Polymer compound including polymerizable boronic acid compound and polymerizable cationic compound as constituent units, and use thereof

Abstract

The purpose of the present invention is to provide a polymer compound which includes a polymerizable boronic acid compound as a constituent unit and which is capable of high-sensitivity detection of changes in glucose concentration. The abovementioned purpose is achieved with a polymer compound, etc., including as constituent units: a polymerizable boronic acid compound, in particular, represented by general formula 1 (wherein, at least one of R1 to R7 represents a substituent having a polymerizable group, and the remainder each independently represent a substituent selected from the group consisting of a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, and an alkyl group); a polymerizable compound having a cationic moiety; and a compound copolymerizable with the polymerizable boronic acid compound and the polymerizable compound having a cationic moiety.

Description

Polymeric compounds containing polymerizable boronic acid compounds and polymerizable cationic compounds as structural units and uses thereof

[0001] The present invention relates to a polymeric compound containing a polymerizable boronic acid compound and a polymerizable cationic compound as constituent units, and a polymeric compound for detecting a compound having a cis-diol structure in the molecule, such as glucose.

[0002] Glucose is the energy source for almost all cells and is an important compound for maintaining biological activity. However, since glucose levels increase when there is an abnormality in the body, blood glucose levels can be used as an indicator to monitor the health of the body.

[0003] The most common method for measuring blood glucose levels involves pricking the fingertip with a special lancing device to collect blood, and then measuring the glucose concentration in the blood directly with a simple blood glucose meter. However, this method is invasive and places a heavy burden on the user.

[0004] Therefore, instead of directly measuring the glucose concentration in blood, there is a method to measure blood glucose levels indirectly and non-invasively by detecting changes in glucose concentration in bodily fluids that are different from blood and have a correlation with blood glucose levels, such as sweat, saliva, and tears.

[0005] Among these, tears contain various biochemical components that reflect the physiological state of the living body, and it has been reported that changes in their concentrations correlate with the state of blood. For example, it is known that the glucose concentration in tears is about one-tenth of the blood glucose level, and that changes in the glucose concentration in tears follow the blood glucose level with a delay of about five minutes.

[0006] By using a glucose sensor applicable to the eye that can detect changes in glucose concentration in tears, it becomes possible to measure blood glucose levels non-invasively without invasively sampling blood. For example, a glucose sensor applicable to the eye can detect changes in glucose concentration by utilizing changes in optical properties caused by a chemical reaction between glucose and components of a contact lens substrate.

[0007] As an example of a material applicable to such a method, boronic acids that can form cyclic boronate esters by reversible ester bonds with cis-diols such as glucose in aqueous solution have attracted attention as new glucose probes (see Figure 1). For example, it is known that an azo compound having a boronic acid at its terminal dissolved in aqueous solution undergoes an ester bond with glucose to form a cyclic boronate ester, resulting in a change in the absorption wavelength of the molecule, and that this change in absorption wavelength can be used to detect changes in glucose concentration (see, for example, Non-Patent Document 1).

[0008] Nicolas DiCesare et al., Organic Letters, 3(24):3891-3 (2001)

[0009] However, the boronic acid compound described in Non-Patent Document 1 does not have a polymerizable moiety and therefore cannot be used as a component of a contact lens, which is a polymer compound. Therefore, it is very difficult to manufacture a glucose sensor applicable to the eye using the boronic acid compound described in Non-Patent Document 1.

[0010] Meanwhile, the present inventors have created a novel polymerizable boronic acid compound and filed a patent application (see Japanese Patent Application No. 2024-069077). A polymeric compound that contains a polymerizable boronic acid compound as a constituent unit and can detect changes in glucose concentration with higher sensitivity is useful as a glucose sensor that can be applied to the eye.

[0011] Therefore, an object of the present invention is to provide a polymer compound that contains a polymerizable boronic acid compound as a constituent unit and that can detect changes in glucose concentration with high sensitivity.

[0012] In order to solve the above problems, the present inventors have conducted extensive research into how to make it possible to detect changes in glucose concentration with higher sensitivity using polymeric compounds containing polymerizable boronic acid compounds as constituent units.

[0013] As shown in Figure 1, boronic acid has an electrically neutral trigonal planar structure, -B(OH), in aqueous media.２ and anionic tetrahedral structure -B(OH) ３ When boronic acid in this state comes into contact with a compound having a cis-diol moiety, -B(OH) ２ and a cis-diol moiety form a cyclic ester, and a trigonal planar cyclic boronic acid ester, -B(OH) ３ The state changes to an acid dissociation equilibrium with a tetrahedral cyclic boronic acid ester in which the cis-diol moiety forms a cyclic ester (Figure 1, bottom panel).

[0014] The acid dissociation constant of boronic acid is approximately 9. Therefore, at physiological conditions, pH 7.4, the trigonal planar structure of boronic acid (-B(OH) ２ ) are predominantly present (upper left panel of Figure 1), and when they come into contact with the cis-diol moiety, they form a triangular planar boronic acid ester (lower left panel of Figure 1). Furthermore, the acid dissociation constant of cyclic boronic acid esters is approximately 7. Therefore, tetrahedral cyclic boronic acid esters are predominantly present (lower right panel of Figure 1).

[0015] According to the above, when glucose, which has a structure containing a cis-diol in its molecule, comes into contact with boronic acid under physiological conditions in the presence of body fluids such as tears, the boronic acid, which has a triangular planar structure, changes in structure to a cyclic boronate ester with a tetrahedral structure.

[0016] Because the structural change of the boronic acid molecule is reversible, the boronic acid molecule can change from a tetrahedral structure to a triangular planar structure again due to external influences. Furthermore, the color of the polymer compound containing the boronic acid molecule as a structural unit also changes in response to the structural change of the boronic acid molecule. Therefore, in order to accurately measure the presence or absence of glucose in a sample solution, it is desirable to stably maintain the tetrahedral structure of the boronic acid molecule in the polymer compound.

[0017] Therefore, the present inventors focused on the anionic nature of tetrahedral boronic acid molecules, and hypothesized that the tetrahedral structure might be maintained by maintaining the anionic state of the boronic acid molecules. They conducted repeated trial and error to find a method for maintaining this anionic state.

[0018] In the process, they came to the idea that by bringing a cationic compound into close proximity with an anionic tetrahedral boronic acid molecule, the anionic nature is maintained and the tetrahedral structure is stabilized. Based on this idea, they continued their intensive research and found that by disposing a compound having a cationic moiety in a polymer compound, the stability of the anionic tetrahedral boronic acid ester can be improved, and changes in glucose concentration can be detected as a clear change in color tone.

[0019] Based on the above findings, the present inventors have finally succeeded in creating a polymer compound that can solve the problems of the present invention. The present invention has been completed based on the findings and successful examples first obtained by the present inventors.

