Adhesive patch

Abstract

The purpose of present invention is to provide a local anesthetic-containing patch that is practical as a pharmaceutical in terms of skin permeability, aggregation power, and adhesiveness. The patch according to the present invention is characterized by having an adhesive agent layer on a support, wherein the adhesive agent layer contains at least a local anesthetic, a thermoplastic elastomer, a higher fatty acid ester, and a fatty acid monoester of a polyhydric alcohol, and the ratio of the higher fatty acid ester with respect to 100 parts by mass of the thermoplastic elastomer is 25-200 parts by mass.

Description

[Technical Field]

[0001] The present invention relates to a patch containing a local anesthetic. [Background technology]

[0002] Topical anesthetic patches are widely used to reduce pain during medical procedures such as needle insertion, intravenous catheter insertion, and minor skin surgeries. For example, lidocaine patches are commercially available in Japan. However, lidocaine patches do not provide sufficient anesthetic effect. In addition, a local anesthetic cream formulation containing a mixture of lidocaine and prilocaine as active ingredients is also commercially available in Japan. This cream formulation has been shown to have a stronger anesthetic effect than lidocaine patches (Patent Document 1). However, it has problems with its complicated and time-consuming procedure, such as the need to spread the cream thickly on the skin and seal it with an ODT (Optical Discharge Therapy) using a film or the like, and the need to wipe off the cream thoroughly after use. In Europe and the United States, a gel containing tetracaine as the active ingredient (product name: AMETOP) (R) These are commercially available and have a faster onset of anesthetic effect than topical anesthetic creams. However, like creams, gel formulations also need to be wiped off after use, so there is a need in medical settings for the development of formulations that are easier to handle. Therefore, the use of transdermal patches can be considered. For example, Patent Document 2 discloses a transdermal drug patch that has low skin irritation and excellent pharmacological efficacy, in which the adhesive layer contains a drug, a transdermal penetration enhancer, an adhesive resin, and additives. Patent Document 3 discloses a transdermal patch that has sufficient drug solubility, skin permeability, and sufficient adhesion to the skin, while having low skin irritation, in which the adhesive layer contains a drug, a thermoplastic elastomer, and a higher fatty acid ester, the ratio of the higher fatty acid ester to the thermoplastic elastomer is adjusted, and the content of the tackifier is reduced. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 54-101414 [Patent Document 2] Japanese Patent Application Publication No. 6-205839 [Patent Document 3] International Publication No. 2017 / 099246 Brochure [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] As mentioned above, transdermal patches containing drugs in the adhesive layer have been developed. However, while Patent Documents 2 and 3 exemplify local anesthetics as drugs to be incorporated into the adhesive layer, in reality, the transdermal patch in Patent Document 2 mainly contains nonsteroidal anti-inflammatory drugs such as ketoprofen, and the transdermal patch in Patent Document 3 mainly contains anticholinergic drugs such as scopolamine, donepezil hydrochloride (a progression inhibitor for Alzheimer's disease, etc.), or nonsteroidal anti-inflammatory drugs. No specific transdermal patch containing a local anesthetic has been disclosed. Furthermore, a transdermal patch containing a local anesthetic that is excellent in all aspects of skin permeability, cohesiveness, and adhesiveness has not yet been developed. Therefore, the present invention aims to provide a local anesthetic-containing patch that exhibits practical skin permeability, cohesiveness, and adhesiveness as a pharmaceutical product. [Means for solving the problem]

[0005] The inventors diligently conducted research to solve the above problems. As a result, they discovered that by incorporating at least a local anesthetic, a thermoplastic elastomer, a higher fatty acid ester, and a polyhydric alcohol fatty acid monoester into the adhesive layer, and by appropriately adjusting the ratio of the higher fatty acid ester to the thermoplastic elastomer, a local anesthetic-containing patch with practical adhesive strength and cohesive strength as a pharmaceutical product, and sufficient drug skin permeability, can be obtained, thus completing the present invention. The present invention is described below.

[0006] [1] Having an adhesive layer on a support, The adhesive layer comprises at least a local anesthetic, a thermoplastic elastomer, a higher fatty acid ester, and a fatty acid monoester of a polyhydric alcohol. A patch characterized in that 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 200 parts by mass or less. [2] The adhesive patch according to [1], wherein the ratio of the higher fatty acid ester to 100 parts by mass of the thermoplastic elastomer is 30 parts by mass or more and 150 parts by mass or less. [3] The adhesive patch according to [1] or [2] above, wherein the content of the higher fatty acid ester in the adhesive layer is 60% by mass or less. [4] The transdermal patch according to any one of the above [1] to [3], wherein the ester portion of the higher fatty acid ester has 12 to 30 carbon atoms. [5] The adhesive patch according to any one of the above [1] to [4], wherein the thermoplastic elastomer is a styrene-based block copolymer. [6] The patch according to [5], wherein the styrene-based block copolymer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer. [7] The adhesive 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 the above [5] to [7], wherein the viscosity of a 25% by mass toluene solution of the styrene-based block copolymer at 25°C is 500 mPa·s or more and 2000 mPa·s or less. [9] The adhesive patch according to any one of the above [1] to [8], wherein the adhesive layer contains 5% by mass or more of a tackifier.

[10] The transdermal patch according to any one of the above [1] to [9], wherein the fatty acid monoester of the polyhydric alcohol is a propylene glycol fatty acid monoester.

[11] The adhesive patch according to any one of the above [1] to

[10] , wherein the adhesive layer further contains a higher alcohol.

[12] The patch according to

[11] above, wherein the higher alcohol has 12 to 30 carbon atoms.

[13] The patch according to

[11] or

[12] above, wherein the higher alcohol is oleyl alcohol and / or lauryl alcohol.

[14] The patch according to any one of [1] to

[13] above, wherein the local anesthetic is at least one selected from the group consisting of tetracaine, lidocaine, prilocaine, bupivacaine, mepivacaine, benzocaine, levobupivacaine, and ropivacaine.

[15] The patch according to any one of [1] to

[13] above, wherein the local anesthetic is tetracaine.

[16] Use of a local anesthetic, a thermoplastic elastomer, a higher fatty acid ester, and a fatty acid monoester of a polyhydric alcohol for local anesthesia, wherein the local anesthetic, the thermoplastic elastomer, the higher fatty acid ester, and the fatty acid monoester of the polyhydric alcohol are included in the adhesive layer of the patch, the patch includes the adhesive layer and a support, and the adhesive layer is located on the support, Use 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 200 parts by mass or less.

