Patch, method for manufacturing patch, hydrolysis inhibitor, and hydrolysis inhibition method

Abstract

To suppress the formation of a hydrolysate of an ester-based local anesthetic.SOLUTION: A pharmaceutical composition contains (a) an ester-based local anesthetic or a pharmaceutically acceptable salt thereof, and (b) fatty acid glycerol macrogol ester.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition and a patch. [Background technology]

[0002] Local anesthetic preparations applied to the skin are widely used to reduce pain during medical procedures such as injection needle or intravenous catheter insertion, and minor skin surgery. For example, a gel containing tetracaine as the active ingredient (trade name: AMETOP(R)) is commercially available in Europe and the United States. However, because gel preparations must be wiped off after use, there is a need in the medical field for the development of a preparation that is easy to handle. Therefore, the use of a patch is considered. For example, Patent Document 1 discloses a tetracaine-containing patch, and discloses that by using a thermoplastic elastomer, a higher fatty acid ester, and a fatty acid monoester of a polyhydric alcohol as additives, the patch exhibits skin permeability, cohesive strength, and adhesive strength that are practical for use as a pharmaceutical. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2020 / 184208 Summary of the Invention [Problem to be solved by the invention]

[0004] Ester-type local anesthetics such as tetracaine enter the body through the skin and exert their medicinal effects, and then react with enzymes such as esterases and water to be hydrolyzed and eliminated. However, if the hydrolysis is too rapid, there are problems in that the ester-type local anesthetic may not provide sufficient anesthetic strength or the duration of the anesthetic effect may be insufficient.

[0005] Therefore, as a result of intensive research, the inventors have found that the production of hydrolysates of ester-type local anesthetics can be suppressed by adding fatty acid glycerol macrogol esters to compositions containing ester-type local anesthetics. [Means for solving the problem]

[0006] As a result of extensive research conducted by the present inventors to achieve the above-mentioned object, they discovered that the production of hydrolysates of ester-type local anesthetics can be suppressed by a pharmaceutical composition comprising (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and (b) a fatty acid glycerol macrogol ester.

[0007] 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> The pharmaceutical composition comprises (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and (b) a fatty acid glycerol macrogol ester. [Effects of the Invention]

[0008] According to the present invention, the production of hydrolysis products of ester-type local anesthetics can be suppressed. DETAILED DESCRIPTION OF THE INVENTION

[0009] (Pharmaceutical composition) The pharmaceutical composition contains (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and (b) a fatty acid glycerol macrogol ester, and may further contain another component (A).

[0010] <(a) Ester-type local anesthetic or a pharmaceutically acceptable salt thereof>

[0011] The ester-type local anesthetic refers to one containing an aromatic ring, an ester group, and a hydrocarbon chain having two or more carbon atoms. The hydrocarbon chain having two or more carbon atoms may be an alkyl chain containing a tertiary amine.

[0012] The ester-type local anesthetic is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include tetracaine, procaine, chloroprocaine, benzocaine, and cocaine. Among these, tetracaine is preferred.

[0013] The pharmaceutically acceptable salt is not particularly limited, and may be an inorganic salt or an organic salt. Examples of the inorganic salts include hydrochlorides, hydrobromides, nitrates, sulfates, and phosphates, and examples of the organic acid salts include formates, acetates, trifluoroacetates, propionates, lactates, tartrates, oxalates, fumarates, maleates, citrates, malonates, and methanesulfonates. Among these, hydrochloric acid wire is preferred from the viewpoint of availability.

[0014] The (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof may absorb water to form a hydrate, or may form a solvate with a solvent used in the purification process, and may have multiple crystalline polymorphs. The present invention also includes such hydrates, solvates, and crystalline polymorphs.

[0015] The content of the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof in the pharmaceutical composition, i.e., the proportion of the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof in 100% by mass of the total components of the pharmaceutical composition, is not particularly limited and can be appropriately selected depending on the purpose. However, from the viewpoint of uniformly retaining the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof in the pharmaceutical composition without precipitation, 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.

