Patch and manufacturing method thereof

Abstract

The present invention is: a patch characterized by having an adhesive agent layer, the adhesive agent layer containing (a) 3-[(3R*,4R*)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) at least one selected from organic acids, amides, and alcohols, the component (b) being contained in an amount of 50 parts by mass or more relative to 100 parts by mass of the component (a); and a method for producing a patch, the method comprising an adhesive agent layer formation step of forming an adhesive agent layer using a mixture obtained by mixing (a) 3-[(3R*,4R*)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar group at 80°C or lower.

Description

[Technical Field]

[0001] The present invention relates to a method for producing a 3-[(3R * ,4R * The present invention relates to a patch containing 3-(dimethylaminomethyl)-3-(tetrahydropyran-4-yl)phenol, and a method for producing the same. [Background technology]

[0002] Pain is a biological warning signal, but when it becomes excessively strong or chronic, it becomes a medical condition that requires treatment. Many systemic analgesics developed for pain treatment have low skin permeability due to their structure and physical properties, so they are administered orally or by injection. However, oral preparations have problems such as being difficult to administer to elderly patients and other patients who have difficulty swallowing, and the efficacy of the medicine may not last long enough. Injectable preparations have problems such as being invasive and requiring the assistance of a medical professional for administration.

[0003] On the other hand, transdermal absorption preparations, especially patches, have advantages such as easy administration, long-lasting efficacy, non-invasiveness, and ease of discontinuing medication. Because pain treatment often requires a long period of time, there is a need for the development of patches containing drugs with efficacy equal to or greater than that of existing analgesics. Drugs that have a strong analgesic effect and also show excellent percutaneous absorption include, for example, 3-[(3R * ,4R * )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol (hereinafter sometimes referred to as "Compound 1") is known (Patent Document 1). Patent Document 1 also describes that Compound 1 can be used as a patch, and that Compound 1 has excellent solubility in compositions used in patches. Furthermore, the patent document also discloses the component composition of a patch containing Compound 1 and a method for producing the same. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2019 / 156074 Brochure Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have prepared a 3-[(3R * ,4R * When a patch containing 3-[(3R * ,4R * It was observed that crystals of 1-(dimethylaminomethyl)-3-(tetrahydropyran-4-yl)phenol precipitated and adhered to the release liner. This phenomenon was observed even when the type of release liner was changed.

[0006] If the drug adheres to the release liner as crystals, the drug content in the patch decreases, making it impossible to ensure sufficient medicinal efficacy. Furthermore, if the drug not only precipitates on the surface of the adhesive layer of the patch but also adheres to the release liner, the drug crystals can be easily recovered from the release liner, leading to misuse and abuse of the drug. The composition of the adhesive layer in the patch described in Patent Document 1 does not provide sufficient uniformity in the drug content, and in addition to not being able to fully demonstrate its effectiveness as a patch, there is a high risk of drug misuse or abuse due to crystals adhering to the liner.

[0007] Furthermore, the manufacturing method described in Patent Document 1 is a method of manufacturing a patch containing Compound 1 by heating Compound 1, a styrene-isoprene-styrene block copolymer, liquid paraffin, and rosin to 150°C and melt-mixing them, which is not a desirable method of manufacturing a patch from the viewpoints of ensuring safety for manufacturers, reducing the burden on manufacturing equipment, and suppressing decomposition of active ingredients and additives.

[0008] The present inventors attempted to produce a patch having the composition described in Patent Document 1 at 80°C or less, but found that 3-[(3R * ,4R * It was found that the phenol was not dissolved in the adhesive layer, making it impossible to produce a uniform adhesive patch.

[0009] Therefore, the present invention aims to solve the above-mentioned problems in the prior art and achieve the following object. * ,4R * )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is uniformly retained in the adhesive layer without precipitation, and * ,4R * The objective of this invention is to develop a method for producing a patch that has good cohesive strength and adhesive strength, in which [3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is dissolved in the adhesive layer, while ensuring safety for the manufacturer, reducing the burden on manufacturing equipment, and suppressing decomposition of the active ingredient and additives. [Means for solving the problem]

[0010] As a result of extensive research by the present inventors to achieve the above object, it has been found that a 3-[(3R * ,4R * and (b) at least one selected from organic acids, amides, and alcohols, wherein the content of (b) is 50 parts by mass or more per 100 parts by mass of (a), and * ,4R * )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is uniformly retained in the adhesive layer without precipitation, and (a) 3-[(3R * ,4R *and (b) an organic compound having a polar functional group, at 80°C or less to obtain a mixture, and then forming an adhesive layer using the mixture. * ,4R * The present inventors have discovered that a method for producing a patch having good cohesive strength and adhesiveness, in which [2-(dimethylaminomethyl)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is dissolved in the adhesive layer, can be provided, which ensures safety for the manufacturer, reduces the burden on manufacturing equipment, and inhibits decomposition of the active ingredient and additives.

[0011] The present invention is based on the above findings by the present inventors, and the means for solving the above problems are as follows: <1> a pressure-sensitive adhesive layer, the pressure-sensitive adhesive layer comprising (a) 3-[(3R * ,4R * and (b) at least one selected from organic acids, amides, and alcohols, wherein the content of (b) is 50 parts by mass or more per 100 parts by mass of (a). <2> The aforementioned <1> A method for producing the patch according to claim 1, wherein (a) 3-[(3R * ,4R * (b) a method for producing a patch, comprising a mixing step of mixing 100 parts by mass of [(3-(dimethylaminomethyl)tetrahydropyran-4-yl)phenol] with 50 parts by mass or more of at least one selected from organic acids, amides, and alcohols. <3> (a)3-[(3R * ,4R * The method for producing a patch comprises a step of forming an adhesive layer using a mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar functional group at 80°C or less to form an adhesive layer. [Effects of the Invention]

[0012] According to the present invention, the above-mentioned problems in the prior art can be solved and the above-mentioned object can be achieved, and 3-[(3R * ,4R * )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is uniformly retained in the adhesive layer without precipitation, and * ,4R * The present invention provides a method for producing a patch having good cohesive strength and adhesive strength, in which [[(dimethylaminomethyl)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol] is dissolved in the adhesive layer, ensuring safety for the manufacturer, reducing the burden on manufacturing equipment, and suppressing decomposition of the active ingredient and additives. DETAILED DESCRIPTION OF THE INVENTION

[0013] (patch) The patch has an adhesive layer and may further have other elements.

[0014] <Adhesive layer> The pressure-sensitive adhesive layer comprises (a) 3-[(3R * ,4R * (b) at least one selected from organic acids, amides, and alcohols, and may further contain other components. The pressure-sensitive adhesive layer is a mixture of the above-mentioned components, and the content of the solvent used during production is preferably 0.5% by mass or less, more preferably 0% by mass, relative to 100% by mass of the total components of the pressure-sensitive adhesive layer.

[0015] (a)3-[(3R * ,4R * )-3-(Dimethylaminomethyl)tetrahydropyran-4-yl]phenol The structural formula of (a) and its synthesis method are as described in Example 1 of International Publication No. 2019 / 156074.

[0016] Since the above (a) exhibits a strong analgesic effect, the patch of the present application can be used for the treatment and / or prevention of chronic pain.

[0017] The content of (a) in the pressure-sensitive adhesive layer, i.e., the proportion of (a) in a total of 100% by mass of the components of the pressure-sensitive adhesive layer, is not particularly limited and can be selected appropriately depending on the purpose. However, in order to ensure that (a) is uniformly retained in the pressure-sensitive adhesive layer without precipitating, the lower limit is preferably 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 1.5% by mass or more, and particularly preferably 2% by mass or more, and the upper limit is preferably 30% by mass or less, more preferably 25% by mass or less, even more preferably 20% by mass or less, and particularly preferably 10% by mass or less.

[0018] (b) at least one selected from organic acids, amides, and alcohols The (b) is not particularly limited as long as it contains at least one selected from organic acids, amides, and alcohols, and can be appropriately selected depending on the purpose. However, from the viewpoint of efficiently suppressing crystal precipitation, it is preferable that it contains an organic acid. The (b) preferably contains at least two selected from organic acids, amides, and alcohols, and more preferably contains organic acids, amides, and alcohols.

[0019] -Organic acid- In this specification, the organic acid refers to an organic compound having at least one carboxyl group in the molecule, and may have functional groups other than the carboxyl group in the molecule. The organic acid is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include aliphatic monocarboxylic acids such as propionic acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, and levulinic acid; aliphatic unsaturated monocarboxylic acids such as oleic acid, linoleic acid, and sorbic acid; hydroxycarboxylic acids such as lactic acid (DL-lactic acid or a mixture of L-lactic acid and / or D-lactic acid with lactic anhydride) and gluconic acid; polycarboxylic acids such as adipic acid, succinic acid, citric acid, tartaric acid, fumaric acid, maleic acid, malonic acid, and malic acid; aromatic carboxylic acids such as benzoic acid and salicylic acid; and sugar derivatives such as alginic acid and phytic acid. These may be used alone or in combination.

