WO2014017595A1 - 貼付剤 - Google Patents
貼付剤 Download PDFInfo
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- WO2014017595A1 WO2014017595A1 PCT/JP2013/070197 JP2013070197W WO2014017595A1 WO 2014017595 A1 WO2014017595 A1 WO 2014017595A1 JP 2013070197 W JP2013070197 W JP 2013070197W WO 2014017595 A1 WO2014017595 A1 WO 2014017595A1
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- WIPO (PCT)
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- adhesive layer
- asenapine
- pressure
- sensitive adhesive
- patch
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- 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
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
-
- 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
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a patch, and more particularly to a patch using asenapine as a drug.
- Asenapine trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-c] pyrrole
- CNS central nervous system
- Asenapine trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-c] pyrrole
- CNS central nervous system
- Asenapine trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-c] pyrrole
- CNS central nervous system
- Patent Document 1 As a preparation containing asenapine, for example, International Publication No. 2010/127474 (Patent Document 1) describes external preparations such as sprays, aerosols, patches, ointments and the like.
- Patent Document 2 describes a transdermal absorption preparation containing a skin irritation inhibitor comprising a cholesterol compound, a drug and a combination drug, and asenapine is mentioned as the drug. It has been.
- the patch containing asenapine in the adhesive layer has a problem that the skin permeability of asenapine is not sufficient, and it is difficult to maintain the plasma concentration of asenapine effective for treatment.
- the present inventors can improve the release of asenapine from the adhesive layer by using a rubber adhesive as the adhesive base of the adhesive layer in the patch containing asenapine. It has been found that it is possible to improve the performance. On the other hand, the present inventors have found that when asenapine and the rubber-based pressure-sensitive adhesive are contained in the pressure-sensitive adhesive layer, the pressure-sensitive adhesive strength of the pressure-sensitive adhesive layer is reduced.
- the present invention has been made in view of the above-mentioned problems of the prior art, and is a patch excellent in the release of asenapine from the adhesive layer and the skin permeability, and having a sufficiently large adhesive force in the adhesive layer.
- the purpose is to provide.
- the present inventors have found that in an adhesive patch comprising a support layer and an adhesive layer, the adhesive layer has an asenapine-free body as a drug, and an adhesive group.
- the combination of a rubber-based pressure-sensitive adhesive as an adhesive and maleic acid alkali salt can sufficiently increase the release of asenapine from the pressure-sensitive adhesive layer and the skin permeability, and asenapine and rubber-based
- the present inventors have found that a sufficient adhesive force can be exhibited by suppressing a decrease in the adhesive force due to the combination with the adhesive, and the present invention has been completed.
- the patch of the present invention is A patch comprising a support layer and an adhesive layer,
- the pressure-sensitive adhesive layer contains an asenapine-free material, an alkali maleate and a rubber-based pressure-sensitive adhesive.
- the mass ratio of the asenapine-free body to the maleic acid alkali salt is 1: 0.1 to 1 : 3 is preferable. Furthermore, in the adhesive patch of the present invention, it is preferable that the content of the rubber adhesive in the adhesive layer is 10 to 50% by mass.
- the rubber-based adhesive is preferably at least one selected from the group consisting of styrene-isoprene-styrene block copolymer, polyisobutylene and silicone rubber.
- the alkali maleate is preferably disodium maleate and / or sodium maleate.
- the asenapine-free body and the alkali maleate are produced from asenapine maleate and an alkali metal ion-containing desalting agent in the pressure-sensitive adhesive layer. Is preferred.
- Example 6 is a graph showing the relationship between the skin permeation rate of asenapine and the elapsed time from application in the patches obtained in Example 1 and Comparative Examples 10 to 12.
- the patch of the present invention is a patch comprising a support layer and a pressure-sensitive adhesive layer, and the pressure-sensitive adhesive layer contains an asenapine-free body, an alkali maleate and a rubber-based pressure-sensitive adhesive.
- the patch of the present invention comprises a support layer and an adhesive layer disposed on at least one surface of the support layer.
- the support layer according to the present invention, conventionally known layers can be used as appropriate.
- the material of such a support layer include polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, vinyl acetate.
- -Synthetic resins such as vinyl chloride copolymers, polyamides such as polyvinyl chloride and nylon, polyesters, cellulose derivatives and polyurethane.
- Examples of the form of the support layer include films; sheets; sheet-like porous bodies; sheet-like foams; fabrics such as woven fabrics, knitted fabrics, and nonwoven fabrics; and laminates thereof.
- the thickness of the support layer is not particularly limited, but is usually preferably about 2 to 3000 ⁇ m.
- the patch of the present invention may further include a release liner on the surface of the pressure-sensitive adhesive layer opposite to the support layer.
- a release liner any material may be used as long as it covers the pressure-sensitive adhesive layer before use of the patch and can be peeled off and removed when used.
