Adhesive agent composition for living body and adhesive sheet

Abstract

Provided are: an adhesive agent composition for a living body, said composition containing (meth)acrylic resin particles having a glass transition temperature of -60°C to -20°C, a nonaromatic nonionic surfactant, and water, wherein the nonaromatic nonionic surfactant is constituted by a polyoxyalkylene alkyl ether compound (X) and a polyoxyalkylene alkyl ether compound (Y) having different average numbers of moles of added oxyalkylene units, and, when the average number of moles of added oxyalkylene units in the polyoxyalkylene alkyl ether compound (X) is denoted by "x1" and the average number of moles of added oxyalkylene units in the polyoxyalkylene alkyl ether compound (Y) is denoted by "y1", y1 is at least 7 times greater than x1, x1 is at least 20, and y1 is less than 63; and an adhesive sheet.

Description

Biological Adhesive Composition and Adhesive Sheet

[0001] The present disclosure relates to a biological adhesive composition and an adhesive sheet.

[0002] Conventionally, a water-dispersed acrylic adhesive composition using a surfactant having a nonylphenol skeleton has been known. The water-dispersed acrylic adhesive composition is used, for example, as a medical adhesive for forming an adhesive layer of a body-adhesive medical adhesive tape and a medical adhesive sheet, and related technologies have also been reported.

[0003] For example, in Japanese Patent Application Laid-Open No. 2018-166834, a constituent unit A derived from an alkyl (meth)acrylate having a glass transition temperature of 0°C or higher when made into a homopolymer is 50% to 94.5% by mass with respect to all constituent units, and a constituent unit B derived from an alkyl (meth)acrylate having a glass transition temperature of -50°C or lower when made into a homopolymer is 5% to 49.5% by mass with respect to all constituent units, and a constituent unit C derived from a monomer having a carboxy group is 0.5% to 10% by mass with respect to all constituent units. A biological resin composition containing a (meth)acrylic polymer and a surfactant has been reported.

[0004] By the way, nonylphenol has recently been confirmed to be harmful to organisms, and regulations are being advanced in various countries. When a surfactant having a nonylphenol skeleton is released into the natural environment, it is known to be decomposed to produce nonylphenol. Therefore, regulations are also being advanced in various countries for surfactants having a nonylphenol skeleton. Considering such regulatory situations, the conventional water-dispersed acrylic adhesive composition using a surfactant having a nonylphenol skeleton needs to be replaced with a water-dispersed acrylic adhesive composition that does not use a surfactant having a nonylphenol skeleton.

[0005] The inventors prepared a water-dispersible acrylic adhesive composition using a non-aromatic nonionic surfactant instead of a surfactant having a nonylphenol skeleton, and manufactured an adhesive sheet for biological use. They found that the tack strength of the adhesive layer changed during storage of the adhesive sheet. When the tack strength of the adhesive layer changes, the adhesion strength of the adhesive layer to the biological surface changes, impairing the feel of the adhesive sheet. Therefore, the adhesive layer of an adhesive sheet for biological use is required to have an adhesion strength that does not easily change over time. In addition, generally, the adhesive layer of an adhesive sheet for biological use is required to be resistant to the bleed-out of additive components such as medicinal ingredients over time.

[0006] This disclosure has been made in view of the circumstances described above. One embodiment of this disclosure aims to solve the problem of providing a biocompatible adhesive composition that can form an adhesive layer in which bleed-out of additive components such as pharmacoactive ingredients over time is less likely to occur, and the adhesive strength does not change easily over time. Another embodiment of this disclosure aims to solve the problem of providing an adhesive sheet comprising an adhesive layer formed by the biocompatible adhesive composition described above.

[0007] The following embodiments are included as specific means for solving the problem: <1> A bio-adhesive composition comprising (meth)acrylic resin particles having a glass transition temperature of -60°C to -20°C, a non-aromatic nonionic surfactant, and water, wherein the non-aromatic nonionic surfactant is a polyoxyalkylene alkyl ether compound (X) and a polyoxyalkylene alkyl ether compound (Y) with different average mole addition numbers of oxyalkylene units, where x1 is the average mole addition number of oxyalkylene units of the polyoxyalkylene alkyl ether compound (X) and y1 is the average mole addition number of oxyalkylene units of the polyoxyalkylene alkyl ether compound (Y), and y1 is 7 or more greater than x1, x1 is 20 or more, and y1 is less than 63. <2> The bio-adhesive composition according to <1>, wherein x1 is 35 or more. <3> The bio-adhesive composition according to <1> or <2>, wherein the oxyalkylene units of the polyoxyalkylene alkyl ether compound (X) and the oxyalkylene units of the polyoxyalkylene alkyl ether compound (Y) are both oxyethylene units. <4> The bio-adhesive composition according to any one of <1> to <3>, wherein the HLB value of the non-aromatic nonionic surfactant is 17.0 to 18.6. <5> The bio-adhesive composition according to any one of <1> to <4>, wherein the total content of the polyoxyalkylene alkyl ether compound (X) and the polyoxyalkylene alkyl ether compound (Y) is 0.1 to 10.0 parts by mass per 100 parts by mass of the (meth)acrylic resin particles. <6> The bioadhesive composition according to any one of <1> to <5>, wherein the content ratio of the polyoxyalkylene alkyl ether compound (X) to the polyoxyalkylene alkyl ether compound (Y) is 1:10 to 10:1 by mass.<7> The bio-adhesive composition according to any one of <1> to <6>, wherein the (meth)acrylic resin particles contain 70.0% by mass or less of constituent units (a) derived from an alkyl (meth)acrylate monomer having a glass transition temperature of 0°C or higher when used as a homopolymer, and 20.0% by mass to 90.0% by mass of constituent units (b) derived from an alkyl (meth)acrylate monomer having a glass transition temperature of -50°C or lower when used as a homopolymer, relative to the total constituent units. <8> The bio-adhesive composition according to <7>, wherein the constituent unit (a) contains at least one of a constituent unit derived from methyl acrylate and a constituent unit derived from methyl methacrylate. <9> The bio-adhesive composition according to any one of <1> to <8>, wherein the average particle size of the (meth)acrylic resin particles is 150 nm to 500 nm. <10> An adhesive sheet comprising a base material and an adhesive layer provided on the base material and formed from any one of the biocompatible adhesive compositions described in <1> to <9>.

[0008] According to one embodiment of the present disclosure, a biocompatible adhesive composition is provided that allows for the formation of an adhesive layer in which bleed-out of additive components such as pharmacoactive ingredients over time is less likely to occur, and the adhesive strength does not change easily over time. According to another embodiment of the present disclosure, an adhesive sheet is provided comprising an adhesive layer formed by the above-mentioned biocompatible adhesive composition.

[0009] The biocompatible adhesive compositions and adhesive sheets of this disclosure will be described in detail below. The descriptions of requirements below may be based on typical embodiments of this disclosure, but this disclosure is not limited to such embodiments and may be modified as appropriate within the scope of the purpose of this disclosure.

[0010] In this disclosure, numerical ranges indicated using "~" mean ranges that include the numerical values ​​before and after "~" as the lower and upper limits, respectively. In numerical ranges described in stages in this disclosure, the upper or lower limit stated in one numerical range may be replaced with the upper or lower limit of another numerical range described in stages. Furthermore, in numerical ranges described in this disclosure, the upper or lower limit stated in one numerical range may be replaced with the values ​​shown in the examples.

[0011] In this disclosure, a combination of two or more preferred embodiments is a more preferred embodiment.

[0012] In this disclosure, the amount of each component in the composition means the total amount of any multiple substances present in the composition, unless otherwise specified, if there are multiple substances corresponding to each component in the composition.

[0013] In this disclosure, unless otherwise specified, "solids" means components other than the solvent contained in the composition, and "solvent" means water and organic solvents. For example, if the solvent contained in the composition is only water, then "solids" means components other than water contained in the composition; if the solvent contained in the composition is only an organic solvent, then "solids" means components other than the organic solvent contained in the composition; and if the solvent contained in the composition is both water and an organic solvent, then "solids" means components other than water and organic solvents contained in the composition.

[0014] In this disclosure, "(meth)acrylic resin" means a resin that contains constituent units derived from a (meth)acrylic monomer, and in which the proportion of constituent units derived from the (meth)acrylic monomer is 50% by mass or more. In this disclosure, "(meth)acrylic monomer" means a monomer having a (meth)acryloyl group.

[0015] In this disclosure, "(meth)acrylic" is a term that encompasses both "acrylic" and "methacrylic," "(meth)acrylate" is a term that encompasses both "acrylate" and "methacrylate," and "(meth)acryloyl" is a term that encompasses both "acryloyl" and "methacryloyl."

