WO2014199455A1 - Préparation de mémantine sous forme de patch à absorption percutanée - Google Patents

Préparation de mémantine sous forme de patch à absorption percutanée Download PDF

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Publication number
WO2014199455A1
WO2014199455A1 PCT/JP2013/066158 JP2013066158W WO2014199455A1 WO 2014199455 A1 WO2014199455 A1 WO 2014199455A1 JP 2013066158 W JP2013066158 W JP 2013066158W WO 2014199455 A1 WO2014199455 A1 WO 2014199455A1
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WO
WIPO (PCT)
Prior art keywords
patch preparation
carboxyl group
memantine
drug
free carboxyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2013/066158
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English (en)
Japanese (ja)
Inventor
吉武　誠
健太 西村
真由子 沖
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Yutoku Pharmaceutical Industries Co Ltd
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Yutoku Pharmaceutical Industries Co Ltd
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Priority to PCT/JP2013/066158 priority Critical patent/WO2014199455A1/fr
Publication of WO2014199455A1 publication Critical patent/WO2014199455A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/13—Amines
    • 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
    • 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 memantine transdermal absorption patch preparation, and more particularly to a memantine transdermal absorption patch preparation that can effectively prevent a decrease in memantine content due to volatilization.
  • Memantine is an N-methyl-D-aspartate (NMDA) receptor inhibitor and is currently used as a therapeutic agent for Alzheimer-type dementia in clinical settings.
  • NMDA N-methyl-D-aspartate
  • the NMDA receptor is involved in the development of neurotoxicity by glutamate, and inhibition of this receptor by memantine can suppress the loss of neurons in patients with Alzheimer-type dementia and delay the progression of the disease state It is said that.
  • Memantine preparations currently on the market are memantine hydrochloride tablets, which are prescribed to Alzheimer type dementia patients under trade names such as “Namenda” and “MEMARY”.
  • Patent Documents 1 to 3 are examples of patients with Alzheimer-type dementia.
  • Patent Document 1 discloses a transdermal preparation containing memantine or a pharmaceutically acceptable salt thereof in an adhesive composition such as an acrylic polymer or a rubber polymer.
  • Patent Document 1 discloses that when memantine is used as a pharmaceutically acceptable acid addition salt, a memantine acid addition salt is added by adding a base to the preparation in order to obtain high skin permeability of memantines. It is described that it is preferable to add them.
  • Patent Documents 2 and 3 describe a so-called reservoir-type transdermal therapeutic system in which an adhesive layer is combined with an active substance layer containing an active ingredient such as memantine hydrochloride in a polymer matrix such as polyacrylate or silicone polymer. Is disclosed. Among these, Patent Document 3 describes that when a pharmaceutically acceptable salt of memantine is contained, a base such as an organic base or an inorganic base is contained in order to make memantine free base. .
  • memantine which is an oral preparation
  • memantine hydrochloride is water-soluble, it is extremely difficult to dissolve in oily adhesives such as acrylic adhesives and rubber adhesives that are commonly used as adhesive bases in transdermal patch preparations. It is. Furthermore, even if memantine hydrochloride can be dissolved in the oil-based adhesive, there is a problem that the memantine salt crystallizes and precipitates over time.
  • the present inventors tried to produce a memantine-containing transdermal absorption patch preparation using memantine hydrochloride as a drug and adopting a matrix type that is relatively easy to produce than the reservoir type and has a low production cost. It was found that in the state of commercially available memantine hydrochloride as it is, crystals were deposited in the drug-containing pressure-sensitive adhesive layer, causing problems such as a decrease in adhesive strength and a decrease in percutaneous absorption.
  • a matrix-type transdermal absorption patch preparation in which memantine hydrochloride is further neutralized with a base, etc., and crystal precipitation of memantine hydrochloride is suppressed during production or preparation, and the transdermal absorbability of memantine is improved. Attempting to manufacture, it was found that in this case, another problem of reduction in drug content due to volatilization of memantine (free body) occurred.
  • the present invention has been made in the above circumstances, and its problem is a matrix-type transdermal absorption patch preparation containing memantine or a pharmaceutically acceptable salt thereof, which suppresses volatilization of memantine at the time of manufacture.
  • the object is to provide a transdermal absorption patch preparation.
  • the present inventors have conducted intensive research. As a result, the above-mentioned problems can be solved by including a pressure-sensitive adhesive composition containing a free carboxyl group and / or a phenolic hydroxyl group in the drug-containing layer. The inventors have found that this can be solved and completed the present invention.
  • the present invention relates to a percutaneously absorbable patch preparation comprising at least a support, a drug-containing layer and a release liner, and memantine or a pharmaceutically acceptable salt thereof, a free carboxyl group and / or a phenolic substance in the drug-containing layer.
  • a transdermally absorbable patch preparation comprising a pressure-sensitive adhesive composition containing a hydroxyl group.
  • the present invention also provides the transdermal absorption, wherein the drug-containing layer contains at least one adhesive base selected from the group consisting of a rubber-based adhesive base, an acrylic polymer, and a silicone-based polymer as a base component. It is a mold patch preparation.
  • the present invention is the above-mentioned transdermal patch preparation containing a memantine mixture of a pharmaceutically acceptable salt and a base as memantine.
  • the present invention provides a drug comprising a support and memantine or a pharmaceutically acceptable salt thereof and a pressure-sensitive adhesive composition containing a free carboxyl group and / or a phenolic hydroxyl group on the skin of an Alzheimer type dementia patient.
  • a method for delaying the progression of Alzheimer-type dementia comprising pasting a transdermal absorption patch preparation comprising a containing layer.
