Hydrogel composition

Abstract

The present invention addresses the problem of providing a hydrogel composition having excellent strain resistance. A hydrogel composition according to the present invention comprises a polymer and water. The polymer includes: a first repeating unit derived from at least one specific crosslinking agent selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II); and a second repeating unit derived from a monofunctional polymerizable monomer. In the polymer, the contained amount of the first repeating unit is less than 1.0 mass% with respect to the contained amount of the second repeating unit.

Description

Hydrogel Composition

[0001] The present invention relates to hydrogel compositions.

[0002] Synovial joints, such as those in the knee, elbow, and hip, have a structure in which the joint cavity between the bones that make up the joint is filled with synovial fluid, which acts as a lubricant. The causes of arthritis in mammals, such as humans, horses, dogs, and cats, are diverse, with typical examples including a decrease in lubricant and a decrease in viscosity. When lubricant levels or viscosity decrease, bones or cartilage come into direct contact with each other, resulting in symptoms such as pain, inflammation, and impaired movement. Symptomatic treatments for arthritis include the administration of painkillers and anti-inflammatory agents, but these symptomatic treatments are only temporary, and longer-term effective treatment methods are needed. Specifically, such methods include intra-articular injection of a component that functions as a lubricant. A typical example is the injection of hyaluronic acid, but when low-molecular-weight components are used, they decompose within several months after injection. Under these circumstances, a lubricant that can be stably retained within the joint for a long period of time is desired for the treatment and / or prevention of arthritis.

[0003] As an example of a composition that is expected to be used as a lubricant as described above, Patent Document 1 discloses a gel composition for measuring radiation dosimetry, which contains a radical polymerizable monomer, a gelling agent, glycol, and glucose oxidase.

[0004] International Publication No. 2022 / 114081

[0005] The inventors have studied the above composition and found that further improvement in strain tolerance is necessary when the composition is used as an intra-articular lubricant. The term "strain tolerance" refers to maintaining the elastic properties of the gel over a range from low to high strain. More specifically, when the tan δ of the composition is measured using a rheometer, it is preferable that the tan δ be 0.70 or less over the entire strain range of 0.1 to 1000%.

[0006] Therefore, an object of the present invention is to provide a hydrogel composition that has excellent strain resistance.

[0007] As a result of extensive research into solving the above problems, the present inventors have found that the problems can be solved by the following configuration.

[0008] [1] A hydrogel composition comprising a polymer and water, wherein the polymer comprises a first repeating unit derived from at least one specific crosslinking agent selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II) described below, and a second repeating unit derived from a monofunctional polymerizable monomer, wherein the content of the first repeating unit relative to the content of the second repeating unit in the polymer is less than 1.0 mass%. [2] The hydrogel composition according to [1], wherein the specific crosslinking agent is a compound represented by formula (IV) described below. [3] The hydrogel composition according to [1] or [2], wherein the specific crosslinking agent is N-[tris(3-acrylamidopropoxymethyl)methyl]acrylamide. [4] The hydrogel composition according to any one of [1] to [3], wherein the monofunctional polymerizable monomer is selected from the group consisting of an acrylamide-based monomer and a methacrylamide-based monomer. [5] The hydrogel composition according to any one of [1] to [4], wherein the monofunctional polymerizable monomer is at least one selected from the group consisting of N,N-dimethylacrylamide and N,N-dimethylmethacrylamide. [6] The hydrogel composition according to any one of [1] to [5], which is used as an intra-articular lubricant. [7] The hydrogel composition according to any one of [1] to [6], which is used as an intra-articular lubricant for mammals. [8] The hydrogel composition according to any one of [1] to [7], which is used as an intra-articular lubricant for racehorses.

[0009] According to the present invention, a hydrogel composition having excellent strain resistance can be provided.

[0010] The present invention will be described in detail below. The following description of the components may be based on representative embodiments of the present invention, but the present invention is not limited to such embodiments.

[0011] In this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​written before and after "to" as the lower and upper limits. Furthermore, in this specification, when two or more types of a certain component are present, the "content" of that component means the total content of those two or more components. In this specification, in a numerical range described in stages, the upper or lower limit value described in a certain numerical range may be replaced with the upper or lower limit value of another numerical range described in stages. Furthermore, in a numerical range described in this specification, the upper or lower limit value described in a certain numerical range may be replaced with a value shown in the Examples. In this specification, a combination of two or more preferred embodiments is a more preferred embodiment.

