Temperature-responsive polymers and aqueous temperature-responsive compositions

Abstract

The purpose of the present invention is to provide a polymer material of which the temperature responsiveness including a lower critical solution temperature (LCST) can be varied by various factors and which shows temperature responsiveness in water. Provided is a temperature-responsive polymer which contains a structural unit represented by formula (1) and has a polar bond and a carboxylate group in side chains, in which, in formula (1), M's independently represent a hydrogen atom or a monovalent cation, A's independently represent a polar bond selected from the group consisting of an amide bond, an ester bond, a carbonate bond, a urethane bond and an urea bond, circled Cy's independently represent a hydrocarbon ring structure having 4 to 30 carbon atoms in which a carbon atom constituting the hydrocarbon ring structure and binding to A and a carbon atom constituting the hydrocarbon ring structure and binding to COOM are located in a vicinal position each other, R1's independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R2's independently represent a single bond or an alkanediyl group having 1 to 3 carbon atoms.

Description

[Technical Field]

[0001] This disclosure relates to temperature-responsive polymers and aqueous temperature-responsive compositions. [Background technology]

[0002] Temperature-responsive polymers are functional polymers whose affinity for a solvent changes with temperature. They are expected to have applications in functional cell sheets, drug transport carriers, and other areas. Recently, it has been reported that adding a third component molecule (also called an "effector") to a two-component system of polymer and solvent can cause polymer materials to exhibit temperature-responsive behavior.

[0003] Non-patent literature 1 (Angew. Chem. Int. Ed. 2005, 44, 5658-5661) and Non-patent literature 2 (Angew. Chem. Int. Ed. 2007, 46, 2708-2711) describe temperature-responsive polymers using cyclodextrin as an effector.

[0004] Non-patent document 3 (J. Am. Chem. Soc. 2012, 134, 8344-8347) describes a temperature-responsive polymer using an organic compound with hydrogen bond-forming properties as an effector.

[0005] Non-patent document 4 (Angew. Chem. 2013, 125, 4268-4272) describes a temperature-responsive polymer using an organic compound that forms a charge-transfer complex as an effector. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Angew. Chem. Int. Ed. 2005, 44, 5658-5661 [Non-Patent Document 2] Angew. Chem. Int. Ed. 2007, 46, 2708-2711 [Non-Patent Document 3] J. Am. Chem. Soc. 2012, 134, 8344-8347 [Non-Patent Document 4] Angew. Chem. 2013, 125, 4268-4272 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Among polymer materials that exhibit temperature responsiveness in the presence of an effector, the only known system that exhibits temperature responsiveness in water is the system described in Non-Patent Documents 1 and 2, which uses a polymer having a 2-(2-bromoisobutyryloxy)ethyl group or adamantyl group in its side chain and a cyclodextrin (effector). The temperature-responsive polymers described in Non-Patent Documents 3 and 4 exhibit stimulus responsiveness in organic solvents and do not exhibit temperature responsiveness in water.

[0008] The present disclosure aims to provide a polymer material that exhibits temperature responsiveness in water, such as its lower critical dissolution temperature (LCST), which can be altered by various factors. [Means for solving the problem]

[0009] The inventors have discovered that polymers having a specific ring structure in their side chains, such as polar bonds like amide bonds and carboxylate groups, exhibit temperature responsiveness when polyvalent cations, such as calcium ions, are present in water as effectors.

[0010] The present invention encompasses the following aspects.

[0011] [Aspect 1] A temperature-responsive polymer having polar bonds and carboxylate groups in its side chains, wherein the temperature-responsive polymer is of formula (1) [ka] Includes structural units represented by, In formula (1), M independently represents a hydrogen atom or a monovalent cation, A independently represents a polar bond selected from the group consisting of amide bonds, ester bonds, carbonate bonds, urethane bonds and urea bonds, Cy enclosed in circles independently represents a hydrocarbon ring structure having 4 to 30 carbon atoms, the hydrocarbon ring structure may have one or more substituents selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms and alkoxy groups having 1 to 4 carbon atoms, the carbon atom constituting the hydrocarbon ring structure and bonded to A and the carbon atom constituting the hydrocarbon ring structure and bonded to COOM are in vicinal positions relative to each other, and R 1 Each of these independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 Each of these independently represents a single bond or an alkanediyl group with 1 to 3 carbon atoms, forming a temperature-responsive polymer. [Aspect 2] The temperature-responsive polymer according to embodiment 1, wherein the polar bond is selected from the group consisting of amide bonds and ester bonds. [Aspect 3] The temperature-responsive polymer is a temperature-responsive polymer having an amide bond and a carboxylate group in its side chain, and is defined by formula (2) [ka] Includes structural units represented by, In formula (2), M independently represents a hydrogen atom or a monovalent cation, A represents an amide bond, and Cy enclosed in a hexagon independently represents a six-membered ring structure selected from the group consisting of a benzene ring, a cyclohexane ring, a cyclohexene ring, and a cyclohexadiene ring, and R 1 Each of these independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 Each of these independently represents a single bond or an alkanediyl group with 1 to 3 carbon atoms, R 3 , R 4 , R 5 , and R 6each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R 3 、R 4 、R 5 、and R 6 among 6 , two groups may form an aliphatic ring, an aromatic ring or a bridged structure, the temperature-responsive polymer according to Embodiment 1. [Embodiment 4] The structural unit represented by formula (2) contains the structural unit represented by formula (3a) [Chemical formula] In formula (3a), M each independently represents a hydrogen atom or a monovalent cation, and R 1 each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 each independently represents a single bond or an alkanediyl group having 1 to 3 carbon atoms, R 3 、R 4 、R 5 、and R 6 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, R 3 、R 4 、R 5 、and R 6 among 6 , two groups may form an aliphatic ring, an aromatic ring or a bridged structure, and R 7 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, the temperature-responsive polymer according to Embodiment 3. [Embodiment 5] The structural unit represented by formula (2) contains the structural unit represented by formula (4a) [Chemical formula] In formula (4a), M each independently represents a hydrogen atom or a monovalent cation, and R 1 each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 each independently represents a single bond or an alkanediyl group having 1 to 3 carbon atoms, R 3 、R 4 、R5 , and R 6 Each of these independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R 3 , R 4 , R 5 , and R 6 Of these, two groups may form an aliphatic ring, an aromatic ring, or a crosslinking structure, R 7 The temperature-responsive polymer according to embodiment 3, wherein is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. [Aspect 6] R 1 is a hydrogen atom, and R 2 A temperature-responsive polymer according to any one of embodiments 1 to 5, wherein the group is a methanediyl group. [Aspect 7] R 3 , R 4 , R 5 , R 6 , and R 7 A temperature-responsive polymer according to any one of embodiments 3 to 6, wherein is a hydrogen atom. [Aspect 8] A water-based temperature-responsive composition comprising a temperature-responsive polymer according to any one of embodiments 1 to 7 and a polyvalent cation. [Aspect 9] The aqueous temperature-responsive composition according to embodiment 8, wherein the polyvalent cation comprises at least one selected from the group consisting of magnesium ions, calcium ions, and strontium ions. [Aspect 10] An aqueous temperature-responsive composition according to embodiment 8 or 9, wherein the pH is 4 to 9. [Aspect 11] The aqueous temperature-responsive composition according to any one of embodiments 8 to 10, wherein the concentration of the polyvalent cation is 0.1 to 200 mM. [Aspect 12] An aqueous temperature-responsive composition according to any one of embodiments 8 to 11, wherein the lower critical solution temperature is 25°C to 80°C. [Effects of the Invention]

