WO2012165253A1 - ロピニロール含有貼付剤及びその包装体 - Google Patents
ロピニロール含有貼付剤及びその包装体 Download PDFInfo
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- WO2012165253A1 WO2012165253A1 PCT/JP2012/063160 JP2012063160W WO2012165253A1 WO 2012165253 A1 WO2012165253 A1 WO 2012165253A1 JP 2012063160 W JP2012063160 W JP 2012063160W WO 2012165253 A1 WO2012165253 A1 WO 2012165253A1
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- ropinirole
- adhesive layer
- sensitive adhesive
- pressure
- mass
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—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
- A61K31/403—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 carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Definitions
- the present invention relates to a ropinirole-containing patch and its package.
- L-Dopa therapy in which dopamine is supplemented by administration of L-dopa (L-Dopa), which is known as a therapeutic preparation, is known as a treatment for Parkinson's disease.
- L-Dopa therapy has problems that it requires long-term continuous administration, the effect of drugs gradually decreases with long-term continuous administration, and the daily fluctuation of symptoms becomes severe. . Therefore, ropinirole has been developed as a drug that solves such problems in L-Dopa therapy. In recent years, ropinirole and / or its pharmaceutically acceptable drugs are used for the treatment of diseases such as Parkinson's disease and restless leg syndrome. Various studies have been made on preparations containing salts.
- Patent Document 1 JP-T-2009-518376
- Patent Document 2 JP-T-2007-516265
- Patent Document 3 discloses a patch comprising a support layer and an adhesive layer containing ropinirole as a transdermal absorption preparation containing ropinirole. ing.
- Patent Document 4 discloses a patch comprising a support layer and an adhesive layer containing ropinirole as a transdermal absorption preparation containing ropinirole. ing.
- the skin permeability of ropinirole is still not sufficient, and it is difficult to maintain the plasma concentration of ropinirole at a sufficiently high level. Had.
- drugs are on the market in the form of acid addition salts because of their handleability and stability.
- the acid addition salts of drugs are used as they are in percutaneous absorption preparations and the like, the drugs penetrate the skin.
- a drug free form in terms of skin permeability.
- Patent Document 5 ropinirole free form formed by the reaction of ropinirole acid addition salt and a metal ion-containing desalting agent having an equivalent mole or less of the acid addition salt.
- a patch containing a metal salt and an adhesive base having no hydroxyl group or carboxyl group in an adhesive layer is disclosed.
- the present inventors have prepared a transdermal absorption preparation in which ropinirole acid addition salt is desalted during production or preparation for the purpose of improving the skin permeability of ropinirole.
- the content of ropinirole acid addition salt in the pressure-sensitive adhesive layer is 5% by mass as described in the examples of the same document (4.4% by mass in terms of ropinirole free form)
- the amount of ropinirole permeated through the skin is still insufficient.
- the content of ropinirole and / or its pharmaceutically acceptable salt in the adhesive layer is adjusted so that the skin permeation amount of ropinirole is sufficient, the adhesive properties of the patch are maintained.
- the adhesive group contained in the pressure-sensitive adhesive layer is surprisingly caused by the fact that ropinirole educt is solid at room temperature.
- the present inventors have found that there is an action of plasticizing the agent and reducing the cohesive force of the pressure-sensitive adhesive layer.
- the present invention has been made in view of the above-described problems of the prior art, and is a ropinirole-containing patch having excellent skin permeability of ropinirole and having sufficient adhesiveness, and a package thereof, wherein An object is to provide a package having excellent stability.
- the present inventors have a pressure-sensitive adhesive layer and a support layer, and the pressure-sensitive adhesive layer contains ropinirole and / or a pharmaceutically acceptable salt thereof.
- the ropinirole-containing patch when the content of ropinirole and / or pharmaceutically acceptable salt of ropinirole in the pressure-sensitive adhesive layer is within a specific range, excellent ropinirole skin permeability is exhibited. And found that sufficient tackiness is achieved.
- the present inventors have found that the ropinirole-containing patch is sealed and stored together with an oxygen scavenger to further improve the stability of ropinirole over time, and have completed the present invention.
- the ropinirole-containing patch of the present invention is a ropinirole-containing patch comprising an adhesive layer and a support layer, wherein the adhesive layer contains ropinirole and / or a pharmaceutically acceptable salt thereof,
- the ropinirole and / or its pharmaceutically acceptable salt in the pressure-sensitive adhesive layer has a content converted to ropinirole free form of 5 to 13.2% by mass with respect to the total mass of the pressure-sensitive adhesive layer. is there.
- the pressure-sensitive adhesive layer further comprises at least one compound selected from the group consisting of benzyl alcohol, oleyl alcohol, octyldodecanol, and dimethyl isosorbide, the ropinirole and / or It is preferable to contain 5 to 50 parts by mass with respect to 100 parts by mass in terms of ropinirole free form of the pharmaceutically acceptable salt.
- the adhesive layer further comprises isopropyl myristate, isopropyl palmitate, lauryl alcohol, glycerol monooleate, propylene glycol monolaurate, polyoxyethylene sorbitan monooleate, laurin 10 to 150 parts by mass with respect to 100 parts by mass of at least one compound selected from the group consisting of acid diethanolamides converted to ropinirole free form of ropinirole and / or a pharmaceutically acceptable salt thereof. It is more preferable to contain part.
- the pressure-sensitive adhesive layer further contains 15 to 35% by mass of a rubber-based pressure-sensitive adhesive with respect to the total mass of the pressure-sensitive adhesive layer. It is also preferable to further contain 0.5 to 1.0 mole of sodium hydroxide with respect to 1 mole in terms of the number of moles converted to ropinirole free form of the pharmaceutically acceptable salt thereof.
- the package of the present invention is such that the ropinirole-containing patch of the present invention is sealed in a packaging bag together with an oxygen scavenger.
- a ropinirole-containing patch having excellent skin permeability of ropinirole and sufficient adhesiveness, and a package thereof having excellent temporal stability of ropinirole. It becomes.
- FIG. 3 is a graph showing results of skin permeation tests performed on patches obtained in Examples 1 and 2 and Comparative Examples 1 and 2.
- 6 is a graph showing the results of skin permeation tests performed on patches obtained in Examples 3 to 8.
- 3 is a graph showing the results of skin permeation tests performed on patches obtained in Examples 3 and 9-12.
- 6 is a graph showing the results of skin permeation tests performed on patches obtained in Examples 13 to 19. It is a graph which shows the result of having performed the skin permeation test about the patch obtained in Example 20, 23, 25, 29.
- FIG. 1 is a schematic longitudinal sectional view schematically showing a preferred embodiment of the ropinirole-containing patch of the present invention.
- a patch 1 includes a support layer 2, a pressure-sensitive adhesive layer 3 laminated on the support layer 2, and a release sheet 4 stuck on the pressure-sensitive adhesive layer 3.
- the release sheet 4 is peeled off.
- the ropinirole-containing patch of the present invention is not limited to the embodiment shown in FIG.
- two or more pressure-sensitive adhesive layers may be laminated, and may be laminated not only on one surface of the support layer 2 but also on both surfaces.