- polyethylene terephthalate, polyethylene naphthalate Polyester such as polyethylene; Polypropylene such as polypropylene; Film such as polyvinyl chloride and polyvinylidene chloride; Laminated film of fine paper and polyolefin; Film such as nylon and aluminum.
- release liners those having a surface coat (release treatment) applied with a release agent such as silicone or polytetrafluoroethylene are preferably used from the viewpoint that they can be easily released from the pressure-sensitive adhesive layer.
- the pressure-sensitive adhesive layer according to the present invention contains an asenapine-free material, an alkali maleate and a rubber-based pressure-sensitive adhesive.
- the thickness of such an adhesive layer is not particularly limited, and is usually about 10 to 1000 ⁇ m.
- Asenapine according to the present invention is trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-c] pyrrole.
- Asenapine has central nervous system (CNS) inhibitory activity, antihistamine activity, and antiserotonin activity, and is generally known as a drug used for the treatment of central nervous system diseases such as schizophrenia.
- CNS central nervous system
- such asenapine needs to be an asenapine-free body which is a free form.
- the inventors of the present invention will significantly reduce the adhesive strength of an adhesive layer when simply containing asenapine and / or a pharmaceutically acceptable salt thereof in an adhesive layer using a rubber adhesive as an adhesive base.
- the adhesive strength of the pressure-sensitive adhesive layer can be sufficiently increased by using an asenapine-free form as a drug and further combining with an alkali maleate and a rubber-based pressure-sensitive adhesive.
- the asenapine-free body according to the present invention may be added as an asenapine-free body at the time of manufacture of the patch, and from the viewpoint of handleability and stability of the raw material, It may be produced from a pharmaceutically acceptable salt or a mixture of both.
- a pharmaceutically acceptable salt of asenapine hereinafter sometimes referred to as a salt of asenapine
- a method of desalting the salt of asenapine by blending a salt and a metal ion-containing desalting agent (neutralizing agent) is mentioned.
- the salt of asenapine is preferably an acid adduct from the viewpoint of being easily desalted by the metal ion-containing desalting agent.
- the acid include hydrochloric acid, hydrobromic acid, methanesulfonic acid and the like.
- Basic acids; polybasic acids such as fumaric acid, maleic acid, citric acid, and tartaric acid can be used, and one of these may be used alone or two or more may be used in combination.
- the salt of asenapine when an alkali metal ion-containing desalting agent is used as the metal ion-containing desalting agent, the asenapine-free body and the maleic acid alkali salt according to the present invention can be produced. From this point of view, it is particularly preferable to be a maleate (acenapine maleate).
- examples of the metal ion-containing desalting agent include metal hydroxides, metal acetates, and the like, and examples of the metal include sodium, potassium, and magnesium. One of these is used alone. Alternatively, two or more kinds may be used in combination. Among these, it is easy to handle at the time of manufacture, and when the asenapine maleate is used as the salt of asenapine, the asenapine-free body and alkali maleate according to the present invention can be produced, and asena From the viewpoint of further improving the temporal stability of the pin-free body, the metal ion-containing desalting agent is preferably an alkali metal ion-containing desalting agent, particularly preferably sodium hydroxide or sodium acetate.
- the amount of the metal ion-containing desalting agent is 0.5 to 6 equivalents relative to the acid-base equivalent of the salt of asenapine.
- the amount is preferably 0.75 to 4 equivalents.
- the content of the asenapine-free body depends on the object and purpose of treatment, and thus cannot be generally stated. It is preferably 15% by mass, more preferably 1.5 to 12% by mass, and further preferably 2 to 10% by mass.
- the content of asenapine-free body is less than the lower limit, it is necessary to increase the area of the patch because the skin permeation amount tends to decrease.
- the content exceeds the upper limit skin irritation occurs. Such as local side effects such as adhesion to the skin, tackiness properties such as tackiness tend to be reduced.
- the pressure-sensitive adhesive layer according to the present invention contains an alkali maleate.
- the inventors of the present invention have reported that the adhesive strength of the pressure-sensitive adhesive layer is reduced when an alkali salt of maleic acid is simply contained in the pressure-sensitive adhesive layer using a rubber-based pressure-sensitive adhesive as the pressure-sensitive adhesive base, whereas the asenapine-free body and the maleic acid are reduced. It has been found that a sufficiently large adhesive force can be exerted on the pressure-sensitive adhesive layer by using a combination of an acid alkali salt and a rubber-based pressure-sensitive adhesive.
- the maleic acid alkali salt may be added as a maleic acid alkali salt during the manufacture of the patch, and from the viewpoint of handling and stability of the raw material, the maleate and the maleate It may be generated from an alkali metal ion-containing desalting agent, or may be a mixture of both.