[17] The use according to

[16] above, wherein the ratio of the higher fatty acid ester to 100 parts by mass of the thermoplastic elastomer is 30 parts by mass or more and 150 parts by mass or less.

[18] The use according to

[16] or

[17] above, wherein the content of the higher fatty acid ester in the adhesive layer is 60% by mass or less.

[19] The use according to any one of

[16] to

[18] above, wherein the carbon number of the ester moiety of the higher fatty acid ester is 12 to 30.

[20] The use according to any one of

[16] to

[19] above, wherein the thermoplastic elastomer is a styrene-based block copolymer.

[21] The use according to

[20] above, wherein the styrene-based block copolymer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.

[22] The use according to

[21] , wherein the ratio of the styrene-isoprene block copolymer in the mixture is 50% by mass or more.

[23] The use according to any one of the above

[20] to

[22] , wherein the viscosity of a 25% by mass toluene solution of the styrene-based block copolymer at 25°C is 500 mPa·s or more and 2000 mPa·s or less.

[24] The use according to any one of the above

[16] to

[23] , wherein the adhesive layer contains 5% by mass or more of a tackifier.

[25] The use according to any one of the above

[16] to

[24] , wherein the fatty acid monoester of the polyhydric alcohol is a propylene glycol fatty acid monoester.

[26] The use according to any one of the above

[16] to

[25] , wherein the adhesive layer further contains a higher alcohol.

[27] The use described in

[26] above, wherein the higher alcohol has 12 or more carbon atoms and 30 or less.

[28] The use according to

[26] or

[27] above, wherein the higher alcohol is oleyl alcohol and / or lauryl alcohol.

[29] The use described in any one of the above

[16] to

[28] , wherein the local anesthetic is one or more selected from the group consisting of tetracaine, lidocaine, prilocaine, bupivacaine, mepivacaine, benzocaine, levobupivacaine, and ropivacaine.

[30] The use described in any one of the above

[16] to

[28] , wherein the local anesthetic is tetracaine.

[31] A method of local anesthesia comprising the step of applying a patch to the skin, The aforementioned adhesive has an adhesive layer on a support, The adhesive layer comprises at least a local anesthetic, a thermoplastic elastomer, a higher fatty acid ester, and a fatty acid monoester of a polyhydric alcohol. A method for local anesthesia characterized in that 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 200 parts by mass or less.

[32] The local anesthesia method according to

[31] , wherein the ratio of the higher fatty acid ester to 100 parts by mass of the thermoplastic elastomer is 30 parts by mass or more and 150 parts by mass or less.

[33] The method for local anesthesia according to

[31] or

[32] above, wherein the content of the higher fatty acid ester in the adhesive layer is 60% by mass or less.

[34] The local anesthesia method according to any one of the above

[31] to

[33] , wherein the number of carbon atoms in the ester portion of the higher fatty acid ester is 12 or more and 30 or less.

[35] The method for local anesthesia according to any one of the above

[31] to

[34] , wherein the thermoplastic elastomer is a styrene-based block copolymer.

[36] The method for local anesthesia according to

[35] , wherein the styrene-based block copolymer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.

[37] The method for local anesthesia according to

[36] , wherein the ratio of the styrene-isoprene block copolymer in the mixture is 50% by mass or more.

[38] The method of local anesthesia according to any one of the above

[35] to

[37] , wherein the viscosity of a 25% by mass toluene solution of the styrene-based block copolymer at 25°C is 500 mPa·s or more and 2000 mPa·s or less.

[39] The method of local anesthesia according to any one of the above

[31] to

[38] , wherein the adhesive layer contains 5% by mass or more of a tackifier.

[40] The method of local anesthesia according to any one of the above

[31] to

[39] , wherein the fatty acid monoester of the polyhydric alcohol is a propylene glycol fatty acid monoester.

[41] The method of local anesthesia according to any one of the above

[31] to

[40] , wherein the adhesive layer further contains a higher alcohol.

[42] The local anesthesia method according to

[41] above, wherein the higher alcohol has 12 or more carbon atoms and 30 or fewer.

[43] The local anesthesia method according to

[41] or

[42] above, wherein the higher alcohol is oleyl alcohol and / or lauryl alcohol.

[44] The method of local anesthesia according to any one of the above

[31] to

[43] , wherein the local anesthetic is one or more selected from the group consisting of tetracaine, lidocaine, prilocaine, bupivacaine, mepivacaine, benzocaine, levobupivacaine, and ropivacaine.

[45] The method of local anesthesia according to any one of the above

[31] to

[43] , wherein the local anesthetic is tetracaine.

[46] A method of local anesthesia characterized by including the step of applying a patch described in any one of the above items [1] to

[15] to the skin. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a local anesthetic-containing patch that has practical adhesive strength and cohesive strength as a pharmaceutical product and exhibits sufficient drug skin permeability. [Modes for carrying out the invention]

[0008] The patch according to the present invention has an adhesive layer formed on a support. In the present invention, the "support" is not particularly limited, and those commonly used in adhesive sheets for skin application and transdermal absorption preparations can be used. Examples include stretchable or non-stretchable woven or nonwoven fabrics such as polyethylene, polypropylene, and polyethylene terephthalate; films such as polyester such as polyethylene terephthalate, polyolefins such as polyethylene and polypropylene, polyurethane, ethylene vinyl acetate copolymer, and polyvinyl chloride; and foamed supports such as polyolefin and polyurethane. These may be used individually or in laminates of multiple types. Furthermore, to prevent the accumulation of static electricity on the support, an antistatic agent may be included in the woven fabric, nonwoven fabric, film, etc. that constitute the support. In addition, to obtain good anchoring properties with the adhesive layer, a nonwoven fabric or woven fabric, or a laminate of these and a film, can be used as the support. When a laminate of film and nonwoven fabric or woven fabric is used as the support, it is preferable to place the nonwoven fabric or woven fabric on the side that comes into contact with the adhesive layer.

[0009] The thickness of the support is typically 10 μm to 100 μm for films, preferably 15 μm to 50 μm, and typically 50 μm to 2,000 μm for porous sheets such as woven fabrics, nonwoven fabrics, and foamed supports, preferably 100 μm to 1,000 μm.

