Brolanceptin-containing patch and method for producing the same

Abstract

A patch comprising a support and a pressure-sensitive adhesive layer disposed thereon, characterized in that the pressure-sensitive adhesive layer comprises blonanserin or a salt thereof, a thermoplastic elastomer, and an ester of a higher fatty acid.

Description

Technical Field

[0001] The present invention relates to a patch containing bronanocerin and a method for producing the same. More specifically, the present invention relates to a bronanocerin-containing patch in which crystals are less likely to precipitate and a method for producing the same.

Background Art

[0002] In the treatment of schizophrenia, recurrence and relapse due to poor medication adherence of antipsychotic drugs (oral preparations) are problems. Lonasen (registered trademark) tape, which was launched in September 2019, is a patch for treating schizophrenia with bronanocerin as an active ingredient. By proposing a new dosage form in the treatment of schizophrenia, which has hitherto had only oral medications, it is expected to increase the options for therapeutic drugs and lead to improved medication adherence in patients.

[0003] The drug utilization rate of Lonasen (registered trademark) tape is low (Non-Patent Document 1), and it was necessary to increase the size of the preparation in order to absorb a sufficient amount of the drug through the skin and obtain the drug blood concentration required for treatment.

[0004] In addition, bronanocerin has high crystallinity, and crystals of bronanocerin may precipitate on the surface of the adhesive layer during storage of the bronanocerin-containing patch, resulting in problems in terms of storage stability.

[0005] Therefore, there is a demand for a bronanocerin-containing patch with high skin permeability of bronanocerin and excellent storage stability in which crystal precipitation is less likely to occur, and a method for producing the same.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] The present invention aims to solve the above-mentioned problems in the prior art and to achieve the following objects: That is, the present invention aims to provide a blonanserin-containing patch which is resistant to crystal precipitation, has excellent storage stability, and has high skin permeability, and a method for producing the same. [Means for solving the problem]

[0008] As a result of intensive research conducted by the present inventors to solve the above problems, the present invention has a support and an adhesive layer on the support, and the adhesive layer is made of a bromine ン The present invention has been completed based on the discovery that a patch containing serine or a salt thereof, a thermoplastic elastomer, and a higher fatty acid ester can provide a blonanserin-containing patch that is resistant to crystallization, has excellent storage stability, and has high skin permeability. The present invention is based on the above findings by the present inventors, and the means for solving the above problems are as follows.

[0009] <1> A support and an adhesive layer on the support, the adhesive layer being made of a material selected from the group consisting of bromine and methacrylic acid. ン The patch is characterized by comprising serine or a salt thereof, a thermoplastic elastomer, and a higher fatty acid ester. <2> The above <1> The method for producing the patch according to claim 1, further comprising the step of laminating the support and the pressure-sensitive adhesive layer. Effect of the Invention

[0010] According to the present invention, it is possible to solve the above-mentioned conventional problems and achieve the above-mentioned object, and it is possible to provide a blonanserin-containing patch that suppresses crystal precipitation and has high skin permeability, and a production method thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] (Patch) The patch has a support and an adhesive layer on the support, and may further have other elements.

[0012] <Support> There are no particular restrictions on the support, and it can be appropriately selected according to the purpose. For example, an adhesive sheet for skin application or a commonly used one in transdermal absorption preparations can be used.

[0013] There are no particular restrictions on the material of the support, and it can be appropriately selected according to the purpose. For example, polyesters such as polyethylene terephthalate, polyolefins such as polyethylene and polypropylene, polyurethane, ethylene vinyl acetate copolymer, polyvinyl chloride, etc. can be mentioned.

[0014] The structure of the support may be a single-layer structure or a multi-layer structure. Also, it may be a knitted fabric, non-woven fabric, film, foam, porous, mesh structure, sheet-like, or flat-plate-like.

[0015] Furthermore, in order to prevent the accumulation of static electricity in the support, an antistatic agent may be contained in the knitted fabric, non-woven fabric, film, etc. constituting the support. Also, in order to obtain good anchoring properties with the adhesive layer, a non-woven fabric or knitted fabric, or a laminate of these and a film can be used as the support.

[0016] There are no particular restrictions on the thickness of the support, and it can be appropriately selected according to the purpose. However, for a film, 10 μm or more and 100 μm or less is preferable, and 15 μm or more and 50 μm or less is more preferable. For a porous sheet such as a knitted fabric, non-woven fabric, or foamed support, 50 μm or more and 2,000 μm or less is preferable, and 100 μm or more and 1,000 μm or less is more preferable.

[0017] <Adhesive layer> The adhesive layer contains (a) bronantherine or a salt thereof, (b) a thermoplastic elastomer, and (c) a higher fatty acid ester, and may further have other components.

[0018] (a) Bromanocerin or a salt thereof The above-mentioned "bromanocerin" is a compound represented by the chemical name 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydroxycyclooct[a]pyridine, which is classified as an SDA (serotonin-dopamine antagonist) and is commercially available as an antipsychotic drug (atypical antipsychotic drug).

[0019] The above-mentioned bromanocerin may be in the free form or a pharmaceutically acceptable salt, and is not particularly limited. There is no particular limitation on the above-mentioned pharmaceutically acceptable salt, and it can be appropriately selected according to the purpose. For example, pharmaceutically acceptable acid addition salts and the like can be mentioned, and they may be inorganic salts or organic salts.

[0020] Only one kind of the above-mentioned pharmaceutically acceptable salt may be used, or two or more kinds may be used in combination. Furthermore, the free form and the salt may be mixed and used.

[0021] There is no particular limitation on the above-mentioned inorganic salt, and it can be appropriately selected according to the purpose. For example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like can be mentioned.

[0022] Examples of the above-mentioned organic acid salts include formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonate, methanesulfonate and the like. From the viewpoint of easy availability, the free form or hydrochloride is preferred, and from the viewpoint of skin permeability, it is more preferable to use the free form.