- the maleate and the alkali metal ion-containing desalting agent are blended in the composition of the pressure-sensitive adhesive layer at the time of producing a patch.
- a method of desalting an acid salt is mentioned.
- the maleate is preferably asenapine maleate from the viewpoint that an asenapine-free product and an alkali maleate can be formed. Further, when the maleic acid alkali salt is produced from the maleate and the alkali metal ion-containing desalting agent, the blending amount of the alkali metal ion-containing desalting agent is the acid-base equivalent of the maleate. It is the same as the compounding quantity of a metal ion containing desalting agent.
- alkali maleate examples include disodium maleate, sodium maleate, dipotassium maleate, potassium maleate and the like, and may be a hydrate having water of crystallization. You may use it, or may use it in combination of 2 or more types. Among these, disodium maleate and / or sodium maleate are preferred from the viewpoint that they are excellent in handleability and tend to facilitate a desalting reaction.
- the content of the alkali maleic acid salt is preferably 0.5 to 15% by mass, and preferably 1 to 10% by mass with respect to the entire pressure-sensitive adhesive layer. More preferred.
- the mass ratio of the asenapine-free body to the maleic acid alkali salt is 1: 0.1 to 1 : 3 is preferable, and 1: 0.25 to 1: 2 is more preferable.
- ⁇ Rubber adhesive> In the patch of the present invention, it is necessary to use a rubber-based adhesive as the adhesive base.
- the rubber-based pressure-sensitive adhesive include natural rubber, polyisobutylene, alkyl vinyl ether (co) polymer, polyisoprene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, and styrene-isoprene-styrene block copolymer.
- a polymer, silicone rubber, etc. are mentioned, and one of these may be used alone, or two or more may be used in combination.
- the rubber-based pressure-sensitive adhesive according to the present invention from the viewpoint that the releasability of asenapine from the pressure-sensitive adhesive layer is further improved and the pressure-sensitive adhesive layer tends to exhibit more sufficient adhesive force.
- At least one selected from the group consisting of styrene-isoprene-styrene block copolymer, polyisobutylene and silicone rubber is preferable, and styrene-isoprene-styrene block copolymer and polyisobutylene are more preferable.
- the mass ratio of the styrene-isoprene-styrene block copolymer to the polyisobutylene is 15: 2 to 2:15. Particularly preferred.
- the content of such a rubber-based pressure-sensitive adhesive is preferably 10 to 50% by mass, and more preferably 12 to 40% by mass with respect to the entire pressure-sensitive adhesive layer.
- the mass ratio of the asenapine-free body and the rubber-based adhesive is 1:17 to 1: 1 in the adhesive layer. .2 is preferable, and 1:14 to 1: 1.4 is more preferable.
- the content of the rubber-based adhesive is less than the lower limit, the adhesiveness of the patch tends to be reduced.
- the content exceeds the upper limit the release of asenapine from the adhesive layer Tends to decrease, making it difficult to achieve sufficient skin permeability.
- the pressure-sensitive adhesive layer according to the present invention is blended at the time of manufacturing the patch and free of asenapine. It may further contain the salt of asenapine remaining without becoming a body.
- the pressure-sensitive adhesive layer according to the present invention further contains such an asenapine salt, the content thereof is 3.5% by mass or less based on the whole pressure-sensitive adhesive layer in terms of the asenapine-free body. It is preferable that it is 2% by mass or less.
- the pressure-sensitive adhesive layer according to the present invention when the asenapine-free body and / or the alkali maleate is formed by the desalting (neutralization) in the pressure-sensitive adhesive layer, the pressure-sensitive adhesive layer according to the present invention May further contain a metal salt other than the metal ion-containing desalting agent (preferably the alkali metal ion-containing desalting agent) or the alkali maleate produced by the desalting.
- the metal salt is determined by the combination of the salt of asenapine and the metal ion-containing desalting agent, but at least selected from the group consisting of metal chloride, metal bromide, metal iodide, and organic acid metal salt.
- the pressure-sensitive adhesive layer according to the present invention further contains such a metal salt, when the content of the metal salt in the pressure-sensitive adhesive layer increases, the dispersion thereof becomes uneven and the pressure-sensitive adhesive force of the pressure-sensitive adhesive layer decreases.
- the content is preferably 4% by mass or less with respect to the entire pressure-sensitive adhesive layer.
- a drug other than asenapine a drug other than asenapine; a pressure-sensitive adhesive base other than a rubber-based pressure-sensitive adhesive; a tackifier, a softener, and a stabilization, as long as the effects of the present invention are not impaired.
- An additive such as an agent and an absorption accelerator may be further contained.
- Examples of the adhesive base other than the rubber adhesive include (meth) acrylic acid ester (co) polymers, silicone polymers other than the silicone rubber, polyurethane adhesives, and the like.
