WO2013047410A1 - Timbre cutané adhésif à action longue pour le traitement de la maladie d'alzheimer et procédé pour le produire - Google Patents

Timbre cutané adhésif à action longue pour le traitement de la maladie d'alzheimer et procédé pour le produire Download PDF

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Publication number
WO2013047410A1
WO2013047410A1 PCT/JP2012/074345 JP2012074345W WO2013047410A1 WO 2013047410 A1 WO2013047410 A1 WO 2013047410A1 JP 2012074345 W JP2012074345 W JP 2012074345W WO 2013047410 A1 WO2013047410 A1 WO 2013047410A1
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WO
WIPO (PCT)
Prior art keywords
patch
rivastigmine
adhesive layer
sensitive adhesive
skin
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PCT/JP2012/074345
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English (en)
Japanese (ja)
Inventor
川原康慈
平岡孝夫
中並秀太
Original Assignee
ニチバン株式会社
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Publication of WO2013047410A1 publication Critical patent/WO2013047410A1/fr

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Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a continuous Alzheimer's disease treatment patch comprising a support, an adhesive layer containing rivastigmine, and a liner, and a method for producing the same.
  • transdermal administration of an antidementia drug is useful for patients with advanced symptoms because the drug can be administered continuously for a long period of time while avoiding difficulty in taking it.
  • the skin since the skin generally has low drug permeability, it is difficult to absorb a sufficient amount from the skin into the body. In order to overcome these difficulties, transdermal absorption preparations of antidementia drugs have been studied.
  • JP-A-11-3151616 (corresponding to Patent Document 1 and US Pat. No. 6,193,993) discloses a transdermal preparation containing an anti-dementia drug and a transdermal absorption enhancer comprising a higher alcohol or an ester derivative thereof.
  • dosage forms such as ointments, creams, patches, lotions and the like are mentioned.
  • WO 03/032960 (corresponding to Patent Document 2, US Patent Application Publication No.
  • an adhesive composition having an active ingredient skin permeation rate of at least 1.2 ⁇ g / cm 2 per hour And a percutaneous absorption type dementia treatment preparation that can be retained on the skin surface for at least 12 hours, and as a specific example, administered for 24 hours (ie, skin) Held on the surface) or administered for 48 hours.
  • a percutaneous absorption type dementia treatment preparation that can be retained on the skin surface for at least 12 hours, and as a specific example, administered for 24 hours (ie, skin) Held on the surface) or administered for 48 hours.
  • the content of the backing layer made of polyethylene terephthalate (PET) cloth and the pharmaceutically active ingredient buprenorphine is 10% by weight. Disclosure of wearing a TTS (transdermal therapeutic system) with a pressure-sensitive adhesive reservoir for 168 hours (ie, 7 days) and using a film web with funnel-shaped pores as the backing layer Has been.
  • Rivastigmine an antidementia drug
  • Rivastigmine an antidementia drug
  • Rivastigmine is known to be useful in the treatment of patients with symptoms of dementia and traumatic brain injury associated with mild to moderate Alzheimer's disease and Parkinson's disease.
  • a once-a-day patch type patch (24-hour preparation) comprising this in an adhesive layer is known.
  • a long-lasting patch with a smaller number of times of application has been desired from the viewpoint of caregiver complexity and compliance.
  • a long-lasting patch is required to be able to be applied to the skin for a long period of about one week or more and to maintain adhesiveness that can withstand bathing.
  • skin irritation may occur when applied to the same part of the skin for a long period of time, it is conceivable to reduce the amount of rivastigmine permeated through the skin in order to avoid irritation. Then, as a result, the area of the patch and the area of the skin may be unnecessarily increased.
  • the adhesive layer of the patch is usually produced by applying an adhesive-containing solution, that is, a solvent-based adhesive to a substrate or a support. Since the thickness of the pressure-sensitive adhesive layer that can be applied in one operation is limited in terms of foaming and residual solvent, the solvent-based pressure-sensitive adhesive is applied several times and the pressure-sensitive adhesive layer is bonded together. There is a need. However, the adhesive performance of the patch may fluctuate due to variations in coating amount, coating components, etc., resulting in manufacturing difficulties.
  • an adhesive layer is formed by applying an emulsion-based adhesive to a substrate or a support, there is no problem of residual solvent, so that the adhesive with a thickness of, for example, 150 ⁇ m can be obtained by a single application. It is possible to form up to the agent layer, but because the emulsion adhesive contains a surfactant, it has high skin irritation and lacks long-term adhesion, so it is a long-lasting patch. It was difficult to manufacture.
  • the administration period of rivastigmine, an anti-dementia drug is set to a long period of about one week or more, and during the administration period, rivastigmine can be stably released and permeated through the skin, and the patch is applied to the skin.
  • An object of the present invention is to provide a patch having stable rivastigmine skin permeation performance suitable for long-term administration, good skin adhesion performance and less skin irritation, and the patch. It is to provide an efficient manufacturing method.
  • the present inventors have found that the problem can be solved by adjusting the composition of the adhesive of the patch and controlling the skin permeation rate of rivastigmine. As a result, the present invention has been completed. Moreover, the efficient manufacturing method was found.
  • a patch for treating continuous Alzheimer's disease comprising a support, an acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more, and a liner,
  • the acrylic pressure-sensitive adhesive layer contains 3 to 14% by mass of rivastigmine, and
  • the skin permeation rate of rivastigmine is 0.5 to 25 ⁇ g / cm 2 ⁇ hr every day, A patch for the treatment of type Alzheimer's disease is provided.
  • the following patches (1) to (6) for the treatment of continuous Alzheimer's disease are provided as embodiments.
  • the above-mentioned patch for treatment of continuous Alzheimer's disease which is obtained by applying a rivastigmine solution to a liner or a support and bonding it to an acrylic pressure-sensitive adhesive layer.
  • the aforementioned adhesive patch for treating Alzheimer's disease which is obtained by laminating a liner-side acrylic adhesive layer comprising a solvent-based acrylic adhesive layer having a thickness of 50 ⁇ m or less.
  • the adhesive patch for treating continuous Alzheimer's disease wherein the acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more contains a (meth) acrylic acid alkyl ester / vinyl acetate copolymer.
  • a method for producing the above-mentioned patch for treating Alzheimer's disease which comprises applying a rivastigmine solution to a liner or a support and laminating it with an acrylic adhesive layer.
  • the following (7) and (8) the method for producing a patch for treating continuous Alzheimer's disease is provided.
