Method of inhibiting the formation of diclofenac indolequinone species

Abstract

Disclosed is a method for inhibiting the generation of indole ketone of diclofenac in a patch. The patch is a patch having a support layer and an adhesive layer laminated on the support layer, and the method includes a step of mixing diclofenac free acid with an adhesive base to obtain an adhesive composition, and a step of shaping the adhesive composition to obtain the patch. In addition, the content of the diclofenac free acid is 0.5 to 8 mass% based on the total mass of the adhesive layer.

Description

Technical Field

[0001] This invention relates to a method for inhibiting the formation of diclofenac indole ketone bodies. Background Technology

[0002] Patches containing diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), are known to have analgesic / anti-inflammatory effects on various diseases and symptoms, including low back pain, frozen shoulder, cervical-shoulder-wrist syndrome, tenosynovitis, Achilles tendonitis, lateral epicondylitis (tennis elbow, etc.), muscle pain (muscle / fascial low back pain, etc.), and swelling / pain after trauma, as well as analgesic effects on various cancers. Extensive research has been conducted to date. For example, Patent Document 1 describes a patch containing diclofenac or a pharmaceutically acceptable salt thereof, citric acid, and dimethyl sulfoxide, wherein the mass ratio of diclofenac or a pharmaceutically acceptable salt thereof to citric acid and the mass ratio of diclofenac or a pharmaceutically acceptable salt thereof to dimethyl sulfoxide are within specified ranges. In addition, Patent Document 2 describes an adhesive patch containing an active substance, comprising: an impermeable auxiliary membrane; diclofenac or a pharmaceutically acceptable salt thereof; a matrix-forming polymer selected from styrene-isoprene-styrene block copolymers and ethylene-vinyl acetate copolymers; a tackifier comprising aliphatic hydrocarbon resins and thermoplastic terpene resins; and one or more solvents selected from oleic acid and its derivatives, fatty acid alkyl esters, and N-alkyl-pyrrolidone; and a peelable protective film.

[0003] Existing technical documents

[0004] Patent documents

[0005] Patent Document 1: International Publication No. 2013 / 191128

[0006] Patent Document 2: Japanese Patent Publication No. 2004-508397 Summary of the Invention

[0007] The problem that the invention aims to solve

[0008] Previous studies on diclofenac-containing patches have mostly focused on patches containing pharmaceutically acceptable salts of diclofenac (specifically, diclofenac sodium). For patches containing pharmaceutically acceptable salts of diclofenac, it is known that diclofenac indole bodies, a degradation product of diclofenac, are formed. Inhibiting the formation of diclofenac indole bodies is important for providing patches with high stability. Therefore, the object of this invention is to provide a method for inhibiting the formation of diclofenac indole bodies in a patch. Furthermore, the object of this invention is to provide a patch for inhibiting the formation of diclofenac indole bodies and a method for manufacturing the same.

[0009] Methods for solving problems

[0010] The inventors conducted research on patches containing diclofenac free acid (free diclofenac) and found that patches containing a specified amount of diclofenac free acid were more effective at inhibiting the formation of diclofenac indole bodies than patches containing diclofenac sodium, thus completing the present invention.

[0011] That is, the present invention provides a method for inhibiting the formation of diclofenac indolone bodies in an adhesive layer of a patch having a support layer and an adhesive layer laminated on the support layer, the method comprising: a step of mixing diclofenac free acid with an adhesive base agent to obtain an adhesive composition, and a step of molding the adhesive composition to obtain the patch, wherein the content of diclofenac free acid is 0.5% to 8% by mass based on the total mass of the adhesive layer.

[0012] The present invention also provides a method for manufacturing a patch, wherein the patch comprises a support layer and an adhesive layer laminated on the support layer, the method comprising: a step of mixing diclofenac free acid with an adhesive base agent to obtain an adhesive composition, and a step of molding the adhesive composition to obtain the patch, wherein the content of diclofenac free acid is 0.5% to 8% by mass based on the total mass of the adhesive layer. The present invention also provides a patch comprising a support layer and an adhesive layer laminated on the support layer, the adhesive layer containing diclofenac free acid and an adhesive base agent, wherein the content of diclofenac free acid is 0.5% to 8% by mass based on the total mass of the adhesive layer.

[0013] Invention Effects

[0014] According to the present invention, the formation of diclofenac indole bodies can be inhibited in the patch (especially the formation of diclofenac indole bodies during storage). Detailed Implementation

[0015] The present invention will now be described in detail by showing embodiments thereof.

[0016] The patch according to one embodiment of the present invention comprises a support layer and an adhesive layer laminated on the support layer. The adhesive layer contains diclofenac free acid and an adhesive base agent, and the content of the diclofenac free acid is 0.5% to 8% by mass based on the total mass of the adhesive layer.