[0020] Among these, 3-[(3R * ,4R * Since the hydroxybenzoate is uniformly retained in the adhesive layer without precipitating, fatty acids are preferred, aliphatic monocarboxylic acids, aliphatic unsaturated monocarboxylic acids, hydroxycarboxylic acids, or polycarboxylic acids are more preferred, capric acid, isostearic acid, or oleic acid are even more preferred, capric acid or oleic acid are particularly preferred, and oleic acid is most preferred.

[0021] The content of the organic acid is not particularly limited and can be selected appropriately depending on the purpose, but in order to ensure that 3-[(3R*,4R*)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is uniformly retained in the adhesive layer without precipitating, the lower limit is preferably 50 parts by mass or more, more preferably 100 parts by mass or more, even more preferably 150 parts by mass or more, even more preferably 200 parts by mass or more, and particularly preferably 300 parts by mass or more, per 100 parts by mass of (a), and the upper limit is preferably 4000 parts by mass or less, more preferably 3000 parts by mass or less, and even more preferably 2000 parts by mass or less, per 100 parts by mass of (a).

[0022] The molar equivalent of the organic acid relative to 1 molar equivalent of (a) is not particularly limited and can be selected appropriately depending on the purpose, but in order to ensure that 3-[(3R*,4R*)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is uniformly retained in the adhesive layer without precipitating, the lower limit is preferably 0.5 molar equivalents or more relative to 1 molar equivalent of (a), more preferably 1 molar equivalent or more, even more preferably 1.5 molar equivalents or more, and even more preferably 2 molar equivalents or more, and the upper limit is preferably 6 molar equivalents or less relative to 1 molar equivalent of (a), more preferably 5 molar equivalents or less, and even more preferably 3 molar equivalents or less.

[0023] -Amids- In this specification, amides refer to organic compounds having at least one amide group in the molecule, and may have functional groups other than the amide group in the molecule, but do not include those having a carboxyl group in the molecule. The amides are not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include pyrrolidones such as N-methyl-2-pyrrolidone, laurylpyrrolidone, and 2-pyrrolidone; aromatic amides such as acetanilide, crotamiton, and nicotinamide; and aliphatic amides such as N,N-dimethylacetamide and lauric acid diethanolamide. These may be used alone or in combination of two or more.

[0024] Among these, 3-[(3R * ,4R * In terms of improving the solubility and dispersibility of N-(dimethylaminomethyl)-3-(tetrahydropyran-4-yl)phenol, pyrrolidone or aromatic amide is preferred, N-methyl-2-pyrrolidone or crotamiton is more preferred, and crotamiton is even more preferred.

[0025] The content of the amides is not particularly limited and can be selected appropriately depending on the purpose, but in order to ensure that 3-[(3R*,4R*)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is uniformly retained in the adhesive layer without precipitating, the lower limit is preferably 50 parts by mass or more, more preferably 100 parts by mass or more, even more preferably 150 parts by mass or more, and even more preferably 200 parts by mass or more, per 100 parts by mass of (a), and the upper limit is preferably 4000 parts by mass or less, more preferably 3000 parts by mass or less, and even more preferably 2000 parts by mass or less, per 100 parts by mass of (a).

[0026] -Alcoholic beverages- In this specification, alcohols refer to organic compounds having at least one hydroxyl group in the molecule, and may have functional groups other than hydroxyl groups in the molecule, but do not include those having a carboxyl group and / or an amide group in the molecule. The alcohols are not particularly limited and can be appropriately selected depending on the purpose. Examples of the alcohols include linear saturated aliphatic alcohols such as lauryl alcohol, myristyl alcohol, cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; branched saturated aliphatic alcohols such as isostearyl alcohol, hexyldecanol, and octyldodecanol; unsaturated aliphatic alcohols such as oleyl alcohol and geraniol; polyhydric alcohols such as ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, dipropylene glycol, triethylene glycol, 2-ethyl-1,3-hexanediol, and 1,2,6-hexanetriol; polyethylene glycol 200, polyethylene glycol 400, polyoxyethylene(2) ethyl ether (diethylene glycol monoethyl ether), polyoxyethylene(2) lauryl ether, polyoxyethylene(4) lauryl ether, polyoxyethylene(9) lauryl ether, and polyoxyethylene(2) cetyl ether. Polyether alcohols such as polyoxyethylene (2) stearyl ether and ethylene glycol monostearate; propylene glycol monofatty acid esters such as propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monomyristate, propylene glycol monostearate, and propylene glycol monopalmitostearate; aromatic alcohols such as benzyl alcohol, phenylethyl alcohol, phenoxyethanol, thymol, eugenol, 2-naphthol, and vanillin; cyclic alcohols such as maltol and ethyl maltol; alkyl lactates such as ethyl lactate, lauryl lactate, and cetyl lactate; salicylic acid derivatives such as ethylene glycol salicylate, phenyl salicylate, and methyl salicylate; citric acid derivatives such as triethyl citrate and tributyl citrate; terpenes such as α-terpineol, D-borneol, DL-borneol, L-menthol, and DL-menthol;Sorbitans such as sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan trioleate, and polyoxyethylene sorbitan tetraoleate; glycerin monooleate, glycerin monostearate, glycerin monomyristate, diglyceryl monooleate, and decaglyceryl laurate. Glycerin derivatives such as ceryl, α-monoisostearyl glyceryl ether, diglyceryl monoisostearate, diglyceryl monostearate, polyoxyethylene glycerin monostearate, polyoxyethylene glyceryl triisostearate, and polyoxyethylene coconut oil fatty acid glyceryl; stearic acid derivatives such as propylene glycol monostearate and ethylene glycol monostearate; and amines such as monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. These may be used alone or in combination of two or more.

[0027] Among these, 3-[(3R * ,4R * From the viewpoint of improving the solubility of [3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, propylene glycol monocaprylate, propylene glycol monolaurate, alkyl lactate, or benzyl alcohol is preferred, propylene glycol monocaprylate, alkyl lactate, or benzyl alcohol is more preferred, propylene glycol monocaprylate or alkyl lactate is even more preferred, and propylene glycol monocaprylate is particularly preferred.

[0028] Commercially available propylene glycol monocaprylate products include, for example, Gattefosse's "CAPRYOL™ 90" and "CAPRYOL™ PGMC," ABITEC's "CAPMUL™ PG-8," Nippon Surfactant Industries' "NIKKOL SEFSOL-218," and Croda's "CRODAMOL™ PC." Propylene glycol monolaurate products include, for example, Gattefosse's "LAUROGLYCOL™ 90" and "LAUROGLYCOL™ FCC," and ABITEC's "CAPMUL™ PG-12." Alkyl lactates include, for example, Ashland's "CERAPHYL 41™" and "CERAPHYL 31™."

[0029] The content of the alcohols is not particularly limited and can be selected appropriately depending on the purpose, but in order to ensure that 3-[(3R*,4R*)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is uniformly retained in the adhesive layer without precipitating, the lower limit is preferably 50 parts by mass or more, more preferably 100 parts by mass or more, even more preferably 150 parts by mass or more, even more preferably 200 parts by mass or more, and particularly preferably 300 parts by mass or more, per 100 parts by mass of (a), and the upper limit is preferably 4000 parts by mass or less, more preferably 3000 parts by mass or less, and even more preferably 2000 parts by mass or less, per 100 parts by mass of (a).

[0030] The content of (b) is not particularly limited as long as it is 50 parts by mass or more per 100 parts by mass of (a), and can be appropriately selected depending on the purpose. * ,4R *In order to ensure that the hydroxybenzoate is uniformly retained in the adhesive layer without precipitating, the lower limit is preferably 100 parts by mass or more, more preferably 200 parts by mass or more, even more preferably 300 parts by mass or more, and particularly preferably 500 parts by mass or more, relative to 100 parts by mass of the (a), and the upper limit is preferably 4000 parts by mass or less, more preferably 3000 parts by mass or less, and even more preferably 2000 parts by mass or less, relative to 100 parts by mass of the (a). When two or more types of (b) are contained, the total amount thereof is defined as the content mentioned above.

[0031] -Other ingredients- The other components are not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include (c) base polymers, (d) plasticizers, (e) tackifiers, (f) esters, (g) ethers, (h) antioxidants, and (i) fillers.

