WO2010058844A1 - ５－メチル－１－フェニル－２－（１ｈ）－ピリドン含有貼付剤 - Google Patents

５－メチル－１－フェニル－２－（１ｈ）－ピリドン含有貼付剤 Download PDF

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Publication number
WO2010058844A1
WO2010058844A1 PCT/JP2009/069720 JP2009069720W WO2010058844A1 WO 2010058844 A1 WO2010058844 A1 WO 2010058844A1 JP 2009069720 W JP2009069720 W JP 2009069720W WO 2010058844 A1 WO2010058844 A1 WO 2010058844A1
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Prior art keywords
methyl
pyridone
phenyl
patch
medicinal component
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PCT/JP2009/069720
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English (en)
French (fr)
Japanese (ja)
Inventor
孝泰 松沢
環 堀内
誠二郎 山
直 竹内
亮 竹内
Original Assignee
リードケミカル株式会社
塩野義製薬株式会社
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Application filed by リードケミカル株式会社, 塩野義製薬株式会社 filed Critical リードケミカル株式会社
Priority to BRPI0916140A priority Critical patent/BRPI0916140B8/pt
Priority to CN2009801544109A priority patent/CN102281879B/zh
Priority to ES09827625.6T priority patent/ES2453199T3/es
Priority to EP09827625.6A priority patent/EP2359827B1/en
Priority to US13/130,461 priority patent/US8568770B2/en
Publication of WO2010058844A1 publication Critical patent/WO2010058844A1/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations

Definitions

  • the present invention is an active pharmaceutical ingredient effective for the prevention and treatment of skin diseases such as hypertrophic scars, keloids, contact dermatitis, infectious warts, palmar pustulosis or fibrotic skin diseases.
  • the present invention relates to a patch containing a containing layer. More specifically, it contains a high concentration of 5-methyl-1-phenyl-2- (1H) -pyridone (generic name: pirfenidone) or a medically acceptable salt thereof as an active pharmaceutical ingredient.
  • the present invention relates to an oily type patch characterized by using a specific compound as a solubilizer.
  • 5-Methyl-1-phenyl-2- (1H) -pyridone (hereinafter also referred to as PFD) is used for the prevention and treatment of fibrotic diseases such as pulmonary fibrosis, prostatic fibrosis and nephrosclerosis.
  • Tablets containing 5-methyl-1-phenyl-2- (1H) -pyridone as an active ingredient as a drug for treating pulmonary fibrosis have been known to be useful so far (Patent Document 1)
  • a solution-like pharmaceutical composition see Patent Document 2 has been proposed as a drug of another dosage form for the treatment of fibrotic skin diseases.
  • a patch for preventing or treating skin diseases using 5-methyl-1-phenyl-2- (1H) -pyridone or a medically acceptable salt thereof as an active pharmaceutical ingredient has not been known.
  • Japanese Patent Application No. 2007-139653 uses 5-methyl-1-phenyl-2- (1H) -pyridone or a medically acceptable salt thereof as an active pharmaceutical ingredient. Based on the total amount of the active medicinal component-containing layer, a patch containing 0.1 to 30% by mass is proposed. However, in this proposed patch containing PFD, in order to enable more effective prevention and treatment of skin diseases, further improvements in the skin permeability of active medicinal ingredients and the sustainability of the medicinal effects are made. I wanted to do it.
  • an oil-based PFD-containing patch that dissolves 5-methyl-1-phenyl-2- (1H) -pyridone, which is an active pharmaceutical ingredient, at a high concentration
  • a specific solubilizer that is, other than glycerin and medium chain fatty acid triglyceride, together with the oily base
  • the skin permeation effect of the active medicinal component and the sustained effect of the medicinal effect can be enhanced
  • the use of butylene glycol, polyethylene glycol, N-methyl-pyrrolidone, propylene carbonate, isopropyl myristate, crotamiton and diisopropyl adipate, especially crotamiton and diisopropyl adipate, as solubilizers is the first to be able to further enhance these effects.