[0017] The support layer retains the adhesive layer. The support layer is preferably formed by making fibers into a fabric-like structure (woven fabric, non-woven fabric, or braided fabric), or a single layer or laminate of a non-porous or porous membrane (sheet). The material of the support layer is preferably selected from one or more materials chosen from polyester (polyethylene terephthalate, polyethylene isophthalate, polypropylene terephthalate, polypropylene isophthalate, polybutylene terephthalate, or polyethylene naphthalate, etc.), polyolefin (polymers or copolymers of vinyl monomers such as ethylene, propylene, vinyl acetate, or acrylonitrile), polyamide (nylon or silk, etc.), polyurethane, or cellulose (kapok or hemp, etc.). A rubber composition may also be coated onto the fabric (woven fabric, non-woven fabric, or braided fabric). The rubber composition contains a rubber-based adhesive base. Rubber-based adhesives include, for example, polyisoprene, polyisobutylene, polybutadiene, styrene-butadiene-styrene block copolymers, styrene-isoprene-styrene block copolymers, styrene-butadiene rubber, styrene-isoprene rubber, or combinations thereof. The rubber composition may contain a tackifying resin. Tackifying resins include, for example, alicyclic saturated hydrocarbon resins, hydrogenated rosin glycerol esters, terpene resins, or combinations thereof. Additionally, the rubber composition may contain additives such as plasticizers and fillers. The thickness of the support layer is, for example, 0.1–2 mm. The weight per unit area of ​​the support layer is, for example, 30–200 g / m². 2 In this specification, the thickness and weight per unit area of ​​the support layer are measured in accordance with JISL 1906:2000.

[0018] The optimal moisture permeability of the support layer is 400 g / m². 2 • More than 24 hours, preferably 1000g / m 2 • More than 24 hours, further optimized to 4000g / m 2 • Over 24 hours. When using such a highly moisture-permeable support layer, dimethyl sulfoxide slowly evaporates from the patch applied to the skin, thus improving the patch's adhesion and preventing it from peeling off even after prolonged use. The upper limit of moisture permeability can be 20,000 g / m². 2 • 24 hours. When the moisture permeability of the support layer is within this range, dimethyl sulfoxide evaporates more easily from the adhesive layer, thus more effectively improving the adhesion of the patch. It should be noted that the moisture permeability of the support layer refers to the moisture permeability at 40°C as defined in JIS Z0208:1976 (Test Method for Moisture Permeability of Moisture-Proof Packaging Materials (Cup Method)).

[0019] When the support layer is fabric-like, the 50% modulus (JIS L 1018:1999) in either the longitudinal (material flow direction) or transverse (material width direction) direction of the support layer is preferably 1 N / 50 mm to 12 N / 50 mm. When the 50% modulus is below 12 N / 50 mm, the patch experiences less stress due to skin stretching, thus resulting in better skin adhesion.

[0020] When the support layer is a membrane, the material is preferably polyurethane with high moisture permeability (high dimethyl sulfoxide permeability). Membranes containing polyurethane have excellent elasticity, and are therefore preferred from the viewpoint of improving the patch's adhesion to the skin and its ability to follow stretch.

[0021] The support layer is preferably, for example, a nonwoven fabric or film containing polyurethane, a woven fabric containing polyethylene terephthalate, a nonwoven fabric or film, a polyester fabric coated with a rubber composition, or a combination thereof. More specifically, the support layer is more preferably a laminate of a polyurethane-containing film and a polyurethane-containing nonwoven fabric, a woven fabric or nonwoven fabric containing polyethylene terephthalate, or a polyester fabric coated with a rubber composition.

[0022] The adhesive layer is formed from an adhesive composition obtained by mixing diclofenac free acid, an adhesive base agent, and any of the components described below. From the viewpoint of ensuring proper adhesion of the patch to the skin, the overall mass of the adhesive layer is preferably 10 g / m². 2 ~1000g / m 2 More preferably 30g / m 2 ~300g / m 2 Further preferred is 100g / m 2 ~250g / m 2 .

[0023] Diclofenac free acid is a compound also known as 2-[(2,6-dichlorophenyl)amino]phenylacetic acid. Based on the total mass of the adhesive layer, the content of diclofenac free acid is 0.5% to 8% by mass, or can be 1% to 7%, 1% to 5%, or 1% to 4.65% by mass.