[0020] That is, the present invention provides the following aspects. [1] A polymer compound comprising a polymerizable boronic acid compound and a polymerizable compound having a cationic moiety as constituent units. [2] The polymer compound according to item [1], wherein the amount of the polymerizable boronic acid compound added externally is 0.01 mol % to 5 mol % relative to 100 mol % of the total amount of components constituting the polymer compound, and / or the content of the polymerizable compound having a cationic moiety is 5 mol % to 30 mol %. [3] The polymerizable boronic acid compound is represented by the following general formula (1): (In the formula, R １ ~R ７ [4] The polymer compound according to item [1] or [2], wherein at least one of the substituents having a polymerizable group is a substituent having a polymerizable group, and the remaining groups are each independently a substituent selected from the group consisting of a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, and an alkyl group. (In the formula, R ８ represents a hydrogen atom or a methyl group, R ９ represents an oxygen atom or an amino group, and the wavy line represents a bonding site with the compound of general formula (1). (In the formula, R １０represents a hydrogen atom or a methyl group, R １１ and R １２ are each independently an oxygen atom or an amino group, m is an integer of 1 to 3, n is an integer of 1 to 3, and the wavy line is a bonding site to the compound of general formula (1). [5] The polymer compound according to item [1] or [2], wherein the polymerizable compound having a cationic moiety is at least one polymerizable compound having a cationic moiety selected from the group consisting of 3-(methacrylamido)propyltrimethylammonium chloride, 3-(methacrylamido)propyldimethylbenzylammonium chloride, 2-(methacryloxy)ethyltrimethylammonium chloride, 2-(methacryloxy)ethyldimethylbenzylammonium chloride, 2-(methacryloxy)ethyltrimethylammonium methyl sulfate, 3-ethyl-1-vinylimidazolium bromide, 2-methacryloyloxyethyl phosphorylcholine, and 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate. [6] The polymer compound according to item [1] or [2], wherein the polymer compound is used to detect a compound having a cis-diol structure in the molecule. [7] The polymer compound according to item [6], wherein the compound having a cis-diol structure within the molecule is a compound selected from the group consisting of glucose, fructose, lactose, and dopamine. [8] The polymer compound according to item [1] or [2], further comprising a polymerizable compound having a hydrophilic moiety as a constituent unit. [9] The polymer compound according to item [8], wherein the polymer compound is a hydrogel.

[10] The polymer compound according to item [9], wherein the hydrogel has a water content of 25% or more.

[11] A method for detecting a compound having a cis-diol structure within the molecule, comprising the step of detecting a compound having a cis-diol structure within the molecule in a solution based on a change in color tone of the polymer compound according to item [1] before and after contacting the polymer compound with a solution.

[0021] According to the present invention, changes in glucose concentration in an aqueous medium such as tears can be clearly detected visually, and by applying the present invention to ophthalmic lenses, etc., changes in glucose concentration in tears can be easily and stably observed externally.

[0022] FIG. 1 is a schematic diagram showing the reaction mechanism between boronic acid and cis-diol. FIG. 2 is a diagram showing the UV-visible absorption spectrum and a photograph of the appearance of hydrogel 1 of Example 1 immersed in PBS ("0 M") or Glc ("1 M"), as described in the Examples below. The spectrum was normalized by peak absorbance. FIG. 3 is a diagram showing the UV-visible absorption spectrum and a photograph of the appearance of hydrogel 16 of Reference Example 1 immersed in PBS ("0 M") or Glc ("1 M"), as described in the Examples below. The spectrum was normalized by peak absorbance.

[0023] Each aspect of the present invention will be described in detail below, but the technical scope of the present invention is not limited to the details of these items, and the present invention can take various forms as long as it achieves its object.

[0024] Unless otherwise specified, each term in this specification is used in the meaning commonly used by a person skilled in the chemical industry and should not be construed as having an unduly limiting meaning. Furthermore, the speculations and theories made in this specification are based on the inventors' knowledge and experience to date, and therefore the present invention is not limited solely to such speculations and theories.

[0025] "Independent" substituents may all be the same or some or all may be different. "And / or" refers to any one of the listed related items, or any or all combinations of two or more. "Comprise" means that elements other than those explicitly stated as included can be added (synonymous with "comprise at least"), but also encompasses "consist" and "essentially consist." That is, "comprise" can mean including the explicitly stated elements and any one or more elements, consisting of the explicitly stated elements, or consisting essentially of the explicitly stated elements. Elements include limitations such as components, steps, conditions, and parameters. "Content" is synonymous with concentration and amount used (added amount). In this specification, it refers to the proportion of the amount of cationic monomer or copolymerizable monomer in the total amount of a polymerizable compound having a cationic moiety (cationic monomer) and a compound copolymerizable therewith (copolymerizable monomer). "Externally added amount" refers to an amount relative to a reference amount and is not included in the reference amount. For example, if the amount of externally added component B is 1 mol% relative to 100 mol% of component A, the total amount of components A and B is 101 mol%. When using commercially available products, the component content is preferably the amount of the component contained in the commercially available product, but it may also be the amount of the commercially available product itself. The "to" in a numerical range includes the numerical values ​​before and after it, and also includes ranges excluding one of the included limits. For example, "0% to 100%" may be 0% or more, 100% or less, or 0% or more, 100% or less. "About" means an amount within ±10% of the quantity following the term. For example, "about 100" means 100±10%, i.e., 90 to 110. The number of digits in an integer value matches the number of significant digits. For example, 1 has one significant digit, and 10 has two significant digits. Furthermore, for decimal values, the number of digits after the decimal point matches the number of significant digits. For example, 0.1 has one significant digit, and 0.10 has two significant digits.

[0026] One aspect of the present invention is a polymer compound comprising, as structural units, a polymerizable boronic acid compound and a polymerizable compound having a cationic moiety. The polymer compound of one aspect of the present invention can be used to detect compounds having a cis-diol structure in the molecule, such as glucose.

[0027] A polymeric compound is also called a polymer or a polymer. A polymer is formed by polymerizing a monomer compound (monomer), which is a polymerizable compound. The constituent units derived from each monomer in a polymer are also called moieties. A polymeric compound (polymer) according to one embodiment of the present invention has a constituent unit (polymerizable boronic acid compound moiety) derived from a polymerizable boronic acid compound (monomer) and a constituent unit (cationic monomer moiety) derived from a polymerizable compound (monomer) having a cationic moiety. In this specification, "comprising a polymerizable compound as a constituent unit" is synonymous with "comprising a moiety derived from a polymerizable compound (i.e., a moiety in which the monomer is copolymerized)."

[0028] The polymer compound of one embodiment of the present invention can be produced by subjecting a polymerizable boronic acid compound and a polymerizable compound having a cationic moiety to a copolymerization reaction.

[0029] (Polymerizable boronic acid compound) The polymerizable boronic acid compound has at least one —B(OH) group in the molecule. ２ The polymerizable boronic acid compound may be any compound having a polymerizable group and a boronic acid group. Examples of the polymerizable boronic acid compound include compounds represented by the following general formula (1):

[0030]

[0031] In general formula (1), R １ ~R ７ represents a substituent having at least one polymerizable group.

[0032] The polymerizable group is a group that can participate in a polymerization reaction, specifically, a group that can participate in a polymerization reaction by an active radical generated from a polymerization initiator, an acid, or the like. The polymerizable group may be any group having a double bond between two carbon atoms, and examples thereof include a vinyl group, an isopropenyl group, and a (meth)acryloyl group. Note that a (meth)acryloyl group is a general term for an acryloyl group and a methacryloyl group.