[0032] (c) Base polymer The base polymer is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include thermoplastic elastomers and thermosetting elastomers. The thermoplastic elastomer is an elastomer that exhibits thermoplasticity, softening and becoming fluid when heated and returning to a rubber-like elastic body when cooled. Various types of thermoplastic elastomers are known, including urethane-based, acrylic-based, styrene-based, olefin-based, and silicone-based elastomers. The thermosetting elastomer is an elastomer that does not soften even when heated and has relatively high heat resistance, and various types of thermosetting elastomers are known, such as acrylic, silicone, and natural rubber. Among these, from the viewpoint of improving the production efficiency of the pressure-sensitive adhesive layer (they soften and become fluid when heated, thereby improving mixing efficiency), and from the viewpoint of being able to incorporate additives such as (b) and (d) without significantly impairing the adhesive strength or cohesive strength of the pressure-sensitive adhesive layer, thermoplastic elastomers are preferred, styrene-based thermoplastic elastomers are more preferred, and styrene-based block copolymers are even more preferred.

[0033] The styrene-based block copolymer is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include 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, and styrene-isobutylene-styrene block copolymer. The term "ethylene / butylene" refers to a copolymer block of ethylene and butylene, and the term "ethylene / propylene" refers to a copolymer block of ethylene and propylene. These styrene-based block copolymers may be used alone or in combination of two or more.

[0034] Among the above styrene-based block copolymers, one or more selected from the group consisting of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are particularly preferred from the viewpoints of both sufficient skin adhesion and suppression of adhesive residue by improving the cohesive strength of the adhesive layer, as well as the availability and ease of handling of patch products. The most preferred styrene-based block copolymer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.

[0035] When a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer is used as the styrene-based block copolymer, the content of the styrene-isoprene block copolymer in the mixture is preferably 15% by mass or more, more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 40% by mass or more, and particularly preferably 50% by mass or more. The upper limit of the content of the styrene-isoprene block copolymer in the mixture is preferably 80% by mass or less.

[0036] The styrene-isoprene-styrene block copolymer preferably has a styrene content of 5% by mass to 60% by mass, more preferably 10% by mass to 50% by mass, and has a weight-average molecular weight measured by gel permeation chromatography (GPC) of 20,000 to 500,000, more preferably 30,000 to 300,000. The styrene-isoprene block copolymer preferably has a styrene content of 5% by mass or more and 50% by mass or less, more preferably 10% by mass or more and 40% by mass or less, and has a weight-average molecular weight measured by GPC of 10,000 to 500,000, more preferably 20,000 to 300,000.

[0037] The styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer can each be copolymers produced by methods known per se. Alternatively, commercially available products that satisfy the above-mentioned properties can be used for the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer. Furthermore, blends of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are also commercially available, and commercially available blends of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers in the above-mentioned blend ratios that satisfy the above-mentioned properties can be preferably used.

[0038] Examples of commercially available products include "KRATON (registered trademark) D1111," "KRATON (registered trademark) D1163," "KRATON (registered trademark) D1113," and "KRATON (registered trademark) D1119" manufactured by KRATON POLYMERS; "JSR SIS (registered trademark) 5229," "JSR SIS (registered trademark) 5002," "JSR SIS (registered trademark) 5403," and "JSR SIS (registered trademark) 5505" manufactured by JSR Corporation; and "Quintac (registered trademark) 3421," "Quintac (registered trademark) 3433N," "Quintac (registered trademark) 3520," "Quintac (registered trademark) 3450," and "Quintac 3270" manufactured by Zeon Corporation.

[0039] Among these, in terms of the blending ratio of the triblock copolymer and the diblock copolymer and the solution viscosity, "KRATON (registered trademark) D1163," "KRATON (registered trademark) D1113," "JSR SIS (registered trademark) 5403," "JSR SIS (registered trademark) 5505," "Quintac (registered trademark) 3433N," and "Quintac (registered trademark) 3520" are preferred, and "JSR SIS (registered trademark) 5505" and "Quintac (registered trademark) 3520" are more preferred. These styrene-based block copolymers are mixtures of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, and the content of the styrene-isoprene block copolymer in the mixture is 50 mass% or more.

[0040] The content of the base polymer in the adhesive layer, i.e., the proportion of the base polymer in a total of 100% by mass of the components of the adhesive layer, is not particularly limited and can be selected appropriately depending on the purpose. From the viewpoints of maintaining the shape of the adhesive layer and skin adhesion, the lower limit is preferably 10% by mass or more, more preferably 15% by mass or more, and even more preferably 20% by mass or more, and the upper limit is preferably 50% by mass or less, more preferably 40% by mass or less, and even more preferably 35% by mass or less.

[0041] (d) Plasticizer The plasticizer is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include liquid paraffin, squalene, squalane, pristane, hexadecyl isostearate, octyldodecyl myristate, etc. These may be used alone or in combination of two or more. Among these, liquid paraffin, hexadecyl isostearate, or octyldodecyl myristate is preferred, and octyldodecyl myristate is more preferred.

[0042] The liquid paraffin is a colorless, odorless, liquid mixture of saturated hydrocarbons, and it is preferable to use one that complies with the standards prescribed in the Japanese Pharmacopoeia, the United States Pharmacopoeia, etc. Among these, liquid paraffin, which has high viscosity, is preferred from the viewpoint of adhesiveness. Specifically, the kinematic viscosity at 40°C is 60mm 2 / s or more is preferable, and 70 mm 2 / s or more, more preferably 80 mm 2 / s or more. The upper limit of the kinematic viscosity is not particularly limited, but from the viewpoint of ease of handling and availability, for example, 500 mm 2 / s or less is preferable, 250 mm 2 / s or less is more preferable.

[0043] The "kinematic viscosity" referred to here is the value converted from the viscosity (mPa·s) measured in accordance with "Method 2, Rotational Viscometer Method (2.12 Single Cylindrical Rotational Viscometer (Brookfield Viscometer)" in "2.53 Viscosity Measurement Method" of the General Test Methods of the "Japanese Pharmacopoeia, 17th Edition."

[0044] The content of the plasticizer in the pressure-sensitive adhesive layer, i.e., the proportion of the plasticizer in a total of 100% by mass of the components of the pressure-sensitive adhesive layer, is not particularly limited and can be selected appropriately depending on the purpose. The lower limit is, for example, preferably 1% by mass or more, more preferably 2% by mass or more, and even more preferably 3% by mass or more, and the upper limit is, for example, preferably 60% by mass or less, more preferably 55% by mass or less, and even more preferably 50% by mass or less.

[0045] (e) Tackifier The tackifier is a tackifier generally used in the field of patches, and examples thereof include rosin-based resins, polyterpene-based resins, coumarone-indene resins, petroleum-based resins, terpene resins, terpene-phenol resins, alicyclic saturated hydrocarbon resins, etc. These may be used alone or in combination of two or more. Among these, rosin resins, terpene resins, and alicyclic saturated hydrocarbon resins are preferred. The rosin-based resin is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include rosin esters.

[0046] The content of the tackifier in the pressure-sensitive adhesive layer, i.e., the proportion of the tackifier in 100% by mass of the total of the constituent components of the pressure-sensitive adhesive layer, is not particularly limited and can be selected appropriately depending on the purpose. The lower limit is, for example, preferably 5% by mass or more, more preferably 10% by mass or more, and even more preferably 15% by mass or more, and the upper limit is, for example, preferably 40% by mass or less, more preferably 35% by mass or less, and even more preferably 30% by mass or less.

[0047] (f) Esters In this specification, the term "esters" refers to organic compounds having at least one ester group in the molecule, excluding those having a carboxyl group and / or a hydroxyl group and / or an amide group in the molecule. The esters are not particularly limited and can be appropriately selected depending on the purpose. Examples of the esters include esters of fatty acids and monohydric aliphatic alcohols such as isoamyl isovalerate, isostearyl palmitate, cetyl 2-ethylhexanoate (cetyl isooctanoate), ethyl oleate, decyl oleate, isopropyl palmitate, cetyl palmitate, isopropyl myristate, cetyl myristate, myristyl myristate, batyl monostearate, hexyl laurate, methyl laurate, isopropyl linoleate, ethyl linoleate, and cocoyl capryl caprate; diesters such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, and diethyl sebacate; and propylene glycol dicaprylate, propylene glycol dicaprylate, propylene glycol diisopropyl esters ... Examples of suitable glycerin esters include propylene glycol diesters such as glycol dicaprate, propylene glycol dicaprylocaprate, and propylene glycol diacetate; glycerin esters such as triacetin, tricaprylin (glycerin trioctanoate), tri(caprylic / capric acid)glycerin, glycerin triisooctanoate (triethylhexanoin), triglycerol diisostearate, and medium-chain fatty acid triglycerides; citric acid esters such as triethyl O-acetylcitrate and tributyl O-acetylcitrate; cyclic carbonates such as ethylene carbonate, propylene carbonate, and maleic anhydride; and aromatic esters such as benzyl benzoate, benzyl acetate, diethyl phthalate, dibutyl phthalate, and butylphthalyl butyl glycolate.