[0023] The content of bronantherine or its salt in the pressure-sensitive adhesive layer, that is, the ratio of bronantherine or its salt to the total 100% by mass of the components constituting the pressure-sensitive adhesive layer, is not particularly limited and can be appropriately selected according to the purpose. However, from the viewpoints of ensuring dispersibility in the pressure-sensitive adhesive layer and good skin permeability, the lower limit is preferably 0.5% by mass or more, more preferably 0.75% by mass or more, still more preferably 1% by mass or more, and particularly preferably 1.5% by mass or more. The upper limit is preferably 30% by mass or less, more preferably 25% by mass or less, still more preferably 20% by mass or less, and particularly preferably 15% by mass or more.

[0024] (b) Thermoplastic elastomer The "thermoplastic elastomer" according to the present invention is an elastomer that exhibits thermoplasticity, softening and showing fluidity when heated and returning to a rubbery elastic body when cooled.

[0025] The thermoplastic elastomer is not particularly limited and can be appropriately selected according to the purpose. Examples include various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based, and olefin-based. In particular, from the viewpoint of achieving both sufficient skin adhesiveness and low skin irritation, styrene-based thermoplastic elastomers, particularly styrene-based block copolymers, are preferred.

[0026] The styrenic block copolymer is not particularly limited and can be appropriately selected according to the purpose. For example, styrene-butadiene block copolymer, styrene-butadiene-styrene block copolymer, styrene-isoprene block copolymer, styrene-isoprene-styrene block copolymer, styrene-ethylene / butylene block copolymer, styrene-ethylene / butylene-styrene block copolymer, styrene-ethylene / propylene block copolymer, styrene-ethylene / propylene-styrene block copolymer, styrene-isobutylene block copolymer, styrene-isobutylene-styrene block copolymer, etc. may be mentioned. Note that the "ethylene / butylene" represents a copolymer block of ethylene and butylene, and the "ethylene / propylene" represents a copolymer block of ethylene and propylene. These styrenic block copolymers may be used alone or in combination of two or more.

[0027] Among the above-mentioned styrenic block copolymers, from the viewpoints of achieving both sufficient skin adhesiveness of the adhesive layer and suppression of adhesive residue due to improved cohesion, as well as availability and handleability, one or more selected from the group consisting of styrene-isoprene-styrene block copolymer and styrene-isoprene block copolymer are preferred, and in particular, a mixture of styrene-isoprene block copolymer and styrene-isoprene-styrene block copolymer is preferred.

[0028] The lower limit of the proportion of the styrene-isoprene block copolymer in the mixture is not particularly limited and can be appropriately selected according to the purpose, but is preferably 10% by mass or more, more preferably 15% by mass or more, further preferably 20% by mass or more, particularly preferably 40% by mass or more, and most preferably 50% by mass or more.

[0029] The upper limit of the proportion of the styrene-isoprene block copolymer in the mixture is not particularly limited and can be appropriately selected according to the purpose, but is preferably 95% by mass or less, more preferably 90% by mass or less, further preferably 85% by mass or less, and particularly preferably 80% by mass or less.

[0030] The styrene content in the styrene-isoprene-styrene block copolymer is not particularly limited and can be appropriately selected according to the purpose. However, it is preferably 5% by mass or more and 60% by mass or less, more preferably 10% by mass or more and 50% by mass or less, in the copolymer.

[0031] The molecular weight of the styrene-isoprene-styrene block copolymer is not particularly limited and can be appropriately selected according to the purpose. However, it is preferably 20,000 or more and 500,000 or less, more preferably 30,000 or more and 300,000 or less, in terms of the weight average molecular weight measured by gel permeation chromatography (GPC).

[0032] The styrene content in the styrene-isoprene block copolymer is not particularly limited and can be appropriately selected according to the purpose. However, it is preferably 5% by mass or more and 50% by mass or less, more preferably 10% by mass or more and 40% by mass or less, in the copolymer.

[0033] The molecular weight of the styrene-isoprene block copolymer is not particularly limited and can be appropriately selected according to the purpose. However, it is preferably 10,000 or more and 500,000 or less, more preferably 20,000 or more and 300,000 or less, in terms of the weight average molecular weight measured by GPC.

[0034] The viscosity of the styrenic block copolymer is not particularly limited and can be appropriately selected according to the purpose. However, from the viewpoint of improving the balance of the adhesive substances, the lower limit of the solution viscosity at 25 °C of a 25% by mass toluene solution is preferably 500 mPa·s or more, more preferably 900 mPa·s or more, and the upper limit is preferably 2000 mPa·s or less, more preferably 1800 mPa·s or less. The "solution viscosity at 25 °C of a 25% by mass toluene solution" is a value measured based on the viscosity measurement method of styrene-isoprene-styrene block copolymer described on page 395 of "Pharmaceutical Additive Standards 2013" (published by Yakujutsu Shimbunsha).

[0035] As for the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, copolymers produced by known methods can be used respectively. Also, commercially available products that satisfy the above characteristics can be used for the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer respectively. In addition, mixtures of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer are also commercially available, and commercially available products of mixtures in which the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer that satisfy the above characteristics are mixed at the above mixing ratio can be preferably used.

[0036] Examples of commercially available styrene block copolymers include "KRATON (registered trademark) D1111", "KRATON (registered trademark) D1163", "KRATON (registered trademark) D1113", and "KRATON (registered trademark) D1119" manufactured by KRATON POLYMERS; "JSR (registered trademark) SIS5229", "JSR (registered trademark) SIS5002", "JSR (registered trademark) SIS5403", and "JSR (registered trademark) SIS5505" manufactured by JSR; and "Quintac (registered trademark) 3421", "Quintac (registered trademark) 3433N", "Quintac (registered trademark) 3520", "Quintac (registered trademark) 3450", and "Quintac (registered trademark) 3270" manufactured by Nippon Zeon Co., Ltd.

[0037] Among these, from the viewpoints of the mixing ratio of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer and the solution viscosity, "KRATON (registered trademark) D1163", "KRATON (registered trademark) D1113", "JSR (registered trademark) SIS5403", "JSR (registered trademark) SIS5505", "Quintac (registered trademark) 3433N", and "Quintac (registered trademark) 3520" are preferred, and "JSR (registered trademark) SIS5505" and / or "Quintac (registered trademark) 3520" are particularly preferred.