[0033] The substituent having a polymerizable group may be any as long as it has a polymerizable group. For example, in the substituent having a polymerizable group, the number of polymerizable groups contained therein may be one or two or more; the type of polymerizable group may be one or two or more; and the position of the polymerizable group may be the terminal end of the functional group or may be inside the functional group.

[0034] Preferred specific examples of the substituent having a polymerizable group are the substituents represented by general formula (2) and general formula (3).

[0035]

[0036]

[0037] In general formula (2), R ８ represents a hydrogen atom or a methyl group, and R ９ represents an oxygen atom or an amino group.

[0038] In general formula (3), R １０ represents a hydrogen atom or a methyl group, and R １１ and R １２ each independently represents an oxygen atom or an amino group. In general formula (3), m is an integer of 1, 2 or 3, and n is an integer of 1, 2 or 3.

[0039] In general formula (2) and general formula (3), the wavy line indicates the bonding site with the compound of general formula (1). Therefore, the substituents shown in general formula (2) and general formula (3) are bonded to R of the compound of general formula (1) at the wavy line portion. １ ~R ７ Concatenate with either

[0040] The polymerizable boronic acid compound represented by general formula (1) has a phenylboronic acid group at one end of the azo group, which is a chromophore, and a naphthalene ring at the other end. The bulky structure of the naphthalene ring suppresses rotational movement around the azo group, thereby reducing photoisomerization caused by ultraviolet light.

[0041] R in general formula (1) １ ~R ７ In the above, the number of substituents having a polymerizable group may be one or two or more, but it is preferable that the number of substituents having a polymerizable group is one so that the polymerizable groups in the polymerizable boronic acid compound do not polymerize with each other. １ ~R ７ are each independently a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, or an alkyl group. For example, in consideration of compatibility with hydrophilic monomers, R １ ~R ７ Preferably, at least one of the alkyl groups is a hydroxy group. The alkyl group is preferably a linear or branched alkyl group having 1 to 5 carbon atoms, and more preferably a linear alkyl group having 1 to 3 carbon atoms.

[0042] As an embodiment of the polymerizable boronic acid compound represented by the general formula (1), for example, in the general formula (1), R １ ~R ７ is a substituent having a polymerizable group, another is a hydroxy group, and the remaining all are hydrogen atoms, and further examples include polymerizable boronic acid compounds [I] to [V] represented by the following formulae, but are not limited to these.

[0043]

[0044]

[0045]

[0046]

[0047]

[0048] The polymerizable boronic acid compound may be used alone or in combination of two or more kinds.

[0049] (Method for Producing Polymerizable Boronic Acid Compound) The polymerizable boronic acid compound can be produced, for example, by the method described in the Examples below, or by a method in which the method is appropriately modified to obtain the desired polymerizable boronic acid compound.

[0050] Specific examples of methods for producing polymerizable boronic acid compounds include, but are not limited to, a method in which a naphthalene compound is reacted with a compound having a polymerizable group to obtain an intermediate that is a naphthalene compound having a substituent with a polymerizable group, and the obtained intermediate is then reacted with a dioxaborolane aniline compound to obtain a polymerizable boronic acid compound.

[0051] (Polymerizable Compound Having a Cationic Moiety) From the viewpoint of structural stability of the tetrahedral structure of the boronic acid ester in the molecule, the polymer compound of one embodiment of the present invention contains a polymerizable compound having a cationic moiety as a constituent unit.

[0052] The polymerizable compound having a cationic moiety may be any polymerizable compound having at least one cationic moiety and a polymerizable group in the molecule. The cationic moiety is a moiety having a positive (+) charge. The polymerizable compound having a cationic moiety may be a zwitterionic compound having a cationic moiety and an anionic moiety (a moiety having a negative (-) charge), in addition to a compound having only a cationic moiety as an ionic moiety, i.e., a zwitterionic polymerizable compound. However, it is preferable that the counter anion of the zwitterionic polymerizable compound does not interact with the boronic acid group.

[0053] Examples of polymerizable compounds having only one cationic moiety include 3-(methacrylamido)propyltrimethylammonium chloride (MAPTAC), 3-(methacrylamido)propyldimethylbenzylammonium chloride (MAPBAC), 2-(methacryloxy)ethyltrimethylammonium chloride (MOETAC), 2-(methacryloxy)ethyldimethylbenzylammonium chloride (MOEBAC), 2-(methacryloxy)ethyltrimethylammonium methyl sulfate (MOETAS), and 3-ethyl-1-vinylimidazolium bromide ([EVIm][Br]). Examples of zwitterionic polymerizable compounds having one anionic moiety and one anionic moiety include 2-methacryloyloxyethylphosphorylcholine and 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate. The polymerizable compounds having a cationic moiety may be used alone or in combination of two or more. The polymerizable compound having a cationic moiety may be one produced according to a conventional method or may be a commercially available compound.

[0054] (Polymer Compound) The polymer compound of one embodiment of the present invention can detect cis-diol compounds having a cis-diol structure in the molecule due to the polymerizable boronic acid compound moiety, which is a structural unit. When the polymer compound of one embodiment of the present invention comes into contact with the cis-diol compound, the boronic acid in the polymerizable boronic acid compound moiety forms a cyclic boronic acid ester, which changes the electronic state in the polymerizable boronic acid compound moiety and the color-developing state of the azo group, which is the chromophore in the polymerizable boronic acid compound moiety, also changes. As a result, the color-developing state of the polymer compound of one embodiment of the present invention, specifically, the color tone and / or absorption spectrum, changes. Therefore, the presence of cis-diol compounds in an environment can be detected by observing the color tone of the polymer compound of one embodiment of the present invention before and after placement in the environment and / or detecting a change in the absorption spectrum.

[0055] The cis-diol compound is not particularly limited as long as it has a cis-diol structure in the molecule, and examples thereof include glucose, fructose, lactose, dopamine, etc. Hereinafter, the present invention will be described assuming that the cis-diol compound is glucose.

[0056] The polymer compound of one embodiment of the present invention preferably contains, as a structural unit, a polymerizable boronic acid compound, a polymerizable compound having a cationic moiety (cationic monomer), and a compound copolymerizable with these (copolymerizable monomer). The polymer compound of one embodiment of the present invention can be produced by subjecting the polymerizable boronic acid compound, the polymerizable compound having a cationic moiety, and the copolymerizable monomer to a copolymerization reaction. The polymer compound obtained in this manner has, as structural units, a polymerizable boronic acid compound portion, a cationic monomer portion, and a copolymerizable monomer portion.