  • the headline and the present invention were completed.
  • the first aspect of the present invention is a patch having an active medicinal component-containing layer, wherein the active medicinal component-containing layer excludes an oily base and a solubilizer (however, glycerin and medium-chain fatty acid triglycerides are excluded). And 5-methyl-1-phenyl-2- (1H) -pyridone or a medically acceptable salt thereof, It relates to a patch containing pyridone.
  • the solubilizer is selected from the group consisting of butylene glycol, polyethylene glycol, N-methyl-pyrrolidone, propylene carbonate, isopropyl myristate, crotamiton, and diisopropyl adipate.
  • the solubilizer is selected from the group consisting of crotamiton and diisopropyl adipate, containing 5-methyl-1-phenyl-2- (1H) -pyridone according to claim 2 It relates to patches.
  • the fourth aspect of the present invention is the 5-methyl-1-phenyl-2- (4) according to any one of claims 1 to 3, wherein the active medicinal component-containing layer further contains a permeation enhancer. 1H) -pyridone-containing patch.
  • the fifth aspect of the present invention provides 5-methyl-1-phenyl-2- (1H) -pyridone or a medically acceptable amount thereof in an amount of 3 to 20% by mass based on the total amount of the active medicinal component-containing layer.
  • the 5-methyl-1-phenyl-2- (1H) -pyridone-containing patch according to any one of claims 1 to 3, which contains the above-mentioned salts.
  • the 5-methyl-1-phenyl-2- (1H) -pyridone-containing patch of the present invention contains 5-methyl-1-phenyl-2- (1H) -pyridone, which is an effective medicinal component for an oily base.
  • a specific solubilizer that is, other than glycerin and medium-chain fatty acid triglycerides, at high concentrations, especially under conditions that dissolve in an amount of 3 to 20% by weight based on the total amount of the active medicinal component-containing layer.
  • a high effect is exerted in the skin permeability of the active medicinal component.
  • the effect of improving skin permeability of this active medicinal ingredient in particular, by using butylene glycol, polyethylene glycol, N-methyl-pyrrolidone, propylene carbonate, isopropyl myristate, crotamiton and diisopropyl adipate as a solubilizer, A higher effect can be obtained. Further, among these solubilizers, the use of crotamiton and diisopropyl adipate can dramatically increase the skin permeability of the active medicinal component.
  • the 5-methyl-1-phenyl-2- (1H) -pyridone-containing patch of the present invention contains 5-methyl-1-phenyl-2- (1H) -pyridone which is an active pharmaceutical ingredient in the base.
  • the active medicinal component in the solid state dissolves sequentially. As a result, it is considered that the saturated state of the active medicinal component can be maintained. As a result, it has been found that the medicinal effect is sustained for a long time. Therefore, by using the patch containing 5-methyl-1-phenyl-2- (1H) -pyridone of the present invention, hypertrophic scars, keloids, contact dermatitis, infectious warts, palms It is possible to effectively prevent and treat skin diseases such as pyocystosis or fibrotic skin diseases.
  • the 5-methyl-1-phenyl-2- (1H) -pyridone-containing patch of the present invention can be used in combination with the above-mentioned specific solubilizing agent in combination with a permeation enhancer so that the skin permeation of an active medicinal ingredient can be improved. Can be further increased.
  • FIG. 1 is a graph showing the relationship between the elapsed time after applying the PFD-containing patches of Examples 1 to 4 to the rat skin and the cumulative amount of PFD permeated.
  • FIG. 2 is a graph showing the relationship between the elapsed time and the skin permeation rate after the PFD-containing patches of Examples 1 to 4 were applied to the rat skin.
  • FIG. 3 is a graph showing the relationship between the elapsed time after applying the PFD-containing patches of Examples 1, 5 to 10 and Comparative Examples 1 to 3 to the skin of rats and the cumulative permeation amount of PFD.