- the (meth) acrylic acid ester (co) polymer is a (co) polymer in which an acrylic acid ester and / or a methacrylic acid ester is a main monomer unit and an optional submonomer is copolymerized as necessary.
- Examples of the main monomer include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, hexyl (meth) acrylate, heptyl (meth) acrylate, octyl (meth) acrylate, Examples thereof include 2-ethylhexyl (meth) acrylate, and one of these may be used alone, or two or more may be used in combination.
- the submonomer is not particularly limited, and examples thereof include N-vinyl-2-pyrrolidone, methylvinylpyrrolidone, (meth) acrylic acid, vinyl acetate and the like.
- the pressure-sensitive adhesive layer according to the present invention further contains a pressure-sensitive adhesive base other than such a rubber-based pressure-sensitive adhesive
- the content of the pressure-sensitive adhesive is selected from the viewpoint that the skin permeability of asenapine tends to decrease. It is preferable that it is 30 mass% or less with respect to the whole layer.
- tackifier examples include alicyclic saturated hydrocarbon resins; rosin, rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester, rosin pentaerythritol ester, maleated rosin and other rosin derivatives; Giving resin; petroleum-based tackifying resin and the like can be mentioned, and one of these may be used alone, or two or more may be used in combination. In the present invention, it is preferable to use a petroleum-based tackifier resin from the viewpoint of physical properties of the preparation such as cohesiveness and adhesion.
- the content thereof is such that the mass ratio to the rubber-based pressure-sensitive adhesive (rubber-based pressure-sensitive adhesive: tackifier) is 1: 6 to It is preferably 1.5: 1 (more preferably 1: 5 to 1: 1). If the content of the tackifier is less than the lower limit, the adhesive force to the skin tends to decrease. Tend to become stronger.
- the softener examples include paraffin oil such as liquid paraffin; animal oil such as squalane and squalene; vegetable oil such as almond oil, olive oil, camellia oil, castor oil, tall oil and peanut oil; silicone oil; polybutene, polyisoprene, etc.
- paraffin oil such as liquid paraffin
- animal oil such as squalane and squalene
- vegetable oil such as almond oil, olive oil, camellia oil, castor oil, tall oil and peanut oil
- silicone oil polybutene, polyisoprene, etc.
- liquid paraffin is preferably used from the viewpoint of physical properties of the preparation.
- the content thereof is such that the mass ratio to the rubber-based pressure-sensitive adhesive (rubber-based pressure-sensitive adhesive: softening agent) is 1: 6 to 5: 1 (more preferably 1: 4 to 3: 1) is preferable. If the content of the softening agent is less than the lower limit, the adhesive force to the skin tends to be reduced. On the other hand, if the upper limit is exceeded, the cohesive force of the adhesive layer is reduced, and the adhesive layer on the skin after peeling. There is a tendency for stickiness to remain.
- the stabilizer examples include tocopherol and its ester derivatives, ascorbic acid and its ester derivatives, dibutylhydroxytoluene, butylhydroxyanisole, and the like. You may use it, or may use it in combination of 2 or more types. In the present invention, it is more preferable to use dibutylhydroxytoluene from the viewpoint of the physical properties and appearance of the preparation and the drug stabilization effect.
- the content of the stabilizer is less than the lower limit, the stability of each component in the patch tends to be reduced. On the other hand, when the content exceeds the upper limit, the cohesive force of the pressure-sensitive adhesive layer tends to be reduced.
- absorption promoter examples include aliphatic alcohols such as isostearyl alcohol; fatty acids such as capric acid; propylene glycol monolaurate, isopropyl myristate, isopropyl palmitate, lauric acid diethanolamide, and the like. Fatty acid derivatives; glycols such as propylene glycol and polyethylene glycol, and the like. One of these may be used alone, or two or more may be used in combination. In the present invention, propylene glycol monolaurate and isopropyl palmitate are preferably used, and isopropyl palmitate is more preferably used from the viewpoint that the skin permeability of asenapine tends to be remarkably improved.
- the content thereof is preferably 2 to 40% by mass with respect to the whole pressure-sensitive adhesive layer.
- the absorption promoter is the isopropyl palmitate
- the content thereof is preferably 2 to 15% by mass, more preferably 5 to 12% by mass with respect to the entire pressure-sensitive adhesive layer.
- the content of the absorption accelerator is less than the lower limit, the skin permeability of asenapine tends to decrease.
- the content exceeds the upper limit the absorption accelerator is separated from the adhesive layer, and the adhesive property of the adhesive layer is reduced. And local side effects such as skin irritation tend to occur.
- the total content is preferably 85% by mass or less based on the whole pressure-sensitive adhesive layer.
- the pressure-sensitive adhesive layer according to the present invention does not substantially contain water. Since the pressure-sensitive adhesive layer according to the present invention is mainly composed of hydrophobic components, when the water content exceeds 10% by mass, moisture tends to be separated from the pressure-sensitive adhesive layer and impair the pressure-sensitive adhesive layer. is there.