[0016] <(b) Fatty acid glycerol macrogol ester> The fatty acid glycerol macrogol ester is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include caprylocaproyl macrogol-8 glyceride, linoleoyl macrogol-6 glyceride, oleoyl macrogol-6 glyceride, and lauroyl macrogol-6 glyceride. Among these, caprylocaproyl macrogol-8 glyceride or linoleoyl macrogol-6 glyceride is preferred, and caprylocaproyl macrogol-8 glyceride is more preferred.

[0017] Commercially available products of the caprylocaproyl macrogol-8 glyceride include, for example, "LABRASOL" manufactured by Gattefosse. An example of a commercially available product of the linoleoyl macrogol-6 glyceride is "LABRAFIL M 1944CS" manufactured by Gattefosse. Commercially available products of the oleoyl macrogol-6 glyceride include, for example, "LABRAFIL M 2125CS" manufactured by Gattefosse. Commercially available products of lauroyl macrogol-6 glyceride include, for example, "LABRAFIL M 2130CS" manufactured by Gattefosse.

[0018] The content of the (b) fatty acid glycerol macrogol ester in the pharmaceutical composition, i.e., the proportion of the (b) fatty acid glycerol macrogol ester in 100% by mass of the total of the components of the pharmaceutical composition, is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of increasing the efficiency of inhibiting the degradation of ester-type local anesthetics, the lower limit is preferably 0.05% by mass or more, more preferably 0.1% by mass or more, even more preferably 0.5% by mass or more, and particularly preferably 1% by mass or more. From the viewpoint of increasing the shape retention of the pharmaceutical composition or increasing the cohesive strength of the patch, the upper limit is preferably 30% by mass or less, more preferably 20% by mass or less, even more preferably 10% by mass or less, and particularly preferably 5% by mass or less.

[0019] <Other ingredients (A)> The other component (A) in the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include excipients, binders, lubricants, surfactants, sweeteners, flavorings, fluidizing agents, colorants, stabilizers, pH adjusters, coating agents, etc. These may be used alone or in combination of two or more.

[0020] (patch) The patch contains the pharmaceutical composition and may further contain another ingredient (B). The pharmaceutical composition is as described above. The patch is a mixture of the above-mentioned components, and the amount 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 patch.

[0021] The content of the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof in the patch, i.e., the proportion of the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof in 100% by mass of the total components of the patch, is not particularly limited and can be selected appropriately depending on the purpose, but from the viewpoint of uniformly retaining the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof in the patch without precipitation, 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.

[0022] <Other ingredients (B)> The other component (B) in the patch is not particularly limited and can be appropriately selected depending on the purpose. Examples include base polymers, plasticizers, solubilizers / absorption enhancers, salt dissolving agents, softeners, adsorbents, tackifiers, and antioxidants.

[0023] -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 elastomers, acrylic elastomers, styrene elastomers, olefin elastomers, and silicone 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 elastomers, silicone elastomers, and natural rubber. The various elastomers mentioned above include their derivatives. Among these, from the viewpoint of increasing the production efficiency of the patch (they soften and become fluid when heated, thereby increasing mixing efficiency), and from the viewpoint of being able to incorporate additives such as the organic acids, amides, alcohols, esters, and ethers without significantly impairing the adhesive strength and cohesive strength of the patch, thermoplastic elastomers are preferred, styrene-based thermoplastic elastomers are more preferred, and styrene-based block copolymers are even more preferred.

[0024] 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.

[0025] 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 patch, 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.

[0026] When a mixture of the styrene-isoprene-styrene block copolymer and the 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.

[0027] The styrene content in the styrene-isoprene-styrene block copolymer is not particularly limited and can be selected appropriately depending on the purpose, but the lower limit is preferably 5% by mass or more, more preferably 10% by mass or more. The upper limit is preferably 60% by mass or less, more preferably 50% by mass or less. Furthermore, the weight-average molecular weight of the styrene-isoprene-styrene block copolymer measured by gel permeation chromatography (GPC) is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 20,000 to 500,000, more preferably 30,000 to 300,000. The styrene content of the styrene-isoprene block copolymer is not particularly limited and can be selected appropriately depending on the purpose, but the lower limit is preferably 5% by mass or more, more preferably 10% by mass or more. The upper limit is preferably 50% by mass or less, more preferably 40% by mass or less. The weight-average molecular weight of the styrene-isoprene block copolymer measured by GPC is not particularly limited and can be selected appropriately depending on the purpose, but is preferably 10,000 to 500,000, more preferably 20,000 to 300,000.

