Biological adhesive composition and biological adhesive composition kit

Abstract

A biological adhesive composition contains: a blended composition that contains a compound (A) having a polymerizable unsaturated bond and a polymer (B); and a polymerization initiator composition (C) that contains an organic boron compound. The biological adhesive composition has a glass transition temperature of less than 80°C obtained from measurement results by the method described in a specific "measurement conditions." The glass transition temperature is preferably from 10°C to less than 80°C. The compound (A) is preferably one or both of a compound represented by general formula (A)-1 and a compound having an amide structure and at least one polymerizable double bond.

Description

Biomedical adhesive composition and biomedical adhesive composition kit

[0001] The present invention relates to a bioadhesive composition and a bioadhesive composition kit. This application claims priority under Japanese Patent Application No. 2024-170748, filed in Japan on September 30, 2024, the contents of which are incorporated herein by reference.

[0002] Surgical sutures, staples, surgical tapes, and skin adhesives are known methods for closing wounds caused by surgery or trauma. Among these, skin adhesives have the advantage of not requiring the removal of threads or needles compared to the use of sutures or staples, and they do not cause additional trauma.

[0003] For example, Patent Document 1 discloses a soft tissue adhesive, a wound dressing adhesive composition, or a wound dressing composition comprising a monomer, a polymer, and a specific polymerization initiator composition.

[0004] Patent No. 5855079

[0005] The technology disclosed in Patent Document 1 is excellent in that it has low toxicity and harmfulness and exhibits high adhesive strength, but there was room for improvement in terms of elongation that can follow the skin stretching associated with the patient's movements. The present invention has been made in view of the above circumstances and aims to provide a biocompatible adhesive composition that can follow the skin stretching well. Hereinafter, the property of being able to follow the skin stretching well will be referred to as "skin conformability".

[0006] In other words, the present invention includes the following embodiments: [1] A bioadhesive composition comprising a compound (A) having polymerizable unsaturated bonds, a compound composition (B) comprising a polymer, and a polymerization initiator composition (C) comprising an organoboron compound, wherein the bioadhesive composition has a glass transition temperature of less than 80°C, as obtained from the measurement results by the method described in [Measurement Conditions] below. [Measurement Conditions] The bioadhesive composition is applied to a release film and cured in room temperature air for 24 hours to form a thin film with a thickness of 100 μm. The formed film is peeled off the release film and cut into a 5 mm × 40 mm piece to be used as a test film. The dynamic viscoelasticity of the test film is measured in a nitrogen atmosphere at a frequency of 1 Hz, with a temperature ranging from -60°C to the measurable range, and a heating rate of 3°C / min. [2] The bioadhesive composition according to [1], wherein the glass transition temperature is 10°C or more and less than 80°C. [3] The bioadhesive composition for biological use according to [1] or [2], wherein compound (A) is either or both of the following: a compound represented by general formula (A)-1, and a compound having an amide structure and at least one polymerizable double bond. [In formula (A)-1, R １ R is a hydrogen atom or a methyl group, ２ [4] The polymer (B) is a polymer represented by general formula (B)-1, an acrylamide polymer, or a copolymer of a polymer represented by general formula (B)-1 and an acrylamide polymer, according to any one of [1] to [3]. [In general formula (B)-1, R １ R is a hydrogen atom or a methyl group, ３[1] to [4] is a linear, branched, or cyclic hydrocarbon group having 2 to 20 carbon atoms, which may have substituents. n is an integer of 2 or more. [5] When the total amount of compound (A) and polymer (B) is 100 parts by mass, the content of compound (A) relative to the total amount is 60 parts by mass or more and 90 parts by mass or less, and the content of polymer (B) relative to the total amount is 10 parts by mass or more and 40 parts by mass or less, the bio-adhesive composition according to any one of [1] to [4]. [6] When the total amount of compound (A) and polymer (B) is 100 parts by mass, the content of polymerization initiator composition (C) relative to the total amount is 0.9 parts by mass or more and 11 parts by mass or less, the bio-adhesive composition according to any one of [1] to [5]. [7] The storage modulus at 40°C obtained from the measurement results by the method described in [Measurement Conditions] is 1.0 × 10 ４ Pa or more 9.0×10 ８ A bioadhesive composition according to any one of [1] to [6], wherein the pressure is Pa or less. [8] A medical adhesive composition, a medical dressing composition, a skin adhesive composition, a wound dressing composition, a wound dressing adhesive composition, or a skin dressing composition comprising the bioadhesive composition according to any one of [1] to [7]. [9] A bioadhesive composition comprising a compound (A1) having polymerizable unsaturated bonds, a polymer (B) and a polymerization initiator composition (C) containing an organoboron compound, wherein the compound (A1) has an amide structure and contains a compound having at least one polymerizable double bond.

[10] A bioadhesive composition kit comprising a compound (A1) having polymerizable unsaturated bonds, a polymer (B) and a polymerization initiator composition (C) containing an organoboron compound, wherein the compound (A1) has an amide structure and contains a compound having at least one polymerizable double bond.

[0007] According to the present invention, it is possible to provide a biocompatible adhesive composition that can follow skin stretching well.

[0008] Embodiments of the present invention will be described below. In this specification, when a numerical range is described as, for example, "1 to 10", unless otherwise specified, it means a range of "1 or more and 10 or less", and includes a lower limit of 1 and an upper limit of 10.

[0009] <Bioadhesive Composition for Biomedical Use> The bioadhesive composition of this embodiment comprises a compound (A) having polymerizable unsaturated bonds, a polymer (B), and a polymerization initiator composition (C) containing an organoboron compound. Each component will be described later.

[0010] The inventors of the present invention have diligently investigated the composition and physical properties of a biocompatible adhesive composition for use as a medical adhesive, with the aim of improving skin conformability without damaging the surrounding healthy skin covered by the adhesive. As a result, they found that skin conformability improves when the glass transition temperature (Tg) of a predetermined test film is below 80°C.

[0011] The biocompatible adhesive composition of this embodiment has a glass transition temperature of less than 80°C, as determined by dynamic viscoelasticity measurement using the method described in [Measurement Conditions] below.