- substantially free of water means that no intentional addition of water is carried out during production, and the water content required by measurement by the Karl Fischer method in accordance with the Japanese Pharmacopoeia is the pressure-sensitive adhesive layer. It means less than 10% of the whole.
- the patch of the present invention is not particularly limited and can be produced by appropriately adopting a known method for producing a patch. For example, first, asenapine-free body, maleic acid alkali salt, rubber adhesive, If necessary, the additive, solvent, and the like are kneaded according to a conventional method to obtain a uniform pressure-sensitive adhesive layer composition. Next, the pressure-sensitive adhesive layer composition is applied on the surface of the support layer (usually on one surface) at a predetermined thickness, and then heated as necessary to dry-remove the solvent to obtain a desired thickness.
- the patch of the present invention can be obtained by cutting into sizes.
- the solvent examples include toluene, ethanol, methanol, ethyl acetate, and the like. One of these may be used alone, or two or more may be used in combination.
- the heating condition can be appropriately selected depending on the solvent, but the temperature condition is preferably 60 to 120 ° C., and the heating time is usually 2 to 30 minutes. It is preferable that
- an asenapine-free body produced from an asenapine salt for example, by blending the asenapine salt and the metal ion-containing desalting agent into the adhesive layer composition.
- An asenapine-free body can be produced and contained in the resulting pressure-sensitive adhesive layer.
- the said maleate and said alkali metal ion containing are contained in the said adhesive layer composition.
- an alkali maleate can be produced and contained in the resulting pressure-sensitive adhesive layer.
- asenapine maleate and the alkali metal ion-containing desalting agent are added to the pressure-sensitive adhesive layer composition. It is preferable to mix.
- the method for producing the patch of the present invention may further include a step of bonding the release liner on the surface of the pressure-sensitive adhesive layer opposite to the support layer. First, a pressure-sensitive adhesive layer is formed on one surface of the release liner to form a pressure-sensitive adhesive layer, and then the support layer is bonded to the surface of the pressure-sensitive adhesive layer opposite to the release liner to obtain a predetermined shape.
- the patch of the present invention may be obtained by cutting into pieces.
- the present invention will be described more specifically based on examples and comparative examples, but the present invention is not limited to the following examples.
- the peel test, the underwater release test, and the skin permeation test were each performed by the method shown below.
- each patch was cut out to a size of 3.16 cm ⁇ 3.16 cm, and the release liner was peeled off so that the pressure-sensitive adhesive layer was on the outer side (dissolved water bath type dissolution tester, Toyama Sangyo Co., Ltd.).
- dissolved water bath type dissolution tester Toyama Sangyo Co., Ltd.
- a round bottom flask containing 900 ml of dissolution test solution dissolution test second solution described in Japanese Pharmacopoeia
- the rotating cylinder was immersed.
- the elution test solution was sampled by 10 ml every predetermined time from the start of rotation to 24 hours while rotating the rotating cylinder at a speed of 50 rpm, and the asena released into the water during the 24 hours from the start of rotation by high-speed liquid chromatography.
- Skin permeation amount ( ⁇ g / cm 2 ) [drug concentration ( ⁇ g / ml) ⁇ flow rate (ml)] / patch area (cm 2 ) From this, the amount of skin permeation per hour (skin permeation rate, flux [ ⁇ g / cm 2 / hr]) was determined.
- Example 1 First, 70 parts by mass of styrene-isoprene-styrene block copolymer (SIS), 30 parts by mass of polyisobutylene (PIB), 250 parts by mass of petroleum-based tackifier resin (trade name: Alcon, manufactured by Arakawa Chemical Industries), and flow 60 parts by mass of paraffin were mixed to obtain a uniform adhesive base composition.
- SIS styrene-isoprene-styrene block copolymer
- PIB polyisobutylene
- Alcon petroleum-based tackifier resin
- this pressure-sensitive adhesive layer composition is applied on one surface of a 75 ⁇ m-thick polyester film (release liner) subjected to a release treatment so that the thickness after drying becomes 100 ⁇ m and dried at 60 ° C. for 20 minutes. Thus, toluene was removed to form an adhesive layer.
- a 25 ⁇ m thick polyester film (support layer) was laminated on the surface of the pressure-sensitive adhesive layer opposite to the release liner, and then cut to obtain a patch.
- Example 2 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition (excluding toluene) was changed to the composition shown in Table 1.
- Example 4 instead of disodium maleate (maleic acid 2Na), sodium maleate trihydrate (maleic acid Na trihydrate) was used, and the composition of the adhesive layer composition (excluding toluene) was as shown in Table 1. A patch was obtained in the same manner as in Example 1 except that.