[0028] The styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer can each be a copolymer produced by a method known per se. Alternatively, the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer can each be a commercially available product that satisfies the above-mentioned properties. Mixtures of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer are also commercially available, and commercially available mixtures of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer in the above-mentioned mixing ratio that satisfy the above-mentioned properties can be preferably used.

[0029] 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.

[0030] Among these, from the viewpoints 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, with "JSR SIS (registered trademark) 5505" and "Quintac (registered trademark) 3520" being 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% by mass or more.

[0031] The content of the base polymer in the patch, i.e., the proportion of the base polymer in 100% by mass of the total of the constituent components of the patch, is not particularly limited and can be selected appropriately depending on the purpose, but from the viewpoint of maintaining the shape of the patch 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.

[0032] -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, etc. These may be used alone or in combination of two or more. Among these, liquid paraffin is preferred.

[0033] 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.

[0034] The upper limit of the kinematic viscosity of the plasticizer at 40°C is not particularly limited and can be appropriately selected depending on the purpose.2 / s or less is preferable, and 100 mm 2 / s or less is preferable, and 70 mm 2 / s or less is more preferable, and 60 mm 2 / s or less is even more preferable, 40mm 2 / s or less is particularly preferable, and 20 mm 2 / s or less is most preferable. The lower limit of the kinematic viscosity of the plasticizer at 40°C is not particularly limited and can be appropriately selected depending on the purpose. 2 / s or more is preferable, 2 mm 2 / s or more is preferable, and 3mm 2 / s or more is more preferable, and 5mm 2 / s or more is particularly preferred.

[0035] 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."

[0036] Examples of commercially available plasticizers include "Hicol M-52" manufactured by Kaneda Co., Ltd., "Hicol M-72" manufactured by Kaneda Co., Ltd., "Hicol M-172" manufactured by Kaneda Co., Ltd., "Kaydol" manufactured by Sonneborn Co., Ltd., "Rudol" manufactured by Sonneborn Co., Ltd., "Ervol" manufactured by Sonneborn Co., Ltd., "Benol" manufactured by Sonneborn Co., Ltd., "Blandol" manufactured by Sonneborn Co., Ltd., "Carnation" manufactured by Sonneborn Co., Ltd., "Klearol" manufactured by Sonneborn Co., Ltd., "Lytol" manufactured by Sonneborn Co., Ltd., and "Squalane" manufactured by Kishimoto Tokushu Katanyu Kogyosho Co., Ltd. Among these, "Hicol M-52" manufactured by Kaneda Co., Ltd., "Hicol M-72" manufactured by Kaneda Co., Ltd., "Hicol M-172" manufactured by Kaneda Co., Ltd., "Carnation" manufactured by Sonneborn, and "Klearol" manufactured by Sonneborn are preferred.

[0037] The content of the plasticizer in the patch, i.e., the proportion of the plasticizer in 100% by mass of the total of the constituent components of the patch, is not particularly limited and can be selected appropriately depending on the purpose, but the lower limit is 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 preferably 60% by mass or less, more preferably 55% by mass or less, and even more preferably 50% by mass or less.