[0012] According to the present invention, the temperature responsiveness of a temperature-responsive polymer can be adjusted by changing one or more factors among the structure of the side chains of the temperature-responsive polymer, the type and concentration of polyvalent cations used as effectors, and the pH of the aqueous temperature-responsive composition. Therefore, aqueous temperature-responsive compositions containing temperature-responsive polymers can be designed according to various applications.

[0013] The foregoing description shall not be deemed to disclose all embodiments of the present invention and all advantages relating to the present invention. [Brief explanation of the drawing]

[0014] [Figure 1] This is the 1H-NMR chart of PAA-Pht. [Figure 2] This is the 1H-NMR chart of PAA-CHex. [Figure 3] This graph shows the effect of the presence and type of cations on transmittance in aqueous compositions containing PAA-Pht. [Figure 4] This graph shows the reversibility of the temperature responsiveness of PAA-Pht in the presence of Ca2+. [Figure 5] This graph shows the temperature response of PAA-Pht in the presence of Ca2+, depending on the Ca2+ concentration. [Figure 6] This graph shows the temperature response of PAA-Pht in the presence of Ca2+, depending on the polymer concentration. [Figure 7] This graph shows the pH dependence of the temperature responsiveness of PAA-Pht in the presence of Ca2+. [Figure 8A] This graph shows the effect of the type of divalent cation on aqueous temperature-responsive compositions containing PAA-Pht. [Figure 8B] This is another graph showing the effect of the type of divalent cation in an aqueous temperature-responsive composition containing PAA-Pht. [Figure 9] This graph shows the temperature response of PAA-CHex in the presence of Ca2+, depending on the Ca2+ concentration. [Figure 10]This graph shows the polymer concentration dependence of the temperature response of PAA-CHex in the presence of Ca2+. [Modes for carrying out the invention]

[0015] The following describes representative embodiments of the present invention in more detail, but the present invention is not limited to these embodiments.

[0016] [Temperature-responsive polymer] One embodiment of the temperature-responsive polymer has polar bonds and carboxylate groups in its side chains, and formula (1) [ka] It includes structural units represented by .

[0017] In formula (1), M independently represents a hydrogen atom or a monovalent cation, A independently represents a polar bond selected from the group consisting of amide bonds, ester bonds, carbonate bonds, urethane bonds and urea bonds, Cy enclosed in circles independently represents a hydrocarbon ring structure having 4 to 30 carbon atoms, the hydrocarbon ring structure may have one or more substituents selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms and alkoxy groups having 1 to 4 carbon atoms, the carbon atoms constituting the hydrocarbon ring structure and bonded to A and the carbon atoms constituting the hydrocarbon ring structure and bonded to COOM are in vicinal positions relative to each other, and R 1 Each of these independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 Each of these independently represents a single bond or an alkanediyl group with 1 to 3 carbon atoms.

[0018] While not bound by any particular theory, the mechanism by which the temperature-responsive polymers disclosed herein exhibit temperature responsiveness in water in the presence of polyvalent cations is thought to be as follows: The hydrocarbon ring structure, such as a six-membered ring structure, pendanted to the polymer backbone ensures that the temperature-responsive polymer exhibits hydrophobicity at temperatures above its lower critical dissolution temperature (LCST). The groups constituting polar bonds, such as amide and ester groups in the side chains, are sites that hydrate with water molecules in the system, causing the temperature-responsive polymer to dissolve in water at temperatures below the LCST. The carboxylate groups in the side chains interact with the coexisting polyvalent cations, changing the conformation of the temperature-responsive polymer in response to temperature. The pKa of the carboxylate group differs depending on the hydrocarbon ring structure to which the carboxylate group is bonded, such as a benzene ring or an aliphatic ring (cyclohexane ring, cyclohexene ring, and cyclohexadiene ring). For example, aliphatic rings are more hydrophobic than benzene rings. The LCST of temperature-responsive polymers changes due to differences in the pKa of the carboxylate group and the hydrophobicity of the hydrocarbon ring structure, such as a six-membered ring structure. Generally, temperature-responsive polymers in which the carboxylate group is bonded to an aliphatic ring tend to exhibit a lower LCST than temperature-responsive polymers in which the carboxylate group is bonded to a benzene ring. Groups such as amide groups and ester groups that constitute polar bonds are bonded to carbon atoms in hydrocarbon ring structures such as a six-membered ring structure, and the carboxylate group is bonded to the carbon atom at the vicinal position of the carbon atom to which the amide group, ester group, etc., is bonded. Therefore, the orientation of the carboxylate group relative to the polymer backbone and the amide group, ester group, etc., is restricted. Specifically, the carboxylate group is in a state where it is difficult to orient away from the polymer backbone. For this reason, in the temperature-responsive polymers of this disclosure, it is considered that conformational changes within the polymer molecule, rather than intermolecular interactions of the polymer molecule, mainly contribute to the expression of temperature responsiveness.

[0019] In formula (1), M independently represents either a hydrogen atom or a monovalent cation. Examples of monovalent cations include lithium ions, sodium ions, potassium ions, and ammonium ions. M is preferably a hydrogen atom or a sodium ion.

[0020] In formula (1), A independently represents a polar bond selected from the group consisting of amide bonds, ester bonds, carbonate bonds, urethane bonds, and urea bonds. To effectively restrict the orientation of the carboxylate group, A is preferably selected from the group consisting of amide bonds and ester bonds, and more preferably an amide bond due to its higher hydrolysis resistance.