  • FIG. 1 is a graph showing the relationship between the elapsed time after applying the PFD-containing patches of Examples 1 to 4 to the rat skin and the cumulative amount of PFD.
  • FIG. 4 is a graph showing the relationship between the elapsed time after the PFDs of Examples 1, 5 to 10 and Comparative Examples 1 to 3 are applied to the skin of rats and the skin permeation rate.
  • FIG. 5 is a graph showing the relationship between the elapsed time after applying the PFD-containing patches of Example 1 and Example 11 to the rat skin and the cumulative amount of PFD permeated.
  • FIG. 6 is a graph showing the relationship between the elapsed time and the skin permeation rate after the PFD-containing patches of Example 1 and Example 11 were applied to the rat skin.
  • the effective medicinal component of the patch of the present invention is 5-methyl-1-phenyl-2- (1H) -pyridone.
  • 5-methyl-1-phenyl-2- (1H) -pyridone which is an effective medicinal component, may be a medically acceptable salt thereof.
  • salts include acid addition salts with acids such as hydrochloric acid, sulfuric acid, phosphoric acid, paratoluenesulfonic acid, methanesulfonic acid, and salts with alkalis such as sodium salts and potassium salts.
  • the compounding amount of the active medicinal component varies depending on the prescription, but it is desirable to blend it in an amount of 3 to 20% by mass based on the total amount of the active medicinal component containing layer.
  • the solubilizer used in the patch of the present invention is one generally used in oily bases excluding glycerin and medium chain fatty acid triglycerides, preferably butylene glycol, polyethylene glycol, N-methyl-pyrrolidone, Selected from the group consisting of propylene carbonate, isopropyl myristate, crotamiton and diisopropyl adipate, most preferably crotamiton and diisopropyl adipate. Only 1 type may be used for these solubilizers, or 2 or more types may be mixed suitably and used. The amount of these solubilizers is about 0.1 to 20% by mass based on the total amount of the active medicinal component-containing layer.
  • the base of the patch of the present invention is an oily base.
  • the oil base for example, a mixture of component 1): oily polymer, component 2): plasticizer, component 3): tackifier can be used.
  • component 1) oily polymer examples include, but are not limited to, styrene isoprene styrene block copolymer, styrene butadiene block copolymer, polyisobutylene, raw rubber, polyisoprene, polybutene and the like. These oily polymers may be used alone or in a suitable mixture of two or more. The blending amount of these oily polymers is about 10 to 50% by mass based on the total amount of the active medicinal component-containing layer.
  • plasticizer of component 2 examples include liquid paraffin, vegetable oil, animal oil, polybutene, low molecular weight polyisobutylene, petrolatum, lanolin, and higher aliphatic esters, but are not limited thereto. Moreover, these plasticizers may use only 1 type, or may mix and use 2 or more types suitably. The blending amount of these plasticizers is about 10 to 50% by mass based on the total amount of the active medicinal component-containing layer.
  • tackifier of component 3 examples include petroleum resins, rosin resins, hydrogenated rosins, rosin esters, terpene resins, modified terpene resins, aromatic hydrocarbon resins, aliphatic hydrocarbon resins, and the like. This is not the case. These tackifiers may be used alone or in a suitable mixture of two or more. The blending amount of these tackifiers is about 5 to 50% by mass based on the total amount of the active medicinal component-containing layer.
  • the oily base contains 10 to 40% by mass of the oily polymer, 10 to 40% by mass of the plasticizer, and 5 to 40% by mass of the tackifier based on the total amount.
  • a permeation enhancer is blended together with the above specific solubilizer.
  • permeation enhancers are not particularly limited as long as they are conventionally used in conventional percutaneous absorption preparations.