[0038] -Solubilizer / Absorption enhancer- The solubilizer / absorption enhancer is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof 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, laurate ... Glycerin derivatives such as decaglyceryl phosphate, α-monoisostearyl glyceryl ether, diglyceryl monoisostearate, diglyceryl monostearate, polyoxyethylene glycerin monostearate, polyoxyethylene glyceryl triisostearate, polyoxyethylene coconut oil fatty acid glyceryl, stearic acid derivatives such as propylene glycol monostearate and ethylene glycol monostearate, isoamyl isovalerate, isostearyl palmitate, cetyl 2-ethylhexanoate (cetyl isooctanoate), ethyl oleate Esters of fatty acids and monohydric fatty alcohols such as decyl oleate, isopropyl palmitate, cetyl palmitate, isopropyl myristate, cetyl myristate, myristyl myristate, batyl monostearate, hexyl laurate, methyl laurate, isopropyl linoleate, ethyl linoleate, cocoyl capryl caprate, octyldodecyl myristate, and hexadecyl isostearate; diesters such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, and diethyl sebacate; propylene glycol Propylene glycol diesters such as glyceryl dicaprylate, propylene glycol dicaprate, propylene glycol dicaprylocaprate, and propylene glycol diacetate; glycerin esters such as triacetin, tricaprylin (glyceryl trioctanoate), tri(caprylic / capric)glycerin, glyceryl triisooctanoate (triethylhexanoin), triglycerol diisostearate, and medium-chain triglycerides; citric acid esters such as triethyl O-acetylcitrate and tributyl O-acetylcitrate;Examples of suitable carboxylic acids include cyclic carbonates such as ethylene carbonate, propylene carbonate, and maleic anhydride; aromatic esters such as benzyl benzoate, benzyl acetate, diethyl phthalate, dibutyl phthalate, and butylphthalyl butyl glycolate; organic acids such as lactic acid, caprylic acid, capric acid, isostearic acid, oleic acid, and levulinic acid; and amides such as crotamiton and N-methylpyrrolidone. These may be used alone or in combination.

[0039] Among these, oleyl alcohol, propylene glycol monocaprylate, and diisopropyl adipate are preferred from the viewpoint of improving the solubility of the drug.

[0040] -Salinating agent- The salting agent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include amines such as monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine; aminoalkyl polymers such as aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, and aminoalkyl methacrylate copolymer RL; and inorganic salts such as sodium hydroxide and sodium carbonate. These may be used alone or in combination of two or more. Among these, diethanolamine or diisopropanolamine is preferred from the viewpoint of improving the solubility of the components in the pressure-sensitive adhesive layer.

[0041] -Softener- The softener is not particularly limited and can be appropriately selected depending on the purpose. Examples of the softener include polybutene and polyisobutylene.

[0042] -Adsorbent- The adsorbent 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. These may be used alone or in combination of two or more. Among these, light anhydrous silicic acid is preferred from the viewpoint of uniform dispersion.

[0043] -Tackifier- The tackifier is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include rosin-based resins such as rosin esters, 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, terpene resins or alicyclic saturated hydrocarbon resins are preferred from the viewpoint of improving skin permeability of drugs.

[0044] -Antioxidants- The antioxidant is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include phenolic antioxidants such as dibutylhydroxytoluene, butylhydroxyanisole, and propyl gallate; sulfur-containing antioxidants such as 2-mercaptobenzimidazole and alpha-thioglycerin; and vitamins such as ascorbic acid, riboflavin, hesperidin, and tocopherol.

[0045] The structure of the patch is not particularly limited and can be appropriately selected depending on the purpose. Examples include matrix type and reservoir type, with the matrix type being preferred. The patch may have a structure that includes an adhesive layer and further includes other elements.

[0046] The adhesive layer contains the pharmaceutical composition, and may further contain another component (B). The pharmaceutical composition is as described above. The other component (B) is as described above as the other component (B) in the patch.

[0047] The content of the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof in the adhesive layer, i.e., the proportion of the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof 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 viewpoint of uniformly retaining the (a) ester-type local anesthetic or pharmaceutically acceptable salt thereof 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.

[0048] 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 viewpoint of maintaining the shape of the adhesive layer and skin adhesion, the lower limit is preferably 10% by mass or more, 15% by mass or more, or 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.

[0049] The content of the plasticizer in the pressure-sensitive adhesive layer, i.e., the proportion of the plasticizer 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, but the lower limit is 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 preferably 60% by mass or less, more preferably 55% by mass or less, and even more preferably 50% by mass or less.

[0050] 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, but the lower limit is 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 preferably 40% by mass or less, more preferably 35% by mass or less, and even more preferably 30% by mass or less.