[0021] In equation (1), each Cy enclosed in a circle independently represents a hydrocarbon ring structure with 4 to 30 carbon atoms. The carbon atoms that constitute the hydrocarbon ring structure and bond to A and the carbon atoms that constitute the hydrocarbon ring structure and bond to COOM are in vicinal positions relative to each other. The hydrocarbon ring structure may be a saturated or unsaturated aliphatic ring or an aromatic ring. The hydrocarbon ring structure may be a monoring, a fused ring, a spiroring, or a bridging ring.

[0022] In one embodiment, each Cy enclosed in a circle independently has a six-membered ring structure. It is preferable that a double bond exists between the carbon atom of the six-membered ring structure to which polar bond A is bonded and the carbon atom of the six-membered ring structure to which COOM (carboxylate group) is bonded. In this embodiment, it is thought that precise temperature responsiveness can be obtained by further restricting the orientation of the carboxylate group relative to the polymer backbone and polar bond A. It is more preferable that the six-membered ring structure is a benzene ring or a cyclohexene ring.

[0023] The hydrocarbon ring structure may have one or more substituents selected from the group consisting of halogen atoms, C1-C4 alkyl groups, and C1-C4 alkoxy groups. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine. Examples of C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl groups. Examples of C1-C4 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy groups. The substituents are preferably methyl, ethyl, methoxy, or ethoxy groups. In one embodiment, the hydrocarbon ring structure has no substituents.

[0024] In equation (1), R 1 Each of these independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups having 1 to 4 carbon atoms include the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and t-butyl group. 1 It is preferably a hydrogen atom, a methyl group, or an ethyl group, and more preferably a hydrogen atom.

[0025] In equation (1), R 2 Each of these independently represents a single bond or an alkanediyl group having 1 to 3 carbon atoms. Examples of alkanediyl groups having 1 to 3 carbon atoms include methanediyl group (-CH2-), ethane-1,2-diyl group (-CH2CH2-), ethane-1,1-diyl group (-CH(CH3)-), propane-1,3-diyl group (-CH2CH2CH2-), propane-1,2-diyl group (-CH2CH(CH3)-), and propane-2,2-diyl group (-C(CH3)2-). 2 It is preferably a single bond or a methanediyl group, and more preferably a methanediyl group.

[0026] Temperature-responsive polymers have amide bonds and carboxylate groups in their side chains, and are given by formula (2) [ka] It is preferable that the structural unit represented by [the symbol] is included.

[0027] In formula (2), M independently represents a hydrogen atom or a monovalent cation, A represents an amide bond, and Cy enclosed in a hexagon independently represents a six-membered ring structure selected from the group consisting of a benzene ring, a cyclohexane ring, a cyclohexene ring, and a cyclohexadiene ring, and R 1 Each of these independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 Each of these independently represents a single bond or an alkanediyl group with 1 to 3 carbon atoms, R 3 , R 4 , R 5 , and R 6 Each of these independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R 3 , R 4 , R 5 , and R 6 Of these, two groups may form an aliphatic ring, an aromatic ring, or a cross-linking structure.

[0028] In formula (2), M independently represents either a hydrogen atom or a monovalent cation. Examples of monovalent cations include lithium ions, sodium ions, potassium ions, and ammonium ions. M is preferably a hydrogen atom or a sodium ion.

[0029] In formula (2), each Cy enclosed in a hexagon independently represents a six-membered ring structure selected from the group consisting of a benzene ring, a cyclohexane ring, a cyclohexene ring, and a cyclohexadiene ring. The position of the double bond in the cyclohexene ring and the cyclohexadiene ring is not particularly limited. In one embodiment, a double bond exists between the carbon atom of the six-membered ring structure to which the amide group is bonded and the carbon atom of the six-membered ring structure to which the carboxylate group is bonded. In this embodiment, it is thought that a precise temperature response can be obtained by further restricting the orientation of the carboxylate group relative to the polymer backbone and the amide group. It is preferable that the Cy enclosed in a hexagon is a benzene ring or a cyclohexene ring.

[0030] In equation (2), R 1 Each of these independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups having 1 to 4 carbon atoms include the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and t-butyl group. 1 It is preferably a hydrogen atom, a methyl group, or an ethyl group, and more preferably a hydrogen atom.

[0031] In equation (2), R 2 Each of these independently represents a single bond or an alkanediyl group having 1 to 3 carbon atoms. Examples of alkanediyl groups having 1 to 3 carbon atoms include methanediyl group (-CH2-), ethane-1,2-diyl group (-CH2CH2-), ethane-1,1-diyl group (-CH(CH3)-), propane-1,3-diyl group (-CH2CH2CH2-), propane-1,2-diyl group (-CH2CH(CH3)-), and propane-2,2-diyl group (-C(CH3)2-). 2 It is preferably a single bond or a methanediyl group, and more preferably a methanediyl group.

[0032] In equation (2), R 3 , R 4 , R 5 , and R 6Each of these independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine. Examples of alkyl groups having 1 to 4 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl groups. Examples of alkoxy groups having 1 to 4 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy groups. 3 , R 4 , R 5 , and R 6 It is preferably a hydrogen atom, a methyl group, an ethyl group, a methoxy group, or an ethoxy group, and more preferably a hydrogen atom.

[0033] In equation (2), R 3 , R 4 , R 5 , and R 6 Of these, two groups may form an aliphatic ring, an aromatic ring, or a crosslinking structure. In one embodiment, R 3 , R 4 , R 5 , and R 6 Of these, two adjacent groups form an aliphatic or aromatic ring. For example, if Cy is a benzene ring, R 4 and R 5 When Cy forms a benzene ring as an aromatic ring, together with the benzene ring to which the amide group and carboxylate group are bonded, it forms a naphthalene ring as shown in formula (3c) below. For example, if Cy is a cyclohexene ring, R 4 and R 5 When R forms a cyclohexane ring as an aliphatic ring, it forms an octahydronaphthalene ring as shown in formula (4c) below, together with the cyclohexene ring to which the amide group and carboxylate group are bonded. In another embodiment, R 3 , R 4 , R 5 , and R 6 Of these, two groups form a bridging structure. For example, Cy is a cyclohexane ring, and R3 and R 6 forms a bridged structure with a methylene group (-CH2-), a norbornane ring (bicyclo[2.2.1]heptane ring) is formed. R 3 , R 4 , R 5 , and R 6 Among them, the aliphatic ring, aromatic ring or bridged structure formed by two groups may have one or more substituents selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms. The plurality of substituents may be the same or different. Exemplary and preferred substituents are the same as those described for R 3 , R 4 , R 5 , and R 6 . The same as those described for R 3 , R 4 , R 5 , and R 6 Among them, the total number of carbon atoms of the ring structure formed by the aliphatic ring, aromatic ring or bridged structure formed by two groups and the six-membered ring structure represented by Cy in formula (2) is preferably 8 to 18.