  • the percutaneous absorption type patch preparation of the present invention is a patch preparation that can improve the difficulty in taking due to dysphagia, which is a problem with oral preparations, by applying it to the skin of a patient.
  • a certain amount of free carboxyl group and / or phenolic hydroxyl group is contained in the drug-containing layer of the patch preparation against the decrease in memantine content due to volatilization of memantine (free form) during production
  • the present inventors have found for the first time that it is effective to contain a pressure-sensitive adhesive composition. As a result, it was possible to produce a preparation with no decrease in content with good reproducibility, and it was possible to store the preparation for a long time.
  • the transdermally absorbable patch preparation of the present invention includes that the blood concentration of memantine can be controlled, and it can be easily administered in a smaller amount than necessary for the development of drug efficacy and side effects. Even if an undesirable effect appears, the administration can be stopped immediately by removing the patch preparation. Therefore, the transdermally absorbable patch preparation of the present invention is an excellent preparation from the viewpoint of safety as compared with oral preparations and the like.
  • the transdermal absorption type patch preparation of the present invention is a matrix type preparation composed of at least a support, a drug-containing layer and a release liner.
  • memantine or a pharmaceutically acceptable salt thereof as an active ingredient and a pressure-sensitive adhesive composition containing a free carboxyl group and / or a phenolic hydroxyl group are contained in the drug-containing layer.
  • the transdermal absorption patch preparation is a medical adhesive patch preparation, which is attached to the skin and means that a therapeutically effective amount of an active ingredient reaches the bloodstream through the skin.
  • Memantine used as an active ingredient in the drug-containing layer of the transdermally absorbable patch preparation of the present invention has the chemical name 1-amino-3,5-dimethyladamantane. As described above, the compound is used as a therapeutic agent for Alzheimer-type dementia in clinical settings.
  • Examples of the pharmaceutically acceptable salt of memantine include acid addition salts of memantine and inorganic acid or organic acid, and hydrochloride, hydrobromide, nitrate, phosphate, sulfate, acetate, Ascorbate, benzoate, cinnamate, citrate, formate, fumarate, glutamate, lactate, maleate, malate, malonate, mandelate, methanesulfonate ( Mesylate), phthalate, salicylate, stearate, succinate, tartrate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), etc. Is not to be done.
  • the pharmaceutically acceptable salt of memantine may be used, or a memantine free form may be used.
  • memantine hydrochloride is a drug that has been used as an oral preparation for suppressing the progression of dementia symptoms in Alzheimer-type dementia, and is preferable.
  • the drug-containing layer of the patch preparation of the present invention must contain a therapeutically effective amount of memantine or a pharmaceutically acceptable salt thereof.
  • a certain amount of the active ingredient in the drug-containing layer is added. It is important to include.
  • the drug concentration in the pressure-sensitive adhesive layer of the patch preparation of the present invention is about 1 to 50% by mass (hereinafter simply referred to as “%”), preferably 5 to 40%, based on the whole pressure-sensitive adhesive layer. If it is less than 1%, the therapeutic effect may not be sufficient. If it is more than 50%, the content of the pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer may be low, and sufficient skin adhesiveness may not be obtained. It is also economically disadvantageous.
  • a memantic acid addition salt can be neutralized by adding a base in advance during the preparation of the patch preparation or in the preparation.
  • a base and neutralizing the acid addition salt of memantine By adding a base and neutralizing the acid addition salt of memantine as described above, free memantine can be obtained, and crystal precipitation derived from memantine such as memantine acid addition salt can be suppressed.
  • the base used for this purpose include potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, organic amine derivatives (such as diethylamine) and the like, which are generally used as neutralizing agents. Among them, sodium hydroxide is more preferable.
  • the required amounts of memantine hydrochloride and sodium hydroxide are added to the transdermal patch of the present invention. It is preferable to mix just before manufacture.
  • the blending amount of the base may be an amount that can suppress the precipitation of crystals derived from memantine, and is preferably 0.1 to 10%, preferably 0.9 to 8% with respect to the entire pressure-sensitive adhesive layer. More preferably.
  • the drug-containing layer of the patch preparation of the present invention contains a carboxyl group in a free state (hereinafter referred to as “free carboxyl group”) and / or a phenolic hydroxyl group in order to suppress memantine volatilization during production or in the preparation.
  • An adhesive composition (hereinafter referred to as “carboxyl group-containing adhesive composition”) is contained.
  • this carboxyl group-containing pressure-sensitive adhesive composition is not particularly limited, it is generally one or two materials such as a pressure-sensitive adhesive component, a tackifier, a plasticizer, and an excipient that are generally used for pressure-sensitive adhesives. It is preferable to be comprised by the above.
  • carboxyl group-containing pressure-sensitive adhesive composition examples include pressure-sensitive adhesive compositions containing an acrylic polymer, a tackifying resin, a rubber-based pressure-sensitive adhesive component, and the like, and among them, an acrylic pressure-sensitive adhesive containing a free carboxyl group Or a (meth) acrylic acid copolymer containing a free carboxyl group, a rosin resin containing a free carboxyl group and / or a phenolic hydroxyl group, a maleic acid resin, a phenol resin or a modified product thereof, and a rubber system containing a free carboxyl group
  • an adhesive component is preferable, it is not particularly limited to these, and one or more of these are used.
  • the acrylic pressure-sensitive adhesive containing the free carboxyl group (hereinafter sometimes referred to as “carboxyl group-containing acrylic pressure-sensitive adhesive”) is at least a (meth) acrylic acid ester having a free carboxyl group in the side chain in the monomer structural unit. It is not particularly limited as long as it is a polymer or copolymer having one kind of constituent monomer.