  • alcohols, fatty acids, fatty acid esters, fatty acid ethers, lactate esters, acetate esters, terpene compounds, pyrrolidone derivatives Organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbide, azone or derivatives thereof.
  • permeation enhancers ethanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, cyclodextrin, calcium thioglycolate, ethyl lactate, cetyl lactate, lactic acid, urea, 1-menthol, d-limonene, dl-
  • permeation accelerators may be used alone or in a suitable mixture of two or more.
  • the blending amount of these permeation enhancers is about 0.1 to 20% by mass based on the total amount of the active medicinal component-containing layer.
  • the active medicinal component-containing layer of the patch of the present invention has an active medicinal component 5-methyl-1-phenyl-2- (1H) -pyridone or a medically acceptable salt thereof, a solubilizing agent and an oily base.
  • various other additives such as tackifiers, softeners, antioxidants, anti-aging agents, preservatives, flavoring agents, pH, etc., which are commonly used in conventional percutaneous absorption preparations
  • a regulator, an emulsifier, a dispersant, a stabilizer, an antiseptic, an excipient, and the like can also be blended.
  • tackifiers include, but are not limited to, silicone rubber, polyisobutylene rubber, acrylic rubber, and natural oil-based adhesive substances. These tackifiers may be used alone or in a suitable mixture of two or more. The blending amount of these tackifiers is about 5 to 50% by mass based on the total amount of the active medicinal component-containing layer.
  • softeners examples include liquid paraffin, polybutene, castor oil, cottonseed oil, palm oil, coconut oil, and process oil, but are not limited thereto. These softeners may be used alone or in a suitable mixture of two or more. The blending amount of these softeners is about 1 to 50% by mass based on the total amount of the active medicinal component-containing layer.
  • antioxidants include ascorbic acid, ascorbic acid palmitate, sodium bisulfite, sodium edetate, tetrasodium edetate, dry sodium sulfite, citric acid, sodium citrate, tocopherol acetate, dl- ⁇ -tocopherol, di Potassium chloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, soy lecithin, sodium pyrosulfite, benzotriazole, pentaerythryl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate], Examples include, but are not limited to, propyl gallate and 2-mercaptobenzimidazole. These antioxidants may be used alone or in combination of two or more. The blending amount of these antioxidants is about 0.005 to 20% by mass based on the total amount of the active medicinal component-containing layer.
  • anti-aging agents examples include amino acids such as glycine, proline, hydroxyproline, leucine, alanine, ⁇ -aminobutyric acid, and ⁇ -aminoproic acid, vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acid, glycol Examples include, but are not limited to, hydroxy acids such as acid, lactic acid and salicylic acid, tannins, flavonoids, saponins, allantoin, and plant-derived components such as chamomile, licorice, roman chamomile, carrot and rice, extracts and essential oils. These anti-aging agents may be used alone or in combination of two or more. The blending amount of these anti-aging agents is about 0.005 to 20% by mass based on the total amount of the active medicinal component-containing layer.
  • preservatives include, but are not limited to, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, and the like. These preservatives may be used alone or in a suitable mixture of two or more. The amount of these preservatives is about 0.005 to 5% by mass based on the total amount of the active medicinal component-containing layer.
  • flavoring agents include fragrance substances such as benzyl, linalyl acetate, amyl acetate, benzaldehyde, cinnamaldehyde, citronellal, menthol, citral, cis jasmon, and medicinal substances such as methyl salicylate, camphor, and cresol. These flavoring agents may be used alone or in combination of two or more. The blending amount of these flavoring agents is about 0.05 to 5% by mass based on the total amount of the active medicinal component-containing layer.
  • the pH adjuster is not particularly limited as long as it is a conventional one in conventional percutaneous absorption preparations.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid or salts thereof, acetic acid
  • Organic acids such as succinic acid, fumaric acid, malic acid, oxalic acid, lactic acid, glutaric acid, salicylic acid, tartaric acid or salts thereof, fatty acids such as palmitic acid, stearic acid, oleic acid, linoleic acid, or salts thereof, and water
  • inorganic bases such as sodium oxide and calcium hydroxide
  • organic bases such as ammonia, diisopropanolamine, diethanolamine, triethanolamine, and triethylamine.