- there are a plurality of pressure-sensitive adhesive layers at least one of them may be the pressure-sensitive adhesive layer 3 according to the present invention.
- the material for the support layer 2 is not particularly limited, and any material that can be normally used as a support layer for patches can be used as appropriate, and may be stretchable or non-stretchable. Specific examples include synthetic resins such as polyethylene terephthalate, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate polymer, polyvinyl chloride, polyester, nylon, and polyurethane, and paper materials. Examples of the form of the support layer 2 include films, sheets, and laminates thereof; porous membranes; foams; woven fabrics and non-woven fabrics.
- the material of the release sheet 4 is not particularly limited, and any material that can be normally used as a release sheet for a patch can be used as appropriate. Examples thereof include polyester, polypropylene, polyethylene, paper, and a film made of a laminate thereof. Such a film is preferably subjected to a release treatment such as a silicone coat so that it can be easily peeled off.
- the pressure-sensitive adhesive layer 3 contains at least a pressure-sensitive adhesive base and ropinirole and / or a pharmaceutically acceptable salt thereof.
- the adhesive base examples include rubber-based adhesives, acrylic-based adhesives, silicone-based adhesives, etc., and one of these may be used alone or two or more of them may be used in combination.
- the cohesive force is strong, and from the viewpoint that the plasticizing action of the adhesive base by ropinirole free substance is suppressed, at least one of the adhesive bases may be a rubber-based adhesive.
- the rubber-based pressure-sensitive adhesive include natural rubber and synthetic rubber, and the generation of ropinirole decomposition products (ropinirole-related substances) in the pressure-sensitive adhesive layer 3 can be sufficiently suppressed, and ropinirole is stable over time.
- SIS styrene-isoprene-styrene block copolymer
- PIB polyisobutylene
- SBS styrene-butadiene-styrene block copolymer A polymer
- SBR styrene-butadiene rubber
- rubber-based pressure-sensitive adhesives one kind may be used alone or two or more kinds may be used in combination, but it has a preferable cohesive force and exhibits a preferable pressure-sensitive adhesive force in a patch.
- ropinirole when combined with sodium hydroxide, ropinirole is more stable with time, and SIS is used alone, or the mass ratio of SIS and PIB (mass of SIS: mass of PIB) is 9: It is particularly preferable to use in combination so as to be in the range of 1: 1 to 1: 1.
- the content of the rubber-based adhesive is preferably 15 to 35% by mass with respect to the total mass of the adhesive layer 3.
- the content is less than the lower limit, in the patch of the present invention containing the ropinirole free substance at a high concentration, it becomes difficult to give the adhesive layer 3 sufficient cohesive force.
- the adhesive base is a tendency for the adhesive base to remain on the skin after it is applied to the skin and peeled off.
- the content exceeds the upper limit, the pressure-sensitive adhesive layer 3 becomes too hard and the adhesiveness of the patch tends to be lowered.
- the acrylic pressure-sensitive adhesive is listed as a pressure-sensitive adhesive in “Pharmaceutical Additives Dictionary 2000 (edited by the Japan Pharmaceutical Additives Association, published first on April 28, 2000)”.
- acrylic polymers such as coalescence, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and acrylic resin alkanolamine liquid.
- commercially available DURO-TAK acrylic adhesive series National Starch and Chemi Made by Le Co., Ltd.
- Eudragit series Higuchi commerce company, Ltd.
- the silicone adhesive it is preferable to use a polymer having an organopolysiloxane skeleton as the silicone adhesive.
- the polymer having an organopolysiloxane skeleton has a hydroxyl group (for example, a silanol group)
- the polymer having the organopolysiloxane skeleton has adhesiveness.
- the capping with the trimethylsilyl group includes an embodiment in which the terminal silanol group of the polymer having an organopolysiloxane skeleton is endcapped with a trimethylsilyl group.
- Examples of such a polymer having an organopolysiloxane skeleton include polydimethylsiloxane (polymer represented by MQ in the case of ASTM D-1418), polymethylvinylsiloxane (polymer represented by VMQ in the representation of ASTM D-1418, etc.) ), Polymethylphenylsiloxane (polymer represented by PVMQ in the display by ASTM D-1418), and the like.
- the total content of the pressure-sensitive adhesive layer 3 is from the viewpoint of excellent formability of the pressure-sensitive adhesive layer 3 and skin permeability of the active ingredient.
- the amount is preferably 10 to 90% by mass, more preferably 15 to 80% by mass, and particularly preferably 20 to 70% by mass.
- the ropinirole contained in the pressure-sensitive adhesive layer 3 may be a free form or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable ropinirole is produced during production and / or in the produced preparation.
- the salt may be desalted to form a free form, and one of these may be used, or two or more may be mixed.
- the content of ropinirole and / or a pharmaceutically acceptable salt thereof in the pressure-sensitive adhesive layer 3 needs to be 5 to 13.2% by mass in terms of ropinirole free substance.
- the content When the content is less than the lower limit, the amount of ropinirole permeated through the skin is reduced, and a sufficient amount of skin permeation cannot be maintained for a long time, and the plasma concentration of ropinirole is increased to a high level. It cannot be maintained.
- the content exceeds the above upper limit, the cohesive force of the pressure-sensitive adhesive layer 3 is lowered and the adhesiveness of the patch is lowered because the action of plasticizing the pressure-sensitive adhesive base by the ropinirole free substance is strengthened. Furthermore, the stability of ropinirole with time decreases, and ropinirole-related substances are likely to be generated.
- ropinirole acid adduct is preferable.
- the acid include monobasic acids such as hydrochloric acid, hydrobromic acid, and methanesulfonic acid; and polybasic acids such as fumaric acid, maleic acid, citric acid, and tartaric acid.
- the pressure-sensitive adhesive layer 3 includes a metal ion-containing desalting agent (neutralization). It is preferable to further contain an agent.
- a ropinirole free body in the form of salt and free base is obtained, and as a result, a ropinirole free body having higher tissue absorbability can be present in the pressure-sensitive adhesive layer 3 when the preparation is applied.
- the metal ion-containing desalting agent include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and magnesium hydroxide. Among these, handling is easy during production, and From the viewpoint of further improving the temporal stability of ropinirole when combined with a rubber adhesive (more preferably SIS), sodium hydroxide is preferred.
- the addition may be performed once in the production process, may be performed in several times, or two or more may be added alone. You may add in combination. Further, the content thereof is 0.5 to 4 equivalents relative to the acid-base equivalent of the ropinirole acid adduct from the viewpoint of preventing decomposition of ropinirole by an excessive metal ion-containing desalting agent. It is preferable that
- the content of the metal ion-containing desalting agent is more preferably 0.5 to 1 equivalent to the acid-base equivalent of the ropinirole acid adduct, 0.6 to More preferably, the amount is 1 equivalent. That is, as the pressure-sensitive adhesive layer 3 according to the present invention, 0.5 to 1.0 mol per mol of the ropinirole and / or its pharmaceutically acceptable salt converted to ropinirole free form, Preferably, it further contains 0.6 to 1.0 mol of sodium hydroxide.