[0010] The adhesive of the present invention may also include a release liner, which is common in this field. That is, the adhesive of the present invention may have a support, an adhesive layer, and a release liner laminated in that order. As the release liner, glassine paper, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, resin films such as polystyrene, aluminum films, foamed polyethylene films or foamed polypropylene films, or laminates of two or more of the above can be used. Furthermore, the release liner may be silicone processed, fluororesin processed, embossed, hydrophilic processed, hydrophobic processed, etc. The thickness of the release liner is usually 10 μm to 200 μm, preferably 15 μm to 150 μm.

[0011] The adhesive layer of the patch according to the present invention comprises at least (a) a local anesthetic as a drug, (b) a thermoplastic elastomer, (c) a higher fatty acid ester, and (d) a fatty acid monoester of a polyhydric alcohol.

[0012] (a) Local anesthetic The "local anesthetic" that can be used in the present invention refers to a drug that dulls or eliminates sensation at a target site and reduces local pain, and is not particularly limited as long as it has a basic skeleton containing an aromatic ring, an alkyl chain, and an amino group, and the aromatic ring and alkyl chain are linked by an ester bond or an amide bond. For example, one or more local anesthetics selected from the group consisting of tetracaine, lidocaine, prilocaine, bupivacaine, mepivacaine, benzocaine, levobupivacaine, and ropivacaine are examples, with one or more local anesthetics selected from the group consisting of tetracaine, lidocaine, and prilocaine being preferred, and tetracaine being more preferred.

[0013] The local anesthetic used as a raw material may be in the form of a free form or a pharmaceutically acceptable salt, and is not particularly limited. The pharmaceutically acceptable salt is not particularly limited and may be an inorganic salt or an organic salt. Only one type of salt may be used, or two or more types may be used in combination. Furthermore, the free form and the salt may be used in mixture form. Examples of inorganic salts include hydrochloride, hydrobromide, nitrate, sulfate, and phosphate, while examples of organic salts include formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonate, and methanesulfonate. From the viewpoint of availability, the free form or hydrochloride is preferred, and from the viewpoint of dispersibility in the adhesive, the free form is more preferred.

[0014] The content of the local anesthetic in the adhesive layer of the patch according to the present invention, that is, the proportion of the local anesthetic in 100% by mass of the total components of the adhesive layer, is preferably 0.5% by mass or more and 30% by mass or less, from the viewpoint of ensuring dispersibility in the adhesive layer and good skin permeability. More preferably, the content is 1% by mass or more, even more preferably 3% by mass or more, even more preferably 20% by mass or less, and even more preferably 15% by mass or less.

[0015] (b) Thermoplastic elastomers The "thermoplastic elastomer" used in this invention refers to an elastomer that exhibits thermoplastic properties, softening and becoming fluid when heated, and returning to a rubbery elastic state when cooled. Examples include various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based, and olefin-based elastomers. In particular, from the viewpoint of achieving both sufficient skin adhesion and low skin irritation, styrene-based thermoplastic elastomers, especially styrene-based block copolymers, are preferably used.

[0016] Examples of styrene-based block copolymers used as thermoplastic elastomers 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. In the above, "ethylene / butylene" refers to a copolymer block of ethylene and butylene, and "ethylene / propylene" refers to a copolymer block of ethylene and propylene. These styrene-based block copolymers may be used individually or in combination of two or more types.

[0017] Of the styrene-based block copolymers mentioned above, one or more selected from the group consisting of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are preferably used, in order to achieve both sufficient skin adhesion of the adhesive layer and suppression of adhesive residue by improving cohesive force, as well as from the viewpoint of availability and handling, and in particular a mixture of styrene-isoprene block copolymer and styrene-isoprene-styrene block copolymer is preferably used. The proportion of styrene-isoprene block copolymer in the mixture is preferably 50% by mass or more, more preferably 60% by mass or more, preferably 90% by mass or less, and more preferably 80% by mass or less.

[0018] The object of the present invention is to provide a styrene-isoprene-styrene block copolymer in which the styrene content in the copolymer is preferably 5% to 60% by mass, and more preferably 10% to 50% by mass. Furthermore, the weight-average molecular weight measured by gel permeation chromatography (GPC) is preferably 20,000 to 500,000, and more preferably 30,000 to 300,000. Furthermore, the styrene-isoprene block copolymer in which the styrene content in the copolymer is preferably 5% to 50% by mass, and more preferably 10% to 40% by mass. Furthermore, the weight-average molecular weight measured by GPC is preferably 10,000 to 500,000, and more preferably 20,000 to 300,000.

[0019] Regarding the viscosity of the styrene-based block copolymer, from the viewpoint of achieving a good balance of adhesive substances, it is preferable that the solution viscosity of a 25% by mass toluene solution at 25°C is 500 mPa·s or more and 2000 mPa·s or less. More preferably, the viscosity is 500 mPa·s or more, even more preferably 900 mPa·s or more, and even more preferably 1800 mPa·s or less. The above "solution viscosity of a 25% by mass toluene solution at 25°C" is a value measured based on the viscosity measurement method for styrene-isoprene-styrene block copolymer described on page 395 of the "Pharmaceutical Additives Standards 2013" (published by Yakuji Nippo Co., Ltd.).

[0020] For the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, copolymers produced by known methods can be used respectively. Also, for the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, commercially available products satisfying the above characteristics can be used respectively. Further, 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 satisfying the above characteristics are mixed at the above mixing ratio can be preferably used.

[0021] Examples of commercially available products of styrene-based block copolymers include, for example, "KRATON (R) D1111", "KRATON (R) D1163", "KRATON (R) D1113", and "KRATON (R) D1119" manufactured by KRATON POLYMERS; "JSR (R) SIS5229", "JSR (R) SIS5002", "JSR (R) SIS5403", and "JSR (R) SIS5505" manufactured by JSR; "Quintac (R) 3421", "Quintac (R) 3433N", "Quintac (R) 3520", "Quintac (R) 3450", and "Quintac (R) 3270" manufactured by Nippon Zeon Co., Ltd. etc. Among these, from the viewpoints of the mixing ratio and solution viscosity of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, "KRATON (R) D1163", "KRATON (R) D1113", "JSR (R) SIS5403", "JSR (R) SIS5505", "Quintac (R) 3433N", and "Quintac (R) 3520" are preferable, and "JSR(R) SIS5505" and / or "Quintac (R) "3520" is particularly preferred.