[0012] [Measurement Conditions] The bio-adhesive composition is applied to a release film and cured in room temperature air for 24 hours to form a thin film with a thickness of 100 μm. The formed film is peeled off the release film and cut into 5 mm x 40 mm pieces to be used as the test film. The dynamic viscoelasticity of the test film is measured at a frequency of 1 Hz, with the temperature ranging from -60°C to the measurable range, at a heating rate of 3°C / min, under a nitrogen atmosphere.

[0013] In this invention, the glass transition temperature is the temperature at which tanδ, the ratio of the storage modulus to the loss modulus obtained by dynamic viscoelasticity measurement, is maximized.

[0014] The glass transition temperature measured by the above method is less than 80°C, preferably 10°C or more and less than 80°C, and more preferably 15 to 75°C. When the glass transition temperature is less than the above upper limit value, a bioadhesive composition with high skin followability can be obtained, and the wound can be closed without damaging the healthy skin around the coated area. Also, when the glass transition temperature is not less than the above lower limit value, it is more preferable because the coated area is less sticky.

[0015] As the storage elastic modulus satisfying the above-described glass transition temperature, when the dynamic viscoelasticity measurement is performed on the bioadhesive composition of the present embodiment according to the method described in the [measurement conditions], the storage elastic modulus at 40°C is 1.0×10 ４ ~9.0×10 ８ Pa is preferable, 1.0×10 ５ ~9.0×10 ８ Pa is more preferable, and 1.0×10 ６ ~9.0×10 ８ Pa is even more preferable.

[0016] Hereinafter, each component constituting the bioadhesive composition of the present embodiment will be described.

[0017] <<Formulation composition>> The formulation composition contains a compound (A) having a polymerizable unsaturated bond and a polymer (B). When the glass transition temperature of the formulation composition is less than 80°C, the glass transition temperature of the bioadhesive composition will also be less than 80°C. The compound (A) and the polymer (B) may be used alone or in combination. In this case, the glass transition temperature of the formulation composition can be calculated using the FOX equation.

[0018] The FOX equation is a general equation for estimating the Tg of a copolymer of a multi-component system. When the Tg of homopolymers 1, 2,..., n are Tg1, Tg2,..., Tgn and the weight ratios are C1, C2,..., Cn, respectively, the glass transition temperature is represented by the following equation (the unit is Kelvin K). 1 / Tg = C1 / Tg1 + C2 / Tg2 +... + Cn / Tgn

[0019] - Compound (A) The compound (A) used in the composition may have at least one polymerizable unsaturated bond in the molecular chain that reacts with the radical active species generated from the polymerization initiator composition (C) described below in the molecular chain.

[0020] From the viewpoint that the stimulation to the human body is relatively low, acrylate monomers and methacrylate monomers are preferable for the compound (A), and among them, methacrylate monomers are more preferable. Hereinafter, acrylate monomers and methacrylate monomers may be collectively referred to as (meth)acrylate monomers.

[0021] The compound (A) is preferably a compound represented by the following general formula (A)-1.

[0022]

[0023] In formula (A)-1, R １ is a hydrogen atom or a methyl group. In formula (A)-1, R ２ is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, which may have a substituent.

[0024] R ２ is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a cyclopentyl group, a cyclohexyl group. R ２ is preferably an alkyl group having 4 to 10 carbon atoms, and more preferably an alkyl group having 4 to 8 carbon atoms.

[0025] R ２ Examples of the substituent that R

[0026] may have include a hydroxy group, a carboxy group, an amino group, an amide group, a sulfo group, an ether group, and a halogen atom.

[0027]

[0028] In formula (A)-1-1, R １ is a hydrogen atom or a methyl group, and R ２０This is a linear, branched, or cyclic alkyl group having 4 to 8 carbon atoms, which may have substituents.

[0029] Furthermore, compound (A) preferably contains a compound having an amide structure and at least one polymerizable double bond. Examples of compounds having an amide structure and at least one polymerizable double bond include 2-(2-oxopyrrolidine-1-yl)ethyl acrylate and 2-(2-oxopyrrolidine-1-yl)ethyl methacrylate. Other preferred compounds include, for example, (meth)acrylamide monomers, and N-alkyl group-containing (meth)acrylamide monomers, N-hydroxyalkyl group-containing (meth)acrylamide monomers, N-aminoalkyl group-containing (meth)acrylamide monomers, N-alkoxy group-containing (meth)acrylamide monomers, N-mercaptoalkyl group-containing (meth)acrylamide monomers, and heterocyclic-containing (meth)acrylamide monomers.

[0030] Examples of N-alkyl group-containing (meth)acrylamide monomers include N-methyl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide, N-isopropyl(meth)acrylamide, N-butyl(meth)acrylamide, and N-hexyl(meth)acrylamide.

[0031] Examples of N-hydroxyalkyl group-containing (meth)acrylamide monomers include N-methylol(meth)acrylamide, N-hydroxyethyl(meth)acrylamide, and N-methylol-N-propane(meth)acrylamide.

[0032] Examples of N-aminoalkyl group-containing (meth)acrylamide monomers include aminomethyl (meth)acrylamide and aminoethyl (meth)acrylamide.

[0033] Examples of N-alkoxy group-containing (meth)acrylamide monomers include N-methoxymethyl(meth)acrylamide and N-ethoxymethyl(meth)acrylamide.

[0034] Examples of N-mercaptoalkyl group-containing (meth)acrylamide monomers include mercaptomethyl(meth)acrylamide and mercaptoethyl(meth)acrylamide.

[0035] Examples of heterocyclic (meth)acrylamide monomers such as N-acryloylpyrrolidine include 4-acryloylmorpholine, N-acryloylpiperidine, and N-methacryloylpiperidine.

[0036] Compound (A) is preferable because it contains a (meth)acrylamide monomer, which improves wound closure. Among these, N,N-diethyl(meth)acrylamide, N-isopropyl(meth)acrylamide, or 4-acryloylmorpholine are preferred, and 4-acryloylmorpholine is even more preferred.