Chemical formula

Chemical formula

[0034] A in formula (2) is an amide bond, specifically a group represented by the formula: -NRCO- (R is a hydrogen atom or a monovalent group). In one embodiment, depending on whether the carbonyl carbon of the amide bond is bonded to R 2 on the polymer main chain side or to the carbon atom of the six-membered ring structure, formula (2) includes two types of structures of formula (2a) and formula (2b) shown below.

Chemical formula

[0035] In formula (2a) and (2b), M, Cy surrounded by a hexagon, R 1 , R 2 , R3 , R 4 , R 5 , and R 6 This is the same as equation (2).

[0036] In equations (2a) and (2b), R 7 Each of these independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups having 1 to 4 carbon atoms include the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and t-butyl group. 7 It is preferably a hydrogen atom, a methyl group, or an ethyl group, and more preferably a hydrogen atom.

[0037] In the structural unit represented by formula (2a), the carbonyl carbon of the amide bond is bonded to the carbon atom of the six-membered ring structure. On the other hand, in the structural unit represented by formula (2b), the nitrogen atom of the amide bond is bonded to the carbon atom of the six-membered ring structure. This difference in the bonding mode of the amide bond changes the lower critical solution temperature of the temperature-responsive polymer. Generally, temperature-responsive polymers containing the structural unit represented by formula (2a) often exhibit a higher lower critical solution temperature than temperature-responsive polymers containing the structural unit represented by formula (2b), which has a similar structure except for the bonding mode of the amide bond. Thus, the temperature responsiveness of a temperature-responsive polymer can also be changed by selecting the amide bond mode.

[0038] In one embodiment, the structural unit represented by formula (2) includes or consists of the structural unit represented by formula (3a). In formula (3a), M, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 This is the same as equation (2a). [ka]

[0039] In another embodiment, the structural unit represented by formula (2) includes or consists of the structural unit represented by formula (4a). In formula (4a), M, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 This is the same as equation (2a). [ka]

[0040] The temperature-responsive polymer may be a monopolymer or a copolymer. The structural units represented by formula (1) or formula (2) contained in the temperature-responsive polymer are preferably 5 mol% or more, more preferably 20 mol% or more, and even more preferably 50 mol% or more, when expressed as a molar ratio based on the total structural units. By containing 5 mol% or more of the above structural units in total, the temperature-responsive polymer can be imparted with temperature responsiveness. The structural units represented by formula (1) or formula (2) contained in the temperature-responsive polymer can be 100 mol% or less, 90 mol% or less, or 80 mol% or less, when expressed as a molar ratio based on the total structural units.

[0041] The weight-average molecular weight of the temperature-responsive polymer is preferably 5,000 to 1,000,000, more preferably 7,500 to 500,000, and even more preferably 10,000 to 100,000. In this disclosure, "weight-average molecular weight" means the molecular weight calculated using standard polystyrene by gel permeation chromatography (GPC).

[0042] [Method for producing temperature-responsive polymers] Temperature-responsive polymers have the same polymer backbone as temperature-responsive polymers, as schematically shown in the reaction equation below, and contain functional groups such as hydroxyl groups, amino groups, carboxyl groups, alkoxycarbonyl groups, and isocyanate groups. 1A precursor polymer having a functional group A, which is a compound corresponding to the side chain, such as an acid anhydride, an acid halide, an amine, a hydroxyl group-containing compound, or an isocyanate group-containing compound. 2 It can be obtained by reacting a pendant reagent having functional group A. If necessary, 1 and functional group A 2 Compound A has a site that reacts with both. 3 You may also use the following. The pendant reagent is A 2 The acid anhydride may be obtained by intramolecular condensation of and COOM. A catalyst or dehydrating condensation agent may be used to carry out the above reaction. In the following reaction formula, n is the degree of polymerization of the precursor polymer, preferably 20 to 5,000, more preferably 30 to 2,500, and even more preferably 40 to 500. Formula (1A) represents a temperature-responsive polymer. [ka]

[0043] For example, a temperature-responsive polymer in formula (1) where A is an amide bond can be obtained by reacting a precursor polymer having an amino group with an acid anhydride or acid halide, or by reacting a precursor polymer having a carboxyl group or alkoxycarbonyl group with an amine. A temperature-responsive polymer in formula (1) where A is an ester bond can be obtained by reacting a precursor polymer having a hydroxyl group with an acid anhydride or acid halide, or by reacting a precursor polymer having a carboxyl group or alkoxycarbonyl group with a hydroxyl group-containing compound. A temperature-responsive polymer in formula (1) where A is a carbonate bond can be obtained by reacting a precursor polymer having a hydroxyl group with a hydroxyl group-containing compound with a carbonate compound such as dimethyl carbonate, diethyl carbonate, or diphenyl carbonate. In formula (1), a temperature-responsive polymer in which A is a urethane bond can be obtained by reacting a precursor polymer having a hydroxyl group with an isocyanate group-containing compound, or by reacting a precursor polymer having an isocyanate group with a hydroxyl group-containing compound. In formula (1), a temperature-responsive polymer in which A is a urea bond can be obtained by reacting a precursor polymer having an amino group with an isocyanate group-containing compound, or by reacting a precursor polymer having an isocyanate group with an amine.

[0044] Temperature-responsive polymers can also be obtained by radical polymerization of polymerizable monomers corresponding to the constituent units of the temperature-responsive polymer, as schematically shown in the reaction equation below. A radical polymerization initiator may be used to initiate radical polymerization. The COOM may be protected with a protective agent before radical polymerization and then deprotected and regenerated after the completion of radical polymerization. In the reaction equation below, n is the degree of polymerization of the precursor polymer, preferably 20 to 5,000, more preferably 30 to 2,500, and even more preferably 40 to 500. Equation (1A) represents the temperature-responsive polymer. [ka]

[0045] The following describes in detail, for illustrative purposes, a method for producing a temperature-responsive polymer containing the structural unit represented by formula (2). Those skilled in organic synthesis and polymer synthesis can appropriately produce temperature-responsive polymers containing structural units other than those represented by formula (2) by referring to the following description.