[0022] The content of thermoplastic elastomer in the adhesive layer, that is, the proportion of thermoplastic elastomer in 100% by mass of the total components of the adhesive layer, is preferably 20% by mass or more and 70% by mass or less. If this proportion is 20% by mass or more, the shape of the adhesive layer can be maintained more reliably, and if it is 70% by mass or less, the adhesiveness of the adhesive layer to the skin is exhibited more reliably. More preferably, the content is 25% by mass or more, even more preferably 30% by mass or more, even more preferably 65% ​​by mass or less, and even more preferably 60% by mass or less.

[0023] (c) Higher fatty acid esters In this invention, "higher fatty acid ester" refers to a compound in which the carboxyl group of a higher fatty acid is esterified with an aliphatic alcohol. Higher fatty acid esters have the effect of moderately plasticizing thermoplastic elastomers and contribute to imparting tackiness. Furthermore, because they have a moderate affinity for local anesthetics, they also contribute to improving the solubility of local anesthetics and suppressing crystal precipitation.

[0024] The higher fatty acids constituting the higher fatty acid ester may be linear or branched. Furthermore, the higher fatty acids may be saturated or unsaturated, but saturated fatty acids are preferred from the viewpoint of plasticizing effect and thermal stability of the thermoplastic elastomer. The carbon number of the higher fatty acids is preferably 12 or more, more preferably 14 or more, even more preferably 16 or more, preferably 30 or less, more preferably 24 or less, and even more preferably 20 or less.

[0025] Examples of saturated higher fatty acids include capric acid (10 carbon atoms), lauric acid (12 carbon atoms), myristic acid (14 carbon atoms), palmitic acid (16 carbon atoms), stearic acid (18 carbon atoms), isostearic acid (18 carbon atoms), arachidic acid (20 carbon atoms), behenic acid (22 carbon atoms), lignoceric acid (24 carbon atoms), cerotic acid (26 carbon atoms), montanic acid (28 carbon atoms), and melisic acid (30 carbon atoms). Among these, myristic acid, palmitic acid, and stearic acid are preferred.

[0026] Examples of unsaturated higher fatty acids include palmitoleic acid (16 carbon atoms), oleic acid (18 carbon atoms), linoleic acid (18 carbon atoms), (9,12,15)-linolenic acid (18 carbon atoms), (6,9,12)-linolenic acid (18 carbon atoms), and eleostearic acid (18 carbon atoms). Among these, oleic acid and linoleic acid are preferred.

[0027] The aliphatic alcohol constituting the higher fatty acid ester is preferably a saturated or unsaturated aliphatic alcohol having 1 to 30 carbon atoms. Examples include methanol, ethanol, propanol, isopropanol, butanol, hexanol, heptanol, octanol, decanol, cetanol, myristyl alcohol, hexyldecanol, oleyl alcohol, and octyldodecanol. The number of carbon atoms in the aliphatic alcohol corresponds to the number of carbon atoms in the ester portion of the higher fatty acid ester. The number of carbon atoms in the aliphatic alcohol is preferably 12 to 30. If the number of carbon atoms is 12 or more, the plasticizing effect of the aliphatic alcohol is more reliably exhibited, while if it is 30 or less, sufficient solubility of the local anesthetic can be ensured.

[0028] Suitable examples of higher fatty acid esters 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; and linoleic acid esters such as ethyl linoleate.

[0029] The ratio of higher fatty acid ester to 100 parts by mass of thermoplastic elastomer in the adhesive layer is preferably 25 parts by mass or more and 200 parts by mass or less. If the ratio is 25 parts by mass or more, the good adhesiveness of the adhesive layer and the solubility of the local anesthetic are more reliably exhibited, and if it is 200 parts by mass or less, the shape of the adhesive layer can be more reliably maintained. The ratio is more preferably 30 parts by mass or more and 150 parts by mass or less. Furthermore, for similar reasons, the proportion of higher fatty acid ester in the 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 also preferably 70% by mass or less, more preferably 65% ​​by mass or less, and even more preferably 60% by mass or less.

[0030] (d) Fatty acid monoesters of polyhydric alcohols In this invention, "fatty acid monoester of polyhydric alcohol" refers to a compound in which one hydroxyl group of a polyhydric alcohol is esterified with a fatty acid. The fatty acid monoester of polyhydric alcohol contributes to improved drug solubility without drastically reducing the cohesive force of the adhesive base and has an effect of promoting the transdermal absorption of local anesthetics, particularly tetracaine.

[0031] Examples of polyhydric alcohols that constitute polyhydric alcohol fatty acid monoesters include dihydric alcohols such as ethylene glycol, propylene glycol, and butylene glycol; trihydric alcohols such as glycerin; and tetrahydric alcohols such as pentaerythritol. Preferred fatty acids that constitute propylene glycol fatty acid monoesters are those with 8 to 18 carbon atoms, such as capric acid, caprylic acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, and linoleic acid. Suitable specific examples of polyhydric alcohol fatty acid monoesters are propylene glycol monocaprylate and propylene glycol monolaurate.

[0032] The content of polyhydric alcohol fatty acid monoester in the adhesive layer, that is, the proportion of polyhydric alcohol fatty acid monoester in 100% by mass of the total components of the adhesive layer, is preferably 2% by mass or more and 30% by mass or less. If the proportion is 2% by mass or more, the solubility and absorption-enhancing effect of the local anesthetic can be more reliably enhanced, and if the proportion is 30% by mass or less, the cohesive force and adhesiveness of the adhesive layer can be more reliably ensured. A proportion of 5% by mass or more is more preferable.

[0033] The adhesive layer of the patch according to the present invention may contain components other than local anesthetics, thermoplastic elastomers, higher fatty acid esters, and polyhydric alcohol fatty acid monoesters. Such optional components are not particularly limited as long as they are common components that are incorporated into the adhesive layer of a patch, but examples include tackifiers, higher alcohols, solvents, carboxylates, lactones, surfactants, fillers, and crystal precipitation inhibitors.

[0034] (e) Tackifier In the present invention, the "tackifier" is a component that enhances the adhesive strength of the adhesive layer, and can be any component commonly used in general adhesive patches, such as rosin resins, polyterpene resins, coumarone-indene resins, petroleum resins, terpene resins, terpene-phenol resins, and alicyclic saturated hydrocarbon resins.