[0037] In this embodiment, compound (A) is preferably of the following forms: • Consists of the compound represented by the general formula (A)-1 above. • Consists of the compound represented by the general formula (A)-1-1 above. • Includes a compound having at least one polymerizable double bond having an amide structure. • Includes the compound represented by the general formula (A)-1 above and a (meth)acrylamide monomer. • Includes the compound represented by the general formula (A)-1-1 above and a (meth)acrylamide monomer.

[0038] • Polymer (B) Polymer (B) is a component that acts as a thickening agent, and (meth)acrylic polymers, (meth)acrylamide polymers, or copolymers thereof are preferred. Polymer (B) acts as a thickening agent and can adjust the viscosity of the biocompatible adhesive composition before it hardens to form a biocompatible adhesive layer. Furthermore, by using already polymerized polymer (B) as a thickening agent, the hardening shrinkage of the biocompatible adhesive layer formed using the biocompatible adhesive composition can be suppressed.

[0039] When polymer (B) is a (meth)acrylic polymer, polymer (B) is preferably a polymer represented by the following general formula (B)-1.

[0040]

[0041] In general formula (B)-1, R １is a hydrogen atom or a methyl group. In general formula (B)-1, n is an integer of 2 or more. In general formula (B)-1, R ３ R is a linear, branched, or cyclic hydrocarbon group having 2 to 20 carbon atoms, which may have substituents. ３ For example, this may be a linear or branched alkyl group having 2 to 10 carbon atoms. ３ Examples include ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, 2-ethylhexyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, etc.

[0042] In general formula (B)-1, R ３ The substituents that may be present include hydroxyl groups, carboxyl groups, amino groups, amide groups, sulfo groups, ether groups, and halogen atoms.

[0043] R ３ R may be, for example, a monocyclic alicyclic hydrocarbon group, such as a cycloalkyl group like a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, methylcyclohexyl group, dimethylcyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, or cyclodecyl group. ３ This group may be, for example, a polycyclic alicyclic hydrocarbon group, such as a decahydronaphthyl group, an adamantyl group, a 2-alkyladamantan-2-yl group, a 1-(adamantan-1-yl)alkane-1-yl group, a norbornyl group, a methylnorbornyl group, or an isobornyl group.

[0044] When polymer (B) is a (meth)acrylamide polymer, polymer (B) is preferably a polymer represented by the following general formula (B)-2.

[0045]

[0046] In general formula (B)-2, R １ is a hydrogen atom or a methyl group. In general formula (B)-2, n is an integer of 2 or more. In general formula (B)-2, R ４ , R５ Each of these is independently a linear, branched, or cyclic hydrocarbon group having 1 to 20 carbon atoms, which may have a hydrogen atom or a substituent.

[0047] R ４ , R ５ If it is a hydrocarbon group, for example, it may be a linear or branched alkyl group having 1 to 10 carbon atoms. ４ , R ５ When the group is a hydrocarbon group, examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, 2-ethylhexyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, etc.

[0048] R ４ , R ５ When R is a hydrocarbon group, it may be a monocyclic or alicyclic hydrocarbon group, for example, a cycloalkyl group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, methylcyclohexyl group, dimethylcyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, or cyclodecyl group. ４ , R ５ When is a hydrocarbon group, it may be a polycyclic or alicyclic hydrocarbon group, such as a decahydronaphthyl group, adamantyl group, 2-alkyladamantan-2-yl group, 1-(adamantan-1-yl)alkane-1-yl group, norbornyl group, methylnorbornyl group, isobornyl group, etc.

[0049] In general formula (B)-2, R ４ , R ５ The substituents that may be present include hydroxyl groups, carboxyl groups, amino groups, amide groups, sulfo groups, ether groups, and halogen atoms.

[0050] The weight-average molecular weight of polymer (B) is preferably 10,000 to 1,000,000, and more preferably 10,000 to 1,000,000.

[0051] When the total amount of compound (A) and polymer (B) is 100 parts by mass, the content of compound (A) relative to the total amount is preferably 60 to 90 parts by mass, and the content of polymer (B) relative to the total amount is preferably 10 to 40 parts by mass.

[0052] The compound may contain a crosslinking agent. As the crosslinking agent, a compound having two or more polymerizable functional groups can be used. For example, polymethylene glycol diacrylate or polymethylene glycol dimethacrylate can be used. Examples of polymethylene glycol diacrylate include nonamethylene glycol diacrylate, tridecamethylene glycol diacrylate, tetradecamethylene glycol diacrylate, tricosamethylene glycol diacrylate, etc. Examples of polymethylene glycol dimethacrylate include nonamethylene glycol dimethacrylate, tridecamethylene glycol dimethacrylate, tetradecamethylene glycol dimethacrylate, tricosamethylene glycol dimethacrylate, etc.

[0053] When the compound composition contains a crosslinking agent, the amount of the crosslinking agent relative to the total amount of the compound composition is preferably 1 to 5 parts by mass, and more preferably 2 to 4 parts by mass, when the total amount of the compound composition is 100 parts by mass.

[0054] If it is necessary to adjust the viscosity of the formulation, any non-reactive organic solvent may be added to the formulation. Suitable non-reactive organic solvents are, for example, organic solvents that are volatile at room temperature (e.g., 20°C to 25°C) and atmospheric pressure. In this specification, with respect to a non-reactive organic solvent, "volatile" means that it can evaporate rapidly at normal temperatures and pressures.

[0055] Examples of nonreactive organic solvents include various volatile nonpolar solvents, polar solvents, aprotic solvents, solvents containing organosilicon compounds, and mixtures thereof. Examples of volatile nonpolar solvents include volatile linear alkanes, volatile branched alkanes, or volatile cyclic alkanes. More specifically, examples include, but are not limited to, propane, isobutane, (e.g., under pressure) liquid butane, pentane, hexane, heptane, octane, petroleum distillates, cyclohexane, and isooctane.

