JP2005171045A - Segmented polyurethane urea - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a segmented polyurethane urea intended for medical applications, which has improved processability, handleability and physical properties without sacrificing blood compatibility and safety. <P>SOLUTION: This segmented polyurethane urea having excellent processability, handleability, physical properties, blood compatibility and safety is obtained by using a charging group-containing component constituting the segmented polyurethane urea, using both an aromatic and an aliphatic diisocyanates as diisocyanates and using both an amine and a diamine as chain extenders and by controlling a chain extension reaction which decreases the water content of a raw material diol. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a material excellent in blood compatibility for medical use. In particular, the present invention relates to a segmented polyurethane urea having high antithrombotic performance and excellent workability and handleability. The segmented polyurethaneurea of the present invention is obtained by specific components and specific synthesis methods.

  Various medical devices such as catheters, stents, medical tubes, blood circuits, and blood storage containers are now frequently used in clinical practice and are indispensable in clinical settings. In the development of medical materials that are semi-permanently embedded in a living body, indwelled for a certain period of time, or in contact with living tissue such as blood, the strength and durability of the material and the complex shape that matches the living body Processability to make it, compatibility with blood and biological tissues, etc. are important points.

  Naturally, since the medical material is in direct contact with the living tissue, high safety is required. However, for biochemical characteristics including safety of medical materials, evaluation according to use conditions has not been sufficiently established. In particular, it is difficult to say that sufficient consideration has been given to the presence or amount of oligomers, residual raw materials, additives, by-products, and other eluates caused by contact with body fluids.

  For example, in most cases, polyvinyl chloride (PVC) widely used as a medical polymer material is added with a plasticizer for improving physical properties. A typical plasticizer to be added is a phthalate ester, and medical PVC added with this compound has been used for many years. However, in recent years, it has been found that phthalate esters have a serious impact on living organisms, and there is concern about the possibility of elution of plasticizers when PVC is used and its effects.

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

  Polyurethane and / or polyurea and / or polyurethaneurea (hereinafter may be abbreviated as polyurethanes), by appropriately setting the compounding ratio of macroglycol as a soft segment, diisocyanate as a hard segment and chain extender, It is possible to prepare a material having a preferable strength without using an additive. In addition, segmented polyurethane is known to form a microphase-separated structure, thereby exhibiting excellent blood compatibility. In addition, for example, by using an amino group-containing diol as one of the raw materials, it is relatively easy to prepare a material having a preferable functional group, such as an amino group-containing polyurethane. Due to these advantages, polyurethane is one of polymer materials that are favorably used as medical materials. However, on the other hand, strength reduction and generation of eluate have been reported due to sterilization treatment or hydrolysis reaction during use in vivo, which may be a problem in terms of safety.

The inventors have applied for Patent Document 1, Patent Document 2, Patent Document 3, and Patent Document 4 as high safety polymer compositions. In these technologies, we focus on polymer materials with excellent biocompatibility and blood compatibility and eluents from medical devices, and through thorough purification or washing steps, in extracted liquids extracted under certain conditions. It is disclosed that the amount of effluent is kept low. However, these materials have problems in processability and physical properties.
JP 2003-82054 A (pages 1 to 2) JP 2003-138144 A (pages 1 to 3) JP 2003-144540 A (pages 1 to 3) JP 2003-147194 A (pages 1 to 2)

A technique using polyurethane and / or polyurethane urea and / or polyurea in which aliphatic diisocyanate and aromatic diisocyanate are used together for the purpose of improving various physical properties required as materials has been already reported. For example, Patent Documents 5 to 13 disclose polyurethanes in which aliphatic diisocyanate and aromatic diisocyanate are used in combination with a clear intention.
JP-A-5-295063 (pages 1 to 2) JP-A-7-26096 (pages 1 to 2) JP 7-97560 A (pages 1 to 2) JP-A-7-166052 (pages 1 to 2) JP-A-8-52939 (pages 1 to 2) JP-A-8-67814 (pages 1 to 2) JP-A-9-255866 (pages 1 to 2) JP-A-11-349805 (pages 1 to 3) JP 2000-34439 A (pages 1 to 2)

  Among these, Patent Document 5, Patent Document 6, Patent Document 11, Patent Document 12, and Patent Document 13 disclose a crosslinkable polyurethane prepared by using a diisocyanate to form a polyisocyanate by forming an isocyanurate group and using this. Yes. Since these polyurethanes clearly have a cross-linked structure, the processability and handleability intended in the present application cannot be satisfied. In the present invention, processability and handleability mean solubility of the obtained polyurethane in a solvent, compatibility with a base polymer, thermal stability, and the like. Moreover, since these are assumed to be used as paints and adhesives, no consideration is given to the safety of living bodies assuming medical use.

  Patent Document 9 discloses a polyisocyanate containing an allophanate group, and it is described that the polyisocyanate is derived from an aromatic diisocyanate and an aliphatic diisocyanate. Thus, a crosslinked structure is positively introduced into the obtained material, and it is difficult to satisfy processability and handleability as in the case of using a polyisocyanate by isocyanurate group formation.

  Furthermore, Patent Document 7 and Patent Document 8 disclose polyurethanes in which aromatic diisocyanate and aliphatic diisocyanate are used in combination, each assuming use as an adhesive and charging member, both of which are assumed for medical use. Safety is not considered.

  Patent Document 10 discloses a resin composition containing, as a component, a polyurethane resin using as a raw material an aliphatic diisocyanate and / or a mixed diisocyanate of an alicyclic diisocyanate and an aromatic diisocyanate. These are polyurethanes with improved yellowing resistance, chemical resistance, solvent solubility, and scratch resistance, and are not intended for safety suitable for medical use, and are particularly susceptible to hydrolysis. There is a problem in material safety in that polycaprolactone polyol is an essential component.

In addition, the present inventors have applied for Patent Document 14, Patent Document 15, Patent Document 16 and the like as biocompatible and antithrombotic materials. In these techniques, polyurethane or polyurethane urea obtained by using a diol having a phosphorylcholine structure as at least a part of a component of the diol is disclosed for the purpose of improving biocompatibility and antithrombogenicity. In Patent Document 15 and Patent Document 16, the use of two or more types of diisocyanates, particularly two or more types of aliphatic diisocyanates (including alicyclic systems) promotes segmentation of the material and forms a microphase separation structure. It is disclosed that antithrombogenicity is improved by doing so. However, while these materials are mainly used for medical purposes, they have many disadvantages such as a large amount of eluate and lack of processability and handleability.
WO98 / 46659 (1-7 pages) JP 2000-128950 A (pages 1 to 2) JP 2000-126666 A (pages 1 to 2)

Patent Document 17 discloses polyether polyurethane for the purpose of improving physical properties, particularly elasticity and flexibility. This technology aims to improve physical properties by limiting the properties of polyoxytetramethylene glycol, which is one of the raw materials. However, these materials are considered to be safe for living organisms assuming medical use. Absent.
WO 01/014444 (1 to 3 pages)

  The present invention provides a segmented polyurethane urea for medical use, which can improve the processability, handleability and physical properties that have been problematic in the prior art, and can simultaneously achieve other desirable properties. For the purpose.