[0057] The polymer compound of one embodiment of the present invention has a polymerizable boronic acid compound moiety in an amount that is responsive to glucose, i.e., an amount that causes a change in color tone and / or absorption spectrum, preferably color tone, upon contact with glucose. From this perspective, the amount of externally added polymerizable boronic acid compound in the polymer compound of one embodiment of the present invention is, for example, preferably 0.01 mol% or more, more preferably 0.03 mol% or more, relative to 100 mol% of the total amount of the polymerizable compound having a cationic moiety and the copolymerizable monomer. From the viewpoint of good absorbance intensity of the polymer compound, it is even more preferably 0.05 mol% or more. The upper limit of the amount of externally added polymerizable boronic acid compound is not particularly limited, but is, for example, preferably 5 mol% or less, more preferably 3 mol% or less, and even more preferably 1 mol% or less.

[0058] When the polymer compound according to one embodiment of the present invention is used as an ophthalmic lens such as a contact lens, the polymer compound preferably has good luminous transmittance. In this case, the amount of the externally added polymerizable boronic acid compound may hinder light transmission through the polymer compound by absorbing visible light as a dye compound. Therefore, the amount of the externally added polymerizable boronic acid compound in this case is preferably 0.01 mol% to 5 mol%, more preferably 0.03 mol% to 3 mol%, or more preferably 0.05 mol% to 1 mol%.

[0059] The polymer compound of one embodiment of the present invention has a cationic monomer moiety in an amount that allows the tetrahedral structure of the boronic acid ester in the polymerizable boronic acid compound moiety to be stably maintained. From this viewpoint, the content of the polymerizable compound having a cationic moiety in the polymer compound of one embodiment of the present invention is, for example, preferably 5 mol % to 30 mol %, and more preferably 5 mol % to 25 mol %. A content of the polymerizable compound having a cationic moiety of 30 mol % or more is undesirable because it may cause strong adhesion to negatively charged solid surfaces in aqueous solution.

[0060] The polymer compound of one embodiment of the present invention is preferably a hydrogel in a water-containing state from the viewpoint of responsiveness to glucose.

[0061] A hydrogel is a polymer matrix that swells with and retains an aqueous liquid, such as water or a solution containing water. In this specification, the polymer itself, excluding the aqueous liquid, is referred to as the hydrogel substrate.

[0062] Hydrogels are based on polymerizable compounds having hydrophilic moieties, i.e., polymers containing hydrophilic monomers as structural units. Specific examples of hydrogels include hydrogels produced using hydrophilic monomers, hydrophilic and hydrophobic monomers, and hydrogels produced using hydrophilic monomers and copolymerizable monomers such as crosslinkable monomers.

[0063] When the polymer compound of one embodiment of the present invention is a hydrogel with a low water content, the amount of glucose that comes into contact with the polymer compound is reduced, which may result in poor responsiveness to glucose. Therefore, the water content of the polymer compound of one embodiment of the present invention is preferably such that responsiveness to glucose is observed, more preferably 10% to 90%, even more preferably 20% to 85%, and even more preferably 30% to 80% or 40% to 80%. The water content of the hydrogel is measured by the method described in the Examples below.

[0064] The polymer compound of one embodiment of the present invention has glucose responsiveness. The glucose responsiveness of the polymer compound of one embodiment of the present invention is preferably such that the glucose responsiveness (color tone) is evaluated as "○" and / or the glucose responsiveness (absorption spectrum) is evaluated as "○", more preferably such that the glucose responsiveness (color tone) is evaluated as "○", and even more preferably such that the glucose responsiveness (color tone) is evaluated as "○" and the glucose responsiveness (absorption spectrum) is evaluated as "○".

[0065] In order for the polymer compound of one embodiment of the present invention to be a hydrogel, it preferably contains a hydrophilic monomer as one of the copolymerizable monomers.

[0066] The hydrophilic monomer (polymerizable compound having a hydrophilic site) may be any polymerizable compound having at least one hydrophilic group and a polymerizable group in the molecule, and examples thereof include (meth)acrylic monomers such as N,N-dimethylacrylamide, hydroxymethyl(meth)acrylate, 2-hydroxyethyl(meth)acrylate, 2-hydroxypropyl(meth)acrylate, (meth)acrylic acid, 2,3-dihydroxypropyl(meth)acrylate, 2-polyethylene glycol mono(meth)acrylate, 2-polypropylene glycol (meth)acrylate, glycerol (meth)acrylate, N,N-dimethyl(meth)acrylamide, and N,N-diethyl(meth)acrylamide; and vinyl monomers such as N-vinylpyrrolidone, N-vinyl-N-methylacetamide, N-vinyl-N-ethylacetamide, N-vinyl-N-ethylformamide, and N-vinylformamide. Of these, 2-hydroxyethyl(meth)acrylate, 2-hydroxypropyl(meth)acrylate, and (meth)acrylic acid are preferred. The hydrophilic monomer may be used alone or in combination of two or more kinds.

[0067] The content of the hydrophilic monomer may be any amount that allows the polymer compound of one embodiment of the present invention to form a hydrogel through the hydrophilic monomer moiety, and is preferably, for example, 15 mol% or more. In order to ensure that the water content of the resulting hydrogel is at a level that is responsive to glucose, the content is more preferably 15 mol% to 99.9 mol%, even more preferably 20 mol% to 99.9 mol%, and even more preferably 50 mol% to 99.9 mol%, 70 mol% to 99.9 mol%, 80 mol% to 99.9 mol%, 90 mol% to 99.9 mol%, or 95 mol% to 99.9 mol%. If the content of the hydrophilic monomer is less than 15 mol%, the water content of the resulting hydrogel may be at a level that is not responsive to glucose, and further, the softness may be reduced, which may result in a reduced wearing comfort.

[0068] The polymer compound of one embodiment of the present invention may contain a crosslinkable monomer as one type of copolymerizable monomer in order to form a network structure in the molecule and to impart heat resistance and mechanical strength.

[0069] The crosslinkable monomer may be any polymerizable compound having two or more polymerizable groups in the molecule, for example, ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, pentaerythritol tri(meth)acrylate, and other (meth)acrylate-based crosslinkable monomers; allyl methacrylate, diallyl maleate, diallyl fumarate, diallyl succinate, diallyl phthalate, triallyl cyanurate, triallyl isocyanurate, diethylene glycol bisallyl carbonate, triallyl phosphate, triallyl trimellitate, diallyl ether, N,N-diallyl melamine, divinylbenzene, and other vinyl-based crosslinkable monomers, and among these, ethylene glycol di(meth)acrylate is preferred. The crosslinkable monomer may be used alone or in combination of two or more types depending on the desired physical properties.

[0070] The content of the crosslinking monomer may be appropriately set depending on the desired network structure formability, heat resistance, and mechanical strength, and is, for example, preferably 0.01 mol % to 5 mol %, more preferably 0.1 mol % to 5 mol %, and even more preferably 0.2 mol % to 1 mol %. If the content of the crosslinking monomer exceeds 5 mol %, the flexibility of the resulting hydrogel may decrease.

[0071] The polymer compound of one embodiment of the present invention can contain, as a constituent unit, a hydrophobic monomer, a silicon-containing monomer, or the like as a copolymerizable monomer in order to provide the polymer compound with desired physical properties such as oxygen permeability, mechanical strength, shape stability, flexibility, and optical properties.