[0056] Examples of volatile polar solvents include, but are not limited to, ethanol and isopropanol. Examples of volatile aprotic solvents include, but are not limited to, volatile acetates, volatile ketones, and volatile ethers. Examples of volatile acetates include methyl acetate, ethyl acetate, or propylene glycol diacetate. Examples of volatile ketones include acetone or methyl ethyl ketone. Examples of volatile ethers include diethyl ether, ethyl propyl ether, dipropyl ether, or dipropylene glycol dimethyl ether.

[0057] Examples of volatile organosilicon compounds include, but are not limited to, tetramethylsilane and hexamethyldisiloxane. Furthermore, volatile gases such as carbon dioxide can also be used as the non-reactive organic solvent.

[0058] One embodiment of the formulation may optionally contain water.

[0059] • Polymerization initiator composition (C) The polymerization initiator composition (C) contained in the bio-adhesive composition of this embodiment contains an organoboron compound (c1) as an essential component. The polymerization initiator composition (C) may optionally contain an aprotic solvent (c2) or an alcohol (c3).

[0060] The bioadhesive composition of this embodiment, which includes polymerization initiator composition (C), leaves less residue of compound (A) when applied to a wound and the entire composition hardens, compared to compositions using peroxide as a polymerization initiator. Therefore, the bioadhesive composition of this embodiment, which includes polymerization initiator composition (C), is suitable for use on living organisms.

[0061] As the organoboron compound (c1), trialkylboron, alkoxyalkylboron, dialkylborane, and partially oxidized trialkylboron, as well as compounds that form complexes with amine compounds or other coordinating compounds can be used.

[0062] Examples of trialkylborons include triethylboron, tripropylboron, triisopropylboron, tributylboron, tri-sec-butylboron, triisobutylboron, tripentylboron, trihexylboron, triheptylboron, trioctylboron, tricyclopentylboron, and tricyclohexylboron, which are trialkylborons having an alkyl group with 2 to 8 carbon atoms. The alkyl group may be a linear alkyl group, a branched alkyl group, or a cycloalkyl group, and the three alkyl groups contained in the trialkylboron may be the same or different.

[0063] Examples of alkoxyalkylborons include monoalkoxydialkylborons and dialoxymonoalkylborons. Examples of the above alkoxyalkylborons include monoalkoxydialkylborons such as butoxydibutylboron. The alkyl group of the alkoxyalkylboron and the alkyl portion of the alkoxy group may be the same or different.

[0064] Examples of dialkylboranes include dicyclohexylborane and diisoamylborane. The two alkyl groups in a dialkylborane may be the same or different. Furthermore, the two alkyl groups in the above-mentioned dialkylborane may be bonded together to form a monocyclic or bicyclic structure. Examples of such compounds include 9-borabicyclo[3.3.1]nonane.

[0065] Partially oxidized trialkylboron is a partial oxide of the above-mentioned trialkylboron. Partially oxidized tributylboron is preferred as the partially oxidized trialkylboron. Furthermore, as the partially oxidized trialkylboron, it is possible to use a product in which oxygen is added in an amount of preferably 0.3 to 0.9 moles, more preferably 0.4 to 0.6 moles, per mole of trialkylboron.

[0066] Compounds that form complexes with amine compounds or other coordinating compounds are compounds that exhibit radical polymerization initiation ability by reacting with acids, or acids generated by physical or chemical stimuli such as heat or active energy rays, thereby liberating organoboron compounds. Examples of organoboron compounds that form complexes include triethylborane-1,3-diaminopropane complexes.

[0067] In one embodiment of the present invention, among these organoboron compounds, partially oxidized tributylboron is an essential component, and tributylboron may also be included. When tributylboron or partially oxidized tributylboron is used as the organoboron compound (c1), not only is the operability improved, but it also tends to exhibit appropriate reactivity to living organisms containing moisture. Furthermore, when tributylboron or partially oxidized tributylboron is used as the organoboron compound (c1), the reaction starts and proceeds even in living organisms with high moisture content, so compound (A) is less likely to remain at the interface between the adhesive or wound dressing and the living organism, and therefore the harmfulness to living organisms is extremely low. These organoboron compounds (c1) can be used alone or in combination of two or more.

[0068] In one embodiment of the present invention, among these organoboron compounds, it is preferable to use a compound that forms a complex with an amine compound or other coordinating compound. When a compound that forms a complex with an amine compound or other coordinating compound is used as the organoboron compound (c1), a bioadhesive composition can be obtained by pre-mixing the compounding composition and the polymerization initiator composition (C). This composition may also contain a compound that generates acid upon physical or chemical stimulation such as heat or active energy rays. Alternatively, the bioadhesive composition containing the compound that forms a complex with an amine compound or other coordinating compound may be mixed with an acid immediately before use.

[0069] The polymerization initiator composition (C) may further contain an aprotic solvent (c2). The inclusion of an aprotic solvent in the polymerization initiator composition (C) dilutes the organoboron compound, thereby mitigating the exothermic properties of the flammable organoboron compound (c1), suppressing ignition, and facilitating handling during transport, storage, and mixing.

[0070] Furthermore, by moderately reducing the heat generation, even when a very large amount of adhesive or wound dressing is used, rapid heat generation can be suppressed, and as a result, damage to the tissue in contact with the adhesive or wound dressing of the present invention tends to be reduced. The boiling point of the above aprotic solvent (c2) at 1 atmosphere is usually 30°C to 150°C, preferably 50°C to 120°C. When the boiling point is above the above lower limit, the aprotic solvent is less likely to volatilize and scatter from the polymerization initiator composition during transport or storage. Therefore, it is preferable because the ignition suppression effect of the organoboron compound (c1) does not decrease easily. Also, when the boiling point is below the above upper limit, less aprotic solvent remains in the cured product formed from the adhesive composition or wound dressing composition of the present invention, and the adhesive performance of the composition does not decrease easily, which is preferable.