３．荷電性基を含む成分が、下記化学式（２）の構造を有する１または２記載のセグメント化ポリウレタンウレア。

［上記化学式（２）において、Ｒは炭素数１〜１０のアルキレン基、炭素数６〜１２のアリーレン基、または炭素数７〜１５のアラルキレン基であり、各基の水素原子は他の原子や官能基で置換されていてもよい。］
４．荷電性基を含む成分が、下記化学式（３）もしくは化学式（４）の構造を有する１〜３記載のセグメント化ポリウレタンウレア。

［上記化学式（３）および化学式（４）において、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁶は炭素数１〜１０のアルキレン基、炭素数６〜１２のアリーレン基、または炭素数７〜１５のアラルキレン基であり、それぞれ同じであっても異なっていてもよく、水素原子は他の原子や官能基で置換されていてもよい。Ｒ⁴、Ｒ⁵、Ｒ⁸は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、それぞれ同じでもよく、異なっていてもよく、各基の水素原子は他の原子や官能基で置換されていてもよい。Ｒ⁷は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基、または下記化学式（５）の構造を有する基である。ＸはＮ、Ｈ−Ｃもしくは下記化学式（６）の構造を有する基である。］

［式中、Ａは炭素数２〜１０のオキシアルキレン基であり、１種または２種以上のオキシアルキレン基が混在していてもよく、それらの結合の順はブロックでもランダムでもよい。またｎは１〜３０の整数である。Ｒ⁹、Ｒ¹⁰は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、各基の水素原子は他の原子や官能基で置換されていてもよい。］
５．１記載のセグメント化ポリウレタンウレアを含有する医療用材料。 The inventors of the present invention have arrived at the present invention as a result of intensive studies in order to solve the above problems. That is, the segmented polyurethane urea of the present invention is
1. As a component, at least all of (1) to (6) are included,
(1) At least one component selected from a component having a structure containing a charged group in the molecule, or a component having a structure capable of introducing a charged group (2) At least selected from the group consisting of aromatic diisocyanates At least one diisocyanate (3) at least one diisocyanate selected from the group consisting of aliphatic diisocyanates (4) polyether polyol (5) at least one chain extender selected from the group consisting of low molecular weight diols (6) A segmented polyurethane urea comprising at least one chain extender selected from the group consisting of low molecular weight diamines and (7), (8) and (9).
(7) The water content of all the diols of the constituent components is less than 2% (8) The low molecular weight diol and the low molecular weight diamine are reacted stepwise (9) Excellent storage stability 2. The segmented polyurethane urea according to 1, wherein the component containing a chargeable group has a structure represented by the following chemical formula (1).

3. 3. The segmented polyurethane urea according to 1 or 2, wherein the component containing a chargeable group has a structure represented by the following chemical formula (2).

[In the above chemical formula (2), 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 other atom or It may be substituted with a functional group. ]
4). The segmented polyurethane urea according to 1 to 3, wherein the component containing a chargeable group has a structure represented by the following chemical formula (3) or chemical formula (4).

[In the above chemical formula (3) and chemical formula (4), R ¹ , R ² , R ³ and R ⁶ are each an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an alkyl group having 7 to 15 carbon atoms. 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 an aralkyl group having 7 to 15 carbon atoms, which may be the same or different, The hydrogen atom of each group may be substituted with other atoms or functional groups. 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 represented by the following chemical formula (5). X is N, HC or a group having the structure of the following chemical formula (6). ]

[Wherein, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or two or more oxyalkylene groups may be mixed, and the order of bonding may be block or random. N is an integer of 1-30. 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 May be. ]
A medical material containing the segmented polyurethaneurea according to 5.1.

  It is a segmented polyurethane urea for medical purposes, and by synthesizing specific components with specific synthesis methods, without sacrificing the original characteristics of biocompatibility, antithrombogenicity, and safety It became possible to obtain segmented polyurethaneurea excellent in processability, handleability and physical properties.

  The segmented polyurethane urea of the present invention is mainly prepared from three components: a diisocyanate, a macro polyol serving as a soft segment, and a chain extender.

  The component having a structure containing a charged group in the molecule, which is one of the components of the segmented polyurethane urea of the present invention, is a compound having one or more ionic functional groups in the molecule. Examples of ionic functional groups include quaternary ammonium and carboxyl groups, but components containing quaternary ammonium in the molecular structure are preferable because they do not easily interfere with the polyurethane synthesis reaction. The component having a structure capable of introducing a chargeable group means a compound having at least one functional group that can be converted into an ionic functional group by a simple reaction in the molecule. A component containing ammonium in the molecule is preferred. One or more of these components having a chargeable group in the molecule or a component having a structure capable of introducing a chargeable group in the molecule is included as a component of the segmented polyurethaneurea. . Two or more kinds of components having a charged group in the molecule or components having a structure capable of introducing a charged group into the molecule may be used. A component having a charged group in the molecule or a component having a structure capable of introducing a charged group in the molecule is one of the components of the segmented polyurethane urea, so that a compound with a special structure is placed on the side of the polyurethane urea. It becomes possible to introduce into the chain.

  The aromatic diisocyanate, which is one of the constituent components of the segmented polyurethane urea of the present invention, is preferable because the molecular weight of the resulting polyurethane and polyurethane urea is improved during preparation of the polyurethane and polyurethane urea because of relatively high reactivity. However, on the other hand, it is difficult to control the polymerization reaction, and often gels during the reaction.

  A polyurethane synthesized from an aliphatic diisocyanate, which is one of the components of the segmented polyurethane urea of the present invention, has a low possibility of coloring. However, the reactivity is slightly inferior to that of aromatic diisocyanate, and more severe conditions or addition of a catalyst may be required when preparing a polymer.

  In the present invention, it is preferable to use an aromatic diisocyanate and an aliphatic diisocyanate in combination as the diisocyanate component. By using an aromatic diisocyanate and an aliphatic diisocyanate together, the synthetic reaction of the segmented polyurethane proceeds smoothly, and the obtained segmented polyurethane is excellent in physical properties and can be efficiently purified after preparation.

  Examples of the aromatic diisocyanate in the present invention include tolylene diisocyanate, xylylene diisocyanate, phenylene diisocyanate, naphthalene diisocyanate, isocyanatobenzyl isocyanate, 4,4′-methylenebis (phenyl isocyanate), and the like. It is not limited. Moreover, the hydrogen atom of the hydrocarbon skeleton forming the diisocyanate may be substituted with another atom or a functional group. Of these, 4,4'-methylenebis (phenylisocyanate) is particularly preferred because it is readily available and relatively reactive. Two or more kinds of aromatic diisocyanates used in the present invention may be mixed and used.

  The aliphatic diisocyanate referred to in the present invention is, for example, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, dodecamethylene diisocyanate, 3,3′-diisyl. Examples include, but are not limited to, isocyanatopropyl ether, cyclopentane diisocyanate, cyclohexane diisocyanate, 4,4′-methylenebis (cyclohexyl isocyanate) and the like. Moreover, the hydrogen atom of the hydrocarbon skeleton forming the diisocyanate may be substituted with another atom or a functional group. The aliphatic diisocyanate that is a component of the segmented polyurethane urea of the present invention is preferably a linear hydrocarbon diisocyanate having isocyanate groups at both ends. Specific examples include, but are not limited to, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, and dodecamethylene diisocyanate. The hydrogen atom of the hydrocarbon skeleton forming the diisocyanate may be substituted with another atom or a functional group. Among these, tetramethylene diisocyanate, hexamethylene diisocyanate, and octamethylene diisocyanate are preferable, and hexamethylene diisocyanate is particularly preferable because it is easily available and has excellent reactivity. Two or more kinds of the aliphatic diisocyanates used in the present invention may be mixed and used.