[0024] Adhesive base agents are used to impart adhesiveness to the adhesive layer, and examples include rubber-based adhesive base agents, acrylic adhesive base agents, and silicone adhesive base agents. The adhesive base agent is preferably selected from one or more of rubber-based, acrylic, and silicone adhesive base agents. The adhesive base agent is preferably water-free (non-aqueous adhesive base agent). The adhesive base agent can be any one of rubber-based, acrylic, and silicone adhesive base agents, or a combination thereof. Based on the total mass of the adhesive layer, the total content of the adhesive base agent can be 10% to 90% by mass, or 20% to 90% by mass.

[0025] Examples of rubber-based adhesive base agents include: natural rubber, polyisobutylene, alkyl vinyl ether (co)polymers, polyisoprene, polybutadiene, styrene-butadiene copolymers, styrene-isoprene copolymers, styrene-isoprene-styrene block copolymers, and styrene-butadiene-styrene block copolymers. One of these rubber-based adhesive base agents can be used alone, or two or more can be used in combination. Specifically, from the viewpoint of maximizing the adhesive strength of the adhesive layer, the rubber-based adhesive base agent of this embodiment is preferably selected from at least one of styrene-isoprene-styrene block copolymers and polyisobutylene, more preferably styrene-isoprene-styrene block copolymers, or styrene-isoprene-styrene block copolymers and polyisobutylene.

[0026] Specific examples of rubber-based adhesive bases include: Quintac (registered trademark) 3570C (trade name, manufactured by Zeon Corporation of Japan), SIS5002, SIS5229, SIS5505, SIS5505P (trade name, manufactured by JSR Corporation), and SIBSTAR (registered trademark) T102 (trade name, manufactured by Kaneka Corporation). Additionally, polyisobutylene also includes so-called butyl rubber (isobutylene-isoprene rubber), and specific examples include: Oppanol (registered trademark) N50, N80, N100, and N15. 0, B11, B12, B50, B80, B100, B120, B150, B220 (trade names, manufactured by BASF), JSR (registered trademark) Butyl065, 268, 365 (trade names, manufactured by JSR), X_Butyl (registered trademark) RB100, 101-3, 301, 402 (trade names, manufactured by ARLANXEO), Exxon (registered trademark) Butyl065, 065S, 068, 068S, 268, 268S, 365, 365S (trade names, manufactured by Exxon Mobile), etc.

[0027] Based on the total mass of the adhesive layer, the content of the rubber-based adhesive base can be 10% to 90% by mass, or 15% to 60% by mass, 15% to 40% by mass, or 15% to 30% by mass. When using a mixture of styrene-isoprene-styrene block copolymer and polyisobutylene as the rubber-based adhesive base, the preferred mass ratio is 4:1 to 1:4, 3:1 to 1:1, or 3:1 to 2:1.

[0028] Acrylic adhesive bases are components that impart adhesive properties to adhesive layers, and are, for example, (co)polymers of one or more alkyl (meth)acrylates. Examples of alkyl (meth)acrylates include, for example, butyl (meth)acrylate, isobutyl (meth)acrylate, hexyl (meth)acrylate, octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, etc. It should be noted that in this specification, the term "(meth)acrylate" refers to either or both of acrylic acid and methacrylic acid, and similar expressions have the same meaning.

[0029] Acrylic adhesives can be copolymers formed from alkyl (meth)acrylates (main monomers) and comonomers. Examples of main monomers include: methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, and 2-ethylhexyl (meth)acrylate. One of these monomers can be used alone, or in combination of two or more. The comonomers simply need to be components that can copolymerize with alkyl (meth)acrylates. Examples of comonomers include: hydroxyalkyl (meth)acrylate, ethylene, propylene, styrene, vinyl acetate, N-vinylpyrrolidone, (meth)acrylic acid, and (meth)acrylamide. The comonomers can be one or a combination of two or more.

[0030] Specific examples of acrylic adhesive bases include: acrylic acid-octyl acrylate copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer solution, acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymer, methyl acrylate-2-ethylhexyl acrylate copolymer resin emulsion, and acrylic polymers contained in acrylic resin alkanolamine liquid, etc. Specific examples of such acrylic adhesives include: DURO-TAK (registered trademark) 387-2510, DURO-TAK (registered trademark) 87-2510, DURO-TAK (registered trademark) 387-2287, DURO-TAK (registered trademark) 87-2287, DURO-TAK (registered trademark) 87-4287, DURO-TAK (registered trademark) 387-2516, DURO-TAK (registered trademark) 87-2516, DURO-TAK (registered trademark) 87-2074, DURO-TAK (registered trademark) 87-900A, DURO-TAK (registered trademark) 87-901A, DURO-TAK (registered trademark) 87-9301, DURO-TAK (registered trademark) 87-4098, etc., the DURO-TAK series (manufactured by Henkel); GELVA (registered trademark) GMS. 788, GELVA (registered trademark) GMS 3083, GELVA (registered trademark) GMS 3253, etc. GELVA series (manufactured by Henkel); MAS811 (trade name), MAS683 (trade name), etc. MAS series (manufactured by Cosmedy Pharmaceutical Company); Eudragit (registered trademark) series (manufactured by Evonik Company), Nikasol (registered trademark) series (manufactured by Japan Carbide Industry Co., Ltd.), Ultrazore (registered trademark) series (manufactured by Aica Industry Co., Ltd.).