- the ropinirole acid adduct is reacted with the metal ion-containing desalting agent in an equivalent amount equal to or less than the acid-base equivalent of the acid adduct.
- the pressure-sensitive adhesive layer 3 according to the present invention may further contain such a metal salt.
- the metal salt is not particularly limited as long as it is generated by the desalting (neutralization) reaction, and the ropinirole acid addition salt and the metal ion-containing desalting agent (neutralizing agent) for desalting the salt. ), But is preferably at least one selected from the group consisting of metal chlorides, metal bromides, metal iodides, and organic acid metal salts. Among these, sodium chloride, calcium chloride And at least one selected from the group consisting of aluminum chloride, stannous chloride, ferric chloride, magnesium chloride, potassium chloride, sodium citrate, sodium oxalate, sodium tartrate, sodium bromide and sodium succinate It is more preferable.
- the metal salt produced by the neutralization reaction as described above is converted into a crystal after a short period of time after formation if a polar solvent such as water used in the production process remains in the pressure-sensitive adhesive layer 3 in a trace amount. It tends to agglomerate and grow. Therefore, in order to suppress such agglomeration / growth of metal salt crystals or to uniformly disperse the crystals, it is more preferable that the pressure-sensitive adhesive layer 3 according to the present invention further contains an adsorbent.
- the adsorbent may be any hygroscopic inorganic and / or organic substance, and is not particularly limited as long as it does not impair the effects of the present invention.
- additives listed in “Additives Association Edited, April 28, 2000, First Printing”) the inorganic and organic substances described as having hygroscopicity, moisture proofing, and adsorbing properties, and the above An aminoalkyl methacrylate copolymer, zinc oxide, etc., which are not described in the “Pharmaceutical Additive Dictionary 2000” but are known to have hygroscopicity, can be mentioned. You may use combining more than a seed.
- Such adsorbents include minerals such as talc, kaolin and bentonite; silicon compounds such as fumed silica (Aerosil (registered trademark)) and hydrous silica; metal compounds such as zinc oxide and dry aluminum hydroxide gel; lactic acid And weak acids such as acetic acid; sugars such as dextrin; and polymer polymers such as polyvinylpyrrolidone, propylene glycol, aminoalkyl methacrylate copolymer, crospovidone, and carboxyvinyl polymer.
- minerals such as talc, kaolin and bentonite
- silicon compounds such as fumed silica (Aerosil (registered trademark)) and hydrous silica
- metal compounds such as zinc oxide and dry aluminum hydroxide gel
- lactic acid And weak acids such as acetic acid
- sugars such as dextrin
- polymer polymers such as polyvinylpyrrolidone, propylene glycol, aminoalkyl meth
- the content thereof is preferably 0.5 to 50% by mass with respect to the total mass of the pressure-sensitive adhesive layer 3.
- the content is less than the lower limit, the effect of suppressing the aggregation / growth of metal salt crystals and uniformly dispersing the crystals tends not to be obtained.
- the content exceeds the upper limit, the adhesive strength of the pressure-sensitive adhesive layer 3 tends to be reduced and sticking becomes difficult.
- the pressure-sensitive adhesive layer 3 is at least one compound selected from the group consisting of benzyl alcohol, oleyl alcohol, octyldodecanol, and dimethylisosorbide (hereinafter, compound (A It is preferable to further contain), and among these, it is more preferable to further contain octyldodecanol.
- compound (A) particularly octyldodecanol
- the content of such compound (A) is 1 to 80 parts by mass with respect to 100 parts by mass in terms of the ropinirole free form of ropinirole and / or a pharmaceutically acceptable salt thereof.
- the amount is preferably 5 to 50 parts by mass, more preferably 10 to 40 parts by mass.
- the adhesive layer 3 is composed of isopropyl myristate, isopropyl palmitate, lauryl alcohol, glycerin monooleate (GMO), propylene glycol from the viewpoint that the skin permeability of ropinirole is further improved.
- At least one compound selected from the group consisting of monolaurate (PGML), polyoxyethylene sorbitan monooleate (Tween 80), and lauric acid diethanolamide (LADA) hereinafter sometimes referred to as compound (B)
- PGML monolaurate
- Tween 80 polyoxyethylene sorbitan monooleate
- LADA lauric acid diethanolamide
- the skin permeability of ropinirole may be reduced.
- the decrease in permeability is suppressed by further containing the compound (B) (particularly isopropyl palmitate) in the pressure-sensitive adhesive layer 3, and the skin permeation amount of ropinirole is maintained at a very high level for a long time.
- the content of such a compound (B) is 5 to 200 parts by mass with respect to 100 parts by mass in terms of ropinirole free form of ropinirole and / or a pharmaceutically acceptable salt thereof.
- the amount is preferably 10 to 150 parts by weight, more preferably 15 to 120 parts by weight.
- the compound (B) may be contained exceeding the upper limit. Further, not only the skin permeation improvement effect cannot be obtained, but the compound (B) oozes out from the pressure-sensitive adhesive layer 3 and tends to reduce the adhesive strength of the patch.
- the agent layer 3 further preferably contains the compound (A) and the compound (B), and particularly preferably contains the octyldodecanol and the isopropyl palmitate.
- the mixing ratio of the compound (A) and the compound (B) is preferably 1/10 to 1/2.
- the mixing ratio is less than the lower limit, the precipitation of ropinirole crystals tends not to be sufficiently suppressed.
- the upper limit is exceeded, the skin permeability of ropinirole is reduced or the pressure-sensitive adhesive The layer 3 tends to bleed.
- the pressure-sensitive adhesive layer 3 includes a tackifier, a plasticizer, an absorption accelerator, and an antioxidant as long as the effects of the present invention are not impaired.
- Fillers, preservatives, ultraviolet absorbers and the like may be further contained.
- the tackifier include “Ester gum (trade name, manufactured by Arakawa Chemical Co., Ltd.)”, “Harri Star (trade name, manufactured by Harima Chemicals)”, “Pentalin (trade name, manufactured by Eastman Chemical Co., Ltd.).
- System resin include alicyclic hydrocarbon resins such as xylene resins, may be used in combination or two or more kinds thereof may be used one of these singly.
- a tackifier included in the pressure-sensitive adhesive layer 3
- the content thereof is based on the total mass of the pressure-sensitive adhesive layer 3 in consideration of sufficient adhesive strength of the patch and local irritation at the time of peeling.
- the amount is preferably 10 to 80% by mass, more preferably 15 to 70% by mass, and further preferably 20 to 60% by mass.
- plasticizer examples include petroleum oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil; squalane, squalene; olive oil, camellia oil, castor oil, tall oil, peanut oil, and other vegetable oils.
- Dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; and diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol and the like, and one of these may be used alone. May also be used in combination of two or more.
- the plasticizer is preferably liquid paraffin or liquid polybutene from the viewpoint that a preferable adhesive force can be imparted to the adhesive layer 3.