  As the polyether polyol which is a soft segment component of the segmented polyurethane urea of the present invention, polyether polyols used in general polyurethanes can be widely used. Specifically, polyethylene glycol, polypropylene glycol, Examples include polyether diols such as tetramethylene glycol. Of these, polytetramethylene glycol is preferred because it has a track record as a medical polyurethane. In addition, the polyether polyol which is the soft segment component of the segmented polyurethane urea of the present invention has a narrow molecular weight distribution, a molecular weight within a certain range, an extremely low content of a high molecular weight component, A low rate is preferred. Specifically, the number average molecular weight Mn analyzed by GPC under the conditions described later is preferably 1000 to 3000, and more preferably 1300 to 2800. 1500 to 2500 is more preferable. When the number average molecular weight is less than 1000, microphase separation is hardly formed, and thus antithrombogenicity may be inferior. If the number average molecular weight exceeds 3000, the yield of segmented urethane urea may be lowered, or the purification efficiency may be lowered. The molecular weight distribution (Mw / Mn) is preferably 2.0 or less, more preferably 1.7 or less, and even more preferably 1.5 or less. If the molecular weight distribution exceeds 2.0, the purification efficiency of the segmented polyurethane is poor, the phase separation is ambiguous, and the antithrombogenicity may be poor. The lower limit of the molecular weight distribution is theoretically 1.0, but 1.1 or more is preferable because it is at a level that does not cause a problem in practical use and suppresses the manufacturing cost. The extremely high molecular component means a component having a molecular weight of 10,000 or more. It is preferable that the ratio of the area having a molecular weight of 10,000 or more when measured by GPC is less than 2%. More preferably, it is less than 1%. If the content of the polymer having a molecular weight of 10,000 or more is 2% or more, the purification efficiency of the segmented polyurethane is lowered, which may cause a problem in safety. Examples of polytetramethylene glycol having such characteristics include PTG2000 manufactured by Hodogaya Chemical Co., Ltd., polytetramethylene glycol 2000 manufactured by BASF, polytetramethylene glycol 2000 manufactured by DuPont, and polytetramethylene glycol 2000 manufactured by Mitsubishi Chemical Corporation. The preferred embodiment is to use polytetramethylene glycol which is commercially available under the trade name.

  In addition, the water content in the polyether polyol is preferably less than 2% by mass. More preferably, it is less than 1.5 mass%, More preferably, it is less than 1.0 mass%. In particular, the mixing of moisture during urethane preparation may cause branching of urethane bonds and reaction termination, which may be disadvantageous for the safety and storage stability of the segmented polyurethane urea of the present invention, so it should be kept low. preferable. Polyurethane urea prepared using a polyether polyol having such a narrow molecular weight and low water content is more regular in microphase separation, and the urethane bond is not complicated three-dimensionally. Good compatibility and improved handling. In addition, since the structure is linear, the purification efficiency is high, the safety to the living body is high, and the characteristics of exhibiting superior performance due to blood compatibility can be expressed. The polyether polyol used in the present invention may be purified by a general method such as dehydration, distillation, column chromatography, or phase separation.

  The chain extender of the segmented polyurethane urea of the present invention is preferably selected one or more from the group consisting of low molecular weight diols and the group consisting of low molecular weight diamines. As the low molecular weight diol and low molecular weight diamine used, chain extenders used for general polyurethanes and chain extenders that will be developed in the future are widely available. Specifically, examples of the low molecular weight diol include ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol, 2,2-dimethyltrimethylene glycol, 1, Examples include 4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, diethylene glycol, and trimethylene glycol. Examples of the low molecular weight diamine include ethylene diamine, propylene diamine, butylene diamine, hexamethylene diamine, xylylene diamine, phenylene diamine, 4,4′-methylene bis (phenylamine), and further dihydrazide (for example, oxalic acid dihydrazide, Examples thereof include diamines in a broad sense such as malonic acid dihydrazide, succinic acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, and isophthalic acid dihydrazide. The low molecular weight diols and diamines are not limited to these, and can be all applied regardless of whether they are publicly known, novel or applied to polyurethanes. Each of the low molecular weight diol and the low molecular weight diamine may be used alone or in combination of two or more.

  The segmented polyurethaneurea of the present invention is characterized in that at least one of the low molecular weight diol and the low molecular weight diamine is used as a chain extender. Further, the low molecular weight diol and the low molecular weight diamine are each added separately. The order of addition is characterized by being obtained by adding a low molecular weight diol and allowing the reaction to proceed, followed by stepwise addition of chain extension in the order of low molecular weight diamine. Due to the chain extension by the low molecular weight diol, a urethane bond with a relatively gentle interaction is localized in the polymer chain, and the interaction generated by the chain extension by the low molecular weight diamine is By adopting a structure in which strong urea bonds are dispersed, the interaction between polymer chains is gentler than when urea bonds are localized or when urethane bonds and urea bonds exist randomly. Become. Therefore, in addition to mechanical strength and decomposition resistance, compatibility with other bases is also improved, and more favorable characteristics can be realized for application to medical materials.

  The water content of the diol used in the segmented polyurethane urea of the present invention is preferably sufficiently low. Some diol compounds are hygroscopic, which affects the opening and closing of containers during weighing, the humidity in the laboratory, the storage period, and the storage location. When such a raw material is used, the target reaction does not proceed, resulting in a decrease in molecular weight or gelation. In particular, this is an important point for obtaining segmented polyurethane urea, which is intended to control the moisture content of the hygroscopic raw material. In order to prevent moisture absorption to the raw material, it is preferable that the storage environment is low humidity or a nitrogen atmosphere. The reaction is preferably carried out in a nitrogen atmosphere when the container is opened and closed or weighed. The raw material having a high water content can be made to have a low water content by, for example, re-refining such as distillation after dehydration with a molecular sieve. Specifically, the water content of the diol used in the segmented polyurethane urea of the present invention is preferably less than 2% by mass. More preferably, it is less than 1.5 mass%, Furthermore, less than 1.0 mass% is preferable. When the water content is 2% by mass or more, the isocyanate group and water react to form a urea bond, and gelation occurs due to a side reaction in which the isocyanate reacts with this urea bond. It causes the stability to decrease.

  In the present invention, a segmented polyurethane urea may be prepared by adding components other than diisocyanate, polyether polyol, and chain extender. For example, with application to medical materials in mind, a method of adding a tertiary amino group-containing diol for immobilizing heparin, a method of adding a diol having a phosphorylcholine secondary structure, which is a cell membrane component, and gas permeation Examples include a method of adding polydimethylsiloxane diol in consideration of application to a functional material.

［上記化学式（７）および化学式（８）において、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁶は炭素数１〜１０のアルキレン基、炭素数６〜１２のアリーレン基、または炭素数７〜１５のアラルキレン基であり、それぞれ同じであっても異なっていてもよく、水素原子は他の原子や官能基で置換されていてもよい。Ｒ⁴、Ｒ⁵、Ｒ⁸は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、それぞれ同じでもよく、異なっていてもよく、各基の水素原子は他の原子や官能基で置換されていてもよい。Ｒ⁷は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基、または下記化学式（９）の構造を有する基である。ＸはＮ、Ｈ−Ｃもしくは下記化学式（１０）の構造を有する基である。］

［式中、Ａは炭素数２〜１０のオキシアルキレン基であり、１種または２種以上のオキシアルキレン基が混在していてもよく、それらの結合の順はブロックでもランダムでもよい。またｎは１〜３０の整数である。Ｒ⁹、Ｒ¹⁰は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、各基の水素原子は他の原子や官能基で置換されていてもよい。］ In particular, the method of using the phosphorylcholine-like structure-containing diol represented by the following chemical formula (7) or the following chemical formula (8) as one of the raw materials is effective in improving the blood compatibility of the obtained material.