[0046] For example, a temperature-responsive polymer represented by formula (3A) or formula (4A) can be obtained by reacting a precursor polymer having an amino group represented by formula (5), such as polyvinylamine or polyallylamine, with a phthalic anhydride compound represented by formula (6a) or a 3,4,5,6-tetrahydrophthalic anhydride compound represented by formula (7a). In formula (5), R 1 and R 2 As explained in equation (2), R 7 The formula (2a) is as described above. n is the degree of polymerization of the precursor polymer, preferably 20 to 5,000, more preferably 30 to 2,500, and even more preferably 40 to 500. R in formulas (6a) and (7a) 3 , R 4 , R 5 , and R 6 This is as explained in equation (2).

[0047] [ka] [ka]

[0048] The precursor polymer having an amino group may be in a form having a free amino group, or it may be in the form of a salt such as a hydrochloride salt, hydrobromide salt, sulfate salt, phosphate salt, or acetate salt.

[0049] The precursor polymer having an amino group is preferably selected from the group consisting of polyvinylamine and polyallylamine, and more preferably polyallylamine.

[0050] Methods for producing polyvinylamine and its salts are well known. For example, as described in Japanese Patent Publication No. 2012-077099, polyvinylamine can be obtained by polymerizing N-vinylformamide using an azo-based initiator as a polymerization initiator, and then hydrolyzing the resulting polyvinylformamide.

[0051] Methods for producing polyallylamines and their salts are well known. For example, as described in Japanese Patent Publication No. 58-201811 and Japanese Patent Publication No. 60-104107, an inorganic salt of polyallylamine can be obtained by polymerizing an inorganic salt of monoallylamine in a polar solvent in the presence of a radical initiator containing an azo group and a cationic nitrogen atom in the molecule, or a specific azo-based initiator. Polyallylamine may also be obtained by dialyzing the obtained inorganic salt of polyallylamine.

[0052] Commercially available polyvinylamines and polyallylamines can also be used. For example, PVAM (manufactured by Mitsubishi Chemical Corporation) is an example of polyvinylamine. The PAA® series (manufactured by Nitto Boseki Medical Co., Ltd.) is an example of polyallylamine and its salts.

[0053] The reaction between the precursor polymer and the acid anhydride compound can be carried out by dissolving the precursor polymer in a buffer such as a carbonate buffer, and then adding the acid anhydride compound at 10°C to 50°C while adjusting the pH of the buffer to 9-10 using an alkaline compound such as sodium hydroxide or potassium hydroxide. The reaction time can be appropriately determined depending on the reactivity and amount of the acid anhydride compound used, for example, from 10 minutes to 48 hours. Afterwards, if necessary, salt exchange can be performed using sodium chloride, etc., and post-treatment such as dialysis or freeze-drying can be performed to obtain a temperature-responsive polymer.

[0054] Alternatively, a temperature-responsive polymer represented by formula (3B) or formula (4B) can be obtained by radical polymerization of a monomer composition containing an ethylenically unsaturated monomer represented by formula (6b) or formula (7b), for example. M, R in formulas (6b) and (7b) 1 , R 2 , R 3 , R 4 , R 5 , and R 6 As explained in equation (2), R 7 The formula is as described for equation (2b). n is the degree of polymerization of the temperature-responsive polymer, preferably 20 to 5,000, more preferably 30 to 2,500, and even more preferably 40 to 500.

[0055] [ka] [ka]

[0056] Ethylene-unsaturated monomers represented by formula (6b) include, for example, methacrylic acid (R 1 is a methyl group, R 2 (When it is a single bond) or acrylic acid (R 1 is a hydrogen atom, R 2The carboxyl group (in the case of a single bond) can be formed with the amino group of an anthranilic acid ester compound corresponding to the structure shown in formula (6b), such as methyl anthranilate, and the anthranilic acid moiety can be obtained by hydrolysis of the ester. Alternatively, the ethylenically unsaturated monomer represented by formula (6b) can also be obtained by activating the esterification of the carboxyl group of methacrylic acid or acrylic acid with an alcohol such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), or ethyl (hydroxyimino)cyanoacetate, using a dehydrating agent such as a water-soluble carbodiimide, and then carrying out a condensation reaction with the amino group of an anthranilic acid compound corresponding to the structure shown in formula (6b). Similarly, the ethylenically unsaturated monomer represented by formula (7b) can be obtained by using a 2-amino-1-cyclohexene-1-carboxylic acid ester compound or a 2-amino-1-cyclohexene-1-carboxylic acid compound corresponding to the structure shown in formula (7b) instead of an anthranilic acid ester compound or anthranilic acid compound corresponding to the structure shown in formula (6b).

[0057] The monomer composition may further contain monomers other than the ethylenically unsaturated monomer corresponding to the structural unit represented by formula (2). Examples of such monomers include vinyl compounds such as styrene, vinyltoluene, vinyl acetate, vinyl chloride, and N-vinylpyrrolidone; (meth)acrylate compounds such as methyl (meth)acrylate, ethyl (meth)acrylate, and butyl (meth)acrylate; and (meth)acrylamide compounds such as (meth)acrylamide, N,N-dimethyl(meth)acrylamide, and N-isopropyl(meth)acrylamide. In this disclosure, "(meth)acrylic" means acrylic or methacrylic, and "(meth)acrylate" means acrylate or methacrylate. The copolymerization ratio of these monomers can be appropriately determined within a range that does not impair the temperature responsiveness of the temperature-responsive polymer.

[0058] Radical polymerization can be carried out in an organic solvent using known radical polymerization initiators. Examples of radical polymerization initiators include organic peroxides such as benzoyl peroxide, cumene peroxide, and di-t-butyl peroxide; azo compounds such as 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile), and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile); and redox initiators. Radical polymerization initiators may be used alone or in combination of two or more.

[0059] The amount of radical polymerization initiator used is preferably 0.1 to 20 mol%, and more preferably 0.5 to 10 mol%, relative to the total amount of monomers in the monomer composition.

[0060] Examples of organic solvents include ketones such as acetone and methyl ethyl ketone (MEK); alcohols such as ethanol, methanol, and isopropyl alcohol (IPA); ethers such as ethylene glycol dimethyl ether and propylene glycol monomethyl ether; esters such as ethyl acetate, propylene glycol monomethyl ether acetate, and 2-ethoxyethyl acetate; aromatic hydrocarbons such as toluene and xylene; sulfoxides such as dimethyl sulfoxide; and amides such as dimethylformamide and dimethylacetamide. Organic solvents may be used individually or in combination of two or more.

[0061] The polymerization temperature is preferably 20 to 100°C, and more preferably 30 to 80°C. The polymerization time can be appropriately determined according to the desired molecular weight, and can be, for example, 10 minutes to 120 hours.