[0048] (g) Ethers In this specification, the term "ethers" refers to organic compounds having at least one ether group in the molecule, excluding those having a carboxyl group and / or a hydroxyl group and / or an amide group in the molecule. The ethers are not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include dimethyl isosorbide and piperonyl butoxide.

[0049] (h) antioxidants The antioxidant is not particularly limited and can be appropriately selected depending on the purpose. Examples of the antioxidant include phenols such as 2,6-di-tert-butyl-hydroxyltoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, hydroquinone, oxybenzone, pentaerythrityl-tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], rutin, and catechin; triazoles such as 1,2,3-benzotriazole; sulfur, L-cysteine, L-cystine, DL-methionine, L-methionine, alpha-thioglycerin, Examples include sulfur-containing compounds such as allyl isothiocyanate, thioglycolic acid, sodium thioglycolate, potassium thiocyanate, sodium thiosulfate, sodium thiomalate, 2-mercaptobenzimidazole, thiourea, and N,N-dimethylthiourea; amines such as EDTA-2Na; and vitamins such as tocopherol, tocopherol acetate, ascorbic acid, isoascorbic acid, ascorbic acid stearate, ascorbic palmitate, erythorbic acid, hesperidin, methylhesperidin, riboflavin, and riboflavin butyrate. These may be used alone or in combination of two or more. Among these, dibutylhydroxyltoluene or 2-mercaptobenzimidazole is preferred.

[0050] (i) Filler The filler is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include silicon compounds such as silicic acid anhydride, light silicic acid anhydride, and hydrous silicic acid, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, water-soluble polymers such as polyvinyl alcohol, aluminum compounds such as dried aluminum hydroxide gel and hydrous aluminum silicate, kaolin, titanium oxide, etc. The fillers may be used alone or in combination of two or more.

[0051] <Other elements> The other elements are not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include a backing, a release liner, etc. That is, the patch of the present invention may be one in which a backing, a pressure-sensitive adhesive layer, and a release liner are laminated in this order.

[0052] The support is not particularly limited and can be appropriately selected depending on the purpose. For example, adhesive sheets for skin application or those generally used for transdermal absorption preparations can be used. The material of the support is not particularly limited and can be appropriately selected depending on the purpose. Examples include polyesters such as polyethylene terephthalate, polyolefins such as polyethylene and polypropylene, polyurethane, ethylene-vinyl acetate copolymer, and polyvinyl chloride. The support may have a single layer structure or a multilayer structure, and may be in the form of a knitted fabric, a woven fabric, a nonwoven fabric, a film, a foam, a porous material, a mesh structure, a sheet, or a flat plate.

[0053] Furthermore, in order to prevent static electricity from accumulating on the support, an antistatic agent may be contained in the woven fabric, nonwoven fabric, film, etc. constituting the support. In order to obtain good anchoring properties with the PSA layer, a nonwoven fabric or woven fabric, or a laminate of these with a film, can be used as the support.

[0054] The thickness of the support is not particularly limited and can be appropriately selected depending on the purpose, but for films, the lower limit is, for example, preferably 10 μm or more, more preferably 15 μm or more, and the upper limit is, for example, preferably 100 μm or less, more preferably 50 μm or less. For porous sheets such as woven fabrics, nonwoven fabrics, and foamable supports, the lower limit is preferably 50 μm or more, more preferably 100 μm or more, and the upper limit is preferably 2,000 μm or less, more preferably 1,000 μm or less.

[0055] The release liner is not particularly limited and can be appropriately selected depending on the purpose, and examples that can be used include glassine paper, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, and resin films such as polystyrene; aluminum films; foamed polyethylene films or foamed polypropylene films; laminates of two or more of the above; and the release liner can also be silicone-treated, fluororesin-treated, embossed, hydrophilically treated, hydrophobically treated, or the like.

[0056] The thickness of the release liner is not particularly limited and can be appropriately selected depending on the purpose, but the lower limit is preferably 10 μm or more, more preferably 15 μm or more, and the upper limit is preferably 200 μm or less, more preferably 150 μm or less.

[0057] (Method for manufacturing patch: First embodiment) In a first aspect, the method for producing the patch comprises the steps of: (a) forming a 3-[(3R * ,4R * The method includes a mixing step of mixing 100 parts by mass of (b)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol with 50 parts by mass or more of at least one selected from organic acids, amides, and alcohols, and may further include other steps. (a)3-[(3R * ,4R * )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, and the (b) at least one selected from organic acids, amides, and alcohols are as described above in (Patch).

[0058] <Mixing process> The mixing step is not particularly limited and can be appropriately selected depending on the purpose, but a method in which mixing is performed in the presence of a volatile solvent is preferred. The volatile solvent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include 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, acetates such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate, etc. These may be used alone or in combination of two or more. From the viewpoint of good solubility of each component constituting the pressure-sensitive adhesive layer, it is preferable to use aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, and aliphatic hydrocarbons such as hexane and heptane, either alone or in combination.

[0059] The mixing method in the mixing step may be: (a) 3-[(3R * ,4R * The method is not particularly limited as long as it involves mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol with (b) at least one selected from organic acids, amides, and alcohols, and can be appropriately selected depending on the purpose.

[0060] Among these, (a) 3-[(3R * ,4R * (a) 3-[(3R dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) at least one selected from organic acids, amides, and alcohols, and then mixing the base polymer with the resulting mixture; * ,4R * More preferably, the process comprises mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol with (b) at least one selected from organic acids, amides, and alcohols, mixing the plasticizer with the resulting mixture, and then mixing the base polymer.

[0061] When two or more of the (b) organic acids, amides, and alcohols are used, it is preferable to add them all at once.

[0062] (a)3-[(3R * ,4R * The temperature at which (b)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol is mixed with at least one selected from organic acids, amides, and alcohols is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 80°C or less, more preferably 70°C or less, even more preferably 60°C or less, particularly preferably 50°C or less, and most preferably 40°C or less. The temperature at which (a) and (b) are mixed together is 80° C. or lower, meaning that the internal temperature of the mixture is 80° C. or lower. When the mixture is heated using an external device such as an oil bath, a hot plate, or a mixer with a temperature control function, the set temperature of the external device is not particularly limited as long as the temperature of the mixture itself is 80° C. or lower. Specifically, there is no problem even if the set temperature exceeds 80° C.

[0063] (a)3-[(3R * ,4R * The temperature at which the mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol with (b) at least one selected from organic acids, amides, and alcohols is mixed with the thermoplastic elastomer is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 80°C or less, more preferably 70°C or less, even more preferably 60°C or less, particularly preferably 50°C or less, and most preferably 40°C or less. As mentioned above, the temperature at which the mixture obtained by mixing (a) and (b) is mixed with the base polymer may be set to a temperature higher than 80°C in the external equipment.

[0064] (a)3-[(3R * ,4R *The temperature for mixing the mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol with (b) at least one selected from organic acids, amides, and alcohols with the plasticizer is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 80° C. or lower, more preferably 70° C. or lower, even more preferably 60° C. or lower, particularly preferably 50° C. or lower, and most preferably 40° C. or lower. The temperature for subsequent mixing with the thermoplastic elastomer is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 80° C. or lower, more preferably 70° C. or lower, even more preferably 60° C. or lower, particularly preferably 50° C. or lower, and most preferably 40° C. or lower. As mentioned above, there is no problem even if the temperature set for the external device when mixing the mixture obtained by mixing (a) and (b) with the plasticizer exceeds 80°C.

[0065] <Other processes> The other steps are not particularly limited and can be appropriately selected depending on the purpose. Examples of the other steps include a coating step after the mixing step, a lamination step of the support and the pressure-sensitive adhesive layer, and a lamination step of the release liner. The backing, the pressure-sensitive adhesive layer, and the release liner are as described above in (Patch).

[0066] - Coating process after the mixing process - The coating liquid for forming the pressure-sensitive adhesive layer obtained in the mixing step can be applied onto the support or the release liner using a conventional coater such as a roll coater, a die coater, a gravure roll coater, a reverse roll coater, a kiss roll coater, a dip roll coater, a bar coater, a knife coater, or a spray coater. The coating liquid is dried under heating, for example, preferably at 40° C. or higher, and preferably at 150° C. or lower, more preferably at 100° C. or lower, even more preferably at 90° C. or lower, and particularly preferably at 80° C. or lower. Among these, drying is preferably performed at a temperature of 40° C. or higher and 150° C. or lower, more preferably at a temperature of 40° C. or higher and 100° C. or lower, even more preferably at a temperature of 40° C. or higher and 90° C. or lower, and particularly preferably at a temperature of 40° C. or higher and 80° C. The drying temperature, drying time, and drying method can be adjusted depending on the solvent used and the amount used.

[0067] -Laminating process of support and adhesive layer- The step of laminating the support and the pressure-sensitive adhesive layer is not particularly limited and can be appropriately selected depending on the purpose. For example, a method of laminating the support and the pressure-sensitive adhesive layer by pressure bonding can be mentioned.