[In the above chemical formula (7) and chemical formula (8), R ¹ , R ² , R ³ , R ⁶ are each an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an alkyl group having 7 to 15 carbon atoms. 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 an aralkyl group having 7 to 15 carbon atoms, which may be the same or different, The hydrogen atom of each group may be substituted with other atoms or functional groups. 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 represented by the following chemical formula (9). X is N, HC or a group having the structure of the following chemical formula (10). ]

[Wherein, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or two or more oxyalkylene groups may be mixed, and the order of bonding may be block or random. N is an integer of 1-30. 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 May be. ]

  The method for polymerizing the segmented polyurethane urea of the present invention is not particularly limited except for the chain extension reaction described above. For example, the following method is exemplified. A diol containing quaternary ammonium in the molecule and an aliphatic diisocyanate are mixed and reacted in an appropriate solvent, and this is subsequently reacted with an aromatic diisocyanate, followed by a reaction with a polyether polyol. A polymer is prepared. Here, a low molecular weight diol is added little by little to increase the molecular weight to a certain extent, and then a low molecular weight diamine is further added to obtain a high molecular weight polyurethane urea. In this case, the reaction between the diol and the aliphatic diisocyanate and the subsequent reaction with the aromatic diisocyanate are generally more active than the aliphatic diisocyanate, and therefore the reaction temperature of the aliphatic diisocyanate is increased. It is preferable to set it higher than the reaction temperature of the aromatic diisocyanate. If an aromatic diisocyanate is added at a temperature suitable for the reaction of the aliphatic diisocyanate, the reaction proceeds rapidly and may cause gelation. When the reaction of the aliphatic diisocyanate is carried out at a temperature suitable for the reaction of the aromatic diisocyanate, the reaction does not proceed sufficiently, the yield of the resulting polyurethaneurea is remarkably low, and the physical properties are difficult to use as a material. There is a possibility. Moreover, the raw material and solvent to be used preferably have higher purity, and the water content is particularly preferably low for all raw materials and solvents. Furthermore, in order to avoid moisture absorption during weighing, addition and reaction of the raw materials, it is preferable to carry out in a nitrogen atmosphere and to make contact with air as little as possible.

  Although a manufacturing method is shown concretely, the following conditions do not restrict | limit this invention. The use ratio of the aliphatic diisocyanate and the aromatic diisocyanate is a molar ratio of aliphatic diisocyanate / aromatic diisocyanate = 9/1 to 1/9, more preferably 2/8 to 7/3, and even more preferably 2. / 8 to 6/4. By using an aliphatic diisocyanate and an aromatic diisocyanate together in an appropriate ratio, both rapid reaction progress and avoidance of coloring can be achieved. The reaction temperature when the aliphatic diisocyanate is reacted is 40 ° C to 120 ° C, more preferably 50 ° C to 110 ° C. The reaction temperature when the aromatic diisocyanate is reacted is 20 ° C. to 100 ° C., more preferably 30 ° C. to 80 ° C., and preferably lower than the reaction temperature with the aliphatic diisocyanate.

  The ratio of the low molecular weight diol and the low molecular weight diamine used as the chain extender is low molecular weight diol / low molecular weight diamine = 99/1 to 50/50 in molar ratio, more preferably 98/2 to 60/40, still more preferably. Is 97/3 to 70/30. If the amount of the low molecular weight diol is too small, the solubility of the polyurethane urea in the solvent and the compatibility with other materials may be deteriorated, and if it is more than this, gelation will occur during the reaction, resulting in mechanical strength and resistance. There is a possibility that the decomposability is lowered and the production efficiency in the purification process is lowered.

  The solvent used for the reaction is also not particularly limited, but a solvent that is inert to the raw material and excellent in solubility of the raw material is preferable. Specifically, for example, N-methylformamide, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, tetrahydrofuran, dioxane, Examples thereof include dimethyl sulfoxide and toluene, and among them, DMF, DMAc, and NMP are preferable. A solvent may be used individually or may be used in mixture of 2 or more types. It may be subjected to a purification process such as dehydration and distillation. Moreover, the method of reacting without a solvent is also applicable.

  When synthesizing the segmented polyurethane urea of the present invention, a polymerization catalyst may be used in order to advance the polymerization reaction efficiently. Examples of the polymerization catalyst include a tin-based catalyst such as tin dibutyldilaurate and a titanium-based catalyst such as tetrabutoxy titanium.

  In order to make the segmented polyurethane urea of the present invention a safer polymer, it is one of effective techniques to perform sufficient washing after the polymer is prepared. Specifically, for example, a technique of removing impurities while being immersed and stirred in warm water can be employed. Under the present circumstances, the temperature of warm water is 40 to 95 degreeC, More preferably, it is 50 to 90 degreeC, More preferably, it is 60 to 80 degreeC, Cleaning time is 30 minutes to 48 hours, More preferably, it is 60 minutes to 24 hours More preferably, it is 90 minutes to 12 hours. The ratio of the polymer to the washing water is 1 g / 10 ml to 1 g / 500 ml, preferably 1 g / 20 ml to 1 g / 400 ml, and more preferably 1 g / 50 ml to 1 g / 200 ml. Cleaning at a lower temperature and shorter time than this is not sufficient to remove impurities, and cleaning at a higher temperature and longer time may cause degradation and degradation of the polymer. Also, if the bath ratio is less than this, the polymer is not sufficiently soaked in the washing hot water, so that it is difficult to obtain the effect. If the bath ratio is higher than this, a large amount of washing hot water is used, which is not efficient. Although a method using an organic solvent can be used for washing, washing with warm water as described above is more preferable from the viewpoint of the possibility of remaining solvent and the treatment of the washing solvent. By such a washing step, unreacted monomers, oligomers and reaction solvent are removed.

  The segmented polyurethaneurea of the present invention may be used alone or added to other materials by methods such as blending, coating, grafting, and copolymerization. Further, the segmented polyurethane urea of the present invention can be used as a base for modification by blending, coating, grafting, copolymerization or the like.

  Polyurethanes are different from PVC and the like in that they have a great feature that they can realize the required mechanical properties without adding any additives, but the segmented polyurethaneurea of the present invention is not limited to add additives. For example, an antibacterial agent can be blended for the purpose of imparting antibacterial properties to the material. The type of antibacterial agent is not particularly limited, and for example, an inorganic or organic type can be used.

  The segmented polyurethaneurea of the present invention is characterized by excellent storage stability. Storage stability as used herein means that segmented polyurethane urea is immersed in 20.00 ml of physiological saline after opening the segmented polyurethane urea in an unsealed state for 40 months at a relative humidity of 75% and storing it for 6 months. Then, an extraction operation is performed at 50 ° C. for 72 hours, and the total organic carbon content (TOC) in the extract is measured and evaluated. When the storage stability is excellent, the molecular chain in the polyurethane during the storage period is not decomposed, and the monomer or oligomer extracted under the above extraction conditions is not generated, so the TOC value is low. On the other hand, when the storage stability is not excellent, the molecular chain is cleaved during storage, so that the TOC value becomes an extremely large value compared with that before storage. In consideration of safety to the living body, the TOC value after storage is preferably 400 ppm or less. More preferably, it is 350 ppm or less, More preferably, it is 300 ppm or less.