[0012] In this specification, "(meth)acrylic" is a concept that encompasses both acrylic and methacrylic, "(meth)acryloyl" is a concept that encompasses both acryloyl and methacryloyl, "(meth)acrylate" is a concept that encompasses both acrylate and methacrylate, and "(meth)acrylamide" is a concept that encompasses both acrylamide and methacrylamide. In this specification, the bonding direction of a divalent group (e.g., -COO-) is not limited unless otherwise specified. For example, when Y is -COO- in a compound represented by the formula "X-Y-Z", the compound may be "X-O-CO-Z" or "X-CO-O-Z".

[0013] [Hydrogel Composition] The hydrogel composition of the present invention is described in detail below. The hydrogel composition of the present invention comprises a polymer and water, the polymer comprising a first repeating unit derived from at least one specific crosslinking agent selected from the group consisting of compounds represented by formula (1) and compounds represented by formula (2) described below, and a second repeating unit derived from a monofunctional polymerizable monomer, and the content of the first repeating unit relative to the content of the second repeating unit in the polymer is less than 1.0% by mass.

[0014] Although the reason why the hydrogel composition having the above-described configuration can solve the problems of the present invention is not entirely clear, the inventors speculate as follows. Note that the following speculation does not limit the mechanism by which the effect is obtained. In other words, even if the effect is obtained by a mechanism other than the one described below, it is still within the scope of the present invention. The polymer contained in the hydrogel composition of the present invention has crosslinking points derived from a specific trifunctional or higher (meth)acrylamide-based crosslinking agent and repeating units derived from a monofunctional polymerizable monomer in a predetermined ratio. It is speculated that the above structure appropriately adjusts the crosslinking density of the hydrogel and the flexibility between crosslinking points, resulting in excellent strain resistance.

[0015] [Polymer] The polymer contains a first repeating unit derived from a specific crosslinking agent described below and a second repeating unit derived from a monofunctional polymerizable monomer.

[0016] <First Repeating Unit> The first repeating unit is a repeating unit derived from at least one specific crosslinking agent selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II). The specific crosslinking agent is preferably a compound represented by formula (I) in that the effects of the present invention are more excellent.

[0017]

[0018] In formula (I), R １１ Each of R independently represents a hydrogen atom or a methyl group, and a hydrogen atom is preferred in that the effects of the present invention are more excellent. １１ may be the same or different, but all R １１ is preferably a hydrogen atom.

[0019] In formula (I), L １１ each independently represents -O-, an alkylene group having 2 to 4 carbon atoms, or a divalent linking group formed by combining these. The alkylene group having 2 to 4 carbon atoms is preferably linear or branched, and more preferably linear. １１The atom adjacent to the nitrogen atom in the amide group adjacent to the nitrogen atom is preferably a carbon atom. In other words, the group adjacent to the nitrogen atom in the amide group is preferably an alkylene group having 2 to 4 carbon atoms. Examples of the above-mentioned "divalent linking group formed by combining these" include, for example, -O-CH ２ CH ２ --, --O-CH ２ CH ２ CH ２ --, --O-CH ２ CH ２ CH ２ CH ２ --, --O-CH ２ CH (CH ３ ) CH ２ -, -CH ２ -O-CH ２ -, -CH ２ -O-CH ２ CH ２ -, -CH ２ -O-CH ２ CH ２ CH ２ - and -CH ２ CH ２ -O-CH ２ CH ２ alkylene groups having 2 to 4 carbon atoms containing —O—, such as —, and —(O-alkylene group having 2 to 4 carbon atoms). ｎ n represents an integer of 2 or more. There is no particular upper limit to n, but it is preferably 100 or less, more preferably 50 or less, and even more preferably 6 or less. L １１ As the alkylene group, an alkylene group having 2 to 4 carbon atoms containing —O— is preferred in terms of achieving better effects of the present invention.

[0020] The compound represented by formula (I) is preferably a compound represented by formula (IV).

[0021]

[0022] In formula (IV), R ４１ Each of R independently represents a hydrogen atom or a methyl group, and a hydrogen atom is preferred in that the effects of the present invention are more excellent. ４１ may be the same or different, but all R ４１is preferably a hydrogen atom.

[0023] In formula (IV), R ４２ each independently represents a linear or branched alkylene group having 2 to 4 carbon atoms. ４２ The oxygen atom and the nitrogen atom bonded to R are not bonded to the same carbon atom. ４２ As the alkyl group, a linear or branched alkylene group having 3 to 4 carbon atoms is preferred, and an n-propylene group is more preferred.

[0024] In formula (IV), R ４３ R each independently represents a single bond or an alkylene group having 1 to 4 carbon atoms. ４３ As the alkyl group, a linear or branched alkylene group having 1 to 4 carbon atoms is preferred, a linear alkylene group having 1 to 3 carbon atoms is more preferred, and a methylene group is even more preferred.