[0068] -Lamination process of release liner- The step of laminating the release liner is not particularly limited and can be appropriately selected depending on the purpose. Examples include a step of spreading the coating liquid for forming the pressure-sensitive adhesive layer onto a release liner before the step of laminating the support and the pressure-sensitive adhesive layer, drying the solvent in the coating liquid, and laminating the pressure-sensitive adhesive layer on the surface of the release liner (spreading and drying step), and a step of pressing the release liner onto the pressure-sensitive adhesive layer after the step of laminating the support and the pressure-sensitive adhesive layer.

[0069] (Method for manufacturing patch: second embodiment) In a second embodiment, the method for producing the patch comprises: (a) forming a 3-[(3R * ,4R * The method includes a pressure-sensitive adhesive layer-forming step of forming a pressure-sensitive adhesive layer using a mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar functional group at 80°C or less, and may further include other steps.

[0070] <Adhesive layer formation process> The pressure-sensitive adhesive layer forming step includes: (a) 3-[(3R* ,4R * (b) a mixture of (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar functional group, and then forming a pressure-sensitive adhesive layer using the mixture.

[0071] In the pressure-sensitive adhesive layer forming step, at least (a) 3-[(3R * ,4R * A mixture obtained by mixing (a) 1-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol with (b) an organic compound having a polar functional group is used, but a mixture obtained by further mixing (c) other components can also be used.

[0072] (a)3-[(3R * ,4R * )-3-(Dimethylaminomethyl)tetrahydropyran-4-yl]phenol The structural formula of (a) and its synthesis method are as described in Example 1 of International Publication No. 2019 / 156074.

[0073] Since the compound (a) exhibits a strong analgesic effect, the patch produced by the patch production method of the present application can be used for the treatment and / or prevention of chronic pain.

[0074] The content of (a) in the pressure-sensitive adhesive layer, i.e., the proportion of (a) in 100% by mass of the total of the components of the pressure-sensitive adhesive layer, is not particularly limited and can be appropriately selected depending on the purpose. * ,4R * In order to ensure that the hydroxybenzoate is uniformly retained in the adhesive layer without precipitating, the lower limit is preferably 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 1.5% by mass or more, and particularly preferably 2% by mass or more, and the upper limit is preferably 30% by mass or less, more preferably 25% by mass or less, even more preferably 20% by mass or less, and particularly preferably 10% by mass or less.

[0075] (b) Organic compounds with polar functional groups The organic compound having a polar functional group is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include organic acids, amides, alcohols, esters, and ethers.

[0076] Among these, it is preferable to include at least one selected from organic acids, amides, and alcohols, it is more preferable to include at least two selected from organic acids, amides, and alcohols, and it is even more preferable to include organic acids, amides, and alcohols. The organic acids, amides, alcohols, esters, and ethers are as described above in (Patches).

[0077] The content of (b) is not particularly limited and can be selected appropriately depending on the purpose, but the lower limit is preferably 50 parts by mass or more, more preferably 100 parts by mass or more, even more preferably 200 parts by mass or more, particularly preferably 300 parts by mass or more, and most preferably 500 parts by mass or more, relative to 100 parts by mass of (a), and the upper limit is preferably 4000 parts by mass or less, more preferably 3000 parts by mass or less, and even more preferably 2000 parts by mass or less, relative to 100 parts by mass of (a). When two or more types of (b) are contained, the total amount thereof is defined as the content mentioned above.

[0078] (c) Other ingredients The other components are not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include base polymers, plasticizers, tackifiers, antioxidants, and fillers. The plasticizer, the tackifier, the antioxidant, and the filler are as described above in (Patch).

[0079] -Base polymer- The base polymer is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include thermoplastic elastomers and thermosetting elastomers. The thermoplastic elastomer is an elastomer that exhibits thermoplasticity, softening and becoming fluid when heated and returning to a rubber-like elastic body when cooled. Various types of thermoplastic elastomers are known, including urethane-based, acrylic-based, styrene-based, olefin-based, and silicone-based elastomers. The thermosetting elastomer is an elastomer that does not soften even when heated and has relatively high heat resistance, and various types of thermosetting elastomers are known, such as acrylic, silicone, and natural rubber. Among these, from the viewpoint of improving the production efficiency of the pressure-sensitive adhesive layer (they soften and become fluid when heated, thereby improving mixing efficiency), and from the viewpoint of being able to incorporate additives such as (b) and the plasticizer without significantly impairing the adhesive strength or cohesive strength of the pressure-sensitive adhesive layer, thermoplastic elastomers are preferred, styrene-based thermoplastic elastomers are more preferred, and styrene-based block copolymers are even more preferred. The styrene-based block copolymer is as described above in (Patch).

[0080] The content of the base polymer in the adhesive layer, i.e., the proportion of the base polymer in 100% by mass of the total of the constituent components of the adhesive layer, is not particularly limited and can be selected appropriately depending on the purpose. From the viewpoints of maintaining the shape of the adhesive layer and skin adhesion, however, it is preferably 10% by mass or more and 50% by mass or less, more preferably 15% by mass or more and 40% by mass or less, and even more preferably 20% by mass or more and 35% by mass or less.

[0081] <<Adhesive layer formation method>> The pressure-sensitive adhesive layer forming method includes: (a) forming a 3-[(3R * ,4R * The method is not particularly limited, and can be appropriately selected depending on the purpose, as long as it is a method of forming an adhesive layer using a mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar functional group.

[0082] Among these, (a) 3-[(3R * ,4R *(a) 3-[(3R * ,4R * More preferably, the adhesive layer is formed by mixing (a) (3-(dimethylaminomethyl)tetrahydropyran-4-yl)phenol and (b) an organic compound having a polar functional group, mixing the plasticizer with the resulting mixture, and then mixing the base polymer with the resulting mixture.

[0083] When two or more kinds of (b) organic compounds having a polar functional group are used, it is preferable to add them all at once.

[0084] (a)3-[(3R * ,4R * The temperature for mixing (b)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar functional group is not particularly limited as long as it is 80°C or less and can be appropriately selected depending on the purpose, but is preferably 70°C or less, more preferably 60°C or less, even more preferably 50°C or less, and particularly preferably 40°C or less. The temperature at which (a) and (b) are mixed together is 80° C. or lower, meaning that the internal temperature of the mixture is 80° C. or lower. When the mixture is heated using an external device such as an oil bath, a hot plate, or a mixer with a temperature control function, the set temperature of the external device is not particularly limited as long as the temperature of the mixture itself is 80° C. or lower. Specifically, there is no problem even if the set temperature exceeds 80° C.

[0085] (a)3-[(3R * ,4R *The temperature at which the mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar functional group is mixed with the base polymer is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 80°C or less, more preferably 70°C or less, even more preferably 60°C or less, particularly preferably 50°C or less, and most preferably 40°C or less. As mentioned above, the temperature at which the mixture obtained by mixing (a) and (b) is mixed with the base polymer may be set to a temperature higher than 80°C in the external equipment.

[0086] (a)3-[(3R * ,4R * The temperature for mixing the mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar functional group with the plasticizer is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 80° C. or lower, more preferably 70° C. or lower, even more preferably 60° C. or lower, particularly preferably 50° C. or lower, and most preferably 40° C. or lower. The temperature for subsequent mixing with the base polymer is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 80° C. or lower, more preferably 70° C. or lower, even more preferably 60° C. or lower, particularly preferably 50° C. or lower, and most preferably 40° C. or lower. As mentioned above, there is no problem even if the temperature set for the external device when mixing the mixture obtained by mixing (a) and (b) with the plasticizer exceeds 80°C.

[0087] The mixing method is not particularly limited and can be appropriately selected depending on the purpose, but a method in which mixing is performed in the presence of a volatile solvent is preferred. The volatile solvent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include 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, acetates such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate, etc. These may be used alone or in combination of two or more.

[0088] Among these, aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, and aliphatic hydrocarbons such as hexane and heptane are preferably used alone or in combination, in view of the good solubility of each component constituting the pressure-sensitive adhesive layer.

[0089] The base polymer is the (a) 3-[(3R * ,4R * )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) an organic compound having a polar functional group, or before mixing with the mixture obtained by mixing the (a) 3-[(3R * ,4R * The volatile solvent can be mixed with the mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol with (b) an organic compound having a polar functional group and a plasticizer. The temperature at which the base polymer and the volatile solvent are mixed is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 80° C. or lower.

[0090] When a tackifier is used, the tackifier can be added to the mixture of the base polymer and the volatile solvent.