[0016] In this disclosure, "n-" means normal, "i-" means iso, "s-" means secondary, and "t-" means tertiary.

[0017] In this disclosure, "constituent units derived from monomers" means constituent units formed by the addition polymerization of monomers.

[0018] In this disclosure, "mass%" and "weight%" are synonymous, and "parts by mass" and "parts by weight" are synonymous. In this disclosure, "monomer" and "monomer" are synonymous, and "polymer" and "polymer" are synonymous.

[0019] In this disclosure, the term "process" includes not only independent processes but also processes that cannot be clearly distinguished from other processes, as long as their intended purpose is achieved.

[0020] [Biochemical Adhesive Composition] The biochemical adhesive composition of the present disclosure comprises (meth)acrylic resin particles having a glass transition temperature of -60°C to -20°C, a non-aromatic nonionic surfactant, and water, wherein the non-aromatic nonionic surfactant is a polyoxyalkylene alkyl ether compound (X) and a polyoxyalkylene alkyl ether compound (Y) with different average mole addition numbers of oxyalkylene units, where x1 is the average mole addition number of oxyalkylene units of the polyoxyalkylene alkyl ether compound (X) and y1 is the average mole addition number of oxyalkylene units of the polyoxyalkylene alkyl ether compound (Y), and y1 is 7 or more greater than x1, x1 is 20 or more, and y1 is less than 63.

[0021] The adhesive composition of this disclosure, having the above-described structure, makes it possible to form an adhesive layer in which bleed-out of additive components such as pharmacoactive ingredients over time is less likely to occur, and the adhesive strength does not change easily over time.

[0022] [Specific (meth)acrylic resin particles] The bio-adhesive composition of this disclosure contains (meth)acrylic resin particles having a glass transition temperature of -60°C to -20°C. In this disclosure, "(meth)acrylic resin particles having a glass transition temperature of -60°C to -20°C" is also referred to as "specific (meth)acrylic resin particles." In the bio-adhesive composition of this disclosure, the specific (meth)acrylic resin particles exist dispersed in a water-containing medium. The bio-adhesive composition of this disclosure may contain one type of specific (meth)acrylic resin particle alone, or two or more types.

[0023] The (meth)acrylic resin constituting the specific (meth)acrylic resin particles may be a homopolymer or a copolymer. The (meth)acrylic resin may be, for example, a homopolymer of (meth)acrylic monomers, a copolymer of two or more (meth)acrylic monomers, or a copolymer of one or more (meth)acrylic monomers and one or more monomers other than (meth)acrylic monomers.

[0024] <Glass Transition Temperature of Specific (Meth)acrylic Resin Particles> Specific (meth)acrylic resin particles are (meth)acrylic resin particles with a glass transition temperature (also called "Tg") of -60°C to -20°C. When the glass transition temperature of (meth)acrylic resin particles is -60°C or higher, it tends to form an adhesive layer with moderately low tack force and less pain when peeled from the body. From this viewpoint, it is preferable that the glass transition temperature of specific (meth)acrylic resin particles be -58°C or higher. When the glass transition temperature of (meth)acrylic resin particles is -20°C or lower, it tends to form an adhesive layer with moderately high tack force and sufficient adhesion for biological applications. From this viewpoint, it is preferable that the glass transition temperature of specific (meth)acrylic resin particles be -25°C or lower. In one embodiment, the glass transition temperature of the specific (meth)acrylic resin particles may be -60°C to -25°C, -58°C to -20°C, or -58°C to -25°C.

[0025] The glass transition temperature of specific (meth)acrylic resin particles is the absolute temperature (unit: K) calculated from the following equation 1 and converted to Celsius temperature (unit: °C): 1 / Tg = m1 / Tg1 + m2 / Tg2 + ... + m(k-1) / Tg(k-1) + mk / Tgk (Equation 1)

[0026] In Equation 1, Tg1, Tg2, ..., Tg(k-1), and Tgk represent the glass transition temperatures expressed in absolute temperature when each monomer forming the specific (meth)acrylic resin particles is a homopolymer. m1, m2, ..., m(k-1), and mk represent the mass fractions of each monomer forming the specific (meth)acrylic resin particles, where m1 + m2 + ... + m(k-1) + mk = 1. Note that absolute temperature can be converted to Celsius temperature by subtracting 273 from it, and Celsius temperature can be converted to absolute temperature by adding 273 to it.

[0027] In this disclosure, the "glass transition temperature when used as a homopolymer" shall be the value described in publicly available documents or the value measured using a differential scanning calorimetry (DSC). Specifically, the choice of which value to adopt is as follows:

[0028] For the "glass transition temperatures when homopolymerized" of the monomers listed below, the values ​​in parentheses should be used. Methyl acrylate (10°C), methyl methacrylate (105°C), ethyl acrylate (-22°C), ethyl methacrylate (65°C), n-butyl acrylate (-54°C), n-butyl methacrylate (20°C), i-butyl methacrylate (53°C), t-butyl acrylate (43°C), t-butyl methacrylate (118°C), 2-ethylhexyl acrylate (-70°C), 2-ethylhexyl methacrylate (-10°C), n-octyl acrylate (-65°C), stearyl acrylate (30°C), stearyl methacrylate (38°C), lauryl acrylate (-3°C), lauryl methacrylate (-65°C), cyclohexyl methacrylate (104°C), isobornyl acrylate (94°C), isobornyl methacrylate (180°C), benzyl acrylate (6°C), phenoxyethyl acrylate (-22°C), 2-methoxyethyl acrylate (-50°C), glycidyl methacrylate (74°C), 2-hydroxyethyl acrylate (-15°C), 2-hydroxyethyl methacrylate (85°C), 4-hydroxybutyl acrylate (-80°C), acrylic acid (106°C), methacrylic acid (228°C), dimethylaminoethyl methacrylate (18°C), ω-carboxy-polycaprolactone (n≒2) monoacrylate (-30°C), acrylonitrile (125°C), itaconic acid (154°C).

[0029] For monomers other than those mentioned above, the "glass transition temperature when used as a homopolymer" will be based on the values ​​listed in the Polymer Handbook (4th edition, Wiley-Interscience; hereinafter the same). If the value is not listed in the Polymer Handbook, the glass transition temperature of the homopolymer obtained by the following measurement method will be used.

[0030] Specifically, a differential scanning calorimetry (DSC) is used to measure the temperature under conditions of a nitrogen atmosphere, with a sample of 10 mg (i.e., homopolymer) and a heating rate of 10°C / min. The inflection point of the resulting DSC curve is defined as the glass transition temperature of the homopolymer. As a differential scanning calorimetry device, for example, a differential scanning calorimetry device manufactured by T.A. Instrument Japan Co., Ltd. (product name: Discovery DSC 2500) can be suitably used. However, the differential scanning calorimetry device is not limited to this.

[0031] The glass transition temperature of specific (meth)acrylic resin particles can be set to a desired value, for example, by adjusting the type and proportion of monomers that form the specific (meth)acrylic resin particles.

[0032] <Constituent Units of Specific (Meth)acrylic Resin Particles> The constituent units of specific (meth)acrylic resin particles are not particularly limited. The constituent units that specific (meth)acrylic resin particles may contain are described below.

[0033] <<Constituent units derived from (meth)acrylate alkyl ester monomers>> Specific (meth)acrylic resin particles preferably contain constituent units derived from (meth)acrylate alkyl ester monomers, for example, from the viewpoint of controlling the adhesive strength of the adhesive layer. In this disclosure, "(meth)acrylate alkyl ester monomer" refers to an (meth)acrylate alkyl ester monomer that does not have a carboxyl group. In other words, in this disclosure, "(meth)acrylate alkyl ester monomer having a carboxyl group" is classified as a monomer having a carboxyl group.

[0034] The type of alkyl (meth)acrylate monomer is not particularly limited. The alkyl (meth)acrylate monomer may be an alkyl acrylate monomer or an alkyl methacrylate monomer. The alkyl group of the alkyl (meth)acrylate monomer may be unsubstituted or substituted, but it is preferable that it be unsubstituted. The alkyl group of the alkyl (meth)acrylate monomer may be linear, branched, or cyclic. The number of carbon atoms in the alkyl group of the alkyl (meth)acrylate monomer is preferably 1 to 18, more preferably 1 to 12, and even more preferably 1 to 8.

[0035] Specific examples of alkyl (meth)acrylate monomers include methyl (meth)acrylate, ethyl (meth)acrylate, n-butyl (meth)acrylate, i-butyl (meth)acrylate, s-butyl (meth)acrylate, t-butyl (meth)acrylate, n-octyl (meth)acrylate, i-octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, n-nonyl (meth)acrylate, i-nonyl (meth)acrylate, n-decyl (meth)acrylate, stearyl (meth)acrylate, lauryl (meth)acrylate, cyclohexyl (meth)acrylate, and isobornyl (meth)acrylate.