  • (meth) acrylic acid / (meth) alkyl acrylate copolymer examples include alkyl acrylate / vinyl acetate copolymer, and specifically acrylic acid / 2-ethylhexyl acrylate copolymer, acrylic acid / butyl acrylate copolymer, acrylic acid / octyl acrylate copolymer , Acrylic acid / acrylic acid-2-ethylhexyl / vinyl acetate copolymer, methyl acrylate / methacrylic acid Copolymers, n- butyl methacrylate copolymer, acrylic acid, methacrylic acid-methyl methacrylate copolymer and the like.
  • DURO-TAK acrylic pressure-sensitive adhesive series (manufactured by Henkel Japan), carboxyl group-containing types (DURO-TAK (registered trademark) 87-2194, 87-2052, 87 -2051, 87-2054, 87-2777, 87-2196, 87-2825 (acrylic acid / vinyl acetate copolymer), 87-235A, 87-2353, 87-207A, 87-2100, 87-210A, 87 -2852 (acrylic acid polymer), etc.) and hydroxyl group / carboxyl group-containing type (DURO-TAK (registered trademark) 87-2979 (acrylic acid / vinyl acetate copolymer), 87-2074 (acrylic acid polymer), etc.) , HiPAS10, HiPAS-MS10, HiPAS-HGA and MASCOS10 Cosmetics di Pharmaceutical Co., Ltd.), and the like.
  • the (meth) acrylic acid copolymer containing the free carboxyl group (hereinafter sometimes referred to as “carboxyl group-containing (meth) acrylic acid copolymer”) has a free carboxyl group on the side chain in the monomer structural unit.
  • the copolymer is not particularly limited as long as it is a copolymer having at least one (meth) acrylic ester contained therein as a constituent monomer.
  • the tackifying resin containing a free carboxyl group and / or a phenolic hydroxyl group (hereinafter sometimes referred to as “carboxyl group / hydroxyl group-containing tackifying resin”) is not particularly limited thereto.
  • pine crystal series of ultra-light rosin ester (KE-311 (acid value 2 to 10), KE-100 (acid value 2 to 10), KE-359 (acid value 10 to 20).
  • KE-604 (acid number 230 to 245), KR-85 (acid number 165 to 175), KR-612 (acid number 165 to 175), KR-614 (acid number 170 to 180), etc.)
  • maleic acid Resin marquide series No.
  • the above-mentioned rubber-based adhesive component containing a free carboxyl group (hereinafter sometimes referred to as “carboxyl group-containing rubber-based adhesive component”) is not particularly limited, but liquid polybutadiene, liquid poly Liquid rubbers such as isoprene and liquid polybutene, synthetic rubbers such as acrylonitrile / butadiene rubber, block copolymers, natural rubbers and the like can be used.
  • an acid value measuring method can be used as a method of confirming content of the free carboxyl group and / or phenolic hydroxyl group in an adhesive composition.
  • the acid value measurement method is performed by the following method according to the method of the Japanese Pharmacopoeia.
  • About 1 to 3 g of the sample is accurately weighed in a 100 mL Erlenmeyer flask and dissolved in about 40 mL of a mixed solution of ethanol / toluene (1: 2). Titrate with 0.5 mol / L potassium hydroxide (ethanol solution) using phenolphthalein as an indicator. When the slight red color does not disappear for 30 seconds, the end point of neutralization is set, and the acid value is calculated by the following formula.
  • Acid value (a ⁇ f ⁇ 28.05) / sample (g) a: Titration volume of 0.5 mol / L potassium hydroxide (ethanol solution) (mL) f: Potency of 0.5 mol / L potassium hydroxide (ethanol solution)
  • the carboxyl group-containing pressure-sensitive adhesive composition used in the patch preparation of the present invention preferably has an acid value of 2 or more measured by the above method.
  • the content thereof is preferably 4 to 99%, more preferably 11 to 95% with respect to the drug-containing layer. If it is less than 4%, the memantine volatilization inhibitory effect may not be observed, while if it exceeds 99%, the therapeutic effect of memantine may not be sufficient.
  • the content thereof is preferably 0.1 to 30%, more preferably 1 to 15% with respect to the drug-containing layer. Range. If it is less than 0.1%, the memantine volatilization inhibitory effect may not be observed, while if it exceeds 30%, it may be difficult to maintain good physical properties of the patch preparation.
  • the content thereof is preferably 0.4 to 70%, more preferably 2 to 50% with respect to the drug-containing layer. It is. If it is less than 0.4%, the memantine volatilization inhibitory effect may not be observed. On the other hand, if it exceeds 70%, it may be difficult to maintain good physical properties of the patch preparation.
  • the transdermal patch preparation of the present invention is a matrix-type patch preparation comprising a support and a release liner in addition to the above-mentioned drug-containing layer. Since the matrix-type patch preparation is easy to design and is not a complicated structure like a reservoir-type patch preparation, the cost for manufacturing the patch preparation can be reduced.
  • the carboxyl group-containing pressure-sensitive adhesive composition used in the patch preparation of the present invention includes the above-described carboxyl group-containing acrylic pressure-sensitive adhesive, carboxyl group-containing (meth) acrylic acid copolymer, carboxyl group / hydroxyl group-containing tackifier resin, and carboxyl group-containing
  • the rubber-based pressure-sensitive adhesive component can be prepared by combining one or two or more of them and, if necessary, adding another pressure-sensitive adhesive component or another tackifier and homogenizing it.
  • a release-controlling film or the like may be formed on the skin-attached side of the drug-containing layer in order to control the percutaneous absorption of the active ingredient.
  • adhesive components that can be used in the preparation of the adhesive preparation of the present invention for the preparation of a pressure-sensitive adhesive composition containing a carboxyl group and the like include rubber-based adhesive components, acrylic polymers, and silicone polymers that are generally used in adhesive preparations. 1 type selected from these, or a combination of two or more types.