- the content thereof is 5 to 60 mass with respect to the total mass of the pressure-sensitive adhesive layer 3 in consideration of maintaining sufficient adhesive strength as a patch. %, More preferably 5 to 50% by mass, and even more preferably 7 to 40% by mass.
- the absorption accelerator examples include aliphatic alcohols such as isostearyl alcohol, fatty acids such as capric acid, fatty acid derivatives, polyethylene glycol, etc., except for the compound (B), and one of these is used alone. Alternatively, two or more kinds may be used in combination.
- the content thereof is determined in consideration of sufficient permeability of the active ingredient to the tissue as a preparation, local irritation, etc. Except for the content of the compound (B) with respect to the mass, the content is preferably 1 to 30% by mass, more preferably 3 to 20% by mass, and further preferably 5 to 15% by mass. preferable.
- antioxidants examples include tocopherol and ester derivatives thereof, ascorbic acid, ascorbic acid stearate ester, nordihuman logger ayaretic acid, dibutylhydroxytoluene (hereinafter abbreviated as BHT), butylhydroxyanisole, and the like.
- BHT dibutylhydroxytoluene
- BHT butylhydroxyanisole
- Examples of the filler include aluminum hydroxide, calcium carbonate, magnesium carbonate; silicates such as aluminum silicate and magnesium silicate; silicic acid; barium sulfate, calcium sulfate; calcium zincate; zinc oxide, titanium oxide and the like. It is done.
- Examples of the preservative include edetate disodium, edetate tetrasodium, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.
- ultraviolet absorber examples include p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, and the like.
- the total content is 5% by mass with respect to the total mass of the pressure-sensitive adhesive layer 3. Is preferably 3% by mass or less, more preferably 1% by mass or less.
- the thickness of the pressure-sensitive adhesive layer 3 according to the present invention is preferably such that the mass per unit area of the pressure-sensitive adhesive layer 3 is 25 to 200 g / m 2, and the thickness is 25 to 180 g / m 2. More preferably.
- the thickness is less than the lower limit, it tends to be difficult to maintain a sufficient amount of ropinirole through the skin, and even when the thickness exceeds the upper limit, ropinirole penetrates the skin.
- the sustainability of the amount does not increase any more, and the amount of ropinirole and / or its pharmaceutically acceptable salt required increases with the increase in thickness, which increases the production cost. Tend to be.
- the area of the sticking surface per sheet is preferably 0.5 to 100 cm 2 .
- the area is less than the lower limit or exceeds the upper limit, handling tends to be difficult.
- the ropinirole-containing patch of the present invention can be appropriately adjusted in its application period, but is preferably applied once every 1 to 7 days.
- the adhesive base, the ropinirole and / or a pharmaceutically acceptable salt thereof, and, if necessary, the other composition described above are mixed in a solvent.
- a release sheet 4 for protecting the pressure-sensitive adhesive layer 3 is adhered to the pressure-sensitive adhesive layer 3.
- the pressure-sensitive adhesive layer composition is spread on the release sheet 4 to form the pressure-sensitive adhesive layer 3, the support layer 2 is placed thereon, and the pressure-sensitive adhesive layer 3 is pressed onto the support layer 2.
- the method of transferring is mentioned.
- the solvent is not particularly limited and can be appropriately selected depending on the components to be dissolved or dispersed.
- One of these may be used alone, or two or more may be used in combination.
- the package of the present invention is such that the ropinirole-containing patch of the present invention is sealed in a packaging bag together with an oxygen scavenger.
- the packaging with the oxygen scavenger is used after the production until the time of use. It is preferable to be sealed in the bag.
- the packaging bag is not particularly limited, and can be appropriately used what can be used as a packaging bag for a patch.
- a plastic packaging bag a plastic packaging bag in which a metal layer (for example, an aluminum layer) is formed.
- a metal packaging bag for example, an aluminum packaging bag
- the oxygen scavenger include those using iron powder and those mainly composed of vitamin C. More specifically, the AGELESS series (manufactured by Mitsubishi Gas Chemical Company), the PharmaKeep series (Mitsubishi Gas) Chemical Co., Ltd.).
- the amount of the oxygen scavenger can be appropriately adjusted according to the mass of the patch, the material and volume of the container, etc., but the mass of the oxygen absorber should be 2.0 ⁇ l or more. Is preferred.
- 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 skin permeation test, the temporal stability evaluation test, the cohesiveness evaluation test of the pressure-sensitive adhesive layer, the adhesive evaluation test, and the storage stability evaluation test were performed by the following methods.
- the patch is hermetically sealed in a packaging bag made of cerium together with an oxygen scavenger (Ageless ZJ-15PT, manufactured by Mitsubishi Gas Chemical Company), and left to stand at 60 ° C. for 2 weeks (14 days).
- an oxygen scavenger Ageless ZJ-15PT, manufactured by Mitsubishi Gas Chemical Company
- the maximum permeation rate (Flux) and the utilization rate were determined in the same manner as above except that the patch after storage was used.
- Residual drug amount (%) Ropinirole content / [Ropinirole content + Ropinirole related substances total content] ⁇ 100 Calculated by
- the patch is hermetically sealed in a packaging bag made of cerium together with an oxygen scavenger (Ageless ZJ-15PT, manufactured by Mitsubishi Gas Chemical Company), and left to stand at 60 ° C. for 2 weeks (14 days). Measurement was performed in the same manner as above except that the patch after storage was used, and the amount of the remaining drug was determined.
- an oxygen scavenger Ageless ZJ-15PT, manufactured by Mitsubishi Gas Chemical Company
- Adhesiveness evaluation test of adhesive layer The surface of the adhesive layer of the patch from which the release sheet has been removed is strongly suppressed with a finger, and the amount of the adhesive base remaining on the finger when peeling off is visually observed, and the following criteria: A: Adhesive base does not remain and has good cohesive strength B: Adhesive base remains slightly and has cohesive strength C: Adhesive base remains in a large amount and evaluated as cohesive strength is weak did.
- the release sheet is removed from the patch immediately after production (within 72 hours from production), and a tacking tester (TAC-2, manufactured by RHESCA) is used with a stainless probe at a contact time of 1 sec and a measurement speed of 5 mm / sec.
- TAC-2 tacking tester
- the tack value (gF) was measured. A preparation having a large tack value is recognized as having excellent adhesiveness.
- the patch is hermetically sealed in a packaging bag made of cerium together with an oxygen scavenger (Ageless ZJ-15PT, manufactured by Mitsubishi Gas Chemical Company), and left to stand at 60 ° C. for 2 weeks (14 days).
- an oxygen scavenger (Ageless ZJ-15PT, manufactured by Mitsubishi Gas Chemical Company)
- the tack value was determined in the same manner as above except that the patch after storage was used.
- the patch was hermetically packaged in a packaging bag together with an oxygen scavenger, and stored at 4 ° C. for 30 days.
- the adhesive layer of the patch after storage for 30 days was observed visually and under a microscope, and the following criteria: A: Crystal precipitation is not observed in the pressure-sensitive adhesive layer.