[0035] The content of the tackifier in the adhesive layer, that is, the proportion of the tackifier to 100% by mass of the total components of the adhesive layer, can be adjusted as appropriate, but for example, 5% by mass or more and 50% by mass or less is preferred. If the proportion is 5% by mass or more, the adhesive strength necessary to obtain sufficient therapeutic effect can be more reliably secured, and if it is 50% by mass or less, the decrease in drug release and the increase in skin irritation can be more reliably suppressed. More preferably, the proportion is 7% by mass or more, and even more preferably 10% by mass or more.

[0036] (f) Higher alcohol In the present invention, "higher alcohol" is a component that enhances the solubility of local anesthetics in the adhesive layer and their transdermal absorption. Examples include higher saturated aliphatic alcohols with 12 to 30 carbon atoms that are liquid at room temperature, such as lauryl alcohol and isostearyl alcohol; and higher unsaturated aliphatic alcohols with 12 to 30 carbon atoms that are liquid at room temperature, such as oleyl alcohol. From the viewpoint of enhancing the solubility and transdermal absorption-promoting effect of local anesthetics, oleyl alcohol and / or lauryl alcohol are preferred as higher alcohols.

[0037] The content of higher alcohols in the adhesive layer, that is, the proportion of higher alcohols in the total 100% by mass of the components of the adhesive layer, can be adjusted as appropriate, but for example, it can be between 1% by mass and 30% by mass. If the proportion is 1% by mass or more, the solubility of the local anesthetic in the adhesive layer and the transdermal absorption of the local anesthetic are more reliably improved, and if it is 30% by mass or less, the cohesive force and adhesive force of the adhesive layer are more reliably ensured. Preferably, the proportion is 3% by mass or more.

[0038] (g) solvent In the present invention, "solvent" refers to a component that is liquid at room temperature and pressure and exhibits appropriate solubility with respect to the adhesive component. The solvents that can be used in the present invention are not particularly limited, but examples include one or more solvents selected from the group consisting of ester solvents, alcohol solvents, amide solvents, and liquid organic acids.

[0039] The amount of solvent used can be adjusted as appropriate, but for example, the solvent content in the adhesive layer, that is, the proportion of solvent to 100% by mass of the total components of the adhesive layer, can be 0.1% by mass or more and 20% by mass or less, and preferably 0.5% by mass or more and 15% by mass or less.

[0040] (g1) Ester solvent Among solvents, ester-based solvents are preferred from the viewpoint of improving the solubility of local anesthetics in the adhesive layer and the transdermal absorption of local anesthetics. Examples of ester-based solvents include diesters of dihydric alcohols and carboxylic acids, medium-chain fatty acid triglycerides, esters of polyhydric carboxylic acids and monohydric aliphatic alcohols, and carbonate esters.

[0041] Examples of diesters of dihydric alcohols and carboxylic acids include diesters composed of propylene glycol and caprylic acid, capric acid, lauric acid, oleic acid, etc.

[0042] Medium-chain triglycerides are triglycerides composed of fatty acids with 6 to 12 carbon atoms, such as caproic acid, caprylic acid, capric acid, and lauric acid, and glycerol. In the present invention, liquid caprylic acid triglyceride at room temperature, a mixture of caprylic and capric acid triglycerides, or a mixture of caprylic, capric, and lauric acid triglycerides can be used. Liquid oils and fats containing a large amount of these can also be used. Examples of such oils and fats include peanut oil, olive oil, and castor oil.

[0043] In addition, in the present invention, products commercially available for pharmaceutical use can be used as medium-chain fatty acid triglycerides that are liquid at room temperature, or medium-chain fatty acid triglyceride-containing oils that are liquid at room temperature.

[0044] Examples of esters of polycarboxylic acids and monohydric aliphatic alcohols include liquid adipate diesters such as diethyl adipate and diisopropyl adipate, which are liquid at room temperature; and liquid sebacate diesters such as diethyl sebacate, diisopropyl sebacate, and dioctyldodecyl sebacate, which are liquid at room temperature. These are liquid diesters of dicarboxylic acids having 2 to 12 carbon atoms and monohydric aliphatic alcohols having 1 to 20 carbon atoms.

[0045] Examples of carbonate esters include cyclic carbonate esters of carbonic acid and diols having 2 to 10 carbon atoms, such as ethylene carbonate, propylene carbonate, and vinylene carbonate, with propylene carbonate being preferred.

[0046] Among the ester solvents mentioned above, medium-chain fatty acid triglyceride mixtures, sebacate diesters, and carbonate esters are preferred, and caprylic and capric triglyceride mixtures, diethyl sebacate, or propylene carbonate are more preferred.

[0047] (g2) Alcohol-based solvents Examples of alcoholic solvents include polyhydric alcohols that are liquid at room temperature, such as ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, and polyethylene glycol with a molecular weight of 100 to 600; monoalkyl ethers of polyhydric alcohols, such as diethylene glycol monoethyl ether; and monofatty acid esters of polyhydric alcohols, such as glycerol monolinoleate and glycerol monooleate.

[0048] In particular, from the viewpoint of improving the solubility of local anesthetics, one or more alcohol-based solvents selected from the group consisting of ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, and diethylene glycol monoethyl ether are preferred.

[0049] (g3) Amide solvents Examples of amide solvents include pyrrolidones such as N-methyl-2-pyrrolidone and 2-pyrrolidone; imidazolidinones such as 1,3-dimethyl-2-imidazolidinone; N-substituted toluidines such as crotamiton; and alkanamides such as formamide, N-methylformamide, N,N-dimethylformamide, N-methylacetamide, N,N-dimethylacetamide, and N-methylpropanamide.

[0050] Of the above amide solvents, N-methyl-2-pyrrolidone, crotamiton, N,N-dimethylformamide, and N,N-dimethylacetamide are preferred from the viewpoint of improving the solubility, dispersibility, and transdermal absorption of local anesthetics, and N-methyl-2-pyrrolidone and / or crotamiton are more preferred.

[0051] (g4) Liquid organic acid Examples of liquid organic acids include aliphatic monocarboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid (heptanoic acid), caprylic acid, and pelargonic acid (nonanoic acid); aliphatic unsaturated monocarboxylic acids such as oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid; hydroxycarboxylic acids such as lactic acid; liquid carboxylic acids substituted with alkoxy groups such as methoxyacetic acid; and sulfonic acids such as methanesulfonic acid. Lactic acid may be L-lactic acid, D-lactic acid, lactic anhydride, or a mixture of two or more of these.