[0025] In formula (IV), k represents 2 or 3. ｋ H ２ｋ The O-group may be either linear or branched, with linear being preferred.

[0026] In formula (IV), x, y, and z each independently represent an integer of 0 to 6, preferably an integer of 0 to 5, more preferably an integer of 0 to 3, and still more preferably 0 or 1. x + y + z represents an integer of 0 to 18, preferably an integer of 0 to 15, more preferably an integer of 0 to 9, and still more preferably an integer of 0 to 3.

[0027] Specific examples of the compound represented by formula (I) are shown below.

[0028]

[0029] In formula (II), R ２１ Each of R independently represents a hydrogen atom or a methyl group, and a hydrogen atom is preferred in that the effects of the present invention are more excellent. ２１ may be the same or different, but all R ２１ is preferably a hydrogen atom.

[0030] In formula (II), R ２２ and R ２４R each independently represents -O-, an alkylene group having 1 to 4 carbon atoms, or a divalent linking group formed by combining these. ２２ or R ２４ The atom adjacent to the nitrogen atom in the amide group adjacent to the nitrogen atom is preferably a carbon atom. In other words, the group adjacent to the nitrogen atom in the amide group is preferably an alkylene group having 1 to 4 carbon atoms. Examples of the "divalent linking group formed by combining these" include -O-CH ２ --, --O-CH ２ CH ２ --, --O-CH ２ CH ２ CH ２ --, --O-CH ２ CH ２ CH ２ CH ２ --, --O-CH ２ CH (CH ３ ) CH ２ -, -CH ２ -O-CH ２ -, -CH ２ -O-CH ２ CH ２ -, -CH ２ -O-CH ２ CH ２ CH ２ - and -CH ２ CH ２ -O-CH ２ CH ２ alkylene groups having 1 to 4 carbon atoms containing —O—, such as —, and —(O-alkylene group having 1 to 4 carbon atoms). ｍ -. m represents an integer of 2 or more. There is no particular upper limit to m, but it is preferably 100 or less, more preferably 50 or less, and even more preferably 10 or less. R ２２ and R ２４ As the alkylene group, an alkylene group having 1 to 4 carbon atoms or an alkylene group having 1 to 4 carbon atoms containing —O— is preferred, and an alkylene group having 1 to 4 carbon atoms is more preferred, in terms of better effects of the present invention.

[0031] In formula (II), R ２３represents -O-, an alkylene group having 1 to 4 carbon atoms, a group represented by formula (III) described below, or a divalent linking group formed by combining these. Examples of the "divalent linking group formed by combining these" include, for example, R ２２ and R ２４ and a group obtained by combining a group represented by formula (III) with at least one group selected from -O- and an alkylene group having 1 to 4 carbon atoms. When a group represented by formula (III) is combined with another group, it is preferable that the group represented by formula (III) is adjacent to an alkylene group having 1 to 4 carbon atoms. ２３ Among these, alkylene groups having 1 to 4 carbon atoms, alkylene groups having 1 to 4 carbon atoms containing —O—, or groups represented by formula (III) are preferred.

[0032] In formula (II), L ２１ and L ２２ R each independently represents a single bond or a group represented by formula (III). ２３ is a group represented by formula (III), L ２１ and L ２２ is preferably a single bond.

[0033] In formula (II), R ２３ , L ２１ , and L ２２ At least one of L contains a group represented by formula (III). ２１ and L ２２ At least one of R is a group represented by formula (III), or ２３ is a group containing a group represented by formula (III). The group containing a group represented by formula (III) may be a group represented by formula (III), or may be a group in which a group represented by formula (III) is combined with at least one of -O- and an alkylene group having 1 to 4 carbon atoms. Among these, R ２３ is a group represented by formula (III), and L ２１ and L ２２ is a single bond, or R ２３ is an alkylene group having 1 to 4 carbon atoms or an alkylene group having 1 to 4 carbon atoms containing —O—, and L ２１ and L ２２is preferably a group represented by formula (III). In formula (II), the number of groups represented by formula (III) is 1 or more, preferably 1 to 3, and more preferably 1 or 2.

[0034] In formula (III), R ３１ represents a hydrogen atom or a methyl group, and is preferably a hydrogen atom in that the effects of the present invention are more excellent. In formula (III), * represents a bonding position.

[0035] Specific examples of the compound represented by formula (II) are shown below.