- Example 6 Except for using sodium acetate instead of sodium hydroxide so that the molar ratio of asenapine maleate to sodium acetate (mole number of asenapine maleate: mole number of sodium acetate) was 1: 2.
- a pressure-sensitive adhesive layer composition and a patch were obtained.
- 100 mass parts (except for toluene) of the obtained pressure-sensitive adhesive layer composition 4.27 parts by mass of asenapine-free material and 2.39 parts by mass of disodium maleate are contained.
- Table 1 shows the composition of raw materials (excluding toluene) blended in the pressure-sensitive adhesive layer composition at this time.
- Example 1 A patch was obtained in the same manner as in Example 1 except that maleic acid 2Na was not used and the composition of the adhesive layer composition (excluding toluene) was changed to the composition shown in Table 1.
- Table 4 shows the composition of the adhesive layer composition (excluding toluene) using an acrylic adhesive base having no functional group (DuroTak87-900A, manufactured by Henkel) instead of the adhesive base composition.
- a patch was obtained in the same manner as in Example 1 except that.
- Tables 1 to 3 show the results of the peel test conducted on the patches obtained in each Example and Comparative Example, together with the composition of each adhesive layer composition (excluding toluene). Further, the improvement rate of the adhesive strength is shown together with reference to Comparative Example 1 for Examples 1 to 6 and Comparative Example 2 to Comparative Examples 3 to 5. In Table 3, “ND” indicates that measurement could not be performed due to throwing destruction. Table 1 also shows the results of the underwater release test for the patches obtained in each Example and Comparative Example, and the improvement rate of the water release rate based on Comparative Example 1 for Examples 1-6. Are also shown.
- FIG. 1 is a graph showing the relationship between the skin permeation rate of asenapine and the elapsed time from application in the patches obtained in Example 1 and Comparative Examples 10 to 12.
- the patch of the present invention was excellent in the skin permeability of asenapine.
- an acrylic adhesive was used as the adhesive base, it was confirmed that sufficient skin permeability of asenapine was not exhibited.
- improvement in the pressure-sensitive adhesive strength of the pressure-sensitive adhesive layer could not be confirmed even when an asenapine-free material and an alkali maleate were combined.