[0036] The specific (meth)acrylic resin particles preferably contain, for example, a constituent unit (a) derived from an alkyl (meth)acrylate monomer whose glass transition temperature when used as a homopolymer is 0°C or higher, and a constituent unit (b) derived from an alkyl (meth)acrylate monomer whose glass transition temperature when used as a homopolymer is -50°C or lower, from the viewpoint of controlling the glass transition temperature. The glass transition temperature when the alkyl (meth)acrylate monomer is used as a homopolymer is as described in the section on <Glass Transition Temperature> above.

[0037] In this disclosure, "constituent unit (a) derived from an alkyl (meth)acrylate monomer having a glass transition temperature of 0°C or higher when used as a homopolymer" is also simply referred to as "constituent unit (a)," and "constituent unit (b) derived from an alkyl (meth)acrylate monomer having a glass transition temperature of -50°C or lower when used as a homopolymer" is also simply referred to as "constituent unit (b)."

[0038] The specific (meth)acrylic resin particles preferably contain, for example, constituent unit (a) in a proportion of 70.0% by mass or less of the total constituent units, and constituent unit (b) in a proportion of 20.0% by mass to 90.0% by mass of the total constituent units, more preferably constituent unit (a) in a proportion of 10.0% by mass to 70.0% by mass of the total constituent units, and constituent unit (b) in a proportion of 30.0% by mass to 90.0% by mass of the total constituent units, and even more preferably constituent unit (a) in a proportion of 10.0% by mass to 60.0% by mass of the total constituent units, and constituent unit (b) in a proportion of 40.0% by mass to 90.0% by mass of the total constituent units.

[0039] The constituent unit (a) is not particularly limited, but preferably includes at least one of a constituent unit derived from methyl acrylate and a constituent unit derived from methyl methacrylate, more preferably at least one of a constituent unit derived from methyl acrylate and a constituent unit derived from methyl methacrylate, and even more preferably a constituent unit derived from methyl acrylate or a constituent unit derived from methyl methacrylate.

[0040] The constituent unit (b) is not particularly limited, but preferably includes at least one of a constituent unit derived from n-butyl acrylate and a constituent unit derived from 2-ethylhexyl acrylate, more preferably at least one of a constituent unit derived from n-butyl acrylate and a constituent unit derived from 2-ethylhexyl acrylate, and even more preferably a constituent unit derived from n-butyl acrylate or a constituent unit derived from 2-ethylhexyl acrylate.

[0041] When the specific (meth)acrylic resin particles contain a structural unit derived from a (meth)acrylic acid alkyl ester monomer, they may contain the structural unit derived from the (meth)acrylic acid alkyl ester monomer alone or in combination of two or more kinds.

[0042] When the specific (meth)acrylic resin particles contain a structural unit derived from a (meth)acrylic acid alkyl ester monomer, the content ratio of the structural unit derived from the (meth)acrylic acid alkyl ester monomer is not particularly limited. For example, it may be 50.0% by mass or more, 60.0% by mass or more, 70.0% by mass or more, 80.0% by mass or more, 90.0% by mass or more, or for example, 100% by mass, based on all the structural units of the specific (meth)acrylic resin particles.

[0043] <<Structural unit derived from a monomer having a carboxy group>> From the viewpoint of production suitability, for example, the specific (meth)acrylic resin particles preferably contain a structural unit derived from a monomer having a carboxy group.

[0044] The type of the monomer having a carboxy group is not particularly limited. Examples of the monomer having a carboxy group include monomers having at least one carboxy group and an ethylenically unsaturated group in one molecule. Examples of the ethylenically unsaturated group include a vinyl group, an allyl group, a vinylphenyl group, and a (meth)acryloyl group.

[0045] Specific examples of the monomer having a carboxy group include (meth)acrylic acid, crotonic acid, maleic acid, fumaric acid, itaconic acid, glutaconic acid, citraconic acid, ω-carboxy-polycaprolactone mono(meth)acrylate [for example, ω-carboxy-polycaprolactone (n≈2) monoacrylate], and succinic acid derivatives (for example, 2-acryloyloxyethyl-succinic acid). The monomer having a carboxy group preferably contains acrylic acid, and more preferably is acrylic acid.

[0046] When the specific (meth)acrylic resin particles contain a structural unit derived from a monomer having a carboxy group, the structural unit derived from the monomer having a carboxy group may be contained alone or in combination of two or more kinds.

[0047] When the specific (meth)acrylic resin particles contain a structural unit derived from a monomer having a carboxy group, the content of the structural unit derived from the monomer having a carboxy group is not particularly limited. For example, from the viewpoint of the production stability of the specific (meth)acrylic resin particles, it is preferably 0.1% by mass to 5.0% by mass, more preferably 0.5% by mass to 5.0% by mass, and still more preferably 0.5% by mass to 4.0% by mass based on all the structural units of the specific (meth)acrylic resin particles.

[0048] <<Other Structural Units>> The specific (meth)acrylic resin particles may contain a structural unit that does not fall under either the structural unit derived from an alkyl (meth)acrylate monomer or the structural unit derived from a monomer having a carboxy group (so-called other structural units). Examples of the other structural units include structural units derived from (meth)acrylates having an aromatic ring represented by benzyl (meth)acrylate and phenoxyethyl (meth)acrylate; structural units derived from alkoxyalkyl (meth)acrylates represented by methoxyethyl (meth)acrylate and ethoxyethyl (meth)acrylate; structural units derived from vinyl cyanide represented by acrylonitrile and methacrylonitrile; structural units derived from aromatic monovinyls represented by styrene, α-methylstyrene, t-butylstyrene, p-chlorostyrene, chloromethylstyrene, and vinyltoluene; structural units derived from vinyl esters represented by vinyl formate, vinyl acetate, vinyl propionate, and vinyl versatate; and the like.

[0049] When the specific (meth)acrylic resin particles contain other structural units, the other structural units may be contained alone or in combination of two or more kinds.

[0050] If the specific (meth)acrylic resin particles contain other constituent units, the content of the other constituent units can be set appropriately within a range that does not impair the effect of the bio-adhesive composition of this disclosure.

[0051] <Shape of Specific (Meth)acrylic Resin Particles> The shape of the specific (meth)acrylic resin particles is not particularly limited. A spherical shape is preferred for the specific (meth)acrylic resin particles. In this disclosure, "spherical" includes not only perfectly spherical shapes but also substantially spherical shapes.

[0052] <Average Particle Diameter of Specific (Meth)acrylic Resin Particles> The average particle diameter of specific (meth)acrylic resin particles is not particularly limited. In this disclosure, "average particle diameter" refers to the average primary particle diameter. From the viewpoint of the manufacturability of the specific (meth)acrylic resin particles, the average particle diameter is preferably 150 nm or more, and more preferably 200 nm or more. Furthermore, from the viewpoint of the dispersibility of the specific (meth)acrylic resin particles, the average particle diameter is preferably 500 nm or less, and more preferably 400 nm or less. In some embodiments, the average particle diameter of specific (meth)acrylic resin particles may be 150 nm to 500 nm, 200 nm to 500 nm, or 200 nm to 400 nm.

[0053] The average particle size of specific (meth)acrylic resin particles refers to the volume-average particle size and is measured using a laser diffraction particle size distribution analyzer by the following method: The specific (meth)acrylic resin particles are diluted with distilled water, thoroughly stirred and mixed, and then collected in a 10 mm × 75 mm × 85 mm glass cell using a Pasteur pipette. This is then placed in a laser diffraction particle size distribution analyzer. The concentration of the diluted solution of the specific (meth)acrylic resin particles is adjusted so that the transmittance of the laser light is 85%, and then the particle size distribution is measured at a measurement temperature of 25°C. The volume-average particle size of the specific (meth)acrylic resin particles is determined by processing the measurement results with a computer. Specifically, the particle size at 50% of the cumulative value (volume basis) in the obtained particle size distribution is taken as the volume-average particle size. As a laser diffraction particle size distribution analyzer, for example, the "Laser Scattering Particle Size Distribution Analyzer LA-960" manufactured by Horiba, Ltd. can be suitably used. However, the laser diffraction particle size distribution analyzer is not limited to this.

[0054] <Content of specific (meth)acrylic resin particles> The content of specific (meth)acrylic resin particles in the bio-adhesive composition of this disclosure is not particularly limited and may be, for example, 5% to 95% by mass with respect to the total solid content in the bio-adhesive composition.

[0055] In this disclosure, "total solid content in the bio-adhesive composition" means the mass of the residue remaining after removing the solvent from the bio-adhesive composition.