[0072] The hydrophobic monomer may be a polymerizable compound that does not have a hydrophilic group in the molecule and has a polymerizable group, and examples thereof include (meth)acrylic monomers such as trifluoroethyl (meth)acrylate, siloxanyl (meth)acrylate, methyl (meth)acrylate, n-butyl (meth)acrylate, tert-butyl (meth)acrylate, benzyl (meth)acrylate, ethylhexyl (meth)acrylate, and lauryl (meth)acrylate. The hydrophobic monomer may be used alone or in combination of two or more types depending on the desired physical properties.

[0073] The silicon-containing monomer may be any polymerizable compound having a siloxane bond structure in the molecule and a polymerizable group, and examples thereof include α-mono(methacryloyloxymethyl)polydimethylsiloxane, α,ω-di(methacryloyloxymethyl)polydimethylsiloxane, α-mono(3-methacryloyloxypropyl)polydimethylsiloxane, α,ω-di(3-methacryloyloxypropyl)polydimethylsiloxane, α-mono(3-methacryloyloxybutyl)polydimethylsiloxane, α,ω-di(3-methacryloyloxybutyl)polydimethylsiloxane, and α-monovinylpolydimethylsiloxane. Examples of the silicon-containing monomer include methylsiloxane, α,ω-divinylpolydimethylsiloxane, 3-tris(trimethylsiloxy)silylmethyl(meth)acrylate, 3-tris(trimethylsiloxy)silylpropyl(meth)acrylate, 3-methylbis(trimethylsiloxy)silylmethyl(meth)acrylate, 3-methylbis(trimethylsiloxy)silylpropyl(meth)acrylate, 3-trimethylsiloxydimethylsilylmethyl(meth)acrylate, 3-trimethylsiloxydimethylsilylpropyl(meth)acrylate, and 3-methyldimethoxysilylpropyl(meth)acrylate. The silicon-containing monomer may be used alone or in combination of two or more, depending on the desired physical properties.

[0074] The contents of the hydrophobic monomer and silicon-containing monomer may be any amount that does not interfere with the solution of the problems of the present invention, and can be appropriately set, for example, so that the resulting polymer compound has desired physicochemical properties such as oxygen permeability and water content.

[0075] The polymer compound according to one embodiment of the present invention may contain, as a copolymerizable monomer, an anionic monomer such as 2-methacryloxyethylsuccinic acid (HO-MS) or (meth)acrylic acid, or a nonionic monomer such as N-[3-(dimethylamino)propyl]acrylamide (DMAPAA) as a constituent unit.

[0076] The polymer compound according to one embodiment of the present invention may contain, in addition to monomer components such as a polymerizable boronic acid compound, a polymerizable compound having a cationic moiety, and a copolymerizable monomer, additives or components such as a diluent, a stabilizer, a dye, a pigment, an antibacterial compound, and a release agent.

[0077] (Method for Producing Polymer Compound) The polymer compound of one embodiment of the present invention can be produced by combining steps known to those skilled in the art. For example, the polymer compound of one embodiment of the present invention can be produced by a method for obtaining a polymer from a monomer that has been known so far, or a method for obtaining a hydrogel from the obtained polymer.

[0078] A method for producing a polymer compound according to one embodiment of the present invention includes, for example, a method for obtaining a hydrogel, the method comprising the following steps (1) to (3): (1) a step of stirring and dissolving a mixture of monomer components, including the polymerizable boronic acid compound according to one embodiment of the present invention, a polymerizable compound having a cationic moiety, and a copolymerizable monomer, and a polymerization initiator, to obtain a monomer mixture; (2) a step of pouring the obtained monomer mixture into a desired mold and subjecting it to a copolymerization reaction to obtain a copolymer; and (3) a step of peeling the obtained copolymer from the mold that has been cooled after the copolymerization reaction, cutting and / or polishing as necessary, and then hydrating and swelling the copolymer to obtain a hydrogel.

[0079] In step (1) of obtaining the monomer mixture, a mixture of the monomer components and the polymerization initiator may be stirred and dissolved according to a conventional method. For example, the monomer mixture may be prepared by stirring and mixing the monomer components and the polymerization initiator using a stirring device, a stirrer, or the like. The monomer mixture may also contain other additives or components known in the art, as needed. Such additives or other components are, for example, as described in the above section (Polymer Compound).

[0080] The polymerization initiator may be appropriately selected depending on the properties of the monomers used, and examples thereof include peroxide-based polymerization initiators such as lauroyl peroxide, cumene hydroperoxide, and benzoyl peroxide, which are common radical polymerization initiators; and azo-based polymerization initiators such as azobisdimethylvaleronitrile and azobisisobutyronitrile (AIBN). As the polymerization initiator, one of these may be used alone, or two or more may be used in combination. The amount of polymerization initiator added may be an amount that can achieve a copolymerization reaction of the monomers.

[0081] In step (2) of obtaining the copolymer, the monomer mixture is placed in a mold consisting of a male and female mold made of metal, glass, plastic, or the like, and the mold is then sealed, and the mold containing the monomer mixture is then heated stepwise or continuously in a thermostatic bath or the like to a temperature in the range of 25°C to 120°C, and subjected to a copolymerization reaction for 5 to 120 hours. The copolymerization reaction may be carried out so as to induce radical polymerization, and may be a copolymerization reaction by heating, a copolymerization reaction using light such as ultraviolet light, electron beams, or gamma rays, or a copolymerization reaction in which a solvent such as water or an organic solvent is added to the monomer mixture and solution polymerization is carried out.

[0082] In step (3) of obtaining the hydrogel, the mold used in the copolymerization reaction is cooled to room temperature, the polymer is then peeled from the mold, and the resulting polymer is cut and / or polished as necessary, followed by hydration and swelling to form the hydrogel. Examples of the liquid (swelling liquid) used for hydration and swelling include water, physiological saline, isotonic buffer solution, alcohol, and combinations thereof. The hydration and swelling treatment is preferably carried out by immersing the copolymer in a swelling liquid heated to 60°C to 100°C for a certain period of time to bring the copolymer into a swollen state. Furthermore, in the hydration and swelling treatment, it is preferable to remove unpolymerized monomers contained in the polymer.

[0083] After hydration and swelling, the hydrogel can contain about 20% to about 70% by weight of the copolymer (polymer). That is, the hydrogel matrix accounts for about 20% to about 70% by weight of the hydrogel. The remainder of the hydrogel is typically formed from the liquid component (e.g., water) that hydrates the hydrogel matrix.

[0084] (Embodiments of Polymer Compounds) The polymer compound of one aspect of the present invention is in the form of a hydrogel, and is therefore responsive to glucose and usable as a hydrogel for glucose detection, even when the content of the polymerizable boronic acid compound is small, for example, even when the amount of the externally added polymerizable boronic acid compound is 1 mol % or less. As a result, the polymer compound of one aspect of the present invention can be largely composed of monomer components for use in a specific application.

[0085] The polymer compound of one embodiment of the present invention can be, for example, hydrophilic, flexible, transparent, and oxygen permeable. Because of these properties, the polymer compound of one embodiment of the present invention can be applied to, for example, ophthalmic lenses used on or inside the eye, and can be preferably used as contact lenses, intraocular lenses, etc. The contact lenses are hydrophilic lenses, and can be soft contact lenses or hard contact lenses (i.e., rigid gas permeable (RGP)).