[0031] Based on the total mass of the adhesive layer, the content of acrylic adhesive base can be 10% to 90% by mass or 20% to 90% by mass.

[0032] Organosilicon adhesives are compounds with an organopolysiloxane backbone. Examples of organosilicon adhesives include dimethylpolysiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane. Specific examples of organosilicon adhesives include MD7-4502 and MD7-4602 silicone adhesives, etc., from the MD series (DuPont Toray Specialty). Materials Inc.); BIO-PSA (registered trademark) 7-4301 silicone adhesive, BIO-PSA (registered trademark) 7-4302 silicone adhesive, BIO-PSA (registered trademark) 7-4201 silicone adhesive, BIO-PSA (registered trademark) 7-4202 silicone adhesive, BIO-PSA (registered trademark) 7-4101 silicone adhesive, BIO-PSA (registered trademark) 7-4102 silicone adhesive, BIO-PSA (registered trademark) 7-4601 silicone adhesive, BIO-PSA (registered trademark) 7-4602 silicone adhesive, BIO-PSA (registered trademark) 7-4501 silicone adhesive, BIO-PSA (registered trademark) 7-4502 silicone adhesive, BIO-PSA (registered trademark) 7-4401 silicone adhesive, BIO-PSA (registered trademark) 7-4402 silicone adhesive, etc., BIO-PSA series (DuPont Toray Special). (Made by ty Materials), Dow Corning (registered trademark) 7-9800A, Dow Corning (registered trademark) 7-9800B, Dow Corning (registered trademark) 7-9700A, Dow Corning (registered trademark) 7-9700B.

[0033] Based on the total mass of the adhesive layer, the content of the silicone adhesive base can be 10% to 90% by mass or 20% to 90% by mass.

[0034] To dissolve the free acid of diclofenac and improve its skin permeability, the adhesive layer may also contain dimethyl sulfoxide (DMSO). Based on the total mass of the adhesive layer, the DMSO content is preferably 1%–20% by mass, 1%–7% by mass, 2%–10% by mass, 3%–10% by mass, or 4%–8% by mass.

[0035] From the perspective of improving the skin permeability of diclofenac free acid and preventing the crystallization of diclofenac, the preferred ratio of diclofenac free acid to dimethyl sulfoxide is 1:0.3 to 1:14, 1:0.4 to 1:7, 1:0.6 to 1:3, or 1:0.7 to 1:3.

[0036] The adhesive layer may also optionally contain other additives. Examples of other additives include: tackifying resins, plasticizers, absorption promoters, solvents, stabilizers, fillers, fragrances, etc.

[0037] Tackifying resins are components that adjust the adhesiveness of adhesive layers. Examples of tackifying resins include petroleum-based resins, terpene-based resins, rosin-based resins, phenolic resins, and xylene-based resins. Examples of petroleum-based resins include alicyclic petroleum resins (such as alicyclic saturated hydrocarbon resins), aliphatic petroleum resins (such as aliphatic hydrocarbon resins), and aromatic petroleum resins. More specifically, examples include ARKON P-70, ARKON P-85, ARKON P-90, ARKON P-100, ARKON P-115, ARKON P-125, ARKON M-70, ARKON M-85, ARKON M-90, ARKON M-100, ARKON M-115, and ARKON M-125 (trade names manufactured by Arakawa Chemical Industry Co., Ltd.), and Escorez 8000 (trade name manufactured by ExxonMobil). Examples of terpene-based resins include: pinene polymers (α-pinene polymers, β-pinene polymers, etc.), terpene polymers, dipentene polymers, terpene-phenol polymers, aromatic modified terpene polymers, and pinene-phenol copolymers. More specifically, examples include: YS resins (YS resin PXN (1150N, 300N), YS resin PX1000, YS resin TO125, YS resin TO105, etc.), Cleanon P105, Cleanon M115, Cleanon K100 (these are trade names, manufactured by Yasuhara Chemical Co., Ltd.), and Tamanol 901 (trade name, manufactured by Arakawa Chemical Co., Ltd.). Examples of rosin-based resins include hydrogenated rosin glycerol esters, ultra-light-colored rosin, ultra-light-colored rosin esters, and acid-modified ultra-light-colored rosin. More specifically, examples include Pinecrystal (KE-311, PE-590, KE-359, KE-100, etc.) (trade name, manufactured by Arakawa Chemical Industry Co., Ltd.). One of these tackifying resins can be used alone, or two or more can be used in combination. Preferably, alicyclic saturated hydrocarbon resins, terpene resins, hydrogenated rosin glycerol esters, or combinations thereof, more preferably alicyclic saturated hydrocarbon resins, hydrogenated rosin glycerol esters, or combinations thereof. When the adhesive layer contains tackifying resin, the content of tackifying resin can be 15% to 80% by mass, or 30% to 65% by mass, based on the total mass of the adhesive layer. When using alicyclic saturated hydrocarbon resin and hydrogenated rosin glycerol ester as the tackifying resin, the preferred mass ratio of the two is 4:1 to 1:4, 4:1 to 2:3, or 3:1 to 2:1.