[0038] The content of the thermoplastic elastomer in the pressure-sensitive adhesive layer, that is, the ratio of the thermoplastic elastomer in the total 100% by mass of the components constituting the pressure-sensitive adhesive layer, is not particularly limited and can be appropriately selected according to the purpose. However, the lower limit is preferably 20% by mass or more, more preferably 25% by mass or more, and still more preferably 30% by mass or more, and the upper limit is preferably 70% by mass or less, more preferably 65% by mass or less, and still more preferably 60% by mass or less. If the ratio is 20% by mass or more, the shape of the pressure-sensitive adhesive layer can be more reliably maintained, and if it is 70% by mass or less, the adhesiveness of the pressure-sensitive adhesive layer to the skin can be more reliably exhibited.

[0039] (c) Higher fatty acid ester In the present invention, the "higher fatty acid ester" is a compound in which the carboxyl group of a higher fatty acid is ester-bonded to an aliphatic alcohol. The higher fatty acid ester has the effect of moderately plasticizing the thermoplastic elastomer and contributes to imparting adhesiveness. Further, the higher fatty acid ester exhibits an appropriate affinity with bronantherine and also contributes to improving the solubility of bronantherine in the adhesive layer and suppressing crystal precipitation.

[0040] The higher fatty acid constituting the higher fatty acid ester may be either linear or branched. Further, the higher fatty acid may be either saturated or unsaturated, but saturated fatty acids are preferred from the viewpoints of the plasticizing effect and thermal stability of the thermoplastic elastomer. The number of carbon atoms of the higher fatty acid is preferably 12 or more, more preferably 14 or more, still more preferably 16 or more, and preferably 30 or less, more preferably 24 or less, still more preferably 20 or less.

[0041] Examples of the saturated higher fatty acids include capric acid (C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16), stearic acid (C18), isostearic acid (C18), arachidic acid (C20), behenic acid (C22), lignoceric acid (C24), cerotic acid (C26), montanic acid (C28), melissic acid (C30), and the like. Among these, myristic acid, palmitic acid, and stearic acid are preferred.

[0042] Examples of the unsaturated higher fatty acids include palmitoleic acid (C16), oleic acid (C18), linoleic acid (C18), (9,12,15)-linolenic acid (C18), (6,9,12)-linolenic acid (C18), eleostearic acid (C18), and the like. Among these, oleic acid and linoleic acid are preferred.

[0043] The aliphatic alcohol constituting the higher fatty acid ester is a saturated or unsaturated aliphatic alcohol having 1 to 30 carbon atoms. Examples thereof include methanol, ethanol, propanol, isopropanol, butanol, hexanol, heptanol, octanol, decanol, cetanol, myristyl alcohol, hexyl decanol, oleyl alcohol, and octyldodecanol. The number of carbon atoms of the aliphatic alcohol corresponds to the number of carbon atoms in the ester moiety of the higher fatty acid ester. The number of carbon atoms of the aliphatic alcohol is preferably 12 or more and 30 or less. If the number of carbon atoms is 12 or more, the plasticizing effect by the aliphatic alcohol is more surely exhibited. On the other hand, if it is 30 or less, sufficient solubility in the pressure-sensitive adhesive layer of bronantherine can be ensured.

[0044] Preferable specific examples of the higher fatty acid ester include, for example, myristic acid esters such as isopropyl myristate, ethyl myristate, and octyldodecyl myristate; palmitic acid esters such as isopropyl palmitate and ethyl palmitate; stearic acid esters such as isopropyl stearate; oleic acid esters such as decyl oleate, octyldodecyl oleate, and oleyl oleate; linoleic acid esters such as ethyl linoleate, and the like. Among them, octyldodecyl myristate is particularly preferable from the viewpoints of plasticity and solubility of bronantherine.

[0045] The ratio of the higher fatty acid ester to 100 parts by mass of the thermoplastic elastomer in the pressure-sensitive adhesive layer is preferably 25 parts by mass or more and 300 parts by mass or less. If the ratio is 25 parts by mass or more, good adhesiveness of the pressure-sensitive adhesive layer and solubility of bronanzelin are more surely exhibited. If it is 300 parts by mass or less, the shape of the pressure-sensitive adhesive layer can be more surely maintained. The ratio is more preferably 30 parts by mass or more and 200 parts by mass or less. Further, for the same reason, the content of the higher fatty acid ester in the pressure-sensitive adhesive layer of the patch according to the present invention is preferably 10% by mass or more, more preferably 15% by mass or more, even more preferably 20% by mass or more, and preferably 75% by mass or less, more preferably 70% by mass or less, even more preferably 65% by mass or less.

[0046] -Other Components- In the pressure-sensitive adhesive layer, as other components, if necessary, (d) polyisobutylene, (e) aliphatic dicarboxylic acid ester, (f) glycerin monoether, (g1) fatty acid monoester of polyhydric alcohol, (g2) higher alcohol, (g3) alcoholic solvent, (g4) amide solvent, (g5) ester solvent, (g6) liquid organic acid, (g7) carboxylate, (g8) lactone, (g9) surfactant, (g10) filler, (g11) crystal precipitation inhibitor, (h) tackifier, etc. can be blended.

[0047] (d) Polyisobutylene Polyisobutylene can be added for adjusting the adhesive physical properties. The "polyisobutylene" used in the pressure-sensitive adhesive layer of the present invention is a polymer of isobutylene, an elastic rubbery semi-solid or viscous substance, and is added in the present invention to impart sufficient skin adhesiveness.

[0048] The polyisobutylene can be used alone or as a mixture of a low molecular weight polyisobutylene having a viscosity average molecular weight of 30,000 to 100,000, a medium molecular weight polyisobutylene having a viscosity average molecular weight of 100,000 to 500,000, and a high molecular weight polyisobutylene having a viscosity average molecular weight of 500,000 to 5,000,000. In particular, mixing the low molecular weight polyisobutylene and the high molecular weight polyisobutylene, or using the medium molecular weight polyisobutylene alone is preferable for achieving a balance between low skin irritation and high skin adhesiveness.