[0056] [Non-aromatic Nonionic Surfactants] The bio-adhesive compositions of the present disclosure include specific non-aromatic nonionic surfactants. More specifically, the non-aromatic nonionic surfactants included in the bio-adhesive compositions of the present disclosure are polyoxyalkylene alkyl ether compounds (X) and polyoxyalkylene alkyl ether compounds (Y) with different average mole addition numbers of oxyalkylene units, wherein, when the average mole addition number of oxyalkylene units of the polyoxyalkylene alkyl ether compound (X) is x1 and the average mole addition number of oxyalkylene units of the polyoxyalkylene alkyl ether compound (Y) is y1, then y1 is 7 or more greater than x1, x1 is 20 or more, and y1 is less than 63.

[0057] The non-aromatic nonionic surfactant contained in the bioadhesive composition of this disclosure is two types of polyoxyalkylene alkyl ether compounds with different average mole numbers of oxyalkylene units added, namely, polyoxyalkylene alkyl ether compound (X) and polyoxyalkylene alkyl ether compound (Y), and when the average number of moles of oxyalkylene units added by polyoxyalkylene alkyl ether compound (Y) y1 is 7 or more greater than the average number of moles of oxyalkylene units added by polyoxyalkylene alkyl ether compound (X) x1, when an adhesive layer is formed, a gap is formed between the two types of oxyalkylene moieties, long and short, of the polyoxyalkylene alkyl ether compound. Additive components such as pharmacoactive ingredients enter this gap, strengthening the entanglement between the oxyalkylene moieties of the polyoxyalkylene alkyl ether compound and the additive components, and the additive components are well retained in the adhesive layer. For this reason, the formed adhesive layer tends to be less prone to the migration of additive components such as pharmacoactive ingredients to the adhesive layer interface over time (so-called bleed-out).

[0058] The average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (Y) y1 is preferably 8 or more greater than the average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (X) x1. The upper limit is not particularly limited, but for example, it is preferably 30 or less, more preferably 25 or less, and even more preferably 20 or less. In one embodiment, the average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (Y) y1 may be greater than the average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (X) x1 in the range of 7 to 30, 7 to 25, 7 to 20, 8 to 30, 8 to 25, and 8 to 20.

[0059] The average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (X) x1 is 20 or more. When the average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (X) x1 is 20 or more, gaps of an appropriate size are formed in the adhesive layer. Because the added components that enter these gaps and the oxyalkylene moieties of the polyoxyalkylene alkyl ether compound (X) intertwine sufficiently, the resulting adhesive layer tends to be less prone to the migration of added components such as medicinal components to the adhesive layer interface over time (so-called bleed-out).

[0060] The average number of moles of oxyalkylene units added x1 of the polyoxyalkylene alkyl ether compound (X) is preferably 30 or more, and more preferably 35 or more. The upper limit is not particularly limited, but for example, it is preferably 50 or less, and more preferably 45 or less. In some embodiments, the average number of moles of oxyalkylene units added x1 of the polyoxyalkylene alkyl ether compound (X) may be in the range of 20 to 50, 20 to 45, 30 to 50, 30 to 45, 35 to 50, or 35 to 45.

[0061] The average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (Y) y1 is less than 63. When the average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (Y) y1 is less than 63, the hydrophilicity of the surfactant is not excessively high, resulting in low water absorption of the formed adhesive layer. Therefore, the adhesive strength of the adhesive layer tends not to change easily over time.

[0062] The average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (Y) y1 is preferably 60 or less. The lower limit is not particularly limited, but for example, it is preferably 27 or more, more preferably 37 or more, and even more preferably 42 or more. In some embodiments, the average number of moles of oxyalkylene units added to the polyoxyalkylene alkyl ether compound (Y) y1 may be in the range of 27 or more and less than 63, in the range of 37 or more and less than 63, in the range of 42 or more and less than 63, in the range of 27 or more and 60 or less, in the range of 37 or more and 60 or less, and in the range of 42 or more and 60 or less.

[0063] A preferred embodiment of the non-aromatic nonionic surfactant is one in which y1 is greater than x1 by a range of 7 to 30, x1 is in the range of 20 to 50, and y1 is in the range of 27 to less than 63. A more preferred embodiment is one in which y1 is greater than x1 by a range of 7 to 20, x1 is in the range of 35 to 45, and y1 is in the range of 42 to 60. For example, an embodiment of the non-aromatic nonionic surfactant may be one in which y1 is greater than x1 by a range of 7 to 30, x1 is in the range of 20 to 45, and y1 is in the range of 27 to 60, or one in which y1 is greater than x1 by a range of 7 to 25, x1 is in the range of 30 to 50, and y1 is in the range of 37 to less than 63, or one in which y1 is greater than x1 by a range of 7 to 25, x1 is in the range of 30 to 45, and y1 is in the range of 37 to 60. It may be in one embodiment that y1 is greater than x1 by 8 or more and 25 or less, x1 is in the range of 30 or more and 50 or less, and y1 is in the range of 42 or more and less than 63, it may be in one embodiment that y1 is greater than x1 by 8 or more and 25 or less, x1 is in the range of 30 or more and 45 or less, and y1 is in the range of 42 or more and 60 or less, and it may be in one embodiment that y1 is greater than x1 by 7 or more and 20 or less, x1 is in the range of 35 or more and 50 or less, and y1 is in the range of 42 or more and less than 63.

[0064] In this disclosure, the average number of moles of oxyalkylene units added to a polyoxyalkylene alkyl ether compound is a value obtained by the following formulas (1) and (2). In formula (1), "hydrophilic portion of the polyoxyalkylene alkyl ether compound" refers to the polyoxyalkylene structural portion of the polyoxyalkylene alkyl ether compound, and "hydrophobic portion of the polyoxyalkylene alkyl ether compound" refers to the portion of the polyoxyalkylene alkyl ether compound other than the hydrophilic portion.

[0065] Molecular weight of the hydrophilic portion of a polyoxyalkylene alkyl ether compound = [(HLB value of the polyoxyalkylene alkyl ether compound) × (Molecular weight of the hydrophobic portion of the polyoxyalkylene alkyl ether compound)] / [20 - (HLB value of the polyoxyalkylene alkyl ether compound)] ... (1)

[0066] Average number of moles of oxyalkylene units added = (Molecular weight of the hydrophilic portion of the polyoxyalkylene alkyl ether compound) / (Molecular weight of one oxyalkylene unit contained in the polyoxyalkylene alkyl ether compound) ... (2)

[0067] The HLB (Hydrophile Lipophile Balance) value of the non-aromatic nonionic surfactant [i.e., polyoxyalkylene alkyl ether compound (X) and polyoxyalkylene alkyl ether compound (Y); the same applies hereinafter] is not particularly limited, but from the viewpoint of the manufacturing stability of specific (meth)acrylic resin particles, it is preferably 17.0 to 18.6 and more preferably 18.0 to 18.5.

[0068] In this disclosure, the HLB value of the non-aromatic nonionic surfactant is a value calculated using the Griffin method. If a commercially available non-aromatic nonionic surfactant is used, and the catalog of the commercially available product lists an HLB value calculated using the Griffin method, the catalog value of the commercially available product shall be given priority as the HLB value of the non-aromatic nonionic surfactant.

[0069] The type of oxyalkylene units in polyoxyalkylene alkyl ether compound (X) and polyoxyalkylene alkyl ether compound (Y) is not particularly limited, and may be, for example, oxyethylene units, oxypropylene units, or oxybutylene units. The oxyalkylene units of polyoxyalkylene alkyl ether compound (X) and the oxyalkylene units of polyoxyalkylene alkyl ether compound (Y) may be the same or different. From the viewpoint of ease of availability of commercially available products, it is preferable that both the oxyalkylene units of polyoxyalkylene alkyl ether compound (X) and the oxyalkylene units of polyoxyalkylene alkyl ether compound (Y) are oxyethylene units.

[0070] The non-aromatic nonionic surfactant is preferably at least one of polyoxyethylene stearyl ether and polyoxyethylene lauryl ether, for example, from the viewpoint of readily available commercial products.

[0071] Commercially available non-aromatic nonionic surfactants can be used. Examples of commercially available non-aromatic nonionic surfactants include "Emulgen 130K," "Emulgen 150," and "Emulgen 350" manufactured by Kao Corporation, and "DKS NL-100," "DKS NL-250," "DKS NL-450F," and "DKS NL-600F" manufactured by Daiichi Kogyo Co., Ltd. Note that "Emulgen" is a registered trademark.