- Example 1 First, using a mixer, 10.0 parts by mass of ropinirole hydrochloride (8.8 parts by mass in terms of ropinirole free form), 1.1 parts by mass of sodium hydroxide (desalting agent), 29.6 parts by weight of liquid paraffin Part, toluene (solvent), styrene-isoprene-styrene block copolymer (SIS) (SIS5000, manufactured by JSR) 29.6 parts by mass, and alicyclic hydrocarbon resin 29.6 parts by mass are mixed. A layer composition was obtained.
- SIS styrene-isoprene-styrene block copolymer
- the obtained pressure-sensitive adhesive layer composition was spread on a release sheet made of a film (made of polyester) that had been release-treated with silicone, and toluene was removed by drying to form a pressure-sensitive adhesive layer. Subsequently, a film (made of polyester) was laminated as a support layer on the surface of the pressure-sensitive adhesive layer opposite to the release sheet to obtain a patch.
- Table 1 shows the composition of the pressure-sensitive adhesive layer composition (excluding toluene).
- the thickness of the pressure-sensitive adhesive layer was such that the mass per unit area of the pressure-sensitive adhesive layer was 100 g / m 2 .
- Example 2 Comparative Examples 1 and 2
- 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 was changed to the composition shown in Table 1.
- the patches obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were subjected to a skin permeation test and an adhesive layer cohesiveness evaluation test, respectively.
- the results of the cohesiveness evaluation test of the pressure-sensitive adhesive layer are shown in Table 1 together with the composition of the pressure-sensitive adhesive layer composition in each Example and Comparative Example, and the results of the skin permeation test are shown in FIG.
- the patch of the present invention has excellent skin permeability of ropinirole and has a strong cohesive force in the adhesive layer and can exhibit sufficient adhesiveness. It was done.
- the patch (Comparative Example 1) having a low content of ropinirole and / or a pharmaceutically acceptable salt thereof has a low skin permeation amount of ropinirole and maintains a sufficient skin permeation amount for a long time. It was confirmed that it was not possible.
- a patch (Comparative Example 2) having a high content of ropinirole and / or a pharmaceutically acceptable salt thereof has a weak cohesive force in the pressure-sensitive adhesive layer, has extremely poor stickability, and can be used as a patch. It was confirmed that it was difficult.
- Example 3 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was changed to the composition shown in Table 2.
- Example 4 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 2, and 5.0 parts by mass of isopropyl myristate was further added.
- Example 5 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 2, and 5.0 parts by mass of isopropyl palmitate was further added.
- Example 6 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 2, and 5.0 parts by mass of octyldodecanol was further added.
- Example 7 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 2, and 5.0 parts by mass of lauryl alcohol was further added.
- Example 8 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 2, and 5.0 parts by mass of oleyl alcohol was further added.
- Example 9 The adhesive layer composition was changed to the composition shown in Table 2, and a patch was obtained in the same manner as in Example 1 except that 5.0 parts by mass of glycerin monooleate (GMO) was further added.
- GMO glycerin monooleate
- Example 10 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 2, and 5.0 parts by mass of propylene glycol monolaurate (PGML) was further added.
- PGML propylene glycol monolaurate
- Example 11 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 2, and 5.0 parts by mass of polyoxyethylene sorbitan monooleate (Tween 80) was further added.
- Example 12 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 2, and 5.0 parts by mass of lauric acid diethanolamide (LADA) was further added.
- LADA lauric acid diethanolamide
- Table 2 shows the composition of the pressure-sensitive adhesive layer composition for the patches obtained in Examples 3 to 12. Further, skin penetration tests were conducted on the patches obtained in Examples 3 to 12, respectively. The results obtained in Examples 3 to 8 are shown in FIG. 3, and the results obtained in Examples 3 and 9 to 12 are shown in FIG.
- the patch of the present invention was excellent in the skin permeability of ropinirole, and this effect was exhibited by isopropyl myristate, isopropyl palmitate, lauryl alcohol, glycerol monooleate. It has been confirmed that it can be achieved or improved even if any of the compounds of acrylate, propylene glycol monolaurate, polyoxyethylene sorbitan monooleate, and lauric acid diethanolamide is used in combination. .
- Examples 13 to 19 A patch was obtained in the same manner as in Example 5 except that the composition of the pressure-sensitive adhesive layer composition was changed to the composition shown in Table 3, respectively.
- Table 3 shows the composition of the pressure-sensitive adhesive layer composition for the patches obtained in Examples 13 to 19.
- FIG. 5 shows the results of skin permeation tests performed on the patches obtained in Examples 13 to 19.
- the patch of the present invention was excellent in the skin permeability of ropinirole, and this effect was obtained when the concentration of isopropyl palmitate was constant when isopropyl palmitate was further used in combination. It improved with the increase in the concentration until the value became.
- Example 20 A patch was obtained in the same manner as in Example 5 except that the composition of the pressure-sensitive adhesive layer composition was changed to the composition shown in Table 4.
- Example 21 A patch was obtained in the same manner as in Example 20 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 4, and 5.0 parts by mass of benzyl alcohol was further added.
- Example 22 A patch was obtained in the same manner as in Example 20 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 4 and 5.0 parts by mass of oleyl alcohol was further added.
- Example 23 A patch was obtained in the same manner as in Example 20 except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 4 and 5.0 parts by mass of octyldodecanol was added.
- Example 24 A patch was obtained in the same manner as in Example 20, except that the composition of the pressure-sensitive adhesive layer composition was as shown in Table 4, and 5.0 parts by mass of dimethyl isosorbide was further added.
- Example 25 to 29 A patch was obtained in the same manner as in Example 23 except that the composition of the pressure-sensitive adhesive layer composition was changed to the composition shown in Table 4, respectively.
- the pressure-sensitive adhesive layer further contains any compound of benzyl alcohol, oleyl alcohol, octyldodecanol, and dimethylisosorbide at a specific content. It was confirmed that even when the patch was stored for a long period of time, it was suppressed that crystals derived from ropinirole free substance were precipitated over time. Further, the patch of the present invention further comprising isopropyl palmitate and any one of benzyl alcohol, oleyl alcohol, octyldodecanol, and dimethylisosorbide at a specific content is excellent in ropinirole skin permeability.
- Examples 30 to 31, Comparative Examples 3 to 4 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was changed to the composition shown in Table 5.
- the patches obtained in Examples 30 to 31 and Comparative Examples 3 to 4 were subjected to a skin permeation test, a temporal stability evaluation test, and a pressure-sensitive adhesive layer adhesive evaluation test, respectively.
- the utilization rate determined by the skin permeation test, the maximum permeation rate for 24 hours from the start of measurement, and the tack value determined by the pressure-sensitive adhesive layer evaluation test of the pressure-sensitive adhesive layer composition in each Example and Comparative Example It shows in Table 5 with a composition, and Table 6 shows the result of a time-dependent stability evaluation test.
- the patch of the present invention was excellent in ropinirole skin permeability and stability over time and exhibited sufficient adhesiveness. Further, it was confirmed that when the content of ropinirole and / or a pharmaceutically acceptable salt thereof is increased, the skin permeability of ropinirole is improved, but the stability with time and the adhesiveness are decreased. Further, it was confirmed that the stability of ropinirole over time was further improved by packaging and storing the patch of the present invention together with an oxygen scavenger.