[0062] [Aqueous temperature-responsive composition] One embodiment of the aqueous temperature-responsive composition comprises the above-mentioned temperature-responsive polymer and a polyvalent cation. Generally, aqueous temperature-responsive compositions exhibit reversible temperature responsiveness.

[0063] The aqueous temperature-responsive composition contains water as a solvent. The aqueous temperature-responsive composition may further contain an organic solvent. Examples of organic solvents include alcohols such as methanol, ethanol, n-propanol, and isopropanol; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate and butyl acetate; sulfoxides such as dimethyl sulfoxide; and amides such as dimethylformamide and dimethylacetamide. In embodiments in which the solvent contains an organic solvent, the content of the organic solvent is preferably 0.1% to 50% by mass, more preferably 0.2% to 30% by mass, and even more preferably 0.5% to 20% by mass, when the total amount of the solvent is 100% by mass.

[0064] Polyvalent cations interact with two or more carboxylate groups in the side chains of temperature-responsive polymers, particularly two or more carboxylate groups within the polymer molecule, thereby determining the conformation of the temperature-responsive polymer, and the conformation of the temperature-responsive polymer is thought to change with temperature. Since each polyvalent cation has its own unique hydration Gibbs energy, changing the type of polyvalent cation changes the hydration state of the temperature-responsive polymer. Therefore, the LCST of the temperature-responsive polymer can be adjusted by using different polyvalent cations. Polyvalent cations may be used alone or in combination of two or more types. By using two or more polyvalent cations in combination and appropriately determining their ratio, the LCST of the temperature-responsive polymer can be adjusted more precisely.

[0065] Examples of polyvalent cations include, but are not limited to, divalent cations such as magnesium ions, calcium ions, strontium ions, and barium ions. It is more preferable that the polyvalent cation includes at least one selected from the group consisting of magnesium ions, calcium ions, and strontium ions. When used in biomaterials, it is advantageous for the polyvalent cation to be a calcium ion.

[0066] The LCST of a temperature-responsive polymer can also be adjusted by changing the concentration of polyvalent cations. In one embodiment, when the concentration of polyvalent cations exceeds a certain value (saturation concentration), the LCST of the temperature-responsive polymer hardly changes. The concentration of polyvalent cations can be appropriately determined depending on the type of temperature-responsive polymer and polyvalent cation used, as well as the desired LCST. The concentration of polyvalent cations can be, for example, 0.01 mM to 1000 mM, 0.1 mM to 500 mM, or 0.5 mM to 250 mM, but is not limited to these ranges.

[0067] The concentration of the temperature-responsive polymer has little effect on its LCST. This suggests that conformational changes of the molecular chains are more dominant to the temperature responsiveness of the temperature-responsive polymer than intermolecular interactions. The concentration of the temperature-responsive polymer can be, for example, 0.1 mg / mL to 20 mg / mL, 0.2 mg / mL to 10 mg / mL, or 0.4 mg / mL to 5 mg / mL, but is not limited to these ranges.

[0068] The LCST of a temperature-responsive polymer can also be adjusted by changing the pH of the aqueous temperature-responsive composition. While not bound by any particular theory, in higher pH ranges, for example above pH 6, the interaction between the carboxylate groups and polyvalent cations of the temperature-responsive polymer affects the conformation of the temperature-responsive polymer. In lower pH ranges, for example below pH 5, the carboxylate groups of the temperature-responsive polymer are protonated to carboxyl groups, and hydrogen bonding between carboxyl groups has a greater influence on temperature responsiveness than the interaction between carboxylate groups and polyvalent cations. Since hydrogen bonding between carboxyl groups is generally weaker than the interaction between carboxylate groups and polyvalent cations, it is thought that the LCST gradually decreases as the pH decreases, and then decreases sharply below a certain pH value. The pH of the aqueous temperature-responsive composition is preferably 4 to 9, more preferably 4.5 to 8, and even more preferably 5 to 7.5.

[0069] The aqueous temperature-responsive composition may contain monovalent cations to the extent that they do not impair the LCST of the temperature-responsive polymer. Examples of monovalent cations include lithium ions, sodium ions, potassium ions, and ammonium ions. The concentration of the monovalent cation is preferably 1000 mM or less, more preferably 500 mM or less, and even more preferably 150 mM or less.

[0070] As described above, the LCST of an aqueous temperature-responsive composition can be adjusted by one or more of the following: the structure of the side chains of the temperature-responsive polymer, the type and concentration of polyvalent cations, and the pH of the aqueous temperature-responsive composition. In one embodiment, the LCST of the aqueous temperature-responsive composition is 25°C to 80°C. When used in biomaterials, the LCST of the aqueous temperature-responsive composition is preferably 30°C to 42°C, more preferably 35°C to 40°C. In this disclosure, the LCST is defined as the temperature at which the transmittance of the aqueous temperature-responsive composition reaches 90% when the transmittance is measured at a measurement wavelength of 500 nm and a heating rate of 1°C / min, and a graph is created with the vertical axis representing transmittance (%) and the horizontal axis representing temperature (°C).

[0071] [Method for producing aqueous temperature-responsive compositions] Aqueous temperature-responsive compositions can be prepared by dissolving a temperature-responsive polymer and a polyvalent cation source in a solvent containing water and, optionally, an organic solvent.

[0072] Examples of polyvalent cation sources include salts containing the element of the polyvalent cation. Examples of such salts include chlorides such as calcium chloride, magnesium chloride, and strontium chloride; sulfates such as calcium sulfate, magnesium sulfate, and strontium sulfate; and phosphates such as calcium phosphate, magnesium phosphate, and strontium phosphate.

[0073] [Applications of temperature-responsive polymers and aqueous temperature-responsive compositions] The temperature-responsive polymers and aqueous temperature-responsive compositions disclosed herein can be suitably used in functional materials used in aqueous systems, such as functional cell sheets, drug transport carriers, mechanochemical materials, temperature sensors, separation membranes, and water-retaining agents. [Examples]

[0074] The present invention will be described more specifically below based on examples, but the present invention is not limited to these examples.