[0072] The content of the non-aromatic nonionic surfactant in the bioadhesive composition of this disclosure [i.e., the total content of polyoxyalkylene alkyl ether compound (X) and polyoxyalkylene alkyl ether compound (Y)] is not particularly limited, but for example, from the viewpoint of the dispersibility of specific (meth)acrylic resin particles, it is preferably 0.1 to 10.0 parts by mass, more preferably 0.1 to 7.0 parts by mass, and even more preferably 0.5 to 5.0 parts by mass per 100 parts by mass of specific (meth)acrylic resin particles.

[0073] The content ratio of polyoxyalkylene alkyl ether compound (X) to polyoxyalkylene alkyl ether compound (Y) in the bio-adhesive composition of this disclosure [polyoxyalkylene alkyl ether compound (X) / polyoxyalkylene alkyl ether compound (Y)] is not particularly limited and may be, for example, 1:10 to 10:1, 1:9 to 9:1, 1:8 to 8:1, or 1:7 to 7:1 by mass.

[0074] [Water] The bioadhesive composition of this disclosure contains water. The water is not particularly limited, but from the viewpoint of having fewer impurities, for example, distilled water, deionized water, pure water, etc. are preferred.

[0075] The water content in the bio-adhesive composition of this disclosure is not particularly limited and may be, for example, 10% to 80% by mass or 20% to 70% by mass, based on the total mass of the bio-adhesive composition.

[0076] [Other Components] The bio-adhesive composition of this disclosure may contain components other than those described above (so-called other components) as necessary, to the extent that it does not impair its effects.

[0077] Other ingredients include, for example, additives commonly used in pharmaceuticals, quasi-drugs, and cosmetics. Examples of additives include functional ingredients that exhibit useful pharmacological effects and cosmetic effects (e.g., moisturizing effect, skin conditioning effect, whitening effect, etc.) when used in biocompatible adhesive compositions. Such functional ingredients are also referred to as medicinal ingredients, moisturizing ingredients, skin conditioning ingredients, whitening ingredients, etc. These additives may have more than one function. Additives also include, for example, formulations of functional ingredients.

[0078] Other components include resin particles other than specific (meth)acrylic resin particles, surfactants other than non-aromatic nonionic surfactants, aqueous media other than water, defoamers, preservatives, thickeners, pH adjusters, buffers, antibacterial agents, antimicrobial agents, etc.

[0079] <<pH of the bio-adhesive composition>> The pH of the bio-adhesive composition of this disclosure is not particularly limited and can be set as appropriate, for example, taking into consideration the stability of the pharmacoactive ingredient contained in the bio-adhesive composition.

[0080] The pH of the bio-adhesive composition disclosed herein is measured using a pH meter in accordance with JIS Z 8802:2011, at a liquid temperature of 25°C. For example, a pH meter (model number: F-51) manufactured by Horiba, Ltd. can be used as the measuring device. However, the measuring device is not limited to this.

[0081] [Applications] The bio-adhesive composition of this disclosure is an adhesive composition for use in living organisms. Specifically, the bio-adhesive composition of this disclosure is an adhesive composition for use in adhering to living surfaces [e.g., skin (including nails)]. The adhesive layer formed by the bio-adhesive composition of this disclosure is less prone to bleed-out of additive components such as pharmacoactive ingredients over time, and the adhesive strength does not change easily over time. Therefore, the bio-adhesive composition of this disclosure is suitable for forming the adhesive layer of a patch (especially a poultices). The bio-adhesive composition of this disclosure can be applied to forming the adhesive layer of either topical formulations or transdermal formulations. Furthermore, the bio-adhesive composition of this disclosure can be used as a skin drug as is. The bio-adhesive composition of this disclosure is also applicable to applications other than living organisms.

[0082] [Method for Manufacturing Biomedical Adhesive Compositions] The method for manufacturing the biomedical adhesive composition of this disclosure is not particularly limited. The biomedical adhesive composition of this disclosure can be manufactured, for example, by a method that includes a step of manufacturing specific (meth)acrylic resin particles by emulsion polymerization.

[0083] Examples of emulsion polymerization methods for producing specific (meth)acrylic resin particles include the methods described in [1] to [3] below. In this disclosure, monomers that form the constituent units of specific (meth)acrylic resin particles are also referred to as "monomer components".

[0084] [1] A method in which monomer components, a specific non-aromatic nonionic surfactant, and water are charged into a reactor equipped with a thermometer, stirrer, raw material introduction pipe, reflux condenser, nitrogen introduction pipe, etc., and the temperature is raised while stirring under a nitrogen gas stream, after which polymerization initiators, reducing agents, etc. are added as appropriate to proceed with the emulsion polymerization reaction (so-called batch charging method). [2] A method in which a specific non-aromatic nonionic surfactant and water are charged into a reactor equipped with a thermometer, stirrer, raw material introduction pipe, reflux condenser, nitrogen introduction pipe, etc., and the temperature is raised while stirring under a nitrogen gas stream, after which monomer components are added dropwise, and polymerization initiators, reducing agents, etc. are added as appropriate to proceed with the emulsion polymerization reaction (so-called monomer dropwise method). [3] Water is charged into a reactor equipped with a thermometer, stirrer, raw material introduction pipe, reflux condenser, nitrogen introduction pipe, etc., and the reactor is purged with nitrogen. In a separate container, a specific non-aromatic nonionic surfactant and water are charged and stirred to prepare an aqueous surfactant solution. Next, a mixture of monomer components is added to the prepared aqueous surfactant solution and stirred to prepare a monomer emulsion. Next, the water in the reactor is heated while stirring. Next, when the water temperature reaches the polymerization temperature, a polymerization initiator, a reducing agent, etc. are added to the reactor, and then the monomer emulsion and polymerization initiator are added sequentially to proceed with the emulsion polymerization reaction (so-called emulsion monomer dropping method). Among these, as an emulsion polymerization method for producing specific (meth)acrylic resin particles, for example, the emulsion monomer dropping method described in [3] above is preferred from the viewpoint of industrial productivity.

[0085] The specific (meth)acrylic resin particles obtained by the emulsion polymerization method described above are obtained in the form of a dispersion in which they are dispersed in a medium containing at least water.

[0086] Details regarding monomer components, specific non-aromatic nonionic surfactants, and water are as described in the section on [Adhesive Compositions for Biomedical Use], and therefore will be omitted here.

[0087] Polymerization initiators are not particularly limited as long as they are used in ordinary emulsion polymerization. Examples of polymerization initiators include persulfates, organic peroxides, and azo compounds. Specific examples of persulfates include ammonium persulfate, sodium persulfate, and potassium persulfate. Specific examples of organic peroxides include t-butyl hydroperoxide, benzoyl peroxide, lauroyl peroxide, caproyl peroxide, di-i-propyl peroxydicarbonate, di-2-ethylhexyl peroxydicarbonate, and t-butyl peroxypivalate. Specific examples of azo compounds include 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 1,1'-azobis(cyclohexane-1-carbonitride), and 2,2'-azobis(isobutyric acid)dimethyl.

[0088] In an emulsion polymerization method for producing specific (meth)acrylic resin particles, one polymerization initiator may be used alone, or two or more may be used.

[0089] The polymerization initiator is used in the amount typically used. The amount of polymerization initiator used is preferably 0.15 to 0.45 parts by mass per 100 parts by mass of the total monomer components.

[0090] The reducing agent is not particularly limited as long as it can be used in normal emulsion polymerization. Examples of reducing agents include sodium metabisulfite, sodium sulfite, sodium bisulfite, sodium pyrosulfite, sodium hydroxymethanesulfinate, sodium pyrophosphate, thioglycolic acid, sodium thiosulfate, thiourea dioxide, L-ascorbic acid, tartaric acid, citric acid, and glucose.

[0091] In the emulsion polymerization method for producing specific (meth)acrylic resin particles, one reducing agent may be used alone, or two or more reducing agents may be used.

[0092] The reducing agent is used in the amount typically used. The amount of reducing agent used is preferably 0.01 to 0.45 parts by mass per 100 parts by mass of the total monomer components.

[0093] The polymerization temperature is preferably, for example, 50°C to 90°C. The polymerization time is preferably, for example, 4 hours to 10 hours.

[0094] The method for producing the bio-adhesive composition of this disclosure may include a step of adjusting the pH of the dispersion containing the specific (meth)acrylic resin particles obtained above. The method for adjusting the pH of the dispersion containing the specific (meth)acrylic resin particles is not particularly limited, and for example, a method using a pH adjusting agent can be cited. Examples of pH adjusting agents include sodium hydroxide and ammonia.

[0095] The pH of the dispersion containing specific (meth)acrylic resin particles is not particularly limited and can be set appropriately, for example, taking into consideration the stability of the active ingredient contained in the biocompatible adhesive composition.