- Comparative Examples 5 to 16 A patch was obtained in the same manner as in Example 1 except that the composition of the pressure-sensitive adhesive layer composition was changed to the composition shown in Table 7.
- the patches obtained in Comparative Examples 5 to 16 were subjected to a skin permeation test and a temporal stability evaluation test, respectively.
- Table 8 shows the results of the maximum permeation rate and stability evaluation test over 24 hours from the start of measurement obtained by the skin permeation test.
- Examples 32 to 34 A patch was obtained in the same manner as in Example 1 except that the composition of the adhesive layer composition was changed to the composition shown in Table 9.
- the patches obtained in Examples 32 to 34 were subjected to a skin permeation test and a temporal stability evaluation test, respectively.
- Table 10 shows the utilization rate determined by the skin permeation test, the maximum permeation rate for 24 hours from the start of measurement, and the results of the stability evaluation test over time.
- a ropinirole-containing patch having excellent skin permeability of ropinirole and sufficient adhesiveness and a package thereof, the package having excellent temporal stability of ropinirole can be provided.
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Abstract
Description
前記粘着付与剤としては、例えば、「エステルガム(商品名、荒川化学工業社製)」、「ハリエスター(商品名、ハリマ化成社製)」、「ペンタリン(商品名、イーストマンケミカル社製)」、「フォーラル(商品名、イーストマンケミカル社製)」等のロジン系樹脂;「YSレジン(商品名、ヤスハラケミカル社製)」、「ピコライト(商品名、ルースアンドディルワース社製)」等のテルペン系樹脂;「アルコン(商品名、荒川化学工業社製)」、「リガレッツ(商品名、イーストマンケミカル社製)」、「ピコラスチック(商品名、イーストマンケミカル社製)」、「エスコレッツ(商品名、エクソン社製)」、「ウイングタック(商品名、グッドイヤー社製)」、「クイントン(商品名、日本ゼオン社製)」等の石油樹脂;フェノール系樹脂、キシレン系樹脂等の脂環族炭化水素樹脂が挙げられ、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。このような粘着付与剤を粘着剤層3に含有せしめる場合、その含有量としては、貼付剤の十分な粘着力及び剥離時の局所刺激性を考慮すると、粘着剤層3の全質量に対し、10~80質量%であることが好ましく、15~70質量%であることがより好ましく、20~60質量%であることがさらに好ましい。
先ず、ヘアレスマウスの背部皮膚を剥離し、その真皮側がレセプター層側になるようにして、32℃の温水を外周部に循環させたフランツ型フロースルーセルに装着した。次いで、この皮膚の角質層側に5cm2の大きさに切断して剥離シートを除去した製造直後(製造から72時間以内)の貼付剤を貼付した。前記フロースルーセルのレセプター層にはpH7.4のリン酸緩衝溶液(PBS)を一定の流量でフローして、レセプター層から2時間毎に24時間まで試料液を採取し、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(ロピニロール)の濃度を定量し、各時間毎に皮膚を透過した薬物の量を求め、薬物の最大透過速度(Flux:μg/cm2/hr)を、以下の式:
Flux(μg/cm2/hr)=[薬物濃度(μg/ml)×流量(ml)]/貼付剤面積(cm2)/時間(hr)
により算出した。また、貼付剤製造時に含有させた薬物の質量(初期量)に対する測定開始から24時間で透過した薬物の合計質量(累積透過量)の割合(利用率:%)を以下の式:
利用率(%)=[累積透過量(μg/cm2)/初期量(μg/cm2)]×100
により算出した。最大透過速度及び利用率の値が大きい製剤は、薬物の皮膚透過性に優れたものと認められる。
製造直後(製造から72時間以内)の貼付剤から試料として6.25cm2を採取し、ここにテトラヒドロフラン10mlを加えて粘着剤層を溶解させた。この溶液に50%メタノール水溶液を全量が50mlとなるように加えた後、フィルター濾過により測定サンプルを得た。得られた測定サンプルについて、高速液体クロマトグラフィー装置((株)島津製作所製、カラム:ODSカラム、移動相:10mMノナンスルホン酸ナトリウム-0.2%リン酸水溶液/メタノール(50/50(体積比))、検出波長:250nm)を用いてロピニロール及び未知化合物(ロピニロール類縁物質)の含有量(質量%)の測定を行った。また、残存薬物量(%)を以下の式:
残存薬物量(%)=ロピニロール含有量/[ロピニロール含有量+ロピニロール類縁物質合計含有量]×100
により算出した。
剥離シートを除去した貼付剤の粘着剤層表面を指で強く抑え、引き剥がす際に指に残る粘着基剤の量を目視にて観察し、以下の基準:
A:粘着基剤が残ることがなく、良好な凝集力を有する
B:粘着基剤が僅かに残る程度であり、凝集力を有する
C:粘着基剤が多量に残り、凝集力が弱い
に従って評価した。
製造直後(製造から72時間以内)の貼付剤から剥離シートを除去し、タッキング試験器(TAC-2、RHESCA社製)を用いて、ステンレスプローブで接触時間1sec、測定速度5mm/secの条件でタック値(gF)を測定した。タック値が大きい製剤は、粘着性に優れたものと認められる。
貼付剤を脱酸素剤と共に包装袋内に密封包装し、4℃において30日間静置して保管した。30日間保管後の貼付剤の粘着剤層を目視及び顕微鏡にて観察し、以下の基準:
A:粘着剤層に結晶析出が観察されない
B:粘着剤層の一部もしくは全面に放射状の針状結晶が観察される
に従って評価した。
先ず、混合機を用いて、塩酸ロピニロール10.0質量部(ロピニロール遊離体に換算して8.8質量部)、水酸化ナトリウム(脱塩剤)1.1質量部、流動パラフィン29.6質量部、トルエン(溶媒)、スチレン-イソプレン-スチレンブロック共重合体(SIS)(SIS5000、JSR社製)29.6質量部、及び脂環族炭化水素樹脂29.6質量部を混合し、粘着剤層組成物を得た。得られた粘着剤層組成物をシリコーンにより離型処理されたフィルム(ポリエステル製)からなる剥離シート上に展延し、トルエンを乾燥除去することにより粘着剤層を形成した。次いで、前記粘着剤層の前記剥離シートとは反対の面上に支持体層としてフィルム(ポリエステル製)を積層して貼付剤を得た。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。なお、得られた貼付剤において粘着剤層の厚さは、粘着剤層の単位面積当たりの質量が100g/m2となる厚さであった。
粘着剤層組成物の組成を表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。実施例1~2及び比較例1~2において得られた貼付剤について、それぞれ皮膚透過試験及び粘着剤層の凝集性評価試験を行った。粘着剤層の凝集性評価試験の結果を各実施例及び比較例における粘着剤層組成物の組成と共に表1に示し、皮膚透過試験の結果を図2に示す。
粘着剤層組成物の組成を表2に示す組成としたこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにミリスチン酸イソプロピルを5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにパルミチン酸イソプロピルを5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにオクチルドデカノールを5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにラウリルアルコールを5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにオレイルアルコールを5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにグリセリンモノオレエート(GMO)を5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにプロピレングリコールモノラウレート(PGML)を5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにポリオキシエチレンソルビタンモノオレエート(Tween80)を5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成を表2に示す組成とし、さらにラウリン酸ジエタノールアミド(LADA)を5.0質量部添加したこと以外は実施例1と同様にして貼付剤を得た。