[0086] When the polymer compound of one embodiment of the present invention is used as an ophthalmic lens, it preferably has a thickness of 50 μm to 150 μm.

[0087] When the polymer compound of one embodiment of the present invention is used as an ophthalmic lens, it is preferable that the polymer compound has high transparency. For example, the luminous transmittance measured by the method described in the Examples below is more preferably 60% or more, even more preferably 70% or more, and still more preferably 80% or more.

[0088] (Method of Using Polymer Compound) Another aspect of the present invention is a method for detecting cis-diol compounds such as glucose, fructose, lactose, and dopamine using the polymer compound of one embodiment of the present invention. The method of one embodiment of the present invention includes a step of detecting the cis-diol compound in a solution based on a change in color tone of the polymer compound of one embodiment of the present invention before and after contacting the polymer compound with the solution.

[0089] The change in color tone can be confirmed by visually observing the color of the polymer compound or by measuring the absorbance of the polymer compound. The change in absorbance can be confirmed by measuring the wavelength (λ ｍｉｎ ) after contact with the solution (A ｍｉｎ ) 、 and the wavelength at which the change in absorbance is greatest (λ ｍａｘ ) after contact with the solution (A ｍａｘ ) and the absorbance ratio (R = A ｍａｘ / A ｍｉｎ ) is compared with the absorbance ratio measured and calculated using a control solution containing no cis-diol compound instead of the solution, and based on the presence of a difference between the two, it can be determined that the cis-diol compound has been detected in the solution.

[0090] The present invention will be explained in more detail below with reference to examples. However, the present invention is not limited to these examples, and the present invention can take various forms as long as the object of the present invention can be achieved.

[0091] [1. Synthesis of polymerizable boronic acid compound [1]] 1-1. Overview According to the following scheme (I), polymerizable boronic acid compound [I] was synthesized from 2,6-dihydroxynaphthalene via intermediate [I].

[0092]

[0093] 1-2. Synthesis of Intermediate [I] A mixture of 2,6-dihydroxynaphthalene (3.34 g, 20.85 mmol), triethylamine (1.06 g, 10.43 mmol), and dehydrated dichloromethane (23 mL) was cooled to 0°C with stirring. To the cooled mixture, methacrylic acid chloride (0.73 g, 6.95 mmol) was added dropwise over 30 minutes, and the resulting mixture was stirred at room temperature for 18 hours to obtain a reaction solution. After stirring, the reaction solution was washed with purified water and saturated brine, and then dried over anhydrous magnesium sulfate. Solids were removed from the dried solution by filtration, and the resulting filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 0.66 g of Intermediate [I].

[0094] The NMR spectrum of the obtained intermediate [I] was as follows: １ H-NMR (500MHz, CD ３ OD) δ7.54 (d, 1H), 7.50 (d, 1H), 7.45 (s, 1H), 7.15 (d, 1H), 6.98 (d, 1H) 6.91 (s, 1H), 6.42 (s, 1H), 5.81 (s, 1H), 2.10 (s, 3H)

[0095] 1-3. Synthesis of Polymerizable Boronic Acid Compound [I] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.50 g, 2.28 mmol), concentrated hydrochloric acid (0.75 mL), and tetrahydrofuran (5 mL) was cooled to 0°C with stirring. To the cooled mixture, sodium nitrite (0.17 g, 2.39 mmol) dissolved in 7.5 mL of pure water was added dropwise in small portions, and the resulting mixture was stirred for 15 minutes. To the stirred mixture, intermediate [I] dissolved in 7.5 mL of tetrahydrofuran was added dropwise, and the resulting mixture was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with 20% aqueous sodium hydroxide solution (1 mL). Ethyl acetate was added to the neutralized reaction solution, and the solution was washed with pure water and saturated brine, followed by drying over anhydrous magnesium sulfate. The solid content was removed by filtration from the dried solution, and the resulting filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 0.20 g of polymerizable boronic acid compound [I].

[0096] The NMR spectrum of the resulting polymerizable boronic acid compound [I] was as follows: １ H-NMR (500MHz, DMSO-d6) δppm: 8.52 (d, 1H), 7.96 (d, 2H), 7.89 (d, 1H), 7.78 (d, 2H), 7.58 (d, 1H), 7.39 (d, 1H), 6.90 (d, 1H), 6.33 (s, 1H), 5.93 (s, 1H), 2.03 (s, 3H)

[0097] [2. Synthesis of polymerizable boronic acid compound [II]] 2-1. Overview According to the following scheme (II), polymerizable boronic acid compound [II] was synthesized from 5-amino-2-naphthol via intermediate [II].

[0098]

[0099] 2-2. Synthesis of Intermediate [II] 5-amino-2-naphthol (1.00 g, 6.28 mmol), methacrylic acid (0.59 g, 6.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.54 mmol), and 4-dimethylaminopyridine (0.92 g, 7.54 mmol) were dissolved in dehydrated dichloromethane (25 mL), and the resulting solution was stirred at room temperature for 18 hours to obtain a reaction solution. After stirring, the reaction solution was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, in that order, and then subjected to purification by column chromatography to obtain Intermediate [II] (0.61 g, 2.68 mmol).

[0100] The NMR spectrum of the obtained intermediate [II] was as follows: １ H-NMR (500MHz, CD ３ OD) 8.02 (d, 1H), 7.47 (d, 1H), 7.25 (t, 1H), 7.17 (t, 2H), 6.79 (d, 1H), 6.37 (s, 1H), 5.83 (s, 1H), 2.07 (s, 3H)

[0101] 2-3. Synthesis of Polymerizable Boronic Acid Compound [II] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.55 g, 2.50 mmol), concentrated hydrochloric acid (0.8 mL), and tetrahydrofuran (5.5 mL) was cooled to 0°C with stirring. After cooling, sodium nitrite (0.18 g, 2.63 mmol) dissolved in 0.8 mL of purified water was added dropwise to the cooled mixture, and the resulting mixture was stirred for 15 minutes. After stirring, intermediate [II] (0.61 g, 2.68 mmol) dissolved in 8.2 mL of tetrahydrofuran was added dropwise to the stirred mixture, and the resulting mixture was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with 20% aqueous sodium hydroxide solution. Ethyl acetate was added to the neutralized reaction solution, and the resulting solution was washed with pure water and saturated brine in this order, and then purified by column chromatography to obtain 0.30 g of polymerizable boronic acid compound [II].

[0102] The NMR spectrum of the resulting polymerizable boronic acid compound [II] was as follows:１ H-NMR (500MHz, DMSO-d6) δ8.57 (s, 1H), 8.29 (d, 1H), 8.15 (s, 2H), 7.93 (m, 3H), 7.82 ( d, 2H), 7.33 (d, 1H), 7.07 (s, 1H), 6.79 (d, 1H), 6.37 (s, 1H), 5.95 (s, 1H), 2.06 (s, 3H)

[0103] [3. Synthesis of polymerizable boronic acid compound [III]] 3-1. Overview According to the following scheme (III), a polymerizable boronic acid compound [III] was synthesized from 3-amino-2-naphthol via an intermediate [III].

