Preparation of Functional Polyurethane Blend Hollow Fiber) (Anticoagulant) A hollow fiber C was prepared in the same manner as in Example 1, and the anticoagulant was examined in the same manner as in Example 1. The results are shown in Table 2.

Comparative Example 3 (Preparation of Polyurethane) Choline diol: 10.00
12.77 g of PTMG having a number average molecular weight of 1320 was weighed in a separable flask, and 300 ml of N, N-dimethylacetamide (DMAc) was added and dissolved.
The following operations were all performed under a nitrogen atmosphere. 10 solution
The mixture was heated to 0 ° C., 4,4′-methylenebis (cyclohexyl isocyanate) (HMDI): 52.71 g was slowly added, and the mixture was stirred for 5 hours after the addition. HDI: 14.4
8 g was slowly added, and after the addition, the mixture was stirred at 100 ° C. for 10 hours. BD: 18.28 g was added slowly, and another 10
The mixture was stirred at 0 ° C for 5 hours. After the reaction, the reaction mixture was mixed with 10
I dropped it in 1 liter of water. The resulting precipitate is filtered off and TH
The polymer was dissolved in F and poured into methanol again, and the resulting precipitate was collected and dried under reduced pressure to obtain a polymer D.

(Molecular weight) (Eluate) (Cytotoxicity) In the same manner as in Example 1, the molecular weight of Polymer D, the eluate,
Cytotoxicity was analyzed. The results are shown in Table 1.

(Production of Film) (Anti-plasma coagulation) A film D was produced in the same manner as in Example 1 and
The anti-plasma coagulant property was examined by the same method as in. The results are shown in Table 1.

(Preparation of Functional Polyurethane Blend Hollow Fiber) (Anticoagulant) A hollow fiber D was prepared in the same manner as in Example 1, and the anticoagulant was examined in the same manner as in Example 1. The results are shown in Table 2.

Comparative Example 4 (Preparation of Hollow Fiber) (Anticoagulant) Polyethersulfone hollow fiber E was prepared in the same manner as in Example 1 except that polymer A was not added. The anticoagulant property was examined in the same manner as in Example 1. The results are shown in Table 2.

[0061]

EFFECTS OF THE INVENTION As is clear from the comparison between the examples and the comparative examples, the polyurethane of the present invention has low eluate and cytotoxicity and, at the same time, sufficiently exhibits the functionality considered to be derived from the functional polyol. Was found (the anticoagulant function of the diol containing a phospholipid-like structure in Examples and Comparative Examples). Although the detailed mechanism is not clear, complementary aliphatic diisocyanate and aromatic diisocyanate,
Due to the effects that are considered to be synergistic, better stability and safety are realized, and at the same time, the functional polyol is added with the aliphatic diisocyanate, which has a relatively high degree of freedom in the molecular chain, to form a domain structure. It is thought that this is an effect of doing. Taking advantage of these advantages,
INDUSTRIAL APPLICABILITY The polyurethane and / or polyurethane urea of the present invention can be widely used as a medical material, not to mention all the applications to which polyurethane and polyurethane urea have been conventionally applied.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C081 BA02 BA15 BB09 CA21 DA02                       DA04                 4J034 BA08 CA04 CA15 CB02 CC02                       CD07 DG01 HA07 HC02 HC03                       HC12 JA42 JA43 RA02

Claims (9)

[Claims] 1. A functional polyol, a macropolyol,
A functional polyurethane and / or a polyurethaneurea obtained by using a chain extender, an aliphatic diisocyanate and an aromatic diisocyanate as at least a part of raw materials, wherein the functional polyol is a domain structure in which the functional polyol is exclusively added to the aliphatic diisocyanate. Forming a functional polyurethane and / or polyurethane urea. 2. The component according to claim 1, which is obtained by adding an aromatic diisocyanate and a macropolyol to a component obtained by reacting a functional polyol with an aliphatic diisocyanate, and further extending the chain with a chain extender. Functional polyurethane and / or polyurethane urea. 3. The reaction of the functional polyol with the aliphatic diisocyanate is performed at a higher temperature than the reaction of adding the aromatic diisocyanate and the macropolyol to the reaction product of the functional polyol and the aliphatic diisocyanate. The functional polyurethane and / or polyurethane urea according to claim 2. 4. A functional polyol having an amino group and / or an ammonio group and / or an organic acid group and / or in the molecule.
Alternatively, the functional polyurethane and / or polyurethane urea according to any one of claims 1 to 3, which has a structure that mimics a biological component. 5. The functional polyurethane and / or polyurethane urea according to claim 1, 2, 3 or 4, wherein the functional polyol has a structure represented by the following chemical formula (1). [Chemical 1] [In the above chemical formula (1), R is an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an aralkylene group having 7 to 15 carbon atoms, and the hydrogen atom of each group is another atom or It may be substituted with a functional group. ] 6. The functional polyurethane and / or polyurethane urea according to claim 5, wherein the functional polyol has a structure represented by the following chemical formula (2) or chemical formula (3). [Chemical 2] [Chemical 3] [In the above chemical formulas (2) and (3),
R ¹ , R ² , R ³ and R ⁶ are alkylene groups having 1 to 10 carbon atoms,
Arylene group having 6 to 12 carbon atoms or 7 to 15 carbon atoms
Of aralkylene groups, which may be the same or different, and the hydrogen atom may be substituted with another atom or a functional group. R ⁴ , R ⁵ and R ⁸ are each an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a carbon number of 7 to 1
5 aralkyl groups, which may be the same or different, and the hydrogen atom of each group may be substituted with another atom or a functional group. R ⁷ is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure of the following chemical formula (4). X is N, HC or the following chemical formula (5)
Is a group having the structure of ] [Chemical 4] [Chemical 5] [In the formula, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more kinds of oxyalkylene groups may be mixed, and the bonding order thereof may be block or random. In addition, n is an integer of 1 to 30. R ⁹ and R ¹⁰ are an alkyl group having 1 to ¹⁰ carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group is substituted with another atom or a functional group. It may have been done. ] 7. A medical material containing the functional polyurethane and / or polyurethane urea according to any one of claims 1, 2, 3, 4, 5 to 6. 8. A medical material containing the functional polyurethane and / or polyurethane urea according to any one of claims 1, 2, 3, 4, 5 to 6 as a main component. 9. A functional polyurethane characterized in that an aromatic diisocyanate and a macropolyol are added to a component obtained by reacting a functional polyol with an aliphatic diisocyanate, and the chain is extended by a chain extender. / Or a method for producing a polyurethane urea.