[0049] As the polyisobutylene, a polymer of isobutylene produced by a method known per se can be used. In particular, in the pressure-sensitive adhesive layer of the present invention for skin application, those conforming to the standards specified in pharmaceutical additive standards, the United States Pharmacopeia, etc. can be preferably used. Also, as the polyisobutylene, commercially available products satisfying the above viscosity average molecular weight can be used respectively.

[0050] Examples of the commercially available products include, as the low molecular weight polyisobutylene, "Oppanol® B10SFN", "Oppanol® B10N", "Oppanol® B12SFN", "Oppanol® B15SFN", "Oppanol® B15N", etc. manufactured by BASF; as the medium molecular weight polyisobutylene, "Oppanol® N50SF", "Oppanol® N50", etc. manufactured by BASF; and as the high molecular weight polyisobutylene, "Oppanol® N80", "Oppanol® N100", "Oppanol® N150", etc. manufactured by BASF.

[0051] Among these, from the viewpoints of solubility when used as a coating liquid and the balance of the adhesive physical properties of the obtained pressure-sensitive adhesive, as the low-molecular-weight polyisobutylene, “Oppanol® B15SFN” and “Oppanol® B15N” with a viscosity-average molecular weight of 50,000 to 100,000 are particularly preferred, as the medium-molecular-weight polyisobutylene, “Oppanol® N50SF” and “Oppanol® N50” are particularly preferred, and as the high-molecular-weight polyisobutylene, “Oppanol® N80” is particularly preferred.

[0052] The content of polyisobutylene in the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected according to the purpose. However, if the content of polyisobutylene in the pressure-sensitive adhesive layer is too small, the enhancement of skin adhesiveness will be insufficient, and if it is too large, problems such as deterioration of skin irritation due to excessive enhancement of skin adhesiveness, glue residue during peeling, and poor drug solubility may occur. Therefore, the lower limit of the content of polyisobutylene in the pressure-sensitive adhesive layer is 0.1 part by weight or more, preferably 0.3 part by weight or more, more preferably 0.5 part by weight or more, and still more preferably 1 part by weight or more with respect to 100 parts by weight of the thermoplastic elastomer. The upper limit of the content of polyisobutylene in the pressure-sensitive adhesive layer is 300 parts by weight or less, preferably 100 parts by weight or less, more preferably 50 parts by weight or less, and still more preferably 30 parts by weight or less with respect to 100 parts by weight of the thermoplastic elastomer.

[0053] As a more specific preferred embodiment, the polyisobutylene content in the pressure-sensitive adhesive layer can be 0.1% by mass to 50% by mass, more preferably 0.2% by mass to 40% by mass, still more preferably 0.3% by mass to 30% by mass, and particularly preferably 0.5% by mass to 25% by mass.

[0054] (e) aliphatic dicarboxylic acid ester The aliphatic dicarboxylic acid ester is not particularly limited and can be appropriately selected according to the purpose. For example, liquid aliphatic dicarboxylic acid esters at room temperature such as diethyl adipate, diisopropyl adipate, and diisobutyl adipate, and liquid sebacic acid diesters at room temperature such as diethyl sebacate, diisopropyl sebacate, and dioctyldodecyl sebacate. Examples include diesters that are liquid at room temperature and are composed of a dicarboxylic acid having 2 to 12 carbon atoms and a monovalent aliphatic alcohol having 1 to 20 carbon atoms. Among them, diisopropyl adipate and diisobutyl adipate are preferred from the viewpoints of enhancing the solubility of the drug and the absorption promoting effect.

[0055] The lower limit of the content of the aliphatic dicarboxylic acid ester in the total 100% by mass of the components constituting the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected according to the purpose. However, 0.2% by mass or more is preferable, 0.5% by mass or more is more preferable, 1% by mass or more is still more preferable, and 1.5% by mass or more is particularly preferable. The upper limit of the content of the aliphatic dicarboxylic acid ester in the total 100% by mass of the components constituting the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected according to the purpose. However, 20% by mass or less is preferable, 10% by mass or less is more preferable, 5% by mass or less is still more preferable, and 3% by mass or less is particularly preferable.

[0056] (f) Glycerin monoether The glycerin monoether is not particularly limited and can be appropriately selected according to the purpose. For example, α-monoisostearyl glyceryl monoether and the like can be mentioned.

[0057] The lower limit of the content of the glycerin monoether in the total 100% by mass of the components constituting the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected according to the purpose. However, 0.05% by mass or more is preferable, 0.1% by mass or more is more preferable, 0.2% by mass or more is still more preferable, and 0.3% by mass or more is particularly preferable. The upper limit of the content of the glycerin monoether in the total 100% by mass of the components of the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected according to the purpose. However, it is preferably 10% by mass or less, more preferably 5% by mass or less, still more preferably 1.5% by mass or less, and particularly preferably 1.0% by mass or less.

[0058] (g1) Fatty acid monoesters of polyhydric alcohols In the present invention, the "fatty acid monoesters of polyhydric alcohols" are compounds in which one hydroxyl group of a polyhydric alcohol such as ethylene glycol, propylene glycol, glycerin, etc. and a fatty acid are ester-bonded. The fatty acid monoesters of polyhydric alcohols contribute to the improvement of drug solubility without extremely reducing the cohesive force of the pressure-sensitive adhesive base, and have an absorption-promoting effect.

[0059] The polyhydric alcohol constituting the fatty acid monoesters of polyhydric alcohols is not particularly limited and can be appropriately selected according to the purpose. Examples include ethylene glycol, propylene glycol, butylene glycol, glycerin, etc. The fatty acid constituting the fatty acid monoesters of polyhydric alcohols is not particularly limited and can be appropriately selected according to the purpose. However, fatty acids having 8 to 18 carbon atoms are preferred, and examples include capric acid, caprylic acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, etc.