  • At least one layer has an emulsion-based acrylic pressure-sensitive adhesive layer with a thickness of 50 ⁇ m or more, and as an acrylic pressure-sensitive adhesive layer on the liner side, the thickness of at least one layer is 50 ⁇ m or less.
  • a method for producing the above-mentioned patch for treating Alzheimer's disease comprising pasting together a solvent-based acrylic pressure-sensitive adhesive layer to form an acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more.
  • a continuous Alzheimer's disease treatment patch comprising a support, an acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more, and a liner, wherein the acrylic pressure-sensitive adhesive layer is 3 to 14% by mass.
  • the skin permeation rate of rivastigmine is 0.5 to 25 ⁇ g / cm 2 ⁇ hr on any day.
  • the method for producing a patch for treating continuous Alzheimer's disease comprising applying a rivastigmine solution to a liner or a support and bonding the rivastigmine solution to an acrylic pressure-sensitive adhesive layer, The effect that an efficient manufacturing method of a patch can be provided is produced.
  • the patch for treating continuous Alzheimer's disease of the present invention is a patch for treating continuous Alzheimer's disease comprising a support, an acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more, and a liner.
  • Support The support in the patch for treatment of continuous Alzheimer's disease of the present invention is not particularly limited.
  • paper such as impregnated paper, coated paper, fine paper, kraft paper, Japanese paper, glassine paper; polyester film, polyethylene Films, polypropylene films, polyvinyl chloride films, polycarbonate films, polyurethane films, cellophane films and other plastic films; foams; non-woven fabrics, woven fabrics, knitted fabrics and other fabrics; .
  • Polyester, polyurethane, polyethylene, polypropylene, etc. are mentioned as materials of cloth, such as a nonwoven fabric, a woven fabric, and a knitted fabric.
  • non-woven fabrics, woven fabrics, knitted fabrics, and the like are preferable, and non-woven fabrics are particularly preferable in terms of excellent stretchability and excellent followability to the movement of the skin surface under application.
  • the plastic film excellent in transparency is preferable at the point which is easy to show through the color tone of the skin under sticking.
  • Supports such as cloth can be colored in a color tone such as skin color with a colorant.
  • the thickness of the support is usually about 5 ⁇ m to 1 mm. When the support is a cloth, the thickness is preferably 50 ⁇ m to 1 mm, more preferably 100 to 800 ⁇ m, still more preferably 200 to 700 ⁇ m.
  • the thickness is preferably 10 to 300 ⁇ m, more preferably 12 to 200 ⁇ m, and still more preferably 15 to 150 ⁇ m.
  • the thickness of the support is about 5 ⁇ m to 30 ⁇ m, it is preferable to provide a peelable carrier film layer on the surface opposite to the pressure-sensitive adhesive layer of the support because the handleability as a patch is improved. If the thickness of the support is smaller than this, the strength and handleability of the patch will be reduced, making it difficult to apply to the skin, and it may be broken by contact with other members, etc., or contact with water such as bathing May peel off the skin in a short time. If the thickness of the support is too large, it will be difficult for the patch to follow the movement of the skin, and it will be easy to form a trigger that peels off at the edge of the patch. May increase.
  • the pressure-sensitive adhesive layer in the patch for treating continuous Alzheimer's disease of the present invention is an acrylic pressure-sensitive adhesive layer formed from an acrylic pressure-sensitive adhesive containing an acrylic polymer.
  • the acrylic polymer is a homopolymer or copolymer of an alkyl (meth) acrylate having an alkyl acrylate ester and / or an alkyl methacrylate ester monomer as a main component.
  • the acrylic polymer is not particularly limited as long as it does not prevent retention of rivastigmine, which is an anti-Alzheimer's disease therapeutic agent, and penetration into the skin.
  • the alkyl group moiety in the (meth) acrylic acid alkyl ester has a carbon number of 1 Is in the range of -15, more preferably in the range of 1-12, still more preferably in the range of 1-10.
  • (meth) acrylic acid alkyl esters include methyl acrylate, ethyl acrylate, isopropyl acrylate, n-butyl acrylate, t-butyl acrylate, isoamyl acrylate, 2-ethylhexyl acrylate, and n-acrylate.
  • -Acrylic acid alkyl esters such as octyl, isooctyl acrylate, isononyl acrylate, decyl acrylate, dodecyl acrylate; methyl methacrylate, ethyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, t-butyl methacrylate, methacryl Methacrylic acid alkyl esters such as isoamyl acid, 2-ethylhexyl methacrylate, n-octyl methacrylate, isooctyl methacrylate, isononyl methacrylate, decyl methacrylate, dodecyl methacrylate; It can gel.
  • These (meth) acrylic acid alkyl esters can be used alone or in combination of two or more kinds. For example, n-butyl acrylate and methyl methacrylate can be used in combination.
  • other monomers than (meth) acrylic acid alkyl ester may be copolymerized.
  • Other monomers include carboxyl group-containing monomers such as acrylic acid, methacrylic acid, maleic acid, itaconic acid, and crotonic acid; hydroxyl group-containing monomers such as 2-hydroxyethyl acrylate and 2-hydroxypropyl acrylate Body; amino group-containing monomers such as N, N-dimethylaminomethyl acrylate, N, N-dimethylaminoethyl methacrylate and Nt-butylaminoethyl acrylate; amide group-containing monomers such as acrylamide and methacrylamide; Glycidyl group-containing monomers such as glycidyl methacrylate; Vinyl esters such as vinyl acetate; Unsaturated nitriles such as acrylonitrile and methacrylonitrile; Vinyl aromatic compounds such as styrene; Other vinyl monomers
  • the (meth) acrylic acid alkyl ester is usually used in a proportion of 60% by mass or more, preferably 70 to 97% by mass, more preferably 75 to 95% by mass.
  • the other monomer is usually used in a proportion of 40% by mass or less, preferably 30 to 3% by mass, more preferably 25 to 5% by mass.
  • the production method of the acrylic polymer is not particularly limited, and can be produced by a generally employed solution polymerization method, suspension polymerization method or emulsion polymerization method. That is, as an acrylic pressure-sensitive adhesive, a monomer mainly composed of the above (meth) acrylic acid alkyl ester is used as a peroxide such as benzoyl peroxide in an organic solvent such as toluene, hexane or ethyl acetate. After being emulsified and dispersed using an emulsifier in water together with an initiator such as ammonium persulfate, a solvent-based acrylic pressure-sensitive adhesive obtained by polymerization under a nitrogen atmosphere, etc. Any emulsion-based acrylic pressure-sensitive adhesive obtained by polymerization can be used.