[0051] The average thickness of the pressure-sensitive adhesive layer after drying is not particularly limited and can be selected appropriately depending on the purpose. From the viewpoint of improving the adhesiveness of the pressure-sensitive adhesive layer, the lower limit is preferably 50 μm or more, more preferably 100 μm or more, and even more preferably 200 μm or more. From the viewpoint of production efficiency, the upper limit is preferably 1000 μm or less, and more preferably 500 μm or less.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] The average thickness of the support is not particularly limited and can be appropriately selected depending on the purpose, but for films, the lower limit is preferably 10 μm or more, more preferably 15 μm or more, and the upper limit is 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.

[0056] 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.

[0057] The average 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.

[0058] (Method of producing pharmaceutical composition) The method for producing the pharmaceutical composition includes a mixing step of mixing (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof and (b) a fatty acid glycerol macrogol ester. The (a) ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and (b) fatty acid glycerol macrogol ester are as described above.

[0059] <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. 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.

[0060] (Method of manufacturing patch) The method for producing the patch includes a mixing step of mixing (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof with (b) a fatty acid glycerol macrogol ester, and may further include other steps. The (a) ester-type local anesthetic or a pharmaceutically acceptable salt thereof, (b) fatty acid glycerol macrogol ester, and mixing step are as described above.

[0061] <Other processes> The other steps are not particularly limited and can be appropriately selected depending on the purpose. Examples include a coating step after the mixing step, a lamination step of the pressure-sensitive adhesive layer and a release liner, and a lamination step of the pressure-sensitive adhesive layer and a support. The support, the pressure-sensitive adhesive layer, and the release liner are as described above.

[0062] - Coating process after the mixing process - The coating method for forming the pressure-sensitive adhesive layer obtained in the mixing step is not particularly limited and can be appropriately selected depending on the purpose, and can be applied onto the release liner or the support using a conventional coater such as a roll coater, die coater, gravure roll coater, reverse roll coater, kiss roll coater, dip roll coater, bar coater, knife coater, spray coater, etc. The coating liquid is preferably dried under heating, for example, at a temperature of 40° C. or higher and 150° C. or lower, and the drying temperature, drying time, and drying method can be adjusted depending on the solvent used and its amount.

[0063] -Laminating process of adhesive layer and release liner- The step of laminating the pressure-sensitive adhesive layer and 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, 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), or a step of laminating the pressure-sensitive adhesive layer and the support, followed by pressing the release liner onto the pressure-sensitive adhesive layer.

[0064] -Laminating process of adhesive layer and backing- 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. Examples include a step of spreading the coating liquid for forming the pressure-sensitive adhesive layer onto the support, drying the solvent in the coating liquid, and laminating the pressure-sensitive adhesive layer on the surface of the support (spreading and drying step), or a step of laminating the pressure-sensitive adhesive layer and the release liner, followed by pressing the support onto the pressure-sensitive adhesive layer.

[0065] (hydrolysis inhibitor) The hydrolysis inhibitor is a hydrolysis inhibitor that inhibits the hydrolysis of an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and includes a fatty acid glycerol macrogol ester. The ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and the fatty acid glycerol macrogol ester are as described above.

[0066] Ester-type local anesthetics or pharmaceutically acceptable salts thereof are hydrolyzed by reacting with enzymes such as esterases or water, but the fatty acid glycerol macrogol ester inhibits the hydrolysis of the ester-type local anesthetics or pharmaceutically acceptable salts thereof. Therefore, the fatty acid glycerol macrogol ester can be used as a hydrolysis inhibitor for ester-type local anesthetics or pharmaceutically acceptable salts thereof.

[0067] (Hydrolysis suppression method) The hydrolysis inhibition method is a method for inhibiting the hydrolysis of an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and is a method using the hydrolysis inhibitor. The hydrolysis inhibitor is as described above. [Example]

[0068] Examples of the present invention will be described below, but the present invention is not limited to these examples in any way.