[0075] <Polymer synthesis> Synthesis Example 1: Synthesis of PAA-Pht Polyallylamine hydrochloride (PAA-HCl, weight-average molecular weight of polyallylamine Mw 15,000, manufactured by Nitto Boseki Medical Co., Ltd.) was dissolved in carbonate buffer to a concentration of 2.5 mg / mL, and the pH of the solution was adjusted to 9.5 using an aqueous sodium hydroxide solution. Three equivalents of phthalic anhydride were added to the side chain amino groups of the polyallylamine, one equivalent at a time every hour. The pH of the solution was adjusted to 9.5 each time phthalic anhydride was added. After stirring for 24 hours, sodium chloride equivalent to 100 molars relative to the side chain amino groups of the polyallylamine was added, and the mixture was stirred overnight. Using a dialysis membrane with a molecular weight cutoff of 2000, the solution was dialyzed against distilled water adjusted to pH 9.5 by adding an aqueous sodium hydroxide solution, and the resulting dialysate was freeze-dried to obtain a white solid. 1 The synthesis of PAA-Pht was confirmed by 1H-NMR. 1 The 1H-NMR chart is shown in Figure 1. 1 H-NMR (D2O+NaOD, 400MHz): δ0.8-2.2(3H), 3.0-3.7(2H), 6.8-7.7(4H)

[0076] PAA-Pht has the following structural units, where M is Na. [ka]

[0077] Synthesis Example 2: Synthesis of PAA-CHex The PAA-HCl used in Synthesis Example 1 was dissolved in carbonate buffer to a concentration of 2.5 mg / mL, and the pH of the solution was adjusted to 9.5 using an aqueous sodium hydroxide solution. Three equivalents of 1-cyclohexene 1,2-dicarboxylic acid anhydride were added to the side chain amino groups of polyallylamine at one equivalent every hour. The pH of the solution was adjusted to 9.5 each time 1-cyclohexene 1,2-dicarboxylic acid anhydride was added. After stirring for 24 hours, sodium chloride equivalent to 100 molars relative to the side chain amino groups of polyallylamine was added and the mixture was stirred overnight. Using a dialysis membrane with a molecular weight cutoff of 2000, the solution was dialyzed against distilled water adjusted to pH 9.5 by adding an aqueous sodium hydroxide solution, and the resulting dialysate was freeze-dried to obtain a white solid. 1 The synthesis of PAA-CHex was confirmed by 1H-NMR. 1 The H-NMR chart is shown in Figure 2. 1 H-NMR (D2O+NaOD, 400MHz): δ0.8-2.0(7H), 2.1-2.5(4H), 2.9-3.6(2H)

[0078] PAA-CHex has the following structural units, where M is Na. [ka]

[0079] <Evaluation Method and Results> The following items were evaluated by measuring the permeability of the obtained PAA-Pht and PAA-CHex solutions.

[0080] Transmittance measurements were performed using a V-550 ultraviolet-visible-near-infrared spectrophotometer (manufactured by JASCO Corporation).

[0081] Sodium chloride, magnesium chloride, calcium chloride, and strontium chloride were used as cation sources.

[0082] 1. The effect of the presence and type of cations on transmittance. Sample solutions (pH 5.2, polymer concentration 4 mg / mL) were prepared by dissolving PAA-Pht in three types of solutions (ultrapure water, 150 mM NaCl aqueous solution, and 150 mM CaCl2 aqueous solution), and the change in transmittance was measured under conditions of a measurement wavelength of 500 nm and a heating rate of 1 °C / min. The measurement results are shown in Figure 3 as a graph with transmittance (%) on the vertical axis and temperature (°C) on the horizontal axis.

[0083] Figure 3 shows that PAA-Pht does not exhibit temperature responsiveness in aqueous compositions that do not contain polyvalent cations or contain monovalent sodium ions. On the other hand, in aqueous compositions containing divalent calcium ions, PAA-Pht exhibits temperature responsiveness, with its transmittance decreasing sharply at high temperatures starting around 38.6°C.

[0084] 2.Ca 2+ Temperature-responsive behavior of PAA-Pht in the presence of: reversible A sample solution (pH 5.2, polymer concentration 4 mg / mL) was prepared by dissolving PAA-Pht in a 150 mM CaCl2 aqueous solution. The solution was heated from 32°C to 40°C without stirring, and then cooled back down to 32°C. The change in transmittance was measured under conditions of a measurement wavelength of 500 nm and a temperature gradient of 0.1°C / min. The measurement results are shown in Figure 4 as a graph with transmittance (%) on the vertical axis and temperature (°C) on the horizontal axis.

[0085] Figure 4 shows that the aqueous temperature-responsive composition containing PAA-Pht and calcium ions exhibits reversible temperature responsiveness.

[0086] 3. Ca 2+ Temperature-responsive behavior of PAA-Pht in the presence of Ca 2+ Concentration dependence Sample solutions (pH approximately 5.2, polymer concentration 4 mg / mL) were prepared by dissolving PAA-Pht in CaCl2 aqueous solutions of varying concentrations (150 mM, 120 mM, 90 mM, 60 mM, 30 mM, 10 mM, 5 mM, 1 mM, 0.1 mM, 0 mM), and the change in transmittance was measured under conditions of a measurement wavelength of 500 nm and a heating rate of 1 °C / min. The lower critical solution temperature (LCST) (the temperature at which the transmittance reaches 90%) was determined from a graph with transmittance (%) on the vertical axis and temperature (°C) on the horizontal axis. Figure 5 shows LCST (°C) on the vertical axis and Ca on the horizontal axis. 2+ A graph showing the concentration (mM) is provided.

[0087] Figure 5 shows that LCST decreases rapidly as the calcium ion concentration increases from 0 mM, but LCST hardly changes once the calcium ion concentration exceeds 30 mM.

[0088] 4. Ca 2+ Temperature-responsive behavior of PAA-Pht in the presence of polymer concentration: polymer concentration dependence Sample solutions were prepared by dissolving PAA-Pht in 150 mM CaCl2 aqueous solution at varying concentrations (pH approximately 5.2, polymer concentrations of 4 mg / mL, 3 mg / mL, 2 mg / mL, 1 mg / mL, and 0.5 mg / mL). The change in transmittance was measured under conditions of a measurement wavelength of 500 nm and a heating rate of 1 °C / min. The LCST (temperature at which transmittance reaches 90%) was determined from a graph with transmittance (%) on the vertical axis and temperature (°C) on the horizontal axis. Figure 6 shows a graph with LCST (°C) on the vertical axis and polymer concentration (mg / mL) on the horizontal axis.

[0089] Figure 6 shows that the LCST hardly changes even when the concentration of PAA-Pht is changed, meaning that the temperature responsiveness is not dependent on the concentration of PAA-Pht. This suggests that in aqueous temperature-responsive compositions containing PAA-Pht and calcium ions, conformational changes of polymer molecular chains are more dominant in determining the temperature responsiveness than intermolecular interactions of the polymer.