[0038] Examples of plasticizers include: paraffin oil (liquid paraffin, etc.); squalane, squalene, vegetable oils (olive oil, camellia oil, castor oil, tall oil, peanut oil, peppermint oil, eucalyptus oil, jojoba oil, camphor oil, sunflower seed oil, orange oil, etc.); oils and fats (dibutyl phthalate, dioctyl phthalate, etc.); and liquid rubbers (liquid polybutene, liquid isoprene rubber, etc.). Liquid paraffin is a preferred plasticizer. A single plasticizer can be used, or two or more can be used in combination. When the adhesive layer contains a plasticizer, the content of the plasticizer, based on the total mass of the adhesive layer, is, for example, 3% to 50% by mass, 5% to 30% by mass, or 7% to 20% by mass.

[0039] Absorption enhancers can be any compounds known to promote transdermal absorption. Examples of absorption enhancers include: organic acids and their salts (e.g., aliphatic carboxylic acids (hereinafter also called "fatty acids") with 6 to 20 carbon atoms and their salts, cinnamic acid and its salts), organic acid esters (e.g., fatty acid esters, cinnamic acid esters), organic amides (e.g., fatty amides), aliphatic alcohols, polyols, ethers (e.g., aliphatic ethers, polyoxyethylene alkyl ethers), etc. These absorption enhancers can have unsaturated bonds and can have cyclic, linear, or branched chemical structures. Furthermore, absorption enhancers can be monoterpenoid compounds, sesquiterpenoid compounds, and vegetable oils (e.g., olive oil). These absorption enhancers can be used alone or in combination of two or more.

[0040] Examples of the aforementioned organic acids include: aliphatic (mono, di, or tri) carboxylic acids (e.g., acetic acid, propionic acid, isobutyric acid, hexanoic acid, octanoic acid, fatty acids, lactic acid, maleic acid, pyruvic acid, oxalic acid, succinic acid, tartaric acid, etc.), aromatic carboxylic acids (e.g., phthalic acid, salicylic acid, benzoic acid, acetylsalicylic acid, etc.), cinnamic acid, alkyl sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid), alkyl sulfonic acid derivatives (e.g., polyoxyethylene alkyl ether sulfonic acid, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), and cholic acid derivatives (e.g., dehydrocholic acid, etc.). These organic acids may also be alkali metal salts such as sodium salts. Aliphatic carboxylic acids, aromatic carboxylic acids, or their salts are preferred, with acetic acid or sodium acetate being particularly preferred. Examples of fatty acids include: lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, and linolenic acid.

[0041] In another embodiment, the adhesive layer is free of citric acid (including citric anhydride) and its salts. Patches having an adhesive layer free of citric acid and its salts can further inhibit the formation of diclofenac indolone bodies.

[0042] Examples of organic acid esters include: ethyl acetate, propyl acetate, cetyl lactate, lauryl lactate, methyl salicylate, ethylene glycol salicylate, methyl cinnamate, and fatty acid esters. Examples of fatty acid esters include: methyl laurate, hexyl laurate, isopropyl myristate, myristyl myristate, octyl dodecyl myristate, isopropyl palmitate, and cetyl palmitate. Fatty acid esters can be glycerol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, or polyoxyethylene hydrogenated castor oil. Specific examples of fatty acid esters include: glyceryl monocaprylate, glyceryl monodecanoate, glyceryl monolaurate, glyceryl monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20 (trade name), propylene glycol monolaurate, polyethylene glycol monolaurate, polyethylene glycol monostearate, Span 40, Span 60, Span 80, Span 120 (trade name, manufactured by Croda Japan), Tween (registered trademark) 20, Tween (registered trademark) 21, Tween (registered trademark) 40, Tween (registered trademark) 60, Tween (registered trademark) 80, and NIKKOL (registered trademark) HCO-60 (trade name, manufactured by Nikko Chemical Co., Ltd.).