  • These pH adjusters may be used alone or in a suitable mixture of two or more. The blending amount of these pH adjusters is about 0.05 to 10% by mass based on the total amount of the active medicinal component
  • emulsifiers examples include sorbitan monooleate, polyacrylic acid, polyacrylamide, poly N-vinyl pyrrolidone, chitin, chitosan, and cellulose, but are not limited thereto. These emulsifiers may use only 1 type, or may mix and use 2 or more types suitably. The amount of these emulsifiers is about 0.05 to 10% by mass based on the total amount of the active medicinal component-containing layer.
  • dispersant examples are not particularly limited as long as they increase the dispersibility of various components in the active medicinal component-containing layer.
  • synthetic aluminum silicate, hydrous aluminum silicate, aluminum hydroxide, magnesium silicate examples include zinc oxide, titanium oxide, and fatty acid metal salts such as stearic acid metal salts.
  • These dispersants may be used alone or in a suitable mixture of two or more. The amount of these dispersants is about 0.5 to 50% by mass based on the total amount of the active medicinal component-containing layer.
  • the stabilizer for example, those exemplified above as the pH adjuster can be used. Further, as the stabilizer, sodium bisulfite, ascorbic acid, sodium ascorbate, butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, tocopherol acetate, D- ⁇ -tocopherol and the like can be used. These stabilizers may be used alone or in a suitable mixture of two or more. The blending amount of these stabilizers is about 0.005 to 20% by mass based on the total amount of the active medicinal component-containing layer.
  • preservatives include, but are not limited to, methylparaben, ethylparaben, propylparaben, butylparaben, phenoxyethanol and the like. These preservatives may be used alone or in combination of two or more. The blending amount of these preservatives is about 0.005 to 5% by mass based on the total amount of the active medicinal component-containing layer.
  • excipients examples include glucose, fructose, galactose, mannose, palatinose, sucrose, maltose, lactose, trehalose, oligosaccharides, saccharides such as dextrin, crystalline cellulose, methylcellulose, carboxymethylcellulose or salts thereof, hydroxypropylcellulose, Examples thereof include, but are not limited to, celluloses such as hydroxypropylmethylcellulose.
  • excipients may be used alone or in combination of two or more. The blending amount of these excipients is about 0.1 to 40% by mass based on the total amount of the active pharmaceutical ingredient-containing layer.
  • the patch of the present invention may be in the form of various patches such as a poultice, a plaster, and a tape depending on the application.
  • the patch of the present invention is, for example, a product obtained by adding a predetermined amount of 5-methyl-1-phenyl-2- (1H) -pyridone and a solubilizer to an oily base (transdermal absorption preparation) as a suitable support. It can be produced by coating with a predetermined thickness to form an active medicinal component-containing layer, coating with a predetermined liner from above, and cutting it into a desired size.
  • the patch of the present invention may be prepared by using, for example, a base (transdermal absorption preparation) containing 5-methyl-1-phenyl-2- (1H) -pyridone and a solubilizing agent as a liner.
  • the active medicinal component-containing layer may be formed by coating and coated with a support from above, and the active medicinal component-containing layer may be transferred onto the support.
  • the patch of the present invention is in direct contact with the affected area, it is preferable to sterilize after being manufactured as described above.
  • the sterilization method is not particularly limited as long as it is a conventional method for sterilization of conventional drugs.
  • ⁇ -ray sterilization method, electron beam sterilization method, high-pressure steam sterilization method, ethylene oxide gas sterilization method and the like are used.
  • the support used in the patch of the present invention is not particularly limited, and a conventional material can be used as the support for the patch.