  • a monomer mainly composed of the above (meth) acrylic acid alkyl ester is used as a peroxide such as benzoyl peroxide in an organic solvent such as toluene, hex
  • acrylic polymers examples include DuroTAK (registered trademark) 87-9301, 87-202A, 87-2074, 87-200A, 87-235A, 87-4098, 387-2516 (manufactured by Henkel), and GME. (Registered trademark) 2397 (manufactured by Cytec Industries Inc.) and the like.
  • Preferred (meth) acrylic polymers are acrylic acid alkyl ester / vinyl acetate copolymers, and solvent-based acrylic pressure-sensitive adhesives such as DuroTAK387-2516 and DuroTAK87-4098 are known.
  • GME registered trademark
  • 2397 manufactured by Cytec Industries Inc.
  • a tackifier in order to adjust the pressure-sensitive adhesive property of the acrylic polymer, a tackifier can be blended in the acrylic polymer as desired.
  • the tackifier include tackifier resins such as terpene, terpene phenol, coumarone indene, styrene, rosin, xylene, phenol, and petroleum.
  • additives that are usually used in patches and the like, such as cross-linking agents, softeners, fillers, antioxidants and other low molecular weight components, can be added to the acrylic polymer as necessary.
  • tackifiers and additives are often 15 parts by weight or less, preferably 10 parts by weight or less, more preferably 0.01 to 5 parts by weight, based on 100 parts by weight of the acrylic polymer. Depending on the case, it may be more preferably used in a proportion of 0.05 to 2 parts by mass.
  • crosslinking agents can be further added to the pressure-sensitive adhesive layer for the purpose of increasing the cohesive strength of the acrylic pressure-sensitive adhesive.
  • the crosslinking agent include polyfunctional isocyanate compounds, polyfunctional epoxy compounds, and polyvalent metal salts.
  • polyisocyanate for example, Coronate (registered trademark) HL (hexamethylene diisocyanate HDI-TMP adduct, manufactured by Nippon Polyurethane Industry Co., Ltd.)
  • the filler calcium carbonate, magnesium carbonate, silicate, zinc oxide, titanium oxide, magnesium sulfate, calcium sulfate and the like can be blended.
  • antioxidant various vitamins, butylhydroxytoluene and the like can be blended, and ⁇ -tocopherol (vitamin E) is particularly preferable in combination with rivastigmine from the viewpoint of preventing a decrease in the content with time.
  • solubilizer examples include polyhydric alcohols (glycerin, sorbitol, propylene glycol, 1,3-butylene glycol, 1,3-tetramethylene glycol, polyethylene glycol, etc.), phenols (thymol, safrole, isosafrole, Eugenol, isoeugenol, etc.), higher alcohols (benzyl alcohol, oleyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, octyldodecanol, etc.), ester surfactants (sorbitan sesquioleate, polyoxyethylene hydrogenated castor oil) ), Fatty acid esters (isopropyl myristate, octyldode
  • permeation enhancers examples include fatty acids, fatty acid esters (isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, diethyl adipate, etc.), fatty acid amides, fatty alcohols, 2- (2-ethoxyethoxy) -ethanol, ester of glycerol, glycerol monolaurate, propylene glycol, polyethylene glycol, unsaturated polyglycolized glyceride, saturated polyglyceride, ⁇ -hydroxy acid, dimethyl sulfoxide, decylmethyl sulfoxide, pyrrolidones, Salicylic acid, lactic acid, dimethylformamide, dimethylacetamide, sodium dodecyl sulfate, phospholipid, oleic acid, oleic acid / 2- (2-ethoxyethoxy) ester Nord, there is perme
  • the acrylic pressure-sensitive adhesive layer in the patch for treating continuous Alzheimer's disease of the present invention has a thickness of 150 ⁇ m or more.
  • the thickness of the acrylic pressure-sensitive adhesive layer is preferably 180 ⁇ m or more, more preferably 220 ⁇ m or more, still more preferably 280 ⁇ m or more, and particularly preferably 300 ⁇ m or more. If the thickness of the acrylic pressure-sensitive adhesive layer is too small, the sustainability of Alzheimer's disease treatment will be insufficient.
  • the thickness of the acrylic pressure-sensitive adhesive layer is not particularly limited, but is usually 800 ⁇ m or less, preferably 700 ⁇ m or less from the viewpoints of handleability and skin irritation.
  • the acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more may be formed as a single acrylic pressure-sensitive adhesive layer, or may be formed by laminating a plurality of acrylic pressure-sensitive adhesive layers.
  • the acrylic pressure-sensitive adhesive layer is formed by laminating a plurality of acrylic pressure-sensitive adhesive layers, for example, a combination of a solvent-based acrylic pressure-sensitive adhesive layer and an emulsion-based acrylic pressure-sensitive adhesive layer is laminated. It can also be formed or laminated by combining a crosslinked acrylic pressure-sensitive adhesive layer and an uncrosslinked acrylic pressure-sensitive adhesive layer.
  • the acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more in the patch for treating continuous Alzheimer's disease of the present invention contains 3-14% by mass, preferably 3.5-13% by mass, of rivastigmine, which is an anti-Alzheimer's disease therapeutic agent. It is preferably contained in an amount in the range of 4 to 12% by mass.
  • rivastigmine which is an anti-Alzheimer's disease therapeutic agent
  • into the skin is reduced, and the persistence of Alzheimer's disease treatment is insufficient.
  • rate of rivastigmine to the skin will become large, and skin irritation will increase.
  • the adhesive protects the adhesive layer and prevents its alteration until the patch is applied to the skin, and the adhesive is applied when the patch is applied to the skin. It means a layer that is peeled off from the layer, and is commonly used in patches.
  • the liner in the present invention is not particularly limited as long as it has the above-mentioned function. Examples of the liner include silicone-treated PET, silicone-treated polypropylene, silicone-treated polyethylene, fluorine resin-coated PET, fluorine resin-coated polypropylene, and fluorine resin-coated polyethylene.
  • Examples of the release-treated resin film include laminates of these release-treated resin films and paper, aluminum-deposited resin films, paper coated with silicone oil, and the like.
  • the mold release treatment can be performed not only on the adhesive surface but also on the opposite surface.
  • an uneven shape can be provided on one or both sides of the liner.
  • the liner is preferably formed of a material that hardly absorbs or adsorbs rivastigmine.
  • the thickness of the liner is not particularly limited, but is usually in the range of 10 ⁇ m to 1 mm, preferably 20 to 500 ⁇ m, more preferably 50 to 200 ⁇ m.