[0036]

[0037] Of these, the specific cross-linking agent is preferably N,N-bis(2-acrylamidoethyl)acrylamide, N,N-1,2-ethanediylbis{N-[2-(acryloylamino)ethyl]acrylamide}, or N-[tris(3-acrylamidopropoxymethyl)methyl]acrylamide, and more preferably N-[tris(3-acrylamidopropoxymethyl)methyl]acrylamide.

[0038] The specific crosslinking agent may be used alone or in combination of two or more. In other words, the polymer may contain only one type of first repeating unit, or may contain two or more types. The content of the first repeating unit is preferably less than 1.0 mass%, more preferably less than 0.7 mass%, based on the total repeating units of the polymer. Furthermore, the content of the first repeating unit is preferably 0.01 mass% or more, more preferably 0.1 mass% or more, and even more preferably 0.3 mass% or more, based on the total repeating units of the polymer.

[0039] <Second Repeating Unit> The second repeating unit is a repeating unit derived from a monofunctional polymerizable monomer. The monofunctional polymerizable monomer is a compound having one polymerizable group. The polymerizable group is preferably a radically polymerizable group. The radically polymerizable group is preferably a group having an ethylenically unsaturated double bond. Examples of the group having an ethylenically unsaturated double bond include a (meth)acryloyl group, a (meth)acrylamide group, a vinyl group, a styryl group, an allyl group, and a vinyl ether group. A (meth)acrylamide group, a (meth)acryloyl group, or a vinyl group is preferred, a (meth)acrylamide group is more preferred, and an acrylamide group is even more preferred.

[0040] The monofunctional polymerizable monomer is also preferably a water-soluble monomer.

[0041] Examples of monofunctional polymerizable monomers include (meth)acrylamide-based monomers, (meth)acrylate monomers, (meth)acrylic acid, and N-vinylpyrrolidone, with (meth)acrylamide-based monomers being preferred. The (meth)acrylamide-based monomer refers to a monomer having a (meth)acrylamide group, and the (meth)acrylate monomer refers to a monomer having a (meth)acryloyloxy group.

[0042] The (meth)acrylamide-based monomer includes a compound represented by formula (M1), and the (meth)acrylate monomer includes a compound represented by formula (M2).

[0043]

[0044] In formula (M1), R ｍ１ represents a hydrogen atom or a methyl group, and preferably a hydrogen atom. That is, the (meth)acrylamide-based monomer is preferably an acrylamide-based monomer.

[0045] In formula (M1), R ｍ２ and R ｍ３ R each independently represents a hydrogen atom or a substituent. ｍ２ and R ｍ３may be the same or different. Among them, from the viewpoint of safety, R ｍ１ When is a hydrogen atom, it is preferable that at least one of them is a substituent. In other words, it is preferable that the (meth)acrylamide-based monomer is a monomer different from acrylamide. Examples of the substituent include an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and an aryl group which may have a substituent. The alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 6, and even more preferably 1 to 3. The alkenyl group preferably has 2 to 10 carbon atoms, more preferably 2 to 6, and even more preferably 2 or 3. The aryl group is preferably a phenyl group. Examples of substituents that the alkyl group, alkenyl group, and aryl group may have include a hydroxy group, an alkyl group, a phenyl group, an alkoxy group having 1 to 6 carbon atoms, a carboxy group, and a nitrogen-atom-containing group. Examples of the nitrogen-atom-containing group include an amino group and a nitrogen-containing cyclic group. Examples of the nitrogen-containing cyclic group include nitrogen-containing aliphatic heterocyclic groups such as a morpholine cyclic group, a piperazine cyclic group, and a piperidine cyclic group, and nitrogen-containing aromatic heterocyclic groups such as a pyridine cyclic group.

[0046] R ｍ２ and R ｍ３ may be linked to each other to form a ring. The ring is a heterocycle containing a nitrogen atom, and is preferably a nitrogen-containing aliphatic heterocycle. The ring may have a heteroatom different from the nitrogen atom of the amide group specified in formula (M1). The heteroatom is preferably a nitrogen atom, an oxygen atom, or a sulfur atom, and more preferably an oxygen atom. The number of members of the ring is preferably 3 to 10, and more preferably 5 or 6.

[0047] Examples of (meth)acrylamide-based monomers include (meth)acrylamide, N-methyl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, 2-hydroxyethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide, N-butyl(meth)acrylamide, N-isopropyl(meth)acrylamide, N-propyl(meth)acrylamide, 4-(meth)acryloylmorpholine, and N-vinylacetamide.

[0048] In formula (M2), R ｍ４ represents a hydrogen atom or a methyl group.