[0090] 5. Ca 2+ Temperature-dependent behavior of PAA-Pht in the presence of pH: pH dependence Sample solutions were prepared by dissolving PAA-Pht in 150 mM CaCl2 aqueous solution at varying pH levels (pH 5.0, pH 5.1, pH 5.2, pH 5.9, pH 6.2, pH 6.8, pH 7.4, polymer concentration 4 mg / mL). The change in transmittance was measured at a measurement wavelength of 500 nm and a heating rate of 1 °C / min. The LCST (temperature at which transmittance reaches 90%) was determined from a graph with transmittance (%) on the vertical axis and temperature (°C) on the horizontal axis. Table 1 shows the correspondence between pH and degree of protonation, and Figure 7 shows a graph with LCST (°C) on the vertical axis and degree of protonation on the horizontal axis.

[0091] [Table 1]

[0092] Figure 7 shows that the LCST decreases sharply once the degree of protonation exceeds 0.6. This suggests that the carboxylate group of PAA-Pht is protonated to a carboxyl group at around pH 5.2-5.5, and that hydrogen bonding between carboxyl groups becomes dominant over the interaction between calcium ions and carboxylate groups, changing the conformation of the polymer molecular chain.

[0093] 6. Temperature-responsive behavior of PAA-Pht: Influence of divalent cation type Divalent cation (Mg) at a concentration of 150 mM 2+ Ca 2+ , or Sr 2+ A sample solution (pH approximately 5.2, polymer concentration 4 mg / mL) was prepared by dissolving PAA-Pht in an aqueous solution containing ), and the change in transmittance was measured under conditions of a measurement wavelength of 500 nm and a heating rate of 1 °C / min. The measurement results are shown in Figure 8A as a graph with transmittance (%) on the vertical axis and temperature (°C) on the horizontal axis. From the graph shown in Figure 8A, LCST (the temperature at which transmittance reaches 90%) was determined. In Figure 8B, the vertical axis is LCST (°C) and the horizontal axis is Mg 2+ Ca 2+ , and Sr 2+ Hydration Gibbs energy (Δ hyd The graph shows the absolute value (kJ / mol) of G).

[0094] Figures 8A and 8B show that the type of divalent cation used significantly affects LCST. Magnesium ions have a high hydration Gibbs energy and are therefore more easily hydrated in aqueous compositions. This suggests that PAA-Pht can maintain a more stable solubility in water, even at relatively high temperatures, due to the presence of magnesium ions.

[0095] 7.Ca 2+ Temperature-responsive behavior of PAA-CHex in the presence of Ca 2+ Concentration dependence Sample solutions (pH approximately 6.1, polymer concentration 2 mg / mL) were prepared by dissolving PAA-CHex in CaCl2 aqueous solutions of varying concentrations (150 mM, 120 mM, 90 mM, 60 mM, 30 mM, 10 mM, 5 mM, 1 mM, 0 mM), and the change in transmittance was measured under conditions of a measurement wavelength of 500 nm and a heating rate of 1 °C / min. The LCST (temperature at which transmittance reaches 90%) was determined from a graph with transmittance (%) on the vertical axis and temperature (°C) on the horizontal axis. Figure 9 shows the LCST (°C) on the vertical axis and Ca on the horizontal axis. 2+ A graph showing the concentration (mM) is provided.

[0096] Figure 9 shows that PAA-CHex, like PAA-Pht, exhibits temperature responsiveness in water in the presence of polyvalent cations, and its LCST is relatively low. Furthermore, while the LCST decreases sharply as the calcium ion concentration increases from 0 mM, the change in LCST becomes small once the calcium ion concentration exceeds around 60 mM.

[0097] 8.Ca 2+ Temperature-responsive behavior of PAA-CHex in the presence of polymer concentration: Dependence on polymer concentration Sample solutions were prepared by dissolving PAA-CHex in 150 mM CaCl2 aqueous solution at varying concentrations (pH approximately 6.1, polymer concentrations of 4 mg / mL, 3 mg / mL, 2 mg / mL, 1 mg / mL, and 0.5 mg / mL). The change in transmittance was measured under conditions of a measurement wavelength of 500 nm and a heating rate of 1 °C / min. The LCST (temperature at which transmittance reaches 90%) was determined from a graph with transmittance (%) on the vertical axis and temperature (°C) on the horizontal axis. Figure 10 shows a graph with LCST (°C) on the vertical axis and polymer concentration (mg / mL) on the horizontal axis.

[0098] Figure 10 shows that, like PAA-Pht, PAA-CHex does not exhibit a concentration dependence on temperature responsiveness. This suggests that in aqueous temperature-responsive compositions containing PAA-CHex and calcium ions, conformational changes of polymer molecular chains are more dominant in determining temperature responsiveness than intermolecular interactions of the polymers. [Industrial applicability]

[0099] The temperature-responsive polymers and aqueous temperature-responsive compositions disclosed herein can be suitably used in functional materials used in aqueous systems, such as functional cell sheets, drug transport carriers, mechanochemical materials, temperature sensors, separation membranes, and water-retaining agents.

Claims

1. A temperature-responsive polymer having an amide bond and a carboxylate group in its side chain, wherein the temperature-responsive polymer is of formula (4a) 【Chemistry 1】 Includes structural units represented by, In formula (4a), M each independently represents a hydrogen atom or a monovalent cation, and R １ each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ２ each independently represents a single bond or an alkanediyl group having 1 to 3 carbon atoms, and R ３ R ４ R ５ R ６ and R ３ R ４ R ５ and R ６ Among them, two groups may form an aliphatic ring, an aromatic ring or a bridged structure, and R ７ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, a temperature-responsive polymer.

2. (delete)

3. (delete)

4. (delete)

5. (delete)

6. R １ is a hydrogen atom, R ２ The temperature-responsive polymer according to claim 1, wherein the group is a methanediyl group.

7. R ３ , R ４ , R ５ , R ６ , and R ７ The temperature-responsive polymer according to claim 1 or 6, wherein is a hydrogen atom.

8. A water-based temperature-responsive composition comprising a temperature-responsive polymer according to any one of claims 1, 6, and 7, and a polyvalent cation.

9. The aqueous temperature-responsive composition according to claim 8, wherein the polyvalent cation comprises at least one selected from the group consisting of magnesium ions, calcium ions, and strontium ions.

10. The aqueous temperature-responsive composition according to claim 8 or 9, wherein the pH is 4 to 9.

11. The aqueous temperature-responsive composition according to any one of claims 8 to 10, wherein the concentration of the polyvalent cation is 0.1 to 200 mM.

12. The aqueous temperature-responsive composition according to any one of claims 8 to 11, wherein the lower critical solution temperature is 25°C to 80°C.

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