  • the patch for treating continuous Alzheimer's disease of the present invention is a patch for treating continuous Alzheimer's disease comprising a support, an acrylic adhesive layer having a thickness of 150 ⁇ m or more, and a liner. Generally, it has a layer structure in which a support / acrylic pressure-sensitive adhesive layer / liner is laminated in this order. By cutting or punching the sheet-shaped raw material having such a layer configuration into a predetermined shape, a patch can be obtained.
  • the area of the patch (the area of the pressure-sensitive adhesive that comes into contact with human skin) is preferably 2 to 50 cm 2 , particularly 4 to 30 cm 2 , from the viewpoints of drug efficacy, skin irritation, and long-term skin patchability.
  • the shape of the patch is preferably rectangular or round with rounded corners. From the viewpoint of handleability, a frame type in which the liner shape is formed larger than the patch is preferable, and the liner is in a form in which the patch is arranged on a liner divided into two or more. From the viewpoint of
  • the patch for treatment of continuous Alzheimer's disease of the present invention has a skin permeation rate of rivastigmine of 0.5 to 25 ⁇ g / cm on any day in an in vitro skin permeation test (7 days) using hairless mouse skin. 2 ⁇ hr.
  • skin permeation rate during 7 day test is referred to as “skin permeation rate during 7 day test”.
  • the in vitro skin permeation test (7 days) using hairless mouse skin is as follows. That is, using the abdominal skin of a hairless mouse (male, 7 weeks old), the skin is attached to a vertical diffusion cell having a diameter of 20 mm ⁇ with the dermis side being the receptor layer side. Circulating hot water at a temperature of 32 ° C. in a double-structured cell to keep the inside of the cell at a constant temperature condition, and a patch punched to 15 mm ⁇ is applied to the stratum corneum side of the skin. Fill the receiver side layer with the receiver solution (20% polyethylene glycol / purified water), and stir with a stirrer and apply 0.5 mL of the receiver solution every 24 hours after applying the patch to the skin.
  • the receiver solution (20% polyethylene glycol / purified water
  • the skin permeation rate of rivastigmine on the day is calculated by calculating the skin permeation amount of the patch, calculating the skin area of the patch (cm 2 ) and the skin permeation rate of rivastigmine per hour ( ⁇ g / cm 2 ⁇ hr).
  • the receiver solution after sampling is supplemented with the same amount of 20% polyethylene glycol / purified water.
  • the patch for treatment of continuous Alzheimer's disease of the present invention has a skin permeation rate of 0.5 to 25 ⁇ g / cm 2 ⁇ hr during the 7-day test.
  • the skin permeation rate of rivastigmine was 0.5 to 25 ⁇ g / cm 2 ⁇ hr for any day from day 1 to day 7.
  • Means within range. That is, the patch for treating continuous Alzheimer's disease of the present invention has a skin permeation rate of rivastigmine of less than 0.5 ⁇ g / cm 2 ⁇ hr for any day from day 1 to day 7 in the skin permeation test. And does not exceed 25 ⁇ g / cm 2 ⁇ hr.
  • the patch for treating continuous Alzheimer's disease of the present invention is applied to the patch over a long period of about one week or more.
  • the rivastigmine can be stably supplied to the skin to which the agent is applied.
  • Skin permeation rate of 7 days in the test is preferably in the range of 1 ⁇ 24 ⁇ g / cm 2 ⁇ hr , more preferably 2 ⁇ 23 ⁇ g / cm 2 ⁇ hr . If the skin permeation rate during the 7-day test is too low, rivastigmine cannot be stably supplied to the skin to which the patch has been applied over a long period of time. That's not true. Also, if the skin permeation rate during the 7-day test is too high, the skin irritation to the skin to which the patch has been applied increases, which is not preferable.
  • the patch for treating continuous Alzheimer's disease of the present invention usually has a tendency that the skin permeation rate of rivastigmine increases from the start of the pasting until several days, and thereafter the skin permeation rate of rivastigmine tends to decrease.
  • the tendency of fluctuation of the skin permeation rate of rivastigmine is not particularly limited, but in the skin permeation test (7 days), the skin of rivastigmine on the seventh day from the start of the test Sustain rate (hereinafter referred to as “sustain rate (J 7 / J 1 )” expressed by a ratio (J 7 / J 1 ) between the permeation rate J 7 and the skin permeation rate J 1 of rivastigmine on the first day from the start of the test
  • sustain rate (J 7 / J 1 ) expressed by a ratio (J 7 / J 1 ) between the permeation rate J 7 and the skin permeation rate J 1 of rivastigmine on the first day from the start of the test
  • rivastigmine can be supplied more stably to the skin to which the patch has been applied over a long period of about one week or more.
  • the sustain rate (J 7 / J 1 ) is more preferably 0.35 or more, and still more preferably 0.37 or more. There is no particular upper limit on the sustaining rate (J 7 / J 1 ), but it is usually about 0.9, and in many cases about 0.8.
  • the patch for treating continuous Alzheimer's disease of the present invention has little skin irritation to the skin to which the patch is applied, it can be left on the skin for a long period of time of about one week or longer.
  • the skin irritation of the patch can be evaluated by the following rabbit skin irritation test.
  • the application site is covered with gauze, and the gauze is fixed with an adhesive bandage of about 5 cm ⁇ 5 cm (Nichiban Co., Ltd., Elastopore (registered trademark)). Cover and secure, and after wearing the Elizabeth collar, return the rabbit to the gauge.
  • the patch is removed from the rabbit skin after 1, 3, 6, and 7 days (ie, 24 hours, 72 hours, 144 hours, and 168 hours) from the start of application, and the skin reaction is observed with the naked eye. Skin reaction is evaluated for A (erythema and scab formation) according to the Draize criteria. If the evaluation after 1, 3, 6, and 7 days is all 0 (no erythema), the overall evaluation of skin irritation is “Y”, otherwise the skin irritation The overall evaluation is “N”.
  • Adhesion-Adhesive strength The adhesion performance of the patch to the skin is evaluated by measuring the adhesive strength by the following method in accordance with JIS Z0237. That is, the patch is cut to a width of 12 mm, the liner is peeled off and attached to the bakelite panel, and then a 2 kg rubber roller is reciprocated twice for pressure bonding. After leaving for 20 minutes, using Tensilon type universal testing machine RTC-1210A (manufactured by Orientec Co., Ltd.), the adhesive strength when peeled at a peeling angle of 180 ° and a peeling speed of 300 mm / min is set as an initial value.