  • rubber-based adhesive components include styrene / isoprene / styrene block copolymers, styrene / butadiene / styrene block copolymers, styrene / butadiene rubber, polyisobutylene, polybutene, polybutene, which do not contain free carboxyl groups.
  • styrene / isoprene / styrene block copolymers styrene / butadiene / styrene block copolymers
  • styrene / butadiene rubber polyisobutylene
  • polybutene polybutene
  • One or two or more types selected from isoprene, butyl rubber, natural rubber, synthetic rubber and isoprene rubber can be used, and these can be used.
  • a polymer containing at least one (meth) acrylic ester other than an acrylic polymer containing a free carboxyl group or a copolymer thereof can be used.
  • DURO-TAK registered trademark
  • Acrylic pressure-sensitive adhesive series produced by Henkel Japan
  • DURO-TAK registered trademark
  • Functional group-free type DURO-TAK (registered trademark) 87-900A, 87-901A, 87-9301, 87-4098, 87-9086, etc.
  • MAS811B manufactured by Cosmed Pharmaceutical
  • Eudragit registered trademark
  • acrylic acid Copolymer series Evonik Degussa Japan
  • Udragit (R) E100, EPO, RL100, RLP0 can be used RS100,
  • silicone polymer examples include polysiloxane derivatives (for example, silicon polymers such as polydimethylsiloxane and amine-resistant polydimethylsiloxane).
  • examples of other tackifiers used in the preparation of a carboxyl group-containing pressure-sensitive adhesive composition include, for example, a glycerin ester of rosin that does not contain a free carboxyl group and / or a phenolic hydroxyl group, and a glycerin ester of a hydrogenated rosin.
  • Rosin derivatives maleic resin, phenolic resin, petroleum resin, terpene resin, epoxy resin, urethane resin, polyester resin, ketone formamide resin, cresol resin, xylene resin, diallyl phthalate resin, styrene resin, guanamine resin, acrylic resin, polyolefin Resin or modified products thereof, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethyl cellulose Scan, hydroxypropyl cellulose, hypromellose, polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, polyvinyl alcohol and the like.
  • the amount of other tackifiers to be blended is 0 to 47% with respect to the drug-containing layer in consideration of sufficient skin adhesion.
  • the drug-containing layer of the medicated patch of the present invention is preferably a non-aqueous system that does not substantially contain water.
  • the drug-containing layer in the patch preparation of the present invention may contain a plasticizer, an excipient, a cross-linking agent, a colorant, an ultraviolet absorber, You may mix
  • Plasticizers include petroleum oils such as paraffinic process oil, naphthenic process oil, aromatic process oil, liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, and isopropyl linoleate.
  • excipients include acrylic acid copolymers, water-soluble polymers such as polyvinylpyrrolidone, starch derivatives such as cyclodextrin, saccharides such as sorbitol, cellulose derivatives such as hydroxypropylcellulose, talc, titanium dioxide, and the like.
  • crosslinking agent examples include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds.
  • Colorants include indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitive element 201, Kumazasa extract, black iron oxide, ketket, zinc oxide, titanium oxide, iron sesquioxide, amaranth, hydroxide
  • Examples thereof include sodium, talc, copper chlorophyllin sodium, green leaf extract, d-borneol, octyldodecyl myristate, methyl rosaniline chloride, methylene blue, manganese ammonium phosphate, and rose oil.
  • UV absorbers include amino acid compounds such as urocanic acid, benzophenone compounds such as 2,4-dihydroxybenzophenone and 2-hydroxy-4-n-octoxybenzophenone, cinnamic acid such as sinoxate and diethanolamine p-methoxycinnamate.
  • amino acid compounds such as urocanic acid
  • benzophenone compounds such as 2,4-dihydroxybenzophenone and 2-hydroxy-4-n-octoxybenzophenone
  • cinnamic acid such as sinoxate and diethanolamine p-methoxycinnamate.
  • cyanoacrylate derivatives such as 2-ethylhexyl-2-cyano-3,3'-diphenylacrylate
  • p-aminobenzoic acid derivatives such as ethyl p-aminobenzoate and propyl p-aminobenzoate, anthranilate menthyl ester, etc.
  • Anthranilic acid derivatives such as phenyl salicylate and p-octylphenyl salicylate, and coumarin derivatives such as 7-ethylamino-4-methylcoumarin and 7,8-dihydroxycoumarin.
  • Antioxidants include phenolic antioxidants, ascorbic acid, its ester derivatives, sodium bisulfite, sodium pyrosulfite, sodium edetate, citric acid, potassium diisocyanurate, soybean lecithin, thymol, tocopherol and its ester derivatives 1,3-butylene glycol, benzotriazole, monothioglycerin and the like.
  • the percutaneous absorption enhancer may be any compound that has been conventionally recognized to have an absorption promoting effect upon transdermal administration.
  • alkanolamines such as diisopropanolamine and triisopropanolamine, isopropyl myristate, octyldodecyl myristate , Fatty acid esters such as glycerin oleic acid monoester and hexadecyl isostearate, alcohols such as oleyl alcohol, propylene glycol and polyethylene glycol monooleate or ethers thereof, sorbitan such as sorbitan monolaurate and sorbitan monooleate Esters or ethers, phenol ethers such as polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether, castor oil
  • ionic surfactants such as hydrogenated castor oil, oleoyl sarcosine, lauryl dimethylamin
  • the blending amount is in the range of 0.1 to 15%, preferably 1 to 10% with respect to the drug-containing layer. If it is less than 0.1%, the skin permeation promoting effect is not recognized, which is not preferable. If the amount exceeds 15%, skin irritation derived from the percutaneous absorption enhancer is likely to develop, and the physical properties of the preparation are lowered, resulting in a sticky feeling.