[0060] Preferable specific examples of the fatty acid monoesters of polyhydric alcohols are propylene glycol monocaprylate and propylene glycol monolaurate. In order to enhance the solubility and absorption-promoting effect of the drug, the content of the fatty acid monoesters of polyhydric alcohols is preferably 2% by mass or more, more preferably 5% by mass or more, based on the total amount of the pressure-sensitive adhesive components. On the other hand, when a large amount of the fatty acid monoesters of polyhydric alcohols is added, the cohesive force and adhesive force of the adhesive strength decrease. Therefore, the content of the fatty acid monoesters of polyhydric alcohols is preferably 30% by mass or less based on the total amount of the pressure-sensitive adhesive components.

[0061] (g2) Higher alcohol The higher alcohol is not particularly limited and can be appropriately selected according to the purpose. For example, higher saturated aliphatic alcohols having about 12 to 20 carbon atoms and being liquid at room temperature, such as lauryl alcohol and isostearyl alcohol; higher unsaturated aliphatic alcohols having about 12 to 20 carbon atoms and being liquid at room temperature, such as oleyl alcohol, etc. may be mentioned. Among these, lauryl alcohol and oleyl alcohol are preferred from the viewpoint of enhancing the solubility and absorption promoting effect of the drug.

[0062] (g3) Alcohol-based solvent The alcohol-based solvent is not particularly limited and can be appropriately selected according to the purpose. For example, polyhydric alcohols that are liquid at room temperature, such as ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, and polyethylene glycol having a molecular weight of about 100 to 600; monoalkyl ethers of polyhydric alcohols, such as diethylene glycol monoethyl ether; mono-fatty acid esters of polyhydric alcohols, such as glycerol monolinoleate and glycerol monooleate, etc. may be mentioned. Among these, from the viewpoint of improving the solubility of the drug, ethylene glycol, propylene glycol, glycerin, and 1,3-butanediol are preferred.

[0063] (g4) Amide-based solvent The amide-based solvent is not particularly limited and can be appropriately selected according to the purpose. For example, pyrrolidones such as N-methyl-2-pyrrolidone and 2-pyrrolidone; imidazolidinones such as 1,3-dimethyl-2-imidazolidinone; N-substituted toluidines such as crothamide; alkane amides such as formamide, N-methylformamide, N,N-dimethylformamide, N-methylacetamide, N,N-dimethylacetamide, and N-methylpropanamide, etc. may be mentioned. Among the amide solvents, from the viewpoints of improving the solubility, dispersibility, and transdermal absorbability of drugs, N-methyl-2-pyrrolidone, clotrimaton, N,N-dimethylformamide, and N,N-dimethylacetamide are preferred, and N-methyl-2-pyrrolidone and clotrimaton are more preferred.

[0064] (g5) Ester solvents The ester solvents are not particularly limited and can be appropriately selected according to the purpose. For example, diesters of dihydric alcohols and carboxylic acids, medium-chain fatty acid triglycerides, esters of polyvalent carboxylic acids and monohydric aliphatic alcohols, carbonates, etc. can be mentioned.

[0065] The diesters of the dihydric alcohol and the carboxylic acid are not particularly limited and can be appropriately selected according to the purpose. For example, diesters composed of propylene glycol and caprylic acid, capric acid, lauric acid, oleic acid, etc. can be mentioned.

[0066] The medium-chain fatty acid triglyceride is a triglyceride composed of fatty acids having about 6 to 12 carbon atoms such as caproic acid, caprylic acid, capric acid, lauric acid, etc. and glycerin. In the present invention, caprylic acid triglyceride, a triglyceride mixture of caprylic acid and capric acid, a triglyceride mixture of caprylic acid, capric acid, and lauric acid, etc. that are liquid at normal temperature can be used. Also, oils and fats that are liquid at normal temperature and contain a large amount of these can be used. Examples of such oils and fats include olive oil, almond oil, safflower oil, soybean oil, corn oil, sesame oil, coconut oil, orange oil, ginger oil, torreya oil, rapeseed oil, castor oil, sunflower oil, cottonseed oil, peanut oil, etc. In the present invention, commercially available products for pharmaceuticals can also be used as the medium-chain fatty acid triglyceride that is liquid at normal temperature or the oil and fat containing the medium-chain fatty acid triglyceride that is liquid at normal temperature.

[0067] The carbonate ester is not particularly limited and can be appropriately selected according to the purpose. Examples of the cyclic carbonate ester of carbonic acid and a diol having 2 to 10 carbon atoms include ethylene carbonate, propylene carbonate, vinylene carbonate, etc., and propylene carbonate is preferred.

[0068] Among the above ester solvents, a medium-chain fatty acid triglyceride mixture and a carbonate ester are preferred, and a triglyceride mixture of caprylic acid and capric acid and propylene carbonate are more preferred.

[0069] In the present invention, the alcohol solvent, the amide solvent, and the ester solvent can be selected and used singly or in combination of two or more thereof as necessary. The content of these solvents is not particularly limited and can be appropriately selected according to the purpose. However, the proportion in the total amount of the pressure-sensitive adhesive layer is preferably 0.1% by mass or more and 20% by mass or less, more preferably 0.5% by mass or more and 15% by mass or less.

[0070] (g6) Liquid organic acid The liquid organic acid is not particularly limited and can be appropriately selected according to the purpose. Examples include aliphatic monocarboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid (heptanoic acid), caprylic acid, pelargonic acid (nonanoic acid), isostearic acid, and levulinic acid; aliphatic unsaturated monocarboxylic acids such as oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid; liquid carboxylic acids substituted with an alkoxy group such as methoxyacetic acid; and sulfonic acids such as methanesulfonic acid. These liquid organic acids have a function of assisting the dissolution of basic drugs such as bronantherine, can contain a high concentration of basic drugs in the pressure-sensitive adhesive layer, can improve the dispersibility, and further have an effect of improving the transdermal absorbability. From such a viewpoint, among these liquid organic acids, levulinic acid, oleic acid, and isostearic acid are preferred.