  • A The decrease rate of the adhesive strength after 168 hours was less than 5% of the initial value
  • B The rate of decrease in adhesive strength after 168 hours was less than 10% of the initial value
  • C Decreasing rate of adhesive strength after 168 hours is less than 20% of initial value
  • D The patch was peeled off before 168 hours passed
  • E The patch peeled before 24 hours.
  • Adhesion-Adhesion with skin the adhesion performance of the patch to the skin is evaluated by measuring the adhesion with human skin by the following method. That is, the liner of a patch punched out to 5 cm 2 (however, isopropyl myristate is mixed in place of rivastigmine) is peeled off and applied to the upper arms of four subjects (men and healthy subjects). Adhesion after the passage of days is evaluated according to the following criteria.
  • A The patch is attached to everyone.
  • B The patch is attached to three people.
  • C A patch is attached to one or two people.
  • D All the patches are peeled off (dropped off).
  • the patch for treating continuous Alzheimer's disease comprises a support, an acrylic adhesive layer having a thickness of 150 ⁇ m or more, and a liner, and a patch for treating continuous Alzheimer's disease.
  • the acrylic pressure-sensitive adhesive layer contains 3 to 14% by mass of rivastigmine and the skin permeation rate during the 7-day test is 0.5 to 25 ⁇ g / cm 2 ⁇ hr, its production
  • the method is not particularly limited.
  • a method for producing a patch comprising a normal support, an acrylic pressure-sensitive adhesive layer, and a liner can be employed.
  • the melting method is a method in which necessary components are dissolved in a solvent and spread on a liner or a support, and then the solvent is evaporated to bond with the liner or the support, and then cut into an appropriate shape to obtain a patch. It is.
  • an acrylic pressure-sensitive adhesive containing rivastigmine is applied to one of a liner or a support to form an acrylic pressure-sensitive adhesive layer, and then supported. It can be manufactured by integrating the other of the body or the liner.
  • a solvent system containing 10 to 70% by weight, preferably 15 to 55% by weight, more preferably 20 to 50% by weight of an acrylic polymer as a solid content of the pressure-sensitive adhesive can be used.
  • the adhesive patch for treating continuous Alzheimer's disease of the present invention has an acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more, particularly preferably 300 ⁇ m or more. Therefore, the application of the acrylic pressure-sensitive adhesive containing rivastigmine is performed several times.
  • an acrylic adhesive layer with a thickness of 150 ⁇ m or more of the continuous Alzheimer's disease patch may be formed by laminating a plurality of acrylic adhesive layers.
  • the thickness of the solvent-based acrylic pressure-sensitive adhesive layer formed by applying the solvent-based acrylic pressure-sensitive adhesive is the thickness of the emulsion-based acrylic pressure-sensitive adhesive layer formed by applying the emulsion-based acrylic pressure-sensitive adhesive. More generally smaller.
  • emulsion-based acrylic pressure-sensitive adhesives contain a surfactant and therefore have high skin irritation and may have poor adhesion to the skin for a long period of time.
  • the support-side acrylic pressure-sensitive adhesive layer As an emulsion acrylic pressure-sensitive adhesive layer having a thickness of at least one layer of 50 ⁇ m or more, and a solvent-based acrylic pressure-sensitive adhesive layer having a thickness of at least 50 ⁇ m or less as an acrylic pressure-sensitive adhesive layer on the liner side
  • the acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more is preferably formed.
  • the sustained-type Alzheimer's disease treatment patch comprising an acrylic adhesive layer has high skin irritation and may have poor long-term adhesion when the patch is applied to the skin.
  • the emulsion acrylic pressure-sensitive adhesive layer can be prevented from coming into contact with the skin.
  • the adhesive layer in contact with the skin as a patch is a non-emulsion acrylic adhesive layer, so that the surfactant in the emulsion acrylic adhesive layer moves to the skin side and induces skin irritation. It also has the effect of acting as a barrier that can greatly reduce the risk.
  • a patch for treating continuous Alzheimer's disease of the present invention by applying a rivastigmine solution to a liner or a support and bonding it to an acrylic pressure-sensitive adhesive layer, the drug permeation persistence and skin patchability can be improved.
  • a patch can be obtained by forming an acrylic pressure-sensitive adhesive layer having a sufficient thickness of 150 ⁇ m or more.
  • Rivastigmine is one of the components used in adhesives (rubber adhesives such as polymers such as acrylate polymers and styrene / isoprene copolymers, terpene phenol resins, alicyclic resins, hydrogenated rosin resins, etc.)
  • adhesives rubber adhesives such as polymers such as acrylate polymers and styrene / isoprene copolymers, terpene phenol resins, alicyclic resins, hydrogenated rosin resins, etc.
  • a resin usually used for the agent a low molecular weight acrylic resin, a low molecular weight rubber component such as polyisobutylene or polybutene, or a generally called softener such as lanolin
  • a solvent for rivastigmine solution As a solvent for rivastigmine solution, alcohol, ethyl acetate, toluene, hexane or the like can be used. However, if the purpose is to apply at room temperature, a rivastigmine solution can be prepared without using a solvent. it can. In addition, a coating method such as a spray method can be used.
  • the concentration of rivastigmine in the rivastigmine solution is usually in the range of 5 to 98% by mass. Further, it is more preferable that the rivastigmine solution is thickened by adding a methacrylic acid alkyl ester copolymer, since coatability and adhesion to the liner or the support are improved.
  • the thickener can be used in the range of 1 to 30% by mass, preferably 3 to 25% by mass, more preferably 5 to 20% by mass with respect to the total amount of rivastigmine and the thickener.
  • alkyl methacrylate copolymer examples include aminoalkyl methacrylate copolymers such as methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, and examples thereof include Eudragit (registered trademark; Commercially available products such as Evonic Degussa E-100 and Eudragit EPO can be used.
  • the rivastigmine solution is applied to a liner or a support using an ordinary coating / coating tool so that the thickness is usually 10 to 100 ⁇ m, preferably 15 to 90 ⁇ m, more preferably 20 to 80 ⁇ m.
  • the concentration of rivastigmine in the solution can be used at a high concentration of 80 to 98% by mass, and the coating thickness of the rivastigmine solution can be reduced.
  • the acrylic pressure-sensitive adhesive layer to be bonded to the rivastigmine solution coated on the liner or the support may be a single acrylic pressure-sensitive adhesive layer or an acrylic pressure-sensitive adhesive obtained by bonding a plurality of acrylic pressure-sensitive adhesive layers. It may be a layer, and may be any of an emulsion-based acrylic pressure-sensitive adhesive layer, a solvent-based acrylic pressure-sensitive adhesive layer, or a layer obtained by bonding them together. As described above, in consideration of skin irritation, it is desirable that the layer to which a skin irritant such as a surfactant is added is not in contact with the skin.