[0052] These liquid organic acids have the function of assisting in the dissolution of basic local anesthetics. The liquid organic acids allow for high concentrations of local anesthetics within the adhesive layer, improve dispersibility, and further enhance transdermal absorption. From this perspective, among these liquid organic acids, Japanese Pharmacopoeia lactic acid, oleic acid, and isostearic acid are preferably used, with Japanese Pharmacopoeia lactic acid being more preferably used.

[0053] In the present invention, one or more of the above liquid organic acids can be selected and included in the adhesive layer as needed. The content of liquid organic acids in the adhesive layer, that is, the ratio of liquid organic acids to 100% by mass of the total components of the adhesive layer, is preferably 0.1% by mass or more and 20% by mass or less, and more preferably 0.5% by mass or more and 15% by mass or less.

[0054] (h) Carboxylate Examples of carboxylate salts incorporated into the adhesive layer of the patch according to the present invention include salts of aliphatic monocarboxylic acids, alicyclic monocarboxylic acids, and aliphatic dicarboxylic acids.

[0055] Examples of aliphatic monocarboxylic acids include short-chain fatty acids with 2 to 7 carbon atoms, such as acetic acid, butyric acid, and hexanoic acid; medium-chain fatty acids with 8 to 11 carbon atoms, such as octanoic acid and decanoic acid; long-chain fatty acids with 12 or more carbon atoms, such as myristic acid, stearic acid, isostearic acid, and oleic acid; hydroxymonocarboxylic acids such as glycolic acid, lactic acid, 3-hydroxybutyric acid, and mandelic acid; monocarboxylic acids substituted with alkoxy groups, such as methoxyacetic acid; and ketomonocarboxylic acids such as levulinic acid.

[0056] Examples of alicyclic monocarboxylic acids include cyclohexanecarboxylic acid, which has 6 to 8 carbon atoms.

[0057] Examples of aliphatic dicarboxylic acids include sebacic acid, adipic acid, malic acid, maleic acid, and fumaric acid.

[0058] Preferred carboxylic acids include long-chain fatty acids with 12 or more carbon atoms, and hydroxy monocarboxylic acids, such as myristic acid, stearic acid, isostearic acid, oleic acid, and lactic acid. More preferably, oleic acid and / or lactic acid.

[0059] Examples of salts of the above-mentioned carboxylic acid include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts; and amine salts. However, sodium salts are preferred from the viewpoint of availability, stability, and the effect of improving the transdermal absorption of local anesthetics.

[0060] (i) lactone Examples of lactones include five-membered ring lactones such as ascorbic acid and isoascorbic acid.

[0061] In the patch of the present invention, considering the effect of improving the stability and transdermal absorption of local anesthetics, it is preferable to incorporate a carboxylate salt and / or lactone into the adhesive layer, and it is preferable to incorporate one or more selected from the group consisting of sodium oleate, sodium lactate, ascorbic acid, and isoascorbic acid.

[0062] When the patch of the present invention contains a carboxylate and / or lactone, the content in the adhesive layer is not particularly limited, but for example, 0.1 moles to 5 moles per mole of local anesthetic is preferred, and 0.2 moles to 3 moles is more preferred. If the ratio of carboxylate and / or lactone to 1 mole of local anesthetic is 0.1 moles or more, a sufficient effect of improving the transdermal absorption of the local anesthetic can be obtained more reliably, and if it is 5 moles or less, the physical properties of the formulation, such as adhesiveness, can be more reliably ensured.

[0063] (j) Surfactants Any of the following surfactants can be used: nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Examples of nonionic surfactants include: polyoxyethylene fatty acid esters such as polyoxyethylene monolaurate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan tetraoleate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate; sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, 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 alkylphenyl ethers such as polyoxyethylene nonylphenyl ether; polyoxyethylene alkylamino ethers such as polyoxyethylene laurylamine and polyoxyethylene oleylamine; and Pluronic acid. (R) L-31, Pluronic (R) Examples include polyoxyethylene polyoxypropylene copolymers such as L-44. Examples of anionic surfactants include alkyl sodium sulfates such as sodium lauryl sulfate. Examples of cationic surfactants include alkyltrimethylammonium salts and alkyldimethylammonium salts. Examples of amphoteric surfactants include alkyldimethylamine oxide and alkylcarboxybetaine. One or more surfactants can be selected and used.

[0064] Among surfactants, nonionic surfactants that are liquid at room temperature are preferred for enhancing the transdermal absorption of local anesthetics, sorbitan fatty acid esters that are liquid at room temperature are more preferred, and sorbitan monolaurate is even more preferred.

[0065] In the present invention, when a surfactant is used, the surfactant content in the adhesive layer, that is, the ratio of the surfactant to 100% by mass of the total components of the adhesive layer, is preferably 0.01% by mass or more and 10% by mass or less, and more preferably 0.1% by mass or more and 5% by mass or less.

[0066] (k) Antioxidants Examples of antioxidants include dibutylhydroxytoluene, 4-dioxyphenol, tocopherol, tocopherol ester derivatives, disodium ethylenediaminetetraacetate, rutin, N,N-dimethylthiourea, L-cysteine, 1-thioglycerol, and 2-mercaptobenzimidazole. Dibutylhydroxytoluene is particularly preferred. Antioxidants may be used individually or in combination of two or more.

[0067] The antioxidant content is not particularly limited and can be included within a range that maintains high skin permeability of the local anesthetic and sufficient cohesiveness and adhesiveness as a patch. For example, the antioxidant content in the adhesive layer, i.e., the proportion of antioxidants in 100% by mass of the total components of the adhesive layer, can be 10% by mass or less, preferably 5% by mass or less, and more preferably 2% by mass or less. The antioxidant is an optional component, meaning its content in the adhesive layer may be 0% by mass, but a lower limit of 0.01% by mass is preferred.

[0068] (l) Filler To control the flexibility of the adhesive layer, fillers may be included. Examples of fillers include silicon compounds such as anhydrous silicic acid, light anhydrous silicic acid, and hydrated silicic acid; cellulose derivatives such as ethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; water-soluble polymers such as polyvinyl alcohol; aluminum compounds such as dried aluminum hydroxide gel and hydrated aluminum silicate; kaolin; and titanium dioxide. Fillers may be used individually or in combination of two or more types.