  • these supports for example, natural or synthetic polymer woven fabric, nonwoven fabric, sheet, film or laminate thereof, preferably vinyl chloride film, polyethylene film, ethylene copolymer film, polypropylene film, polyurethane
  • a woven fabric and a non-woven fabric and a laminate of these and a plastic are used. Further, the size, shape, thickness and the like of these supports are appropriately selected.
  • the liner used in the patch of the present invention is not particularly limited, and a conventional material can be used as the liner of the patch.
  • These liners include, for example, natural or synthetic polymer sheets, films, or laminates thereof, and preferably release paper or cellophane that has been treated to facilitate peeling (eg, synthetic polymer coating).
  • Example 1 10 parts of polyisobutylene, 20 parts of styrene isoprene styrene block copolymer, 0.5 part of dibutylhydroxytoluene, 18 parts of liquid paraffin, and 11.5 parts of hydrogenated rosin glycerin ester are equivalent to the total amount of the active medicinal component containing layer (100 Part solution) in hexane (solution A).
  • solution A As an effective medicinal ingredient, 20 parts of 5-methyl-1-phenyl-2- (1H) -pyridone was mixed with 10 parts of liquid paraffin and 10 parts of 1,3-butylene glycol (dissolving agent) (Liquid B).
  • liquid B is added to liquid A and mixed uniformly, this mixture is spread on a silicon-treated polyester film (liner), hexane is removed by volatilization, and an active medicinal component containing layer is formed. From above, it was covered with a nonwoven fabric made of polyester (support). This was cut into a desired size to obtain a patch containing 20% of 5-methyl-1-phenyl-2- (1H) -pyridone of Example 1.
  • Example 2 The same procedure as in Example 1 except that the amount of 5-methyl-1-phenyl-2- (1H) -pyridone, which is an active pharmaceutical ingredient, was 3 parts (the amounts of other components are shown in the following table). 1)), and a patch containing 3% of 5-methyl-1-phenyl-2- (1H) -pyridone of Example 2 was obtained.
  • Example 3 The same procedure as in Example 1 except that the amount of 5-methyl-1-phenyl-2- (1H) -pyridone, which is an effective medicinal component, was 5 parts (the amounts of other components are shown in the following table). 1)), and a patch containing 5% of 5-methyl-1-phenyl-2- (1H) -pyridone of Example 3 was obtained.
  • Example 4 The same procedure as in Example 1 except that the amount of 5-methyl-1-phenyl-2- (1H) -pyridone, which is an effective medicinal component, was 10 parts (the amounts of other components are shown in the table below). 1)), and a patch containing 10% of 5-methyl-1-phenyl-2- (1H) -pyridone of Example 4 was obtained.
  • Example 5 As in Example 1, except that polyethylene glycol 400 was used in place of 1,3-butylene glycol as the solubilizer (see Table 1 below for the amount of each component). A patch containing 20% of 5-methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Example 6 Examples were substantially the same as Example 1 except that N-methyl-pyrrolidone was used instead of 1,3-butylene glycol as a solubilizer (see Table 1 below for the amount of each component). A patch containing 20% 6-methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Example 7 Except that propylene carbonate was used in place of 1,3-butylene glycol as a solubilizer, the procedure was the same as in Example 1 (for the amount of each component, see Table 1 below). A patch containing 20% of -methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Example 8 As in Example 1, except that isopropyl myristate was used in place of 1,3-butylene glycol as the solubilizer (see Table 1 below for the amount of each component). A patch containing 20% of 5-methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Example 9 Except that crotamiton was used in place of 1,3-butylene glycol as a solubilizing agent, the procedure was the same as in Example 1 (for the amounts of each component, see Table 1 below). A patch containing 20% of methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Example 10 As in Example 1, except that diisopropyl adipate was used instead of 1,3-butylene glycol as the solubilizer (see Table 1 below for the amount of each component). A patch containing 20% of 5-methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Example 11 In addition to the solubilizer, the procedure of Example 11 was repeated in the same manner as in Example 1 except that 4 parts of 1-menthol was used as a permeation enhancer (see Table 1 below for the amount of each component). A patch containing 20% of 5-methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Comparative Example 1 Except that no solubilizer was used, the procedure was the same as in Example 1 (for the amount of each component, see Table 1 below), and 5-methyl-1-phenyl-2- (1H of Comparative Example 1 was used. A patch containing 20% pyridone was obtained.