[0104]

[0105] 3-2. Synthesis of Intermediate [III] 3-amino-2-naphthol (1.00 g, 6.28 mmol), methacrylic acid (0.59 g, 6.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.54 mmol), and 4-dimethylaminopyridine (0.92 g, 7.54 mmol) were dissolved in dehydrated dichloromethane (25 mL), and the resulting solution was stirred at room temperature for 18 hours to obtain a reaction solution. After stirring, the reaction solution was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, in that order, and then subjected to purification by column chromatography to obtain intermediate [III] (0.42 g, 1.84 mmol).

[0106] The NMR spectrum of the obtained intermediate [III] was as follows: １ H-NMR (500MHz, CD ３ OD) δ8.58 (s, 1H), 7.69 (d, 1H), 7.59 (d, 1H) 7.31 (t, 1H), 7.26 (t, 1H), 7.18 (s, 1H), 5.92 (s, 1H), 5.56 (s, 1H), 2.10 (s, 3H)

[0107] 3-3. Synthesis of Polymerizable Boronic Acid Compound [III] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.36 g, 1.64 mmol), concentrated hydrochloric acid (0.5 mL), and tetrahydrofuran (3.6 mL) was cooled to 0°C with stirring. To the cooled mixture, sodium nitrite (0.12 g, 1.72 mmol) dissolved in 0.5 mL of purified water was added dropwise in small portions, and the resulting mixture was stirred for 15 minutes. To the resulting solution, intermediate [III] (0.40 g, 1.76 mmol) dissolved in 5.4 mL of tetrahydrofuran was added dropwise, and the resulting solution was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with 20% aqueous sodium hydroxide solution. Ethyl acetate was added to the neutralized reaction solution, and the resulting solution was washed with pure water and saturated brine in this order, and then purified by column chromatography to obtain 0.03 g of polymerizable boronic acid compound [III].

[0108] The NMR spectrum of the resulting polymerizable boronic acid compound [III] was as follows: １ H-NMR (500MHz, DMSO-d6) δ8.97 (s, 1H), 8.55 (s, 1H), 8.28 (d, 1H), 8.14 (s, 2H), 7.92 (d, 2H) , 7.72 (d, 2H), 7.58 (d, 1H), 7.44 (t, 1H), 7.36 (t, 1H), 5.93 (s, 1H), 5.59 (s, 1H), 2.03 (s, 3H)

[0109] 4. Production of Hydrogels Containing Polymerizable Boronic Acid Compounds and Cationic Polymerizable Compounds Example 1 Hydrogel 1 According to Table 1, 0.05 mol % of polymerizable boronic acid compound [I], 10 mol % of 3-(methacrylamido)propyltrimethylammonium chloride (MAPTAC), 89.55 mol % of hydroxyethyl methacrylate (HEMA), 0.45 mol % of ethylene glycol dimethacrylate (EGDMA), and 0.25 mol % of AIBN were mixed with stirring at room temperature to prepare a monomer mixture.

[0110] The resulting monomer mixture was placed in a disk-shaped resin mold and subjected to a heating treatment in the range of 30°C to 105°C over approximately 10 hours to obtain a polymer. The resulting polymer was removed from the resin mold, which had been returned to room temperature, and then immersed in 70°C ethanol-containing phosphate-buffered saline (PBS) and then in PBS for 30 minutes, successively, to hydrate and swell, yielding a hydrogel. The resulting hydrogel, while immersed in PBS, was subjected to autoclaving to obtain Hydrogel 1 as a fixed-form device.

[0111] (Examples 2 to 3) Hydrogels 2 and 3 Hydrogels 2 and 3 were obtained in the same manner as in Example 1, except that polymerizable boronic acid compounds [II] and [III] were used instead of polymerizable boronic acid compound [I] according to Table 1.

[0112] (Examples 4 to 6) Hydrogels 4 to 6 According to Table 1, Hydrogels 4 to 6 were obtained in the same manner as in Examples 1 to 3, except that 20 mol % of MAPTAC and 79.55 mol % of HEMA were used instead of 10 mol % of MAPTAC and 89.55 mol % of HEMA.

[0113] (Examples 7 to 11) Hydrogels 7 to 11 According to Table 1, Hydrogels 7 to 11 were obtained by the same method as in Example 1, except that 3-(methacrylamido)propyldimethylbenzylammonium chloride (MAPBAC), 2-(methacryloxy)ethyltrimethylammonium chloride (MOETAC), 2-(methacryloxy)ethyldimethylbenzylammonium chloride (MOEBAC), 2-(methacryloxy)ethyltrimethylammonium methyl sulfate (MOETAS), and 3-ethyl-1-vinylimidazolium bromide ([EVIm][Br]) were used instead of MAPTAC.

[0114] (Example 12) Hydrogel 12 Hydrogel 12 was obtained in the same manner as in Example 11, except that 20 mol% of [EVIm][Br] and 79.55 mol% of HEMA were used instead of 10 mol% of [EVIm][Br] and 89.55 mol% of HEMA according to Table 1.

[0115] 5. Production of Hydrogels Containing Polymerizable Boronic Acid Compounds and Zwitterionic Polymerizable Compounds Examples 13 and 14 Hydrogels 13 and 14 According to Table 1, Hydrogels 13 to 14 were obtained in the same manner as in Example 1, except that 2-methacryloyloxyethyl phosphorylcholine (MPC) and 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate (CBMA) were used instead of MAPTAC.

[0116] 6. Production of Hydrogels Containing Polymerizable Boronic Acid Compounds, Cationic Polymerizable Compounds, and Anionic Polymerizable Compounds Example 15 Hydrogel 15 According to Table 1, Hydrogel 15 was obtained in the same manner as in Example 1, except that 10 mol % of MOEBAC, 10 mol % of 2-methacryloxyethyl succinic acid (HO-MS), and 79.55 mol % of HEMA were used instead of 10 mol % of MAPTAC and 89.55 mol % of HEMA.

[0117] [7. Production of Hydrogels Containing a Polymerizable Boronic Acid Compound and No Ionic Polymerizable Compound] (Reference Examples 1 to 3) Hydrogels 16 to 18 According to Table 1, Hydrogels 16 to 18 were obtained in the same manner as in Examples 1 to 3, except that 99.55 mol% HEMA was used instead of 10 mol% MAPTAC and 89.55 mol% HEMA.

[0118] [8. Production of Hydrogels Containing a Polymerizable Boronic Acid Compound and a Polymerizable Tertiary Ammonium Compound or an Anionic Polymerizable Compound] (Reference Examples 4 and 5) Hydrogels 19 and 20 According to Table 1, Hydrogels 19 to 20 were obtained in the same manner as in Example 1, except that N-[3-(dimethylamino)propyl]acrylamide (DMAPAA) and HO-MS were used instead of MAPTAC.