粘着剤層組成物の組成をそれぞれ表3に示す組成としたこと以外は実施例5と同様にして貼付剤を得た。実施例13~19において得られた貼付剤について、粘着剤層組成物の組成を表3に示す。また、実施例13~19において得られた貼付剤について、それぞれ皮膚透過試験を行った結果を図5に示す。
粘着剤層組成物の組成を表4に示す組成としたこと以外は実施例5と同様にして貼付剤を得た。
粘着剤層組成物の組成を表4に示す組成とし、さらにベンジルアルコールを5.0質量部添加したこと以外は実施例20と同様にして貼付剤を得た。
粘着剤層組成物の組成を表4に示す組成とし、さらにオレイルアルコールを5.0質量部添加したこと以外は実施例20と同様にして貼付剤を得た。
粘着剤層組成物の組成を表4に示す組成とし、さらにオクチルドデカノールを5.0質量部添加したこと以外は実施例20と同様にして貼付剤を得た。
粘着剤層組成物の組成を表4に示す組成とし、さらにジメチルイソソルビドを5.0質量部添加したこと以外は実施例20と同様にして貼付剤を得た。
粘着剤層組成物の組成をそれぞれ表4に示す組成としたこと以外は実施例23と同様にして貼付剤を得た。
粘着剤層組成物の組成を表5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。実施例30~31及び比較例3~4において得られた貼付剤について、それぞれ皮膚透過試験、経時安定性評価試験及び粘着剤層の粘着性評価試験を行った。皮膚透過試験により求められた利用率及び測定開始から24時間の間の最大透過速度、粘着剤層の粘着性評価試験により求められたタック値を各実施例及び比較例における粘着剤層組成物の組成と共に表5に示し、経時安定性評価試験の結果を表6に示す。
粘着剤層組成物の組成を表7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。比較例5~16において得られた貼付剤について、それぞれ皮膚透過試験及び経時安定性評価試験を行った。皮膚透過試験により求められた測定開始から24時間の間の最大透過速度及び経時安定性評価試験の結果を表8に示す。
粘着剤層組成物の組成を表9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。実施例32~34において得られた貼付剤について、それぞれ皮膚透過試験、及び経時安定性評価試験を行った。皮膚透過試験により求められた利用率及び測定開始から24時間の間の最大透過速度、並びに、経時安定性評価試験の結果を表10に示す。
Claims (6)
- 粘着剤層と支持体層とを備え、前記粘着剤層がロピニロール及び/又はその薬学的に許容される塩を含有するロピニロール含有貼付剤であって、前記粘着剤層における前記ロピニロール及び/又はその薬学的に許容される塩のロピニロール遊離体に換算した含有量が、前記粘着剤層の全質量に対して5~13.2質量%であるロピニロール含有貼付剤。
- 前記粘着剤層がさらに、ベンジルアルコール、オレイルアルコール、オクチルドデカノール、ジメチルイソソルビドからなる群から選択される少なくともいずれか1種の化合物を、前記ロピニロール及び/又はその薬学的に許容される塩のロピニロール遊離体に換算した質量100質量部に対して5~50質量部含有する請求項1に記載のロピニロール含有貼付剤。
- 前記粘着剤層がさらに、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、ラウリルアルコール、グリセリンモノオレエート、プロピレングリコールモノラウレート、ポリオキシエチレンソルビタンモノオレエート、ラウリン酸ジエタノールアミドからなる群から選択される少なくともいずれか1種の化合物を、前記ロピニロール及び/又はその薬学的に許容される塩のロピニロール遊離体に換算した質量100質量部に対して10~150質量部含有する請求項1又は2に記載のロピニロール含有貼付剤。
- 前記粘着剤層が、前記粘着剤層の全質量に対して15~35質量%のゴム系粘着剤をさらに含有する請求項1~3のうちのいずれか一項に記載のロピニロール含有貼付剤。
- 前記粘着剤層が、前記ロピニロール及び/又はその薬学的に許容される塩のロピニロール遊離体に換算したモル数1モルに対して0.5~1.0モルの水酸化ナトリウムをさらに含有する請求項1~4のうちのいずれか一項に記載のロピニロール含有貼付剤。
- 請求項1~5のうちのいずれか一項に記載のロピニロール含有貼付剤が脱酸素剤と共に包装袋内に密封されている包装体。
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CN201280026050.6A CN103561738B (zh) | 2011-05-31 | 2012-05-23 | 含有罗匹尼罗的贴附剂及其包装体 |
ES12793578.1T ES2641651T3 (es) | 2011-05-31 | 2012-05-23 | Parche que contiene ropinirol y envase para el mismo |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5415645B1 (ja) * | 2013-06-28 | 2014-02-12 | 久光製薬株式会社 | 貼付剤の製造方法、貼付剤及び包装体 |
WO2014084311A1 (ja) * | 2012-11-30 | 2014-06-05 | 帝國製薬株式会社 | ロピニロール含有貼付剤 |
US8802134B2 (en) | 2012-12-06 | 2014-08-12 | Hisamitsu Pharmaceutical Co., Inc. | Patch and method for producing the same |
US8877235B2 (en) | 2012-12-27 | 2014-11-04 | Hisamitsu Pharmaceutical Co., Inc. | Patch and method for producing the same |
WO2018155390A1 (ja) | 2017-02-24 | 2018-08-30 | 久光製薬株式会社 | 貼付剤及びその包装体 |
US10716763B2 (en) | 2015-04-15 | 2020-07-21 | Hisamitsu Pharmaceutical Co., Inc. | Transdermal patch containing ropinirole |
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WO2021106782A1 (ja) | 2019-11-26 | 2021-06-03 | 久光製薬株式会社 | ロピニロール含有貼付剤の粘着剤層保持力向上方法、及びロピニロール含有保持力改善貼付剤 |
WO2022091925A1 (ja) | 2020-10-29 | 2022-05-05 | 久光製薬株式会社 | ロピニロール含有貼付剤及びロピニロールの皮膚透過性向上方法 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US9155710B2 (en) | 2011-05-31 | 2015-10-13 | Hisamitsu Pharmaceutical Co., Inc. | Ropinirole-containing patch and package thereof |
WO2018198924A1 (ja) * | 2017-04-25 | 2018-11-01 | 久光製薬株式会社 | 貼付剤 |
CN107375249A (zh) * | 2017-07-26 | 2017-11-24 | 徐静 | 一种含罗匹尼罗的缓释透皮贴剂及其应用 |
KR102455157B1 (ko) | 2018-10-31 | 2022-10-17 | 신신제약 주식회사 | 로피니롤 경피흡수제 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11506462A (ja) | 1995-06-06 | 1999-06-08 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | ロピニロールを含有してなる経皮製剤 |
JP2001518058A (ja) | 1995-09-29 | 2001-10-09 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | ロピニロールおよびそのアナログの経皮投与 |
JP2007516265A (ja) | 2003-12-16 | 2007-06-21 | フォーミックス エルティーディー. | 油性の医薬用および化粧用フォーム |
JP2009518376A (ja) | 2005-12-07 | 2009-05-07 | ファーマコデックス リミテッド | 全身効果のための活性薬剤の経皮投与 |
WO2009107479A1 (ja) * | 2008-02-27 | 2009-09-03 | 久光製薬株式会社 | 貼付製剤 |