  • each layer may contain rivastigmine, or a layer containing rivastigmine is bonded to a layer not containing rivastigmine and then aged at about 20 to 40 ° C. for about one week.
  • a method of diffusing rivastigmine or rivastigmine and an antioxidant or other low molecular weight components into the layer not containing rivastigmine can be employed.
  • the patch for the treatment of continuous Alzheimer's disease encapsulated in a packaging material is for preventing contamination of the patch, and for preventing deterioration and volatilization due to oxidation and moisture absorption of rivastigmine. Usually, it is handled in a form encapsulated in a packaging material.
  • the packaging material is not particularly limited as long as it is used for encapsulating a patch comprising a pressure-sensitive adhesive layer in which a drug is blended.
  • a metal foil such as aluminum, polyethylene, polypropylene, ethylene -Packaging materials having a multilayer structure such as those obtained by laminating a heat seal layer made of a vinyl acetate copolymer or the like, and those obtained by laminating polyester, cellophane, paper, etc. on the outside of an aluminum foil or other metal foil.
  • a packaging material in which the innermost layer is a rivastigmine non-adsorbing layer is preferable, and a packaging material in which the innermost layer is a rivastigmine non-adsorbing layer mainly composed of polyacrylonitrile is preferable.
  • the innermost layer is composed of a homopolymer of acrylonitrile or 50 mol% or more of acrylonitrile and other monomers of 50 mol% or less. It means containing 50% by mass or more of a copolymer.
  • the measuring method of the physical property or characteristic in an Example and a comparative example is as follows.
  • the sampled receiver solution was supplemented with the same amount of 20% polyethylene glycol / purified water.
  • Adhesion-Adhesive strength The adhesiveness of the patch was evaluated by measuring the adhesive strength by the following method. That is, the patch was cut to a width of 12 mm, the liner was peeled off, and affixed to a bakelite panel. After leaving for 20 minutes, an adhesive strength when peeled off at a peeling angle of 180 ° and a peeling speed of 300 mm / min using a Tensilon type universal testing machine RTC-1210A (manufactured by Orientec Co., Ltd.) was set as an initial value. Subsequently, the adhesive strength after 24 hours (1 day) and 168 hours (7 days) after the application was measured by the same operation.
  • the bakelite panel with the patch applied was immersed in a hot water bath at a temperature of 40 ° C. for 10 to 15 minutes once a day, and left to dry at a temperature of 25 ° C. for 6 hours.
  • A The decrease rate of the adhesive strength after 168 hours was less than 5% of the initial value
  • B The rate of decrease in adhesive strength after 168 hours was less than 10% of the initial value
  • C Decreasing rate of adhesive strength after 168 hours is less than 20% of initial value
  • D The patch was peeled off before 168 hours passed
  • E The patch peeled before 24 hours.
  • Adhesion-Adhesion with skin The adhesiveness of the patch was evaluated by measuring the adhesiveness with human skin by the following method. That is, the liner of a patch punched out to 5 cm 2 (however, isopropyl myristate is mixed in place of rivastigmine) is peeled off and applied to the upper arms of four subjects (men and healthy subjects). Adhesion after the passage of days was evaluated according to the following criteria.
  • A The patch is attached to everyone.
  • B The patch is attached to three people.
  • C A patch is attached to one or two people.
  • D All the patches are peeled off (dropped off).
  • Example 1 (I) (meth) acrylic acid alkyl ester / vinyl acetate copolymer (DuroTAK (registered trademark) 387-2516 manufactured by Henkel), which is a solution-based acrylic polymer containing 43.6% by mass of the adhesive solid content. (Hereinafter referred to as “acrylic 1”)
  • the viscosity of the solution was adjusted with ethyl acetate, and this solution was subjected to silicone release treatment to serve as a liner for the patch.
  • a 75 ⁇ m thick PET film [Fujimori Industrial Co., Ltd. ) 75E-0010 No. 23] was coated on the silicone-treated surface so that the thickness after drying was 54 ⁇ m and dried to form an acrylic pressure-sensitive adhesive layer.
  • the rivastigmine solution thus formed was applied to a 25 ⁇ m thick PET film [Lumirror S10 (registered trademark) manufactured by Toray Industries, Inc.] serving as a support for the patch so as to have a film thickness of 30 ⁇ m.
  • a 25 ⁇ m thick PET film [Lumirror S10 (registered trademark) manufactured by Toray Industries, Inc.] serving as a support for the patch so as to have a film thickness of 30 ⁇ m.
  • An acrylic pressure-sensitive adhesive layer (thickness 270 ⁇ m) formed from acrylic 1 formed on the above-mentioned silicone release-treated PET film is bonded to face a layer (thickness 30 ⁇ m) formed from rivastigmine solution.
  • an acrylic pressure-sensitive adhesive layer composed of an acrylic pressure-sensitive adhesive layer (total thickness 270 ⁇ m) formed from five layers of acrylic 1 and a layer formed from a rivastigmine solution (thickness 30 ⁇ m) was formed.
  • a patch having a layer structure of support / acrylic pressure-sensitive adhesive layer having a thickness of 300 ⁇ m / liner was obtained.
  • concentration in an acrylic adhesive layer, the skin permeation rate of rivastigmine, skin irritation, and adhesiveness were measured.
  • This patch had an initial adhesive strength of 12.51 N / 12 mm, an adhesive strength after 168 hours of 14.40 N / 12 mm, and a decrease rate of + 15.1% (increase).
  • Rivastigmine concentration, the skin permeation rate of rivastigmine on the first day from the start of the test (hereinafter simply referred to as “skin permeation rate”), the skin permeation rate on the seventh day from the start of the test, and the skin on the seventh day from the start of the test
  • the ratio of the permeation rate J 7 to the skin permeation rate J 1 on the first day from the start of the test (J 7 / J 1 ) (hereinafter simply referred to as “sustainability”), skin irritation, and adhesion measurement results Table 1 shows.