  • examples of the support supporting the drug-containing layer include a drug-impermeable, stretchable or non-stretchable support.
  • examples of such a support include, for example, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), nylon, polyurethane, and other synthetic resin films or sheets, or laminates thereof.
  • Examples include porous bodies, foams, paper, woven fabrics, and nonwoven fabrics.
  • a drug-impermeable release liner can be used as the release liner to be bonded to the drug-containing layer.
  • the release liner include a film made of a polymer material such as polyethylene, polypropylene, and polyester, a film in which aluminum is vapor-deposited on a film, and a film in which silicone oil is coated on paper. .
  • a polyester film is preferable from the viewpoints of no penetration of active ingredients, processability and low cost, and a polyethylene terephthalate (PET) film is particularly preferable.
  • PET polyethylene terephthalate
  • the release liner may be a laminate film obtained by bonding a plurality of materials.
  • the said carboxyl group etc. containing adhesive composition used with this invention patch preparation has preferable adhesiveness, what has low adhesiveness can also be used.
  • an adhesive layer may be added to the patch preparation separately.
  • a release control film or the like may be formed on the skin-attached side of the drug-containing layer in order to control the percutaneous absorption of the active ingredient.
  • the production of the patch preparation of the present invention is not particularly limited, and can be produced according to a known method.
  • a preferable production method for producing the patch preparation of the present invention for example, the following methods can be mentioned. That is, an active ingredient such as memantine and a carboxyl group-containing pressure-sensitive adhesive composition, and if necessary, additional components such as a transdermal absorption enhancer are dissolved in an organic solvent such as ethyl acetate, hexane, toluene or a mixed solvent thereof, The dissolved product is spread on a release liner or a support, the solvent in the solution is evaporated to form a drug-containing layer, and finally the support or the release liner is bonded to the transdermal absorption type patch preparation.
  • the method of obtaining can be mentioned.
  • an adhesive component containing memantine and a carboxyl group as active ingredients and, if necessary, additional components such as a transdermal absorption enhancer are heated and melted, and this melt is then used as a release liner.
  • a method of obtaining a patch preparation by spreading on a support and forming a drug-containing layer and then bonding the support or a release liner can be mentioned.
  • the administration method of memantine using the patch preparation of the present invention described above is as follows. That is, the drug-containing layer side of the patch preparation may be attached to the skin of a patient with Alzheimer-type dementia and attached for a predetermined time. In this way, memantine is absorbed from the skin, which can delay the progression of Alzheimer's disease pathology in the patient.
  • Example 1 According to the blending ratio shown in Table 1, a methanol solution of sodium hydroxide (0.12 g / mL) was added to memantine hydrochloride, and after stirring and mixing, DURO-TAK (registered trademark) 87-2194 (from Henkel Japan) Obtained) and DURO-TAK (registered trademark) 87-9301 were added and mixed by stirring to obtain a uniform dissolved product. Next, using a doctor knife coating machine, this melt is spread on a release film (silicone-treated PET film, manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after drying is 100 ⁇ m, and is dried. After the drug-containing layer was formed, a support (PET film, manufactured by Fujimori Kogyo) was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation (Patch preparation 1).
  • DURO-TAK registered trademark
  • 87-2194 from Henkel Japan
  • transdermal absorption patch preparations (Patch preparations 2 to 10) were obtained in the same manner as in Example 1.
  • Example 11 According to the blending ratio shown in Table 2, a methanol solution of sodium hydroxide (0.12 g / mL) was added to memantine hydrochloride and mixed with stirring, and then DURO-TAK (registered trademark) 87-2194 was added and mixed with stirring. As a result, a uniform dissolved product was obtained. Next, this dissolved material is spread on a release film using a doctor knife coating machine so that the thickness after drying becomes 100 ⁇ m, and after drying to form a drug-containing layer, the support is bonded. It was. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation (Patch preparation 11).
  • DURO-TAK registered trademark
  • transdermal absorption patch preparations (Patch preparations 12 to 16) were obtained in the same manner as in Example 11.
  • Example 17 According to the blending ratio shown in Table 2, transdermal absorption type patch was applied in the same manner as in Example 1 except that DURO-TAK (registered trademark) 87-2194 was used instead of DURO-TAK (registered trademark) 87-2194. A preparation (Patch preparation 17) was obtained.
  • Example 18 According to the blending ratio shown in Table 2, transdermal absorption type patch was applied in the same manner as Example 11 except that DURO-TAK (registered trademark) 87-2194 was used instead of DURO-TAK (registered trademark) 87-2194. A preparation (patch preparation 18) was obtained.
  • Example 19 According to the blending ratio shown in Table 3, a methanol solution of sodium hydroxide (0.12 g / mL) was added to memantine hydrochloride, and after stirring and mixing, Eudragit (registered trademark) S100 (obtained from Evonik Degussa Japan) Of methanol (0.1 g / mL) was added and mixed with stirring. To this, DURO-TAK (registered trademark) 87-9301 was added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved material is spread on a release film using a doctor knife coating machine so that the thickness after drying becomes 100 ⁇ m, and after drying to form a drug-containing layer, the support is bonded. It was. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation (Patch preparation 19).
  • transdermal absorption patch preparations (Patch preparations 20 to 25) were obtained in the same manner as in Example 19.
  • transdermal absorption patch preparations (Patch preparations 26 to 30) were obtained in the same manner as in Example 19.