[0071] The aprotic solvent (c2) described above is preferably a solvent that does not react with the organoboron compound (c1) and can form a homogeneous solution. Examples of aprotic solvents (c2) include hydrocarbons such as pentane, hexane, cyclohexane, heptane, benzene, and toluene. Examples of aprotic solvents (c2) include halogenated hydrocarbons such as fluorobenzene, 1,1-dichloroethane, 1,2-dichloroethane, and so-called chlorofluorocarbons (CFCs). Examples of aprotic solvents (c2) include ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, and tetrahydrofuran. Examples of aprotic solvents (c2) include ketones such as acetone, methyl ethyl ketone, and diethyl ketone. Examples of aprotic solvents (c2) include esters such as methyl acetate, ethyl acetate, and isopropyl acetate.

[0072] Among these, saturated aliphatic hydrocarbons such as pentane, hexane, and heptane, ethers, and esters are preferred, with hexane, diisopropyl ether, and ethyl acetate being more preferred.

[0073] These aprotic solvents (c2) can be used alone or in combination of two or more. The content of the aprotic solvent (c2) in the polymerization initiator composition (C) is preferably 30 to 80 parts by mass per 100 parts by mass of the organoboron compound (c1).

[0074] When the content of the aprotic solvent (c2) is above the lower limit, a sufficient dilution effect is obtained, and the effect of suppressing heat generation or ignition is fully exhibited. On the other hand, when the content of the aprotic solvent (c2) is below the upper limit, the polymerization initiation ability of the polymerization initiator composition (C) is fully exhibited.

[0075] The polymerization initiator composition (C) may also contain an alcohol (3) in addition to the aprotic solvent (c2). The addition of a small amount of alcohol (c3) to the polymerization initiator composition (C) makes the reaction with the organoboron compound (c1) even milder without reducing the polymerization activity, making it easier to suppress scorching and ignition even when in contact with paper or other materials in the air.

[0076] Examples of alcohols (C3) include methanol, ethanol, n-propanol and its isomers, n-butanol and its isomers, n-pentanol and its isomers, n-hexanol and its isomers, n-heptanol and its isomers, and the like.

[0077] Among these alcohols (C3), alcohols with four or fewer carbon atoms, namely methanol, ethanol, n-propanol and their isomers, and n-butanol and its isomers, are preferred, with ethanol and n-propanol being more preferred.

[0078] These alcohols (c3) can be used alone or in combination of two or more. The alcohol (c3) content in the polymerization initiator composition (C) is preferably 0.2 to 5 parts by mass, more preferably 0.3 to 4.5 parts by mass, and even more preferably 0.5 to 4 parts by mass, per 100 parts by mass of the organoboron compound (b1).

[0079] When the alcohol (c3) content is above the lower limit, a sufficient dilution effect is obtained, and the effect of suppressing heat generation or ignition is fully exhibited. On the other hand, when the alcohol (c3) content is below the lower limit, the polymerization initiation ability of the polymerization initiator composition (C) is fully exhibited.

[0080] Furthermore, when an alcohol (c3) and an aprotic solvent (c2) are used in combination, the content of the aprotic solvent (c2) in the polymerization initiator composition (C) is preferably 5 to 40 parts by mass, more preferably 10 to 30 parts by mass, and even more preferably 10 to 25 parts by mass, per 100 parts by mass of the organoboron compound (c1).

[0081] When the content of the aprotic solvent (c2) is equal to or greater than the lower limit per 100 parts by mass of the organoboron compound (c1), the effect of suppressing heat generation or ignition is sufficiently exhibited. On the other hand, when the content of the aprotic solvent (c2) is equal to or less than the upper limit per 100 parts by mass of the organoboron compound (c1), the polymerization initiator composition (C) exhibits sufficient polymerization initiation ability.

[0082] The amount of polymerization initiator composition (C) added is preferably 0.5 to 15 parts by mass, and more preferably 0.9 to 11 parts by mass, based on 100 parts by mass of the total of compound (A) and polymer (B).

[0083] If the amount of polymerization initiator composition (C) added is greater than or equal to the above upper limit, polymerization proceeds more easily, and the adhesive effect is fully exhibited. If the amount of polymerization initiator composition (C) added is less than or equal to the above upper limit, viscosity reduction due to dilution is less likely to occur, and safety can be ensured. If the amount of polymerization initiator composition (C) added is less than or equal to the above upper limit, polymerization does not proceed too rapidly, resulting in good handling properties as an adhesive or wound dressing.

[0084] One aspect of the present invention is a bioadhesive composition containing a compound (A1) having polymerizable unsaturated bonds, a polymer (B), and a polymerization initiator composition (C) containing an organoboron compound. Compound (A1) includes a compound having an amide structure and at least one polymerizable double bond, and the description of a compound having an amide structure and at least one polymerizable double bond is the same as the description of compound (A1) above.

[0085] One aspect of the present invention is a medical adhesive composition, a medical dressing composition, a skin adhesive composition, a wound dressing composition, a wound dressing adhesive composition, or a skin dressing composition, comprising the bio-adhesive composition of the present invention described above.

[0086] Medical adhesive compositions are adhesive compositions used for bonding human or animal tissues. Here, human or animal tissues refer to living tissues such as blood vessels, mucous membranes, skin, organs, and bone tissue. One embodiment of a medical adhesive composition is used for bonding medical devices to skin. Another embodiment of a medical adhesive composition is used, for example, to fix catheter needles to the skin or to bond an artificial anus to organs. Furthermore, one embodiment of a medical adhesive composition can also be used for bonding human or animal tissues to ceramics, metals, plastics, fibers, etc.

[0087] Medical dressing compositions are adhesive compositions used to cover human or animal tissues.

[0088] A skin adhesive composition is any adhesive used on the surface of human or animal skin, and its use is not limited to cosmetic or beauty purposes. For cosmetic or beauty purposes, it is used, for example, for special effects makeup, wig adhesion, nail art, and attaching false eyelashes.

[0089] Wound dressing compositions are compositions for covering wounds caused by trauma or surgery. Wound dressing adhesive compositions are compositions for covering and adhering wounds caused by trauma or surgery. They can be used as an alternative to suturing or stapling for some wounds that would otherwise require suturing or stapling.

[0090] Skin dressing compositions are used to protect the skin surface of humans or animals from contact with irritants by covering erosions, pressure ulcers, etc. on the skin surface.