[0096] The pH of a dispersion containing specific (meth)acrylic resin particles is measured using a pH meter in accordance with JIS Z 8802:2011, at a liquid temperature of 25°C. For example, a pH meter (model number: F-51) manufactured by Horiba, Ltd. can be used as the measuring device. However, the measuring device is not limited to this.

[0097] The viscosity of the dispersion containing specific (meth)acrylic resin particles is preferably 100 mP·s to 2000 mP·s, and more preferably 100 mP·s to 1000 mP·s, from the viewpoint of handling.

[0098] The viscosity of the dispersion of specific (meth)acrylic resin particles was measured using a BL-type rotational viscometer under conditions of a liquid temperature of 25°C and a rotor speed of 12 rpm. For example, a BL-type rotational viscometer (model number: BLII) manufactured by Toki Sangyo Co., Ltd. can be used. However, the measuring device is not limited to this.

[0099] The method for producing the bio-adhesive composition of this disclosure may include a step of mixing a dispersion containing the specific (meth)acrylic resin particles obtained above with an additive component such as a pharmaceutically active ingredient. Details of the additive component are as described in the section on [Bio-adhesive composition], so the explanation is omitted here.

[0100] [Adhesive Sheet] The adhesive sheet of this disclosure comprises a base material and an adhesive layer provided on the base material and formed of the bio-adhesive composition of this disclosure described above. Because the adhesive sheet of this disclosure comprises an adhesive layer formed of the bio-adhesive composition of this disclosure, bleed-out of additive components such as pharmacoactive ingredients over time is less likely to occur, and the adhesive strength does not change easily over time.

[0101] The adhesive sheet of this disclosure comprises a substrate. The substrate is not particularly limited as long as an adhesive layer can be formed thereon. Examples of substrates include polyolefins [e.g., polyethylene (PE) and polypropylene (PP)], polyesters [e.g., polyethylene terephthalate (PET)], acetate resins [e.g., triacetylcellulose], polyethersulfone, polycarbonate (PC), polyamide (PA), polyimide (PI), polyurethane, acrylic resins, polyvinyl chloride (PVC), acrylonitrile / butadiene / styrene resins (ABS resins), films containing resins such as fluororesins, paper (e.g., fine paper and coated paper), cloth (e.g., woven fabrics and nonwoven fabrics), and synthetic paper [e.g., Yupo paper (registered trademark)]. Furthermore, composite sheets obtained by laminating two or more of these substrates are also included.

[0102] When the substrate and the adhesive layer are in contact, the surface of the substrate on which the adhesive layer is provided may be subjected to surface treatment such as corona discharge treatment or plasma discharge treatment (so-called easy-adhesion treatment) from the viewpoint of improving the adhesion between the substrate and the adhesive layer.

[0103] The substrate may contain various additives such as plasticizers, colorants (e.g., dyes and pigments), heat stabilizers, light stabilizers, antistatic agents, flame retardants, antioxidants, and fillers. The substrate may have a pattern applied to part or all of it.

[0104] The thickness of the substrate is not particularly limited and may be, for example, 1 μm to 3000 μm.

[0105] In this disclosure, "substrate thickness" refers to the average thickness of the substrate. The average thickness of the substrate is determined by the following method: Ten randomly selected locations in the thickness direction of the substrate are measured using a film thickness gauge. The arithmetic mean of the measured values ​​is calculated, and the resulting value is taken as the average thickness of the substrate.

[0106] The thickness of the adhesive layer is not particularly limited and may be, for example, 1 μm to 3000 μm.

[0107] In this disclosure, "thickness of the adhesive layer" refers to the average thickness of the adhesive layer. The average thickness of the adhesive layer is determined by the following method: The thickness of 10 randomly selected points in the thickness direction of the adhesive layer is measured using a film thickness gauge. The arithmetic mean of the measured values ​​is calculated, and the resulting value is taken as the average thickness of the adhesive layer.

[0108] If the adhesive sheet of this disclosure is a substrate-type adhesive sheet having an adhesive layer on one side of a substrate, the exposed surface of the adhesive layer in the adhesive sheet of this disclosure may be protected by a release sheet. Generally, the release sheet protects the surface of the adhesive layer until the adhesive sheet is put into practical use and is peeled off when in use.

[0109] The release sheet is not particularly limited as long as it can be easily peeled off from the adhesive layer. Examples of release sheets include resin films, paper, synthetic paper, and composite sheets laminated with two or more of these, all of which have been surface-treated with a release agent (so-called easy-peel treatment) on one or both sides. In this disclosure, a release sheet in which one or both sides of a resin film have been surface-treated with a release agent (so-called easy-peel treatment) is also referred to as a "release film." Examples of release agents include silicone-based release agents (e.g., silicone), wax-based release agents (e.g., paraffin wax), and fluorine-based release agents (e.g., fluorine resins). Examples of resin films include polyester films, such as polyethylene terephthalate (PET) film. Examples of paper include fine paper and coated paper. The film thickness of the release sheet is not particularly limited, and is generally 20 μm to 180 μm.

[0110] [Applications] The adhesive sheet of this disclosure is preferably for use in living organisms. The adhesive layer of the adhesive sheet of this disclosure is less prone to bleed-out of additives such as pharmacoactive ingredients over time, and the adhesive strength does not change easily over time. For this reason, the adhesive sheet of this disclosure is suitable, for example, as a patch (particularly a poultices). The adhesive sheet of this disclosure can be applied as a patch for either topical formulations or transdermal formulations.

[0111] [Method for manufacturing the adhesive sheet] The method for manufacturing the adhesive sheet of this disclosure is not particularly limited. The adhesive sheet of this disclosure can be manufactured by known methods. The following methods are preferred as examples of methods for manufacturing the adhesive sheet of this disclosure.

[0112] A coating film is formed on a substrate by applying the biocompatible adhesive composition of this disclosure to one side of the substrate. Next, an adhesive layer is formed on the substrate by drying the formed coating film. Then, the exposed side of the formed adhesive layer is placed on the easily peelable surface of a release sheet and bonded together. By doing so, an adhesive sheet of this disclosure having a laminated structure of substrate / adhesive layer / release sheet can be produced.

[0113] The adhesive sheet of this disclosure can also be prepared by applying the bio-adhesive composition of this disclosure to one side of a substrate and forming an adhesive layer on the substrate without drying. By applying the bio-adhesive composition of this disclosure to one side of a substrate, an adhesive layer is formed on the substrate. Then, the exposed side of the formed adhesive layer is placed on the easily peeled surface of a release sheet and bonded together. In this way, the adhesive sheet of this disclosure having a laminated structure of substrate / adhesive layer / release sheet can be prepared.

[0114] The method of applying the biocompatible adhesive composition is not particularly limited. Examples of known methods for applying the biocompatible adhesive composition include gravure roll coaters, reverse roll coaters, kiss roll coaters, dip roll coaters, knife coaters, spray coaters, bar coaters, applicators, and the like. The amount of biocompatible adhesive composition applied is not particularly limited and can be set appropriately depending on the purpose.

[0115] The drying method for the coating film is not particularly limited. Examples of drying methods for the coating film include natural drying, heat drying, hot air drying, and vacuum drying. The drying temperature and drying time of the coating film are not particularly limited and are set appropriately according to the thickness of the coating film, the amount of water contained in the coating film, etc. An example of drying conditions is drying at 100°C to 120°C for 60 to 300 seconds using a hot air circulation dryer.

[0116] The bio-adhesive compositions of this disclosure will be described in more detail below with reference to examples. This disclosure is not limited to the following examples unless it exceeds the spirit of the disclosure.

[0117] In the following examples, the pH of the aqueous dispersion of (meth)acrylic resin particles was measured using a pH meter (model number: F-51) manufactured by Horiba, Ltd., in accordance with JIS Z 8802:2011, at a liquid temperature of 25°C. The viscosity of the aqueous dispersion of (meth)acrylic resin particles was measured using a BL-type rotational viscometer (model number: BLII) manufactured by Toki Sangyo Co., Ltd., at a liquid temperature of 25°C and a rotor speed of 12 rpm. The average particle size of the (meth)acrylic resin particles was measured using a laser diffraction particle size distribution analyzer (product name: Laser Scattering Particle Size Distribution Analyzer LA-960) manufactured by Horiba, Ltd., in the same manner as the measurement method for the average particle size of the specific (meth)acrylic resin particles described above. Furthermore, the glass transition temperature (Tg) of the (meth)acrylic resin particles was determined using the same method as described above for determining the glass transition temperature of the specific (meth)acrylic resin particles. The average number of moles of oxyalkylene units (AO units) added to the surfactant was determined using the same method as described above for determining the average number of moles of oxyalkylene units added to the specific non-aromatic nonionic surfactant. The HLB values ​​of the surfactants were taken from the catalog values ​​of commercially available products.