  Long-term storage stability can be achieved for the following reasons. That is, in the segmented polyurethane urea polymerization reaction, the side reaction can be suppressed by optimizing the reaction condition that the target reaction gradually proceeds by adding the raw material stepwise, and further, by managing the water content of the raw material, It is possible to suppress side reactions caused by water, optimize the purification conditions of the segmented polyurethane urea after the polymerization reaction, and remove unreacted monomers, oligomers, reaction solvents, and the like. The poor stability of segmented polyurethaneurea means that the polymer molecular chains are cleaved during storage. It is considered that the polymer molecular cleavage reaction occurs due to moisture in the air, moisture contained in the polymer, unreacted substances, solvents, and the like. The polymer molecule cleavage reaction may be from both the molecular chain end and from the molecular chain end, but the more likely reaction is thought to be from the molecular chain end. Therefore, in order to prevent degradation of the polymer from the end of the molecular chain, it is effective to reduce the number of molecular chain ends in the polymer, that is, the presence of oligomers or branched structures tends to increase the end of the molecular chain. Therefore, suppressing side reactions such as formation of oligomers and branched structures leads to suppression of polymer degradation from the end of the molecular chain of the polymer. In addition, regarding the decomposition reaction in the molecular chain, it is considered that a low molecular weight occurs more easily than a high molecular weight. Therefore, removing the oligomer in the product is effective in suppressing the decomposition in the polymer chain. It is believed that there is. Strengthening the purification of the resulting segmented polyurethane urea means removing unreacted monomers, oligomers, and reaction solvents that cause the polymer decomposition reaction, leading to suppression of the polymer decomposition reaction. .

Usually, segmented polyurethane urea is refined and then processed according to the purpose to obtain a product. These products are considered to have an unspecified storage period or use period before being used.
If the storage stability of the segmented polyurethane urea is improved, it means that the polymer does not decompose even when stored for a long period of time, and it is considered that there is no change in physical properties due to storage. Physical properties are both physical properties such as strength and elasticity, and biochemical properties such as blood compatibility. The fact that these properties do not change by storage means that the strength of the product and biological tissues Means high confidence in the suitability of In addition, the fact that the polymer does not decompose means that the amount of eluate when used is the same as that before storage, so that the safety is high.

  The segmented polyurethaneurea of the present invention has a structure containing a charged group in the polymer chain or a structure capable of introducing a charged group. A structure into which a chargeable group can be introduced can be converted into a chargeable group by chemical reaction during or after preparation of polyurethaneurea. It becomes possible to introduce a substituent into the charged group by a chemical reaction during or after the preparation of the polyurethane urea. For example, heparin can be bound by ionic bonding or a phosphorylcholine structure can be introduced, and biocompatibility, blood compatibility, and antithrombogenicity can be positively provided. Moreover, since the segmented polyurethane urea of the present invention is prepared by using an aliphatic diol and an aromatic diol together, it can react quickly and avoid the coloring problem. Furthermore, the segmented polyurethaneurea of the present invention is suitable for relatively long polyurethane chains because urethane bonds with relatively mild interactions generated by chain extension by low molecular weight diol are localized in the polymer chain. The urea bond is introduced in a dispersed manner. By taking this structure, the segmented polyurethane urea of the present invention is stable against heat during molding and has few decomposition products in addition to the properties inherent to polyurethanes such as mechanical properties and easy processability. It is possible to achieve excellent stability and safety. The polyether polyol having a specific range of molecular weight constituting the soft segment of the segmented polyurethane urea of the present invention dramatically improves blood compatibility and safety. This is presumably because by using a polyether polyol having a molecular weight in a specific range, the side reaction of the urethane polymerization reaction is suppressed, the microphase separation becomes more regular, and the efficiency of the washing process is improved. Moreover, by reducing the water content of the diol as a raw material, the reaction efficiency is improved, and a segmented polyurethane urea having a higher safety can be obtained.

  Taking advantage of such advantages, the segmented polyurethane urea of the present invention is widely used as a medical material as well as various uses to which conventional polyurethanes have been applied. Specifically, the main base of medical devices such as hemodialysis membranes, plasma separation membranes, blood waste adsorbents, artificial lung membranes, intravascular balloons, blood bags, catheters, cannulas, shunts, blood circuits, etc. Examples thereof include materials, modifying additives, laminate materials, coating materials, and the like.

  Hereinafter, the effectiveness of the present invention will be described with reference to examples, but the present invention is not limited thereto.

(Molecular weight measurement)
The molecular weight was measured by gel permeation chromatography (GPC, manufactured by Shimadzu Corporation). As for the column, Shodex AD-803 / S, AD-804 / S, AD-806 / S, and AD-802 / S were connected in series. The temperature of the column oven was set to 50 ° C., and measurement was performed at a flow rate of 1 ml / min using DMF added with lithium bromide 0.1% as a mobile phase. The sample was dissolved in the same solvent as the moving bed so as to have a concentration of 5 mg to 10 mg. The detector is a differential refractometer, and the sample injection volume is 50 μl. The molecular weight was calculated from a calibration curve created with a polyethylene glycol molecular weight marker.

(Measurement of moisture content)
The water content was measured with a Karl Fischer moisture meter (MKA-210, manufactured by Kyoto Electronics Industry). A chloroform / methanol mixture was used as a dehydrating agent.

(Eluate test)
In accordance with the extraction conditions in the dialysis membrane eluate test described in the “Dialyzed Artificial Kidney Approval Criteria” June 20, 1983, Notification of the Director of Pharmacy, Ministry of Health and Welfare, 1.5 ml of sample was added to 150 ml of distilled water for injection. And the elution operation was performed at 70 ° C. for 1 hour. Using this eluate, the ultraviolet absorption spectrum (UV) was evaluated among the items of the eluate test in the quality of the blood circuit and the test. In the artificial kidney device approval criteria, the standard under this condition is 0.1 or less.

(TOC measurement of extract)
In accordance with the method of acute systemic toxicity test described in ASTM F750-82, 4.00 g of polymer A was immersed in 20.00 ml of physiological saline and extracted at 50 ° C. for 72 hours. The total organic carbon content (TOC) in the extract was measured with a total organic carbon meter TOC-5050A manufactured by Shimadzu Corporation.

(Storage stability test)
The synthesized sample was put in a paper envelope and stored for 6 months in a high-temperature humidity chamber at 40 ° C. and a relative humidity of 75%, and the TOC of the extract was measured in the same manner as the TOC of the eluate.

(Solubility evaluation)
Segmented polyurethane is dissolved in NMP to a concentration of 0.5% by weight. The dissolution temperature is set to 100 ° C. and stirred. After 4 hours, it was examined whether or not it was completely dissolved. The criterion for dissolution is turbidity measurement. D. Was 0.3 or less.