  • Comparative Example 2 Comparative Example 2 5 except that concentrated glycerin was used in place of 1,3-butylene glycol as a solubilizer (see Table 1 below for the amount of each component). A patch containing 20% of -methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Comparative Example 3 Comparative Example 3 was carried out in substantially the same manner as in Example 1 except that medium-chain fatty acid triglycerides were used in place of 1,3-butylene glycol as the solubilizer (for the amounts of each component, see Table 1 below). A patch containing 20% of 5-methyl-1-phenyl-2- (1H) -pyridone was obtained.
  • Test Example 1 In Vitro Skin Permeability Test 1 Test Method Under pentobarbital sodium anesthesia, the abdominal skin of hairless rats (HWY / Slc, male, 7 weeks old) was cut out and fat on the dermal side was carefully removed. The patches manufactured in Examples 1 to 11 and Comparative Examples 1 to 3 in which the skin was attached to a vertical diffusion cell in which water at 37 ° C. had been circulated in advance and the dermis side was attached, and punched to a diameter of 1 cm at the center thereof. After pasting, it was clamped with a fixing cell and fixed with a clamp.
  • the skin permeation rate of 5-methyl-1-phenyl-2- (1H) -pyridone is calculated by dividing the amount of PFD that permeated the skin during the collection time (unit time) of the receiver solution by the unit time. Calculated by In short, the skin permeation rate of PFD can be obtained by the following calculation formula where the collection time of the receiver liquid is t1, t2 (t2> t1), and the cumulative skin permeation amounts at t1 and t2 are R1 and R2, respectively. it can.
  • the medicinal properties are high and the medicinal effect lasts for a long time.
  • the excellent effect regarding the skin permeability and the persistence of the medicinal effect is obtained by the PFD in the base. Even if PFD is consumed by permeation through the skin and the amount of PFD in the base is reduced, some of the PFD in the base is dissolved in order, so that the PFD in the base is dissolved in order. This is considered to be due to the fact that the concentration of PFD can always be maintained in a saturated state.
  • Example 9 using clotamiton and diisopropyl adipate, respectively, which are the dissolving agents of the present invention.
  • 10 patches had a higher skin permeation rate. Therefore, among the many solubilizers used in oil-based patches, butylene glycol, polyethylene glycol, N-methyl-, which are the solubilizers of the present invention, for improving the rapid efficacy of drugs (active medicinal ingredients). It has been found that pyrrolidone, propylene carbonate and isopropyl myristate have a high effect, and in particular, crotamiton and diisopropyl adipate have a higher effect.
  • the permeation enhancer compared to the patch of Example 1 which does not contain a permeation enhancer.
  • the patch of Example 11 which used No. 1 had a high skin permeation rate. From this, it is expected that the rapid efficacy of the drug (effective medicinal component) can be further improved by using a permeation accelerator in combination with the specific solubilizer of the present invention.