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Abstract
Description
支持体層と粘着剤層とを備える貼付剤であって、
前記粘着剤層が、アセナピンフリー体とマレイン酸アルカリ塩とゴム系粘着剤とを含有することを特徴とするものである。
本発明に係るアセナピンは、trans-5-クロロ-2-メチル-2,3,3a,12b-テトラヒドロ-1H-ジベンゾ[2,3:6,7]オキセピノ[4,5-c]ピロールのことを指す。アセナピンは、中枢神経系(CNS)抑制活性、抗ヒスタミン活性及び抗セロトニン活性を有し、通常、統合失調症等の中枢神経系疾患の治療に用いられる薬物として知られている。
本発明に係る粘着剤層は、マレイン酸アルカリ塩を含有する。本発明者らは、粘着基剤としてゴム系粘着剤を用いた粘着剤層中に単にマレイン酸アルカリ塩を含有させると粘着剤層の粘着力が低下するのに対し、アセナピンフリー体とマレイン酸アルカリ塩とゴム系粘着剤とを組み合わせて用いることにより、粘着剤層に十分に大きい粘着力を発揮させることができることを見出した。
本発明の貼付剤においては、粘着基剤としてゴム系粘着剤を用いることが必要である。前記ゴム系粘着剤としては、例えば、天然ゴム、ポリイソブチレン、アルキルビニルエーテル(共)重合体、ポリイソプレン、ポリブタジエン、スチレン-ブタジエン共重合体、スチレン-イソプレン共重合体、スチレン-イソプレン-スチレンブロック共重合体、シリコーンゴム等が挙げられ、これらのうちの1種を単独で用いても2種以上を組み合わせて用いてもよい。中でも、本発明に係るゴム系粘着剤としては、粘着剤層からのアセナピンの放出性がより向上し、かつ、粘着剤層のより十分な粘着力を発揮することができる傾向にあるという観点から、スチレン-イソプレン-スチレンブロック共重合体、ポリイソブチレン及びシリコーンゴムからなる群から選択される少なくとも一種であることが好ましく、スチレン-イソプレン-スチレンブロック共重合体及びポリイソブチレンであることがより好ましい。またこのとき、前記スチレン-イソプレン-スチレンブロック共重合体と前記ポリイソブチレンとの質量比(スチレン-イソプレン-スチレンブロック共重合体:ポリイソブチレン)としては、15:2~2:15であることが特に好ましい。
本発明の貼付剤において、前記アセナピンフリー体を前記粘着剤層中において前記アセナピンの塩から生成せしめた場合、本発明に係る粘着剤層としては、貼付剤の製造時に配合されてアセナピンフリー体とならずに残留した前記アセナピンの塩を更に含有していてもよい。本発明に係る粘着剤層がこのようなアセナピンの塩を更に含有する場合、その含有量としては、アセナピンフリー体に換算して、前記粘着剤層全体に対して3.5質量%以下であることが好ましく、2質量%以下であることがより好ましい。前記アセナピンの塩の含有量が前記上限を超えるとアセナピンの粘着剤層からの放出性や皮膚透過性が低下する傾向にある。
本発明の貼付剤は、特に制限されず、公知の貼付剤の製造方法を適宜採用することにより製造することができ、例えば、先ず、アセナピンフリー体とマレイン酸アルカリ塩とゴム系粘着剤と、必要に応じて前記添加剤、溶剤等を常法に従って練合して均一な粘着剤層組成物を得る。次いで、この粘着剤層組成物を前記支持体層の面上(通常は一方の面上)に所定の厚みで塗布した後、必要に応じて加温して前記溶剤を乾燥除去し、所望の大きさに裁断することにより、本発明の貼付剤を得ることができる。
先ず、各貼付剤からそれぞれ1cm×5cmの試験片を3枚ずつ切り抜き、3枚の試験片について剥離ライナーを剥離した後、ベークライト板に貼付して30分間静置した。その後、30cm/minの速度で各試験片をベークライト板から180°剥離した。剥離開始後5mmの位置から、5mm間隔で5点の剥離強さをそれぞれ測定し、その平均値を粘着力[単位:gF/cm]とした。
先ず、各貼付剤をそれぞれ3.16cm×3.16cmの大きさに切り抜き、剥離ライナーを剥離して粘着剤層が外側となるように溶出試験機(恒温水槽式溶出試験器、富山産業株式会社製)の回転シリンダーに装着した。その後、900mlの溶出試験液(日本薬局方に記載の溶出試験第2液)を入れた丸底フラスコを前記溶出試験機に装着して温度を32℃に設定し、前記溶出試験液中に前記回転シリンダーを浸漬した。前記回転シリンダーを速度50rpmで回転させながら溶出試験液を所定時間毎に10mlずつ回転開始から24時間までサンプリングし、高速液体クロマトグラフ法により、回転開始から24時間の間に水中に放出されたアセナピンフリー体の合計質量(水中放出量)を測定し、試験前の粘着剤層中に含有させたアセナピンのアセナピンフリー体換算質量(初期アセナピン量)から、下記式:
水中放出率[%]=(水中放出量/初期アセナピン量)×100
により水中放出率[%]を算出した。
先ず、ヘアレスマウスより摘出した皮膚の角質層側に、3cm2の円形に切断して剥離ライナーを除去した貼付剤を貼付した。次いで、この皮膚の真皮側がレセプター槽側となるように、32℃に保温したフロースルー型拡散セルに装着した。レセプター槽にリン酸緩衝生理食塩水(32℃)を1時間当たり約3mlの流量で導入し、前記レセプター槽から2時間毎に24時間までそれぞれ試料液を採取し、採取したそれぞれの試料液について高速液体クロマトグラフ法により薬物(アセナピン)の濃度を定量した。アセナピンの皮膚透過量を次式:
皮膚透過量(μg/cm2)=[薬物濃度(μg/ml)×流量(ml)]/貼付剤面積(cm2)
により算出し、これより、1時間当たりの皮膚透過量(皮膚透過速度、Flux[μg/cm2/hr])を求めた。