(Compatibility evaluation)
The NMP: triethylene glycol (TEG) ratio was 6: 4 to 0.6 g of segmented polyurethane and 20 g of polyethersulfone, and the total was 100 ml. The mixture was stirred at 100 ° C. for 8 hours, cooled to room temperature, and turbidity was measured. O. D. Is less than 0.3, and is 0.3 or more.

(Coloring evaluation)
The color tone of the purified and dried segmented polyurethane and the segmented polyurethane stored for 3 months at 40 ° C. and 75% relative humidity were examined visually. Only when the sample was clearly discolored compared to the -20 ° C frozen storage product of the same sample, it was determined that there was coloring.

(Evaluation of anti-thrombogenicity (anti-plasma coagulability))
Commercially available polyurethane (Pellethane (trade name), hereinafter abbreviated as PU) was dissolved in NMP to form a 5% solution. To 1000 g of this PU solution, 5.00 g of segmented polyurethane was added to obtain a uniform suspension. 20 g of this blend solution was placed evenly on a 12 cm × 12 cm glass plate kept horizontally, dried at 40 ° C. for 8 hours under a nitrogen stream, and then dried at 40 ° C. under reduced pressure for 15 hours to form a film having a thickness of about 60 μm. Obtained. The film was placed on a glass petri dish and placed in a constant temperature water bath at 37 ° C. On this film, 100 μl of citrated beef plasma was dropped, and 100 μl of 0.025 mol / l calcium chloride aqueous solution was added, and gently shaken so that the solution was mixed. Measure the elapsed time from the time when calcium chloride aqueous solution is added until the plasma clots (when plasma stops moving), and divide by the time required for plasma clotting when the same operation is performed on glass, as the relative clotting time expressed.

(Measurement of breaking strength and yield strength of hollow fiber membranes)
(1) In the case of a dry hollow fiber membrane A hollow fiber membrane test piece having an effective sample length of 10 cm was measured by carrying out a tensile test at a crosshead of 10 cm / min. For the measurement, Tensilon UTMII manufactured by Toyo Baldwin was used. 30 hollow fibers were sampled and measured at random from one module, and the lowest value was taken as the evaluation result.
(2) In the case of a wet hollow fiber membrane The tensile properties were measured in Instron (Model No. TM) manufactured by Instron Engineering Corporation in water at 37 ° C. The distance between chucks was 5 cm, and the tensile speed was 5 cm / min. 30 hollow fibers were sampled and measured at random from one module, and the lowest value was taken as the evaluation result.

(Measurement of bending strength (rigidity) of hollow fiber membrane)
About 24 hollow fiber membranes, the stress at the time of bending to a curvature of 0.5 / cm was measured. The bending moment was converted per yarn. A KES (KAWABATA'S EVALUATION SYSTEM) bending tester (manufactured by KATO IRON WORKS CO. LTD.) Was used for the measurement.

(Measurement of inner diameter and film thickness of hollow fiber membrane)
The hollow fiber membrane was cut with a sharp razor perpendicular to the length direction, and the cross section was observed with a microscope at a magnification of 200 times. The inner diameter value and the outer diameter value were measured at n = 5, and the average value was calculated.
Film thickness [μm] = {(outer diameter) − (inner diameter)} / 2

(Dialyzer blood circulation test)
After washing the dialyzer with a membrane area of 1.5 m ² with 1 L of physiological saline, ² L of ACD-added bovine blood (hematocrit 30%, total protein concentration 6.5 g / dL, 37 ° C.) was flowed at 200 ml / min, and the condition of 20 ml And a circulation test was conducted for 4 hours to return the blood outflow from the dialyzer and the filtrate to the reservoir. The number of platelets was measured before and after the circulation, and the number of residual blood hollow fibers in the dialyzer after the circulation test was measured. The platelet reduction rate after circulation was calculated as the number of platelets before circulation = 100%.

(Tube scissor test)
To 1000 g of a solution prepared by dissolving commercially available polyurethane (Pellethane (trade name)) in NMP to 5%, 5.00 g of segmented polyurethane was added to obtain a uniform suspension. The blend solution was coated on the inner surface, and the tube dried under reduced pressure was sandwiched with forceps, and the coating layer after 10 minutes was observed. The state of adhesiveness, peeling, scratches, cracks, etc. was examined.

Example 1 (Preparation of segmented polyurethane urea (polymer A))
A compound represented by the following chemical formula (11) (hereinafter abbreviated as choline diol): 5.0 g (water content 0.7%) was weighed in a separable flask in a nitrogen atmosphere and distilled NMP (manufactured by Mitsubishi Chemical): 125 Dissolved in 0.0 ml. The following reaction steps were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 27.2 g of HDI (manufactured by Wako Pure Chemical Industries, Ltd.) was added and stirred for 1 hour. After lowering the reaction temperature to 40 ° C., 94.4 g of MDI (manufactured by Nippon Polyurethane) was added and stirred at 40 ° C. for 1 hour. At this time, the molar ratio of the aliphatic diol to the aromatic diol was 3: 7. 18. PTMG having a number average molecular weight of 1930 (polytetramethylene ether glycol 2000, molecular weight distribution: 1.29, content of polymer having a molecular weight of 10,000 or more: less than 0.5%, moisture content: 0.1% or less) 2 g was dissolved in NMP: 55 ml, added, and stirred at 40 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., BD (manufactured by Nacalai Tesque): 39.0 g (water content: 0.15%) was dissolved in 400 ml of NMP, and added over 4 hours. NMP: 600 ml was added to the reaction liquid and stirred, and PDA (manufactured by Nacalai Tesque): 2.0 g was dissolved in NMP: 200 ml and added over 30 minutes. At this time, the ratio of BD to PDA was 95: 5. The reaction solution was returned to room temperature and further diluted by adding 200 ml of NMP. The reaction solution was collected in water and purified with warm water at 70 ° C. for 6 hours. The bath ratio of the polymer to the washing water at this time was 1:50. The solid content was filtered and dried under reduced pressure at 60 ° C. to obtain polymer A. The yield was 49.1%.

  About the obtained polymer A, molecular weight measurement, eluate test, TOC measurement, solubility, compatibility, and coloring were examined. The results are shown in Table 1.

  About the obtained polymer A, the film was produced and antithrombogenicity evaluation was performed. The results are shown in Table 2.

(Production of medical device (dialyzer) containing polymer A)
Polyethersulfone (manufactured by Sumika Chemtex Co., Ltd., Sumika Excel 4800P) as a polymer 18 wt%, NMP (manufactured by Mitsubishi Chemical) 63.8 wt% as a solvent, triethylene glycol (manufactured by Mitsui Chemicals) 16 wt% as a non-solvent, hydrophilic After adding 0.18 wt% of phosphorus-containing polymer B to 1 wt% of polyvinylpyrrolidone (BASF Co., Ltd., Kollidon K90) as an agent, stirring and dissolving at 50 ° C. for 3 hours, standing for 1 hour and degassing, The undissolved material was removed to obtain a spinning dope. Spinning stock solution from the outer slit of a tube-in-orifice nozzle with 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 an internal liquid of 50 wt% water, NMP 40 wt% and triethylene glycol 10 wt% from the inner liquid discharge hole. Discharged. The spinning dope discharged from the nozzle passed through 30 cm in air and led to a coagulation bath directly under the nozzle. The coagulation liquid was 80 wt% water, 16 wt% NMP, 4 wt% triethylene glycol, and the temperature was 60 ° C. The spun hollow fiber membrane was washed with water, dried, and wound up with a winder. The winding speed was 15 m / min. About 10,000 obtained hollow fiber membranes were bundled to assemble a blood purification dialyzer having a membrane area of 1.5 m ² .