[0091] <Other processes> The other steps are not particularly limited and can be appropriately selected depending on the purpose. Examples of the other steps include a coating step after the pressure-sensitive adhesive layer forming step, a lamination step of the support and the pressure-sensitive adhesive layer, and a lamination step of a release liner. The backing, the pressure-sensitive adhesive layer, and the release liner are as described above in (Patch). The step of laminating the backing and the pressure-sensitive adhesive layer, and the step of laminating the release liner are as described above in (Method of producing a patch: First embodiment).

[0092] - Coating step after the pressure-sensitive adhesive layer forming step - The coating liquid for forming the pressure-sensitive adhesive layer obtained in the pressure-sensitive adhesive layer forming step can be applied onto the support or the release liner using a conventional coater such as a roll coater, a die coater, a gravure roll coater, a reverse roll coater, a kiss roll coater, a dip roll coater, a bar coater, a knife coater, or a spray coater. The coating liquid is dried under heating, for example, preferably at 40° C. or higher, and preferably at 150° C. or lower, more preferably at 100° C. or lower, even more preferably at 90° C. or lower, and particularly preferably at 80° C. or lower. Among these, drying is preferably performed at a temperature of 40° C. or higher and 150° C. or lower, more preferably at a temperature of 40° C. or higher and 100° C. or lower, even more preferably at a temperature of 40° C. or higher and 90° C. or lower, and particularly preferably at a temperature of 40° C. or higher and 80° C. The drying temperature, drying time, and drying method can be adjusted depending on the solvent used and the amount used. [Example]

[0093] Examples of the present invention will be described below, but the present invention is not limited to these examples in any way.

[0094] <Comparative Example 1-1> Each component constituting the pressure-sensitive adhesive layer was weighed out according to the formulation (10% by weight of Compound 1, 20% by weight of styrene-isoprene-styrene block copolymer, 40% by weight of liquid paraffin, 30% by weight of rosin) described in Patent Document 1 (International Publication No. WO 2019 / 156074) shown in Comparative Example 1-1 in Table 1. The numerical values ​​for each component in Table 1 are in mass%. First, compound 1 and toluene were mixed and stirred (internal temperature 50-80°C) to obtain mixture A. A mixture of styrene-isoprene-styrene block copolymer and styrene-isoprene block copolymer (JSR Corporation "5002") and rosin ester (Arakawa Chemical Co., Ltd. "KE-311") were dissolved in toluene by mixing and stirring (internal temperature 30-60°C), and then added to mixture A and mixed and stirred (internal temperature 50-80°C). Liquid paraffin (Sonneborn "KAYDOL") was then added and mixed and stirred (internal temperature 50-80°C) to prepare a coating solution for forming the adhesive layer. The coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film (release liner, Fujimori Kogyo Co., Ltd.'s "Film Bina 75E-0010 DG2.5") so that the adhesive layer would have a thickness of approximately 100 μm after drying. After drying in an oven at 80°C for 30 minutes, a PET film (support) was laminated onto the surface of the adhesive layer to obtain a patch.

[0095] The presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated using the following evaluation methods. The results are shown in Table 1.

[0096] (Evaluation method) Presence or absence of crystal precipitation of Compound 1 in the adhesive layer The presence or absence of crystal precipitation of Compound 1 in the adhesive layer was evaluated according to the following criteria. ◯: After storing the patch at 30°C or below for 3 days or more, it was visually confirmed that no crystal precipitation occurred in the adhesive layer. ×: After storing the patch at 30°C or below for 3 days or more, the deposition of crystals in the adhesive layer was confirmed by visual inspection.

[0097] (Evaluation method) Whether or not crystals of Compound 1 adhere to the release liner The presence or absence of crystals of Compound 1 adhering to the release liner was evaluated according to the following criteria. ◯: After storing the patch at 30°C or below for 3 days or more, it was visually confirmed that no crystals were precipitated in the adhesive layer and no crystals were attached to the release liner. ×: After storing the patch at 30°C or below for 3 days or more, crystals were precipitated in the adhesive layer and adhesion of the crystals to the release liner was confirmed visually.

[0098] [Table 1]

[0099] <Comparative Example 1-2> A patch was prepared in the same manner as in Comparative Example 1-1, except that Fujimori Kogyo Co., Ltd.'s "Film Vina 75E-0010 BD" was used as the release liner, and the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The results are shown in Table 1.

[0100] <Comparative Example 1-3> Each component constituting the adhesive layer was weighed out according to the formulation shown in Comparative Example 1-3 in Table 1, and the adhesive layer was prepared so that the thickness after drying would be approximately 500 μm in order to make the content of Compound 1 in the adhesive layer the same as in Comparative Example 1-2, and the drying conditions for the coating liquid for forming the adhesive layer were 80°C for 50 minutes. A patch was produced in the same manner as in Comparative Example 1-2, and the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The results are shown in Table 1.

[0101] The results in Table 1 confirmed that the patch of Comparative Example 1-1, which was prepared according to the formulation described in Patent Document 1, the patch of Comparative Example 1-2, in which the type of release liner in Comparative Example 1-1 was changed, and the patch of Comparative Example 1-3, in which the concentration of Compound 1 in Comparative Example 1-1 was changed to 2% by mass, exhibited crystal precipitation in the adhesive layer of the patch and adhesion of the crystals to the release liner. It became clear that even if the concentration of drug contained in the adhesive layer was reduced, crystals would still come out of the adhesive layer to the extent that they adhered to the release liner, and it was inferred that the composition of the adhesive layer needed to be fundamentally reviewed.

[0102] <Example 1-1> A patch was prepared in the same manner as in Comparative Example 1-3, except that instead of mixing and stirring Compound 1 and toluene, Compound 1 and capric acid were mixed and stirred in toluene (internal temperature 50 to 80°C) according to the formulation shown in Example 1-1 in Table 2, and the patch was evaluated for the presence or absence of crystal precipitation in the adhesive layer and the presence or absence of crystal adhesion to the release liner. The results are shown in Table 2.

[0103] [Table 2]

[0104] <Examples 1-2 to 1-3, Comparative Examples 1-4 to 1-5> Patches were prepared in the same manner as in Example 1-1, except that the components constituting the adhesive layer were weighed out according to the formulations shown in Examples 1-2 to 1-3 and Comparative Examples 1-4 to 1-5 in Table 2, and the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The results are shown in Table 2.

[0105] The results in Table 2 show that in the patch of Example 1-1, in which capric acid, an organic acid, was added to the adhesive layer, the patch of Example 1-2, in which N-methylpyrrolidone, an amide, was added, and the patch of Example 1-3, in which benzyl alcohol, an alcohol, was added, no crystal precipitation in the adhesive layer of the patch or adhesion of crystals to the release liner was observed. On the other hand, in the patch of Comparative Example 1-4, which contained the ester isopropyl myristate, and the patch of Comparative Example 1-5, which contained the ether dimethyl isosorbide, no crystals adhered to the release liner, but crystal precipitation was confirmed in the adhesive layer of the patch.

[0106] <Examples 1-4> Patches were prepared in the same manner as in Comparative Examples 1-3, except that instead of mixing and stirring Compound 1 and toluene, Compound 1, capric acid, crotamiton, alkyl lactate, and benzyl alcohol were mixed and stirred in toluene (internal temperature 20-50°C) according to the formulation shown in Examples 1-4 in Table 3, and the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The results are shown in Table 3.

[0107] [Table 3]

[0108] <Examples 1-5 to 1-8> Patches were prepared in the same manner as in Example 1-4, except that the components constituting the adhesive layer were weighed out according to the formulations shown in Examples 1-5 to 1-8 in Table 3, and the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The results are shown in Table 3.

[0109] <Comparative Example 1-6> Patches were prepared in the same manner as in Comparative Examples 1-3, except that the components constituting the adhesive layer were weighed out according to the formulations shown in Comparative Examples 1-6 in Table 3. The patches were then evaluated for the presence or absence of crystal precipitation in the adhesive layer and the presence or absence of crystal adhesion to the release liner. The results are shown in Table 3.

[0110] The results in Table 3 show that in the patches of Examples 1-4 to 1-8, which contained at least one selected from organic acids, amides, and alcohols, no crystal precipitation in the adhesive layer of the patch or adhesion of crystals to the release liner was observed. On the other hand, in the patch of Comparative Example 1-6, which did not contain at least one selected from organic acids, amides, and alcohols, crystal precipitation in the adhesive layer of the patch and adhesion of crystals to the release liner were confirmed.

[0111] <Examples 1-9> Patches were prepared in the same manner as in Examples 1-4, except that the components constituting the adhesive layer were weighed out according to the formulations shown in Examples 1-9 in Table 4 and the adhesive layer was adjusted to a thickness of approximately 100 μm after drying, and the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The results are shown in Table 4.

[0112] <Examples 1-10> Each component constituting the adhesive layer was weighed out according to the formulation shown in Example 1-10 in Table 4, and the adhesive layer was adjusted to a thickness of approximately 500 μm after drying. Except for the drying conditions of the coating liquid for forming the adhesive layer being 80°C for 50 minutes, a patch was prepared in the same manner as in Example 1-9, and the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The results are shown in Table 4.