  • Example 2 Except that the rivastigmine solution was applied to a PET film having a thickness of 25 ⁇ m so as to have a film thickness of 60 ⁇ m, and the operation of laminating the acrylic pressure-sensitive adhesive layer formed from acrylic 1 was repeated a total of 10 times, The same operation as in Example 1 was carried out to obtain a patch comprising a support / a 600 ⁇ m thick acrylic adhesive layer / liner layer structure. About this patch, the rivastigmine density
  • Example 3 The silicone release surface of a 75 ⁇ m thick PET film subjected to silicone release treatment was coated with an acrylic 1 solution so that the thickness after drying was 57 ⁇ m, and dried to form an acrylic adhesive layer; and Except that the operation of laminating the acrylic adhesive layer formed from acrylic 1 was repeated 10 times in total, the same operation as in Example 1 was performed, and the support / acrylic adhesive layer having a thickness of 600 ⁇ m / A patch comprising the layer structure of the liner was obtained. About this patch, the rivastigmine density
  • Example 4 (Meth) acrylic acid alkyl ester / vinyl acetate copolymer, which is a solution-based acrylic polymer, was changed to DuroTAK (registered trademark) 87-4098 (hereinafter referred to as “acryl 2”) manufactured by Henkel. Then, the same operation as in Example 1 was performed to obtain a patch comprising a support / a 300 ⁇ m thick acrylic pressure-sensitive adhesive layer / liner layer structure. About this patch, the rivastigmine density
  • Example 5 GME (registered trademark) 2397 manufactured by Cytec Industries Inc. (hereinafter referred to as “emulsion-based acrylic polymer”) is formed on the silicone-treated surface of a PET film (hereinafter referred to as “release film”) having a thickness of 75 ⁇ m subjected to silicone release treatment.
  • emulsion-based acrylic polymer registered trademark 2397 manufactured by Cytec Industries Inc.
  • Acrylic 3 (thickness 105 ⁇ m) formed from acrylic 3 in the same manner is bonded to the surface from which the release film is peeled. Subsequently, an acrylic 1 solution was applied to the silicone-treated surface of the release film so that the thickness after drying was 50 ⁇ m, and dried to form an acrylic pressure-sensitive adhesive layer.
  • Example 1 except that the acrylic pressure-sensitive adhesive layer formed from 1 was bonded to the surface from which the release film was peeled off from the acrylic pressure-sensitive adhesive layer formed from the acrylic 3 Thus, a patch comprising a support / a 300 ⁇ m thick acrylic pressure-sensitive adhesive layer / liner layer structure was obtained.
  • the acrylic adhesive layer of this patch was formed from the support side, a layer formed from a solution of rivastigmine (thickness 40 ⁇ m), an acrylic adhesive layer formed from acrylic 3 (thickness 105 ⁇ m), and acrylic 3. It is composed of an acrylic pressure-sensitive adhesive layer (thickness 105 ⁇ m) and an acrylic pressure-sensitive adhesive layer (thickness 50 ⁇ m) formed from acrylic 1.
  • Table 1 shows the measurement results of the rivastigmine concentration, the skin permeation rate on the first day, the skin permeation rate on the seventh day, the persistence rate, the skin irritation, and the adhesion.
  • Example 6 That the rivastigmine solution applied to the PET film was changed to a film thickness of 32 ⁇ m, and that the thickness of each acrylic adhesive layer formed from the acrylic 3 was changed from 105 ⁇ m to 84 ⁇ m Except for this, the same operation as in Example 5 was performed to obtain a patch comprising a layer structure of support / acrylic adhesive layer / liner having a thickness of 250 ⁇ m. About this patch, the rivastigmine density
  • Example 7 The rivastigmine solution applied to the PET film was changed to a film thickness of 27 ⁇ m, the thickness of the acrylic adhesive layer formed from the acrylic 3 was changed from 105 ⁇ m to 123 ⁇ m, and 1 The same operation as in Example 5 was performed except that the pasting was performed twice, and a patch comprising a support / a 200 ⁇ m thick acrylic pressure-sensitive adhesive layer / liner layer structure was obtained. About this patch, the rivastigmine density
  • Example 1 Except that the rivastigmine solution was applied to a PET film having a thickness of 25 ⁇ m so as to have a film thickness of 114 ⁇ m, and the operation of bonding the acrylic pressure-sensitive adhesive layer formed from acrylic 1 was repeated a total of 9 times, The same operation as in Example 1 was carried out to obtain a patch comprising a support / a 600 ⁇ m thick acrylic adhesive layer / liner layer structure. About this patch, the rivastigmine density
  • Table 1 shows the measurement results of the rivastigmine concentration, the skin permeation rate on the first day, the skin permeation rate on the seventh day, the persistence rate, the skin irritation, and the adhesion.
  • a SIS pressure-sensitive adhesive layer containing rivastigmine As a SIS pressure-sensitive adhesive layer containing rivastigmine, a SIS composition composed of 23.1% by mass of SIS5002, 23.1% by mass of QTC3520, 46.3% by mass of KE311, and 7.5% by mass of rivastigmine has a thickness of 720 ⁇ m.
  • a patch comprising a support / 720 ⁇ m thick SIS adhesive layer / liner was obtained.
  • concentration in an adhesive layer, the skin permeation rate of rivastigmine, skin irritation, and adhesiveness were measured.
  • the initial value of the adhesive strength of this patch was 32.74 N / 12 mm, the adhesive strength after 168 hours was 29.24 N / 12 mm, and the reduction rate was 10.7%.
  • Table 1 shows the measurement results of the rivastigmine concentration, the skin permeation rate on the first day, the skin permeation rate on the seventh day, the persistence rate, the skin irritation, and the adhesion.
  • a pressure-sensitive adhesive layer having a thickness of 600 ⁇ m was formed with 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer (MAS811 manufactured by Kosmedy Pharmaceutical Co., Ltd.) containing 18.0% by mass of rivastigmine. Except for this, in the same manner as in Comparative Example 2, a patch comprising a support / a pressure-sensitive adhesive layer / liner having a thickness of 600 ⁇ m was obtained. About this patch, the rivastigmine density
  • the patch of Comparative Example 1 in which the rivastigmine concentration in the acrylic pressure-sensitive adhesive layer is excessively 18.0% by mass and the skin permeation rate during the 7-day test is excessive is It was found that the skin irritation to the skin to which is attached is large and undesirable.
  • the adhesive layers of Comparative Examples 2 and 3 in which the adhesive layer is not the acrylic adhesive in the present invention but is a SIS adhesive widely used in patches have poor adhesion and are long-lasting Alzheimer's. It could not be used as a patch for disease treatment.
  • the patch of Comparative Example 2 shows mild to clear erythema on the skin to which the patch was applied.
  • the patch of Comparative Example 3 was used in 4 subjects in the skin adhesion test.
  • the pressure-sensitive adhesive layer contains acrylic acid 2-ethylhexyl acrylate / methacrylic acid 2-ethylhexyl / methacrylic acid dodecyl copolymer, and the rivastigmine concentration in the pressure-sensitive adhesive layer is 18.0% by mass.