  About the obtained hollow fiber membrane, breaking strength, yield strength, bending strength, inner diameter, and film thickness were measured. The results are shown in Table 3.

  A blood circulation test was performed on the obtained dialyzer. The results are shown in Table 3.

(Production of medical device containing phosphorus-containing polymer A)
5 parts by weight of commercially available medical polyurethane (Tecoflex) as a polymer, 500 parts by weight of NMP and 0.5 part by weight of phosphorus-containing polymer A as a solvent were added and dissolved by stirring at 100 ° C. for 3 hours. After degassing by standing for 1 hour, a phosphorus-containing polymer-polymer mixed solution was obtained. This mixed solution was uniformly applied to the inside of a medical tube made of PVC, and the solvent was completely removed by drying under reduced pressure. The obtained coating tube was washed with warm water at 50 ° C. for 1 hour and then dried again under reduced pressure to obtain a medical device (tube).

  A scissor test was performed on the resulting coated tube. The results are shown in Table 4.

Example 2 (Preparation of segmented polyurethane urea (polymer B))
Cholinediol: 5.0 g (water content: 0.8% by mass) was weighed into a separable flask under a nitrogen atmosphere and dissolved in distilled NMP: 125.0 ml. The following reaction steps were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 45.3 g of HDI was added and stirred for 1 hour. After lowering the reaction temperature to 40 ° C., 67.5 g of MDI was added, and the mixture was stirred at 40 ° C. for 1 hour. At this time, the molar ratio of the aliphatic diol to the aromatic diol was 5: 5. 36.3 g of PTMG having a number average molecular weight of 1790 (PTG2000 molecular weight distribution by Hodogaya Chemical Co., Ltd .: 1.26, content of polymer having molecular weight of 10,000 or more: less than 0.5% by mass, water content: 0.1% by mass or less) NMP: dissolved in 55 ml, added, and stirred at 40 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., BD: 37.9 g (water content: 0.15% by mass) was dissolved in NMP: 400 ml, and added over 4 hours. NMP: 600 ml was added to the reaction solution and stirred, and PDA: 2.0 g was dissolved in NMP: 200 ml and added over 30 minutes. At this time, the ratio of BD to PDA was 95: 5. The reaction solution was returned to room temperature and further diluted by adding 200 ml of NMP. The reaction solution was collected in water and purified with warm water at 70 ° C. for 6 hours. The bath ratio of the polymer to the washing water at this time was 1:50. The solid content was filtered and dried under reduced pressure at 60 ° C. to obtain polymer B. The yield was 52.3%.

  The obtained polymer B was evaluated in the same manner as in Example 1. The results are shown in Tables 1-4.

Example 3 (Preparation of segmented polyurethane urea (polymer C))
Cholinediol: 5.0 g (water content: 0.7% by mass) was weighed in a separable flask under a nitrogen atmosphere and dissolved in 125.0 ml of distilled and purified NMP. The following reaction steps were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 36.3 g of HDI was added, and the mixture was stirred for 1 hour. After the reaction temperature was lowered to 40 ° C., 80.9 g of MDI was added and stirred at 40 ° C. for 1 hour. At this time, the molar ratio of the aliphatic diol to the aromatic diol was 4: 6. PTMG having a number average molecular weight of 1980 (polytetramethylene ether glycol 2000, molecular weight distribution: 1.27, content of polymer having molecular weight of 10,000 or more: less than 0.5% by mass, water content: 0.1% by mass or less) 63 .5 g was dissolved in 55 ml of NMP, added, and stirred at 40 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., and 36.9 g of BD (water content: 0.15% by mass) was dissolved in 400 ml of NMP and added over 4 hours. NMP: 600 ml was added to the reaction liquid and stirred, PDA: 1.9 g was dissolved in NMP: 200 ml and added over 30 minutes. At this time, the ratio of BD to PDA was 95: 5. The reaction solution was returned to room temperature and further diluted by adding 200 ml of NMP. The reaction solution was collected in water and purified with warm water at 70 ° C. for 6 hours. The bath ratio of the polymer to the washing water at this time was 1:50. The solid content was filtered and dried under reduced pressure at 60 ° C. to obtain polymer C. The yield was 52.7%.

  About the obtained polymer C, evaluation similar to Example 1 was performed. The results are shown in Tables 1-4.

Comparative Example 1 (Preparation of segmented polyurethane urea (polymer D))
PTMG having a number average molecular weight of 1790 (PTG2000 molecular weight distribution by Hodogaya Chemical Co., Ltd .: 1.26, content of polymer having a molecular weight of 10,000 or more: less than 0.5% by mass, moisture content: 0.1% by mass or less): 18.7 g Was weighed into a separable flask, and NMP: 50 ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 7.3 g of HDI was added and stirred for 1 hour. The reaction temperature was lowered to 55 ° C., 25.4 g of MDI was added, and the mixture was stirred at 55 ° C. for 1 hour. At this time, the molar ratio of the aliphatic diol to the aromatic diol was 3: 7. NMP (80 ml) was added, and diluted BD (water content: 0.15% by mass): 10.0 g was added over 1 hour. The reaction solution was cooled to 0 ° C., 0.9 g of PDA dissolved in 50 ml of NMP was added over 30 minutes, and the reaction solution was further diluted with 50 ml of NMP. The reaction was returned to room temperature and stirred overnight. The reaction solution was recovered from water and washed with warm water at 70 ° C. for 6 hours. The solid content was collected by filtration and dried under reduced pressure at 60 ° C. to obtain polymer C. The bath ratio of the polymer to the washing water at this time was about 1:80. The solid content was filtered and dried under reduced pressure at 60 ° C. to obtain polymer D. The yield was 74.1%.

  About the obtained polymer D, evaluation similar to Example 1 was performed. The results are shown in Tables 1-4.

  Compared to the examples, since there is no structure that exhibits antithrombogenicity in the polyurethane side chain, the relative coagulation time for blood coagulation is short, and the platelet adsorption rate is high even in the blood perfusion test, so the number of residual blood threads is also high. In many cases, the blood compatibility was relatively low.

Comparative Example 2 (Preparation of segmented polyurethane (polymer E))
Cholinediol: 1.3 g (water content: 0.8% by mass) was weighed in a separable flask under a nitrogen atmosphere and dissolved in distilled NMP: 17.0 ml. The following reaction steps were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 22.7 g of HDI was added, and the mixture was stirred for 3 hours. At this time, the molar ratio of the aliphatic diol to the aromatic diol was 10: 0. PTMG having a number average molecular weight of 1700 (polytetramethylene oxide 2000, molecular weight distribution: 1.22, content of polymer having a molecular weight of 10,000 or more: less than 0.5% by mass, water content: 0.1% by mass or less) 3.5 g was dissolved in 19 ml of NMP and then added and stirred at 40 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., BD: 10.3 g (water content: 0.15% by mass) was dissolved in NMP: 100 ml and added over 4 hours. To the reaction solution, 150 ml of NMP was added and stirred. At this time, the ratio of BD to PDA was 100: 0. The reaction solution was returned to room temperature, and further diluted with NMP (50 ml). The reaction solution was collected in water and purified with warm water at 70 ° C. for 3 hours. At this time, the ratio of the polymer to the washing water was about 1:50. The solid content was filtered and dried under reduced pressure at 60 ° C. to obtain polymer E. The yield was 35.6%.