[0071] In the present invention, one or more can be selected and contained from the liquid organic acids as necessary. The content of the liquid organic acid is not particularly limited and can be appropriately selected according to the purpose. However, the proportion in the total amount of the pressure-sensitive adhesive layer is preferably 0.1% by mass or more and 20% by mass or less, more preferably 0.5% by mass or more and 15% by mass or less.

[0072] (g7) Carboxylate The carboxylate is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include salts of aliphatic monocarboxylic acids, alicyclic monocarboxylic acids, aliphatic dicarboxylic acids, etc. The aliphatic monocarboxylic acid is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include fatty acids having 2 to 7 carbon atoms such as acetic acid, butyric acid, and hexanoic acid, fatty acids having 8 to 11 carbon atoms such as octanoic acid and decanoic acid, fatty acids having 12 or more carbon atoms such as lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid, hydroxy monocarboxylic acids such as glycolic acid, lactic acid, 3-hydroxybutyric acid, and mandelic acid, monocarboxylic acids substituted with an alkoxy group such as methoxyacetic acid, and keto monocarboxylic acids such as levulinic acid. The alicyclic monocarboxylic acid is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include alicyclic monocarboxylic acids having 6 to 8 carbon atoms such as cyclohexanecarboxylic acid. The aliphatic dicarboxylic acid is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include sebacic acid, adipic acid, malic acid, maleic acid, fumaric acid, etc.

[0073] Preferred carboxylic acids include fatty acids having 12 or more carbon atoms and hydroxy monocarboxylic acids. Examples thereof include myristic acid, stearic acid, isostearic acid, oleic acid, etc. More preferably, they are lauric acid and oleic acid. The salt of the carboxylic acid is not particularly limited and can be appropriately selected according to the purpose. Examples include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, and amine salts. From the viewpoints of easy availability and the effect of improving percutaneous absorbability, the sodium salt is preferred.

[0074] (g8) Lactone The lactone is not particularly limited and can be appropriately selected according to the purpose. Examples include 5-membered ring lactones such as ascorbic acid and isoascorbic acid. In the patch of the present invention, considering the effect of improving the stability of the drug or the effect of improving percutaneous absorbability, as the carboxylate or lactone, sodium oleate, sodium lactate, ascorbic acid or isoascorbic acid is preferred.

[0075] When the patch of the present invention contains a carboxylate or lactone, the content in the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected according to the purpose. However, it is preferably 0.1 mol or more and 5 mol or less, more preferably 0.2 mol or more and 3 mol or less, per 1 mol of the drug. When the addition amount per 1 mol of the drug is less than 0.1 mol, a sufficient effect of improving percutaneous absorbability may not be obtained. When the addition amount per 1 mol of the drug is more than 5 mol, the physical properties of the preparation such as adhesive properties may deteriorate.

[0076] (g9) Surfactant There are no particular restrictions on the surfactant, and it can be appropriately selected according to the purpose. For example, polyoxyethylene fatty acid esters such as polyoxyethylene monolaurate, polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monopalmitate, sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate, glycerin fatty acid esters such as glycerin monooleate, polyoxyethylene castor oil derivatives, and polyoxyethylene hydrogenated castor oil, polyoxyethylene higher aliphatic alcohol ethers such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether, polyoxyethylene alkyl phenyl ethers such as polyoxyethylene nonyl phenyl ether, polyoxyethylene alkyl amino ethers such as polyoxyethylene lauryl amine and polyoxyethylene oleyl amine, nonionic surfactants such as Pluronic (registered trademark) L-31 and Pluronic (registered trademark) L-44, anionic surfactants such as sodium alkyl sulfates such as sodium lauryl sulfate, cationic surfactants such as alkyl trimethyl ammonium salts and alkyl dimethyl ammonium salts, and amphoteric surfactants such as alkyl dimethyl amine oxide and alkyl carboxy betaine. One or more of these can be selected and used.

[0077] Among the above surfactants, for enhancing percutaneous absorption, nonionic surfactants that are liquid at normal temperature are preferred, sorbitan fatty acid esters that are liquid at normal temperature are more preferred, and sorbitan monolaurate is particularly preferred. In the patch of the present invention, there are no particular restrictions on the content of the surfactant in the pressure-sensitive adhesive layer when it is contained, and it can be appropriately selected according to the purpose. Preferably, it is 0.01% by mass or more and 10% by mass or less, more preferably 0.1% by mass or more and 5% by mass or less.

[0078] (g10) Filler A filler can be contained to control the flexibility of the pressure-sensitive adhesive layer. There are no particular restrictions on the filler, and it can be appropriately selected according to the purpose. For example, silicon compounds such as silicic anhydride, light silicic anhydride, and hydrous silicic acid, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, water-soluble polymers such as polyvinyl alcohol, aluminum compounds such as dry aluminum hydroxide gel and aluminum hydrous silicate, kaolin, titanium oxide, etc. can be mentioned. The filler may be used alone or in combination of two or more. There are no particular restrictions on the content of the filler, and it can be appropriately selected according to the purpose, and it can be contained within a range where high skin permeability and sufficient cohesive force and adhesiveness as an adhesive can be maintained. Among them, preferably, it is 10% by mass or less based on the total amount of the pressure-sensitive adhesive component, more preferably 5% by mass or less, and most preferably 2% by mass or less.

[0079] (g11) Crystal precipitation inhibitor A crystal precipitation inhibitor can be contained in the pressure-sensitive adhesive layer to inhibit crystal precipitation of the drug. There are no particular restrictions on the crystal precipitation inhibitor, and it can be appropriately selected according to the purpose. For example, polyvinyl pyrrolidone, vinyl acetate-vinyl pyrrolidone copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, ammonioalkyl methacrylate copolymer, etc. can be mentioned. The crystal precipitation inhibitor may be used alone or in combination of two or more.