[0118] [Production of Biomolecular Adhesive Composition] [Example 1] (1) Production of (meth)acrylic resin particles 900 parts by mass of ion-exchanged water was charged into a reactor equipped with a thermometer, stirrer, nitrogen inlet tube and reflux condenser, and then nitrogen was purged into the reactor. In a separate container, 700.0 parts by mass of ion-exchanged water and 67.0 parts by mass [effective value of active ingredient] of the surfactants Emulgen (registered trademark) 150 [manufactured by Kao Corporation] and 67.0 parts by mass [effective value of active ingredient] of Emulgen (registered trademark) 130K [manufactured by Kao Corporation] were charged, and these were mixed and stirred to prepare an aqueous surfactant solution. Next, a monomer mixture consisting of 2835.0 parts by mass of 2-ethylhexyl acrylate (2EHA), 595.0 parts by mass of methyl acrylate (MA), and 70.0 parts by mass of acrylic acid (AA) was added to the prepared aqueous surfactant solution and stirred to obtain a monomer emulsion. Next, the deionized water in the reactor was heated while being stirred under a nitrogen atmosphere. When the temperature of the deionized water reached 70°C, 1.0 part by mass of potassium persulfate [polymerization initiator] and 1.0 part by mass of sodium metabisulfite [reducing agent] were added to the deionized water in the reactor. Then, while maintaining the temperature at 70°C, the monomer emulsion and 600.0 parts by mass of a 2.0% by mass potassium persulfate aqueous solution were sequentially added for about 300 minutes to polymerize the monomer components in the monomer mixture. After that, the contents of the reactor were stirred for 180 minutes while maintaining the temperature at 65°C to obtain an aqueous dispersion of (meth)acrylic resin particles.

[0119] The obtained aqueous dispersion of (meth)acrylic resin particles had a solid content concentration of 60.6% by mass, a pH of 2.0, a viscosity of 500 mPa·s, and an average particle size of 250 nm. Here, "solid content concentration" refers to the mass ratio of (meth)acrylic resin particles in the aqueous dispersion of (meth)acrylic resin particles. The same concept applies to each aqueous dispersion of (meth)acrylic resin particles produced below.

[0120] (2) Mixing of additive components 165 parts by mass [100 parts by mass in terms of solid content] of the aqueous dispersion of (meth)acrylic resin particles obtained in (1) above and 25 parts by mass [25 parts by mass in terms of solid content] of methyl salicylate [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.] as a pharmaceutically active ingredient were thoroughly stirred and mixed to obtain the biocompatible adhesive composition of Example 1.

[0121] [Examples 2-4] Except for changing the monomer composition of the (meth)acrylic resin particles in "(1) Production of (meth)acrylic resin particles" in Example 1 to the monomer composition shown in Table 1, the bio-adhesive compositions for bio-use in Examples 2-4 were obtained in the same manner as in Example 1.

[0122] [Examples 5-11] Except for changing the type and amount of surfactant in "(1) Production of (meth)acrylic resin particles" of Example 1 to the type and amount shown in Table 1, each of the bio-adhesive compositions for biological use in Examples 5-11 was obtained in the same manner as in Example 1.

[0123] In Examples 2 to 11, the "(1) Production of (meth)acrylic resin particles" yielded aqueous dispersions of (meth)acrylic resin particles, all of which had a solid content concentration of 60.6% by mass.

[0124] The pH and viscosity of the aqueous dispersion of (meth)acrylic resin particles obtained in "(1) Production of (meth)acrylic resin particles" of Examples 2 to 11, as well as the average particle size of the (meth)acrylic resin particles, were as follows. <pH> Example 2: 2.0, Example 3: 2.0, Example 4: 2.0, Example 5: 2.0, Example 6: 2.0, Example 7: 2.0, Example 8: 2.0, Example 9: 2.1, Example 10: 2.0, Example 11: 2.1 <Viscosity> Example 2: 292 mPa·s, Example 3: 475 mPa·s, Example 4: 700 mPa·s, Example 5: 525 mPa·s, Example 6: 600 mPa·s, Example 7: 675 mPa·s, Example 8: 612 mPa·s, Example 9: 610 mPa·s, Example 10: 813 mPa·s, Example 11: 245 mPa·s <Average particle size> Example 2: 224 nm, Example 3: 224 nm, Example 4: 274 nm, Example 5: 243 nm, Example 6: 246 nm, Example 7: 233 nm, Example 8: 237 nm, Example 9: 272 nm, Example 10: 310 nm, Example 11: 314 nm

[0125] Table 1 shows the monomer composition and glass transition temperature (Tg) of the (meth)acrylic resin particles contained in each of the bio-adhesive compositions of Examples 1 to 11, as well as the type of surfactant, the average number of moles of AO units added, the amount, and the difference in the average number of moles of AO units added between the two types of surfactants.

[0126] [Comparative Examples 1, 3-7, 9 and 10] The bio-adhesive compositions of Comparative Examples 1, 3-7, 9 and 10 were obtained in the same manner as in Example 1, except that the type and amount of surfactant in "(1) Production of (meth)acrylic resin particles" of Example 1 were changed to the types and amounts shown in Table 2.

[0127] [Comparative Example 2] A bio-adhesive composition for comparative examples was obtained in the same manner as in Example 2, except that the type and amount of surfactant in "(1) Production of (meth)acrylic resin particles" of Example 2 were changed to the type and amount shown in Table 2.

[0128] [Comparative Example 8] A bio-adhesive composition for biological applications of Comparative Example 8 was obtained in the same manner as in Example 1, except that the monomer composition of the (meth)acrylic resin particles was changed to the monomer composition shown in Table 2 in "(1) Production of (meth)acrylic resin particles" of Example 1.

[0129] In Comparative Examples 1 to 10, the solid content concentration of the aqueous dispersions of (meth)acrylic resin particles obtained in "(1) Production of (meth)acrylic resin particles" was 60.6% by mass in all cases.

[0130] Table 2 shows the monomer composition and glass transition temperature (Tg) of the (meth)acrylic resin particles contained in each of the bio-adhesive compositions for Comparative Examples 1 to 10, as well as the type of surfactant, the average number of moles added in AO units, the amount, and the difference in the average number of moles added in AO units.

[0131]

[0132]

[0133] Details of the monomers and surfactants listed in Tables 1 and 2 are as follows. For convenience, in Tables 1 and 2, components corresponding to "(meth)acrylate alkyl ester monomers with a glass transition temperature of 0°C or higher when used as a homopolymer" are labeled "(a)", components corresponding to "(meth)acrylate alkyl ester monomers with a glass transition temperature of -50°C or lower when used as a homopolymer" are labeled "(b)", and "other monomers" are labeled "other". The amounts of surfactants shown in Tables 1 and 2 are all calculated on an active ingredient basis.

[0134] [Monomers] <(a)> "MA": Methyl acrylate (Glass transition temperature when used as a homopolymer: 10°C) "MMA": Methyl methacrylate (Glass transition temperature when used as a homopolymer: 105°C) <(b)> "2EHA": 2-Ethylhexyl acrylate (Glass transition temperature when used as a homopolymer: -70°C) "n-BA": n-Butyl acrylate (Glass transition temperature when used as a homopolymer: -54°C) <Others> "AA": Acrylic acid (monomer with a carboxyl group) (Glass transition temperature when used as a homopolymer: 106°C)

[0135] [Surfactants] <Non-aromatic nonionic surfactants> "Emulgen 130K" [Product name, active ingredient: polyoxyethylene lauryl ether, HLB: 18.1 (catalog value), manufactured by Kao Corporation] "Emulgen 150" [Product name, active ingredient: polyoxyethylene lauryl ether, HLB: 18.4 (catalog value), manufactured by Kao Corporation] "Emulgen 350" [Product name, active ingredient: polyoxyethylene stearyl ether, HLB: 17.8 (catalog value), manufactured by Kao Corporation] "DKS NL-100" [Product name, active ingredient: polyoxyethylene lauryl ether, HLB: 13.8 (catalog value), manufactured by Daiichi Kogyo Co., Ltd.] "DKS NL-250" [Product name, active ingredient: polyoxyethylene lauryl ether, HLB: 17.0 (catalog value), manufactured by Daiichi Kogyo Co., Ltd.] "DKS NL-450F" [Product name, active ingredient: polyoxyethylene lauryl ether, HLB: 18.2 (catalog value), manufactured by Daiichi Kogyo Co., Ltd.] "DKS NL-600F" [Product name, active ingredient: polyoxyethylene lauryl ether, HLB: 18.6 (catalog value), manufactured by Daiichi Kogyo Co., Ltd.] "Nonion K-2100W" [Product name, active ingredient: polyoxyethylene lauryl ether, HLB: 19.2 (catalog value), manufactured by NOF Corporation] <Aromatic nonionic surfactants> "Neugen EM-230D" [Product name, active ingredient: polyoxyethylene nonylphenol ether, HLB: 16.8 (catalog value), manufactured by Daiichi Kogyo Co., Ltd.] "Neugen EM-250" [Product name, active ingredient: polyoxyethylene nonylphenol ether, HLB: 18.2 (catalog value), manufactured by Daiichi Kogyo Co., Ltd.] "Neugen "EA-197D" [Product name, active ingredient: polyoxyethylene distyrenated phenyl ether, HLB: 17.5 (catalog value), manufactured by Daiichi Kogyo Co., Ltd.] "Neugen EA-177D" [Product name, active ingredient: polyoxyethylene distyrenated phenyl ether, HLB: 15.6 (catalog value), manufactured by Daiichi Kogyo Co., Ltd.]