  About the obtained polymer E, evaluation similar to Example 1 was performed. The results are shown in Tables 1-4.

  Since the diol component was one type of aliphatic and one type of chain extender, the reaction was difficult to control, the yield was very low, and yellowing occurred during storage of the polymer, which caused problems in storage stability. there were. Moreover, it is considered that the purification efficiency is poor and the TOC value is high because the polymer has a three-dimensionally complicated structure, that is, there are many effluents and it is considered to be unsafe for medical use. Moreover, since the physical strength was low when the hollow fiber was formed, it is considered that the compatibility is not sufficient.

Comparative Example 3 (Preparation of segmented polyurethane urea (polymer F))
Cholinediol: 5.0 g (water content: 2.1 mass%) was weighed into a separable flask under a nitrogen atmosphere and dissolved in distilled NMP: 125.0 ml. The following reaction steps were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 27.2 g of HDI was added, and the mixture was stirred for 1 hour. After lowering the reaction temperature to 40 ° C., 94.4 g of MDI was added and stirred at 40 ° C. for 1 hour. At this time, the molar ratio of the aliphatic diol to the aromatic diol was 3: 7. PTMG having a number average molecular weight of 1700 (polytetramethylene oxide 2000, molecular weight distribution: 1.22, content of polymer having a molecular weight of 10,000 or more: less than 0.5% by mass, water content: 0.1% by mass or less) 17.1 g was dissolved in NMP: 55 ml, added, and stirred at 40 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., BD: 39.1 g (water content: 0.5 mass%) was dissolved in NMP: 400 ml and added over 4 hours. NMP: 600 ml was added to the reaction liquid and stirred, and PDA: 2.1 g was dissolved in NMP: 200 ml and added over 30 minutes. At this time, the ratio of BD to PDA was 95: 5. The reaction solution was returned to room temperature and further diluted by adding 200 ml of NMP. The reaction solution was collected in water and purified with warm water at 70 ° C. for 6 hours. At this time, the ratio of the polymer to the washing water was about 1:50. The solid content was filtered and dried under reduced pressure at 60 ° C. to obtain polymer F. The yield was 42.7%.

  The obtained polymer F was examined for molecular weight measurement, eluate test, TOC measurement, solubility, compatibility, and coloring. The results are shown in Table 1.

  The water content of the diol component, particularly choline diol, is high, and it is considered that the polyurethane polymerization reaction was inhibited. Due to the influence of water, the polymer structure becomes three-dimensionally complicated, such as gelation, or the reaction has stopped midway. Therefore, the product cannot be sufficiently purified, the amount of eluate is large, and safety is lacking. It became a thing. Also, due to the complexity of the structure, the compatibility of the polymer was extremely poor and the workability was lacking.

Comparative Example 4 (Preparation of segmented polyurethane urea (polymer G))
Cholinediol: 1.3 g (water content: 0.7 mass%) was weighed in a separable flask under a nitrogen atmosphere and dissolved in distilled NMP: 24 ml. The following reaction steps were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 6.8 g of HDI was added, and the mixture was stirred for 1 hour. After lowering the reaction temperature to 40 ° C., 23.6 g of MDI was added and stirred at 40 ° C. for 1 hour. At this time, the molar ratio of the aliphatic diol to the aromatic diol was 3: 7. PTMG having a number average molecular weight of 925 (PTG1000, manufactured by Hodogaya Chemical Co., Ltd., molecular weight distribution: 1.15, content of polymer having a molecular weight of 10,000 or more: less than 0.5 mass%, moisture content: 0.1 mass% or less) 4.3 g NMP: Dissolved in 21 ml, added, and stirred at 40 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., BD: 9.5 g (water content: 0.16% by mass) was dissolved in NMP: 100 ml, and added over 4 hours. To the reaction solution, 150 ml of NMP was added and stirred, and 0.5 g of PDA was dissolved in 50 ml of NMP and added over 30 minutes. At this time, the ratio of BD to PDA was 95: 5. The reaction solution was returned to room temperature, and further diluted with NMP (50 ml). The reaction solution was recovered in water and purified with warm water at 70 ° C. for 4 hours. At this time, the ratio of the polymer to the washing water was about 1:50. The solid content was filtered and dried under reduced pressure at 60 ° C. to obtain polymer G. The yield was 43.1%.

  The obtained polymer G was evaluated in the same manner as in Example 1. The results are shown in Tables 1-4.

  Since the molecular weight of PTMG constituting the soft segment was lowered, a microphase separation structure was hardly formed, resulting in inferior blood compatibility as compared with Examples. The physical strength when blended with the hollow fiber membrane is also insufficient, and it is considered that the compatibility with the hollow fiber raw material was not sufficient.

Reference Example 1 (Commercially available medical polyurethane)
A film of commercially available polyurethane (Pellethane (trade name)) was prepared and evaluated for antithrombogenicity (antiplasma coagulability). The results are shown in Table 2.

Reference example 2 (dialyzer)
The dialyzer which does not add segmented polyurethane urea by the method produced in Example 1 was produced. The hollow fiber membrane and dialyzer were evaluated in the same manner as in Example 1. The results are shown in Table 3.

  In segmented polyurethane urea for medical applications, processability, handleability, and physical properties were improved without compromising blood compatibility and safety. This segmented polyurethane urea can exhibit its performance as a medical device when used alone, blended with other materials, or coated on a surface.

Claims (5)

As a component, at least all of (1) to (6) are included,
(1) At least one component selected from a component having a structure containing a charged group in the molecule, or a component having a structure capable of introducing a charged group (2) At least selected from the group consisting of aromatic diisocyanates At least one diisocyanate (3) at least one diisocyanate selected from the group consisting of aliphatic diisocyanates (4) polyether polyol (5) at least one chain extender selected from the group consisting of low molecular weight diols (6) A segmented polyurethane urea comprising at least one chain extender selected from the group consisting of low molecular weight diamines and (7), (8) and (9).
(7) Moisture content of all diols constituting the component is less than 2% (8) Reacting low molecular weight diol and low molecular weight diamine stepwise (9) Excellent storage stability The segmented polyurethane urea according to claim 1, wherein the component containing a chargeable group has a structure represented by the following chemical formula (1).

The segmented polyurethane urea according to claim 1 or 2, wherein the component containing a chargeable group has a structure represented by the following chemical formula (2).

[In the above chemical formula (2), 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 other atom or It may be substituted with a functional group. ] The segmented polyurethane urea according to any one of claims 1 to 3, wherein the component containing a chargeable group has a structure represented by the following chemical formula (3) or (4).

[In the above chemical formula (3) and chemical formula (4), R ¹ , R ² , R ³ and R ⁶ are each an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an alkyl group having 7 to 15 carbon atoms. 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 an aralkyl group having 7 to 15 carbon atoms, which may be the same or different, The hydrogen atom of each group may be substituted with other atoms or functional groups. 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 represented by the following chemical formula (5). X is N, HC or a group having the structure of the following chemical formula (6). ]

[Wherein, A is an oxyalkylene group having 2 to 10 carbon atoms, and one or two or more oxyalkylene groups may be mixed, and the order of bonding may be block or random. N is an integer of 1-30. 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 May be. ] A medical material containing the segmented polyurethane urea according to any one of claims 1 to 4.