[0069] Example 1 Each component constituting the pressure-sensitive adhesive layer was weighed out according to the formulation shown in Example 1 in Table 1. The numerical value of each component in Table 1 represents mass %. First, tetracaine hydrochloride, diisopropanolamine (manufactured by Mitsui Chemicals Fine Co., Ltd., "Diisopropanolamine"), propylene glycol monocaprylate (manufactured by Gattefosse, "Capryol 90"), diisopropyl adipate (manufactured by Nikko Chemicals Co., Ltd., "DID"), and caprylocapryl macrogol-8 glyceride (manufactured by Gattefosse, "LABRASOL") were mixed and stirred at room temperature to obtain Mixture A. A mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer (manufactured by Nippon Zeon Co., Ltd., "Quintac 3520"), an alicyclic saturated hydrocarbon resin (manufactured by Arakawa Chemical Industries, Ltd., "Alcon P100"), and polybutene (manufactured by INEOS Oligomers, "INDOPOL H-300") were mixed and stirred (internal temperature 20 - 40°C) in toluene until dissolved, then added to Mixture A and mixed and stirred at room temperature. Further, light liquid paraffin (manufactured by Kaneda Co., Ltd., "Hi-Cole M-52") was added and mixed and stirred at room temperature to prepare a coating liquid for forming an adhesive layer.

[0070] The above coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film (release liner, manufactured by Fujimori Kogyo Co., Ltd., "Film Biner 75E-0010 BD") and prepared such that the average thickness of the dried adhesive layer was about 350 μm. 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 an adhesive.

[0071] As described below, an in vitro rat skin permeability test was conducted to measure the permeation amount of each drug. The results are shown in Table 1.

[0072] <In vitro rat skin permeability test> Skin removed from the abdomen of a hairless rat (Japan SLC Co., Ltd., Wistar, male, 5 weeks old) was mounted in a vertical Franz diffusion cell (model number "TP-8s," manufactured by Beadrex Co., Ltd.), and the patch was punched out into a 1.0 cm diameter circle and attached to the rat skin of the Franz diffusion cell. The test was performed using 0.01 mol / L phosphate-buffered saline (pH 7.2 to 7.4) as the buffer, 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 in the buffer that had permeated the rat skin was quantified by HPLC. Measurements were performed three times for each patch, and the average of the measured values ​​was calculated.

[0073] The presence or absence of crystal precipitation in the patch was evaluated according to the following crystal precipitation evaluation criteria. The results are shown in Table 1.

[0074] <Crystallization evaluation criteria> ◯: After storing the patch at 5°C for 1 week, no crystals were observed in the adhesive layer of the patch. ×: After storing the patch at 5°C for 1 week, crystals were found in the adhesive layer of the patch.

[0075] [Table 1]

[0076] <Example 2 and Comparative Examples 1 to 3> Patches were prepared in the same manner as in Example 1, except that the components constituting the adhesive layer were weighed out according to the formulations shown in Table 1, and an in vitro rat skin permeation test and crystal precipitation evaluation were carried out. The results are shown in Table 1.

[0077] The results in Table 1 show that the patch of Example 1, which uses caprylocaproyl macrogol-8 glyceride, a fatty acid glycerol macrogol ester, and the patch of Example 2, which uses linoleoyl macrogol-6 glyceride, had higher skin permeability of tetracaine, suppressed the production of tetracaine hydrolysates, and showed no crystal precipitation, compared to the patches of Comparative Examples 1 and 2, which used lauryl alcohol, and Comparative Example 3, which used dimethyl isosorbide.

[0078] <Test Example 1> During the skin permeation test, tetracaine that had permeated the skin was accumulated in the analytical device filled with physiological saline, and therefore there was a possibility that it had decomposed before the sample was analyzed. Therefore, 190 μg of tetracaine was dissolved in 3 mL of phosphate-buffered saline (PBS), stirred at room temperature for 24 hours, and then analyzed by HPLC to measure the amount of tetracaine hydrolysate produced. The results are shown in Table 2.

[0079] [Table 2]

[0080] <Test Example 2> HPLC analysis was performed in the same manner as in Test Example 1, except that 190 μg of tetracaine was dissolved in 3 mL of PBS and a 1.0 cm diameter circle of skin excised from the abdomen of a hairless rat (Japan SLC, Wistar, male, 5 weeks old) was added, and the amount of hydrolysate produced was measured. The results are shown in Table 2.