[0091] ≪Method for Manufacturing Biomedical Adhesive Compositions≫ The biomedical adhesive composition of this embodiment can be manufactured by first mixing compound (A) and polymer (B) to produce a compound composition, and then further mixing the compound composition with a polymerization initiation composition (C).

[0092] <Bioadhesive Composition Kit> One aspect of the present invention is a bioadhesive composition kit comprising a compound (A1) having polymerizable unsaturated bonds and a polymer (B), and a polymerization initiator composition (C) containing an organoboron compound.

[0093] The bio-adhesive composition kit preferably contains a compound (A1), a polymer (B), and a polymerization initiator composition (C) separately, with the compound and polymerization initiator composition (C) being mixed immediately before use.

[0094] The compounded composition and the polymerization initiator composition (C) can be placed in separate components, such as syringes or other containers, and then packaged in a kit for use as a bioadhesive to provide it as a product.

[0095] Examples of tools used for applying the solution to wounds include brushes, fiber balls, cloths, sponge balls, and sponge pieces. The kit may also include disinfectants such as alcohol, pretreatment solutions for improving adhesion, and covering materials.

[0096] Furthermore, when storing in the kit described above, sterilization may be performed using electromagnetic waves such as visible light, preferably under conditions that do not alter the components (for example, the monomers do not harden). The bioadhesive composition of the present invention can be used, for example, for sealing, protecting, and occluding wound sites, fixing (adhesion) of soft tissue grafts, hemostasis, vascular anastomosis, vascular occlusion, bronchial anastomosis, bronchial occlusion, and adhesion of biological tissues in ophthalmic surgery.

[0097] Furthermore, the bioadhesive composition of the present invention can be directly applied to wounds formed on the outer skin of living organisms, such as skin and mucous membranes, to easily join openings in the wound area. It can also be used to fix grafts to the transplant site during skin grafting.

[0098] When using the biocompatible adhesive composition of the present invention as a wound dressing adhesive, it is usually not applied to the wound surface, but rather applied to the surface of the wound after the wound edges have been brought together, and then used after adhesion and curing. On the other hand, for wounds that do not have an incision surface, such as abrasions, crushing wounds, and contusions, the adhesive can also be applied directly to the affected area.

[0099] Furthermore, the bioadhesive composition of this embodiment may contain antiinfective agents, antibiotics, antibacterial agents, antiviral agents, analgesics, analgesic formulations, appetite suppressants, antihelmintic agents, antiarthritis agents, antiasthmatic agents, anticonvulsants, antidepressants, antidiuretics, antidiarrheal agents, antihistamines, anti-inflammatory agents, anti-migraine agents, antiemetics, antineoplastic agents, antiparkinson's disease agents, antipruritics, antipsychotics, antipyretics, antispasmodics, anticholinergic agents, sympathomimetic agents, cardiovascular agents, antiarrhythmics, antihypertensives, diuretics, vasodilators, immunosuppressants, muscle relaxants, parasympathetic blockers, stimulants, sedatives, tranquilizers, cholinergics, chemotherapy agents, radiopharmaceuticals, bone-inducing agents, bladder-static heparin antagonists, coagulants, hemostatic agents, xanthine derivatives, hormones, naturally derived or genetically engineered materials. The resulting synthetic proteins may include polysaccharides, glycoproteins, lipoproteins, oligonucleotides, antibodies, antigens, vasopressins, vasopressin analogs, epinephrine, selectins, procoagulant toxins, plasminogen activator inhibitors, platelet activators, and synthetic peptides having hemostatic properties, as well as at least one selected from orange oil, grapefruit oil, lemon oil, lime oil, clove oil, wintergreen oil, peppermint oil, peppermint spirit, banana distillate, cucumber distillate, honey distillate, rose water, menthol, anethole, alkyl salicylate, benzaldehyde, monosodium glutamate, ethyl vanillin, thymol, and vanillin.

[0100] Furthermore, the bio-adhesive composition of this embodiment may also contain an ultraviolet absorber, a plasticizer, a preservative, and a colorant.

[0101] As a coloring agent, dyes can be used. Examples of dyes include phthalocyanine copper(II), carbon black, indigo carmine, indigo, quinizalin green, tetrabromofluorescein, quinizalin blue, uranine, and quinizalin yellow. Furthermore, from the viewpoint of improving visibility during use, it is preferable to use phthalocyanine copper(II) as the dye, and the content of phthalocyanine copper(II) relative to the total amount of the compound composition is preferably 10 to 1000 ppm.

[0102] Furthermore, the bioadhesive composition of this embodiment may also contain, in addition to the above-mentioned proteins, angiogenesis factors, basic fibroblast growth factors, epidermal growth factors, etc., for the purpose of promoting tissue repair.

[0103] Other ingredients mentioned above may include orange oil, grapefruit oil, lemon oil, lime oil, clove oil, wintergreen oil, peppermint oil, peppermint spirit, banana distillate, cucumber distillate, honey distillate, rose water, menthol, anethole, alkyl salicylate, benzaldehyde, monosodium glutamate, ethyl vanillin, thymol, and vanillin as fragrances.

[0104] Furthermore, other components may include, for example, inorganic fillers, organic fillers, organic composite fillers, and filler colorants.

[0105] The bio-adhesive composition of this embodiment can also be used by impregnating a base fabric. For example, by uniformly applying the bio-adhesive composition of this embodiment so that it penetrates the entire mesh patch placed on a wound, the wound can be covered and bonded.

[0106] The following provides specific examples of the manufacturing process for the adhesive composition used in the present invention, but the present invention is not limited to these examples. In the following manufacturing examples, "%" refers to mass percent.

[0107] <Production of Polymer (B)> (Production Example 1) 50 g of butyl acetate was charged at room temperature into a four-necked flask equipped with a stirrer, thermometer, nitrogen introduction line, and dropping funnel.

[0108] 125 mg of AIBN (azobisisobutyronitrile) was weighed into a round-bottom flask, and 50 g of isobutyl methacrylate was added and dissolved.