WO2009107478A1 (ja) | 2008-02-27 | 2009-09-03 | 久光製薬株式会社 | 貼付剤及び包装体 |
WO2010123103A1 (ja) * | 2009-04-24 | 2010-10-28 | 久光製薬株式会社 | 貼付剤入り包装袋、及び貼付剤の保存方法 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH066534B2 (ja) | 1986-10-09 | 1994-01-26 | 積水化学工業株式会社 | 経皮吸収貼付剤 |
US5906830A (en) | 1995-09-08 | 1999-05-25 | Cygnus, Inc. | Supersaturated transdermal drug delivery systems, and methods for manufacturing the same |
DE10261696A1 (de) | 2002-12-30 | 2004-07-15 | Schwarz Pharma Ag | Vorrichtung zur transdermalen Verabreichung von Rotigotin-Base |
CA2644311C (en) * | 2006-03-01 | 2012-07-10 | Tristrata, Inc. | Composition and method for topical treatment of tar-responsive dermatological disorders |
JP2008285432A (ja) * | 2007-05-16 | 2008-11-27 | Fujifilm Corp | 皮膚外用剤 |
US9238025B2 (en) | 2009-05-21 | 2016-01-19 | Hisamitsu Pharmaceutical Co., Inc. | Transdermal preparation comprising a ropinirole derivative |
KR101292768B1 (ko) | 2010-04-23 | 2013-08-05 | 아이큐어 주식회사 | 경피 흡수 제제 |
US9155710B2 (en) | 2011-05-31 | 2015-10-13 | Hisamitsu Pharmaceutical Co., Inc. | Ropinirole-containing patch and package thereof |
ES2657016T3 (es) | 2011-05-31 | 2018-03-01 | Hisamitsu Pharmaceutical Co., Inc. | Parche cutáneo adhesivo que contiene ropinirol y producto envasado del mismo |
JP6104173B2 (ja) | 2011-12-01 | 2017-03-29 | 帝國製薬株式会社 | ロピニロール含有貼付剤 |
JP5270035B1 (ja) | 2012-12-06 | 2013-08-21 | 久光製薬株式会社 | 貼付剤及びその製造方法 |
JP5307931B1 (ja) | 2012-12-27 | 2013-10-02 | 久光製薬株式会社 | 貼付剤及びその製造方法 |
-
2012
- 2012-05-23 US US14/123,163 patent/US9155710B2/en active Active
- 2012-05-23 WO PCT/JP2012/063160 patent/WO2012165253A1/ja active Application Filing
- 2012-05-23 JP JP2013517995A patent/JP5823510B2/ja active Active
- 2012-05-23 ES ES12793578.1T patent/ES2641651T3/es active Active
- 2012-05-23 CN CN201280026050.6A patent/CN103561738B/zh active Active
- 2012-05-23 EP EP12793578.1A patent/EP2716286B1/en active Active
- 2012-05-23 KR KR1020137032562A patent/KR101844625B1/ko active IP Right Grant
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11506462A (ja) | 1995-06-06 | 1999-06-08 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | ロピニロールを含有してなる経皮製剤 |
JP2001518058A (ja) | 1995-09-29 | 2001-10-09 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | ロピニロールおよびそのアナログの経皮投与 |
JP2007516265A (ja) | 2003-12-16 | 2007-06-21 | フォーミックス エルティーディー. | 油性の医薬用および化粧用フォーム |
JP2009518376A (ja) | 2005-12-07 | 2009-05-07 | ファーマコデックス リミテッド | 全身効果のための活性薬剤の経皮投与 |
WO2009107479A1 (ja) * | 2008-02-27 | 2009-09-03 | 久光製薬株式会社 | 貼付製剤 |
WO2009107478A1 (ja) | 2008-02-27 | 2009-09-03 | 久光製薬株式会社 | 貼付剤及び包装体 |
WO2010123103A1 (ja) * | 2009-04-24 | 2010-10-28 | 久光製薬株式会社 | 貼付剤入り包装袋、及び貼付剤の保存方法 |
Non-Patent Citations (3)
Title |
---|
"Japanese Pharmaceutical Excipients Directory 2000", 28 April 2000 |
JAPANESE PHARMACEUTICALEXCIPIENTS DIRECTORY, 2000 |
See also references of EP2716286A4 * |
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JPWO2014084311A1 (ja) * | 2012-11-30 | 2017-01-05 | 帝國製薬株式会社 | ロピニロール含有貼付剤 |
US10022336B2 (en) | 2012-11-30 | 2018-07-17 | Teikoku Seiyaku Co., Ltd. | Ropinirole-containing adhesive patch |
US8802134B2 (en) | 2012-12-06 | 2014-08-12 | Hisamitsu Pharmaceutical Co., Inc. | Patch and method for producing the same |
US8877235B2 (en) | 2012-12-27 | 2014-11-04 | Hisamitsu Pharmaceutical Co., Inc. | Patch and method for producing the same |
JP5415645B1 (ja) * | 2013-06-28 | 2014-02-12 | 久光製薬株式会社 | 貼付剤の製造方法、貼付剤及び包装体 |
EP2818161A1 (en) | 2013-06-28 | 2014-12-31 | Hisamitsu Pharmaceutical Co., Inc. | Method for producing supersaturated ropinirole patch |
KR101516122B1 (ko) * | 2013-06-28 | 2015-04-29 | 히사미쓰 세이야꾸 가부시키가이샤 | 첩부제의 제조 방법, 첩부제 및 포장체 |
US9320728B2 (en) | 2013-06-28 | 2016-04-26 | Hisamitsu Pharmaceutical Co., Inc. | Method for producing patch, patch and package |
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ES2641651T3 (es) | 2017-11-10 |
EP2716286B1 (en) | 2017-07-12 |
US20140112974A1 (en) | 2014-04-24 |
KR20140034814A (ko) | 2014-03-20 |
US9155710B2 (en) | 2015-10-13 |
JPWO2012165253A1 (ja) | 2015-02-23 |
JP5823510B2 (ja) | 2015-11-25 |
KR101844625B1 (ko) | 2018-04-02 |
CN103561738A (zh) | 2014-02-05 |
EP2716286A4 (en) | 2014-11-19 |
EP2716286A1 (en) | 2014-04-09 |
CN103561738B (zh) | 2016-01-27 |
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