[0043] Examples of organic amides include: fatty amides (e.g., diethanolamide of laurate), hexahydro-1-dodecyl-2H-aza-amides, etc. -2-keto (also known as "nitrogenone") and its derivatives, pyrothiodecane.

[0044] Aliphatic alcohols refer to aliphatic alcohols with 6 to 20 carbon atoms. Examples of aliphatic alcohols include lauryl alcohol, myristicin, oleyl alcohol, isostearyl alcohol, and cetyl alcohol. Examples of polyols include propylene glycol.

[0045] Aliphatic ethers are ethers having an aliphatic group (e.g., alkyl, alkenyl) with 6 to 20 carbon atoms. Examples of polyoxyethylene alkyl ethers include polyoxyethylene lauryl ether.

[0046] Examples of monoterpenoid compounds include geraniol, thymol, terpineol, L-menthol, borneol, d-limonene, isoborneol, nerol, and dL-camphor. Peppermint oil can also be used as a monoterpenoid compound.

[0047] When the adhesive layer contains an absorption promoter, the content of the absorption promoter, based on the total mass of the adhesive layer, can be 2% to 40% by mass.

[0048] A solvent is a component that makes diclofenac free acid readily soluble in the adhesive composition. Examples of solvents include: alkyl fatty acid esters (e.g., isopropyl myristate, isopropyl palmitate), fatty acid polyol esters (e.g., propylene glycol monolaurate, glyceryl monolaurate, glyceryl monooleate, sorbitan monolaurate), fatty amides (e.g., diethanolamide laurate), aliphatic alcohols (e.g., octyldodecyl alcohol, isostearyl alcohol, oleyl alcohol), polyols (e.g., propylene glycol, dipropylene glycol, polyethylene glycol), pyrrolidone derivatives (e.g., N-methyl-2-pyrrolidone), and amines (e.g., triethanolamine, diethanolamine, monoethanolamine, diisopropanolamine, tromethamine, meglumine). A solvent can be used alone or in combination of two or more. When the adhesive layer contains a solvent, the solvent content can be from 2% to 40% by mass, based on the total mass of the adhesive layer.

[0049] Stabilizers are substances capable of inhibiting the generation of free radicals and the chain reactions caused by ultraviolet light, heat, or reactive chemicals. Examples of stabilizers include tocopherol and its ester derivatives, ascorbic acid and its ester derivatives, 2,6-dibutylhydroxytoluene (BHT), butylated hydroxyanisole, and 2-mercaptobenzimidazole. Stabilizers can be used alone or in combination of two or more. When the adhesive layer contains a stabilizer, the stabilizer content can be 0.05% to 3% by mass, or 0.05% to 1% by mass, 0.05% to 0.25% by mass, or 0.1% to 0.25% by mass, based on the total mass of the adhesive layer.

[0050] Examples of fillers include: powders of metal compounds (alumina, aluminum hydroxide, zinc oxide, titanium dioxide, calcium carbonate, etc.), ceramics (talc, clay, kaolin, silica, hydroxyapatite, synthetic aluminum silicate, magnesium aluminum metasilicate, etc.), or organic compounds (cellulose powder, stearates, etc.) or short fibers of resins containing them. One filler may be used alone, or two or more may be used in combination. When the adhesive layer contains fillers, the filler content may range from 0.1% to 20% by mass, based on the total mass of the adhesive layer.

[0051] The patch may also include a release liner. The release liner is laminated on the surface of the adhesive layer opposite to the support. When a release liner is included, there is a tendency to reduce the adhesion of dirt and other contaminants to the adhesive layer during storage. The surface of the release liner in contact with the adhesive layer is preferably treated with a release agent such as silicone or fluorinated polyolefin.

[0052] There are no particular limitations on the material used for the release liner, and liners known to those skilled in the art can be used. Examples of release liners include: paper; polyesters such as polyethylene terephthalate and polyethylene naphthalate; polyolefins such as polyethylene and polypropylene; and films such as polyvinyl chloride, polyvinylidene chloride, nylon, and aluminum. The release liner can be a laminate of high-quality paper and polyolefin. Preferably, the material used for the release liner is a film made of polypropylene or polyethylene terephthalate.

[0053] A method for manufacturing a patch according to one embodiment of the present invention includes: a step of mixing diclofenac free acid with an adhesive base to obtain an adhesive composition, and a step of molding the adhesive composition to obtain the patch. More specifically, the patch can be manufactured, for example, by the following method: First, the components constituting the adhesive layer are mixed in a predetermined ratio to obtain a homogeneous solution (adhesive composition). Next, the adhesive composition is stretched onto a peelable film (release liner) or a support layer in a predetermined paste mass to form an adhesive layer (forming an adhesive layer). Then, the adhesive layer is pressed onto the support layer or the peelable film in such a way that the adhesive layer is sandwiched between the peelable film and the support layer. Finally, the patch is obtained by cutting it into a desired shape. At this time, the release liner can be removed when the patch is applied.