[0049] In formula (M2), R ｍ５ represents a substituent. ｍ５ Examples of the substituent represented by the formula (M1) include an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and an aryl group which may have a substituent. Preferred embodiments of the alkyl group which may have a substituent, the alkenyl group which may have a substituent, and the aryl group which may have a substituent are those represented by the formula (M1) ｍ２ and R ｍ３ is the same as the group exemplified as the substituent represented by R ｍ５ The substituent represented by the formula (I) may be a group having a poly(oxyalkylene) structure. Examples of the group having a poly(oxyalkylene) structure include -(AL-O) ｌ -R Ｏ AL represents an alkylene group having 1 to 6 carbon atoms (preferably 2 or 3 carbon atoms), l represents an integer of 2 or more, and R Ｏ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

[0050] Examples of the (meth)acrylate monomer include hydroxy group-containing (meth)acrylates such as 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, and glycerin mono(meth)acrylate; nitrogen atom-containing (meth)acrylates such as dimethylaminoethyl (meth)acrylate and 2-morpholinoethyl (meth)acrylate; and (meth)acrylates having an ether bond such as methoxyethyl (meth)acrylate, methoxydipropylene glycol (meth)acrylate, methoxypolyethylene glycol (meth)acrylate, and phenoxyethyl (meth)acrylate.

[0051] The monofunctional polymerizable monomer may be a betaine monomer. A betaine monomer is a monomer that has a positive charge and a negative charge at positions that are not adjacent to each other in the same molecule, has no hydrogen atom bonded to the positively charged atom, and has no charge as a whole molecule. Examples of the betaine monomer include R ｍ２ and R ｍ３ a monomer in which the substituent represented by the formula (M2) is a group having a betaine structure, and ｍ５ The group having a betaine structure is specifically exemplified by a monomer in which the substituent represented by the formula: -R ｍ６ -N ＋ (R ｍ７ ) ２ -R ｍ８ A group represented by —X and —R ｍ９ -O-P(=O)O － -O-R ｍ１０ -N ＋ (CH ３ ) ３ Examples of the group include a group represented by the following formula: ｍ６ , R ｍ８ , R ｍ９ , and R ｍ１０ R each independently represents an alkylene group having 1 to 4 carbon atoms. ｍ７ each independently represents an alkyl group having 1 to 3 carbon atoms (preferably a methyl group); ３－ or -CO ２ － Examples of the betaine monomer include the betaine monomers described in paragraphs

[0029] to

[0054] of WO 2017 / 018146.

[0052] Of these, the monofunctional polymerizable monomer is preferably (meth)acrylic acid, (meth)acrylamide, hydroxyethyl (meth)acrylate, N,N-dimethyl (meth)acrylamide, N,N-diethyl (meth)acrylamide, 4-(meth)acryloylmorpholine, N-vinylpyrrolidone, or N-vinylacetamide, and more preferably N,N-dimethyl (meth)acrylamide.

[0053] The monofunctional polymerizable monomer may be used alone or in combination of two or more. In other words, the polymer may contain only one type of second repeating unit, or two or more types. The content of the second repeating unit is preferably 99.9% by mass or less, more preferably 99.7% by mass or less, based on the total repeating units of the polymer. The content of the second repeating unit is preferably 90.0% by mass or more, more preferably 99.0% by mass or more, and even more preferably 99.3% by mass or more, based on the total repeating units of the polymer. The content of the first repeating unit relative to the content of the second repeating unit is less than 1.0% by mass, and is preferably 0.7% by mass or less, from the viewpoint of more excellent effects of the present invention. The content of the first repeating unit relative to the content of the second repeating unit is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and even more preferably 0.2% by mass or more, from the viewpoint of more excellent strain resistance and injectability. The injectability mentioned above refers to the property of the hydrogel composition being easily inhaled and injected by injection, and when the hydrogel composition of the present invention is used as a joint lubricant, it is preferable that the hydrogel composition has excellent injectability in that it can be easily injected into a joint.

[0054] The polymer may contain repeating units other than the first repeating unit and the second repeating unit. It is also preferable that the polymer does not contain repeating units derived from a crosslinking agent other than the specific crosslinking agent. The total content of the first repeating unit and the second repeating unit in the polymer is preferably 90.0% by mass or more, more preferably 95.0% by mass or more, based on the total repeating units of the polymer. The upper limit is not particularly limited and may be 100% by mass.

[0055] [Water] The hydrogel composition contains water. The content of water is preferably 20 to 30 parts by mass, more preferably 22 to 26 parts by mass, per part by mass of the polymer. The degree of swelling of the hydrogel composition may reach equilibrium swelling.

[0056] [Other Components] The hydrogel composition may contain components other than the polymer and water, such as the polymerization initiator and its decomposition products, organic solvents, surfactants, water-soluble polymers, electrolytes, therapeutic agents (e.g., anti-inflammatory agents and antibiotics), and silver ions, which will be described later.