[0136] In Tables 1 and 2, "-" indicates that there is no corresponding entry in that column.

[0137] [Preparation of evaluation adhesive sheet] The bio-adhesive composition prepared above was applied to one side of a base material, high-quality paper [Model number: KWF-70, manufactured by Oji Tack Co., Ltd.], to form a coating film. The amount of bio-adhesive composition applied was 60 g ± 5 g / m² after drying (i.e., the adhesive layer). ２ The amount was set to the desired level. Next, the formed coating film was dried at 100°C for 180 seconds using a hot air circulation dryer to form an adhesive layer on the surface of the substrate. Then, the easily peelable side of a release sheet [product name: Sumirise SL-80KCM, manufactured by Sumika Kako Paper Co., Ltd.] was placed on top of the exposed surface of the adhesive layer formed on the substrate. In this way, an evaluation adhesive sheet having the configuration of substrate / adhesive layer / release sheet was prepared.

[0138] [Measurement and Evaluation] 1. Bleed-out of additive components The bleed-out of additive components contained in the adhesive layer was evaluated by the rate of increase over time of the water contact angle on the surface of the adhesive layer. This is based on the fact that methyl salicylate, an additive component contained in the adhesive layer of the evaluation adhesive sheet, is an oily component, and therefore, when it bleeds out from the adhesive layer, the water contact angle on the surface of the adhesive layer increases. First, the evaluation adhesive sheet prepared as described above was cut to prepare two test pieces measuring 25 mm x 150 mm. Next, one of the two prepared test pieces was left to stand for 1 hour in an environment with an ambient temperature of 25°C and 50% RH, and was designated as test piece X1. The other test piece was left to stand for 1 week in an environment with an ambient temperature of 40°C and 75% RH, and was designated as test piece Y1. Next, the release sheets were peeled off test piece X1 and test piece Y1 to expose the surface of the adhesive layer. Next, 1 μL of pure water was dropped onto the exposed surface of the adhesive layer, and the water contact angle was measured 1 second after dropping. A contact angle measuring device (product name: Fully Automatic Contact Angle Meter DM-701) manufactured by Kyowa Interface Science Co., Ltd. was used for the measurement. The water contact angle over time (unit: %) was calculated from the measured value θX1 (unit: °) of the water contact angle (so-called initial water contact angle) on test piece X1 and the measured value θY1 (unit: °) of the water contact angle (so-called water contact angle after time) on test piece Y1, based on the following formula, and the evaluation was performed according to the evaluation criteria below. The measured values ​​of the water contact angle, the rate of increase over time, and the evaluation results are shown in Tables 3 and 4. If the evaluation result was "A" or "B", it was judged that there was no practical problem. An evaluation result of "A" is more preferable.

[0139] The rate of increase in the water contact angle over time = (θY1 - θX1) / (θX1) × 100

[0140] -Evaluation Criteria- A: The rate of increase of the water contact angle over time is less than 2.0%. B: The rate of increase of the water contact angle over time is in the range of 2.0% or more and less than 3.0%. C: The rate of increase of the water contact angle over time is 3.0% or more.

[0141] 2. Stability of Adhesion Strength Over Time The stability of the adhesive strength of the adhesive layer over time was evaluated using a method compliant with the J. Dow method (the so-called inclined ball tack method). First, the evaluation adhesive sheet prepared above was cut to prepare two test pieces measuring 25 mm x 100 mm. Of the two test pieces prepared, one was left to stand for 1 hour in an environment with an ambient temperature of 25°C and 50% RH, and was designated as test piece X2. The other test piece was left to stand for 1 week in an environment with an ambient temperature of 40°C and 75% RH, and was designated as test piece Y2. Test pieces X2 and Y2 were attached to the inclined surface of an inclined table with an inclination angle of 30°, with the substrate side of the test piece facing the inclined surface of the inclined table. Next, the release sheets were peeled off test pieces X2 and Y2 to expose the surface of the adhesive layer. Next, a steel ball with a diameter of n / 32 inches was slid down the inclined surface of the test specimen from a position 100 mm above the surface. The n value of the steel ball with the largest diameter that stopped on the exposed surface of the adhesive layer was recorded. Then, the change in n value over time was calculated based on the following formula, and the evaluation was performed according to the evaluation criteria below. The measured values ​​of n value, the change in n value over time, and the evaluation results are shown in Tables 3 and 4. If the evaluation result was "A", it was judged that there were no practical problems.

[0142] Change in n value over time = (n value of test specimen Y2) - (n value of test specimen X2)

[0143] -Evaluation Criteria- A: The change in the n value over time is within ±1. B: The change in the n value over time is +2 or greater, or -2 or less.

[0144] In Table 4, "Not Evaluable" means that the tack strength was too low to be evaluated.

[0145] As shown in Tables 3 and 4, the adhesive layer formed with the adhesive composition of the example was found to be less prone to bleed-out of the active ingredient over time and less prone to changes in adhesive strength over time compared to the adhesive layer formed with the adhesive composition of the comparative example.

[0146] The disclosure of Japanese Patent Application No. 2025-014303, filed on 30 January 2025, is incorporated herein by reference in its entirety. All documents, patent applications, and technical standards described herein are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard were specifically and individually described as being incorporated by reference.

Claims

1. A biocompatible adhesive composition comprising (meth)acrylic resin particles having a glass transition temperature of -60°C to -20°C, a non-aromatic nonionic surfactant, and water, wherein the non-aromatic nonionic surfactant is a polyoxyalkylene alkyl ether compound (X) and a polyoxyalkylene alkyl ether compound (Y) with different average mole addition numbers of oxyalkylene units, where x1 is the average mole addition number of oxyalkylene units of the polyoxyalkylene alkyl ether compound (X), and y1 is the average mole addition number of oxyalkylene units of the polyoxyalkylene alkyl ether compound (Y), such that y1 is 7 or more greater than x1, x1 is 20 or more, and y1 is less than 63.

2. The bio-adhesive composition according to claim 1, wherein x1 is 35 or more.

3. The bioadhesive composition according to claim 1, wherein both the oxyalkylene units of the polyoxyalkylene alkyl ether compound (X) and the oxyalkylene units of the polyoxyalkylene alkyl ether compound (Y) are oxyethylene units.

4. The bioadhesive composition according to claim 1, wherein the HLB value of the non-aromatic nonionic surfactant is 17.0 to 18.

6.

5. The bio-adhesive composition according to claim 1, wherein the total content of the polyoxyalkylene alkyl ether compound (X) and the polyoxyalkylene alkyl ether compound (Y) is 0.1 parts by mass to 10.0 parts by mass per 100 parts by mass of the (meth)acrylic resin particles.

6. The bioadhesive composition according to claim 1, wherein the content ratio of the polyoxyalkylene alkyl ether compound (X) to the polyoxyalkylene alkyl ether compound (Y) is 1:10 to 10:1 by mass.

7. The biocompatible adhesive composition according to claim 1, wherein the (meth)acrylic resin particles contain 70.0% by mass or less of constituent units (a) derived from an alkyl (meth)acrylate monomer having a glass transition temperature of 0°C or higher when used as a homopolymer, and 20.0% by mass to 90.0% by mass of constituent units (b) derived from an alkyl (meth)acrylate monomer having a glass transition temperature of -50°C or lower when used as a homopolymer, relative to the total constituent units.

8. The bio-adhesive composition according to claim 7, wherein the constituent unit (a) comprises at least one of a constituent unit derived from methyl acrylate and a constituent unit derived from methyl methacrylate.

9. The bio-adhesive composition according to claim 1, wherein the average particle size of the (meth)acrylic resin particles is 150 nm to 500 nm.

10. An adhesive sheet comprising: a base material; and an adhesive layer provided on the base material and formed from a biocompatible adhesive composition according to any one of claims 1 to 9.

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