[0054] A method for suppressing the formation of diclofenac indole bodies in an adhesive layer according to an embodiment of the present invention includes: a step of mixing diclofenac free acid with an adhesive base agent to obtain an adhesive composition, and a step of molding the adhesive composition (forming the adhesive composition) to obtain the patch. More specifically, it can be implemented by the same method as the patch manufacturing method described above.

[0055] The patch area can be 5 to 200 cm² 2 It can also be 30-100cm 2 The shape and size of the patch can be, for example, a rectangle with a short side of 3 to 14 cm and a long side of 7 to 20 cm, or a circle with a diameter of 1 to 10 cm.

[0056] Example

[0057] Experiment 1: Evaluation of the formation rate of diclofenac indole ketone bodies in patches using rubber-based adhesives

[0058] 1. Preparation of the patch

[0059] The adhesive composition was obtained by mixing the components according to Table 1 below. The mass of the paste per unit area was 214 g / m². 2The adhesive composition is extended onto a release liner (a polyethylene terephthalate film that has undergone a release treatment) to form an adhesive layer (shaped into an adhesive layer). A support layer (a woven polyethylene terephthalate fabric) is then laminated onto the opposite side of the resulting adhesive layer to obtain an adhesive patch having a support layer / adhesive layer / release liner sequentially laminated.

[0060] 2. Determination of the content of diclofenac indole ketone body

[0061] The content of diclofenac indoleone was determined using freshly manufactured patches and patches that had been stored at 60°C in aluminum packaging bags for one week after manufacturing, in the following order.

[0062] First, remove the adhesive layer of the patch and immerse it in 2 mL of acetone to extract the organic matter.

[0063] Then, 6 mL of diluent (0.1% phosphoric acid aqueous solution / methanol = 60 / 40 (v / v)) was added to make a total volume of 8 mL. After filtering out the insoluble matter, high-performance liquid chromatography (HPLC) under the following analytical conditions was used to obtain a chromatogram showing the peak separation of diclofenac free acid and diclofenac indole ketone. The content of diclofenac indole ketone was calculated by setting the theoretical amount of diclofenac free acid to 100 and based on the peak area under the curve corresponding to diclofenac indole ketone.

[0064] <Analysis Conditions>

[0065] Column: YMC-PacK Pro C8

[0066] Mobile phase: 0.1% aqueous phosphoric acid / methanol = 60 / 40 (v / v)

[0067] Measurement wavelength: 275nm

[0068] Flow rate: 1 mL / min

[0069] Sample injection volume: 30 μL

[0070] Column temperature: 40℃

[0071] [Table 1]

[0072]

[0073] It was confirmed that, compared with the patch of Comparative Example 1 containing diclofenac sodium, the patches of Examples 1-4 containing diclofenac free acid were more effective in inhibiting the formation of diclofenac indole ketone bodies. Furthermore, it was confirmed that the patch of Comparative Example 2 could not inhibit the formation of diclofenac indole ketone bodies. It should be noted that in the patch of Comparative Example 2, the content of diclofenac free acid was 10% by mass, based on the total mass of the adhesive layer.

[0074] Experiment 2: Evaluation of the formation rate of diclofenac indolone bodies in patches using acrylic adhesive bases

[0075] 1. Preparation of the patch

[0076] According to Table 2 below, the components are mixed to obtain the adhesive composition. The mass of the paste per unit area is 120 g / m². 2 The adhesive composition is stretched onto a release liner (a polyethylene terephthalate film subjected to a release treatment) and the solvent is dried to remove it, forming an adhesive layer (shaped into an adhesive layer). A support layer (a polyethylene terephthalate film) is then laminated onto the opposite side of the adhesive layer to obtain an adhesive patch having a support layer / adhesive layer / release liner sequentially laminated.

[0077] 2. Determination of the content of diclofenac indole ketone body

[0078] The measurements were taken in the same manner as in Experiment 1.

[0079] [Table 2]

[0080] Comparative Example 3 Example 5 Diclofenac free acid - 4.65 Diclofenac Sodium 5.00 - Acrylic adhesive base (MAS811B) 77.89 80.35 Oleic acid 5.00 5.00 Dimethyl sulfoxide 7.00 7.00 Citric anhydride 2.11 - other 3.00 3.00 total 100 100 The formation rate (%) of freshly manufactured indole ketone bodies 0.09 0.06 The formation rate (%) of indole ketone bodies after storage at 60℃ for 1 week. 2.05 0.84

[0081] It was confirmed that, when using an acrylic adhesive base, the patch of Example 5, which contains diclofenac free acid, was more effective at inhibiting the formation of diclofenac indole bodies compared to the patch of Comparative Example 3, which contains diclofenac sodium.