[0057] The organic solvent is preferably a water-miscible organic solvent, for example, an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran, or a ketone solvent such as acetone, and an alcohol solvent is preferred.

[0058] [Method for Producing Hydrogel Composition] The hydrogel composition can be produced by a known method, for example, a method including a polymerization step of mixing a specific crosslinking agent, a monofunctional polymerizable monomer, a polymerization initiator, and, if necessary, optional components in water to prepare a hydrogel-forming composition, and polymerizing the resulting composition to synthesize a polymer.

[0059] The concentration of the monomer in the polymerization step is preferably 1.0 to 10.0% by mass, more preferably 2.0 to 6.0% by mass, based on the total mass of the hydrogel-forming composition.

[0060] <Polymerization initiator> The polymerization initiator used for polymer synthesis may be either oil-soluble or water-soluble, but is preferably water-soluble. The polymerization initiator is preferably a radical polymerization initiator. Examples of the radical polymerization initiator include a thermal radical polymerization initiator and a photoradical polymerization initiator.

[0061] Examples of the thermal radical polymerization initiator include azo compounds such as 2,2'-azobisisobutyronitrile, 2,2'-azobis(2-methylbutyronitrile), 1,1'-azobis(cyclohexane-1-carbonitrile), 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile), dimethyl-2,2'-azobis(2-methylpropionate), and 2,2'-azobis(2-hydroxymethylpropionitrile); lauryl peroxidase; Examples of the peroxide include organic peroxides such as benzoyl peroxide, tert-butyl hydroperoxide, benzoyl peroxide, tert-butyl peroxybenzoate, cumene hydroperoxide, diisopropyl peroxydicarbonate, dipropyl peroxydicarbonate, tert-butyl peroxyneodecanoate, tert-butyl peroxypivalate, and (3,5,5-trimethylhexanoyl) peroxide; and inorganic peroxides such as persulfates such as potassium persulfate and ammonium persulfate, and hydrogen peroxide.

[0062] The thermal radical polymerization initiator is preferably a redox polymerization initiator, since polymerization proceeds at a relatively low temperature and decomposition of the monomer can be suppressed. The redox polymerization initiator is an initiator comprising a combination of an oxidizing agent and a reducing agent, and examples thereof include a combination of a persulfate and sodium metabisulfite or sodium bisulfite, a combination of a peroxide or a persulfate and an amine compound, a combination of an organic hydroperoxide and a transition metal, and a combination of cumene hydroperoxide and cobalt naphthate, with a combination of a peroxide or a persulfate and an amine compound being preferred.

[0063] Examples of the photoradical polymerization initiator include aromatic ketones, aromatic onium salt compounds, organic peroxides, hexaarylbiimidazole compounds, ketoxime ester compounds, azide compounds, metallocene compounds, and active ester compounds.

[0064] The concentration of the polymerization initiator is preferably 1 to 5 mass %, more preferably 2 to 3 mass %, based on the total mass of the monomers, where the total mass of the monomers refers to the total mass of all monomers used in the synthesis of the polymer (for example, the specific crosslinking agent and the monofunctional polymerizable monomer).

[0065] <Purification Step> The method for producing a hydrogel composition may include a purification step after the polymerization step to remove impurities from the hydrogel composition (e.g., unreacted monomers and decomposition products of the polymerization initiator, etc.). Examples of the purification method include dialysis and freeze-drying. Known methods can be used for the dialysis method, such as placing the hydrogel composition in a dialysis membrane and contacting it with a dialysis solution. Examples of the dialysis solution include water and organic solvents. Examples of the organic solvent include the organic solvent that may be contained in the hydrogel composition. The dialysis time is preferably 1 to 120 hours, more preferably 24 to 100 hours, and even more preferably 36 to 96 hours.

[0066] The method for producing a hydrogel composition may include a step of adding a predetermined additive after the purification step. Examples of the method for adding the additive include a method in which the solvent is removed as necessary and the resulting mixture is brought into contact with a solution containing the additive.

[0067] In the method for producing a hydrogel composition, it is preferable to carry out a sterilization treatment after the polymerization step (preferably after the purification step) from the viewpoint of safety when applied to a living body. As the sterilization method, a known method can be used, for example, autoclave sterilization, irradiation, ethylene oxide gas sterilization, and filtration sterilization.