  • Comparative Example 1 According to the blending ratio shown in Table 4, a methanolic solution of sodium hydroxide (0.12 g / mL) was added to memantine hydrochloride, and after stirring and mixing, DURO-TAK (registered trademark) 87-9301 was added and stirred and mixed. A homogeneous lysate was obtained. Next, this dissolved material was spread on a release film (silicone-treated PET film, manufactured by Fujimori Kogyo Co., Ltd.) using a doctor knife coating machine so that the thickness after drying was 100 ⁇ m, and dried. After the drug-containing layer was formed, a support (PET film, manufactured by Fujimori Kogyo) was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation (Comparative preparation 1).
  • a release film silicone-treated PET film, manufactured by Fujimori Kogyo Co., Ltd.
  • Comparative Example 2 According to the blending ratio shown in Table 4, a transdermal absorption patch preparation (Comparative preparation 2) was obtained in the same manner as in Comparative Example 1.
  • Example 31 According to the blending ratio shown in Table 5, a methanol solution of sodium hydroxide (0.12 g / mL) was added to memantine hydrochloride, and after stirring and mixing, a styrene-isoprene-styrene block copolymer (Clayton D-KX401CS, JSR) A pressure-sensitive adhesive prepared by stirring and mixing ultra-light rosin ester (Pine Crystal KE-311, acid value 2 to 10) in toluene was added and mixed by stirring to obtain a uniform dissolved product.
  • a methanol solution of sodium hydroxide (0.12 g / mL) was added to memantine hydrochloride, and after stirring and mixing, a styrene-isoprene-styrene block copolymer (Clayton D-KX401CS, JSR)
  • a pressure-sensitive adhesive prepared by stirring and mixing ultra-light rosin ester (Pine Crystal KE-311, acid
  • this dissolved material is spread on a release film using a doctor knife coating machine so that the thickness after drying becomes 100 ⁇ m, and after drying to form a drug-containing layer, the support is bonded. It was. And it cut
  • Example 32 According to the blending ratio shown in Table 5, a methanol solution of sodium hydroxide (0.12 g / mL) was added to memantine hydrochloride, and after stirring and mixing, styrene-isoprene-styrene block copolymer, polyisoprene (Nipol ( (Registered trademark) IR2200 (manufactured by Nippon Zeon), polybutene (HV-300F, manufactured by JX Nippon Mining & Energy) and ultralight rosin ester (Pine Crystal KE-311, acid value 2 to 10) in toluene with stirring and mixing Were added and mixed with stirring to obtain a uniform dissolved product.
  • Nipol (Registered trademark) IR2200 (manufactured by Nippon Zeon)
  • HV-300F polybutene
  • ultralight rosin ester Pine Crystal KE-311, acid value 2 to 10.
  • this dissolved material is spread on a release film using a doctor knife coating machine so that the thickness after drying becomes 100 ⁇ m, and after drying to form a drug-containing layer, the support is bonded. It was. And it cut
  • transdermal absorption patch preparations (Patch preparations 33 and 34) were obtained in the same manner as Example 32.
  • Example 35 According to the blending ratio shown in Table 5, after adding methanol solution of sodium hydroxide (0.12 g / mL) to memantine hydrochloride and stirring and mixing, styrene-isoprene-styrene block copolymer, polyisoprene, polybutene, A pressure-sensitive adhesive in which acid-modified ultra-light rosin (Pine Crystal KE-604, acid value 230 to 245, Arakawa Chemical Industries) and alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa Chemical Industries) are stirred and mixed in toluene. The mixture was stirred and mixed to obtain a uniform dissolved product.
  • acid-modified ultra-light rosin Pine Crystal KE-604, acid value 230 to 245, Arakawa Chemical Industries
  • alicyclic saturated hydrocarbon resin Arcon P-100, Arakawa Chemical Industries
  • this dissolved material is spread on a release film using a doctor knife coating machine so that the thickness after drying becomes 100 ⁇ m, and after drying to form a drug-containing layer, the support is bonded. It was. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation (Patch preparation 35).
  • Example 36 According to the blending ratio shown in Table 5, a transdermal absorption patch preparation (Patch preparation 36) was obtained in the same manner as in Example 35.
  • Examples 37 and 38 In accordance with the blending ratios shown in Table 5, instead of ultra-light rosin ester (Pine Crystal KE-604, acid value 230-245), ultra-light rosin (Pine Crystal KR-85, acid value 165-175, Arakawa Chemical Industries) Except for the use, transdermal absorption patch preparations (Patch preparations 37 and 38) were obtained in the same manner as in Example 35.
  • Examples 39 and 40 According to the blending ratio shown in Table 5, instead of ultra-light rosin ester (Pine Crystal KE-604, acid value 230 to 245), maleic resin (Marquide No. 33, acid value 290 to 320, Arakawa Chemical Industries) is used. Except for the above, transdermal absorption patch preparations (Patch preparations 39 and 40) were obtained in the same manner as in Example 35.
  • transdermal absorption patch preparations (patent preparations 41 to 43) were obtained in the same manner as in Example 39.
  • Examples 44 to 46 According to the blending ratio shown in Table 6, an alkylphenol resin (Tamanol 100S, acid value 85-100, Arakawa Chemical Industries) was used instead of ultra-light rosin ester (Pine Crystal KE-604, acid value 230-245). Except for the above, transdermal absorption patch preparations (patch preparations 44 to 46) were obtained in the same manner as in Example 35.
  • Example 47 According to the blending ratio shown in Table 6, terpene phenol resin (Tamanol 803L, acid value 145 to 160, Arakawa Chemical Industries) was used instead of ultra-light rosin ester (Pine Crystal KE-604, acid value 230 to 245) Except for, a transdermal absorption patch preparation (Patch preparation 47) was obtained in the same manner as in Example 35.