[0109] The polymerization apparatus and the solution in the round-bottom flask were subjected to nitrogen bubbling at a rate of 0.5 mL / min for 30 minutes to replace the system with nitrogen gas. After stopping the nitrogen gas bubbling, the polymerization apparatus was heated to 80°C under nitrogen flow and stirring was started.

[0110] After the internal temperature reached 80°C, the monomer solution in the round-bottom flask was added dropwise to the polymerization apparatus at a rate of 25 mL / min over approximately 2 hours. After stirring for 4 hours, the temperature was raised to 95°C and stirred for another 2 hours.

[0111] Next, 200 μL of PB-O (perbutyl-O: manufactured by NOF Corporation) was added, the temperature was raised to 100°C, and the mixture was stirred for 2 hours.

[0112] This yielded a polyisobutyl methacrylate / butyl acetate solution.

[0113] The obtained isobutyl polymethacrylate / butyl acetate solution was diluted with 400 g of butyl acetate and reprecipitation was performed with 10 times the volume of methanol.

[0114] The solid obtained by reprecipitation was dried under reduced pressure at 40°C for 24 hours to obtain 50 g of polyisobutyl methacrylate powder.

[0115] The molecular weight distribution of the reaction products was measured by gel permeation chromatography (GPC) under the following conditions. The results are shown in Table 1.

[0116] [GPC Measurement Conditions] Detector: Differential Refractometer (RI) Column: Shodex GPC KF-806L x 3 (Resonac Corporation) Mobile Phase: Tetrahydrofuran (THF) Column Temperature: 40°C Flow Rate: 1.0 ml / min Sample Concentration: 5 mg / mL (Tetrahydrofuran solution) Injection Volume: 10 μL

[0117] The weight-average molecular weight was calculated using a calibration curve created from monodisperse standard polystyrene.

[0118] (Manufacturing Examples 2-3) Each polymer powder was obtained using the same method as in Manufacturing Example 1. The formulations were modified according to Table 1.

[0119] The PMMA polymer powder used in formulation examples 17 and 18 was a commercially available product (manufactured by Merck).

[0120]

[0121] In Table 1, each abbreviation refers to the following component: iBMA: Isobutyl methacrylate (R in general formula (B)-1) ３(The number of carbon atoms is 4) nBMA: n-butyl methacrylate (R in general formula (B)-1) ３ (The number of carbon atoms is 4) IBXA: Isobornyl acrylate (R in general formula (B)-1) ３ (The carbon number is 10) AIBN: Azobisisobutyronitrile

[0122] <Preparation of Biomedical Adhesive Composition> (Example 1) 750 mg of t-butyl acrylate, 500 mg of isobutyl polymethacrylate, and 187.5 mg of acryloyl morpholine were weighed into a 3 mL vial and stirred at room temperature for 16 hours using a mix rotor to obtain composition 1. 75 mg of polymerization initiator (a solution of TBBO / EtOH = 85 / 15 (weight ratio)) was added to the prepared composition 1 and shaken for 10 seconds to produce a biomedical adhesive composition. After that, a thin film of the biomedical adhesive composition was prepared on a release film using an applicator.

[0123] The material was cured in room temperature air for 24 hours, and a thin film with a thickness of 100 μm was peeled off from the release film.

[0124] The deposited film was cut into 5 x 40 mm pieces, and the viscoelasticity of the film was measured under the following conditions.

[0125] [Solid Viscoelastic Temperature Dispersion Measurement Conditions] Equipment: RSA-G2 (manufactured by T.A. Instruments) Deformation Mode: Tensile Temperature Range: -60°C to measurable range Heating Rate: 3°C / min Frequency: 1 Hz Environment: Under N2

[0126] Table 3 shows the tanδ peak top temperature and the storage modulus E' at 40°C obtained under the above conditions.

[0127] (Formulations 2-18) Each of the formulations 2-18 was prepared using the same method as for formulation 1. The formulations were modified according to Table 2.

[0128] (Examples 2-16, Comparative Examples 1-2) Furthermore, following the same method as in Example 1, each compound composition and polymerization initiator were mixed to produce the bio-adhesive compositions of Examples 2-16 and Comparative Examples 1-2. Then, the solid viscoelasticity of the films prepared using each bio-adhesive composition was measured, and the tanδ peak top temperature and storage modulus at 40°C were obtained. The results are shown in Table 4. The compositions of the bio-adhesive compositions of Examples 1-16 and Comparative Examples 1-2 are listed in Table 3.

[0129]

[0130]

[0131] In Tables 2 and 3, the abbreviations refer to the following components: PnBMA: Poly-n-butyl methacrylate (R in general formula (B)-1) ３ (The number of carbon atoms is 4) PiBMA: poly-iso-butyl methacrylate (R in general formula (B)-1) ３ (The number of carbon atoms is 4) PIBXA: Polyisobornyl acrylate (R in general formula (B)-1) ３ (The number of carbon atoms is 10) PMMA: Polymethyl methacrylate (R in general formula (B)-1) ３ (The number of carbon atoms is 1) tBA: tert-butyl acrylate (R in general formula (A)-1) ２ (The number of carbon atoms is 4) CHA: Cyclohexyl acrylate (R in general formula (A)-1) ２ (The number of carbon atoms is 6) nBMA: n-butyl methacrylate (R in general formula (A)-1) ２ (The number of carbon atoms is 4) MMA: Methyl methacrylate (R in general formula (A)-1) ２ (The number of carbon atoms is 1) iBA: Isobutyl acrylate (R in general formula (A)-1) ２ (The number of carbon atoms is 4) ACMO: Acryloylmorpholine DMAA: N,N-dimethylacrylamide NIPAM: N-isopropylacrylamide 4HBA: 4-hydroxybutyl acrylate (R in general formula (A)-1) ２ (4 carbon atoms) NGDA: Nonamethylene glycol diacrylate TBBO: Tributylborane partial oxide EtOH: Ethanol

[0132]

[0133] [Wound Closure Test] A wound closure test was performed according to ASTM F2458-05. Yucatan micropig skin samples (manufactured by Sinclair, USA), which had been stored frozen at -80°C, were removed, and the fatty portion was removed with a #24 blade scalpel. Any remaining fat was wiped off with gauze soaked in isopropanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.).