[0068] [Properties of Hydrogel Composition] The storage modulus G' of the hydrogel composition at a temperature of 25°C, a frequency of 1 Hz, and a strain of 0.1% is preferably 10 to 1000 Pa, more preferably 10 to 300 Pa, and even more preferably 50 to 150 Pa, in terms of providing better effects of the present invention. The loss modulus G'' of the hydrogel composition at a temperature of 25°C, a frequency of 1 Hz, and a strain of 0.1% is preferably 1 to 50 Pa, and more preferably 3 to 30 Pa, in terms of providing better effects of the present invention. Furthermore, the storage modulus G' of the hydrogel composition at a temperature of 25°C, a frequency of 1 Hz, and a strain of 1000% is preferably 10 to 1000 Pa, more preferably 10 to 300 Pa, and even more preferably 30 to 150 Pa, in terms of providing better effects of the present invention. The loss modulus G" of the hydrogel composition at a temperature of 25°C, a frequency of 1 Hz, and a strain of 1000% is preferably 1 to 100 Pa, and more preferably 10 to 70 Pa, in terms of better effects of the present invention. The storage modulus G' and loss modulus G" can be calculated from the values ​​of the storage modulus G' and loss modulus G" at each strain obtained by performing strain dispersion measurement at a temperature of 25°C, a measurement frequency of 1 Hz, and a strain of 0.1 to 1000% using a rheometer (e.g., MCR302, manufactured by Anton Paar).

[0069] [Uses] The hydrogel composition of the present invention is preferably used as an intra-articular lubricant. The joint may be either a biological joint or an artificial joint (e.g., a robotic joint or an artificial joint). However, the hydrogel composition of the present invention is highly safe and therefore suitable for use in biological joints. Preferred joints are synovial joints such as hip, knee, shoulder, ankle, elbow, wrist, hoof, toe, finger, and intervertebral joints. Examples of biological joints include mammalian joints, such as those of humans, horses, camels, cats, and dogs. In particular, the hydrogel composition of the present invention is suitable for use in racehorse joints due to its excellent strain resistance.

[0070] When the hydrogel of the present invention is used as an intra-articular lubricant, the method of administration into the joint is not particularly limited, but injection is preferred for convenience.

[0071] The present invention will be described in more detail below with reference to the following examples. The materials, amounts used, ratios, treatment details, and treatment procedures shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the following examples.

[0072] [Preparation of Hydrogel Composition] The hydrogel composition of Example 1 was prepared according to the following procedure. 0.032 g of KPS (potassium peroxodisulfate) (Fujifilm Wako Pure Chemical Industries, Ltd.), 1.19 g of N,N-dimethylacrylamide (Fujifilm Wako Pure Chemical Industries, Ltd.), 0.006 g of N-[tris(3-acrylamidopropoxymethyl)methyl]acrylamide (Fujifilm Wako Pure Chemical Industries, Ltd.), and 28.76 g of distilled water were weighed out and placed in a vial. The mixture was stirred until no visible solid matter remained. 0.014 g of TEMED (N,N,N',N'-tetramethylethylenediamine) (Fujifilm Wako Pure Chemical Industries, Ltd.) was then added and dissolved by stirring. After dissolving, nitrogen was purged by bubbling with nitrogen for approximately 2 minutes, and the vial was capped and sealed. The mixture was then left to stand at room temperature (25°C) for at least 24 hours to obtain the hydrogel composition of Example 1.

[0073] Hydrogel compositions of Examples 2 to 4 and Comparative Examples 1 to 3 were prepared according to the above procedure, except that the amounts and types of each component were changed to obtain the compositions shown in the table below.

[0074] [Evaluation] [Strain Tolerance] The prepared hydrogel compositions were subjected to strain dispersion measurements at strains of 0.1 to 1000% using a rheometer (MCR302, manufactured by Anton Paar) under the following conditions: temperature: 25°C, frequency: 1 Hz, Nf = 1 N, and measurement plate: PP25. For 21 data points acquired using a logarithmic slope within the above strain range, the value of tan δ (loss modulus G" / storage modulus G') was calculated from the values ​​of storage modulus G' and loss modulus G" and strain tolerance was evaluated according to the following evaluation criteria. The lower the tan δ, the better the elasticity of the hydrogel composition is maintained and the better the strain tolerance, which is more preferable. In practice, a rating of B or higher for strain tolerance is preferred.

[0075] A: Tan δ is 0.50 or less over the entire range of strain from 0.1 to 1000%. B: Tan δ is 0.70 or less over the entire range of strain from 0.1 to 1000%, and there is strain in the range of strain from 0.1 to 1000% where tan δ exceeds 0.50. C: There is strain in the range of strain from 0.1 to 1000% where tan δ exceeds 0.70.