  • Example 48 According to the mixing ratio shown in Table 6, except that terpene phenol resin (Tamanol 803L, acid value 145 to 160) was used instead of ultra-light rosin ester (Pine Crystal KE-311, acid value 2 to 10) In the same manner as in Example 32, a transdermal absorption patch preparation (Patch preparation 48) was obtained.
  • Example 49 According to the mixing ratio shown in Table 6, except that terpene phenol resin (Tamanol 803L, acid value 145 to 160) was used instead of ultra-light rosin ester (Pine Crystal KE-311, acid value 2 to 10) As in Example 31, a transdermal absorption patch preparation (Patch preparation 49) was obtained.
  • Example 50 According to the blending ratio shown in Table 6, a transdermal absorption patch preparation (Patch preparation 50) was obtained in the same manner as in Example 48.
  • Comparative Example 3 According to the blending ratio shown in Table 6, after adding a methanolic solution of sodium hydroxide (0.12 g / mL) to memantine hydrochloride and stirring and mixing, styrene-isoprene-styrene block copolymer, polyisoprene, polybutene and A pressure-sensitive adhesive prepared by stirring and mixing an alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa Chemical Industries) in toluene was added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved material is spread on a release film using a doctor knife coating machine so that the thickness after drying becomes 100 ⁇ m, and after drying to form a drug-containing layer, the support is bonded. It was. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation (Comparative preparation 3).
  • Example 51 Instead of DURO-TAK (registered trademark) 87-2194, DURO-TAK (registered trademark) 87-2051, 87-2054, 87-2677, 87-2196, 87-2825, 87-235A, 87-2353, 87- 207A, 87-2100, 87-210A, 87-2852, 87-2979, 87-2074, HiPAS10, HiPAS-MS10, HiPAS-HGA or MASCOS10 and corresponding transdermal absorption patch preparation as in Example 12 Get.
  • DURO-TAK registered trademark
  • 87-2051, 87-2054, 87-2677, 87-2196 87-2825, 87-235A, 87-2353, 87- 207A, 87-2100, 87-210A, 87-2852, 87-2979, 87-2074
  • HiPAS10, HiPAS-MS10, HiPAS-HGA or MASCOS10 and
  • Example 52 Using Eudragit (registered trademark) L100 instead of Eudragit (registered trademark) S100, the corresponding transdermal absorption patch preparation is obtained in the same manner as in Example 23.
  • Example 53 Super light rosin ester (Pine Crystal KE-100, acid value 2-10) instead of super light rosin ester (Pine Crystal KE-604, acid value 230 to 245), Ultra light rosin ester (Pink Crystal KE-359, Acid value 10-20), ultra-light rosin (Pine Crystal KR-612, acid value 165-175), ultra-light rosin (Pine Crystal KR-614, acid value 170-180), styrene maleic resin (Alastar 700, acid) 175 to 200), polymerized rosin (Aradim R-140, acid value 140 or more), polymerized rosin (Aradim R-95, acid value 158 to 168) or rosin-modified phenol resin (Tamanol 135, oxidation 18 or less), The corresponding transdermal absorption patch preparation is obtained in the same manner as in Example 35.
  • Test example 1 Patch preparations 2 to 10, Patch preparations 12 to 13, Patch preparations 17 to 18, Patch preparations 20 to 28, Patch preparations 32 to 33, Patch preparations 35 to 43, Patch preparations 45 to 46, and Comparative preparations 1 to 3 are as follows. The memantine content after storage for 2 days at room temperature was measured by the measurement method described above. The results are shown in Tables 7 and 8.
  • the supernatant was quantified by post-column fluorescence derivatization high performance liquid chromatography using o-phthalaldehyde / N-acetylcysteine as a reaction reagent.
  • the conditions for quantitative measurement are as follows.
  • Test example 2 Patch preparations 2 to 10, Patch preparations 12 to 13, Patch preparations 17 to 18, Patch preparations 20 to 28, Patch preparations 32 to 33, Patch preparations 35 to 43, Patch preparations 45 to 47, Patch preparations 50 and Comparative preparations 1 to About 3, adhesive force was measured with the following method. These results are also shown in Tables 7 and 8.
  • patch preparations 22 to 28 containing 1% or more of a carboxyl group-containing methacrylic acid copolymer (Eudragit (registered trademark) S100) with respect to the drug-containing layer have memantine content within ⁇ 4% of the theoretical value. Was within 1%.
  • the carboxyl group / hydroxyl group-containing tackifier resin was tested using five types of tackifier resins having different acid values.
  • a patch preparation 32 containing 2% or more of a carboxyl group / hydroxyl group-containing tackifier resin (Pine Crystal KE-311, Pine Crystal KE-604, Pine Crystal KR-85, Marquide No. 33 or Tamanol 100S) with respect to the drug-containing layer.
  • patch preparations 35-38, patch preparations 41-43 and patch preparations 45-46 the memantine content was within ⁇ 5% of the theoretical value, and the variation was also within 1%.
  • patch preparations 2 to 10, patch preparations 12 to 15, patch preparations 17 to 15 containing an adhesive composition containing a carboxyl group and / or a phenolic hydroxyl group were obtained.
  • the adhesive preparations 20 to 28, the adhesive preparations 32 to 33, the adhesive preparations 35 to 43, the adhesive preparations 45 to 47, and the adhesive preparation 50 were generally good in adhesive strength.
  • the physical properties of the patch preparation are impaired when a certain amount of a pressure-sensitive adhesive composition containing a free carboxyl group and / or a phenolic hydroxyl group is added to suppress memantine volatilization. Thus, it was revealed that a preparation having good adhesive strength was obtained.