[0134] After removing the fat, approximately 1-2 mm of the skin was cut from all four sides.

[0135] After removing the hair with hair removal cream (made by Kracie), rinsing off the cream with water, and then wiping away any remaining cream residue with gauze soaked in isopropanol.

[0136] A Yucatan micropig skin sample was cut into a rectangle 25 mm wide and 100 mm long.

[0137] The cut-out test pieces were wrapped in gauze soaked in 0.01 mol / L phosphate-buffered saline (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), placed in a resealable plastic bag, and heated in a water bath set to 37°C for 1 hour.

[0138] The test specimen was removed from the water bath, and the moisture was removed by gently tapping the skin surface with gauze.

[0139] To prevent interfacial adhesion of the skin adhesive, a thin layer of silicone grease was applied to the back and sides of the test specimen.

[0140] After arranging two skin test pieces vertically, the bio-adhesive composition of Example 1, which was prepared according to the adhesive composition liquid preparation procedure and to which a polymerization initiator was added, was shaken for 10 seconds, and each bio-adhesive composition was applied to the bonding surface to a width of 1 cm.

[0141] After confirming that the surface tackiness had disappeared, the sample was wrapped in gauze soaked in saline solution, placed in a resealable plastic bag, and warmed in a 37°C water bath for 15 minutes.

[0142] The skin test specimen was removed from the resealable plastic bag, and any surface moisture was wiped off.

[0143] The test specimen was set in the grip of the testing machine so that the load coincided with the long axis of the specimen.

[0144] A tensile test was conducted by applying a load until the test specimen fractured under the following conditions.

[0145] [Wound Closure Force Test Conditions] Apparatus: EZ-SX (manufactured by Shimadzu Corporation) Fixture used: 500N Tensile fixture gripping tooth test speed: 50 mm / min Distance between fixtures: 10 cm

[0146] The test was performed 10 times for each level, and the average stress (N) at fracture was defined as the wound closure force. The results are shown in Table 5.

[0147] The wound closure force of each composition solution in Examples 5, 6, 9, 12, 16 and Comparative Example 1 was measured using the same method as in Example 1. The results are shown in Table 5.

[0148]

[0149] As shown in the results above, Examples 1, 5, 6, 9, 12, and 16, which used biocompatible adhesive compositions with a glass transition temperature of less than 80°C obtained by a predetermined measurement method, followed the skin stretching of the skin test specimens well, resulting in high stress (N) at fracture of 5N or more. Comparative Example 1 failed to follow the skin stretching of the skin test specimen and fractured at approximately 3.7N.

Claims

1. A bioadhesive composition comprising a compound (A) having polymerizable unsaturated bonds, a compound (B) and a polymer, and a polymerization initiator composition (C) containing an organoboron compound, wherein the bioadhesive composition has a glass transition temperature of less than 80°C, as determined by the measurement results obtained by the method described in [Measurement Conditions] below. [Measurement Conditions] The bioadhesive composition is applied to a release film and cured in room temperature air for 24 hours to form a thin film with a thickness of 100 μm. The formed film is peeled off the release film and cut into 5 mm x 40 mm pieces to be used as the test film. The dynamic viscoelasticity of the test film is measured in a nitrogen atmosphere at a frequency of 1 Hz, with the temperature ranging from -60°C to the measurable range, at a heating rate of 3°C / min.

2. The biocompatible adhesive composition according to claim 1, wherein the glass transition temperature is 10°C or higher and less than 80°C.

3. The bioadhesive composition for biological use according to claim 1 or 2, wherein the compound (A) is either or both of the following: a compound represented by general formula (A)-1, and a compound having an amide structure and at least one polymerizable double bond. [In formula (A)-1, R １ R is a hydrogen atom or a methyl group, ２ [This is a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms, which may have substituents.] 4. The bioadhesive composition according to claim 1 or 2, wherein the polymer (B) is a polymer represented by general formula (B)-1, an acrylamide polymer, or a copolymer of a polymer represented by general formula (B)-1 and an acrylamide polymer. [In general formula (B)-1, R １ R is a hydrogen atom or a methyl group, ３ [n is a linear, branched, or cyclic hydrocarbon group having 2 to 20 carbon atoms, which may have substituents. n is an integer of 2 or more.] 5. The bioadhesive composition according to claim 1 or 2, wherein when the total amount of compound (A) and polymer (B) is 100 parts by mass, the content of compound (A) relative to the total amount is 60 parts by mass or more and 90 parts by mass or less, and the content of polymer (B) relative to the total amount is 10 parts by mass or more and 40 parts by mass or less.

6. The bioadhesive composition according to claim 1 or 2, wherein when the total amount of compound (A) and polymer (B) is 100 parts by mass, the content of the polymerization initiator composition (C) relative to the total amount is 0.9 parts by mass or more and 11 parts by mass or less.

7. The storage modulus at 40°C obtained from the measurement results by the method described in [Measurement Conditions] above is 1.0 × 10⁻⁶. ４ Pa or more 9.0×10 ８ A bioadhesive composition according to claim 1 or 2, wherein the pressure is Pa or less.

8. A medical adhesive composition, a medical dressing composition, a skin adhesive composition, a wound dressing composition, a wound dressing adhesive composition, or a skin dressing composition comprising the biocompatible adhesive composition described in claim 1 or 2.

9. A bioadhesive composition comprising a compound (A1) having polymerizable unsaturated bonds and a polymer (B), and a polymerization initiator composition (C) containing an organoboron compound, wherein the compound (A1) has an amide structure and contains a compound having at least one polymerizable double bond.

10. A bioadhesive composition kit comprising a compound (A1) having polymerizable unsaturated bonds and a polymer (B), and a polymerization initiator composition (C) containing an organoboron compound, wherein the compound (A1) has an amide structure and contains a compound having at least one polymerizable double bond.

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