[0080] The content of the crystallization inhibitor is not particularly limited and can be appropriately selected according to the purpose, and can be contained within the range where the adhesive force is maintained as an adhesive. Among them, preferably, it is 0.01% by mass or more and 10% by mass or less based on the total amount of the adhesive component, and more preferably, it is 0.1% by mass or more and 5% by mass or less.

[0081] (h) Adhesion promoter From the viewpoint of enhancing the adhesive force of the adhesive layer, the adhesive may contain an adhesion promoter. In the present invention, the "adhesion promoter" is an adhesion promoter generally used in the field of adhesives, and is not particularly limited and can be appropriately selected according to the purpose. For example, rosin resins, polyterpene resins, coumarone-indene resins, petroleum resins, terpene resins, terpene-phenol resins, alicyclic saturated hydrocarbon resins, etc. can be mentioned. From the viewpoints of having a track record of use in pharmaceuticals and easy availability, terpene resins, rosin resins, and alicyclic saturated hydrocarbon resins are preferred. These may be used alone or in combination of two or more.

[0082] In order to achieve the adhesive force necessary to obtain sufficient drug efficacy, the adhesion promoter can be added. However, if a large amount of the adhesion promoter is added, the drug release property may decrease or the skin irritation may increase. Therefore, the content of the adhesion promoter is preferably 50% by mass or less, more preferably 30% by mass or less, still more preferably 20% by mass or less, and particularly preferably 10% by mass or less based on the total amount of the adhesive component.

[0083] <Other elements> The adhesive can also be provided with a release liner common in the art. That is, the adhesive of the present invention may be one in which a support, an adhesive layer, and a release liner are laminated in this order. The release liner is not particularly limited and can be appropriately selected according to the purpose. For example, resin films such as glassine paper, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, and polystyrene; aluminum films; foamed polyethylene films or foamed polypropylene films; laminates of two or more of the above can be used. Further, as the release liner, those subjected to silicone processing, fluororesin processing, embossing processing, hydrophilic processing, hydrophobic processing, etc. can also be used.

[0084] The thickness of the release liner is not particularly limited and can be appropriately selected according to the purpose, but is preferably 10 μm or more and 200 μm or less, and more preferably 15 μm or more and 150 μm or less.

[0085] (Method for manufacturing an adhesive) The method for manufacturing the adhesive is a method for manufacturing the adhesive, which is not particularly limited and is a generally used manufacturing method such as a solvent method or a hot melt method. For example, when manufacturing an adhesive by the solvent method, it can include a step of spreading a coating liquid for forming an adhesive layer on a release liner and drying the solvent in the coating liquid to obtain an adhesive layer, and a step of laminating the support and the adhesive layer.

[0086] <Spreading and drying step> The spreading and drying step is not particularly limited and can be appropriately selected according to the purpose. For example, methods include dissolving or dispersing (a) bronantherine or a salt thereof, (b) a thermoplastic elastomer, and (c) a higher fatty acid ester in a solvent such as toluene to prepare a coating liquid for forming an adhesive layer, applying the obtained coating liquid to a release liner, and then drying it.

[0087] The coating is not particularly limited and can be appropriately selected according to the purpose. For example, it can be carried out using conventional coaters such as roll coaters, die coaters, gravure roll coaters, reverse roll coaters, kiss roll coaters, dip roll coaters, bar coaters, knife coaters, spray coaters, etc.

[0088] The solvent used in the coating liquid is not particularly limited and can be appropriately selected according to the purpose. However, those that can uniformly dissolve or disperse the components (a), (b), and (c) are preferred. For example, aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, aliphatic hydrocarbons such as hexane and heptane, ethers such as tetrahydrofuran, diethyl ether, and t-butyl methyl ether, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, alcohols such as ethanol, propanol, and butanol, and acetate esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate can be mentioned. These solvents can be used alone or in combination of two or more. Since the solubility of each component constituting the adhesive layer is good, aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, aliphatic hydrocarbons such as hexane and heptane can be used alone or in combination, or aromatic hydrocarbons such as toluene, aliphatic hydrocarbons such as hexane and heptane, and acetate esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate can be used in combination, which is more preferred.

[0089] The drying is not particularly limited and can be appropriately selected according to the purpose. However, it is preferably carried out under heating, for example, at a temperature of about 40°C or higher and 150°C or lower. The drying temperature, drying time, and drying method can be adjusted according to the solvent used and the amount used. The weight per unit area of the adhesive layer after drying may be adjusted according to the required skin adhesiveness and transdermal absorption performance. There are no particular limitations as long as skin adhesiveness can be obtained, and it can be appropriately selected according to the purpose. However, the adhesive layer after drying is preferably 10 g / m 2 or more and 1,000 g / m 2 or less, more preferably 20 g / m 2 or more and 800 g / m 2 or less, even more preferably 30 g / m2 or more and 600 g / m 2 or less.

[0090] <Lamination process> Examples of the lamination process include the lamination process of the support.

[0091] -Lamination process of the support- The lamination process of the support is not particularly limited and can be appropriately selected according to the purpose. For example, a method of laminating the support to the adhesive layer by pressure bonding can be mentioned.

Examples

[0092] Hereinafter, examples of the present invention will be described, but the present invention is not limited to these examples at all.

[0093] <Examples 1 to 8: Production of patches> According to the formulations shown in Table 1, each component constituting the adhesive layer was weighed. The numerical values of each component in Table 1 are in mass%. First, the styrene-based block copolymer was dissolved in toluene, and then bronantherin and octyldodecyl myristate as a higher fatty acid ester were added and mixed and stirred to prepare a coating solution for forming the adhesive layer. The above coating solution was applied to the adhesive layer 1 cm after drying 2The thickness was adjusted so that the bronanocerin content per hit would be the same as that of Lonaseen (registered trademark) tape, and it was applied to a silicone-treated polyethylene terephthalate (PET) film as a release liner. After drying in an oven at 50°C for 60 minutes, a PET film (support) was laminated on the surface of the adhesive layer, and it was cut into a size of 15 cm × 30 cm to obtain an adhesive patch.