[0082] Experiment 3: Evaluation of the formation rate of diclofenac indolone bodies in patches using silicone-based adhesives

[0083] 1. Preparation of the patch

[0084] The patch was manufactured in the same manner as in Experiment 2, according to the composition shown in Table 3 below. However, in this embodiment, the mass of the patch per unit area was 160 g / m². 2 It can be extended in this way.

[0085] 2. Determination of the content of diclofenac indole ketone body

[0086] The measurements were taken in the same manner as in Experiment 1.

[0087] [Table 3]

[0088] Comparative Example 4 Example 6 Diclofenac free acid - 4.65 Diclofenac Sodium 5.00 - Organosilicon adhesive base (BIO-PSA 7-4202) 77.89 80.35 Oleic acid 5.00 5.00 Dimethyl sulfoxide 7.00 7.00 Citric anhydride 2.11 - other 3.00 3.00 total 100 100 The formation rate (%) of freshly manufactured indole ketone bodies 0.21 0.06 The formation rate (%) of indole ketone bodies after storage at 60℃ for 1 week. 5.32 1.23

[0089] It was confirmed that, when using a silicone-based adhesive base, the patch of Example 6, which contains diclofenac free acid, was more effective at inhibiting the formation of diclofenac indole bodies compared to the patch of Comparative Example 4, which contains diclofenac sodium.

[0090] Experiment 4: Evaluation of the formation rate of diclofenac indole ketone bodies in polyisobutylene-free patches

[0091] 1. Preparation of the patch

[0092] The patch was manufactured in the same manner as in Experiment 1, according to the composition shown in Table 4 below.

[0093] 2. Determination of the content of diclofenac indole ketone body

[0094] The measurements were taken in the same manner as in Experiment 1.

[0095] [Table 4]

[0096] Example 7 Diclofenac free acid 4.65 Styrene-isoprene-styrene block copolymer 22.76 Polyisobutylene - Alicyclic saturated hydrocarbon resins 32.10 Hydrogenated rosin glycerides 10.00 Liquid paraffin 14.89 Oleic acid 5.00 Dimethyl sulfoxide 7.00 other 3.60 total 100 The formation rate (%) of freshly manufactured indole ketone bodies 0.17 The formation rate (%) of indole ketone bodies after storage at 60℃ for 1 week. 1.03

[0097] It was confirmed that, in the absence of polyisobutylene, the patch of Example 7, containing diclofenac free acid, was more effective in inhibiting the formation of diclofenac indole bodies than the patch of Comparative Example 1, which contained diclofenac sodium. Furthermore, it was confirmed that the patch of Example 7 exhibited the same rate of diclofenac indole body formation as the patches of Examples 1-4.

[0098] Experiment 5: Evaluation of the formation rate of diclofenac indolone bodies in patches using acrylic or silicone adhesives

[0099] 1. Preparation of the patch

[0100] Patches for Examples 8 and 9 were manufactured in the same manner as in Experiment 2, according to the composition shown in Table 5 below. Patches for Examples 10 and 11 were manufactured in the same manner as in Experiment 3, according to the composition shown in Table 5 below.

[0101] 2. Determination of the content of diclofenac indole ketone body

[0102] The measurements were taken in the same manner as in Experiment 1.

[0103] [Table 5]

[0104]

[0105] It was confirmed that, when using acrylic or silicone adhesives, the patches of Examples 8-10, compared to the patches of Comparative Examples 3 or 4 containing diclofenac sodium, were able to suppress the formation of diclofenac indole bodies. It was explained that in Examples 8-10, the content of free diclofenac acid, based on the total mass of the adhesive layer, varied within the range of 0.5% to 8% by mass. Furthermore, it was confirmed that the patch of Example 11, using a silicone adhesive different from that of Example 6, was even more effective at suppressing the formation of diclofenac indole bodies compared to the patch of Comparative Example 4 containing diclofenac sodium.

Claims

1. A method for suppressing the formation of diclofenac indolone bodies in an adhesive layer of a patch comprising a support layer and an adhesive layer laminated on the support layer. The method includes: The steps of mixing diclofenac free acid with an adhesive base to obtain an adhesive composition and forming the adhesive composition to obtain the patch are described above. The content of diclofenac free acid is 0.5% to 8% by mass, based on the total mass of the adhesive layer.

Images