[0069] The amount of filler is not particularly limited and can be included within a range that maintains high skin permeability of the local anesthetic and sufficient cohesiveness and adhesiveness as a patch. The amount of filler in the adhesive layer, that is, the ratio of filler to 100% by mass of the total components of the adhesive layer, is, for example, 10% by mass or less, preferably 5% by mass or less, and more preferably 2% by mass or less. The filler is an optional component, meaning that its content in the adhesive layer may be 0% by mass, but a lower limit of 0.01% by mass is preferred.

[0070] (m) Crystallization inhibitor To suppress the crystal precipitation of local anesthetics in the adhesive layer, a crystal precipitation inhibitor may be included. Examples of crystal precipitation inhibitors include polyvinylpyrrolidone, vinyl acetate-vinylpyrrolidone copolymer, and polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer. The crystal precipitation inhibitor may be used alone or in a mixture of two or more types.

[0071] The content of the crystal precipitation inhibitor is not particularly limited and can be included in any amount that maintains the adhesive strength of the adhesive. The content of the crystal precipitation inhibitor in the adhesive layer, that is, the ratio of the crystal precipitation inhibitor to 100% by mass of the total components of the adhesive layer, is, for example, 0.01% by mass or more and 10% by mass or less, and preferably 0.1% by mass or more and 5% by mass or less.

[0072] The adhesive patch according to the present invention can be manufactured by conventional methods. For example, it can be manufactured by mixing the components of the adhesive layer, or by dissolving or dispersing the components of the adhesive layer in a low-boiling point solvent other than the solvent constituting the adhesive layer to prepare a coating liquid for forming the adhesive layer, applying the obtained coating liquid to a support, and then drying it. When a release liner is used, the release liner can be pressed onto the adhesive layer to form a laminate. Alternatively, the coating liquid may be applied onto the release liner, dried to form an adhesive layer on the surface of the release liner, and then the support may be pressed onto the adhesive layer to bond them together.

[0073] The low-boiling point solvent used in the coating solution is preferably one that can uniformly dissolve or disperse the adhesive layer components. Examples 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; and acetate esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate. These solvents can be used individually or in combination of two or more. Because of the good solubility of each component constituting the adhesive layer, it is preferable to use aromatic hydrocarbons, alicyclic hydrocarbons, and aliphatic hydrocarbons individually or in combination, or to use aromatic hydrocarbons, aliphatic hydrocarbons, and acetate esters in appropriate combinations.

[0074] The coating liquid for forming the adhesive layer can be applied 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, and spray coaters. Furthermore, drying of the coating liquid is preferably carried out under heating, for example, at a temperature of approximately 40°C to 150°C. The drying temperature, drying time, and drying method can be adjusted depending on the solvent and amount used. The weight per unit area of ​​the dried adhesive layer can be adjusted according to the required skin adhesion and transdermal absorption performance. Within the range where skin adhesion can be achieved, the dried adhesive layer is preferably 10 g / m². 2 More than 1,000g / m 2 The following is more preferable: 20 g / m² 2 More than 800g / m 2 More preferably, 30 g / m 2 More than 600g / m 2 The following applies:

[0075] The patch according to the present invention can be used in the same way as a general patch. For example, if the patch according to the present invention has a release liner, the release liner is peeled off to expose the adhesive layer, and then the adhesive layer is applied to the skin. The number of times the patch according to the present invention can be used can be adjusted as appropriate according to the patient's symptoms, age, gender, etc., but for example, one to ten patches can be used at a time. The application time per patch can also be adjusted as appropriate, but for example, it can be between 10 minutes and 1 hour.

[0076] The patch according to the present invention is applied to the skin of an animal. Target animals include, for example, humans; livestock such as cattle, pigs, sheep, and goats; and pets such as dogs and cats, with humans being preferred. When applying the patch to an animal with a lot of body hair, the hair may be shaved before application.

[0077] This application claims the benefit of priority based on Japanese Patent Application No. 2019-47009, filed on 14 March 2019. The entire specification of Japanese Patent Application No. 2019-47009, filed on 14 March 2019, is incorporated herein by reference. [Examples]

[0078] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited thereto.

[0079] Examples 1-7, Comparative Examples 1-6: Manufacturing of adhesive patches Each component constituting the adhesive layer was weighed according to the formulation shown in Table 1. First, the styrene block copolymer was dissolved in toluene, then octyldodecyl myristate, propylene glycol monocaprylate, terpene resin, and tetracaine were added and mixed and stirred to prepare a coating solution for forming the adhesive layer. The above coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film, which served as a release liner, so that the thickness of the adhesive layer after drying was approximately 400 μm. After drying in a 50°C oven for 60 minutes, a PET film (support) was laminated onto the surface of the adhesive layer, and the sheet was cut to a size of 15 cm x 30 cm to obtain the adhesive.

[0080] [Table 1]

[0081] [Table 2]

[0082] Test Example 1: Evaluation of Skin Permeability Abdominal skin samples from depilated male Wister rats (5 weeks old) were placed in a vertical Franz diffusion cell (model "TP-8s", manufactured by Beadrex). The patches prepared in the examples and comparative examples were punched out into 1.0 cm diameter circles and applied to the rat skin in the Franz diffusion cell. 0.01 mol / L phosphate-buffered saline (pH 7.2 to 7.4) was used as the buffer, and the test was conducted at a buffer temperature of 32°C. Three hours after the start of the test, a portion of the buffer was sampled, and the amount of drug that had permeated through the rat skin into the buffer was quantified by HPLC. A tetracaine-containing control formulation was used: tetracaine 4% gel (product name "Ametop"). (R) The experiment was conducted by applying Franz diffusion cells ("Gel") to rat skin, then covering it with polyvinylidene chloride film ("Saran Wrap®," manufactured by Asahi Kasei Home Products Co., Ltd.) to prevent the water in the gel from evaporating, thereby replicating occlusive therapy. Measurements were taken for three cases for each patch, and the average value of the measurements was calculated. The results are shown in Tables 3 and 4.