[0076] [Injectability] The prepared hydrogel compositions were subjected to strain dispersion measurements at strains of 0.1 to 1000% using a rheometer (MCR302, manufactured by Anton Paar) under the following conditions: temperature: 25°C, frequency: 1 Hz, Nf = 1 N, measurement plate: PP25. The injectability was evaluated from the complex viscosity value at a strain of 0.1% obtained by the above method according to the following evaluation criteria.

[0077] A: Complex viscosity at 0.1% strain is less than 20,000 mPa·s. B: Complex viscosity at 0.1% strain is 20,000 mPa·s or more and less than 40,000 mPa·s. C: Complex viscosity at 0.1% strain is 40,000 mPa·s or more.

[0078] [Results] Table 1 shows the composition, physical properties, and evaluation results of the hydrogel compositions. In the table, the numerical values ​​for each component represent the amount (unit: g) used in preparing the hydrogel composition. In the table, "G' (strain 0.1%)" and "G'' (strain 0.1%)" represent the storage modulus G' and loss modulus G'' values ​​measured by the method described above at a temperature of 25°C, a frequency of 1 Hz, and a strain of 0.1%, respectively. Complex viscosity (strain 0.1%) represents the complex viscosity value measured by the method described above at a temperature of 25°C, a frequency of 1 Hz, and a strain of 0.1%. In the table, the column (B) / (A) [mass %] represents the amount (unit: mass %) of specific crosslinking agent (B) used relative to the amount of monofunctional polymerizable monomer (A) used, and corresponds to the content (unit: mass %) of the first repeating unit relative to the second repeating unit.

[0079]

[0080] The results shown in the table above confirmed that the hydrogel composition of the present invention has excellent strain resistance. It was also confirmed that the hydrogel of the present invention has excellent injectability. A comparison of Examples 1 to 3 confirmed that when the specific crosslinking agent is a compound represented by formula (IV), strain resistance and injectability are superior. A comparison of Examples 1 and 4 confirmed that when the content of the first repeating unit relative to the content of the second repeating unit is 0.2% by mass or more, strain resistance is superior.

Claims

1. A hydrogel composition comprising a polymer and water, wherein the polymer comprises a first repeating unit derived from at least one specific crosslinking agent selected from the group consisting of compounds represented by formula (I) and compounds represented by formula (II), and a second repeating unit derived from a monofunctional polymerizable monomer, and the content of the first repeating unit relative to the content of the second repeating unit in the polymer is less than 1.0 mass%. In formula (I), R １１ each independently represents a hydrogen atom or a methyl group. １１ Each of R independently represents -O-, an alkylene group having 2 to 4 carbon atoms, or a divalent linking group formed by combining these. ２１ R each independently represents a hydrogen atom or a methyl group. ２２ and R ２４ R each independently represents -O-, an alkylene group having 1 to 4 carbon atoms, or a divalent linking group formed by combining these. ２３ represents -O-, an alkylene group having 1 to 4 carbon atoms, a group represented by formula (III), or a divalent linking group formed by combining these. ２１ and L ２２ each independently represents a single bond or a group represented by formula (III). ２３ , L ２１ , and L ２２ At least one of the formulas (III) contains a group represented by the formula (III). ３１ represents a hydrogen atom or a methyl group. * represents the bonding position.

2. The hydrogel composition according to claim 1, wherein the specific crosslinking agent is a compound represented by formula (IV). In formula (IV), R ４１ R each independently represents a hydrogen atom or a methyl group. ４２ each independently represents a linear or branched alkylene group having 2 to 4 carbon atoms. ４２ The oxygen atom and the nitrogen atom bonded to R are not bonded to the same carbon atom. ４３ each independently represents a single bond or an alkylene group having 1 to 4 carbon atoms. k represents 2 or 3. x, y, and z each independently represent an integer of 0 to 6.

3. The hydrogel composition of claim 1, wherein the specific crosslinking agent is N-[tris(3-acrylamidopropoxymethyl)methyl]acrylamide.

4. The hydrogel composition of claim 1, wherein the monofunctional polymerizable monomer is selected from the group consisting of acrylamide-based monomers and methacrylamide-based monomers.

5. The hydrogel composition according to claim 1, wherein the monofunctional polymerizable monomer is at least one selected from the group consisting of N,N-dimethylacrylamide and N,N-dimethylmethacrylamide.

6. The hydrogel composition according to any one of claims 1 to 5, which is used as an intra-articular lubricant.

7. The hydrogel composition according to any one of claims 1 to 5, which is used as an intra-articular lubricant in mammals.

8. The hydrogel composition according to any one of claims 1 to 5, which is used as an intra-articular lubricant for racehorses.

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