先ず、スチレン-イソプレン-スチレンブロック共重合体(SIS)70質量部、ポリイソブチレン(PIB)30質量部、石油系粘着付与樹脂(商品名:アルコン、荒川化学工業社製)250質量部、及び流動パラフィン60質量部を混合して均一な粘着基剤組成物を得た。次いで、アセナピンフリー体6質量部、マレイン酸2ナトリウム(マレイン酸2Na)2質量部、パルミチン酸イソプロピル(IPP)10質量部、前記粘着基剤組成物81.75質量部、その他成分として安定化剤を合計で0.25質量部、及び適当量のトルエンを混合し、均一な粘着剤層組成物を得た。前記粘着剤層組成物の組成(トルエンを除く)を表1に示す。
粘着剤層組成物の組成(トルエンを除く)を表1に示す組成としたこと以外は実施例1と同様にしてそれぞれ貼付剤を得た。
マレイン酸2ナトリウム(マレイン酸2Na)に代えてマレイン酸ナトリウム3水和物(マレイン酸Na3水和物)を用い、粘着剤層組成物の組成(トルエンを除く)を表1に示す組成としたこと以外は実施例1と同様にして貼付剤を得た。
先ず、アセナピンマレイン酸塩6質量部(フリー体換算で4.27質量部)、水酸化ナトリウム1.19質量部(アセナピンマレイン酸塩のモル数:水酸化ナトリウムのモル数=1:2)、パルミチン酸イソプロピル(IPP)10質量部、前記粘着基剤組成物82.56質量部、前記その他成分0.25質量部、及び適当量のトルエンを混合し、均一な粘着剤層組成物を得た。なお、得られた粘着剤層組成物100質量部(トルエンを除く)中には、アセナピンフリー体が4.27質量部、マレイン酸2ナトリウムが2.39質量部含有される。このときの粘着剤層組成物に配合した原料の組成(トルエンを除く)を表1に示す。次いで、前記粘着剤層組成物を用いたこと以外は実施例1と同様にして貼付剤を得た。
水酸化ナトリウムに代えて酢酸ナトリウムをアセナピンマレイン酸塩と酢酸ナトリウムとのモル比(アセナピンマレイン酸塩のモル数:酢酸ナトリウムのモル数)が1:2となるように用いたこと以外は実施例5と同様にして粘着剤層組成物及び貼付剤を得た。なお、得られた粘着剤層組成物100質量部(トルエンを除く)中には、アセナピンフリー体が4.27質量部、マレイン酸2ナトリウムが2.39質量部含有される。このときの粘着剤層組成物に配合した原料の組成(トルエンを除く)を表1に示す。
マレイン酸2Naを用いず、粘着剤層組成物の組成(トルエンを除く)を表1に示す組成としたこと以外は実施例1と同様にして貼付剤を得た。
アセナピンフリー体を用いず、粘着剤層組成物の組成(トルエンを除く)を表2に示す組成としたこと以外は実施例1と同様にしてそれぞれ貼付剤を得た。
アセナピンフリー体に代えてタムスロシンフリー体を用い、粘着剤層組成物の組成(トルエンを除く)を表3に示す組成としたこと以外は実施例1と同様にしてそれぞれ貼付剤を得た。
アセナピンフリー体に代えてビソプロロールフリー体を用い、粘着剤層組成物の組成(トルエンを除く)を表3に示す組成としたこと以外は実施例1と同様にしてそれぞれ貼付剤を得た。
前記粘着基剤組成物に代えてOH基を有するアクリル系粘着基剤(DuroTak87-4287、ヘンケル社製)を用い、粘着剤層組成物の組成(トルエンを除く)を表4に示す組成としたこと以外は実施例1と同様にして貼付剤を得た。
前記粘着基剤組成物に代えてCOOH基を有するアクリル系粘着基剤(DuroTak87-2194、ヘンケル社製)を用い、粘着剤層組成物の組成(トルエンを除く)を表4に示す組成としたこと以外は実施例1と同様にして貼付剤を得た。
前記粘着基剤組成物に代えて官能基を有さないアクリル系粘着基剤(DuroTak87-900A、ヘンケル社製)を用い、粘着剤層組成物の組成(トルエンを除く)を表4に示す組成としたこと以外は実施例1と同様にして貼付剤を得た。
Claims (6)
- 支持体層と粘着剤層とを備える貼付剤であって、
前記粘着剤層が、アセナピンフリー体とマレイン酸アルカリ塩とゴム系粘着剤とを含有する貼付剤。 - 前記粘着剤層において、前記アセナピンフリー体と前記マレイン酸アルカリ塩との質量比(アセナピンフリー体:マレイン酸アルカリ塩)が1:0.1~1:3である請求項1に記載の貼付剤。
- 前記粘着剤層において、前記ゴム系粘着剤の含有量が10~50質量%である請求項1又は2に記載の貼付剤。
- 前記ゴム系粘着剤が、スチレン-イソプレン-スチレンブロック共重合体、ポリイソブチレン及びシリコーンゴムからなる群から選択される少なくとも一種である請求項1~3のうちのいずれか一項に記載の貼付剤。
- 前記マレイン酸アルカリ塩が、マレイン酸二ナトリウム及び/又はマレイン酸ナトリウムである請求項1~4のうちのいずれか一項に記載の貼付剤。
- 前記アセナピンフリー体及び前記マレイン酸アルカリ塩が前記粘着剤層中においてアセナピンマレイン酸塩とアルカリ金属イオン含有脱塩剤とから生成せしめたものである請求項1~5のうちのいずれか一項に記載の貼付剤。
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL13823177T PL2878300T3 (pl) | 2012-07-26 | 2013-07-25 | Plaster |
US14/416,983 US10022445B2 (en) | 2012-07-26 | 2013-07-25 | Patch |
CN201380036224.1A CN104487071B (zh) | 2012-07-26 | 2013-07-25 | 贴附剂 |
JP2014527004A JP6005742B2 (ja) | 2012-07-26 | 2013-07-25 | 貼付剤 |
EP13823177.4A EP2878300B1 (en) | 2012-07-26 | 2013-07-25 | Patch |
ES13823177.4T ES2632946T3 (es) | 2012-07-26 | 2013-07-25 | Parche |
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