[0113] [Table 4]

[0114] The results in Table 4 show that in the patches of Examples 1-9 and 1-10, which contained capric acid and isostearic acid as organic acids, no crystal precipitation in the adhesive layer of the patch or adhesion of crystals to the release liner was observed.

[0115] <Reference Experiment 1> A patch was prepared in the same manner as in Examples 1-10, except that the components constituting the adhesive layer were weighed out according to the formulation shown in Reference Experiment 1 in Table 5.

[0116] Under high temperature and humidity conditions (40°C / 75%RH), the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The patch was stored under high temperature and high humidity conditions (40°C / 75%RH) for 1 day, and then visual inspection was performed to confirm that no crystal precipitation had occurred in the adhesive layer. Furthermore, after storing the patch under high temperature and humidity conditions (40°C / 75% RH) for 1 day, it was visually confirmed that no crystals had precipitated in the adhesive layer and that no crystals had adhered to the release liner.

[0117] [Table 5]

[0118] <Reference Experiment 2> A patch was prepared in the same manner as in Examples 1-10, except that the components constituting the adhesive layer were weighed out according to the formulation shown in Reference Experiment 2 in Table 5.

[0119] Under high temperature and humidity conditions (40°C / 75%RH), the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The patch was stored under high temperature and humidity conditions (40°C / 75%RH) for 1 day, and then the precipitation of crystals in the adhesive layer was confirmed by visual inspection. Furthermore, after storing the patch under high temperature and humidity conditions (40°C / 75% RH) for 1 day, it was visually confirmed that no crystals had precipitated in the adhesive layer and that no crystals had adhered to the release liner.

[0120] The results of Reference Experiments 1 and 2 showed that when stored for one day at high temperature and humidity (40°C / 75%RH), the patch in Reference Experiment 1, which contained oleic acid as an organic acid, did not show any crystal precipitation in the adhesive layer of the patch. However, the patch in Reference Experiment 2, which did not contain any organic acid and contained crotamiton, an amide, and benzyl alcohol, an alcohol, showed crystal precipitation.

[0121] <Reference Experiment 3> A patch was prepared in the same manner as in Examples 1-10, except that the components constituting the adhesive layer were weighed out according to the formulation shown in Reference Experiment 3 in Table 6.

[0122] Under high temperature and humidity conditions (40°C / 75%RH), the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The patch was stored under high temperature and high humidity conditions (40°C / 75%RH) for 14 days, and then visual inspection was performed to confirm that no crystal precipitation had occurred in the adhesive layer. Furthermore, after storing the patch under high temperature and humidity conditions (40°C / 75% RH) for 14 days, it was visually confirmed that no crystals had precipitated in the adhesive layer and that no crystals had adhered to the release liner.

[0123] [Table 6]

[0124] <Reference Experiment 4> A patch was prepared in the same manner as in Examples 1-10, except that the components constituting the adhesive layer were weighed out according to the formulation shown in Reference Experiment 4 in Table 6.

[0125] Under high temperature and humidity conditions (40°C / 75%RH), the presence or absence of crystal precipitation in the adhesive layer of the patch and the presence or absence of crystal adhesion to the release liner were evaluated. The patch was stored under high temperature and high humidity conditions (40°C / 75%RH) for 14 days, and then it was visually confirmed that crystals had precipitated in the adhesive layer. Furthermore, after storing the patch under high temperature and humidity conditions (40°C / 75% RH) for 14 days, it was visually confirmed that no crystals had precipitated in the adhesive layer and that no crystals had adhered to the release liner.

[0126] The results of Reference Experiments 3 and 4 showed that when stored for 14 days at high temperature and humidity (40°C / 75%RH), the patch of Reference Experiment 3, which contained 2 molar equivalents of oleic acid as an organic acid relative to compound 1, did not show any crystal precipitation in the adhesive layer of the patch, whereas the patch of Reference Experiment 4, which contained only 1 molar equivalent of oleic acid relative to compound 1, showed crystal precipitation.

[0127] <Test Example 1: Evaluation of analgesic activity in the tail flick test in hairless rats> In the tail flick test, 10-week-old hairless rats (HWY / Slc, Japan SLC Co., Ltd.) were divided into a patch group and an untreated group (two rats in each group). The patch group received the patch of Example 1-4 (drug content: 5.3 mg), while the untreated group received no patch. Eighteen hours after application of the patch, a thermal laser was irradiated onto the tail of each hairless rat using a tail flick analgesic effect measuring device (manufactured by Ugo Brasile), and the reaction time from the start of irradiation to the movement of the tail was measured. The results are shown in Table 7. The longer the reaction time, the greater the analgesic effect was judged to be.

[0128] [Table 7]

[0129] From the results in Table 7, the reaction time in the patch group was longer than that in the untreated group, demonstrating the analgesic effect of the patch. Furthermore, in the hairless rats in the patch group, no noticeable skin irritation (redness, etc.) was observed at the patch application site, and no side effects such as abnormal behavior were observed.

[0130] <Comparative Example 2-1> Each component constituting the pressure-sensitive adhesive layer was weighed out according to the formulation (10% by weight of Compound 1, 20% by weight of styrene-isoprene-styrene block copolymer, 40% by weight of liquid paraffin, 30% by weight of rosin) described in Patent Document 1 (International Publication No. WO 2019 / 156074) shown in Comparative Example 2-1 in Table 8. The numerical values ​​of each component in Table 8 are in mass%. First, compound 1 and toluene were mixed (internal temperature 50-80°C) to obtain mixture A. A mixture of styrene-isoprene-styrene block copolymer and styrene-isoprene block copolymer (JSR Corporation "5002") and rosin ester (Arakawa Chemical Co., Ltd. "KE-311") were dissolved in toluene by mixing and stirring (internal temperature 30-60°C), and then added to mixture A and mixed and stirred (internal temperature 50-80°C). Liquid paraffin (Sonneborn "KAYDOL") was then added and mixed and stirred (internal temperature 50-80°C) to prepare a coating solution for forming the adhesive layer. The coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film (release liner, "Film Bina 75E-0010 BD" manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness of the adhesive layer after drying would be approximately 100 μm. After drying for 30 minutes in an oven at 80°C, a PET film (support) was laminated onto the surface of the adhesive layer to obtain a patch.

[0131] The patch production success, and the adhesive strength and cohesive strength of the adhesive layer in the patch were evaluated using the following evaluation methods. The results are shown in Table 8.

[0132] (Evaluation method) Possibility of manufacturing patches The practicality of patch production was evaluated according to the following criteria. ○: Dissolution of Compound 1 was visually confirmed during the manufacturing process, and the patch was produced without any problems. ×: Compound 1 did not dissolve during the manufacturing process, and a uniform patch could not be produced.

[0133] (Evaluation method) Adhesive strength The adhesive strength of the adhesive layer of the patch was evaluated based on the feel when the adhesive layer was peeled off from the finger after pressing the finger against the adhesive layer of the patch for at least 1 second, according to the following criteria. ◯: Showed adhesive strength equal to or greater than that of existing tulobuterol patches. Δ: The adhesive strength was relatively weak, but within a range that would not cause any practical problems. ×: The adhesive strength was weak and it was not practical.

[0134] (Evaluation method) Cohesive strength The cohesive strength of the adhesive layer in the patch was evaluated according to the following criteria. ○: No adhesive residue was observed. △: The cohesive strength was slightly insufficient, but within the range of no problem. ×: Adhesive residue, deformation, etc. were observed, and the cohesive strength was significantly insufficient.

[0135] [Table 8]

[0136] <Example 2-1> Instead of mixing and stirring Compound 1 and toluene, Compound 1 and capric acid were mixed and stirred in toluene (internal temperature 50 to 80°C) according to the formulation shown in Example 2-1 in Table 8, adjusted so that the thickness of the adhesive layer after drying would be approximately 500 μm, and the drying conditions for the coating liquid were 80°C for 50 minutes. Except for this, patches were prepared in the same manner as in Comparative Example 2-1, and the feasibility of manufacturing the patches, and the adhesive strength and cohesive strength of the adhesive layer in the patches were evaluated. The results are shown in Table 8.

[0137] <Examples 2-2 to 2-3> Patches were prepared in the same manner as in Example 2-1, except that the components constituting the adhesive layer were weighed out according to the formulations shown in Examples 2-2 and 2-3 in Table 8. The feasibility of patch production, and the adhesive strength and cohesive strength of the adhesive layer in the patch were evaluated. The results are shown in Table 8.