[0081] <Test Example 3> Except for dissolving 190 μg of tetracaine and 190 μg of caprylocaproyl macrogol-8 glyceride in 3 mL of PBS, HPLC analysis was carried out in the same manner as in Test Example 1 to measure the amount of hydrolysate produced. The results are shown in Table 2.

[0082] <Test Example 4> 190 μg of tetracaine and 190 μg of caprylocaproyl macrogol-8 glyceride were dissolved in 3 mL of PBS, and HPLC analysis was carried out in the same manner as in Test Example 1, except that a 1.0 cm diameter circle of skin excised from the abdomen of a hairless rat (Japan SLC, Wistar, male, 5 weeks old) was added to the solution, and the amount of hydrolyzed product was measured. The results are shown in Table 2.

[0083] The results in Table 2 show that almost no hydrolysis of tetracaine occurred in PBS (Test Example 1). On the other hand, significant production of hydrolyzed products was confirmed in the sample of Test Example 2, in which tetracaine and hairless rat skin fragments were allowed to coexist in PBS. However, production of hydrolyzed products was suppressed more than in the sample of Test Example 2, in which tetracaine, caprylocaproyl macrogol-8 glyceride, and hairless rat skin fragments were allowed to coexist in PBS in Test Example 4. Therefore, it was suggested that fatty acid glycerol macrogol ester inhibits the hydrolysis of tetracaine in the skin.

[0084] The present invention includes, for example, the following aspects. <1> The pharmaceutical composition comprises (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and (b) a fatty acid glycerol macrogol ester. <2> The aforementioned <1> 1. A patch comprising the pharmaceutical composition according to claim 1. <3> The thermoplastic elastomer <2> The patch described in 1. <4> The thermoplastic elastomer includes a styrene-based block copolymer. <3> The patch described in 1. <5> The aforementioned <1> or a pharmaceutical composition of the above <2> from <4> The method for producing the patch according to any one of the above items (1) to (4) above, which comprises a step of mixing (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and (b) a fatty acid glycerol macrogol ester. <6> The hydrolysis inhibitor inhibits the hydrolysis of an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, and is characterized by containing a fatty acid glycerol macrogol ester. <7> A method for inhibiting hydrolysis of an ester-type local anesthetic or a pharmaceutically acceptable salt thereof, comprising: <6> The hydrolysis inhibitor according to claim 1, wherein the hydrolysis inhibitor is a hydrolysis inhibitor.

Claims

1. A patch containing a pharmaceutical composition, The pharmaceutical composition comprises: (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof; and (b) a fatty acid glycerol macrogol ester; A patch, characterized in that the content of (b) fatty acid glycerol macrogol ester in the pharmaceutical composition is 0.05% by mass or more and 20% by mass or less.

2. The patch of claim 1 , comprising a thermoplastic elastomer.

3. The patch according to claim 2 , wherein the thermoplastic elastomer comprises a styrene-based block copolymer.

4. A method for producing the patch according to any one of claims 1 to 3, comprising: (a) an ester-type local anesthetic or a pharmaceutically acceptable salt thereof; (b) a fatty acid glycerol macrogol ester.

5. A hydrolysis inhibitor that inhibits the hydrolysis of an ester-type local anesthetic or a pharmaceutically acceptable salt thereof contained in a pharmaceutical composition for a patch, Contains fatty acid glycerol macrogol esters, A hydrolysis inhibitor, characterized in that it is added to the pharmaceutical composition in an amount such that the content of the fatty acid glycerol macrogol ester in the pharmaceutical composition is 0.05% by mass or more and 20% by mass or less.

6. A method for inhibiting hydrolysis of an ester-type local anesthetic or a pharmaceutically acceptable salt thereof contained in a pharmaceutical composition for a patch, comprising: A method for inhibiting hydrolysis, comprising adding a fatty acid glycerol macrogol ester to the pharmaceutical composition in an amount such that the content of the fatty acid glycerol macrogol ester in the pharmaceutical composition is 0.05% by mass or more and 20% by mass or less.

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