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PCT/JP2009/069720 2008-11-21 2009-11-20 ５－メチル－１－フェニル－２－（１ｈ）－ピリドン含有貼付剤 WO2010058844A1 (ja)

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BRPI0916140A BRPI0916140B8 (pt) 2008-11-21 2009-11-20 preparação adesiva contendo 5-metila-1-fenila-2-(1h)-piridona
CN2009801544109A CN102281879B (zh) 2008-11-21 2009-11-20 含有5-甲基-1-苯基-2-(1h)-吡啶酮的贴剂
ES09827625.6T ES2453199T3 (es) 2008-11-21 2009-11-20 Material adhesivo que contiene 5-metil-1-fenil-2(1H)-piridona
EP09827625.6A EP2359827B1 (en) 2008-11-21 2009-11-20 Adhesive material containing 5-methyl-1-phenyl-2-(1h)-pyridone
US13/130,461 US8568770B2 (en) 2008-11-21 2009-11-20 Adhesive material containing 5-methyl-1-phenyl-2-(1H)-pyridone

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WO2012105625A1 (ja) * 2011-02-02 2012-08-09 大日本住友製薬株式会社 経皮吸収促進剤及びそれを含有する経皮吸収型製剤
KR102501180B1 (ko) * 2018-04-24 2023-02-21 시오노기세야쿠 가부시키가이샤 안정성이 우수한 고형 제제
CN114113397A (zh) * 2021-11-30 2022-03-01 江苏知原药业股份有限公司 一种吡非尼酮片有效成分的含量测定方法

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JP2004203795A (ja) 2002-12-26 2004-07-22 Kdl Inc ピリドン誘導体の溶液状医薬組成物
WO2004073713A1 (ja) * 2003-02-21 2004-09-02 Shionogi & Co., Ltd. ピルフェニドンのゲル剤
WO2004073680A1 (ja) * 2003-02-21 2004-09-02 Shionogi & Co., Ltd. 液滴分散型軟膏剤
JP2006298774A (ja) * 2005-04-15 2006-11-02 Lead Chemical Co Ltd 経皮吸収型フリーラジカル抑制製剤
JP2007139653A (ja) 2005-11-21 2007-06-07 Hitachi Ltd 非接触式欠陥検査装置及び非接触式欠陥検査方法

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KR20080000647A (ko) * 2005-04-28 2008-01-02 오노 야꾸힝 고교 가부시키가이샤 경피 흡수 제제
JP2008214337A (ja) * 2007-02-05 2008-09-18 Yuutoku Yakuhin Kogyo Kk 外用貼付剤
JP5248040B2 (ja) * 2007-05-25 2013-07-31 リードケミカル株式会社 ５−メチル−１−フェニル−２−（１ｈ）−ピリドン含有貼付剤

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WO2002060446A1 (en) 2001-01-29 2002-08-08 Shionogi & Co., Ltd. Medicinal preparation containing 5-methyl-1-phenyl-2-(1h)-pyridone as active ingredient
JP2004203795A (ja) 2002-12-26 2004-07-22 Kdl Inc ピリドン誘導体の溶液状医薬組成物
WO2004073713A1 (ja) * 2003-02-21 2004-09-02 Shionogi & Co., Ltd. ピルフェニドンのゲル剤
WO2004073680A1 (ja) * 2003-02-21 2004-09-02 Shionogi & Co., Ltd. 液滴分散型軟膏剤
JP2006298774A (ja) * 2005-04-15 2006-11-02 Lead Chemical Co Ltd 経皮吸収型フリーラジカル抑制製剤
JP2007139653A (ja) 2005-11-21 2007-06-07 Hitachi Ltd 非接触式欠陥検査装置及び非接触式欠陥検査方法

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EP2359827A4 (en) 2013-01-02
KR20110095385A (ko) 2011-08-24
ES2453199T3 (es) 2014-04-04
BRPI0916140B1 (pt) 2021-03-09
EP2359827B1 (en) 2013-12-25
US20110293670A1 (en) 2011-12-01
JP2010120912A (ja) 2010-06-03
KR101654954B1 (ko) 2016-09-06
US8568770B2 (en) 2013-10-29
CN102281879A (zh) 2011-12-14
BRPI0916140B8 (pt) 2021-05-25
CN102281879B (zh) 2013-09-04
EP2359827A1 (en) 2011-08-24

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