[0083] Test Example 2: Evaluation of Cohesive Force The cohesive strength of the adhesive layer of the patch was evaluated on a four-point scale using finger tack according to the following criteria. The results are shown in Tables 3 and 4. 3: No adhesive residue was found at all. 2: Almost no adhesive residue was observed, and it was within an acceptable range. 1: The cohesive force was slightly insufficient, but within an acceptable range. 0: Residual glue, deformation, etc. were observed, indicating a significant lack of cohesive strength.

[0084] Test Example 3: Evaluation of Adhesion The tackiness of the adhesive layer of the patch was evaluated on a four-point scale using finger tacks according to the following criteria. The results are shown in Tables 3 and 4. 3. It showed higher adhesiveness compared to existing local anesthetic patches ("Lidocaine Tape YP," manufactured by Yutoku Pharmaceutical Co., Ltd.). 2: It exhibited adhesiveness comparable to that of existing local anesthetic patches ("Lidocaine Tape YP," manufactured by Yutoku Pharmaceutical Co., Ltd.). 1: It had slightly lower tackiness than existing local anesthetic patches with a rubber-based adhesive base ("Lidocaine Tape YP," manufactured by Yutoku Pharmaceutical Co., Ltd.). 0: It did not adhere at all, and peeling was very noticeable.

[0085] [Table 3]

[0086] [Table 4]

[0087] As shown in Tables 3 and 4, the adhesive strength of the patches in Examples 1 and 6 was slightly low, but still at a level that would not cause problems in practical use, and the cohesive force was good. The adhesive strength of the patch in Example 7 was slightly low, but the adhesive strength was good. The patches in Examples 2 to 5 all showed good cohesive force and adhesive strength. On the other hand, in Comparative Examples 1-3, the ratio of higher fatty acid esters to thermoplastic elastomers was too high, resulting in insufficient cohesive force and inability to maintain the adhesive layer, making it impossible to evaluate the adhesive strength. In Comparative Example 4, the ratio of higher fatty acid esters to thermoplastic elastomers was too low, resulting in cohesive force in the adhesive layer but no adhesive strength. In Comparative Examples 5 and 6, since they did not contain polyhydric alcohol fatty acid monoesters, both cohesive force and adhesive strength were sufficient, but drug skin permeability was not at all sufficient. Furthermore, when comparing Example 4 with Comparative Example 5, and Example 5 with Comparative Example 6, where the ratio of higher fatty acid ester to thermoplastic elastomer was the same, Example 4 showed extremely high skin permeability, approximately 160 times that of Comparative Example 5, and Example 5 showed extremely high skin permeability, 11.5 times that of Comparative Example 6.

[0088] Examples 8-15, Comparative Examples 7-9: Manufacturing of adhesive patches According to the formulations shown in Tables 5 and 6, each component constituting the adhesive layer was weighed out, and each patch was prepared according to the preparation method described above. Furthermore, skin permeability, cohesiveness, and adhesive strength were tested in the same manner as described above. The results are shown in Table 5. However, for skin permeability, the control formulation, tetracaine 4% gel (product name "Ametop"), was used. (R) This shows the ratio of "Gel" to the measured amount of skin permeation.

[0089] [Table 5]

[0090] [Table 6]

[0091] As shown in Tables 5 and 6, the patches of Examples 8 to 15 all exhibited good cohesiveness and adhesive strength. On the other hand, the patch of Comparative Example 8 showed no adhesive strength at all, and leakage of liquid components was observed, so a skin permeability test was not performed. Existing tetracaine-containing gel formulations (product name "Ametop") (R)When the skin permeability of the patches of Examples 8-15 and Comparative Examples 7 and 9 was tested using "Gel" as a control formulation, the cumulative drug skin permeability of the patch of Comparative Example 7, which contained higher alcohols and liquid paraffin instead of higher fatty acid esters, was about the same as that of the gel formulation. Furthermore, the patch of Comparative Example 9, which contained higher fatty acids but did not contain polyhydric alcohol fatty acid monoesters, showed almost no drug skin permeability. In contrast, the cumulative drug skin permeability of the patches of Examples 8-15 was more than twice as high as that of the existing gel formulations.

Claims

1. Having an adhesive layer on a support, The adhesive layer comprises at least a local anesthetic, a thermoplastic elastomer, a higher fatty acid ester, and a fatty acid monoester of a polyhydric alcohol. The thermoplastic elastomer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer. The aforementioned higher fatty acid ester is an ester of capric acid or a higher fatty acid having 12 to 30 carbon atoms with methanol, ethanol, propanol, isopropanol, butanol, hexanol, heptanol, octanol, decanol, cetanol, myristyl alcohol, hexyldecanol, oleyl alcohol, or octyldodecanol. The aforementioned polyhydric alcohol is a dihydric alcohol, The ratio of the styrene-isoprene block copolymer in the mixture is 50% by mass or more. A patch characterized in that 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 200 parts by mass or less.

2. The adhesive patch according to claim 1, wherein the ratio of the higher fatty acid ester to 100 parts by mass of the thermoplastic elastomer is 30 parts by mass or more and 150 parts by mass or less.

3. The adhesive patch according to claim 1 or 2, wherein the content of the higher fatty acid ester in the adhesive layer is 60% by mass or less.

4. The patch according to any one of claims 1 to 3, wherein the higher fatty acid ester is one or more higher fatty acid esters selected from myristic acid ester, palmitic acid ester, stearate ester, oleic acid ester, and linoleic acid ester.

5. The adhesive patch according to any one of claims 1 to 4, wherein the viscosity of a 25% by mass toluene solution of the thermoplastic elastomer at 25°C is 500 mPa·s or more and 2000 mPa·s or less.

6. The adhesive patch according to any one of claims 1 to 5, wherein the adhesive layer contains 5% by mass or more of a tackifier.

7. The patch according to any one of claims 1 to 6, wherein the fatty acid monoester of the polyhydric alcohol is a propylene glycol fatty acid monoester.

8. The adhesive patch according to any one of claims 1 to 7, wherein the adhesive layer further comprises a higher alcohol having 12 to 30 carbon atoms.

9. The patch according to claim 8, wherein the higher alcohol is oleyl alcohol and / or lauryl alcohol.

10. The patch according to any one of claims 1 to 9, wherein the local anesthetic is one or more selected from the group consisting of tetracaine, lidocaine, prilocaine, bupivacaine, mepivacaine, benzocaine, levobupivacaine, and ropivacaine.

11. The patch according to any one of claims 1 to 9, wherein the local anesthetic is tetracaine.

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