[0094]

Table 1

[0095] <Test Example 1: Evaluation of Crystal Precipitation> The adhesive patches of Examples 1 to 8 were packaged with a PET packaging material and stored at 25°C for 1 month. The crystal precipitation situation of bronanocerin after storage was observed visually and under a microscope, and the crystal precipitation of the adhesive patch was evaluated according to the following criteria. The results are shown in Table 1. ○: No crystals were visually observed. △: The particle size was 200 μm or less, and no crystals were visually observed. ×: Crystals were visually observed. <Test Example 2: Evaluation of Cohesion> The cohesion of the adhesive layer of the adhesive patch was evaluated in four grades by finger tack (finger touch test) according to the following criteria. The results are shown in Table 1. 3: No glue residue was observed. 2: Almost no glue residue was observed, and it was within an acceptable range. 1: The cohesion was slightly insufficient, but it was within an acceptable range. 0: Glue residue, mold collapse, etc. were observed, and the lack of cohesion was significant.

[0096] <Test Example 3: Evaluation of Adhesiveness> The adhesiveness of the adhesive layer of the adhesive patch was evaluated in four grades by finger tack (finger touch test) according to the following criteria. The results are shown in Table 1. 3: It showed the same adhesiveness as Lonaseen (registered trademark) tape. 2: It had slightly lower adhesiveness than Lonaseen (registered trademark) tape. 1: The adhesiveness was weak, and the fingers could be easily peeled off. 0: It did not adhere at all, and peeling was remarkable.

[0097] <Comparative Examples 1 - 8: Production of Adhesive Patches> Adhesive patches were produced in the same manner as in Examples 1 - 8, except that the components constituting the adhesive layer were changed to the formulations shown in Table 2. In the same manner as in Examples 1 - 8, crystal precipitation, cohesive force, and adhesive force were evaluated. The results are shown in Table 2.

[0098]

Table 2

[0099] As shown in the results in Table 1, in Examples 1 - 8 using a higher fatty acid ester as a plasticizer, almost no crystal precipitation of bronantherine was observed, and in the comparative examples shown in Table 2, crystal precipitation of bronantherine was seen during storage. On the other hand, the adhesive force and cohesive force of the adhesive patches in the examples were almost the same as those of the adhesive patches in the comparative examples.

[0100] <Test Example 4: Evaluation of Skin Permeability> The abdominal excised skin of hairless male rats (HWY / Slc, SPF, 5 - week - old) that had been depilated was immersed in a buffer solution for 30 minutes, and after wiping off the moisture on the skin surface, it was punched out into a circle with a diameter of 2.5 cm. The adhesive patch prepared in Example 2 was punched out into a circle with a diameter of 1.3 cm, pasted on the rat skin, then set in a vertical diffusion cell, and the test was started using an automatic sampling device for percutaneous absorption test (manufactured by Cosmedi). A buffer solution was used as the buffer, and the test was carried out at a buffer temperature of 32°C. After 24 hours from the start of the test, a part of the buffer was sampled, and the amount of drug that had permeated through the rat skin in the buffer was quantified by HPLC. As a control preparation containing bronantherine, Ronasen (registered trademark) tape (existing preparation) was used. The measurement was performed 3 times for each adhesive patch, the average value of the measured values was calculated, and the skin permeability of the drug was evaluated by how many times it was compared to the value of the Ronasen (registered trademark) tape. The results are shown in Table 3.

[0101]

Table 3

[0102] Examples of the aspects of the present invention include, for example, the following. <1> A patch having a support and an adhesive layer on the support, wherein the adhesive layer contains ン bronze serine or a salt thereof, a thermoplastic elastomer, and a higher fatty acid ester. <2> The patch according to <1>, wherein the ratio of the higher fatty acid ester to 100 parts by mass of the thermoplastic elastomer is 25 parts by mass or more and 300 parts by mass or less. <3> The patch according to <1> or <2>, wherein the content of the higher fatty acid ester in the adhesive layer is 75% by mass or less. <4> The patch according to any one of <1> to <3>, wherein the number of carbon atoms in the ester moiety of the higher fatty acid ester is 12 or more and 30 or less. <5> The patch according to any one of <1> to <4>, wherein the thermoplastic elastomer is a styrene block copolymer. <6> The patch according to <5>, wherein the styrene block copolymer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer. <7> The patch according to <6>, wherein the ratio of the styrene-isoprene block copolymer in the mixture is 50% by mass or more. <8> The patch according to any one of <5> to <7>, wherein the viscosity of a 25% by mass toluene solution of the styrene block copolymer at 25°C is 500 mPa·s or more and 2000 mPa·s or less. <9> The patch according to any one of <1> to <8>, wherein the adhesive layer contains an aliphatic dicarboxylic acid ester. <10> The patch according to any one of <1> to <9> above, wherein the pressure-sensitive adhesive layer contains glycerin monoether. <11> A method for producing the patch according to any one of <1> to <10> above, comprising a step of laminating the support and the pressure-sensitive adhesive layer.

Claims

1. a support, and an adhesive layer on the support, and the adhesive layer contains bronantherine or a salt thereof, a thermoplastic elastomer, and a higher fatty acid ester, the thermoplastic elastomer is a styrene-based block copolymer, and the adhesive is characterized in that the carbon number of the ester moiety of the higher fatty acid ester is 12 or more and 30 or less.

2. The adhesive according to claim 1, wherein the ratio of the higher fatty acid ester to 100 parts by mass of the thermoplastic elastomer is 25 parts by mass or more and 300 parts by mass or less.

3. The adhesive according to claim 1 or 2, wherein the content of the higher fatty acid ester in the adhesive layer is 75% by mass or less.

4. The adhesive according to any one of claims 1 to 3, wherein the adhesive layer contains an aliphatic dicarboxylic acid ester.

5. The adhesive according to any one of claims 1 to 4, wherein the adhesive layer contains glycerin monoether.

6. A method for producing an adhesive according to any one of claims 1 to 5, comprising a step of laminating the support and the adhesive layer.

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