  • the patch of Comparative Example 4 which is excessive and has an excessive skin permeation rate during the 7-day test, has a large skin irritation to the skin to which the patch has been applied, and is a long-lasting patch for treatment of Alzheimer's disease It was not preferable as an agent.
  • the present invention provides a patch for treating continuous Alzheimer's disease comprising a support, an acrylic pressure-sensitive adhesive layer having a thickness of 150 ⁇ m or more, and a liner, wherein the acrylic pressure-sensitive adhesive layer contains 3 to 14% by mass of rivastigmine.
  • the skin permeation rate of rivastigmine is 0.5 to 25 ⁇ g / cm 2 ⁇ hr on any day
  • a patch having stable rivastigmine skin permeation performance suitable for long-term administration, good skin adhesion performance and less skin irritation And applying the rivastigmine solution to a liner or support and laminating with an acrylic pressure-sensitive adhesive layer.

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Abstract

L'invention concerne un timbre cutané adhésif à action longue pour le traitement de la maladie d'Alzheimer, comprenant un support, une couche d'agent adhésif acrylique ayant une épaisseur de 150 µm ou plus et une doublure, la couche d'agent adhésif acrylique contenant 3-14 % en masse de rivastigmine, le taux de perméation de la peau de la rivastigmine étant de 0,5-25 μg/cm2·h chaque jour dans un test in vitro de perméation de la peau (pendant 7 jours) en utilisant la peau d'une souris sans poil, et de préférence, le rapport du taux de perméation de la peau de la rivastigmine 7 jours après le début du test à celui de 1 jour après le début du test (c'est-à-dire, J7/J1) étant de 0,33 ou plus ; et un procédé de production du timbre cutané adhésif, comprenant le revêtement d'une solution de rivastigmine sur une doublure ou un support et l'adhésion du produit obtenu sur une couche d'agent adhésif acrylique.
PCT/JP2012/074345 2011-09-28 2012-09-24 Timbre cutané adhésif à action longue pour le traitement de la maladie d'alzheimer et procédé pour le produire WO2013047410A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10228623A (ja) * 1997-07-28 1998-08-25 Fuji Photo Film Co Ltd 磁気記録媒体
WO2016121805A1 (fr) * 2015-01-30 2016-08-04 積水メディカル株式会社 Timbre adhésif
US9949935B2 (en) 2014-04-08 2018-04-24 Teikoku Pharma Usa, Inc. Rivastigmine transdermal compositions and methods of using the same
EP3238689A4 (fr) * 2014-12-26 2018-08-08 Nichiban Co., Ltd. Emballage pour timbre et procédé d'emballage
JPWO2019017266A1 (ja) * 2017-07-19 2020-05-28 帝國製薬株式会社 リバスチグミン含有経皮吸収型製剤

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JPH0495024A (ja) * 1990-08-09 1992-03-27 Sekisui Chem Co Ltd 経皮吸収製剤
JPH04321623A (ja) * 1991-04-19 1992-11-11 Hisamitsu Pharmaceut Co Inc エストリオール経皮投与貼付剤
JPH11188075A (ja) * 1997-12-26 1999-07-13 Taisho Pharmaceut Co Ltd サリチル酸グリコールを配合した貼付剤
JP2002542277A (ja) * 1999-04-22 2002-12-10 エルティエス ローマン テラピー−ズュステーメ アーゲー 中和されたアクリル性粘着パッチを備えた経皮治療システム
JP2003000694A (ja) * 2001-06-19 2003-01-07 Nitto Denko Corp 貼付剤および貼付製剤、ならびにそれらの製造方法
JP2007535346A (ja) * 2004-03-24 2007-12-06 コリウム インターナショナル， インコーポレイテッド 経皮送達デバイス
WO2009139411A1 (fr) * 2008-05-15 2009-11-19 久光製薬株式会社 Préparation transdermique contenant de la palonosétrone
JP2010500992A (ja) * 2006-08-17 2010-01-14 コア テク ソリューションズ，インク． アルツハイマー病の経皮的治療法及び経皮的治療システム

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0495024A (ja) * 1990-08-09 1992-03-27 Sekisui Chem Co Ltd 経皮吸収製剤
JPH04321623A (ja) * 1991-04-19 1992-11-11 Hisamitsu Pharmaceut Co Inc エストリオール経皮投与貼付剤
JPH11188075A (ja) * 1997-12-26 1999-07-13 Taisho Pharmaceut Co Ltd サリチル酸グリコールを配合した貼付剤
JP2002542277A (ja) * 1999-04-22 2002-12-10 エルティエス ローマン テラピー−ズュステーメ アーゲー 中和されたアクリル性粘着パッチを備えた経皮治療システム
JP2003000694A (ja) * 2001-06-19 2003-01-07 Nitto Denko Corp 貼付剤および貼付製剤、ならびにそれらの製造方法
JP2007535346A (ja) * 2004-03-24 2007-12-06 コリウム インターナショナル， インコーポレイテッド 経皮送達デバイス
JP2010500992A (ja) * 2006-08-17 2010-01-14 コア テク ソリューションズ，インク． アルツハイマー病の経皮的治療法及び経皮的治療システム
WO2009139411A1 (fr) * 2008-05-15 2009-11-19 久光製薬株式会社 Préparation transdermique contenant de la palonosétrone

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10228623A (ja) * 1997-07-28 1998-08-25 Fuji Photo Film Co Ltd 磁気記録媒体
US9949935B2 (en) 2014-04-08 2018-04-24 Teikoku Pharma Usa, Inc. Rivastigmine transdermal compositions and methods of using the same
US10357463B2 (en) 2014-04-08 2019-07-23 Teikoku Pharma Usa, Inc. Rivastigmine transdermal compositions and methods of using the same
EP3238689A4 (fr) * 2014-12-26 2018-08-08 Nichiban Co., Ltd. Emballage pour timbre et procédé d'emballage
WO2016121805A1 (fr) * 2015-01-30 2016-08-04 積水メディカル株式会社 Timbre adhésif
JPWO2016121805A1 (ja) * 2015-01-30 2017-08-10 東洋インキＳｃホールディングス株式会社 貼付剤
JPWO2019017266A1 (ja) * 2017-07-19 2020-05-28 帝國製薬株式会社 リバスチグミン含有経皮吸収型製剤
JP7193863B2 (ja) 2017-07-19 2022-12-21 帝國製薬株式会社 リバスチグミン含有経皮吸収型製剤

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