[0138] The results in Table 8 show that in Comparative Example 2-1, which was prepared according to the formulation described in Patent Document 1, Compound 1 did not dissolve during the manufacturing process, and it was not possible to prepare a coating liquid for forming an adhesive layer in which Compound 1 was completely dissolved. Furthermore, when a patch was forcibly prepared using the coating liquid, the adhesive layer was non-uniform (the content concentration of Compound 1 varied depending on the location in the adhesive layer), and the adhesive strength of the adhesive layer in the patch was weak, so only a patch with poor practicality could be prepared. On the other hand, in Examples 2-1 to 2-3, in which an adhesive layer was formed using a mixture obtained by mixing compound 1 and an organic compound having a polar functional group at 80°C or less, dissolution of compound 1 during the manufacturing process was visually confirmed, patches could be produced without any problems, and it was confirmed that there were no problems with the adhesive strength of the adhesive layer in the patches.

[0139] <Example 2-4> Patches were prepared in the same manner as in Example 2-1, except that instead of mixing and stirring Compound 1 and capric acid in toluene, Compound 1, crotamiton, alkyl lactate, and benzyl alcohol were mixed and stirred in toluene (internal temperature 50 to 80°C) according to the formulation shown in Example 2-4 in Table 9. The feasibility of patch production and the adhesive strength and cohesive strength of the adhesive layer in the patch were evaluated. The results are shown in Table 9.

[0140] [Table 9]

[0141] <Examples 2-5 to 2-6> Patches were prepared in the same manner as in Example 2-1, except that instead of mixing and stirring Compound 1 and capric acid in toluene, Compound 1, capric acid or oleic acid, crotamiton, alkyl lactate, and benzyl alcohol were mixed and stirred in toluene (internal temperature 20 to 50°C) according to the formulations shown in Examples 2-5 and 2-6 in Table 9. The feasibility of patch production, and the adhesive strength and cohesive strength of the adhesive layer in the patch were evaluated. The results are shown in Table 9.

[0142] The results in Table 9 confirm that in the patches of Examples 2-4 to 2-6, in which an adhesive layer was formed using a mixture obtained by mixing compound 1 and an organic compound having a polar functional group at 80°C or less, dissolution of compound 1 was visually confirmed during the manufacturing process, the patches were produced without any problems, and there were no problems with the adhesive strength of the adhesive layer in the patches.

[0143] <Examples 2-7 to 2-8> Patches were prepared in the same manner as in Example 2-4, except that the components constituting the adhesive layer were weighed out according to the formulations shown in Examples 2-7 and 2-8 in Table 10. The feasibility of patch production, and the adhesive strength and cohesive strength of the adhesive layer in the patch were evaluated. The results are shown in Table 10.

[0144] [Table 10]

[0145] The results in Table 10 confirm that in the patches of Examples 2-7 and 2-8, in which an adhesive layer was formed using a mixture obtained by mixing compound 1 and an organic compound having a polar functional group at 80°C or less, dissolution of compound 1 was visually confirmed during the manufacturing process, the patches were produced without any problems, and there were no problems with the adhesive strength of the adhesive layer in the patches.

[0146] The present invention includes, for example, the following aspects. <1> a pressure-sensitive adhesive layer, the pressure-sensitive adhesive layer comprising (a) 3-[(3R * ,4R * and (b) at least one selected from organic acids, amides, and alcohols, wherein the content of (b) is 50 parts by mass or more per 100 parts by mass of (a). <2> The organic acid is a fatty acid. <1> The patch described in 1. <3> The content of (a) is 10% by mass or less based on the entire pressure-sensitive adhesive layer. <1> or <2> The patch described in 1. <4> The pressure-sensitive adhesive layer further contains a thermoplastic elastomer. <1> from <3> The patch according to any one of the above items. <5> The thermoplastic elastomer includes a styrene-based block copolymer. <4> The patch described in 1. <6> The styrene-based block copolymer includes a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer. <5> The patch described in 1. <7> The above-mentioned compound for use in the treatment and / or prevention of chronic pain. <1> from <6> The patch according to any one of the above items. <8> The aforementioned <1> from <7> A method for producing the patch according to any one of the above, wherein (a) 3-[(3R * ,4R *(b) a method for producing a patch, comprising a mixing step of mixing 100 parts by mass of [(3-(dimethylaminomethyl)tetrahydropyran-4-yl)phenol] with 50 parts by mass or more of at least one selected from organic acids, amides, and alcohols. <9> The mixing step is carried out in the presence of a volatile solvent. <8> 1. A method for producing the patch described in 1. <10> (a)3-[(3R * ,4R * (b) (3-(dimethylaminomethyl)tetrahydropyran-4-yl)phenol and (b) at least one selected from organic acids, amides, and alcohols at a temperature of 80° C. or lower; <8> or <9> 1. A method for producing the patch described in 1. <11> (a)3-[(3R * ,4R * (b) at least one selected from organic acids, amides, and alcohols, and a thermoplastic elastomer is mixed with the resulting mixture at 80° C. or less. <8> from <10> 1. A method for producing the patch according to any one of the above. <12> (a)3-[(3R * ,4R * )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, (b) an organic compound having a polar functional group, and a pressure-sensitive adhesive layer-forming step of forming a pressure-sensitive adhesive layer using a mixture obtained by mixing the above at 80°C or less. <13> The pressure-sensitive adhesive layer-forming step further comprises mixing a base polymer with the mixture at 80°C or less. <12> 1. A method for producing the patch described in 1. <14> In the pressure-sensitive adhesive layer forming step, the mixture is obtained in the presence of a volatile solvent. <12> or <13> 1. A method for producing the patch described in 1. <15> The organic compound having a polar functional group includes at least one selected from organic acids, amides, and alcohols. <12> from <14> 1. A method for producing the patch according to any one of the above.

Claims

1. It has a pressure-sensitive adhesive layer, The pressure-sensitive adhesive layer (a) 3-[(3R ＊ , 4R ＊ )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, (b) at least one selected from organic acids, amides, and alcohols; the organic acid is at least one selected from capric acid, oleic acid, and isostearic acid; the amide is at least one selected from N-methyl-2-pyrrolidone and crotamiton, the alcohol is at least one selected from benzyl alcohol, alkyl lactate, and propylene glycol monocaprylate; A patch characterized in that the content of (b) is 50 parts by mass or more per 100 parts by mass of (a).

2. A patch as described in claim 1, wherein the content of (b) is 4,000 mass parts or less per 100 mass parts of (a).

3. The patch according to claim 1 or 2, wherein the content of (a) is 10% by mass or less based on the total mass of the adhesive layer.

4. The patch according to claim 1 , wherein the adhesive layer further comprises a thermoplastic elastomer.

5. The patch according to claim 4, wherein the thermoplastic elastomer comprises a styrene-based block copolymer.

6. The patch according to claim 5, wherein the styrene-based block copolymer comprises a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.

7. 7. The patch according to claim 1, for use in the treatment and / or prevention of chronic pain.

8. A method for producing the patch according to any one of claims 1 to 7, comprising: (a) 3-[(3R ＊ , 4R ＊ )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, (b) a mixing step of mixing 50 parts by mass or more of at least one selected from organic acids, amides, and alcohols; the organic acid is at least one selected from capric acid, oleic acid, and isostearic acid; the amide is at least one selected from N-methyl-2-pyrrolidone and crotamiton, A method for producing a patch, wherein the alcohol is at least one selected from the group consisting of benzyl alcohol, alkyl lactate, and propylene glycol monocaprylate.

9. The method for producing a patch according to claim 8 , wherein the mixing step is carried out in the presence of a volatile solvent.

10. Said (a) 3-[(3R ＊ , 4R ＊ 10. The method for producing a patch according to claim 8 or 9, wherein (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) at least one selected from organic acids, amides, and alcohols are mixed at 80°C or less.

11. Said (a) 3-[(3R ＊ , 4R ＊ 11. The method for producing a patch according to claim 8, further comprising mixing a thermoplastic elastomer with a mixture obtained by mixing (a)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and (b) at least one selected from organic acids, amides, and alcohols at 80°C or less.

12. (a) 3-[(3R ＊ , 4R ＊ )-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, (b) an organic compound having a polar functional group, and a pressure-sensitive adhesive layer-forming step of forming a pressure-sensitive adhesive layer using a mixture obtained by mixing the above at 80°C or less; the (b) organic compound having a polar functional group includes at least one selected from organic acids, amides, and alcohols; the organic acid is at least one selected from capric acid, oleic acid, and isostearic acid; the amide is at least one selected from N-methyl-2-pyrrolidone and crotamiton, A method for producing a patch, wherein the alcohol is at least one selected from the group consisting of benzyl alcohol, alkyl lactate, and propylene glycol monocaprylate.

13. The method for producing a patch according to claim 12, wherein the pressure-sensitive adhesive layer-forming step further comprises mixing a base polymer with the mixture at 80°C or lower.

14. The method for producing a patch according to claim 12 or 13, wherein in the pressure-sensitive adhesive layer-forming step, the mixture is obtained in the presence of a volatile solvent.

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