[0119] [9. Evaluation Method] (1) Water Content After wiping off excess water from the hydrogel, the weight of the hydrogel in the hydrated state (W １ After that, the hydrogel was dried in a dryer at 90°C for 16 hours, and the weight of the dried hydrogel (W ２ ) was measured. From the obtained measurements, the water content was calculated according to the following formula. Three hydrogels were used, and the average of the calculated values ​​was taken as the water content of the hydrogel. Water content (wt%) = [(W １ -W ２ ) / W １ ]×100

[0120] (2) Glucose responsiveness (color tone) The hydrogels were immersed in phosphate buffered saline (PBS) or glucose-containing phosphate buffered saline (Glc) containing 1 mol / L of glucose for 3 hours. The color tone (colorability) of the hydrogels after immersion was visually observed and evaluated according to the following criteria: ○: The difference in color tone between the two hydrogels is very clear ×: The difference in color tone between the two hydrogels is observed but is not clear

[0121] (3) Glucose responsiveness (absorption spectrum) The hydrogel was immersed in PBS or Glc for 3 hours. After wiping off excess water from the hydrogel, the absorption spectrum (wavelength range: 380 nm to 780 nm; interval: 1 nm) was measured using an ultraviolet-visible spectrophotometer ("V-750" manufactured by JASCO Corporation).

[0122] The measurement data after immersion in each saline solution was compared to determine the wavelength (λ) where the change in absorbance due to the presence or absence of glucose was smallest near the absorbance peak. ｍｉｎ ) and the wavelength at which the change in absorbance is greatest (λ ｍａｘ ) and two points were detected. ｍｉｎ and λ ｍａｘ The absorbance (A ｍｉｎ , A ｍａｘ ) to calculate the absorbance ratio R in phosphate buffered saline according to the following formula: ＰＢＳ , and the absorbance ratio R in glucose-containing phosphate buffered saline Ｇｌｃ The absorbance ratio R = A ｍａｘ / Aｍｉｎ

[0123] The obtained R ＰＢＳ and R Ｇｌｃ The significance of the difference was determined using a t-test (significance level 5%) and evaluated according to the following criteria: ○: significant difference ×: no significant difference

[0124] [10. Evaluation Results] The results of evaluating the water content and glucose responsiveness of the hydrogels of Examples 1 to 15 and Reference Examples 1 to 5 are shown in Table 1. Furthermore, for Hydrogel 1 of Example 1 and Hydrogel 16 of Reference Example 1, which are representative examples of the Examples and Reference Examples, the results of measuring the ultraviolet-visible absorption spectrum and photographs of the appearance are shown in Figures 2 and 3, respectively.

[0125] As shown in Table 1, the water contents of the hydrogels of Examples 1 to 15 were in the range of 43% to 79%. This demonstrates that hydrogels having the desired water contents can be obtained even when a polymerizable boronic acid compound is contained as a constituent unit.

[0126] As shown in Table 1 and Figure 2, the hydrogels of Examples 1 to 15 exhibited detectable changes in absorption spectra depending on the presence or absence of glucose, and the color change was also clearly observable visually. This indicates that the hydrogels obtained by incorporating a monomer having a cationic moiety as a constituent unit in addition to a polymerizable boronic acid compound possessed excellent glucose responsiveness.

[0127] On the other hand, as shown in Table 1 and FIG. 3, for the hydrogels of Reference Examples 1 to 5, which did not contain an ionic monomer as a constituent unit or which used a tertiary ammonium monomer or an anionic monomer instead of a cationic monomer, the change in spectrum depending on the presence of glucose in the aqueous solution could be measured, but the change in color tone observed visually was slight and not clear.

[0128] From the above results, it was found that the polymer compound containing a polymerizable boronic acid compound and a polymerizable cationic compound as constituent units was capable of detecting changes in glucose concentration with high sensitivity.

[0129]

[0130] The polymer compound of one embodiment of the present invention can be used as a monomer capable of detecting changes in glucose concentration by forming a cyclic boronic acid ester with glucose via a polymerizable boronic acid compound in the molecule, and can be used, for example, as an ophthalmic hydrogel such as a contact lens. Furthermore, since the polymer compound of one embodiment of the present invention can detect changes in glucose concentration in tears, it can also be used as a medical device for managing blood glucose levels, thereby contributing to the health and welfare of individual organisms. CROSS-REFERENCE TO RELATED APPLICATIONS

[0131] This application claims priority from Japanese Patent Application No. 2024-151087, filed September 3, 2024, the entire disclosure of which is incorporated herein by reference. Furthermore, the entire disclosures of all documents referenced in the detailed description of the invention of this application, including Non-Patent Document 1, are incorporated herein by reference.

Claims

1. A polymeric compound comprising, as constituent units, a polymerizable boronic acid compound and a polymerizable compound having a cationic moiety.

2. The polymer compound according to claim 1, wherein the amount of the externally added polymerizable boronic acid compound is 0.01 mol % to 5 mol % relative to 100 mol % of the total amount of components constituting the polymer compound, and / or the content of the polymerizable compound having a cationic moiety is 5 mol % to 30 mol %.

3. The polymerizable boronic acid compound is represented by the following general formula (1): (In the formula, R １ ~R ７ wherein at least one of the groups represents a substituent having a polymerizable group, and the remaining groups each independently represent a substituent selected from the group consisting of a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, and an alkyl group.

4. The substituent having a polymerizable group is represented by general formula (2): (In the formula, R ８ represents a hydrogen atom or a methyl group, R ９ represents an oxygen atom or an amino group, and the wavy line represents a bonding site with the compound of general formula (1). (In the formula, R １０ represents a hydrogen atom or a methyl group, R １１ and R １２ each independently represent an oxygen atom or an amino group, m is an integer of 1 to 3, n is an integer of 1 to 3, and the wavy line is a bonding site to the compound of general formula (1).

5. The polymer compound according to claim 1 or 2, wherein the polymerizable compound having a cationic moiety is at least one polymerizable compound having a cationic moiety selected from the group consisting of 3-(methacrylamido)propyltrimethylammonium chloride, 3-(methacrylamido)propyldimethylbenzylammonium chloride, 2-(methacryloxy)ethyltrimethylammonium chloride, 2-(methacryloxy)ethyldimethylbenzylammonium chloride, 2-(methacryloxy)ethyltrimethylammonium methyl sulfate, 3-ethyl-1-vinylimidazolium bromide, 2-methacryloyloxyethyl phosphorylcholine, and 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate.

6. The polymer compound according to claim 1 or 2, which is used to detect a compound having a cis-diol structure in the molecule.

7. The polymer compound according to claim 6, wherein the compound having a cis-diol structure in the molecule is a compound selected from the group consisting of glucose, fructose, lactose, and dopamine.

8. The polymer compound according to claim 1 or 2, further comprising a polymerizable compound having a hydrophilic moiety as a constituent unit.

9. The polymer compound according to claim 8, wherein the polymer compound is a hydrogel.

10. The polymer compound according to claim 9, wherein the hydrogel has a water content of 25% or more.

11. A method for detecting a compound having a cis-diol structure in its molecule, the method comprising the step of detecting a compound having a cis-diol structure in its molecule in a solution based on a change in color tone of the polymer compound according to claim 1 before and after contacting the polymer compound with the solution.

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