  • the transdermally absorbable patch preparation of the present invention is a matrix-type patch preparation containing memantine and a pressure-sensitive adhesive composition containing a free carboxyl group and / or a phenolic hydroxyl group. It is a new medicated patch that suppresses volatilization of memantine during storage or storage.
  • the percutaneous absorption type patch preparation of the present invention can store the preparation for a long time, suppresses a decrease in adhesive strength over time, and has an effective pharmacological effect as an active ingredient. It can be used continuously. Therefore, the transdermal absorption patch preparation of the present invention is a preparation useful for suppressing the progression of dementia symptoms in Alzheimer's dementia.

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Abstract

La présente invention concerne une préparation sous forme de patch contenant de la mémantine ou son sel pharmaceutiquement acceptable, la préparation sous forme de patch étant produite en inhibant la volatilisation de la mémantine jusqu'à un niveau suffisant. La préparation sous forme de patch à absorption percutanée comprend un support, une couche contenant une substance médicamenteuse, et une protection antiadhésive, et est caractérisée en ce que la couche contenant une substance médicamenteuse comprend à la fois de la mémantine ou son sel pharmaceutiquement acceptable et une composition adhésive sensible à la pression contenant des groupes carboxyle et/ou des groupes hydroxy phénoliques libres.
PCT/JP2013/066158 2013-06-12 2013-06-12 Préparation de mémantine sous forme de patch à absorption percutanée Ceased WO2014199455A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021098791A1 (fr) * 2019-11-20 2021-05-27 成都康弘药业集团股份有限公司 Timbre transdermique contenant de la mémantine
EP3892678A1 (fr) * 2020-04-09 2021-10-13 tesa SE Adhésif sensible à la pression à base de caoutchouc d'acrylonitrile butadiène
CN115397401A (zh) * 2020-04-13 2022-11-25 考司美德制药株式会社 皮肤用粘合片
WO2023033557A1 (fr) * 2021-09-02 2023-03-09 Dong-A St Co., Ltd. Préparation d'absorption percutanée pour le traitement de la démence comprenant de la mémantine énanthate
JP2023050633A (ja) * 2021-09-30 2023-04-11 東洋インキＳｃホールディングス株式会社 貼付剤
CN115957200A (zh) * 2023-02-23 2023-04-14 广州新济药业科技有限公司 一种美金刚透皮贴剂及制备方法

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JP2008520736A (ja) * 2004-11-23 2008-06-19 アマダス ファーマシューティカルズ インコーポレイテッド 持続放出コーティングまたはマトリックスおよびｎｍｄａ受容体アンタゴニストを含む組成物、そのようなｎｍｄａアンタゴニストの被験体への投与方法
JP2009013171A (ja) * 2007-06-07 2009-01-22 Hisamitsu Pharmaceut Co Inc メマンチン含有経皮吸収製剤
JP2011513447A (ja) * 2008-03-11 2011-04-28 エルテーエス ローマン テラピー−ジステーメ アーゲー 安定化された膜を有する経皮治療システム
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JP2007522248A (ja) * 2004-02-13 2007-08-09 ニューロモレキュラー・インコーポレイテッド てんかんおよび他のｃｎｓ障害の処置のための、ｎｍｄａレセプターアンタゴニストと抗てんかん薬との組み合わせ
JP2008520736A (ja) * 2004-11-23 2008-06-19 アマダス ファーマシューティカルズ インコーポレイテッド 持続放出コーティングまたはマトリックスおよびｎｍｄａ受容体アンタゴニストを含む組成物、そのようなｎｍｄａアンタゴニストの被験体への投与方法
JP2009013171A (ja) * 2007-06-07 2009-01-22 Hisamitsu Pharmaceut Co Inc メマンチン含有経皮吸収製剤
JP2011513447A (ja) * 2008-03-11 2011-04-28 エルテーエス ローマン テラピー−ジステーメ アーゲー 安定化された膜を有する経皮治療システム
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Publication number Priority date Publication date Assignee Title
WO2021098791A1 (fr) * 2019-11-20 2021-05-27 成都康弘药业集团股份有限公司 Timbre transdermique contenant de la mémantine
CN112915071A (zh) * 2019-11-20 2021-06-08 成都康弘药业集团股份有限公司 一种含有美金刚的透皮贴剂
EP3892678A1 (fr) * 2020-04-09 2021-10-13 tesa SE Adhésif sensible à la pression à base de caoutchouc d'acrylonitrile butadiène
CN113528057A (zh) * 2020-04-09 2021-10-22 德莎欧洲股份公司 基于丙烯腈-丁二烯橡胶的压敏胶粘剂
CN113528057B (zh) * 2020-04-09 2024-01-30 德莎欧洲股份公司 基于丙烯腈-丁二烯橡胶的压敏胶粘剂
US12319846B2 (en) 2020-04-09 2025-06-03 Tesa Se Pressure-sensitive adhesive based on acrylonitrile butadiene rubbers
CN115397401A (zh) * 2020-04-13 2022-11-25 考司美德制药株式会社 皮肤用粘合片
WO2023033557A1 (fr) * 2021-09-02 2023-03-09 Dong-A St Co., Ltd. Préparation d'absorption percutanée pour le traitement de la démence comprenant de la mémantine énanthate
JP2023050633A (ja) * 2021-09-30 2023-04-11 東洋インキＳｃホールディングス株式会社 貼付剤
JP7812050B2 (ja) 2021-09-30 2026-02-09 ａｒｔｉｅｎｃｅ株式会社 貼付剤
CN115957200A (zh) * 2023-02-23 2023-04-14 广州新济药业科技有限公司 一种美金刚透皮贴剂及制备方法

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